Guidelines on TaT1 (Non-muscle invasive) Bladder Cancer

Guidelines on TaT 1 (Non-muscle invasive)

Bladder Cancer M. Babjuk, W. Oosterlinck, R. Sylvester, E. Kaasinen, A. Böhle, J. Palou

© European Association of Urology 2009

TABLE OF CONTENTS

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1.

BACKGROUND

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2.

EPIDEMIOLOGY

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3. CLASSIFICATION 3.1 Tumour, Nodes, Metastases classification (TNM) 3.2 Histological grading of non-muscle invasive bladder tumours 3.2.1 WHO/ISUP grading 3.3 Controversial definition of non-muscle invasive (superficial) tumours 3.4 Inter- and intra-observer variability in staging and grading

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4.

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RISK FACTORS

5. DIAGNOSIS 5.1 Symptoms of TaT1 bladder tumours 5.2 Physical examination 5.3 Imaging 5.3.1 Intravenous urography and CT scan 5.3.2 Ultrasonography (US) 5.4 Urinary cytology 5.5 Urine molecular tests 5.6 Cystoscopy 5.7 Transurethral resection of TaT1 bladder tumours 5.8 Bladder and prostatic urethra biopsies 5.9 Fluorescence cystoscopy 5.10 Second resection 5.11 Pathological report 5.12 Recommendations for primary assessment of TaT1 bladder tumours

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6.

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PREDICTING RECURRENCE AND PROGRESSION IN TaT1 TUMOURS

7. ADJUVANT TREATMENT 7.1 Intravesical chemotherapy 7.1.1 One, immediate, post-operative intravesical instillation of chemotherapy 7.1.2 Additional adjuvant intravesical chemotherapy instillations 7.1.3 Optimizing intravesical chemotherapy 7.2 Intravesical BCG immunotherapy 7.2.1 Efficacy of bacillus Calmette-Guérin (BCG) 7.2.2 The optimal BCG schedule 7.2.3 The optimal dose of BCG 7.2.4 BCG toxicity 7.2.5 Indications for BCG 7.3 Treatment of failures of intravesical therapy 7.3.1 Failure of intravesical chemotherapy 7.3.2 Failure of intravesical BCG immunotherapy 7.4 Recommendations for intravesical therapy

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8.

CYSTECTOMY FOR NON-MUSCLE INVASIVE BLADDER CANCER

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9.

FOLLOW-UP OF PATIENTS WITH TaT1 BLADDER TUMOURS 9.1 Recommendations for follow-up cystoscopy

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10.

REFERENCES

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11.

ABBREVIATIONS USED IN THE TEXT

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1. BACKGROUND The first European Association of Urology (EAU) Guidelines on Bladder Cancer were published in 2002 (1). It was later decided to develop separate guidelines for different categories of bladder tumours: • TaT1 papillary tumours (non-muscle invasive bladder cancer) • Upper urinary tract tumours • Carcinoma in situ (CIS) • Muscle invasive bladder tumours. Separate guidelines have been published in European Urology for CIS and upper urinary tract tumours (2-3). This overview represents the updated EAU guidelines on TaT1 (non-muscle invasive) bladder cancer.

2. EPIDEMIOLOGY Bladder carcinoma is the most common malignancy of the urinary tract. In Europe, the highest incidence (given as ASR = age-standardized rate) is reported from its Western (23.6 in males and 5.4 in females) and Southern parts (27.1 in males and 4.1 in females), followed by Northern Europe (16.9 in males and 4.9 in females). The lowest incidence can be observed in Eastern European countries (14.7 in males and 2.2 in females, respectively) (4). Approximately 75-85% of patients with bladder cancer present with disease confined to the mucosa (stage Ta, CIS) or submucosa (stage T1).

3. CLASSIFICATION 3.1 Tumour, Nodes, Metastases Classification (TNM) The 2002 TNM classification approved by the Union International Contre le Cancer (UICC) has been widely accepted (Table 1) (5). It differs from the previous versions in the definition of stage T2 and T3 tumours.

Table 1: 2002 TNM classification of urinary bladder cancer T - Primary tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour Ta Non-invasive papillary carcinoma Tis Carcinoma in situ: ‘flat tumour’ T1 Tumour invades subepithelial connective tissue T2 Tumour invades muscle T2a Tumour invades superficial muscle (inner half) T2b Tumour invades deep muscle (outer half) T3 Tumour invades perivesical tissue: T3a Microscopically T3b Macroscopically (extravesical mass) T4 Tumour invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall T4a Tumour invades prostate, uterus or vagina T4b Tumour invades pelvic wall or abdominal wall N - Lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single lymph node 2 cm or less in greatest dimension N2 Metastasis in a single lymph node more than 2 cm but not more than 5 cm in greatest dimension, or multiple lymph nodes, none more than 5 cm in greatest dimension N3 Metastasis in a lymph node more than 5 cm in greatest dimension

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M - Distant metastasis MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis

3.2

Histological grading of non-muscle invasive bladder tumours

In 1998, the new classification of non-invasive urothelial tumours was proposed by the World Health Organization (WHO) and the International Society of Urological Pathology (ISUP) (1998 WHO/ISUP classification) and published by the WHO in 2004 (6,7) (Table 2). Its major contribution is a detailed histological description of the various grades, employing specific cytological and architectural criteria. A website (www. pathology.jhu.edu/bladder) illustrating examples of various grades was developed to improve accuracy further in using the system.

Table 2: WHO grading in 1973 and in 2004 (6,7) 1973 WHO grading Urothelial papilloma Grade 1: well differentiated Grade 2: moderately differentiated Grade 3: poorly differentiated 2004 WHO grading Urothelial papilloma Papillary urothelial neoplasm of low malignant potential (PUNLMP) Low-grade papillary urothelial carcinoma High-grade papillary urothelial carcinoma

3.2.1 WHO/ISUP grading The 2004 WHO grading differentiates between papillary urothelial neoplasms of low malignant potential (PUNLMP) and low-grade and high-grade urothelial carcinomas. PUNLMP are defined as lesions that do not have cytological features of malignancy but show normal urothelial cells in a papillary configuration. Although they have a negligible risk for progression, they are not completely benign and still have a tendency to recur. The intermediate grade (grade 2), which was the subject of controversy in the 1973 WHO classification, has been eliminated. The use of the 2004 WHO classification is advocated, as this should result in a uniform diagnosis of tumours, which is better classified according to risk potential. However, until the 2004 WHO classification has been validated by more clinical trials, tumours should be graded using both the 1973 and the 2004 WHO classifications (8). The majority of clinical trials published so far on TaT1 bladder tumours have been performed using the 1973 WHO classification, and therefore the following guidelines are based on the 1973 WHO grade classification.

3.3

Controversial definition of non-muscle invasive (superficial) tumours

A papillary tumour confined to the mucosa is classified as stage Ta according to the TNM system. Tumours that have invaded the lamina propria are classified as stage T1. As Ta and T1 tumours can be removed by transurethral resection (TUR), they are grouped under the heading of non-muscle invasive (superficial) bladder cancer for therapeutic purposes. Also included under this heading are flat, high-grade tumours confined to the mucosa, classified as carcinoma in situ (CIS). However, molecular biology techniques and clinical experience have demonstrated the highly malignant, invasive potential of CIS and T1 lesions. Therefore, the terms nonmuscle invasive and superficial bladder cancer are a suboptimal description.

3.4

Inter- and intra-observer variability in staging and grading

Despite well-defined criteria for the diagnosis of urothelial carcinoma, there is significant variability among pathologists defining dysplasia and CIS. There is also important interobserver variability in classifying stage T1 versus Ta tumours and grading tumours (9,10). As a consequence, this working party strongly recommends that the urologist reviews histological findings with the pathologist.

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4. RISK FACTORS Many of the aetiological factors for the development of bladder tumours are known and the urologist should be aware of the types of occupational exposures that may be related to urothelial carcinogens (11). Aromatic amines were the first to be recognized. At-risk groups include workers in the following industries: printing, iron and aluminium processing, industrial painting, gas and tar manufacturing (level of evidence: 3). Another prominent risk factor is cigarette smoking, which triples the risk of developing bladder cancer (12,13) (level of evidence: 3a). Smoking leads to higher mortality from bladder cancer during long-term followup, even though in a multivariate analysis the prognostic effect of smoking was weaker than that of other factors, such as stage, grade, size and multifocality of the tumour (14).

5. DIAGNOSIS 5.1

Symptoms of TaT1 bladder tumours

Haematuria is the most common finding in TaT1 bladder tumours. TaT1 tumours do not cause bladder pain and rarely present with bladder irritation, dysuria or urgency. In patients who do complain of these symptoms, CIS may be suspected.

5.2

Physical examination

Physical examination will not reveal TaT1 bladder tumours.

5.3

Imaging

5.3.1 Intravenous urography and CT scan Large tumours may be seen as filling defects in the bladder. Intravenous urography (IVU) is also used to detect filling defects in the calyces, renal pelvis and ureters, and hydronephrosis, which may indicate the presence of a ureteral tumour. The necessity to perform routine IVP once a bladder tumour has been detected is now questioned because of the low incidence of significant findings obtained with this method (15-17) (level of evidence: 3). The incidence of upper urinary tract tumours is low (1.8%), but increases to 7.5% in tumours located in the trigone (16). The risk of tumour recurrence in the upper urinary tract during follow-up increases in multiple and high-risk tumours (18). In many centres, computed tomography (CT) urography is used as an alternative to conventional IVU (19). Especially in invasive tumours of the upper tract, CT urography gives more information than IVU (level of evidence: 4). However, CT urography has the disadvantage of a much higher radiation exposure than IVU. 5.3.2 Ultrasonography (US) Ultrasonography (US) has been used with increasing frequency as the initial tool to assess the urinary tract. This is not only because it avoids the use of contrast agents, but also because sensitive transducers have improved imaging of the upper urinary tract and bladder. Transabdominal US permits characterization of renal masses, detection of hydronephrosis and visualization of intraluminal filling defects in the bladder. Combined with plain abdominal film, it can be as accurate as IVU in the diagnosis of the cause of haematuria (15,16) (level of evidence: 3).

5.4

Urinary cytology

Examination of a voided urine or bladder-washing specimen for exfoliated cancer cells has high sensitivity in high-grade tumours but low sensitivity in low-grade tumours (level of evidence: 3). It is thus useful when a highgrade malignancy or CIS is present; however, a negative result cannot exclude the presence of a low-grade cancer. Positive urinary cytology may indicate urothelial tumour anywhere in the urinary tract, from the calyx, through the ureters, into the bladder and proximal urethra. Cytological interpretation is user-dependent (20). The evaluation can be hampered by low cellular yield, urinary tract infections, stones or intravesical instillations. In experienced hands however the specificity exceeds 90% (21) (level of evidence: 2b). Cytology should be performed on fresh urine with adequate fixation. Morning urine is not suitable as cytolysis may be often present.

5.5

Urine molecular tests

Many studies have focused on evaluating urinary molecular markers. Several tests based on detection of soluble markers or cell-associated markers are available (21). Most of these tests have a better sensitivity

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for detecting bladder cancer than urinary cytology, but specificity is lower (level of evidence: 2b). It remains unclear whether these tests offer additional information that is useful for decision-making, follow-up, treatment and prognosis of non-muscle invasive bladder tumours (21-24). Moreover, the additional costs of some of these tests should be considered.

5.6

Cystoscopy

The diagnosis of bladder cancer ultimately depends on cystoscopic examination of the bladder and histological evaluation of the resected tissue. In general, cystoscopy is initially performed in the office, using flexible instruments. If a bladder tumour has been visualized in earlier imaging studies, a diagnostic cystoscopy can be omitted since the patient will undergo TUR. A careful description of the finding is necessary. It should include the site, size, number and appearance (papillary or solid) of the tumours as well as a description of mucosal abnormalities. Use of a bladder diagram is recommended.

5.7

Transurethral resection of TaT1 bladder tumours

The goal of the TUR in TaT1 bladder tumours is to make the correct diagnosis and remove all visible lesions. The strategy of resection depends on the size of the lesion. Small tumours (less than 1 cm) can be resected en bloc, where the specimen contains the complete tumour plus a part of the underlying bladder wall. Some experts believe that a deep resection is not necessary in small apparently low grade lesions with a previous history of TaG1 tumour. Larger tumours should be resected separately in fractions, which include the exophytic part of the tumour, the underlying bladder wall with the detrusor muscle and the edges of the resection area. The specimens from different fractions must be referred to the pathologist in separate containers to enable him to make a correct diagnosis. Cauterization has to be avoided as much as possible during the resection to prevent tissue destruction. A complete and correct TUR is essential for the prognosis of the patient (25).

5.8

Bladder and prostatic urethra biopsies

Bladder tumours are often multifocal. Moreover TaT1 tumours can be accompanied by CIS or dysplasia. These lesions may present themselves as velvet-like, reddish areas indistinguishable from inflammation or may be not visible at all. The biopsies from normal-looking mucosa in patients with TaT1 tumours, so called random biopsies (R-biopsies) or selected site mucosal biopsies, are not routinely recommended. The likelihood of detecting CIS, especially in low-risk tumours, is extremely low (less than 2%) and the choice of adjuvant intravesical therapy is not influenced by the biopsy result (26) (level of evidence: 2a). Cold cup biopsies from normal-looking mucosa should be performed when cytology is positive or when exophytic tumour is of non-papillary appearance. When abnormal areas of urothelium are seen, it is advised to take ‘cold cup’ biopsies or biopsies with a resection loop. Material obtained by random or directed biopsies must be sent for pathological assessment in separate containers. The involvement of the prostatic urethra and ducts in male patients with TaT1 bladder tumours has been reported. Although the exact risk is not known, it seems to be higher if tumour is located on the trigone or bladder neck, in the presence of bladder CIS and in multiple tumours (27,28) (level of evidence: 3). In these cases and when cytology is positive, with no evidence of tumour in the bladder, or when abnormalities of prostatic urethra are visible, biopsies of the prostatic urethra are recommended. The biopsy is taken using resection loop from the precolicular area.

5.9

Fluorescence cystoscopy

As a standard procedure, cystoscopy and TUR are performed using white light. However, the use of white light may lead to missing lesions that are present but not visible. Fluorescence cystoscopy is performed using violet light after intravesical instillation of a photosensitizer, usually 5-aminolaevulinic acid (5-ALA) or hexaminolaevulinate (HAL). It has been confirmed that fluorescence-guided biopsy and resection are more sensitive than conventional procedures in detecting malignant tumour, particularly CIS (29-31) (level of evidence: 2a). However, false-positivity can be induced by inflammation and recent TUR or intravesical instillation. The benefit of fluorescence-guided TUR for recurrence-free survival was shown in several, small, randomized clinical trials (32-34), but its value remains to be proven in improving the outcome of patients for progression rates or survival. The additional costs of the equipment should be considered.

5.10

Second resection

The significant risk of residual tumour after the initial TUR of TaT1 lesions has been demonstrated (25,35) (level of evidence: 1). Persistent disease after resection of T1 tumours was observed in 33-53% of patients (35-41).

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Moreover, the tumour may be understaged by the initial resection. The likelihood that a TaT1, high-grade tumour has been understaged and is therefore muscle invasive is 10% (36,37). As the treatment of a TaT1, high-grade tumour and a T2 tumour is completely different, correct staging is important. A second TUR should be considered when the initial resection was incomplete, e.g. when multiple and/or large tumours are present, or when the pathologist has reported that the specimen contained no muscle tissue. Furthermore, a second TUR should be performed when a high-grade, non-muscle invasive tumour or a T1 tumour has been detected at the initial TUR. It has been demonstrated that a second TUR can increase recurrence-free survival (39,40) (level of evidence: 2a). There is no consensus about the strategy and timing of a second TUR. Most authors recommend resection at 2-6 weeks after the initial TUR. The procedure should include a resection of the primary tumour site.

5.11

Pathological report

Pathological investigation of the specimen obtained by TUR and biopsies is an essential step in the diagnosis of bladder cancer. The pathological report should specify the grade of the lesion and the depth of tumour invasion into the bladder wall and should give information about whether the lamina propria and muscle are present in the specimen (42). Close cooperation between urologist and pathologist is recommended.

5.12 Recommendations for primary assessment of TaT1 bladder tumours • • • • • • • •

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Renal and bladder ultrasonography, IVU or CT in selected cases (tumours located in the trigone). (Grade of recommendation: B) Cystoscopy with description of the tumour (site, size, number and appearance) and mucosal abnormalities. A bladder diagram is recommended. (Grade of recommendation: C) Urine analysis Urine cytology TUR in one piece for small tumours (less than 1 cm), including a part from the underlying bladder wall. (Grade of recommendation: B) TUR in fractions (including muscle tissue) for larger tumours. (Grade of recommendation: B) Biopsies of abnormal-looking urothelium, biopsies from normal-looking mucosa when cytology is positive or when exophytic tumour is of non-papillary appearance. (Grade of recommendation: C) Biopsy of the prostatic urethra in the case of bladder neck tumour, when bladder CIS is present or suspected, in the case of positive cytology without evidence of tumour in the bladder or when abnormalities of prostatic urethra are visible. If it was not performed during the initial procedure it can be completed at the time of the second resection. The biopsy is taken using resection loop from the precolicular area (Grade of recommendation: C) If equipment is available, fluorescence-guided biopsy when bladder CIS is suspected (e.g. positive cytology, recurrent tumour with previous history of a high grade lesion) (Grade of recommendation: C) A second TUR at 2-6 weeks after the initial resection when it was incomplete or when a high-grade or T1 tumour was detected. (Grade of recommendation: B) The pathological report should specify the grade, the depth of tumour invasion and whether the lamina propria and muscle are present in the specimen. (Grade of recommendation: C)

6. PREDICTING RECURRENCE AND PROGRESSION IN TaT1 TUMOURS The classic way to categorize patients with TaT1 tumours is to divide them into risk groups based on prognostic factors derived from multivariate analyses. Using such a technique, it was proposed to divide patients into low-risk, intermediate-risk and high-risk groups (43). When using these risk groups, however, no difference is usually made between the risk of recurrence and progression. Although prognostic factors may indicate a high risk for recurrence, the risk of progression may still be low and other tumours may have a high risk of both recurrence and progression. In order to separately predict the short-term and long-term risks of both recurrence and progression in individual patients, the European Organization for Research and Treatment of Cancer (EORTC) developed a scoring system and risk tables (44). The basis for these tables is the EORTC database, which provided

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individual patient data for 2,596 patients diagnosed with TaT1 tumours who were randomized in seven EORTC trials. Patients with CIS only were not included. Seventy eight percent received intravesical treatment, mostly chemotherapy. They did not however have a second TUR or receive maintenance BCG. The scoring system is based on the six most significant clinical and pathological factors: • number of tumours • tumour size • prior recurrence rate • T category • presence of concomitant CIS • tumour grade. Table 3 illustrates the weights applied to various factors for calculating the total scores for recurrence and progression. Table 4 shows the total scores stratified, as in the original article (44), into four categories reflecting various probabilities of recurrence and progression at 1 and 5 years. With combining two of the four categories distinctly in recurrence and progression, the EAU working group suggests to use, as shown in the rightmost column in table 4, a 3-tier system defining low, intermediate and high risk groups for recurrence and progression.

Table 3: Weighting used to calculate recurrence and progression scores Factor Number of tumours Single 2-7 > 8 Tumour diameter < 3 cm > 3 cm Prior recurrence rate Primary < 1 recurrence/year > 1 recurrence/year Category Ta T1 Concomitant CIS No Yes Grade (1973 WHO) G1 G2 G3 Total score CIS = carcinoma in situ

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Recurrence

Progression

0 3 6

0 3 3

0 3

0 3

0 2 4

0 2 2

0 1

0 4

0 1

0 6

0 1 2 0-17

0 0 5 0-23

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Table 4: Probability of recurrence and progression according to total score Recurrence score 0 1-4 5-9 10-17

Probability of recurrence at 1 year % (95% CI) 15 (10-19) 24 (21-26) 38 (35-41) 61 (55-67)

Probability of recurrence at 5 years % (95% CI) 31 (24-37) 46 (42-49) 62 (58-65) 78 (73-84)

Recurrence risk group

Progression score 0 2-6 7-13 14-23

Probability of progression at 1 year % (95% CI) 0.2 (0-0.7) 1 (0.4-1.6) 5 (4-7%) 17 (10-24)

Probability of progression Progression at 5 years risk group % (95% CI) 0.8 (0-1.7) Low risk 6 (5-8) Intermediate risk 17 (14-20) High risk 45 (35-55)

Low risk Intermediate risk High risk

Note: Electronic calculators for Tables 3 and 4 are available at http://www.eortc.be/tools/bladdercalculator/

7. ADJUVANT TREATMENT 7.1

Intravesical chemotherapy

7.1.1 One, immediate, post-operative intravesical instillation of chemotherapy Although a state-of-the-art TUR by itself could eradicate a TaT1 tumour completely, these tumours will recur in a high percentage of cases and progress to muscle invasive bladder cancer in a limited number of cases. The high variability in the 3-month recurrence rate indicates that TUR is incomplete or provokes recurrences in a considerable percentage of patients (25). It is therefore necessary to consider adjuvant therapy in all patients. In a meta-analysis of seven randomized trials (1,476 patients with a median follow-up of 3.4 years), one immediate instillation of chemotherapy after TUR decreased the percentage of patients with recurrence by 12% (from 48.4% to 36.7%) and the odds of recurrence by 39%. The benefit was confirmed in both single and multiple tumours (45) (level of evidence: 1a). The difference of 12% means that in every 100 patients, 12 TURs may be avoided with one postoperative instillation, i.e. that 8.5 patients must be treated to prevent one recurrence. Since the costs of a TUR, anaesthesia and hospitalization in most countries exceed the cost of 8.5 times one instillation, this procedure is considered to be cost-effective. The effect can be explained by the destruction of circulating tumour cells, immediately after TUR, or as an ablative effect (chemoresection) of residual tumour cells at the resection site. The timing of the instillation is crucial. In all studies, the instillation was administered within 24 hours. One study reported that if the first instillation was not given the same day as TUR, there was a twofold increase in the relative risk of recurrence (46) (level of evidence: 2a). There is no single drug that is superior with regards to efficacy. Mitomycin C, epirubicin and doxorubicin have all shown a beneficial effect (45) (level of evidence: 1b). One immediate post-operative instillation of chemotherapy should be given in all patients after TUR of presumably non-muscle invasive bladder cancer. Severe complications have been reported in patients in whom extravasation of the drug occurred (47). Thus, an immediate instillation should be omitted in case of overt or suspected intra- or extra-peritoneal perforation, which is most likely to appear in extensive TUR procedures. Clear instructions should be given to the nursing staff for controlling the free flow of the bladder catheter at the end of the instillation. 7.1.2 Additional adjuvant intravesical chemotherapy instillations The need for further adjuvant intravesical therapy depends on the patient’s prognosis. In patients with a low risk of tumour recurrence (see Table 4), a single immediate instillation reduces the risk of recurrence and may be considered to be the standard treatment in these patients (45) (level of evidence: 1a). No further treatment should be given in these patients prior to a subsequent recurrence. For other patients, however, it remains an incomplete treatment as the likelihood of recurrence and/or progression is considerable. The effect of the immediate instillation of chemotherapy occurs during the first and second year (48,49) (level of evidence: 1b). It has been calculated from the data of five randomized trials (49) that the

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reduction of recurrence lasts for a period of approximately 500 days. The choice between further chemotherapy or immunotherapy largely depends on the risk that needs to be reduced: recurrence or progression. A meta-analysis of EORTC and Medical Research Council data, comparing intravesical chemotherapy to TUR alone, demonstrated that chemotherapy prevents recurrence but not progression (50) (level of evidence: 1a). The efficacy of intravesical chemotherapy in reducing the risk of tumour recurrence was confirmed by two other meta-analyses in primary (51) and recurrent tumours (52). It is still controversial how long and how frequently instillations of intravesical chemotherapy have to be given. From a systematic review of the literature of randomized clinical trials, which compared different schedules of intravesical chemotherapy instillations, one could only conclude that the ideal duration and intensity of the schedule remains undefined because of conflicting data (53). 7.1.3 Optimizing intravesical chemotherapy One randomized trial has demonstrated that adapting the urinary pH, decreasing the urinary excretion and buffering the intravesical solution reduced the recurrence rate (54) (level of evidence: 1b). Another randomized trial documented that concentration was more important than the duration of the treatment (55) (level of evidence: 1b). In view of these data, which need confirmation, it seems advisable to ask the patient not to drink the morning before instillation and to dissolve the drug in a buffered solution at optimal pH.

7.2

Intravesical BCG immunotherapy

7.2.1 Efficacy of Bacillus Calmette-Guérin (BCG) Several meta-analyses have addressed important questions concerning the efficacy of BCG in TaT1 bladder tumours. None of them however are based on individual patient data. Four meta-analyses confirmed that BCG after TUR is superior to TUR alone or TUR and chemotherapy in preventing recurrences of TaT1 tumours (56-59) (level of evidence: 1a). Two meta-analyses demonstrated that BCG therapy prevents, or at least delays, the risk of tumour progression (60,61) (level of evidence: 1a). A meta-analysis carried out by the EORTC evaluated data from 4,863 patients enrolled in 24 randomized trials. A total of 3,967 (81.6%) patients had only papillary tumours and 896 (18.4%) had primary or concomitant CIS. Five different BCG strains were used, and in 20 out of the 24 trials some form of BCG maintenance was used. In four trials only, a 6-week induction course was used. Based on a median follow-up of 2.5 years and a maximum of 15 years, 260 out of 2,658 patients (9.8%) on BCG progressed compared to 304 out of 2,205 (13.8%) in the control groups (TUR alone, TUR plus intravesical chemotherapy, or TUR plus another immunotherapy). This result is a reduction of 27% in the odds of progression with BCG treatment (p = 0.0001). The size of the reduction is similar in patients with TaT1 papillary tumours and in those with CIS (61). However, another two meta-analyses suggested a possible bias in favour of BCG by the inclusion of patients previously treated with intravesical chemotherapy in the studies (62,63). 7.2.2 The optimal BCG schedule For optimal efficacy, BCG must be given in a maintenance schedule (59-61) (level of evidence: 1a). In the EORTC meta-analysis, only patients receiving maintenance BCG benefited. In the four trials where no maintenance was given, no reduction in progression was observed. In the 20 trials in which some form of BCG maintenance was given, a reduction of 37% in the odds of progression was observed (p = 0.00004). The metaanalysis was unable to determine which BCG maintenance schedule was the most effective (61). In their metaanalyses, Böhle et al. concluded that at least 1 year of maintenance BCG was required to show the superiority of BCG over mitomycin C in preventing recurrence or progression (59,60). Although some modifications have been tried, induction BCG instillations are classically given according to the empirical 6-weekly induction schedule introduced by Morales 30 years ago. However, many different maintenance schedules have been used, ranging from a total of 10 instillations given in 18 weeks, to 30 instillations given over 3 years (64). The optimal number of induction instillations and the optimal frequency and duration of maintenance instillations remain unknown. Based on the extent of intravesical immune response, it is suggested that three, consecutive, weekly instillations give a maximum response (65). 7.2.3 The optimal dose of BCG To reduce BCG toxicity, a number of authors have proposed one-third and one-quarter dose instillations of BCG. Comparing one-third dose to full-dose BCG in 500 patients, the Spanish Oncology Group (CUETO) found no overall difference in efficacy. However, there was a suggestion that a full dose of BCG may be more effective in multifocal disease (66,67) (level of evidence: 1b). Although fewer patients reported toxicity with the reduced dose, the incidence of severe systemic toxicity was similar in the standard- and reduced-dose groups. The same Spanish group showed in a prospective randomized trial that one-third of the standard dose of BCG

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may be the minimum effective dose in intermediate-risk tumours. A further reduction to one-sixth dose resulted in a decrease in efficacy for preventing recurrence with no decrease in toxicity (68). 7.2.4 BCG toxicity Assuming that maintenance therapy is necessary for optimal efficacy, the issue of BCG toxicity becomes more relevant. Due to the more pronounced side-effects of BCG compared to intravesical chemotherapy, reluctance still exists about BCG use. Deaths due to BCG sepsis and the high frequency of BCG-induced cystitis have compromised the use of BCG. However, with increased experience in applying BCG, the side-effects now appear to be less prominent. Serious side-effects are encountered in less than 5% of patients and can be effectively treated in virtually all cases (69) (level of evidence: 1b). Major complications can appear after systemic absorption of the drug. Thus, BCG should not be administered during the first 2 weeks after TUR, in patients with haematuria and after traumatic catheterization. 7.2.5 Indications for BCG Although BCG is a very effective treatment, consensus exists that not all patients with non-muscle invasive bladder cancer should be treated with BCG due to the risk of toxicity. Ultimately, the choice of treatment will depend upon the patient’s risk of recurrence and progression. The use of BCG will not alter the natural course of the disease in tumours at low risk of recurrence and progression (see Table 4) and may be considered to be over-treatment for this category. In patients with tumours at high risk of progression, for whom a cystectomy is not carried out, after an immediate instillation of chemotherapy, BCG including a maintenance schedule is indicated. Although patients at intermediate-risk of progression were included in the meta-analyses (59,60), a separate confirmation of the superiority of BCG in these patients is not available. BCG can be offered in this group if chemotherapy is badly tolerated or if the patient continues to have recurrences in spite of repeated chemotherapy instillations. BCG should then be given for at least 1 year.

7.3

Treatment of failures of intravesical therapy

7.3.1 Failure of intravesical chemotherapy Patients with non-muscle invasive recurrences after intravesical chemotherapy can profit from BCG instillations (62). 7.3.2 Failure of intravesical BCG immunotherapy Treatment with BCG is considered to have failed in following situations: a. Whenever muscle invasive tumour is detected during follow-up. b. If high-grade, non-muscle invasive tumour is present at both 3 and 6 months (70). In patients with tumour present at 3 months, an additional BCG course provokes complete response in more than 50% of cases, both in patients with papillary tumours and CIS (70,71). c. Any worsening of the disease under BCG treatment, such as a higher number of recurrences, higher T or higher grade, or appearance of CIS, in spite of an initial response (level of evidence: 3). Patients with a later recurrence after completion of BCG therapy can be treated according to the risk classification (Tables 3 and 4). Changing from BCG to intravesical chemotherapy or device-assisted chemotherapy instillations can yield responses in selected cases with non-muscle invasive BCG failure. However, experience is limited and these strategies are considered experimental. Because of the high risk of development of muscle invasive tumour in these patients (70,72) (level of evidence: 3), immediate cystectomy is strongly advocated upon BCG failure.

7.4

Recommendations for adjuvant therapy

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The type of intravesical therapy is based on the risk groups as shown in Table 4 In patients at low risk of tumour recurrence and progression, one immediate instillation of chemotherapy is strongly recommended as the complete adjuvant treatment. (Grade of recommendation: A) In patients at an intermediate or high risk of recurrence and an intermediate risk of progression, one immediate instillation of chemotherapy should be followed by further instillations of chemotherapy or a minimum of 1 year of BCG. (Grade of recommendation: A) If chemotherapy is given, it is advised to use the drug at its optimal pH and to maintain the concentration of the drug during instillation by reducing fluid intake. The optimal schedule and the duration of the chemotherapy instillations remain unclear, but it should probably be given for 6 to 12 months. (Grade of recommendation: B) In patients at high risk of tumour progression, after an immediate instillation of chemotherapy, intravesical BCG for at least 1 year is indicated. (Grade of recommendation: A)

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Immediate radical cystectomy may be offered to patients at highest risk of tumour progression. In patients with BCG failure, cystectomy is recommended. (Grade of recommendation: C) The absolute risks of recurrence and of progression do not always indicate the risk at which a certain therapy is optimal. The choice of therapy may be considered differently according to what risk is acceptable for the individual patient and the urologist.

8. CYSTECTOMY FOR NON-MUSCLE INVASIVE BLADDER CANCER Many experts consider it is reasonable to propose immediate cystectomy to those patients with non-muscle invasive tumour who are at high risk of progression. According to the risk tables of the EORTC (see Tables 3 and 4) these are: • multiple recurrent high-grade tumours • high-grade T1 tumours • high-grade tumours with concomitant CIS. Cystectomy is advocated in patients with non-muscle invasive BCG failure as mentioned above. Delaying cystectomy in these patients may lead to decreased disease-specific survival (73).

9. FOLLOW-UP OF PATIENTS WITH TaT1 BLADDER TUMOURS Because of the risk of recurrence and progression, patients with TaT1 bladder tumours need be followed; however, the frequency and duration of cystoscopies should reflect the individual patient’s degree of risk. Using risk tables (see Tables 3 and 4), we are able to predict the short-term and long-term risks of both recurrence and progression in individual patients and can adapt the follow-up schedule accordingly (44): a. The prompt detection of muscle invasive and high-grade non-muscle invasive recurrences is critical since a delay in diagnosis and therapy threatens a patient’s life. b. Tumour recurrence in the low-risk group is nearly always low stage and low grade. Small, non-invasive (Ta), low-grade papillary recurrences do not present an immediate danger to the patient and their early detection is not essential for successful therapy (74-81) (level of evidence: 2b). c. The result of the first cystoscopy after TUR at 3 months is a very important prognostic factor for recurrence and for progression (44,72,82,83) (level of evidence: 1a). The first cystoscopy should thus always be performed 3 months after TUR in all patients with TaT1 bladder tumour. Randomized studies investigating the possibility of safely reducing follow-up cystoscopies are lacking. The following recommendations are therefore based only on retrospective experience.

9.1

Recommendations for follow-up cystoscopy

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Patients with tumours at low risk of recurrence and progression should have a cystoscopy at 3 months. If negative, the following cystoscopy is advised at 9 months and consequently yearly for 5 years. (Grade of recommendation: C) Patients with tumours at high risk of progression should have a cystoscopy and urinary cytology at 3 months. If negative, the following cystoscopies and cytologies should be repeated every 3 months for a period of 2 years, every 4 months in the third year, every 6 months thereafter until 5 years, and yearly thereafter. A yearly exploration of the upper tract is recommended. (Grade of recommendation: C) Patients with intermediate-risk of progression (about one-third of all patients) should have an in-between follow-up scheme using cystoscopy and cytology, adapted according to personal and subjective factors. (Grade of recommendation: C)

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Oge O, Erdem E, Atsu N, Ahin A, Ozen H. Proposal for changes in cystoscopic follow-up of patients with low-grade pTa bladder tumor. Eur Urol 2000;37(3):271-4. http://www.ncbi.nlm.nih.gov/pubmed/10720851 Holmäng S, Andius P, Hedelin H, Wester K, Busch C, Johansson SL. Stage progression in Ta papillary urothelial tumors: relationship to grade, immunohistochemical expression of tumor markers, mitotic frequency and DNA ploidy. J Urol 2001;165(4);1124-8. http://www.ncbi.nlm.nih.gov/pubmed/11257652 Fujii Y, Kawakami S, Koga F, Nemoto T, Kihara K. Long-term outcome of bladder papillary urothelial neoplasms of low malignant potential. BJU Int 2003;92(6):559-62. http://www.ncbi.nlm.nih.gov/pubmed/14511033 Leblanc B, Duclos AJ, Bénard F, Côté J, Valiquette L, Paquin JM, Mauffette F, Faucher R, Perreault JP.Long-term follow-up of initial Ta grade 1 transitional cell carcinoma of the bladder. J Urol 1999;162(6);1946-50. http://www.ncbi.nlm.nih.gov/pubmed/10569544 Zieger K, Wolf H, Olsen PR, Hojgaard K. Long-term follow-up of non-invasive bladder tumours (stage Ta): recurrence and progression. BJU Int 2000;85(7):824-8. http://www.ncbi.nlm.nih.gov/pubmed/10792160 Borhan A, Reeder JE, O’Connell MJ, Wright KO, Wheeless LL, di Sant’ Agnese PA, McNally ML, Messing EM. Grade progression and regression in recurrent urothelial cancer. J Urol 2003;169(6):2106-9. http://www.ncbi.nlm.nih.gov/pubmed/12771728 Soloway M, Bruck DS, Kim SS. Expectant management of small recurrent, non-invasive papillary bladder tumours. J Urol 2003;170(2 Pt 1):438-41. http://www.ncbi.nlm.nih.gov/pubmed/12853794 Gofrit ON, Pode D, Lazar A, Katz R, Shapiro A. Watchful waiting policy in recurrent Ta G1 bladder tumors. Eur Urol 2006;49(2):303-7. http://www.ncbi.nlm.nih.gov/pubmed/16413659 Holmang S, Johansson SL. Stage Ta-T1 bladder cancer: the relationship between findings at first followup cystoscopy and subsequent recurrence and progression. J Urol 2002;167(4):1634-7. http://www.ncbi.nlm.nih.gov/pubmed/11912378 Mariappan P, Smith G. A surveillance schedule for G1Ta bladder cancer allowing efficient use of check cystoscopy and safe discharge at 5 years based on a 25-year prospective database. J Urol 2005;173(4):1008-11. http://www.ncbi.nlm.nih.gov/pubmed/15758711

LIMITED TEXT UPDATE MARCH 2009

11. ABBREVIATIONS USED IN THE TEXT

This list is not comprehensive for the most common abbreviations.

5-ALA ASR BCG CIS CT CUETO EAU EORTC HAL ISUP IVU PUNLMP TNM TUR UICC US WHO

5-aminolaevulinic acid age-standardized rate bacillus Calmette-Guérin carcinoma in situ computed tomography Club Urológico Español de Tratamiento Oncológico (Spanish Oncology Group) European Association of Urology European Organization for Research and Treatment of Cancer hexaminolaevulinic acid International Society of Urological Pathology intravenous urography papillary urothelial neoplasms of low malignant potential tumour, node, metastasis transurethral resection Union International Contre le Cancer ultrasonography World Health Organization

Conflict of interest All members of the Non-Muscle Invasive Bladder Cancer guidelines writing panel have provided disclosure statements of all relationships which they have and which may be perceived as a potential source of conflict of interest. This information is kept on file in the European Association of Urology Central Office database. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

LIMITED TEXT UPDATE MARCH 2009

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Guidelines on

Bladder Cancer Muscle-invasive and Metastatic A. Stenzl, N.C. Cowan, M. De Santis, G. Jakse, M. Kuczyk, A.S. Merseburger, M.J. Ribal, A. Sherif, J.A. Witjes

© European Association of Urology 2009

TABLE OF CONTENTS

PAGE

1

INTRODUCTION

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2

EPIDEMIOLOGY AND RISK FACTORS 2.1 Epidemiology 2.2 Risk factors for bladder cancer 2.3 Conclusions 2.4 Recommendation 2.5 References

5 5 6 7 7 7

3 CLASSIFICATION 3.1 Tumour, Nodes, Metastases Classification (TNM) 3.2 Histological grading of non-muscle-invasive bladder tumours 3.2.1 WHO/ISUP grading 3.3 References 3.4 Pathology 3.4.1 Urologist handling of the specimens 3.4.2 Pathologist handling of the specimens 3.4.3 Pathology of muscle-invasive bladder cancer 3.4.4 Guidelines on assessment of tumour specimens 3.5 References

8 8 9 9 9 9 9 10 10 10 10

4 DIAGNOSIS AND STAGING 4.1 Diagnosis 4.1.1 Symptoms 4.1.2 Physical examination 4.1.3 Imaging 4.1.3.1 Intravenous urography and CT scan 4.1.3.2 Ultrasonography 4.1.4 Urinary cytology and urinary markers 4.1.5 Cystoscopy 4.1.6 Transurethral resection of invasive bladder tumours 4.1.7 Bladder and prostatic urethral biopsy 4.1.8 Fluorescence cystoscopy 4.1.9 Second resection 4.1.10 Concomitant prostate cancer 4.1.11 Recommendations for primary assessment of presumably invasive bladder tumours 4.1.12 References 4.2 Imaging for staging in verified bladder tumours 4.2.1 Local staging of invasive bladder cancer 4.2.1.1 MR imaging for local staging of invasive bladder cancer 4.2.1.2 CT for local staging of invasive bladder cancer 4.2.2 Imaging of nodal involvement 4.2.3 Extravesical urothelial carcinoma 4.2.4 Distant metastases other than lymph nodes 4.2.5 Conclusions 4.2.6 Recommendations for staging 4.3 References

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TREATMENT FAILURE OF NON-MUSCLE INVASIVE BLADDER TUMOURS 5.1 High-risk non-muscle-invasive urothelial carcinoma 5.2 Carcinoma in situ 5.3 Recommendations 5.4 References

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NEOADJUVANT CHEMOTHERAPY 6.1 Conclusions 6.2 Recommendations 6.3 References

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7 RADICAL SURGERY AND URINARY DIVERSION 7.1 Removal of the tumour bearing bladder 7.1.1 Background 7.1.2 Timing and delay of cystectomy 7.1.3 Indications 7.1.4 Technique and extent 7.1.5 Laparoscopic cystectomy 7.2 Urinary diversion after radical cystectomy 7.2.1 Ureterocutaneostomy 7.2.2 Ileal conduit 7.2.3 Continent cutaneous urinary diversion 7.2.4 Ureterocolonic diversion 7.2.5 Orthotopic neobladders 7.3 Morbidity and mortality 7.4 Survival 7.5 Conclusions 7.6 Recommendations 7.6.1 Recommendations for radical surgery 7.6.2 Recommendations for urinary diversion 7.7 References

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NON-RESECTABLE TUMOURS 8.1 Palliative cystectomy for muscle-invasive bladder carcinoma 8.2 Conclusions 8.3 Recommendations 8.4 References

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NEOADJUVANT BLADDER CANCER 9 neoadjuvantRADIOTHERAPY radioactivityINinMUSCLE-INVASIVE muscle-invasive bladder cancer 9.1 Pre-operative radiotherapy 9.1.1 Retrospective studies 9.1.2 Randomized studies 9.2 Conclusions 9.3 Recommendation s 9.4 References

32 32 32 32 33 33 33

10 BLADDER-SPARING TREATMENTS 10.1 Transurethral resection of bladder tumour (TURBT) 10.1.1 Conclusion and recommendation 10.1.2 References 10.2 External beam radiotherapy 10.2.1 Conclusions 10.2.2 Recommendation 10.2.3 References 10.3 Chemotherapy 10.3.1 Conclusion 10.3.2 Recommendation 10.3.3 References 10.4 Multimodality treatment 10.4.1 Conclusions 10.4.2 Recommendations 10.4.3 References

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ADJUVANT CHEMOTHERAPY 11.1 Conclusion 11.2 Recommendation 11.3 References

38 39 39 39

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METASTATIC DISEASE 12.1 Prognostic factors and treatment decisions 12.2 Single-agent chemotherapy 12.3 Standard first-line chemotherapy for ‘fit’ patients 12.4 Carboplatin-containing chemotherapy in ‘fit’ patients 12.5 Non-platinum combination chemotherapy 12.6 Chemotherapy in patients ‘unfit”’ for cisplatin 12.7 Second-line treatment 12.8 Low-volume disease and post-chemotherapy surgery 12.9 Conclusions 12.10 Recommendations 12.11 References

40 40 40 41 41 41 41 41 42 42 42 42

13.

QUALITY OF LIFE 13.1 Conclusions 13.2 Recommendations 13.3 References

47 48 48 48

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FOLLOW-UP 14.1 Conclusions and recommendations according to condition 14.2 General recommendations for follow-up 14.3 References

50 50 51 51

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ABBREVIATIONS USED IN THE TEXT

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1. INTRODUCTION The EAU guideline group for muscle-invasive and metastatic bladder cancer (MiM-BC) have prepared this guideline to help urologists assess the evidence-based management of muscle-invasive and metastatic bladder cancer and to incorporate the guideline recommendations into their clinical practice. Publications concerning muscle-invasive and metastatic bladder cancer are mostly based on retrospective analysis, including some larger multicentre studies and well-designed controlled studies. Only a few randomized studies are available, so that it is difficult to obtain high-level evidence-based data. The recommendations provided in the current guidelines are based on a systemic literature search using Medline, the Cochrane Central Register of Systematic Reviews, and reference lists in publications and review articles. There is clearly a need for continuous re-evaluation of the information presented in the current guideline by an expert panel. It has to be emphasized that the current guideline contains information for the treatment of an individual patient according to a standardized approach. The information should be considered as providing recommendations without legal implications. The level of evidence and grade of recommendation provided in this guideline follow the listings in Table 1. The aim of grading the recommendations is to provide transparency between the underlying evidence and the recommendation given. Table 1: Levels of evidence and grade of guideline recommendations as used by EAU (1) Level Type of evidence 1a Evidence obtained from meta-analysis of randomized trials 1b Evidence obtained from at least one randomized trial 2a Evidence obtained from one well-designed controlled study without randomization 2b Evidence obtained from at least one other type of well-designed quasi-experimental study 3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case reports 4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities Grade Nature of recommendations A Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomized trial B Based on well-conducted clinical studies, but without randomized clinical trials C Made despite the absence of directly applicable clinical studies of good quality

1.1

Reference

1.

Modified from Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998. http://www.cebm.net/index.aspx?o=1025 [access date February 2009].

2. EPIDEMIOLOGY AND RISK FACTORS 2.1

Epidemiology

In 2006, in Europe, an estimated 104,400 incident cases of bladder cancer were diagnosed, of which 82,800 were diagnosed in men and 21,600 in women. This represents 6.6% of the total cancers in men and 2.1% in women, with an estimated male-to-female ratio of 3.8:1. In men, bladder cancer was the fourth most common cancer. Bladder cancer resulted in 4.1% of total deaths for cancer in men and 1.8% of total deaths in women (1). At the initial diagnosis of bladder cancer, 70% of cases are diagnosed as non-muscle-invasive disease and 30% as muscle-invasive disease. Among patients treated with radical cystectomy because of muscle-invasive disease, 57% had muscle invasion at presentation, while 43% had been initially diagnosed with non-muscle-invasive disease that progressed despite organ-preserving treatment (2). Approximately onethird of patients diagnosed with muscle-invasive bladder cancer have undetected metastasis at the time of treatment of the primary tumour (3), while 25% of patients submitted to radical cystectomy present with lymph node involvement at the time of surgery.

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2.2

Risk factors for bladder cancer

Tobacco smoking. Tobacco smoking is the most well-established risk factor for bladder cancer, causing about 50-65% of male cases and 20-30% of female cases. A casual relationship has been established between an exposure to tobacco and cancer in studies in which chance, bias and confounding can be ruled out with reasonable confidence (4). The alleged carcinogenic constituents of tobacco smoke include arylamines, particularly the potent carcinogen 4-aminobiphenyl, polycyclic aromatic hydrocarbons (PAHs), N-nitroso compounds, heterocyclic amines and various epoxides. The incidence of bladder cancer is directly related to the duration of smoking and number of cigarettes smoked per day (5). There is also a higher risk of bladder cancer in those who start smoking at a young age and for those exposed to environmental tobacco smoke during childhood (6). An immediate decrease in the risk of bladder cancer has been observed in those who quit smoking. This reduction was about 40% within 1 to 4 years of quitting smoking and reached 60% after 25 years of cessation (5). The promotion of cessation of smoking would result in the incidence of bladder cancer decreasing equally in men and women. Occupational exposure to chemicals. Occupational exposure is the second most important risk factor for bladder cancer. Work-related cases account for 20-25% of all bladder cancer cases in several series. The substances involved in chemical exposure have been benzene derivatives and arylamines (2-naphthylamine, 4-ABP, 4,4’-methylenedianiline and o-toluidine). Professions in which this exposure occurs include those that use dyes, rubbers, textiles, paints, leathers and chemicals (7). Because of strict regulations, these chemicals have contributed minimally to the current incidence of bladder cancer in Western countries. In fact, a trend towards a decrease in bladder cancer due to occupational exposure has been reported in a pooled analysis of 11 case-control studies on bladder cancer conducted in European countries between 1976 and 1996 (8). An example of occupational exposure is aromatic amines, which are established carcinogens for urothelium and which can be inactivated by a metabolic acetylation pathway. It has been postulated that patients with slow acetylation capability were more susceptible to bladder cancer than rapid acetylators. NAT1 and NAT-2 are N-acetyltransferase genes located on the short arm of human chromosome 8 and involved in amine inactivation. The presence of an NAT2 slow acetylation genotype has been related to a higher risk of bladder cancer (9). Other risk factors include phenacetin, which was included in 1987 among proven human carcinogens by the International Agency for Research on Cancer (IARC). Some studies have suggested that the risk of bladder cancer due to phenacetin is dose-dependent; however, the data is controversial concerning its metabolite acetaminophen (10). External beam radiation therapy. Increased rates of secondary bladder malignancies have been reported after external beam radiation therapy (EBRT) for gynaecological malignancies with relative risks of 2 to 4 (11). In patients treated for prostate cancer, the incidence of bladder cancer was significantly lower in patients treated with radical prostatectomy than in patients who underwent EBRT (12). Dietary factors. Several dietary factors had been related to bladder cancer, but the results of different studies have been controversial. Currently, there is limited evidence of a causal relationship between bladder cancer and dietary factors. A meta-analysis of 38 articles reporting data on diet and bladder cancer supported the hypothesis that vegetable and fruit intake reduced the risk of bladder cancer (13). Chronic urinary tract infection. Muscle-invasive bladder cancer, particularly invasive squamous cell carcinoma, is directly related to the presence of chronic urinary tract infection. Bladder schistosomiasis has been considered a definitive cause of urinary bladder cancer with an associated five-fold risk. Schistosomiasis is the second most common parasitic infection after malaria, with about 600 million people exposed to infection in Africa, Asia, South America and the Caribbean (14). In the same way as cyclophosphamide, an alkylating agent used for treatment of lymphoproliferative diseases and other non-neoplastic diseases, it has been correlated with posterior development of muscle-invasive bladder cancer with a period of latency of 6-13 years. Acrolein is a metabolite of cyclophosphamide and is responsible for an increase in the incidence of bladder cancer, which is independent of the occurrence of haemorrhagic cystitis related to the same treatment (15, 16). Gender. Finally, differences in bladder cancer incidence by gender have been studied. In a retrospective study of patients submitted to radical cystectomy, it was demonstrated that women are more likely to be diagnosed with primary muscle-invasive disease than men (85% vs 51%) (2). It has been proposed that women are more likely to be older than men when diagnosed with a direct effect on their survival. In addition, delayed diagnosis is more likely in women after haematuria is observed because the differential diagnosis in women includes diseases more prevalent than bladder cancer (17). Differences in the gender prevalence of bladder cancer may also be due to other factors than tobacco and chemical exposure. In a large prospective cohort study, post-menopausal status was associated with

6

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an increase in bladder cancer risk even after adjusting for smoking status. Thus, the differences in oestrogen and androgen levels between men and women could be responsible for some of the difference in gender prevalence of bladder cancer (18).

2.3

Conclusions

• •

The incidence of muscle invasive disease has not changed for a period of 5 years. Active and passive tobacco smoking continues to be the major risk factor while exposure-related incidence is decreasing (Level of evidence: 2a). The estimated male to female ratio was 3.8:1, with women more likely to be diagnosed with primary muscle invasive disease than men. Currently, treatment decisions cannot be based on molecular markers.

• •

2.4

Recommendation

•

The most important primary prevention for muscle-invasive bladder cancer is to eliminate active and passive smoking (Grade of recommendation: B).

2.5

References

1.

Ferlay J, Autier P, Boniol M. Heanue M, Colombet M, Boyle P. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 2007;18(3):581-92. http://www.ncbi.nlm.nih.gov/pubmed/17287242 Vaidya A, Soloway MS, Hawke C, Tiguert R, Civantos F. De novo muscle invasive bladder cancer: is there a change in trend?. J Urol 2001;165(1):47-50. http://www.ncbi.nlm.nih.gov/pubmed/11125361 Prout GR Jr, Griffin PP, Shipley WU. Bladder carcinoma as a systemic disease. Cancer 1979;43(6):2532-9. http://www.ncbi.nlm.nih.gov/pubmed/455239 IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Tobacco smoke and involuntary smoking. IARC Monogr Eval Carcinog Risks Hum 2004;83:1-1438. http://www.ncbi.nlm.nih.gov/pubmed/15285078 Brennan P, Bogillot O, Cordier S, Greiser E, Schill W, Vineis P, Lopez-Abente G, Tzonou A, ChangClaude J, Bolm-Audorff U, Jöckel KH, Donato F, Serra C, Wahrendorf J, Hours M, T’Mannetje A, Kogevinas M, Boffetta P. Cigarette smoking and bladder cancer in men: a pooled analysis of 11 casecontrol studies. Int J Cancer 2000;86(2):289-94. http://www.ncbi.nlm.nih.gov/pubmed/10738259 Bjerregaard BK, Raaschou-Nielsen O, Sørensen M, Frederiksen K, Christensen J, Tjønneland A, Overvad K, Chapelon FC, Nagel G, Chang-Claude J, Bergmann MM, Boeing H, Trichopoulos D, Trichopoulou A, Oikonomou E, Berrino F, Palli D, Tumino R, Vineis P, Panico S, Peeters PH, Buenode-Mesquita HB, Kiemeney L, Gram IT, Braaten T, Lund E, Gonzalez CA, Berglund G, Allen N, Roddam A, Bingham S, Riboli E. Tobacco smoke and bladder cancer–in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 2006;119(10):2412-6. http://www.ncbi.nlm.nih.gov/pubmed/16894557 Pashos CL, Botteman MF, Laskin BL, Redaelli A. Bladder cancer: epidemiology, diagnosis, and management. Cancer Pract 2002;10(6):311-22. http://www.ncbi.nlm.nih.gov/pubmed/15285078 Kogevinas M, T’Mannetje A, Cordier S, Ranft U, González CA, Vineis P, Chang-Claude J, Lynge E, Wahrendorf J, Tzonou A, Jöckel KH, Serra C, Porru S, Hours M, Greiser E, Boffetta P. Occupation and bladder cancer among men in Western Europe. Cancer Causes and Control 2003;14(10):907-14. http://www.ncbi.nlm.nih.gov/pubmed/14750529 García-Closas M, Malats N, Silverman D, Dosemeci M, Kogevinas M, Hein DW, Tardón A, Serra C, Carrato A, García-Closas R, Lloreta J, Castaño-Vinyals G, Yeager M, Welch R, Chanock S, Chatterjee N, Wacholder S, Samanic C, Torà M, Fernández F, Real FX, Rothman N. NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses. Lancet 2005;366(9486):649-59. http://www.ncbi.nlm.nih.gov/pubmed/16112301 Castelao JE, Yuan JM, Gago-Dominguez M, Yu MC, Ross RK.Non-steroidal anti-inflammatory drugs and bladder cancer prevention. Br J Cancer 2000;82(7):1364-9. http://www.ncbi.nlm.nih.gov/pubmed/10755416 Chrouser K, Leibovich B, Bergstralh E, Zincke H, Blute M. Bladder cancer risk following primary and adjuvant external beam radiation for prostate cancer. J Urol 2006;174(1):107-10. http://www.ncbi.nlm.nih.gov/pubmed/15947588

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

UPDATE MARCH 2008

7

12.

13.

14.

15.

16.

17.

18.

Boorjian S, Cowan JE, Konety BR, DuChane J, Tewari A, Carroll PR, Kane CJ; Cancer of the Prostate Strategic Urologic Research Endeavor Investigators. Bladder cancer incidence and risk factors in men with prostate cancer: results from Cancer of the Prostate Strategic Urologic Research Endeavor. J Urol 2007;177(3):883-7. http://www.ncbi.nlm.nih.gov/pubmed/17296367 Steinmaus CM, Nuñez S, Smith AH. Diet and bladder cancer: a meta-analysis of six dietary variables. Am J Epidemiol 2000;151(7):693-702. http://www.ncbi.nlm.nih.gov/pubmed/10752797 [No authors listed.] Schistosomes, liver flukes and Helicobacter pylori. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Lyon, 7-14 June, 1994. IARC Monogr Eval Carcinog Risks Hum 1994;61:1-241. http://www.ncbi.nlm.nih.gov/pubmed/7715068 Kaldor JM, Day NE, Kittelmann B, Pettersson F, Langmark F, Pedersen D, Prior P, Neal F, Karjalainen S, Bell J et al. Bladder tumours following chemotherapy and radiotherapy for ovarian cancer: a casecontrol study. Int J Cancer 1995;63(1):1-6. http://www.ncbi.nlm.nih.gov/pubmed/7558434 Travis LB, Curtis RE, Glimelius B, Holowaty EJ, Van Leeuwen FE, Lynch CF, Hagenbeek A, Stovall M, Banks PM, Adami J et al. Bladder and kidney cancer following cyclophosphamide therapy for nonHodgkin’s lymphoma. J Natl Cancer Inst 1995;87(7):524-30. http://www.ncbi.nlm.nih.gov/pubmed/7707439 Cárdenas-Turanzas M, Cooksley C, Pettaway CA, Sabichi A, Grossman HB, Elting L. Comparative outcomes of bladder cancer. Obstet Gynecol 2006;108(1):169-75. http://www.ncbi.nlm.nih.gov/pubmed/16816072 McGrath M, Michaud DS, De Vivo I. Hormonal and reproductive factors and the risk of bladder cancer in women. Am J Epidemiol 2006;163(3):236-44. http://www.ncbi.nlm.nih.gov/pubmed/16319290

3. CLASSIFICATION 3.1

Tumour, Nodes, Metastases Classification (TNM)

The 2002 TNM classification approved by the Union International Contre le Cancer (UICC) has been widely accepted (Table 2) (1). It differs from the previous versions in the definition of stage T2 and T3 tumours.

Table 2: 2002 TNM classification of urinary bladder cancer T - Primary tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour Ta Non-invasive papillary carcinoma Tis Carcinoma in situ: ‘flat tumour’ T1 Tumour invades subepithelial connective tissue T2 Tumour invades muscle T2a Tumour invades superficial muscle (inner half) T2b Tumour invades deep muscle (outer half) T3 Tumour invades perivesical tissue T3a Microscopically T3b Macroscopically (extravesical mass) T4 Tumour invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall T4a Tumour invades prostate, uterus or vagina T4b Tumour invades pelvic wall or abdominal wall N - Lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single lymph node 2 cm or less in greatest dimension N2 Metastasis in a single lymph node more than 2 cm but not more than 5 cm in greatest dimension, or multiple lymph nodes, none more than 5 cm in greatest dimension N3 Metastasis in a lymph node more than 5 cm in greatest dimension

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M - Distant metastasis MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis

3.2

Histological grading of non-muscle-invasive bladder tumours

In 1998, the new classification of non-invasive urothelial tumours was proposed by the World Health Organization (WHO) and the International Society of Urological Pathology (ISUP) (1998 WHO/ISUP classification). It was published by the WHO in 2004 (2, 3) (Table 3). Its major contribution is a detailed histological description of the various grades using specific cytological and architectural criteria. A website (www.pathology.jhu.edu/bladder) illustrating examples of various grades was developed to improve accuracy further in using the system. Table 3: WHO grading in 1973 and in 2004 (2, 3) 1973 WHO grading • Urothelial papilloma • Grade 1: well differentiated • Grade 2: moderately differentiated • Grade 3: poorly differentiated 2004 WHO grading • Urothelial papilloma • Papillary urothelial neoplasm of low malignant potential (PUNLMP) • Low-grade papillary urothelial carcinoma • High-grade papillary urothelial carcinoma 3.2.1 WHO/ISUP grading The 2004 WHO grading differentiates between papillary urothelial neoplasms of low malignant potential (PUNLMP) and low-grade and high-grade urothelial carcinomas. The PUNLMP are defined as lesions that do not have cytological features of malignancy but show normal urothelial cells in a papillary configuration. Although they have a negligible risk for progression, they are not completely benign and still have a tendency to recur. The intermediate grade (grade 2), which was controversial in the 1973 WHO classification, has been eliminated. The use of the 2004 WHO classification is advocated, as this should result in a uniform diagnosis of tumours, which will be better classified according to risk potential. However, until the 2004 WHO classification has been validated by more clinical trials, tumours should be graded using both the 1973 and the 2004 WHO classifications (4). Most clinical trials published so far on bladder tumours have been performed using the 1973 WHO classification and this edition of the guidelines therefore uses the 1973 WHO grade classification.

3.3

References

1.

Sobin DH, Wittekind Ch, eds. In: TNM Classification of Malignant Tumours. 6th edn. New York: WileyLiss, 2002; pp. 199-202. Epstein JI, Amin MB, Reuter VR, Mostofi FK. The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Am J Surg Pathol 1998;22(12):1435-48. http://www.ncbi.nlm.nih.gov/pubmed/9850170 Sauter G, Algaba F, Amin M, Busch C, Cheville J, Gasser T, Grignon DJ, Hofstadter F, Lopez-Beltran A, Epstein JI. Tumours of the urinary system: non-invasive urothelial neoplasias. In: Eble JN, Sauter G, Epstein Jl, Sesterhenn I, eds. WHO classification of classification of tumors of the urinary system and male genital organs. Lyon: IARCC Press, 2004, pp. 29-34. Lopez-Beltran A, Montironi R. Non-invasive urothelial neoplasms: according to the most recent WHO classification. Eur Urol 2004;46(2):170-6. http://www.ncbi.nlm.nih.gov/pubmed/15245809

2.

3.

4.

3.4

Pathology

3.4.1 Urologist handling of the specimens In transurethral resection (TUR) specimens, the superficial and deep areas of the tumour must be sent to pathology separately. If random biopsies of the flat mucosa have been done, each biopsy of the flat mucosa must also be sent separately.

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In radical cystectomy, bladder fixation must be performed as soon as possible. The pathologist must open the specimen from the urethra to the bladder dome and fix the specimen in formalin. In some circumstances, this procedure can also be performed by the urologist. In a female cystectomy specimen, the length of the urethral segment removed en bloc with the specimen should be checked preferably by the urological surgeon (1). 3.4.2 Pathologist handling of the specimens Handling of specimens should follow the general rules as published by a collaborative group of pathologists and urologists (2). It must be stressed that it can be very difficult to certify the presence of a neoplastic lesion using gross examination of the cystectomy specimen after TUR or chemotherapy, and it is therefore necessary to include the entire retracted or ulcerated area. Of the margins, it is mandatory to study the urethra, ureter, the prostate in men, and radial margins (3). In urethra-sparing cystectomy, the level of urethral dissection, the completeness of the prostate specifically at the apex (in men), and the inclusion of the entire bladder neck and the amount of adjacent urethra (in women) should be documented. 3.4.3 Pathology of muscle-invasive bladder cancer At this stage, there are no cases of papillary urothelial neoplasms of low malignant potential and low-grade carcinoma. All cases are high-grade urothelial carcinomas (grade II or grade III in WHO 1973). For this reason, no more prognostic information can be provided by grading muscle-invasive bladder cancer (4). However, some morphological subtypes can be most important for prognosis and treatment decisions, as in: • Small-cell carcinomas • Urothelial carcinomas with squamous and/or glandular partial differentiation • Spindle cell carcinomas • Some urothelial carcinomas with trophoblastic differentiation. For staging, TNM 2002 is recommended. The pattern of muscular invasion can provide some prognostic information. Most cases show nodular or cordonal growth, but about 44% of cases show an infiltrative pattern. According to some authors (4), the median survival time of a patient with an infiltrative pattern is lower than with other pattern types (p = 0.06). Blood vessel invasion and lymph node infiltration have an independent prognostic significance (5). It seems that the pN category is closely associated with the number of lymph nodes studied by the pathologist. For this reason, some authors have observed that more than nine lymph nodes have to be investigated to reflect pN0 appropriately (6). New prognostic markers are under study (7). Currently, insufficient evidence exists to recommend the standard use of p53 as a prognostic marker in high-risk muscle-invasive disease, since it will not yield sufficient data upon which to base treatment in an individual patient. 3.4.4 GUIDELINES ON ASSESSMENT OF TUMOUR SPECIMENS Mandatory evaluations • Depth of invasion (categories pT2 vs pT3a, pT3b or pT4) • Margins with special attention paid to the radial margin • Histological subtype, if it has clinical implications • Extensive lymph node representation (more that eight) Optional evaluations • Bladder wall blood vessel invasion • Pattern of muscle invasion

3.5

REFERENCES

1. 2.

Stenzl A. Current Concepts for Urinary Diversion in Women. Eur Urol(EAU Update Series 1);2003:91-9. Lopez-Beltran A, Bassi PF, Pavone-Macaluso M, Montironi R, European Society of Uropathology; Uropathology Working Group. Handling and pathology reporting of specimens with carcinoma of the urinary bladder, ureter, and renal pelvis. A joint proposal of the European Society of Uropathology and the Uropathology Working Group. Vichows Arch 2004;445(2):103-10. http://www.ncbi.nlm.nih.gov/pubmed/15185074 Herr HW. Pathologic evaluation of radical cystectomy specimens. Cancer 2002;95(3):668-9. http://www.ncbi.nlm.nih.gov/pubmed/12209761

3.

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4.

5.

6. 7.

Jimenez RE, Gheiler E, Oskanian P, Tiguert R, Sakr W, Wood DP Jr, Pontes JE, Grignon DJ. Grading the invasive component of urothelial carcinoma of the bladder and its relationship with progressionfree survival. Am J Surg Pathol 2000;24(7):980-7. http://www.ncbi.nlm.nih.gov/pubmed/10895820 Leissner J, Koeppen C, Wolf HK. Prognostic significance of vascular and perineural invasion in urothelial bladder cancer treated with radical cystectomy. J Urol 2003;169:955-60. http://www.ncbi.nlm.nih.gov/pubmed/12576821 Shariat SF, Karam JA, Lerner SP. Molecular markers in bladder cancer. Curr Opin Urol 2008;18(1):1-8. http://www.ncbi.nlm.nih.gov/pubmed/18090481 Tiguert R, Lessard A, So A, Fradet Y. Prognostic markers in muscle invasive bladder cancer. World J Urol 2002;20:190-5. http://www.ncbi.nlm.nih.gov/pubmed/12196903

4. DIAGNOSIS AND STAGING 4.1

Diagnosis

4.1.1 Symptoms Painless haematuria is a common finding. In addition, there is a group of patients who complain of urgency, dysuria, increased frequency and pelvic pain. Pelvic pain and all the symptoms related to urinary tract obstruction are found in more advanced tumours. 4.1.2 Physical examination Physical examination should include rectal and vaginal bimanual palpation. A palpable pelvic mass can be found in patients with locally advanced tumours. In addition, bimanual examination should be carried out before and after TUR to assess whether there is a palpable mass or the tumour fixed to the pelvic wall (1,2). 4.1.3 Imaging 4.1.3.1 Intravenous urography and CT scan Large tumours may be seen as filling defects in the bladder. Intravenous urography (IVU) is also used to detect filling defects in the calices, renal pelvis and ureters, and hydronephrosis, which may indicate the presence of a ureteral tumour. The necessity to perform routine intravenous pyelography once a bladder tumour has been detected is now questioned because of the low incidence of significant findings obtained with this method (3-5) (Level of evidence: 3). The incidence of upper urinary tract tumours is low (1.8%), but increases to 7.5% in tumours located in the trigone (4). In many centres, computed tomography (CT) urography is used as an alternative to conventional IVU (6). CT tomography gives more information than IVU, especially in invasive tumours of the upper tract (Level of evidence: 2a). 4.1.3.2 Ultrasonography Ultrasonography (US) is increasingly used as the initial tool to assess the urinary tract. This is not only because it avoids the use of contrast agents, but also because sensitive transducers have improved imaging of the upper urinary tract and bladder. Transabdominal US permits characterization of renal masses, detection of hydronephrosis and visualization of intraluminal filling defects in the bladder. Combined with plain abdominal film, it can be as accurate as IVU in diagnosing the cause of haematuria (1, 2) (Level of evidence: 3). 4.1.4 Urinary cytology and urinary markers Examination of a voided urine or bladder-washing specimen for exfoliated cancer cells has high sensitivity in high-grade tumours (Level of evidence: 3). It is therefore useful when a high-grade malignancy or carcinoma in situ (CIS) is present. Positive urinary cytology may indicate urothelial tumour anywhere in the urinary tract from the calix, through the ureters, into the bladder and proximal urethra. Cytological interpretation is user-dependent (7). The evaluation can be hampered by low cellular yield, urinary tract infections, stones or intravesical instillations. In experienced hands, however, specificity exceeds 90% (8) (Level of evidence: 2b). Cytology should be performed on fresh urine with adequate fixation. Morning urine is not suitable as cytolysis may be often present. There is no urinary marker registered specifically for the diagnosis of invasive bladder cancer. However, since most invasive tumours are high-grade, the positive predictive value of markers may be higher.

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4.1.5 Cystoscopy The diagnosis of bladder cancer ultimately depends on cystoscopic examination of the bladder and histological evaluation of the resected tissue. In general, cystoscopy is initially performed in the office, using flexible instruments. If a bladder tumour has been visualized in earlier imaging studies, such as 3D ultrasonography, multidetector row CT or MRI a diagnostic cystoscopy can be omitted since the patient will undergo TUR for a histological diagnosis. A careful description of the finding is necessary. It should include the site, size, number and appearance (papillary or solid) of the tumours as well as a description of mucosal abnormalities. Use of a bladder diagram is recommended. 4.1.6 Transurethral resection of invasive bladder tumours The goal of TUR is to make the correct diagnosis, which means including bladder muscle in the resection biopsies. The strategy of resection depends from the size of the lesion. Small tumours (less than 1 cm) can be resected en bloc, where the specimen contains the complete tumour plus a part of the underlying bladder wall including bladder muscle. Larger tumours have to be resected separately in fractions, which include the exophytic part of the tumour, the underlying bladder wall with the detrusor muscle and the edges of the resection area. The specimens from different fractions must be referred to the pathologist in separate containers to enable him to make a correct diagnosis. Cauterization has to be avoided as much as possible during the resection to prevent tissue destruction. 4.1.7 Bladder and prostatic urethral biopsy Bladder tumours are often multifocal. Moreover tumours can be accompanied by CIS or dysplasia. These lesions may present themselves as velvet-like, reddish areas, indistinguishable from inflammation or may be not visible at all. The biopsies from normal-looking mucosa in patients with bladder tumours, so called random biopsies (R-biopsies) or selected site mucosal biopsies, are only recommended if fluorescent areas are seen with photodynamic diagnosis (PDD). Cold cup biopsies from normal-looking mucosa should be performed when cytology is positive, when exophytic tumour is of non-papillary appearance, or when fluorescent areas are seen with PDD. When abnormal areas of urothelium are seen, it is advised to take ‘cold cup’ biopsies or biopsies with a resection loop. Material obtained by random or directed biopsies must be sent for pathological assessment in separate containers. The involvement of the prostatic urethra and ducts in male patients with bladder tumours has been reported. Although the exact risk is not known, it seems to be higher if tumour is located on the trigone or bladder neck, in the presence of bladder CIS and in multiple tumours (9, 10) (Level of evidence: 3). In these cases and when cytology is positive or when abnormalities of prostatic urethra are visible, biopsies of the prostatic urethra are recommended. The biopsy is taken using resection loop from the precolicular area. Special care must be taken with tumours at the bladder neck and trigone in female patients where urethral preservation in subsequent orthotopic neobladder is planned. Tumour bladder neck biopsies are advisable but not mandatory, provided frozen section at the urethral margin is taken at the time of surgery (Level of evidence 4). 4.1.8 Fluorescence cystoscopy As a standard procedure, cystoscopy and TUR are performed using white light. However, the use of white light may lead to missing lesions that are present but not visible. Fluorescence cystoscopy is performed using filtered blue light after intravesical instillation of a photosensitizer, usually (5-ALA) or hexaminolaevulinate (HAL). It has been confirmed that fluorescenceguided biopsy and resection are more sensitive than conventional procedures in detecting malignant tumour, particularly CIS (11-13) (Level of evidence: 2a). However, false-positive results can be induced by inflammation, a recent TUR, or intravesical instillation therapy. 4.1.9 Second resection There is a significant risk of residual tumour after the initial TUR (14, 15) (Level of evidence: 1). Persistent disease was observed in 33-53% of patients (15-21). Moreover, the tumour may be understaged by the initial resection. There is a 10% probability that tumours initially staged as being of a lower stage are in fact muscleinvasive (16, 17). Correct staging is extremely important since it will directly affect the treatment modality. A second TUR should always be performed when the initial resection has been incomplete, e.g. when multiple and/or large tumours are present, or when the pathologist has reported that the specimen contained no muscle tissue. Furthermore, a second TUR should be performed when a high-grade, non-muscle-invasive tumour or a T1 tumour has been detected at the initial TUR. There is no consensus about the strategy and

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timing of a second TUR. Most authors recommend resection at 2-6 weeks after the initial TUR. The procedure should include a resection of the primary tumour site. 4.1.10 Concomitant prostate cancer Ruling out progressive prostate cancer should be considered since 25-46% of patients submitted to cystectomy for bladder cancer (22) appear to have prostate cancer on final pathology. Unless the entire prostate is to be removed during cystectomy, any type of prostate cancer should be excluded. 4.1.11 Recommendations for primary assessment of presumably invasive bladder tumours • Renal and bladder ultrasonography, IVU or CT prior to TUR (Grade of recommendation: B). • Cystoscopy with description of the tumour (site, size, number and appearance) and mucosal abnormalities. A bladder diagram is recommended (Grade of recommendation: C). • TUR in one piece for small tumours (less than 1 cm), including a part from the underlying bladder muscle wall (Grade of recommendation: B). • TUR in fractions (including muscle tissue) for larger tumours (Grade of recommendation: B). • Biopsies of abnormal-looking urothelium, biopsies from normal-looking mucosa when cytology is positive or when exophytic tumour is of non-papillary appearance or in case of fluorescence if PDD is used (Grade of recommendation: C). • Biopsy of the prostatic urethra in the case of bladder neck tumour, when bladder CIS is present or suspected or when abnormalities of prostatic urethra are visible (Grade of recommendation: C). • Careful inspection with histological evaluation of the bladder neck and urethral margin, either prior to or at the time of cystoscopy in women undergoing a subsequent orthotopic neobladder (Grade of recommendation: C). • A second TUR at 2-6 weeks after the initial resection when it was incomplete or when a high-grade or T1 tumour was detected (Grade of recommendation: B). • The pathological report should specify the grade, the depth of tumour invasion and whether the lamina propria and muscle are present in the specimen (Grade of recommendation: C). 4.1.12 References 1. Fossa SD, Ous S, Berner A. Clinical significance of the ‘palpable mass’ in patients with muscle infiltrating bladder cancer undergoing cystectomy after pre-operative radiotherapy. Br J Urol 1991;67(1):54-60. http://www.ncbi.nlm.nih.gov/pubmed/1993277 2. Wijkstrom H, Norming U, Lagerkvist M, Nilsson B, Naslund I, Wiklund P. Evaluation of clinical staging before cystectomy in transitional cell bladder carcinoma: a long-term follow-up of 276 consecutive patients. Br J Urol 1998;81(5):686-91. http://www.ncbi.nlm.nih.gov/pubmed/9634042 3. Goessl C, Knispel HH, Millar K, Klan R. Is routine excretory urography necessary at first diagnosis of bladder cancer? J Urol 1997;157(2):480-1. http://www.ncbi.nlm.nih.gov/pubmed/8996338 4. Palou J, Rodriguez-Rubio F, Huguet J, Segarra J, Ribal MJ, Alcaraz A, Villavicencio H. Multivariate analysis of clinical parameters of synchronous primary superficial bladder cancer and upper urinary tract tumors. J Urol 2005;174(3):859-61. http://www.ncbi.nlm.nih.gov/pubmed/16093970 5. Holmang S, Hedelin H, Anderstrom C, Holmberg E, Johansson SL. Long-term follow-up of a bladder carcinoma cohort: routine followup urography is not necessary. J Urol 1998;160(1):45-8. http://www.ncbi.nlm.nih.gov/pubmed/9628602 6. Nolte-Ernsting C, Cowan N. Understanding multislice CT urography techniques: many roads lead to Rome. Eur Radiol 2006;16(12):1670-86. http://www.ncbi.nlm.nih.gov/pubmed/16953373 7. Raitanen M-P, Aine R, Rintala E, Kallio J, Rajala P, Juusela H, Tammela TL; FinnBladder Group. Differences between local and review urinary cytology and diagnosis of bladder cancer. An interobserver multicenter analysis. Eur Urol 2002;41(3):284-9. http://www.ncbi.nlm.nih.gov/pubmed/12180229 8. Lokeshwar VB, Habuchi T, Grossman HB, Murphy WM, Hautmann SH, Hemstreet GP 3rd, Bono AV, Getzenberg RH, Goebell P, Schmitz-Dräger BJ, Schalken JA, Fradet Y, Marberger M, Messing E, Droller MJ. Bladder tumor markers beyond cytology: international consensus panel on bladder tumor markers. Urology 2005;66 (6 Suppl 1):35-63. http://www.ncbi.nlm.nih.gov/pubmed/16399415

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Matzkin H, Soloway MS, Hardeman S. Transitional cell carcinoma of the prostate. J Urol 1991;146(5):1207-12. http://www.ncbi.nlm.nih.gov/pubmed/1942262 Mungan MU, Canda AE, Tuzel E, Yorukoglu K, Kirkali Z. Risk factors for mucosal prostatic urethral involvement in superficial transitional cell carcinoma of the bladder. Eur Urol 2005;48(5):760-3. http://www.ncbi.nlm.nih.gov/pubmed/16005563 Schmidbauer J, Witjes F, Schmeller N, Donat R, Susani M, Marberger M; Hexvix PCB301/01 Study Group. Improved detection of urothelial carcinoma in situ with hexaminolevulinate fluorescence cystoscopy. J Urol 2004;171(1):135-8. http://www.ncbi.nlm.nih.gov/pubmed/14665861 Jichlinski P, Guillou L, Karlsen SJ, Malmstrom PU, Jocham D, Brennhovd B, Johansson E, Gartner T, Lange N, van den Bergh H, Leisinger HJ. Hexyl aminolevulinate fluorescence cystoscopy: a new diagnostic tool for photodiagnosis of superficial bladder cancer –a multicenter study. J Urol 2003;170(1):226-9. http://www.ncbi.nlm.nih.gov/pubmed/12796694 Hungerhuber E, Stepp H, Kriegmair M, Stief Ch, Hofstetter A, Hartmann A, Knuechel R, Karl A, Tritschler S, Zaak D. Seven years’ experience with 5-aminolevulinic acid in detection of transitional cell carcinoma of the bladder. Urology 2007;69(2):260-4. http://www.ncbi.nlm.nih.gov/pubmed/17320660 Brausi M, Collette L, Kurth K, van der Meijden A, Oosterlinck W, Witjes JA, Newling D, Bouffioux C, Sylvester R; EORTC Genito-Urinary Tract Cancer Collaborative Group. Variability in the recurrence rate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: a combined analysis of seven EORTC studies. Eur Urol 2002;41(5):523-31. http://www.ncbi.nlm.nih.gov/pubmed/12074794 Miladi M, Peyromaure M, Zerbib M, Saighi D, Debre B. The value of a second transurethral resection in evaluating patients with bladder tumours. Eur Urol 2003;43(3):241-5. http://www.ncbi.nlm.nih.gov/pubmed/12600426 Jakse G, Algaba F, Malmstrom PU, Oosterlinck W. A second-look TUR in T1 transitional cell carcinoma: why? Eur Urol 2004;45(5):539-46. http://www.ncbi.nlm.nih.gov/pubmed/15082193 Brauers A, Buettner R, Jakse G. Second resection and prognosis of primary high risk superficial bladder cancer: is cystectomy often too early? J Urol 2001;165(3):808-10. http://www.ncbi.nlm.nih.gov/pubmed/11176474 Schips L, Augustin H, Zigeuner RE, Gallé G, Habermann H, Trummer H, Pummer K, Hubmer G. Is repeated transurethral resection justified in patients with newly diagnosed superficial bladder cancer? Urology 2002;59(2):220-3. http://www.ncbi.nlm.nih.gov/pubmed/11834389 Grimm MO, Steinhoff Ch, Simon X, Spiegelhalder P, Ackermann R, Vögeli, TA. Effect of routine repeat transurethral resection for superficial bladder cancer: a long-term observational study. J Urol 2003;170(2 Pt 1):433-7. http://www.ncbi.nlm.nih.gov/pubmed/12853793 Divrik RT, Yildirim Ü, Zorlu F, Özen H. The effect of repeat transurethral resection on recurrence and progression rates in patients with T1 tumors of the bladder who received intravesical mitomycin: a prospective, randomized clinical trial. J Urol 2006;175(5):1641-4. http://www.ncbi.nlm.nih.gov/pubmed/16600720 Jahnson S, Wiklund F, Duchek M, Mestad O, Rintala E, Hellsten S, Malmström PU. Results of secondlook resection after primary resection of T1 tumour of the urinary bladder. Scand J Urol Nephrol 2005;39(3):206-10. http://www.ncbi.nlm.nih.gov/pubmed/16127800 Damiano R, Di Lorenzo G, Cantiello F, De Sio M, Perdona S, D’Armiento M, Autorino R. Clinicopathologic features of prostate adenocarcinoma incidentally discovered at the time of radical cystectomy: an evidence-based analysis. Eur Urol 2007;52(3):648-57. http://www.ncbi.nlm.nih.gov/pubmed/17600614

Imaging for staging in verified bladder tumours

Imaging is indicated only if there is a clinical consequence. The treatment and prognosis for invasive bladder cancer is determined by tumour stage and grade (1). Tumour staging must be accurate for selecting the correct treatment In clinical practice. The use of CT scan and magnetic resonance imaging (MRI) has largely replaced other imaging modalities for staging of invasive bladder cancer. The purpose of imaging for staging invasive bladder cancer is to:

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• Assess the extent of local tumour invasion • Detect tumour spread to lymph nodes • Detect tumour spread to other distant organs, (liver, lung, bones, peritoneum, pleura, kidney, adrenal gland and others). 4.2.1 Local staging of invasive bladder cancer Both CT and MRI may be used for assessment of local invasion (2) but they are unable to detect microscopic invasion of perivesical fat (T3a) (3). The aim of CT and MRI is therefore to detect T3b disease or higher. 4.2.1.1 MRI for local staging of invasive bladder cancer MRI has superior soft tissue contrast resolution compared with CT, but poorer spatial resolution. In studies performed before the availability of multidetector-row CT (MDCT), MRI was reported to be more accurate for local assessment. The accuracy of MRI for primary tumour staging varies from 73% to 96% (mean 85%). These values were 10-33% (mean 19%) higher than those obtained with CT (4). Fast dynamic contrast-enhanced MRI helps to differentiate bladder tumour from surrounding tissues because enhancement of the tumour occurs earlier than the normal bladder wall due to neovascularization (5, 6). Fast dynamic MRI with images acquired at one image per second helps to distinguish tumour from postbiopsy reaction (5). 4.2.1.2 CT for local staging of invasive bladder cancer The advantages of CT include shorter acquisition time, wider coverage in a single breath hold, and lower susceptibility to various patient factors. CT scan is unable to differentiate between stages Ta to T3a, but it is useful clinically for detecting invasion into the perivesical fat (T3b) and adjacent organs. The accuracy of CT in determining extravesical tumour extension varies from 55% to 92% (7) and increases with more advanced disease (8). A study by Kim et al. to determine the accuracy of MDCT for detection and staging of bladder cancer showed that CT had lower sensitivity (89%) and higher specificity (95%) compared to MRI for diagnosis of perivesical invasion, while the cancer detection rate and overall accuracy for perivesical invasion were similar (9). These findings are explained by better visualization of perivesical fat invasion on MRI, but because only mild inflammation around bladder cancers mimics perivesical invasion, this results in overstaging with MRI. 4.2.2 Imaging of nodal involvement The assessment of nodal status based simply on size is limited by the inability of both CT and MRI to identify metastases in normal sized or minimally enlarged nodes. Sensitivities for detection of lymph node metastases are low, ranging from 48% to 87%. Specificities are also lowas nodal enlargement may be due to benign pathology. Overall, the results of CT and MRI for detection of lymph node metastases in a variety of primary pelvic tumours are similar (10-14). Pelvic nodes greater than 8 mm and abdominal nodes greater than 10 mm in maximum short axis diameter (MSAD) should be regarded as enlarged on CT and MRI (15, 17). 4.2.3 Extravesical urothelial carcinoma MDCT urography is the technique of choice for diagnosing upper urinary tract urothelial cancer (18, 19). MDCT urography should be incorporated into the CT staging protocol to rule out extravesical carcinoma. 4.2.4 Distant metastases other than lymph nodes Prior to any treatment aimed at cure, it is essential to evaluate the presence of distant metastases. MDCT and MRI are the diagnostic tools of choice to detect metastases to lung and liver. Metastases to bones or brain at presentation of invasive bladder cancer are rare. Bone scan and additional brain imaging are therefore not routinely indicated unless the patient has specific symptoms or signs to suggest bone or brain metastases (20, 21). MRI is more sensitive and specific for diagnosing bone metastases than bone scintigraphy (22, 23) (Level of evidence: 2b). 4.2.5 Conclusions • Diagnosis of invasive bladder cancer is made by cystoscopy and biopsy. • Imaging is used for formal staging only if it will make a difference to the selection of treatment options. • In all T1 tumours considered for conservative treatment, a second TUR is recommended before deciding on definite treatment (Grade of recommendation: B). • MRI is still the preferred modality if the patient is considered for radical treatment. MDCT due to its higher specificity may be equivalvent to MRI regarding local staging.

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•

CT is recommended if there is suspicion of locally advanced or metastatic disease precluding radical treatment (Level of evidence: 2b-3).

4.2.6 Recommendations for staging • For optimal local staging, either MRI with fast dynamic contrast-enhancement or MDCT with contrast enhancement are recommended for patients considered suitable for radical treatment (Grade of Recommendation: B). • For patients with confirmed muscle-invasive bladder cancer, MDCT of the chest, abdomen and pelvis is the optimal form of staging, including MDCT urography for complete examination of the upper urinary tracts. If MDCT is not available, lesser alternatives are excretory urography and a chest X-ray (Grade of Recommendation: B).

4.3

References

1.

Jewett HJ. Proceedings: Cancer of the bladder. Cancer 1973;32(5):1072-4. http://www.ncbi.nlm.nih.gov/pubmed/4757902 Husband JE, Olliff JF, Williams MP, Heron CW, Cherryman GR. Bladder cancer: staging with CT and MR imaging. Radiology 1989;173(2):435-40. http://www.ncbi.nlm.nih.gov/pubmed/2798874 Paik ML, Scolieri MJ, Brown Sl, Spirnak JP, Resnick MI. Limitations of computerized tomography in staging invasive bladder cancer before radical cystectomy. J Urol 2000;163(6):1693-6. http://www.ncbi.nlm.nih.gov/pubmed/10799162 Barentsz JO, Jager GJ, Witjes JA, Ruijs JH. Primary staging of urinary bladder carcinoma: the role of MR imaging and a comparison with CT. Eur Radiol 1996;6(2):129-33. http://www.ncbi.nlm.nih.gov/pubmed/8797968 Barentsz JO, Jager GJ, van Vierzen PB, Witjes JA, Strijk SP, Peters H, Karssemeijer N, Ruijs SH. Staging urinary bladder cancer after transurethral biopsy: value of fast dynamic contrast-enhanced MR imaging. Radiology 1996;201(1):185-93. http://www.ncbi.nlm.nih.gov/pubmed/8816542 Mallampati GK, Siegelman ES. MR imaging of the bladder. Magn Reson Imaging Clin N Am 2004;12(3):545-55. http://www.ncbi.nlm.nih.gov/pubmed/15271370 Kundra V, Silverman PM. Imaging in oncology from the University of Texas M. D. Anderson Cancer Center. Imaging in the diagnosis, staging, and follow-up of cancer of the urinary bladder. AJR Am J Roentgenol 2003 180(4):1045-54. http://www.ncbi.nlm.nih.gov/pubmed/12646453 Kim B, Semelka RC, Ascher SM, Chalpin DB, Carroll PR, Hricak H. Bladder tumor staging: comparison of contrast-enhanced CT, T1- and T2-weighted MR imaging, dynamic gadoliniumenhanced imaging, and late gadolinium-enhanced imaging. Radiology 1994;193(1):239-45. http://www.ncbi.nlm.nih.gov/pubmed/8090898 Kim JK, Park S-Y, Ahn HJ, Kim CS, Cho KS. Bladder cancer: analysis of multidetector row helical CT enhancement pattern and accuracy in tumor detection and perivesical staging. Radiology 2004;231(3):725-31. http://www.ncbi.nlm.nih.gov/pubmed/15118111 Jager GJ, Barentsz JO, Oosterhof GO, Witjes JA, Ruijs SJ. Pelvic adenopathy in prostatic and urinary bladder carcinoma: MR imaging with a three-dimensional TI-weighted magnetization-prepared- rapid gradient-echo sequence. AJR Am J Roentgenol 1996;167(6):1503-7. http://www.ncbi.nlm.nih.gov/pubmed/8956585 Yang WT, Lam WW, Yu MY, Cheung TH, Metreweli C. Comparison of dynamic helical CT and dynamic MR imaging in the evaluation of pelvic lymph nodes in cervical carcinoma. AJR Am J Roentgenol 2000;175(3):759-66. http://www.ncbi.nlm.nih.gov/pubmed/10954463 Kim SH, Kim SC, Choi BI, Han MC. Uterine cervical carcinoma: evaluation of pelvic lymph node metastasis with MR imaging. Radiology 1994;190(3):807-11. http://www.ncbi.nlm.nih.gov/pubmed/8115631 Kim SH, Choi BI, Lee HP, Kang SB, Choi YM, Han MC, Kim CW. Uterine cervical carcinoma: comparison of CT and MR findings. Radiology 1990;175(1):45-51. http://www.ncbi.nlm.nih.gov/pubmed/2315503

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22.

23.

Oyen RH, Van Poppel HP, Ameye FE, Van de Voorde WA, Baert AL, Baert LV. Lymph node staging of localized prostatic carcinoma with CT and CT-guided fine-needle aspiration biopsy: prospective study of 285 patients. Radiology 1994;190(2):315-22. http://www.ncbi.nlm.nih.gov/pubmed/8284375 Barentsz JO, Engelbrecht MR, Witjes JA, de la Rosette JJ, van der Graaf M. MR imaging of the male pelvis. Eur Radiol 1999;9(9):1722-36. http://www.ncbi.nlm.nih.gov/pubmed/10602944 Vinnicombe SJ, Norman AR, Nicolson V, Husband JE. Normal pelvic lymph nodes: evaluation with CT after bipedal lymphangiography [published erratum appears in Radiology 1995 Sep;196(3):800]. Radiology 1995;194(2):349-55. http://www.ncbi.nlm.nih.gov/pubmed/7824709 Dorfman RE, Alpern MB, Gross BH, Sandler MA. Upper abdominal lymph nodes: criteria for normal size determined with CT. Radiology 1991;180(2):319-22. http://www.ncbi.nlm.nih.gov/pubmed/2068292 Cowan NC, Turney BW, Taylor NJ, McCarthy CL, Crew JP. Multidetector computed tomography urography (MDCTU) for diagnosing upper urinary tract tumour. BJU Int 2007;99(6):1363-70. http://www.ncbi.nlm.nih.gov/pubmed/17428251 Van Der Molen AJ, Cowan NC, Mueller-Lisse UG, Nolte-Ernsting CC, Takahashi S, Cohan RH; CT Urography Working Group of the European Society of Urogenital Radiology (ESUR). CT urography: definition, indications and techniques. A guideline for clinical practice. Eur Radiol 2008;18(1):4-17. http://www.ncbi.nlm.nih.gov/pubmed/17973110 Braendengen M, Winderen M, Fosså SD. Clinical significance of routine pre-cytectomy bone scans in patients with muscle-invasive bladder cancer. Br J Urol 1996;77(1):36-40. http://www.ncbi.nlm.nih.gov/pubmed/8653315 Brismar J, Gustafson T. Bone scintigraphy in staging bladder carcinoma. Acta Radiol 1988;29(2):2512. http://www.ncbi.nlm.nih.gov/pubmed/2965914 Lauenstein TC, Goehde SC, Herborn CU, Goyen M, Oberhoff C, Debatin JF, Ruehm SG, Barkhausen J. Whole-body MR imaging: evaluation of patients for metastases. Radiology 2004;233(1):139-48. http://www.ncbi.nlm.nih.gov/pubmed/15317952 Schmidt GP, Schoenberg SO, Reiser MF, Baur-Melnyk A. Whole-body MR imaging of bone marrow. Eur J Radiol 2005;55(1):33-40. http://www.ncbi.nlm.nih.gov/pubmed/15950099

5. TREATMENT FAILURE OF NON-MUSCLE INVASIVE BLADDER TUMOURS 5.1

High-risk non-muscle-invasive urothelial carcinoma

The recurrence and progression rate of non-muscle-invasive bladder cancer is strongly associated with tumour grade and invasion into the lamina propria. The progression to T2 tumours varies from 6% to 25% in Ta and from 27% to 48% in T1 tumours of all grades. Inter- and intra-observer varying abilities in grading as well as staging and completeness of TUR are key variables confounding the results of present long-term studies of TUR, with or without intravesical therapy. The understaging error in TaT1 tumours of 35% to 62% presented in large cystectomy series is due to the presence of recurrent tumours of largely unknown pre-cystectomy therapy and the lack of a second TUR (1-3) (Level of evidence: 3). The latter identifies 24% to 49% T2 tumours diagnosed initially as non-muscleinvasive tumours (4, 5) (Level of evidence: 3). However, in spite of these disadvantages, recent meta-analyses have shown that intravesical therapy with Bacillus Calmette-Guerin (BCG) maintenance therapy prevents recurrence (6) and progression (7) - but not significantly overall- or disease specific survival - compared to no therapy, intravesical chemotherapy or a BCG induction course only (7, 8) (Level of evidence: 1). Especially in patients with small tumours (< 3 cm) and without associated CIS, the progression rate is low (20% within 5 years), with approximately 90% of patients keeping their intact bladder during follow-up of up to 10 years (9) (Level of evidence: 2). The EAU guidelines therefore recommend a complete TUR and intravesical therapy in patients with high-grade TaT1-tumours (10) (Grade of recommendation: C). Initial cystectomy can be considered based on tumour multiplicity, size, concomitant in situ cancer and

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urothelial tumour of the prostatic urethra (10) (Grade of recommendation: C). Although the percentage of patients with primary TaT1 tumours and the indication for cystectomy in TaT1 tumours is not specified in large cystectomy series, the 10-year recurrence-free survival is approximately 80% and similar to TUR and BCG maintenance therapy (1, 3, 11, 12) (Level of evidence: 3). In case of recurrent Ta/T1, mostly associated with carcinoma in situ, the understaging at time of cystectomy is 34%, but the 10-year survival is not significantly different for patients with pT1 and pT2 tumours (13) (Level of evidence: 3). This is in contrast to an earlier report indicating a significant worse outcome for patients with previous TUR(s) (14) (Level of evidence: 3). Undoubtedly, patients with muscle-invasive recurrence are best treated with radical cystectomy. However, the outcome in terms of presence of lymph node metastases and cancer-free survival may be inferior to patients with the same tumour stage, but who receive radical cystectomy at first presentation (15) (Level of evidence: 3). There is uncertainty about the treatment of patients who develop tumour recurrence in spite of BCG therapy because of different BCG therapy schedules and the absence of a uniform definition of BCG failure. It has been indicated that the recurrence (persistence) of tumour at 9 months in spite of BCG therapy is associated with a 30% chance of invasive tumours and death due to metastatic disease (16) (Level of evidence: 3). Solsona et al. demonstrated that 80% of patients who had persistent disease at 3 months progressed to muscle invasive disease (17) (Level of evidence: 3). In addition, adequate tissue sampling from the prostatic urethra is an essential factor in considering the outcome of conservative treatment, since urethral tumours are associated with a significant decrease in tumour-free survival (18) (Level of evidence: 3). However, with careful selection and surveillance a durable complete response can be achieved also in patients diagnosed with superficial bladder transitional cell carcinoma involving the prostatic urethra (19). Based on these findings, cystectomy should be performed in appropriate patients at least at 9 months, because additional BCG therapy yields a response rate of only 27% to 51% and of unknown duration (20, 21) (Grade of recommendation: C). Salvage chemotherapy is associated with minor responses and should not be offered (22, 23) (Level of evidence: 3). Patients with superficial disease recurring within 2 years of initial TUR plus BCG therapy have a better outcome than patients who already have muscle-invasive disease indicating that cystectomy should be performed at first recurrence, even in case of superficial disease (Level of evidence: 3; Grade of recommendation: C) (15).

5.2

Carcinoma in situ

Primary CIS confined to the bladder is treated with intravesical BCG, yielding a complete response rate of 83-93% (24, 25) (Level of evidence: 2). CIS associated with Ta/T1 is treated according to the overt tumour. Approximately 50% of patients develop recurrent disease with muscle invasion or extravesical tumour (24, 26) (Level of evidence: 2). Between 11% and 21% die of the disease within 5-7 years after an initial complete response (24, 27) (Level of evidence: 2). Non-responders or incomplete responders have a significant risk of tumour progression of 33% to 67% (17, 28) (Level of evidence: 2). Cystectomy should be performed in patients with an incomplete response at 9 months, tumour recurrence within the bladder, or extravesical recurrence (Grade of recommendation: B).

5.3

Recommendations

•

In all T1 tumours at high risk of progression (such as high grade, multifocality, CIS present, and tumour size, as outlined in the non-muscle-invasive bladder cancer EAU guideline), immediate radical cystectomy is an option (Grade of recommendation: B). In all T1 patients failing intravesical therapy, cystectomy is an option. A delay in cystectomy increases the risk of progression and cancer-specific death (Grade of recommendation: B).

•

5.4

References

1.

Hautmann RE, Gschwend JE, de Petriconi RC, Kron M, Volkmer BG. Cystectomy for transitional cell carcinoma of the bladder: results of a surgery only series in the neobladder era. J Urol 2006;176(2):486-92. http://www.ncbi.nlm.nih.gov/pubmed/16813874 Madersbacher S, Hochreiter W, Burkhard F, Thalmann GN, Danuser H, Markwalder R, Studer UE. Radical cystectomy for bladder cancer today–a homogeneous series without neoadjuvant therapy. J Clin Oncol 2003;21(4):690-6. http://www.ncbi.nlm.nih.gov/pubmed/12586807 Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S, Skinner E, Bochner B, Thangathurai D, Mikhail M, Raghavan D, Skinner DG. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 2001;19(3):666-75. http://www.ncbi.nlm.nih.gov/pubmed/11157016

2.

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10.

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14.

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16.

17.

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19.

Brauers A, Buettner R, Jakse G. Second resection and prognosis of primary high risk superficial bladder cancer: is cystectomy often too early? J Urol 2001;165(3):808-10. http://www.ncbi.nlm.nih.gov/pubmed/11176474 Herr WH. The value of second transurethral resection in evaluating patients with bladder tumors. J Urol 1999;162(1):74-6. http://www.ncbi.nlm.nih.gov/pubmed/10379743 Shelley MD, Court JB, Kynaston H, Wilt TJ, Coles B, Mason M. Intravesical bacillus Calmette-Guerin versus mitomycin C for Ta and T1 bladder cancer. Cochrane Database Syst Rev. 2003;(3):CD003231. http://www.ncbi.nlm.nih.gov/pubmed/12917955 Sylvester RJ, van der Meijden AP, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol 2002;168(5):1964-70. http://www.ncbi.nlm.nih.gov/pubmed/12394686 Böhle A, Bock PR. Intravesical BCG versus mitomycin C in superficial bladder cancer: formal metaanalysis of comparative studies on tumour progression. Urology 2004;63(4):682-6. http://www.ncbi.nlm.nih.gov/pubmed/15072879 Serretta V, Pavone C, Ingargiola GB, Daricello G, Allegro R, Pavone-Macaluso M. TUR and adjuvant intravesical chemotherapy in T1G3 bladder tumors: recurrence, progression and survival in 137 selected patients followed up to 20 years. Eur Urol 2004;45(6):730-5. http://www.ncbi.nlm.nih.gov/pubmed/15149744 Oosterlinck W, Lobel B, Jakse G, Malmström PU, Stöckle M, Sternberg C; European Association of Urology (EAU) Working Group on Oncological Urology. Guidelines on bladder cancer. Eur Urol 2002;41(2):105-12. http://www.ncbi.nlm.nih.gov/pubmed/12074395 Pansadoro V, Emiliozzi P, de Paula F, Scarpone P, Pansadoro A, Sternberg CN. Long-term follow-up of G3T1 transitional cell carcinoma of the bladder treated with intravesical bacille Calmette-Guérin: 18-year experience. Urology 2002;59(2):227-31. http://www.ncbi.nlm.nih.gov/pubmed/11834391 Margel D, Tal R, Golan S, Kedar D, Engelstein D, Baniel J. Long-term follow-up of patients with Stage T1 high-grade transitional cell carcinoma managed by Bacille Calmette-Guérin immunotherapy. Urology 2007;69(1):78-82. http://www.ncbi.nlm.nih.gov/pubmed/17270621 Freeman JA, Esrig D, Stein JP, Simoneau AR, Skinner EC, Chen SC, Groshen S, Lieskovsky G, Boyd SD, Skinner DG. Radical cystectomy for high risk patients with superficial bladder cancer in the era of orthotopic urinary reconstruction. Cancer 1995;76(5):833-9. http://www.ncbi.nlm.nih.gov/pubmed/8625187 Stöckle M, Alken P, Engelmann U, Jacobi GH, Riedmiller H, Hohenfellner R. Radical cystectomy often too late?. Eur Urol 1987;13(6):361-7. http://www.ncbi.nlm.nih.gov/pubmed/3428318 Herr HW, Sogani PC. Does early cystectomy improve the survival of patients with high risk superficial bladder tumors?. J Urol 2001;166(4):1296-9. http://www.ncbi.nlm.nih.gov/pubmed/11547061 Merz VW, Marth D, Kraft R, Ackermann DK, Zingg EJ, Studer U.E. Analysis of early failures after intravesical instillation therapy with bacille Calmette-Guerin for carcinoma in situ of the bladder. Br J Urol 1995;75(2):180-4. http://www.ncbi.nlm.nih.gov/pubmed/7850322 Solsona E, Iborra I, Rubio J, Casanova J, Almenar S. The optimum timing of radical cystectomy for patients with recurrent high-risk superficial bladder tumour. BJU Int 2004;94(9):1258-62. http://www.ncbi.nlm.nih.gov/pubmed/15610101 Huguet J, Crego M, Sabaté S, Salvador J, Palou J, Villavicencio H. Cystectomy in patients with high risk superficial bladder tumors who fail intravesical BCG therapy: pre-cystectomy prostate involvement as a prognostic factor. Eur Urol 2005;48(1):53-9. http://www.ncbi.nlm.nih.gov/pubmed/15967252 Taylor JH, Davis J, Schellhammer P. Long-term follow-up of intravesical bacillus Calmette-Guérin treatment for superficial transitional-cell carcinoma of the bladder involving the prostatic urethra. Clin Genitourin Cancer 2007;5(6):386-9. http://www.ncbi.nlm.nih.gov/pubmed/17956711

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20.

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27.

28.

Brake M, Loertzer H, Horsch R, Keller H. Recurrence and progression of stage T1, grade 3 transitional cell carcinoma of the bladder following intravesical immunotherapy with bacillus Calmette-Guerin. J Urol 2000;163(6):1697-701. http://www.ncbi.nlm.nih.gov/pubmed/10799163 Pansadoro V, Emiliozzi P, Defidio L, Donadio D, Florio A, Maurelli S, Lauretti S, Sternberg CN. Bacillus Calmette-Guerin in the treatment of stage T1 grade 3 transitional cell carcinoma of the bladder: longterm results. J Urol 1995;154(6):2054-8. http://www.ncbi.nlm.nih.gov/pubmed/7500457 Malmström PU, Wijkström H, Lundholm C, Wester K, Busch C, Norlén BJ. 5-year followup of a randomized prospective study comparing mitomycin C and bacillus Calmette-Guerin in patients with superficial bladder carcinoma. Swedish-Norwegian Bladder Cancer Study Group. J Urol 1999;161(4):1124-7. http://www.ncbi.nlm.nih.gov/pubmed/10081852 Steinberg G, Bahnson R, Brosman S, Middleton R, Wajsman Z, Wehle M. Efficacy and safety of valrubicin for the treatment of Bacillus Calmette-Guerin refractory carcinoma in situ of the bladder. The Valrubicin Study Group. J Urol 2000;163(3):761-7. http://www.ncbi.nlm.nih.gov/pubmed/10687972 Jakse G, Hall R, Bono A, Höltl W, Carpentier P, Spaander JP, van der Meijden AP, Sylvester R. Intravesical BCG in patients with carcinoma in situ of the urinary bladder: long-term results of EORTC GU Group phase II protocol 30861. Eur Urol 2001;40(2):144-50 http://www.ncbi.nlm.nih.gov/pubmed/11528191 Losa A, Hurle R, Lembo A. Low dose bacillus Calmette-Guerin for carcinoma in situ of the bladder: long-term results. J Urol 2000;163(1):68-71. http://www.ncbi.nlm.nih.gov/pubmed/10604316 Lamm DL, Blumenstein BA, Crissman JD, Montie JE, Gottesman JE, Lowe BA, Sarosdy MF, Bohl RD, Grossman HB, Beck TM, Leimert JT, Crawford ED. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol 2000;163(4):1124-9. http://www.ncbi.nlm.nih.gov/pubmed/10737480 de Reijke TM, Kurth KH, Sylvester RJ, Hall RR, Brausi M, van de Beek K, Landsoght KE, Carpentier P; European Organization for the Research and Treatment of Cancer-Genito-Urinary Group. Bacillus Calmette-Guerin versus epirubicin for primary, secondary or concurrent carcinoma in situ of the bladder: results of a European Organization for the Research and Treatment of Cancer--GenitoUrinary Group Phase III Trial (30906). J Urol 2005;173(2):405-9. http://www.ncbi.nlm.nih.gov/pubmed/15643181 Hudson MA, Herr WH. Carcinoma in situ of the bladder. J Urol 1995;53(3 Pt 1):564-72. http://www.ncbi.nlm.nih.gov/pubmed/7861485

6. NEOADJUVANT CHEMOTHERAPY The standard treatment for patients with muscle-invasive bladder cancer is radical cystectomy. However, this ‘gold standard’ only provides 5-year survival in about 50% of patients (1-5). In order to improve these unsatisfactory results, the use of peri-operative chemotherapy has been explored since the 1980s. There are many advantages of neoadjuvant chemotherapy, i.e. administering chemotherapy to patients with operable urothelial carcinoma of the urinary bladder before the planned definitive surgery (or radiation). These advantages include: • Chemotherapy is delivered at the earliest time point, when the burden of micrometastatic disease is expected to be low • In vivo chemosensitivity is tested • The tolerability of chemotherapy is expected to be better before than after cystectomy. The disadvantages of neoadjuvant chemotherapy include: • For clinical staging with CT or MRI, over- and under-staging is likely to happen with a staging accuracy of only 70% (6, 7). Overtreatment is the possible negative consequence • Delayed cystectomy might compromise the outcome in patients not sensitive to chemotherapy (8, 9) • Side effects of chemotherapy might affect outcome of surgery and type of urinary diversion.

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Several randomized phase III trials investigated the question of whether or not neoadjuvant chemotherapy improved survival, with conflicting results (10-27). Most patients were < 70 years old, had a performance status (PS) of 0-1 and a creatinine clearance of > 50-60 mL/minute, due to the kind of chemotherapy (single-agent cisplatin or cisplatin combination chemotherapy) scheduled. Differences in trial design were mainly the type of chemotherapy (i.e. single-agent cisplatin or combination chemotherapy) and the number of cycles planned. From the statistical point of view, the studies differed in size, patient characteristics (e.g. clinical T-stages included), and the kind of definitive treatment allowed (cystectomy or radiotherapy or both). Because of the lack of clarity, even though a considerable number of randomized trials had been performed, three meta-analyses were undertaken to answer the very important question of whether or not neoadjuvant chemotherapy prolongs survival (28-30). The first meta-analysis, published in 2003 (28), included 10 randomized trials (except for results of the INT 0080-study [20]) and showed a 13% reduction in the risk of death, equivalent to 5% absolute benefit at 5 years (increased overall survival from 45% to 50%). The second meta-analysis, published in 2004 (29), included 11 of 16 randomized trials with overall survival data of 2605 patients. A statistically significant decrease in the risk of death (10%) was seen, corresponding to an absolute improvement in overall survival of 5% (from 50% to 55%). In the most recent meta-analysis, published in 2005 (30), with updated independent patient data (IPD) of 11 randomized trials (3,005 patients), a statistically significant survival benefit in favour of neoadjuvant chemotherapy was also seen. The results of this analysis confirmed the previously published data and showed 5% absolute improvement in survival at 5 years. The Nordic combined trial showed an absolute benefit of 8% in survival at 5 years and in the subgroup clinical T3, 11%, translating into 9 patients needed to treat (26). Of note, only cisplatin combination chemotherapy with at least one additional chemotherapeutic agent resulted in a meaningful benefit (28, 30); the regimens tested were MVA(E)C, CMV, CM, cisplatin/adriamycin, cisplatin/5fluorouracil (5-FU), and CarboMV. To date, it is unknown if more modern chemotherapy regimen are as effective. The presence of micrometastases is postulated to be lower in smaller tumours (T2) compared to more extensive tumours (T3b-T4b). T4 stage tumours are prone to a higher degree of clinical understaging because macrometastic nodal deposits are detected more often in post-cystectomy specimens of these extensive tumours (31). Further data is in support of neoadjuvant chemotherapy in the subgroup of T2b-T3b tumours (former classification T3), which has been shown to provide a modest but substantial improvement in long-term survival and significant downstaging.

6.1

Conclusions

•

Neoadjuvant cisplatin-containing combination chemotherapy improves overall survival by 5-7% at 5 years (Level of evidence: 1a), irrespective of the type of definitive treatment used. Neoadjuvant chemotherapy has its limitations regarding patient selection, current development of surgical technique, and current chemotherapy combinations.

•

6.2

Recommendations

•

Neoadjuvant cisplatin-containing combination chemotherapy should be considered in muscleinvasive bladder cancer, irrespective of definitive treatment (Grade of recommendation: A). Neoadjuvant chemotherapy is not recommended in patients with PS > 2 and impaired renal function (Grade of recommendation: B).

•

6.3

References

1.

Stein JP, Skinner DG. Radical cystectomy for invasive bladder cancer: long-term results of a standard procedure. World J Urol 2006;24(3):296-304. http://www.ncbi.nlm.nih.gov/pubmed/16518661 Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S, Skinner E, Bochner B, Thangathurai D, Mikhail M, Raghavan D, Skinner DG. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 2001;19(3):666-75. http://www.ncbi.nlm.nih.gov/pubmed/11157016 Dalbagni G, Genega E, Hashibe M, Zhang ZF, Russo P, Herr H, Reuter V. Cystectomy for bladder cancer: a contemporary series. J Urol 2001;165(4):1111-6. http://www.ncbi.nlm.nih.gov/pubmed/11257649 Bassi P, Ferrante GD, Piazza N, Spinadin R, Carando R, Pappagallo G, Pagano F. Prognostic factors of outcome after radical cystectomy for bladder cancer: a retrospective study of a homogeneous patient cohort. J Urol 1999;161(5):1494-7. http://www.ncbi.nlm.nih.gov/pubmed/10210380

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Ghoneim MA, el-Mekresh MM, el-Baz MA, el-Attar IA, Ashamallah A. Radical cystectomy for carcinoma of the bladder: critical evaluation of the results in 1,026 cases. J Urol 1997;158(2):393-9. http://www.ncbi.nlm.nih.gov/pubmed/9224310 Sternberg CN, Pansadoro V, Calabro F, Schnetzer S, Giannarelli D, Emiliozzi P, De Paula F, Scarpone P, De Carli P, Pizzo M, Platania A, Amini M. Can patient selection for bladder preservation be based on response to chemotherapy? Cancer 2003;97(7):1644-52. http://www.ncbi.nlm.nih.gov/pubmed/12655521 Herr HW, Scher HI. Surgery of invasive bladder cancer: is pathologic staging necessary? Semin Oncol 1990;17(5):590-7. http://www.ncbi.nlm.nih.gov/pubmed/2218571 Sanchez-Ortiz RF, Huang WC, Mick R, Van Arsdalen KN, Wein AJ, Malkowicz SB. An interval longer than 12 weeks between the diagnosis of muscle invasion and cystectomy is associated with worse outcome in bladder carcinoma. J Urol 2003;169(1):110-5; discussion 115. http://www.ncbi.nlm.nih.gov/pubmed/12478115 Stein JP. Contemporary concepts of radical cystectomy and the treatment of bladder cancer. J Urol 2003;169(1):116-7. http://www.ncbi.nlm.nih.gov/pubmed/12478116 Wallace DM, Raghavan D, Kelly KA, Sandeman TF, Conn IG, Teriana N, Dunn J, Boulas J, Latief T. Neo-adjuvant (pre-emptive) cisplatin therapy in invasive transitional cell carcinoma of the bladder. Br J Urol 1991;67(6):608-15. http://www.ncbi.nlm.nih.gov/pubmed/2070206 Font A, Saladie JM, Carles J, Pinsach L, Barnardas A, et al. Improved survival with induction chemotherapy in bladder cancer: preliminary results of a randomized trial. Ann Oncol 1994;5:71, abstr 355. Martinez-Pineiro JA, Gonzalez Martin M, Arocena F, Flores N, Roncero CR, Portillo JA, Escudero A, Jimenez Cruz F, Isorna S. Neoadjuvant cisplatin chemotherapy before radical cystectomy in invasive transitional cell carcinoma of the bladder: a prospective randomized phase III study. J Urol 1995;153(3 Pt 2):964-73. http://www.ncbi.nlm.nih.gov/pubmed/7853584 Rintala E, Hannisdahl E, Fossa SD, Hellsten S, Sander S. Neoadjuvant chemotherapy in bladder cancer: a randomized study. Nordic Cystectomy Trial I. Scand J Urol Nephrol 1993;27(3):355-62. http://www.ncbi.nlm.nih.gov/pubmed/8290916 Malmstrom PU, Rintala E, Wahlqvist R, Hellstrom P, Hellsten S, Hannisdal E. Five-year followup of a prospective trial of radical cystectomy and neoadjuvant chemotherapy: Nordic Cystectomy Trial I. The Nordic Cooperative Bladder Cancer Study Group. J Urol 1996;155(6):1903-6. http://www.ncbi.nlm.nih.gov/pubmed/8618283 [No authors listed] Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscleinvasive bladder cancer: a randomised controlled trial. International collaboration of trialists. Lancet 1999;354(9178):533-40. http://www.ncbi.nlm.nih.gov/pubmed/10470696 Hall R. Updated results of a randomised controlled trial of neoadjuvant cisplatin (C), methotrexate (m) and vinblastin (V) chemotherapy for muscle-invasive bladder cancer. Proc Am Soc Clin Oncol 2002;21:178A, abstr 710. Bassi P PG, Cosciani S, Lembo A, Anselmo G, Sperandio P, et al . Neoadjuvant M-VAC chemotherapy of invasive bladder cancer: The G.U.O.N.E. multicenter phase III trial. Eur Urol 1998 (Suppl);33:142, abstr 567. Sherif A, Rintala E, Mestad O, Nilsson J, Holmberg L, Nilsson S, Malmström PU; Nordic Urothelial Cancer Group. Neoadjuvant cisplatin-methotrexate chemotherapy for invasive bladder cancer–Nordic cystectomy trial 2. Scand J Urol Nephrol 2002;36(6):419-25. http://www.ncbi.nlm.nih.gov/pubmed/12623505 Sengelov L, von der Maase H, Lundbeck F, Barlebo H, Colstrup H, Engelholm SA, Krarup T, Madsen EL, Meyhoff HH, Mommsen S, Nielsen OS, Pedersen D, Steven K, Sørensen B. Neoadjuvant chemotherapy with cisplatin and methotrexate in patients with muscle-invasive bladder tumours. Acta Oncol 2002;41(5):447-56. http://www.ncbi.nlm.nih.gov/pubmed/12442921 Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, deVere White RW, Sarosdy MF, Wood DP Jr, Raghavan D, Crawford ED. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349(9): 859-66. http://www.ncbi.nlm.nih.gov/pubmed/12944571

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30.

31.

Italian Bladder Cancer Study Group (GISTV). Neoadjuvant treatment for locally advanced bladder cancer: a randomized prospective clinical trial. J Chemother 1996;8(suppl 4):345-6. Orsatti M, Curotto A, Canobbio L, Guarneri D, Scarpati D, Venturini M, Franzone P, Giudici S, Martorana G, Boccardo F, et al. Alternating chemo-radiotherapy in bladder cancer: a conservative approach. Int J Radiat Oncol Biol Phys 1995;33(1):173-8. http://www.ncbi.nlm.nih.gov/pubmed/7642415 Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, Donnelly BJ, Venner PM, Perez CA, Murray KJ, Doggett RS, True LD. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol 1998;16(11):3576-83. http://www.ncbi.nlm.nih.gov/pubmed/9817278 Marcuello E TJ, Villavicencio H, Algaba F, Maroto P, Huidobro G, et al. A phase III trial of neoadjuvant chemotherapy (NCT) in patients (PTS) with invasive bladder cancer (IBC). Preliminary results: NCT improves pathological complete response rate. Eur J Cancer 1995;31A:S241, abstr 1155. Cannobio L CA, Boccardo F, Venturini M, Orsatti M, Vitale V, et al. A randomized study between neoadjuvant chemoradiotherapy (CT-RT) before radical cystectomy and cystectomy alone in bladder cancer. A 6 year follow-up. Proc Am Soc Clin Oncol 1995;14:245, abstr 654. Sherif A, Holmberg L, Rintala E, Mestad O, Nilsson J, Nilsson S, Malmström PU; Nordic Urothelial Cancer Group. Neoadjuvant cisplatinum based combination chemotherapy in patients with invasive bladder cancer: a combined analysis of two Nordic studies. Eur Urol 2004;45(3):297-303. http://www.ncbi.nlm.nih.gov/pubmed/15036674 Abol-Enein H E-MM, El Baz M, Ghoneim MA. Neo-adjuvant chemotherapy in the treatment of invasive transitional bladder cancer. A controlled prospective randomized study. Br J Urol 1997;79(Suppl 4):174. Advanced Bladder Cancer Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet 2003;361(9373):1927-34. http://www.ncbi.nlm.nih.gov/pubmed/12801735 Winquist E, Kirchner TS, Segal R, Chin J, Lukka H; Genitourinary Cancer Disease Site Group, Cancer Care Ontario Program in Evidence-based Care Practice Guidelines Initiative. Neoadjuvant chemotherapy for transitional cell carcinoma of the bladder: a systematic review and meta-analysis. J Urol 2004;171(2 Pt 1):561-9. http://www.ncbi.nlm.nih.gov/pubmed/14713760 Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol 2005;48(2):202-205; discussion 205-6. http://www.ncbi.nlm.nih.gov/pubmed/15939524 Sherif A HL, Rintala E, Mestad O, Nilsson J, Nilsson S, Malmstrom PU, Wijkström H; Nordic Urothelial Cancer Group. Downstaging and pathoanatomical outcome following neoadjuvant cisplatinum based combination chemotherapy for muscle invasive bladder carcinoma: An analysis of selected patients from two combined randomised prospective Nordic trials. Urology 2006;68(Suppl 1):137, MP-1307.

7. Radical surgery and urinary diversion 7.1

Removal of the tumour bearing bladder

7.1.1 Background Radical cystectomy is the standard treatment for localized muscle invasive bladder cancer in most countries of the Western Hemisphere (1, 2). New interest in quality-of-life issues has increased the trend toward bladder preservation treatment modalities, like radio- and/or chemotherapy (see Chapters 9 and 10). Performance status and age influence the choice of primary therapy, as well as type of urinary diversion with cystectomy being reserved for younger patients without concomitant disease and better performance status. The value of assessing overall health before recommending and proceeding with surgery was emphasized in a recent multivariate analysis, which demonstrated an association between co-morbid disease and adverse pathological and survival outcome following radical cystectomy (3). There is still controversy about age, radical cystectomy and the type of urinary diversion. Cystectomy is associated with the greatest risk reduction in disease-related and non-disease related death in patients older

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than 80 years (3). The largest retrospective single-institution study on cystectomy to date demonstrated that patients above 80 years did have an increased postoperative morbidity but not an increased mortality. Some patients even successfully underwent a neobladder procedure in this group, but the majority of patients were treated with an ileal conduit diversion (4). 7.1.2 Timing and delay of cystectomy In a retrospective series of 153 patients with a clear indication for radical surgery of locally advanced bladder cancer, a delay of treatment beyond 90 days of primary diagnosis caused a significant increase in extravesical disease (81 vs. 52%) (5). The delay of cystectomy not only affects the outcome but also the type of urinary diversion. In organconfined urothelial cancer of the bladder the average time from the primary diagnosis to cystectomy was 12.2 months in neobladder and 19.1 months in ileal conduit patients. It was even more striking for those patients who had an organ confined invasive cancer diagnosed; in neobladder patients the average time to surgery was 3.1 and in ileal conduit patients 15.1 months (6). Similar results have been observed in a series of 247 patients where superior recurrence-free survival and overall survival was significantly better in those treated within the 90 day period compared to others who were treated after a longer period (7). 7.1.3 Indications Traditionally radical cystectomy is recommended for patients with muscle-invasive bladder cancer T2-T4a, N0-Nx, M0 (1). Other indications include high-risk and recurrent superficial tumours, BCG-resistant Tis, T1G3 (see chapter 5), as well as extensive papillary disease that cannot be controlled with TUR and intravesical therapy alone. Salvage cystectomy is indicated for non-responders to conservative therapy, recurrences after bladder sparing treatments, non-urothelial carcinomas (these tumours respond poorly to chemo- and radiotherapy) and as a purely palliative intervention for e.g. fistula formation, pain or recurrent macrohematuria (see section 8.1: palliative cystectomy). 7.1.4 Technique and extent Radical cystectomy includes the removal of the bladder and adjacent organs, that is prostate and seminal vesicles in men, and uterus and adnexa in women (8). The inclusion of the entire prostate in male patients, and the extent of urethrectomy and vaginal resection in female patients, however, has recently been questioned (9, 10). Various techniques of partial prostate- sparing cystoprostatectomy in male patients with localized tumours have been proposed and results of series with a longer follow-up have been published (11, 12). A randomized study comparing patients with and without remnant portions of the prostate is lacking and will be difficult to perform. Autopsy studies as well as studies looking at the unsuspected incidence of prostate cancer in cystoprostatectomy specimens suggest that in approximately 23-54% of patients a prostate cancer is found in the cystoprostatectomy specimen. Up to twenty-nine percent of these cancers may be clinically significant, locally recurrent or even metastatic in patients with prostatic tissue preserving radical cystectomy (13-15). Furthermore urothelial cancer in the prostate was detected in 32 and 33% (69/240 cases and 77/235 cases, resp.) of patients undergoing radical cystoprostatectomy (14, 16). In another study 50/121 of the cystoprostatectomy specimens (41%) removed for urothelial cancer had unsuspected prostate cancer. Twenty-four of these 50 tumours (48%) were clinically significant. In the same study 58/121 patients (48%) had urothelial carcinoma in the prostate of which 19 (33%) had apical involvement (17). Overall in the above mentioned series only 26 to 33% of the patients undergoing cystoprostatectomy for bladder cancer had neither prostate cancer nor prostatic urothelial cancer in the specimen. Radical cystectomy also includes the dissection of regional lymph nodes. There is a substantial amount of literature about the extent of lymphadenectomy. Yet, data regarding its clinical significance are controversial. In retrospective studies extended lymphadenectomy (removal of the obturator, internal, external, common iliac and presacral nodes as well as nodes at the aortic bifurcation) has been reported to improve survival in patients with muscle invasive bladder cancer. The curative value of lymph node dissection, however, is still unknown and a standardized lymph node dissection has yet to be defined (18-20). There are several localization studies with regards to lymphadenectomy (21, 22) which demonstrated both retrospectively and prospectively that lymph nodes in bladder cancer patients are not found outside the pelvis if the pelvic lymph nodes are free of tumour. Furthermore progression free survival as well as overall survival might be correlated with the amount of lymph nodes removed during surgery. Removal of more than 15 lymph nodes has been postulated to be both sufficient for the evaluation of the lymph node status as well as beneficial for overall survival in retrospective studies (19, 22, 23). Interindividual differences in the number of pelvic and retroperitoneal lymph nodes and difficulties in processing of the removed tissue by pathologists

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were not taken into account in these studies (18). A distal ureteral segment (length not specified) should be resected and in case of CIS a frozen section for evaluation of the surgical margins should be performed (8, 24). Urethrectomy is recommended if there are positive margins at the level of urethral dissection, positive margins anywhere on the bladder specimen (in both sexes), if the primary tumour is located at the bladder neck or in the urethra (in women), or if tumour extensively infiltrates the prostate (1, 25, 26). 7.1.5 Laparoscopic cystectomy Laparoscopic cystectomy has been shown to be feasible both in male and female patients (27, 28). The cystectomy itself and the subsequent urinary diversion can be done hand-assisted, robot-assisted or unaided (29). With the currently available technology and when using intestinal segments for the urinary diversion, to date a majority of authors favour an extracorporeal approach (28). There are no data confirming or declining benefits of laparoscopic cystectomy for the patients’ quality of life, tumour specific and overall survival.

7.2

Urinary Diversion after radical cystectomy

From an anatomical standpoint three alternatives are presently used after cystectomy: • abdominal diversion such as ureterocutaneostomy, ileal or colonic conduit, and various forms of a cutaneous continent pouch • urethral diversion which includes various forms of gastrointestinal pouches attached to the urethra as a continent, orthotopic urinary diversion (neobladder, orthotopic bladder substitution • rectosigmoid diversions, such as uretero(ileo-)rectostomy. Different types of segments of the intestinal tract have been used for reconstruction of the urinary tract, including stomach, ileum, colon, and the appendix (30). Although several studies have compared certain aspects of health-related quality of life, like sexual function, urinary continence and body image in patient cohorts with different types of urinary diversion, more work is necessary in this field with regards to preoperative tumour stage and functional situation, socioeconomic status, time interval to primary surgery etc. Patients undergoing continent urinary diversion have to be both motivated to learn and manually skilful to deal with their diversion. Debilitating neurological and psychiatric illnesses, limited life expectancy, and impaired liver or renal function as well as TCC of the urethral margin or other surgical margins are contraindications to more complex forms of urinary diversion. Relative contraindications specific for an orthotopic neobladder are high-dose preoperative radiation therapy, complex urethral stricture disease and severe urethral sphincter related incontinence (31-33). 7.2.1 Ureterocutaneostomy Ureteral diversion to the abdominal wall is the simplest form of cutaneous diversion. It is considered as a safe procedure and therefore preferred in older or otherwise compromised patients in need of a supravesical diversion (34, 35). Others have demonstrated, however, that in carefully selected elderly patients all other forms of wet and dry urinary diversions including orthotopic bladder substitutions are possible (4). Technically either one ureter to which the other shorter one is attached end-to-side is connected to the skin (transuretero-ureterocutaneostomy) or both ureters are directly anastomosed to the skin. Due to the smaller diameter of the ureters stoma stenosis seems to be more frequent than with intestinal stomas (34). 7.2.2 Ileal conduit The ileal conduit is still an established option with well-known/predictable results. However, up to 48% of the patients develop early complications including urinary tract infections, pyelonephritis, uretero-ileal leakage and stenosis (36). Stomal complications in up to 24% and functional and/or morphological changes of the upper urinary tract in up to 30% are the main complications in long-term follow-up studies (37-39). An increase in complications was seen with increasing follow-up in the Berne series of 131 patients followed for a minimum of 5 years (median follow-up 98 months) (37): the rate of complications increased from 45% at 5 years to 94% in those surviving longer than 15 years. In the latter group 50% and 38% of the patients had upper urinary tract changes and urolithiasis, respectively. 7.2.3 Continent cutaneous urinary diversion A low-pressure detubularized ileal reservoir can be used as a continent cutaneous urinary diversion for selfcatheterization; gastric, ileocecal and sigma pouches have also been described (40-42). Different anti-reflux techniques can be used [8e]. Most patients have a well functioning reservoir with daytime and night time continence approaching 93% (43). A stomal stenosis in 23.5% of patients with appendix stoma and 15% with an efferent intussuscepted ileal nipple was observed in a study reviewing retrospectively the results of

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more than 800 patients. Stone formation in the pouch occurred in 10% of patients (43-45). In a small series of previously irradiated female patients incontinence and stomal stenosis was 18% (8/44 patients) (46). 7.2.4 Ureterocolonic diversion The oldest and most common form was primarily a refluxive and later an antirefluxive connection of ureters into the intact rectosigmoideum (uretero[recto]sigmoidostomy) (47, 48). Most of the indications for this procedure have become obsolete due to a high incidence of upper urinary tract infections and a long term risk of developing colon cancer (49, 50). Bowel frequency and urge incontinence were additional side effects of this type of urinary diversion. A possibility to circumvent the above mentioned problems is to interpose a segment of ileum between ureters and rectum or sigmoid in order to augment capacity and to avoid a direct interaction between urothelium, colonic mucosa, together with faeces and urine (51). 7.2.5 Orthotopic neobladder An orthotopic bladder substitution to the urethra is now commonly used both in men and women. Contemporary reports document the safety and long-term reliability of this procedure. In several large centres this has become the diversion of choice for a majority of patients undergoing cystectomy (33, 52). The gastrointestinal segment most frequently used for bladder substitution is the terminal ileum whereas there is less experience with ascending colon, including coecum, and the sigmoid (1). The emptying of the reservoir anastomosed to the urethra requires abdominal straining, intestinal peristalsis and sphincter relaxation. Early and late morbidity in up to 22 % of the patients is reported (53, 54). Long-term complications include diurnal and nocturnal incontinence (8-10 and 20 to 30%, resp.), ureterointestinal stenosis (3-18%), urinary retention (4-12%) both in males and female patients, metabolic disorders and vitamin B12 deficiency in series with 1,054 and more than 1,300 patients (33, 55). In a recent study, which compared cancer control and patterns of disease recurrence in neobladder and conduit patients, no cancer specific survival difference could be identified between the two groups when adjusting for pathological stage (56). Urethral recurrence in neobladder patients seems rare (1.5-7% both for male and female patients) (33, 57). These results indicate that the choice of a neobladder both in male and female patients does not compromise the oncological outcome of cystectomy. The advantage in the quality of life compared to a non-continent diversion remains a matter of debate (58-60. Various forms of upper tract reflux protection including a simple isoperistaltic tunnel, an ileal intussusception, a tapered ileal prolongation implanted subserosally, and a direct (sub)mucosal or subserosal ureteral implantation, have been described (45, 53, 54). According to the reported long term results the upper urinary tract is protected sufficiently by either method.

7.3

Morbidity and mortality

In a recent comprehensive study regarding long-term results in 1,054 patients, perioperative mortality was 3%, and early complications, defined as any complication within 3 months of surgery, were reported in 28% (52, 55). Late morbidity is usually due to the type of urinary diversion (see above). Early morbidity associated with radical cystectomy for non-muscle invasive disease (at high risk for disease progression) is similar and not less than that associated with muscle invasive tumours (61).

7.4

Survival

The outcome according to a multiinstitutional database of 888 consecutive patients undergoing cystectomy and lymphadenectomy for bladder cancer revealed a mean recurrence-free and bladder cancer specific survival of 58% and 66%, resp. at 5 years (62). The recurrence-free and overall survival in a large single centre study of 1,054 male and female patients was 68% and 66% at 5 years and 60% and 43%, at 10 years, respectively (2). In node positive patients, 10-year disease-specific and overall survival rates in another study have been reported to be 27.7% and 20.9% respectively (63). In this cohort, 10-year disease-specific and overall survival rates were 72.9% vs. 49.1% for organ confined (defined as < pT3a), and 33.3% vs. 22.8% for non-organ confined disease (63). In another study, 5-year recurrence-free survival was 76% in patients with pT1 tumours, 74% for pT2, 52% in pT3, and 36% in pT4 tumours (64). Tumour stage and nodal involvement are the only independent predictors of survival (65).

7.5

Conclusions

• •

Cystectomy is the preferred curative treatment for localised bladder neoplasm (Level of evidence: 3) Radical cystectomy includes removal of regional lymph nodes, the extent of which has not been sufficiently defined (Level of evidence: 3) Radical cystectomy in both sexes must not include the removal of the entire urethra in all cases, which may then serve as outlet for an orthotopic bladder substitution (Level of evidence: 3)

•

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• •

Terminal ileum and colon are the intestinal segments of choice for urinary diversion (Level of evidence: 3) The type of urinary diversion does not affect oncological outcome (Level of evidence: 3)

7.6

Recommendations

7.6.1 Recommendations for radical cystectomy • Radical cystectomy in T2-T4a, N0-NX, M0, and high risk non-muscle invasive BC as outlined above (Grade of recommendation: B) • No preoperative radiotherapy (Grade of recommendation: A) • Lymph node dissection should be an integral part of cystectomy, extent not established (Grade of recommendation: B) • Preservation of the urethra is reasonable if margins are negative. If no bladder substitution is attached the urethra must be checked regularly (Grade of recommendation: B) • Laparoscopic and robot assisted laparoscopic cystectomy may be an option. Current data, however, have not sufficiently proven its advantages or disadvantages (Grade of recommendation: C). 7.6.2 Recommendations for urinary diversion • Treatment is recommended at centers experienced in major types of diversion techniques and postoperative care (Grade of recommendation: B) • Before cystectomy, the patient should be counselled adequately regarding all possible alternatives, and the final decision should be based on a consensus between patient and surgeon (Grade of recommendation: B). • An orthotopic bladder substitute should be offered to male and female patients lacking any contraindications and who have no tumour in the urethra and at the level of urethral dissection (Grade of recommendation: B)

7.7

References

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Haber GP, Campbell SC, Colombo JR, Jr, Fergany AF, Aron M, Kaouk J, Gill IS. Perioperative outcomes with laparoscopic radical cystectomy: “pure laparoscopic” and “open-assisted laparoscopic” approaches. Urology 2007;70(5):910-5. http://www.ncbi.nlm.nih.gov/pubmed/18068447 Cathelineau X, Jaffe J. Laparoscopic radical cystectomy with urinary diversion: what is the optimal technique? Curr Opin Urol 2007;17(2):93-7. http://www.ncbi.nlm.nih.gov/pubmed/17285017 Stenzl A. Bladder substitution. Curr Opin Urol 1999;9(3):241-5. http://www.ncbi.nlm.nih.gov/pubmed/10726098 Tanrikut C, McDougal WS. Acid-base and electrolyte disorders after urinary diversion. World J Urol 2004;22(3):168-71. http://www.ncbi.nlm.nih.gov/pubmed/15290206 Farnham SB, Cookson MS. Surgical complications of urinary diversion. World J Urol 2004;22(3): 157-67. http://www.ncbi.nlm.nih.gov/pubmed/15316737 Hautmann RE, Volkmer BG, Schumacher MC, Gschwend JE, Studer UE. Long-term results of standard procedures in urology: the ileal neobladder. World J Urol 2006;24(3):305-14. http://www.ncbi.nlm.nih.gov/pubmed/16830152 Deliveliotis C, Papatsoris A, Chrisofos M, Dellis A, Liakouras C, Skolarikos A. Urinary diversion in highrisk elderly patients: modified cutaneous ureterostomy or ileal conduit?. Urology 2005;66(2): 299-304. http://www.ncbi.nlm.nih.gov/pubmed/16040096 Kilciler M, Bedir S, Erdemir F, Zeybek N, Erten K, Ozgok Y. Comparison of ileal conduit and transureteroureterostomy with ureterocutaneostomy urinary diversion. Urol Int 2006;77(3):245-50. http://www.ncbi.nlm.nih.gov/pubmed/17033213 Nieuwenhuijzen JA, de Vries RR, Bex A, van der Poel HG, Meinhardt W, Antonini N, Horenblas S. Urinary diversions after cystectomy: the association of clinical factors, complications and functional results of four different diversions. Eur Urol, 2008;53(4):834-44. http://www.ncbi.nlm.nih.gov/pubmed/17904276 Madersbacher S, Schmidt J, Eberle JM, Thoeny HC, Burkhard F, Hochreiter W, Studer UE. Long-term outcome of ileal conduit diversion. J Urol 2003;169(3):985-90. http://www.ncbi.nlm.nih.gov/pubmed/12576827 Wood DN, Allen SE, Hussain M, Greenwell TJ, Shah P.J. Stomal complications of ileal conduits are significantly higher when formed in women with intractable urinary incontinence. J Urol 2004;172(6 Pt 1):2300-3. http://www.ncbi.nlm.nih.gov/pubmed/15538253 Neal DE. Complications of ileal conduit diversion in adults with cancer followed up for at least five years. Br Med J (Clin Res Ed) 1985;290(6483):1695-7. http://www.ncbi.nlm.nih.gov/pubmed/3924218 Benson MC, Olsson CA. Continent urinary diversion. Urol Clin North Am 1999;26(1):125-47, ix. http://www.ncbi.nlm.nih.gov/pubmed/10086055 Gerharz EW, Kohl UN, Melekos MD, Bonfig R, Weingartner K, Riedmiller H. Ten years’ experience with the submucosally embedded in situ appendix in continent cutaneous diversion. Eur Urol 2001;40(6):625-31. http://www.ncbi.nlm.nih.gov/pubmed/11805408 Jonsson O, Olofsson G, Lindholm E, Tornqvist H. Long-time experience with the Kock ileal reservoir for continent urinary diversion. Eur Urol 2001;40(6):632-40. http://www.ncbi.nlm.nih.gov/pubmed/11805409 Wiesner C, Bonfig R, Stein R, Gerharz EW, Pahernik S, Riedmiller H, Thuroff J.W. Continent cutaneous urinary diversion: long-term follow-up of more than 800 patients with ileocecal reservoirs. World J Urol 2006;24(3):315-8. http://www.ncbi.nlm.nih.gov/pubmed/16676186 Wiesner C, Stein R, Pahernik S, Hahn K, Melchior SW, Thuroff JW. Long-term followup of the intussuscepted ileal nipple and the in situ, submucosally embedded appendix as continence mechanisms of continent urinary diversion with the cutaneous ileocecal pouch (Mainz pouch I). J Urol 2006;176(1):155-9; discussion 159-60. http://www.ncbi.nlm.nih.gov/pubmed/16753391

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46.

47.

48. 49.

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Thoeny HC, Sonnenschein MJ, Madersbacher S, Vock P, Studer U.E. Is ileal orthotopic bladder substitution with an afferent tubular segment detrimental to the upper urinary tract in the long term? J Urol 2002;168(5):2030-4; discussion 2034. http://www.ncbi.nlm.nih.gov/pubmed/12394702 Leissner J, Black P, Fisch M, Hockel M, Hohenfellner R. Colon pouch (Mainz pouch III) for continent urinary diversion after pelvic irradiation. Urology 2000;56(5):798-802. http://www.ncbi.nlm.nih.gov/pubmed/11068305 Simon J. Ectopia Vesicae (Absence of the anterior walls of the Bladder and the pubic abdominal parietes) Operation for directing the orifices of the ureteres into the rectum, temporary success. JAMA 1911;56:398. Coffey R. Physiologic implantation of the severed ureter or common bile duct into the intestine. JAMA 1911;56:397. Azimuddin K, Khubchandani IT, Stasik JJ, Rosen L, Riether RD. Neoplasia after ureterosigmoidostomy. Dis Colon Rectum 1999;42(12):1632-8. http://www.ncbi.nlm.nih.gov/pubmed/10613486 Gerharz EW, Turner WH, Kalble T, Woodhouse CR. Metabolic and functional consequences of urinary reconstruction with bowel. BJU Int 2003;91(2):143-9. http://www.ncbi.nlm.nih.gov/pubmed/12519116 Kalble T, Busse K, Amelung F, Waldherr R, Berger MR, Edler L, Riedmiller H. Tumor induction and prophylaxis following different forms of intestinal urinary diversion in a rat model. Urol Res 1995;23(6):365-70. http://www.ncbi.nlm.nih.gov/pubmed/8788273 Stein JP, Skinner DG. Radical cystectomy for invasive bladder cancer: long-term results of a standard procedure. World J Urol 2006;24(3):296-304. http://www.ncbi.nlm.nih.gov/pubmed/16518661 Stein J., Dunn MD, Quek ML, Miranda G, Skinner DG. The orthotopic T pouch ileal neobladder: experience with 209 patients. J Urol 2004;172(2):584-7. http://www.ncbi.nlm.nih.gov/pubmed/15247737 Abol-Enein H, Ghoneim M.A. Functional results of orthotopic ileal neobladder with serous-lined extramural ureteral reimplantation: experience with 450 patients. J Urol 2001;165(5):1427-32. http://www.ncbi.nlm.nih.gov/pubmed/11342891 Stein JP, Skinner DG. Results with radical cystectomy for treating bladder cancer: a ‘reference standard’ for high-grade, invasive bladder cancer. BJU Int 2003;92(1):12-7. http://www.ncbi.nlm.nih.gov/pubmed/12823375 Yossepowitch O, Dalbagni G, Golijanin D, Donat SM, Bochner BH, Herr HW, Fair WR, Russo P. Orthotopic urinary diversion after cystectomy for bladder cancer: implications for cancer control and patterns of disease recurrence. J Urol 2003;169(1):177-81. http://www.ncbi.nlm.nih.gov/pubmed/12478130 Stein JP, Clark P, Miranda G, Cai J, Groshen S, Skinner D.G. Urethral tumor recurrence following cystectomy and urinary diversion: clinical and pathological characteristics in 768 male patients. J Urol 2005;173(4):1163-8. http://www.ncbi.nlm.nih.gov/pubmed/15758728 Gerharz EW, Mansson A, Hunt S, Skinner EC, Mansson W. Quality of life after cystectomy and urinary diversion: an evidence based analysis. J Urol 2005;174(5):1729-36. http://www.ncbi.nlm.nih.gov/pubmed/16217273 Hobisch A, Tosun K, Kinzl J, Kemmler G, Bartsch G, Holtl L, Stenzl A. Life after cystectomy and orthotopic neobladder versus ileal conduit urinary diversion. Semin Urol Oncol 2001;19(1):18-23. http://www.ncbi.nlm.nih.gov/pubmed/11246729 Porter MP, Penson DF. Health related quality of life after radical cystectomy and urinary diversion for bladder cancer: a systematic review and critical analysis of the literature. J Urol 2005;173(4):1318-22. http://www.ncbi.nlm.nih.gov/pubmed/15758789 Cookson MS, Chang SS, Wells N, Parekh DJ, Smith JA Jr. Complications of radical cystectomy for nonmuscle invasive disease: comparison with muscle invasive disease. J Urol 2003;169(1):101-4. http://www.ncbi.nlm.nih.gov/pubmed/12478113 Shariat SF, Karakiewicz PI, Palapattu GS, Lotan Y, Rogers CG, Amiel GE, Vazina A, Gupta A, Bastian PJ, Sagalowsky AI, Schoenberg MP, Lerner S.P. Outcomes of radical cystectomy for transitional cell carcinoma of the bladder: a contemporary series from the Bladder Cancer Research Consortium. J Urol 2006;176(6 Pt 1):2414-22; discussion 2422. http://www.ncbi.nlm.nih.gov/pubmed/17085118

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64.

65.

Gschwend JE, Dahm P, Fair W.R. Disease specific survival as endpoint of outcome for bladder cancer patients following radical cystectomy. Eur Urol 2002;41(4):440-8. http://www.ncbi.nlm.nih.gov/pubmed/12074817 Madersbacher S, Hochreiter W, Burkhard F, Thalmann GN, Danuser H, Markwalder R, Studer UE. Radical cystectomy for bladder cancer today--a homogeneous series without neoadjuvant therapy. J Clin Oncol 2003;21(4):690-6. http://www.ncbi.nlm.nih.gov/pubmed/12586807 Bassi P, Ferrante GD, Piazza N, Spinadin R, Carando R, Pappagallo G, Pagano F. Prognostic factors of outcome after radical cystectomy for bladder cancer: a retrospective study of a homogeneous patient cohort. J Urol 1999;161(5):1494-7. http://www.ncbi.nlm.nih.gov/pubmed/10210380

8. NON-RESECTABLE TUMOURS 8.1

Palliative cystectomy for muscle-invasive bladder carcinoma

For patients with inoperable locally advanced tumours (T4b, invading the pelvic or abdominal wall), radical cystectomy usually is not a therapeutic option (1). Treatment of these patients remains a clinical challenge. These patients are candidates for palliative treatments, such as palliative radiotherapy. Inoperable locally advanced tumours may be accompanied by several debilitating symptoms, including bleeding, pain, dysuria and urinary obstruction. There are several treatment options for patients with these symptoms. In advanced bladder cancer cases complicated by bleeding, cystectomy with urinary diversion is the most invasive treatment. It carries the greatest morbidity and should be considered only if there are no other options (1). In patients with locally advanced pelvic cancer and urinary bladder involvement, palliative radical cystectomy with urinary diversion using intestinal segments is usually performed for the relief of symptoms such as pain, recurrent bleeding, urgency and fistula formation (2). Zebic et al.(3) retrospectively analysed patients aged > 75 years, who had received radical cystectomies with either curative or palliative intent. The indications for palliative cystectomy were advanced pelvic malignancy with severe irritating voiding symptoms, severe pain and recurrent macrohaematuria requiring blood transfusions (3). Zebic et al. concluded that elderly people have a greater risk of perioperative morbidity and mortality, especially those with very advanced pelvic malignancies, who have undergone palliative cystectomy (3). Advanced muscle-invasive bladder cancer can be associated with ureteral obstruction. In invasive tumours, the mechanism of ureteral obstruction is probably caused by a combination of mechanical blockage by the tumour and invasion of ureteral orifices by tumour cells interfering with ureteral peristalsis. Bilateral ureteral obstruction, or unilateral obstruction to a solitary functioning kidney, can result in uraemia. Treatment of such patients is still a dilemma. El-Tabey et al.(4) retrospectively reviewed the records of patients who presented with bladder cancer and obstructive uraemia. Patients with inoperable locally advanced bladder tumours (23 patients, 37.7%) were treated with permanent nephrostomy tubes to relieve obstruction; radical cystectomy was not an option. In 10 patients (26.3%), who underwent surgery, palliative cystectomy without lymphadenectomy was carried out for advanced nodal involvement in four patients and locally advanced disease infiltrating the pelvic wall in six patients. In all patients, local pelvic recurrence was reported within the first year of follow-up (4). In one study post-operative outcome of primary radical cystectomy in 20 T4 bladder cancer patients (of which seven cases were T4b) was reported. The authors concluded that primary cystectomy for the treatment of T4 bladder cancer was technically feasible and had a very tolerable therapy-related morbidity and mortality (5).

8.2

Conclusions

• • •

Primary radical cystectomy in T4b bladder cancer is not a curative option. If there are symptoms, radical cystectomy may be a therapeutic/palliative option. Intestinal or non-intestinal forms of urinary diversion can be used with or without palliative cystectomy.

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8.3

Recommendations

•

For patients with inoperable locally advanced tumours (T4b), primary radical cystectomy is not a curative option (Grade of recommendation: B). The indication for performing a palliative cystectomy is symptom relief. Morbidity of surgery and quality of life should be weighed against other options (Level of evidence: 3; Grade of recommendation: B/C).

• •

8.4

References

1.

Ok JH, Meyers FJ, Evans CP. Medical and surgical palliative care of patients with urological malignancies. J Urol 2005;174(4 Pt 1):1177-82. http://www.ncbi.nlm.nih.gov/pubmed/16145365 Ubrig B, Lazica M, Waldner M, Roth S. Extraperitoneal bilateral cutaneous ureterostomy with midline stoma for palliation of pelvic cancer. Urology 2004;63(5):973-5. http://www.ncbi.nlm.nih.gov/pubmed/15134993 Zebic N, Weinknecht S, Kroepfl D. Radical cystectomy in patients aged > or = 75 years: an updated review of patients treated with curative and palliative intent. BJU Int 2005;95(9):1211-4. http://www.ncbi.nlm.nih.gov/pubmed/15892803 El-Tabey NA, Osman Y, Mosbah A, Mohsen T, Abol-Enein H. Bladder cancer with obstructive uremia: oncologic outcome after definitive surgical management. Urology 2005;66(3):531-5. http://www.ncbi.nlm.nih.gov/pubmed/16140072 Nagele U, Anastasiadis AG, Merseburger AS, Corvin S, Hennenlotter J, Adam M, Sievert KD, Stenzl A, Kuczyk MA. The rationale for radical cystectomy as primary therapy for T4 bladder cancer. World J Urol 2007;25(4):401-5. http://www.ncbi.nlm.nih.gov/pubmed/17525849

2.

3.

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5.

9. NEO-ADJUVANT RADIOTHERAPY IN MUSCLE-INVASIVE BLADDER CANCER 9.1

Pre-operative radiotherapy

9.1.1 Retrospective studies Several retrospective studies have looked at the effect of pre-operative radiotherapy in patients with bladder cancer. The largest retrospective series was from the MD Anderson Cancer Center in the USA (n = 526). It showed that 50 Gy pre-operative radiotherapy resulted in down-staging in 73% of cT3 patients versus 29% of patients who did not receive pre-operative radiotherapy (1, 2). Local control was also improved from 72% to 91% in pT3b patients (n = 91), but not in pT2 or pT3a patients. The improvement in survival in this retrospective series was from 40% to 52%. The results of a non-randomized study comparing 40 Gy, 5-20 Gy and no radiotherapy showed that only 40 Gy pre-operative radiotherapy improved the percentage of local recurrence from 27% to 11% and survival from 21% to 63% (3). Overall, nearly all the retrospective studies investigating the effect of pre-operative radiotherapy with doses of 40-50 Gy, followed after 4-6 weeks by cystectomy, showed (1-9): • down-staging of the tumour stage (40-65% of patients) • lower risk of local recurrence (10-42%) • improved survival (11-12%). Some studies found that the improvement in local control was highest for T3b tumours (2-4). Other studies found that achievement of a pathological complete remission (pCR) is a prognostic factor for survival (3-5). One retrospective study (5) found no significant increase in toxicity due to pre-operative radiotherapy (10% versus 3%). 9.1.2 Randomized studies There are five randomized studies investigating pre-operative radiotherapy. The largest randomized trial (234 evaluable patients), using pre-operative radiotherapy 45 Gy/1.8-2.2 Gy in muscle-invasive tumours, showed a significant increase in pCR (9% to 34%) in favour of pre-operative radiotherapy and no significant increase in 5-year survival of 33% to 45% (10). In patients who were not given adjuvant chemotherapy, survival was significantly better in those who received pre-operative radiotherapy (25–52%). pCR was a prognostic factor for better survival. A major drawback of this study is that almost 50% of patients did not receive the planned treatment and were excluded form the analysis. The Southwest Oncology Group (SWOG) trial (n = 124), which

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used a pre-operative dose of 5 x 4 Gy, did not show a survival advantage (11). A study from Egypt, dealing with patients with bladder cancer caused by bilharzia (predominantly squamous cell carcinoma, n = 92) also showed a significant survival advantage for > T3 tumours, but a marginal and non-significant difference for the whole group (12). A small, randomized study of 44 patients (13) also showed a significant increase in pCR (18–55%) and a small increase in 5-year survival (61–72%, not significant), but the disadvantages of this study were a small patient population and differing radiotherapy schedules (32-54 Gy). Finally, in another small, three-armed study (n = 72), patients were randomized between surgery, surgery with pre-operative radiotherapy (45 Gy in 4-5 weeks) and radiotherapy alone (50-60 Gy in 4-6 weeks) (14). Pre-operative radiotherapy resulted in 24% of patients achieving pCR. There were no significant differences in survival or toxicity between the three arms. There was no reported increase in toxicity due to pre-operative radiotherapy in any of the abovementioned studies. The effect on the local recurrence rate was not specifically documented in any of the studies. Three of the randomized studies looked at down-staging and found an increase in pCR following preoperative radiotherapy from 9% to 34% (10), 0% to 24% (14) and from 18% to 55% (13). Local recurrences were not reported (10, 14) nor were they similar (13). All six randomized studies looked at survival. The largest study found a significant survival advantage from 25% to 52% in those patients who did not receive adjuvant chemotherapy (10). The Egyptian study found a survival advantage only for T3 patients or higher (12). No study found a significant survival advantage for the whole group. A meta-analysis of the randomized trials on the value of pre-operative radiotherapy showed an odds ratio for the difference in 5-year survival of 0.71 (CI: 0.48-1.06). However, the meta-analysis was potentially biased by the many patients in the largest trial, who did not receive the planned treatment. When the results of the largest trial were excluded, the odds ratio became 0.95 (CI: 0.57-1.55), indicating that improved survival with pre-operative radiotherapy had not been proven (15, 16).

9.2

Conclusions

•

It is not proven that pre-operative radiotherapy for operable muscle-invasive bladder cancer increases survival (Level of evidence: 2). It is shown that pre-operative radiotherapy for operable muscle-invasive bladder cancer, using a dose of 45-50 Gy in fractions of 1.8-2 Gy results in down-staging after 4-6 weeks (Level of evidence: 2). Pre-operative radiotherapy with a dose of 45-50 Gy/1.8-2 Gy does not seem to significantly increase toxicity after surgery (Level of evidence: 3). There are suggestions in older literature that pre-operative radiotherapy will result in a decrease in local recurrence of muscle-invasive bladder cancer (Level of evidence: 3).

•

• •

9.3

Recommendations

• •

Pre-operative radiotherapy is not recommended to improve survival (Grade of recommendation: B). Pre-operative radiotherapy for operable muscle-invasive bladder cancer results in tumour downstaging after 4-6 weeks (Grade of recommendation: A-C).

9.4

References

1.

Pollack A, Zagars GK, Dinney CP, Swanson DA, von Eschenbach AC. Preoperative radiotherapy for muscle-invasive bladder carcinoma. Long term follow-up and prognostic factors for 338 patients. Cancer 1994;74(10):2819-27. http://www.ncbi.nlm.nih.gov/pubmed/7954243 Cole CJ, Pollack A, Zagars GK, Dinney CP, Swanson DA, von-Eschenbach AC. Local control of muscle-invasive bladder cancer: preoperative radiotherapy and cystectomy versus cystectomy alone. Int J Radiat Oncol Biol Phys 1995;32(2):331-40. http://www.ncbi.nlm.nih.gov/pubmed/7751174 Spera JA, Whittington R, Littman P, Solin LJ, Wein AJ. A comparison of preoperative radiotherapy regimens for bladder carcinoma. The University of Pennsylvania experience. Cancer 1988;61(2):25562. http://www.ncbi.nlm.nih.gov/pubmed/3334959 Pollack A, Zagars GK, Cole CJ, Dinney CP, Swanson DA, Grossman HB. Significance of downstaging in muscle-invasive bladder cancer treated with preoperative radiotherapy. Int J Radiat Oncol Biol Phys 1997;37(1):41-9. http://www.ncbi.nlm.nih.gov/pubmed/9054875

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16.

Chougule P, Aygun C, Salazar O, Young JJ Jr, Prempree T, Amin P. Radiation therapy for transitional cell bladder carcinoma. A ten-year experience. Urology 1988;32(2):91-5. http://www.ncbi.nlm.nih.gov/pubmed/3135646 Batata MA, Chu FC, Hilaris BS, Whitmore WF, Kim YS, Lee MZ. Bladder cancer in men and women treated by radiation therapy and/or radical cystectomy. Urology 1981;18(1);15-20. http://www.ncbi.nlm.nih.gov/pubmed/6789529 Fossa SD, Ous S, Berner A. Clinical significance of the “palpable mass” in patients with muscleinfiltrating bladder cancer undergoing cystectomy after pre-operative radiotherapy. Br J Urol 1991;67(1):54-60. http://www.ncbi.nlm.nih.gov/pubmed/1993277 Gilloz A, Heritier P. Comparative study of actuarial survival rates in P3 P4 (N+ Mo) transitional cell carcinoma of bladder managed by total cystectomy alone or associated with preoperative radiotherapy and pelvic lymphadenectomy. Prog Clin Biol Res 1984;162B:15-9. http://www.ncbi.nlm.nih.gov/pubmed/6504893 Smith JA, Batata M, Grabstald H, Sogani PC, Herr H, Whitmore WF Jr. Preoperative irradiation and cystectomy for bladder cancer. Cancer 1982;49:869-973. http://www.ncbi.nlm.nih.gov/pubmed/6800628 Slack NH, Bross ID, Prout GR. Five-year follow-up results of a collaborative study of therapies for carcinoma of the bladder. J Surg Oncol 1977;9:393-405. http://www.ncbi.nlm.nih.gov/pubmed/330958 Smith JA, Crawford ED Paradelo JC et al. Treatment of advanced bladder cancer with combined preoperative irradiation and radical cystectomy versus radical cystectomy alone: a phase III intergroup study. J Urol 1997;157:805-7; discussion 807-8. http://www.ncbi.nlm.nih.gov/pubmed/9072571 Ghoneim MA, Ashamallah AK, Awaad HK, Whitmore WF Jr. Randomized trial of cystectomy with or without preoperative radiotherapy for carcinoma of the bilharzial bladder. J Urol 1985;134(2):266-8. http://www.ncbi.nlm.nih.gov/pubmed/3894693 Anderstrom C, Johanson S, Nilsson S, Unsgaard B, Wahlqvist L. A prospective randomized study of preoperative irradiation with cystectomy or cystectomy alone for invasive bladder carcinoma. Eur Urol 1983;9(3):142-7. http://www.ncbi.nlm.nih.gov/pubmed/6861819 Blackard CE, Byar DP. Results of a clinical trial of surgery and radiation in stages II and III carcinoma of the bladder. J Urol 1972;108(6):875-8. http://www.ncbi.nlm.nih.gov/pubmed/5082739 Huncharek M, Muscat J, Geschwind JF. Planned preoperative radiation therapy in muscle invasive bladder cancer; results of a meta-analysis. Anticancer Res 1998;18(3b):1931-4. http://www.ncbi.nlm.nih.gov/pubmed/9677446 Widmark A, Flodgren P, Damber JE, Hellsten S, Cavallin-Stahl E. A systematic overview of radiation therapy effects in urinary bladder cancer. Acta Oncol 2003;42(5-6):567-81. http://www.ncbi.nlm.nih.gov/pubmed/14596515

10. BLADDER-SPARING TREATMENTS 10.1

Transurethral resection of bladder tumour

When patients, with an initially invasive bladder cancer, presenting with pT0 or pT1 status at second resection are selected for transurethral resection of bladder tumour (TURBT) alone, about half of them will have to undergo radical cystectomy for recurrent muscle-invasive cancer, with a disease-specific death rate ranging up to 47% within this group (1, 2). A disease-free status at restaging TUR appears to be crucial in making the decision not to perform radical cystectomy (3, 4). It is only possible to consider TUR alone as a therapeutic option if tumour growth is limited to the superficial muscle layer and if restaging biopsies are negative for residual tumour (5). TUR alone should only be considered as a therapeutic option, when the patient is unfit for cystectomy or a multimodality bladder-preserving approach or refuses open surgery (6).

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10.1.1 Conclusion and recommendation • TUR alone is not a curative treatment option in most patients (Level of evidence: 2a; Grade of recommendation: B). 10.1.2 References 1. Barnes RW, Dick AL, Hadley HL, Johnston OL. Survival following transurethral resection of bladder carcinoma. Cancer Res 1977;37(8 Pt 2):2895-7. http://www.ncbi.nlm.nih.gov/pubmed/872119 2. Herr HW. Transurethral resection of muscle-invasive bladder cancer: 10-year outcome. J Clin Oncol 2001;19(1):89-93. http://www.ncbi.nlm.nih.gov/pubmed/11134199 3. Solsona E, Iborra I, Ricos JV, Monros JL, Casanova J, Calabuig C. Feasibility of transurethral resection for muscle infiltrating carcinoma of the bladder: long-term follow-up of a prospective study. J Urol 1998;159:95-98; discussion 98-99. http://www.ncbi.nlm.nih.gov/pubmed/9400445 4. Holmang S, Hedelin H, Anderstrom C, Johansson SL. Long-term follow-up of all patients with muscle invasive (stages T2, T3 and T4) bladder carcinoma in a geographical region. J Urol 1997;158(2):38992. http://www.ncbi.nlm.nih.gov/pubmed/9224309 5. Herr HW. Conservative management of muscle-infiltrating bladder cancer: prospective experience. J Urol 1987;138(5):1162-3. http://www.ncbi.nlm.nih.gov/pubmed/3669160 6. Whitmore WF Jr, Batata MA, Ghoneim MA, Grabstald H, Unal A. Radical cystectomy with or without prior irradiation in the treatment of bladder cancer. J Urol 1977:118(1 Pt 2):184-7. http://www.ncbi.nlm.nih.gov/pubmed/875217

10.2

External beam radiotherapy

The target field usually comprises the bladder only, with a safety margin of 1.5-2 cm to allow for unavoidable organ movements (1-4). Any beneficial effect with larger pelvic fields has not been demonstrated. The target dose for curative radiotherapy for bladder cancer is 60-66 Gy, with a subsequent boost using external radiotherapy or interstitial brachytherapy. The daily dose is usually 1.8-2 Gy, and the course of radiotherapy should not extend beyond 6-7 weeks to minimize the repopulation of cancer cells. The use of modern standard radiotherapy techniques results in major, related, late morbidity of the urinary bladder or bowel in less than 5% of tumour free-patients (5-9). Besides the response to radiotherapy, important prognostic factors for outcome include tumour size, hydronephrosis and the completeness of the initial TURBT. Overall 5-year survival rates in patients with muscle-invasive bladder cancer range between 30% and 60%, with a cancer-specific survival rate of 20% and 50%, with or without a complete response following radiotherapy, respectively (10-14). Based on available trials, a Cochrane analysis has demonstrated that radical cystectomy has an overall survival benefit compared to radiotherapy (15). 10.2.1 Conclusions • External beam radiotherapy alone should only be considered as a therapeutic option when the patient is unfit for cystectomy or a multimodality bladder-preserving approach (Level of evidence: 3). • Radiotherapy can also be used to stop bleeding from the tumour when local control cannot be achieved by transurethral manipulation because of extensive local tumour growth (Level of evidence: 3). 10.2.2 Recommendation • There is evidence that radiotherapy alone is less effective than curative therapy (surgery or trimodality treatment) (Grade or recommendation: B). 10.2.3 References 1. Gospodarowicz MK, Blandy JP. Radiation therapy for organ-conservation for invasive bladder carcinoma. In: Vogelzang NJ, Scardino PT, Shipley WU, Coffey DS, eds. Comprehensive Textbook of Genitourinary Oncology. Lippincott: Williams and Wilkins, 2000; pp. 487-496. 2. Duncan W, Quilty PM. The results of a series of 963 patients with transitional cell carcinoma of the urinary bladder primarily treated by radical megavoltage X-ray therapy. Radiother Oncol 1986;7(4): 299-310. http://www.ncbi.nlm.nih.gov/pubmed/3101140

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3.

4.

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7.

8.

9.

10.

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12.

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14.

15.

10.3

Gospodarowicz MK, Hawkins NV, Rawlings GA, Connolly JG, Jewett MA, Thomas GM, Herman JG, Garrett PG, Chua T, Duncan W et al. Radical radiotherapy for muscle invasive transitional cell carcinoma of the bladder: failure analysis. J Urol 1989;142(6):1448-53; discussion 1453-4. http://www.ncbi.nlm.nih.gov/pubmed/2585617 Gospodarowicz MK, Quilty PM, Scalliet P, Tsujii H, Fossa SD, Horenblas S, Isaka S, Prout R, Shipley WU, Wijnmaalen AJ et al. The place of radiation therapy as definitive treatment of bladder cancer. Int J Urol 1995;2(Suppl 2):41-8. http://www.ncbi.nlm.nih.gov/pubmed/7553304 Shipley WU, Zietman AL, Kaufman DS, Althausen AF, Heney NM. Invasive bladder cancer: treatment strategies using transurethral surgery, chemotherapy and radiation therapy with selection for bladder conservation. Int J Radiat Oncol Biol Phys 1997;39(4):937-43. http://www.ncbi.nlm.nih.gov/pubmed/9369144 Maciejewski B, Majewski S. Dose fractionation and tumor repopulation in radiotherapy for bladder cancer. Radiother Oncol 1991;21(3):163-70. http://www.ncbi.nlm.nih.gov/pubmed/1924851 De Neve W, Lybeert MLM, Goor C, Crommelin NA, Ribot JG. Radiotherapy for T2 and T3 carcinoma of the bladder: the influence of overall treatment time. Radiother Oncol 1995;36(3):183-8. http://www.ncbi.nlm.nih.gov/pubmed/8532904 Milosevic M, Gospodarowicz M, Zietman A, Abbas F, Haustermans K, Moonen L, Rodel C, Schoenberg M, Shipley W. Radiotherapy for bladder cancer. Urology 2007;69(1 Suppl):80-92. http://www.ncbi.nlm.nih.gov/pubmed/17280910 Whitmore WF Jr, Batata MA, Ghoneim MA, Grabstald H, Unal A. Radical cystectomy with or without prior irradiation in the treatment of bladder cancer. J Urol 1977;118(1 Pt 2):184-7. http://www.ncbi.nlm.nih.gov/pubmed/875217 Pollack A, Zagars GZ. Radiotherapy for stage T3b transitional cell carcinoma of the bladder. Semin Urol Oncol 1996;14(2):86-95. http://www.ncbi.nlm.nih.gov/pubmed/8734736 De Neve W, Lybeert ML, Goor C, Crommelin MA, Ribot JG. Radiotherapy for T2 and T3 carcinoma of the bladder: the influence of overall treatment time. Radiother Oncol 1995;36(3):183-8. http://www.ncbi.nlm.nih.gov/pubmed/8532904 Mameghan H, Fisher R, Mameghan J, Brook S. Analysis of failure following definitive radiotherapy for invasive transitional cell carcinoma of the bladder. Int J Radiat Oncol Biol Phys 1995;31(2):247-54. http://www.ncbi.nlm.nih.gov/pubmed/7836076 Herskovic A, Martz K, Al-Sarraf M, Leichman L, Brindle J, Vaitkevicius V, Cooper J, Byhardt R, Davis L, Emami B. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992;326(24):1593-8. http://www.ncbi.nlm.nih.gov/pubmed/1584260 Naslund I, Nilsson B, Littbrand B. Hyperfractionated radiotherapy of bladder cancer. A ten-year followup of a randomized clinical trial. Acta Oncol 1994;33(4):397-402. http://www.ncbi.nlm.nih.gov/pubmed/8018372 Shelley MD, Barber J, Wilt T, Mason MD. Surgery versus radiotherapy for muscle invasive bladder cancer. Cochrane Database Syst Rev 2002;(1):CD002079. http://www.ncbi.nlm.nih.gov/pubmed/11869621

Chemotherapy

Chemotherapy alone rarely produces durable complete responses. A clinical complete response rate of up to 56% as reported in some series must be weighed against a staging error of > 60% (1-2). In the case of an initially incomplete TUR, a pathological complete response rate of 8-26% can be expected following an additional cisplatin-based systemic therapy (3-5). The use of cisplatin-based chemotherapy as the primary therapy for locally advanced (T3/T4) tumours has resulted in complete and partial local responses in 11% and 34% of cases, respectively (6-7). 10.3.1 Conclusion With cisplatin-based chemotherapy as primary therapy for locally advanced tumours in highly selected patients, complete and partial local responses have been reported (Level of evidence: 2b). 10.3.2 Recommendation Chemotherapy alone is not recommended as primary therapy for localized bladder cancer (Grade of recommendation: A).

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10.3.3 References 1. Scher HI, Yagoda A, Herr HW, Sternberg CN, Bosl G, Morse MJ, Sogani PC, Watson RC, Dershaw DD, Reuter V et al. Neoadjuvant M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) effect on the primary bladder lesion. J Urol 1988;139(3):470-4. http://www.ncbi.nlm.nih.gov/pubmed/3343728 2. Herr HW, Bajorin DF, Scher HI. Neoadjuvant chemotherapy and bladder-sparing surgery for invasive bladder cancer: ten-year outcome. J Clin Oncol 1998;16(4):1298-301. http://www.ncbi.nlm.nih.gov/pubmed/9552029 3. Scattoni V, Da Pozzo L, Nava L, Broglia L, Galli L, Torelli T, Campo B, Maffezzini M, Rigatti P. Five-year results of neoadjuvant cisplatin, methotrexate and vinblastine chemotherapy plus radical cystectomy in locally advanced bladder cancer. Eur Urol 1995;28(2):102-7. http://www.ncbi.nlm.nih.gov/pubmed/8529731 4. Igawa M, Ohkuchi T, Ueki T, Ueda M, Okada K, Usui T. Usefulness and limitations of methotrexate, vinblastine, doxorubicin and cisplatin for the treatment of advanced urothelial cancer. J Urol 1990;144(3):662-5. http://www.ncbi.nlm.nih.gov/pubmed/2388322 5. Angulo JC, Sanchez-Chapado M, Lopez JI, Flores N. Primary cisplatin, methotrexate and vinblastine aiming at bladder preservation in invasive bladder cancer: multivariate analysis on prognostic factors. J Urol 1996;155(6):1897-902. http://www.ncbi.nlm.nih.gov/pubmed/8618282 6. Roberts JT, Fossa SD, Richards B, Kaye SB, White EF, Robinson MC, Uscinska B, Parmar MK. Results of Medical Research Council phase II study of low dose cisplatin and methotrexate in the primary treatment of locally advanced (T3 and T4) transitional cell carcinoma of the bladder. Br J Urol 1991;68(2):162-8. http://www.ncbi.nlm.nih.gov/pubmed/1884143 7. Martinez-Piñeiro JA, Gonzalez Martin M, Arocena F, Flores N, Roncero CR, Portillo JA, Escudero A, Jimenez Cruz F, Isorna S. Neoadjuvant cisplatin chemotherapy before radical cystectomy in invasive transitional cell carcinoma of the bladder: a prospective randomized phase III study. J Urol 1995;153(3 Pt 2):964-73. http://www.ncbi.nlm.nih.gov/pubmed/7853584

10.4

Multimodality treatment

Recent organ-preservation strategies combine TURBT, chemotherapy and radiation (1-5). The rationale for performing TURBT and radiation is to achieve local tumour control. Application of systemic chemotherapy, most commonly as methrotrexate, cisplatin and vinblastine (MCV), aims at the eradication of micrometastasis. Many protocols use cisplatin and/or 5-FU and, recently, gemcitabine with radiation because of their established role as radiosensitizers. Cisplatin-based chemotherapy in combination with radiotherapy, following TURBT, results in a complete response rate of 60-80%. It is recommended that early cystectomy is performed in individuals who do not achieve a complete response following combination therapy. This will allow about 40-45% of patients to survive with an intact bladder at 4-5 years (5). A comparable long-term survival rate of 50-60% at 5 years’ follow-up is reported by both multimodality bladder-preserving trials and cystectomy series. However, both therapeutic approaches have never been directly compared and patients in multimodality series are highly selected (5-7). A bladder-preserving multimodality strategy requires very close multidisciplinary co-operation and a high level of patient compliance. Even if a patient has shown a complete response to a multimodality bladder-preserving strategy, the bladder remains a potential source of recurrence. About half of patients can be expected to survive with their native bladder intact. A T0 status at repeat TUR after the initial transurethral resection of the primary tumor, followed by chemotherapy in combination with radiotherapy, was identified as a prognostically important variable. However, even the latter patients are at a life-long risk of developing intravesical tumor recurrences with the need for meticulous surveillance and multiple invasive procedures. It has been postulated that a delay in radical cystectomy due to an initial bladder-preserving approach increases the risk of lymph node metastases to a lymph-node positive rate of 26% when cystectomy becomes necessary due to treatment failure. 10.4.1 Conclusions • There are comparable long-term survival rates in cases of multimodality treatment success (Level of evidence: 3). • Delay in surgical therapy can compromise survival rates. (Level of evidence: 2b].

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10.4.2 Recommendations • TUR alone is not a curative treatment option in most patients (grade of recommendation: B). • Radiotherapy alone is less effective than surgery (grade of recommendation: B). • Chemotherapy alone is not recommended as primary therapy for localized bladder cancer (grade of recommendation: B). • Multimodality treatment is an alternative in selected, well-informed and compliant patients where cystectomy is not considered for clinical or personal reasons (Grade of recommendation: B). 10.4.3 References 1. Shipley WU, Kaufman DS, Zietman AL, Griffin PP, Heney NM, Althausen AF. Selective bladder preservation by combined modality therapy for invasive bladder cancer. Eur J Cancer 1995:31A(Suppl 5):S239. 2. Shipley WU, Kaufman DS, Heney NM, Althausen AF, Zietman AL. An update of selective bladder preservation by combined modality therapy for invasive bladder cancer. Eur Urol 1998;33 Suppl 4:324. http://www.ncbi.nlm.nih.gov/pubmed/9615208 3. Housset M, Dufour E, Maulard-Durtux C. Concomitant 5-fluouracil (5-FU)-cisplatin (CDDP) and bifractionated split course radiation therapy (BSCRT) for invasive bladder cancer. Proc Am Soc Clin Oncol 1997;16:1139A (abstr). http://www.asco.org/ASCO/Abstracts+&+Virtual+Meeting/Abstracts?&vmview=abst_search_results_vi ew&selectedConfs=17,31,30,29,28&SearchFilter1=Title&SearchTerm1=cisplatin&SearchFilter2=Author &SearchTerm2=&SearchFilter3=Author&SearchTerm3=Housset 4. Weiss C, Wolze C, Engehausen DG, Ott OJ, Krause FS, Schrott KM, Dunst J, Sauer R, Rodel C. Radiochemotherapy after transurethral resection for high-risk T1 bladder cancer: an alternative to intravesical therapy or early cystectomy? J Clin Oncol 24(15):2318-24. http://www.ncbi.nlm.nih.gov/pubmed/16710030 5. Rodel C, Grabenbauer GG, Kuhn R, Papadopoulos T, Dunst J, Meyer M, Schrott KM, Sauer R. Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results. J Clin Oncol 2002;20(14):3061-71. http://www.ncbi.nlm.nih.gov/pubmed/12118019 6. Zietman AL, Grocela J, Zehr E, Kaufman DS, Young RH, Althausen AF, Heney NM, Shipley WU. Selective bladder conservation using transurethral resection, chemotherapy, and radiation: management and consequences of Ta, T1, and Tis recurrence within the retained bladder. Urology 2001;58(3):380-5. http://www.ncbi.nlm.nih.gov/pubmed/11549485 7. Shipley WU, Kaufman DS, Zehr E, Heney NM, Lane SC, Thakral HK, Althausen AF, Zietman AL. Selective bladder preservation by combined modality protocol treatment: long-term outcomes of 190 patients with invasive bladder cancer. Urology 2002;60(1):62-7; discussion 67-8. http://www.ncbi.nlm.nih.gov/pubmed/12100923

11. ADJUVANT CHEMOTHERAPY Adjuvant chemotherapy for patients after radical cystectomy with pT3/4 and/or lymph node positive (N+) disease without clinically detectable metastases (M0) is under debate (1, 2). The benefits of chemotherapy in the adjuvant setting include: • Chemotherapy is administered after accurate pathological staging • Overtreatment in patients at low risk for micrometastases is avoided • No delay in definitive surgical treatment, especially in patients not sensitive to chemotherapy. The drawbacks of adjuvant chemotherapy are: • Assessment of in-vivo chemosensitivity of the tumour is not possible • Delay or intolerability of chemotherapy, due to post-operative morbidity. There is not enough evidence in favour of the routine use of adjuvant chemotherapy (2, 8). To date, there have been only five published randomized trials of adjuvant chemotherapy (3-7) and one meta-analysis (8), with updated individual patient data from six trials and a total of only 491 patients for survival analysis. Furthermore, all these trials are sub-optimal with serious deficiencies, such as low sample size (underpowered), use of substandard chemotherapy, early stopping of patient entry and flaws in design

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and statistical analysis, including irrelevant endpoints or a lack of recommendations concerning salvage chemotherapy for relapse or metastases (2). The data are not convincing enough to give an unequivocal recommendation for the use of adjuvant chemotherapy. From the evidence so far available, it is unclear whether immediate adjuvant chemotherapy or chemotherapy at the time of relapse is superior or if the two approaches are equivalent with respect to the end-point overall survival. In recent trial updates, cisplatin-based combination chemotherapy was able to produce long-term disease-free survival, even in metastatic disease, albeit mainly in patients with lymph node metastases only and in good PS (9-11). Patients with extravesical and/or node positive disease following cystectomy should be enrolled in clinical trials whenever possible. In non-protocol-eligible patients, adjuvant cisplatin-based chemotherapy is an option provided the patient is well informed about the scarce data available. Published trials of randomized adjuvant chemotherapy have used 3-4 cycles of CMV (cisplatin, methotrexate, vinblastine), CISCA (cisplatin, cyclophosphamide, and adriamycine), MVA(E)C (methotrexate, vinblastine, adriamycine or epirubicine, and cisplatin) and CM (cisplatin, methotrexate) (12). There is no evidence that more modern or carboplatin-containing chemotherapy combinations are as effective. Patients ineligible for cisplatin should not receive adjuvant chemotherapy.

11.1 Conclusion •

Adjuvant chemotherapy is under debate. Neither randomized trials nor a meta-analysis have provided sufficient data to support the routine use of adjuvant chemotherapy (Level of evidence: 1a).

11.2 Recommendation •

Adjuvant chemotherapy is advised within clinical trials, but not for routine use because it has not been studied sufficiently (Grade of recommendation: A).

11.3

References

1.

Cohen SM, Goel A, Phillips J, Ennis RD, Grossbard ML. The role of perioperative chemotherapy in the treatment of urothelial cancer. Oncologist 2006;11(6):630-40. http://www.ncbi.nlm.nih.gov/pubmed/16794242 Sylvester R, Sternberg C. The role of adjuvant combination chemotherapy after cystectomy in locally advanced bladder cancer: what we do not know and why. Ann Oncol 2000;11(7):851-6. http://www.ncbi.nlm.nih.gov/pubmed/10997813 Bono A, Benvenuti C, Gibba A, Guazzeri S, Cosciani-Cunico S, Anselmo G. Adjuvant chemotherapy in locally advanced bladder cancer. Final analysis of a controlled multicentre study. Acta Urol Ital 1997;11(1):5-8. Freiha F, Reese J, Torti FM. A randomized trial of radical cystectomy versus radical cystectomy plus cisplatin, vinblastine and methotrexate chemotherapy for muscle invasive bladder cancer. J Urol 1996;155(2):495-9; discussion 499-500. http://www.ncbi.nlm.nih.gov/pubmed/8558644 Stockle M, Meyenburg W, Wellek S, Voges GE, Rossmann M, Gertenbach U, Thuroff JW, Huber C, Hohenfellner R. Adjuvant polychemotherapy of nonorgan-confined bladder cancer after radical cystectomy revisited: long-term results of a controlled prospective study and further clinical experience. J Urol 1995;153(1):47-52. http://www.ncbi.nlm.nih.gov/pubmed/7966789 Studer UE, Bacchi M, Biedermann C, Jaeger P, Kraft R, Mazzucchelli L, Markwalder R, Senn E, Sonntag RW. Adjuvant cisplatin chemotherapy following cystectomy for bladder cancer: results of a prospective randomized trial. J Urol 1994;152(1):81-4. http://www.ncbi.nlm.nih.gov/pubmed/8201695 Skinner DG, Daniels JR, Russell CA, Lieskovsky G, Boyd SD, Krailo M, Groshen S. Adjuvant chemotherapy following cystectomy benefits patients with deeply invasive bladder cancer. Semin Urol 1990;8(4):279-84. http://www.ncbi.nlm.nih.gov/pubmed/2284533 Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Adjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis of individual patient data. Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Eur Urol 2005;48(2):189-199; discussion 99-201. http://www.ncbi.nlm.nih.gov/pubmed/15939530

2.

3.

4.

5.

6.

7.

8.

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9.

10.

11.

12.

von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 2005;23(21):4602-8. http://www.ncbi.nlm.nih.gov/pubmed/16034041 Sternberg CN. Perioperative chemotherapy in muscle-invasive bladder cancer to enhance survival and/or as a strategy for bladder preservation. Semin Oncol 2007;34(2):122-8. http://www.ncbi.nlm.nih.gov/pubmed/17382795 Stadler WM, Hayden A, von der Maase H, Roychowdhur D, Dogliotti L, Seymour L, Kaufmann D, Moore M. Long-term survival in phase II trials of gemcitabine plus cisplatin for advanced transitional cell cancer. Urol Oncol 2002;7(4):153-7. http://www.ncbi.nlm.nih.gov/pubmed/12474531 Lehmann J, Retz M, Wiemers C, Beck J, Thuroff J, Weining C, Albers P, Frohneberg D, Becker T, Funke PJ, Walz P, Langbein S, Reiher F, Schiller M, Miller K, Roth S, Kalbe T, Sternberg D, Wellek S, Stockle M; AUO-AB 05/95. Adjuvant cisplatin plus methotrexate versus methotrexate, vinblastine, epirubicin, and cisplatin in locally advanced bladder cancer: results of a randomized, multicenter, phase III trial (AUO-AB 05/95). J Clin Oncol 2005;23(22):4963-74. http://www.ncbi.nlm.nih.gov/pubmed/15939920

12. METASTATIC DISEASE Approximately 30% of patients with urothelial cancer present with muscle-invasive disease; about half will relapse after radical cystectomy depending on the pathological stage of the primary tumour and the nodal status. Local recurrence accounts for about 30% of relapses, whereas distant metastases are more common. About 10-15% of patients are already metastatic at diagnosis (1). Before the development of effective chemotherapy, patients with metastatic urothelial cancer rarely exceeded the median survival of 3-6 months (2).

12.1

Prognostic factors and treatment decisions

Bladder cancer is a chemosensitive tumour. Response rates differ with respect to patient-related factors and pre-treatment disease. Prognostic factors for response and survival have been established. In a multivariate analysis, Karnofsky PS of 80% or less and the presence of visceral metastases were independently prognostic of poor survival after treatment with MVAC (methotrexate, vinblastine, adriamycine and cisplatin). These so-called ‘Bajorin’ prognostic factors (3) have also been validated for newer combination chemotherapies (4, 5) and are crucial for assessing phase II study results and stratifying phase III trials (6, 7). Additional data on the prognostic value of elevated alkaline phosphatase and the number of disease sites (> or < three) were generated prospectively (8). A retrospective analysis showed that, in elderly patients, an ECOG (Eastern Cooperative Oncology Group) PS 2-3 and a haemoglobin level of 60 mL/min, PS, co-morbidity) (10-14). So far, there is no generally accepted definition for ‘fit’ or ‘unfit’ patients (15).

12.2

Single-agent chemotherapy

Varying response rates of single-agent first-line chemotherapy have been reported with only 12% for cisplatin compared to MVAC (7), 12% for carboplatin (10), 42% for paclitaxel (16), 31% for docetaxel (17), 29% for methotrexate, 19% for adriamycin, 15% for epirubicin, 13% for mitomycin C, 35% for 5-FU, 14% for vinblastine, 29% for ifosfamide and 8% for cyclophosphamide (18, 19). The most robust single-agent data is a response rate of about 25% for gemcitabine for first- and second-line use in several, larger-sized, phase II trials (20-27). Responses with single agents are usually short-lived and complete responses are rare. Of note, no long-term disease-free survival has been reported with single-agent chemotherapy. The median survival in such patients is only about 6-9 months. Patients with PS WHO 3-4, with or without additional negative prognostic factors, are not expected to benefit from combination chemotherapy. The most appropriate approach for this patient group is best supportive care or, at most, single-agent chemotherapy.

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12.3

Standard first-line chemotherapy for ‘fit’ patients

Cisplatin-containing combination chemotherapy has been the standard of care since the late 1980s. MVAC has been superior to cisplatin monotherapy and CISCA (cisplatin, cyclophosphamide and adriamycine) (7, 28) and, more recently, to cisplatin/docetaxel (29). MVAC and gemcitabine/cisplatin (GC) have prolonged survival up to 14.8 and 13.8 months, respectively (30-32). Neither of the two combinations was proven to be superior over the other, but equivalence was not tested, with response rates of 46% and 49% for MVAC and GC, respectively. The long-term survival results confirmed the anticipated equivalence of the two regimens (8). The major difference between the above-mentioned combinations was toxicity, with GC being less toxic (32). MVAC is better tolerated with the use of GCSF (29, 33). High-dose intensity MVAC (HD-MVAC) with GCSF is less toxic and more efficacious than standard MVAC in terms of dose density, complete response and 2-year survival rate. However, there is no significant difference in median survival between the two regimens (34, 35). Further intensification of treatment using new triplets, dose-dense schedules or adding targeted therapies is still being investigated. These approaches should be reserved for clinical trials and are not considered suitable for routine use.

12.4

Carboplatin-containing chemotherapy in ‘fit’ patients

Carboplatin-containing chemotherapy is not proven to be equivalent to cisplatin combinations. However, it is probably inferior and therefore should not be considered interchangeable or standard. The only randomized phase III study of carboplatin-containing chemotherapy had a disappointing response rate of only 28.2% in the investigational arm (paclitaxel/carboplatin) compared to MVAC and had to be closed down early because of a low accrual rate. There is therefore no evidence that this doublet might have adequate efficacy for first-line use (36). Various carboplatin versus cisplatin combination chemotherapies in randomized phase II trials have produced lower complete response rates and a shorter overall survival for the carboplatin arms (37-39).

12.5

Non-platinum combination chemotherapy

Gemcitabine and paclitaxel combinations in different schedules have been studied as both first- and secondline treatments. Apart from severe pulmonary toxicity with a weekly schedule of both drugs, this combination has been well tolerated and produced response rates between 38% and 60% in both lines. Because there has not been a randomized comparison. Because there has not been a randomized comparison to standard cisplatin chemotherapy, non-platinum combination-chemotherapy is not recommended for first-line use in patients who are fit enough (27, 40-45).

12.6

Chemotherapy in patients ‘unfit’ for cisplatin

Up to 50% of patients are unfit for cisplatin-containing chemotherapy, either due to a poor PS and/or impaired renal function, or due to co-morbidity that forbids high-volume hydration (46, 47). In such cases, carboplatin combination or single-agent chemotherapy is reasonable (10, 11). Non-platinum combinations, as front-line chemotherapy in patients with two adverse prognostic factors (GFR < 50-60 mL/min and PS > 2) should be reserved for investigational use because they have not been tested in purely ‘unfit’ patients and might be too toxic. Trials with clearly defined ‘unfit’ patients or patients with multiple adverse prognostic factors are rare. However, the first randomized phase II/III trial in this setting is currently being conducted by the EORTC. It compares carboplatin/vinblastin/methotrexate and carboplatin/gemcitabine in patients unfit for cisplatin (www.eortc.be).

12.7

Second-line treatment

Second-line chemotherapy data are highly variable and prognostic factors are unclear in this setting. Suggested prognostic factors include the choice of front-line chemotherapy (adjuvant/neoadjuvant), prior chemosensitivity, PS and the ‘Bajorin’-prognostic factors. There is not yet enough data to define a chemotherapy standard in this setting. Re-exposition 12 months or more after response to a prior chemotherapeutic regimen is a reasonable strategy. Second-line response rates of paclitaxel (weekly), docetaxel, oxaliplatin, topotecan, lapatinib, gefitinib and bortezomib range between 0% and 13% in small phase II trials (48-55). Gemcitabine has been studied with excellent response rates also for second-line use (20, 24-27). However, most patients already receive this drug as part of their front-line treatment. Vinflunine, a new third-generation vinca-alcaloid, has shown objective response rates of 18% and disease control in 67% (56). Publication of a phase III trial of vinflunine randomized against best supportive care is awaited. In a phase II trial, pemetrexed 500 mg/m2, given every 3 weeks, showed a promising response rate of 28% and manageable toxicity with the addition of vitamin B12 and folinic acid supplementation and

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dexamethasone prophylaxis (57). The excellent response rate could not be confirmed by a second, smallersized trial; however, this may have been due to patient selection (58). Ifosfamide had a response rate of 20% but is prone to considerable toxicity (59). Paclitaxel/gemcitabine showed response rates of 38-60%, depending on pre-treatment response and indication of prior chemotherapy. Unfortunately, no randomized trial has been conducted to assess the true value of this second-line combination (2, 41, 45).

12.8

Low-volume disease and post-chemotherapy surgery

With cisplatin-containing combination chemotherapy, patients with lymph node metastases only, good PS and an adequate renal function may achieve excellent response rates, including a high degree of complete responses, with up to 20% of patients achieving long-term disease-free survival (8, 35, 60, 61). Stage migration may play a role in this positive prognostic development. A retrospective study of post-chemotherapy surgery after a partial or complete response indicated that post-chemotherapy surgery may contribute to long-term disease-free survival in selected patients (62-64).

12.9 Conclusions • •

•

• • •

• • •

Urothelial carcinoma is a chemosensitive tumour. Performance status and the presence or absence of visceral metastases are independent prognostic factors for survival. These factors are at least as important as the type of chemotherapy administered (Level of evidence: 3). Cisplatin-containing combination chemotherapy is able to achieve a median survival of up to 14 months, with long-term disease-free survival reported in about 15% of patients with nodal disease and good PS (Level of evidence: 1b). Single-agent chemotherapy provides low response rates of usually short duration (Level of evidence: 2a). Carboplatin-combination chemotherapy is less effective than cisplatin-based chemotherapy in terms of CR and survival (Level of evidence: 2a). Non-platinum combination chemotherapy has produced substantial responses in first- and secondline use, but has not been tested against standard chemotherapy in fit patients or in a purely unfit patient group (Level of evidence: 2a). To date, there is no defined standard chemotherapy for ‘unfit’ patients with advanced or metastatic urothelial cancer (Level of evidence: 2b). Small-sized phase II trials provide evidence of moderate response rates for single agents or nonplatinum combinations at second-line use (Level of evidence: 2a). Post-chemotherapy surgery after a partial or complete response may contribute to long-term disease-free survival (Level of evidence: 3).

12.10 Recommendations • • • • •

Prognostic factors guide treatment selection (Grade of recommendation: B). First-line treatment for fit patients: use cisplatin-containing combination chemotherapy with GC, MVAC, preferably with GCSF, or HD-MVAC with GCSF (Grade of recommendation: A). Carboplatin and non-platinum combination chemotherapy as first-line treatment in patients fit for cisplatin is not recommended (Grade of recommendation: B). First-line treatment in patients unfit for cisplatin: use carboplatin combination chemotherapy or single agents (Grade of recommendation: C). Second-line treatment: consider single agents or paclitaxel/gemcitabine if the patient has a good PS (Grade of recommendation: C).

12.11 References 1.

2.

3.

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Rosenberg JE, Carroll PR, Small EJ. Update on chemotherapy for advanced bladder cancer. J Urol 2005;174(1):14-20. http://www.ncbi.nlm.nih.gov/pubmed/15947569 Sternberg CN, Vogelzang NJ. Gemcitabine, paclitaxel, pemetrexed and other newer agents in urothelial and kidney cancers. Crit Rev Oncol Hematol 2003;46(Suppl):S105-S115. http://www.ncbi.nlm.nih.gov/pubmed/12850531 Bajorin DF, Dodd PM, Mazumdar M, Fazzari M, McCaffrey JA, Scher HI, Herr H, Higgins G, Boyle MG. Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol 1999;17(10):3173-81. http://www.ncbi.nlm.nih.gov/pubmed/10506615

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4.

5.

6.

7.

8.

9.

10.

11.

12. 13.

14.

15.

16.

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Sternberg CN, de Mulder PH, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes F, Spina M, van Groeningen CJ, de Balincourt C, Collette L; European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol 2001;19(10):2638-46. http://www.ncbi.nlm.nih.gov/pubmed/11352955 Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes JA, Spina M, van Groeningen CJ, Duclos B, Roberts JT, de Balincourt C, Collette L; EORTC GenitoUrinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer 2006;42(1):50-4. http://www.ncbi.nlm.nih.gov/pubmed/16330205 Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, Hudes GR, Wilding G. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer 2004;100(8):1639-45. http://www.ncbi.nlm.nih.gov/pubmed/15073851 Petrioli R, Frediani B, Manganelli A, Barbanti G, De Capua B, De Lauretis A, Salvestrini F, Mondillo S, Francini G. Comparison between a cisplatin-containing regimen and a carboplatin-containing regimen for recurrent or metastatic bladder cancer patients. A randomized phase II study. Cancer 1996;77(2):344-51. http://www.ncbi.nlm.nih.gov/pubmed/8625244 Carteni G, Dogliotti L, Crucitta E, Martoni A, Siena S, Onat H, Bertetto O, Bono A, Amadori D, Marini L. Phase II randomised trial of gemcitabine plus cisplatin (GP) and gemcitabine plus carboplatin (GC) in patients (pts) with advanced or metastatic transitional cell carcinoma of the urothelium (TCCU). Proc Am Soc Clin Oncol 2003;22: abstr 1543. http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid= 76f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=23&abstractI D=102093 Bellmunt J, Ribas A, Eres N, Albanell J, Almanza C, Bermejo B, Sole LA, Baselga J. Carboplatinbased versus cisplatin-based chemotherapy in the treatment of surgically incurable advanced bladder carcinoma. Cancer 1997;80(10):1966-72. http://www.ncbi.nlm.nih.gov/pubmed/9366300 Sternberg CN, Calabro F, Pizzocaro G, Marini L, Schnetzer S, Sella A. Chemotherapy with an every2-week regimen of gemcitabine and paclitaxel in patients with transitional cell carcinoma who have received prior cisplatin-based therapy. Cancer 2001;92(12):2993-8. http://www.ncbi.nlm.nih.gov/pubmed/11753976 Meluch AA, Greco FA, Burris HA 3rd, O’Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol 2001;19(12):3018-24. http://www.ncbi.nlm.nih.gov/pubmed/11408496 Parameswaran R, Fisch MJ, Ansari RH, Fox EP, Sweeney CJ, Einhorn LH. A Hoosier Oncology Group phase II study of weekly paclitaxel and gemcitabine in advanced transitional cell (TCC) carcinoma of the bladder. Proc Am Soc Clin Oncol 2001;200:abstr 798. http://www.asco.org/ASCO/Abstracts+&+Virtual+Meeting/Abstracts?&vmview=abst_detail_ view&confID=10&abstractID=798 Guardino AE, Srinivas S. Gemcitabine and paclitaxel as second line chemotherapy for advanced urothelial malignancies. Proc Am Soc Clin Oncol 2002;21: abstr 2413. http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?abstractID= 2413&confID=16&index=y&vmview=abst_detail_view Fechner GH, Siener R, Reimann M et al. Randomized phase II trial of gemcitabine and paclitaxel with or without maintenance treatment in patients with cisplatin refractory transitional cell carcinoma. J Urol 2002;167(Suppl 4):abstr 284.

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Kaufman DS, Carducci MA, Kuzel T, Todd MB, Raghavan D, Oh WK, Smith MR, Nicol SJ, Stadler WW. Gemcitabine (G) and paclitaxel (P) every two weeks (GP2w): a completed multicenter phase II trial in locally advanced or metastatic urothelial cancer (UC). Proc Am Soc Clin Oncol 2002;21: abstr 767. http://www.asco.org/ASCO/Abstracts+&+Virtual+Meeting/Abstracts?&vmview=abst_detail_ view&confID=16&abstractID=767 Nogue-Aliguer M, Carles J, Arrivi A, Juan O, Alonso L, Font A, Mellado B, Garrido P, Saenz A; Spanish Cooperative Group. Gemcitabine and carboplatin in advanced transitional cell carcinoma of the urinary tract: an alternative therapy. Cancer 2003;97(9):2180-6. http://www.ncbi.nlm.nih.gov/pubmed/12712469 Balducci L. Evidence-based management of cancer in the elderly. Cancer Control 2000;7(4):368-76. http://www.ncbi.nlm.nih.gov/pubmed/10895132 Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol 2002;20(4):937-40. http://www.ncbi.nlm.nih.gov/pubmed/11844814 Papamichael D, Gallagher CJ, Oliver RT, Johnson PW, Waxman J. Phase II study of paclitaxel in pretreated patients with locally advanced/metastatic cancer of the bladder and ureter. Br J Cancer 1997;75(4):606-7. http://www.ncbi.nlm.nih.gov/pubmed/9052419 McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, Bajorin DF. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol 1997;15(5):1853-7. http://www.ncbi.nlm.nih.gov/pubmed/9164195 Moore M, Winquist E, Vokes E, Hirte H, Hoving K, Stadler W. Phase II study of oxaliplatin in patients with inoperable, locally advanced or metastatic transitional cell carcinoma of the urothelial tract (TCC) who have received prior chemotherapy. Proc Am Soc Clin Oncol 2003;22: abstr 1638. http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&c onfID=23&abstractID=100319 Witte RS, Manola J, Burch PA, Kuzel T, Weinshel EL, Loehrer PJ Sr. Topotecan in previously treated advanced urothelial carcinoma: an ECOG phase II trial. Invest New Drugs 1998;16(2):191-5. http://www.ncbi.nlm.nih.gov/pubmed/9848585 Petrylak D, Faulkner J, Van Veldhuizen P, Mansukhani M, Crawford E. Evaluation of ZD1839 for advanced transitional cell carcinoma (TCC) of the urothelium: a Southwest Oncology Group Trial. Proc Am Soc Clin Oncol 2003;22: abstr 1619. http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&c onfID=23&abstractID=104215 Sridhar S, Stadler W, Le L, Hedley D, Pond G, Wright J, Vokes E, Thomas S, Moore M. Phase II study of bortezomib in advanced or metastatic urothelial cancer. A trial of the Princess Margaret Hospital [PMH] Phase II Consortium. J Clin Oncol, 2005 ASCO Annual Meeting Proceedings, Vol 23, No 16S Part I of II (June 1 Suppl), 2005:4677. http://prostateca.asco.org/ASCO/Abstracts+&+Virtual+Meeting/Abstracts?&vmview=abst_detail_view &confID=34&abstractID=33648 Wulfing C, Machiels J, Richiels D, Grimm M, Treiber U, de Groot M, Beuzeboc P, Farrel J, Stone NL, Leopold L, El-Hariry I. A single arm, multicenter, open-label, ph II study of lapatinib as 2L treatment of pts with locally advanced/metastatic transitional cell carcinoma (TCC) of the urothelial tract. J Clin Oncol, 2005 ASCO Annual Meeting Proceedings, Vol 23, No 16S, Part I of II (June 1 Suppl) 2005:4594. http://prostateca.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnex toid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=34&abst ractID=31739 Culine S, Theodore C, De Santis M, Bui B, Demkow T, Lorenz J, Rolland F, Delgado FM, Longerey B, James N. A phase II study of vinflunine in bladder cancer patients progressing after first-line platinumcontaining regimen. Br J Cancer 2006;94(10):1395-401. http://www.ncbi.nlm.nih.gov/pubmed/16622447 Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, Curiel RE, Obasaju CK, Wang Y, NicolSJ, Kaufman DS. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol 2006;24(21):3451-7. http://www.ncbi.nlm.nih.gov/pubmed/16849761

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Galsky MD, Mironov S, Iasonos A, Scattergood J, Boyle MG, Bajorin DF. Phase II trial of pemetrexed as second-line therapy in patients with metastatic urothelial carcinoma. Invest New Drugs 2007;25(3):265-70. http://www.ncbi.nlm.nih.gov/pubmed/17146733 Witte RS, Elson P, Bono B, Knop R, Richardson RR, Dreicer R, Loehrer PJ Sr. Eastern Cooperative Oncology Group phase II trial of ifosfamide in the treatment of previously treated advanced urothelial carcinoma. J Clin Oncol 1997;15(2):589-93. http://www.ncbi.nlm.nih.gov/pubmed/9053481 Stadler WM. Gemcitabine doublets in advanced urothelial cancer. Semin Oncol 2002;29(1 Suppl 3):15-9. http://www.ncbi.nlm.nih.gov/pubmed/11894003 Hussain M, Vaishampayan U, Du W, Redman B, Smith DC. Combination paclitaxel, carboplatin, and gemcitabine is an active treatment for advanced urothelial cancer. J Clin Oncol 2001;19(9):2527-33. http://www.ncbi.nlm.nih.gov/pubmed/11331332 Herr HW, Donat SM, Bajorin DF. Post-chemotherapy surgery in patients with unresectable or regionally metastatic bladder cancer. J Urol 2001;165(3):811-4. http://www.ncbi.nlm.nih.gov/pubmed/1117647 Sweeney P, Millikan R, Donat M, Wood CG, Radtke AS, Pettaway CA, Grossman HB, Dinney CP, Swanson DA, Pisters LL. Is there a therapeutic role for post-chemotherapy retroperitoneal lymph node dissection in metastatic transitional cell carcinoma of the bladder? J Urol 2003;169(6):2113-7. http://www.ncbi.nlm.nih.gov/pubmed/12771730 Siefker-Radtke AO, Walsh GL, Pisters LL, Shen Y, Swanson DA, Logothetis CJ, Millikan RE. Is there a role for surgery in the management of metastatic urothelial cancer? The M. D. Anderson experience. J Urol 2004;171(1):145-8. http://www.ncbi.nlm.nih.gov/pubmed/14665863

13. QUALITY OF LIFE The evaluation of health-related quality of life (HRQL) considers physical, emotional and social functioning. Several questionnaires, e.g. FACT (Functional Assessment of Cancer Therapy)-G (1), EORTC QLQ-C30 (1) and SF (Short Form)-36 (3, 4), have been validated for assessing HRQL in patients with bladder cancer. A psychometrical test such as the FACT-BL should be used for recording bladder cancer morbidity. Recently, new intensive interviewing techniques add valuable information to our knowledge of HRQL, which greatly depends on patients’ individual preferences in life (5). Unfortunately, most retrospective studies do not evaluate the association between HRQL and bladder cancer-specific issues after cystectomy, such as incontinence or potency. Furthermore, important co-variables, such as a patient’s age, mental status, coping ability and gender, have only rarely been considered (6). It remains difficult to predict the impact of post-therapeutic symptoms because of individual differences in symptom tolerance. There is controversy about which type of urinary diversion is best for a patient’s quality of life (7). Some studies have not demonstrated any difference (8, 9). As a result of improvement in surgical techniques and orthotopic bladder substitution, some more recent studies are in favour of the continent bladder substitutes (10-17). In one study (17), a statistically significant difference in HRQL in favour of neobladders was observed. Notably, HRQL parameters have been shown to represent an independent prognostic parameter for overall survival (18). Patients with a continent bladder-substitute generally score more favourably than those with an incontinent diversion, as judged by body image, social activity and physical function (11, 16). In non-curative or metastatic bladder cancer, HRQL is reduced because of associated micturition problems, bleeding, pain and therefore disturbance of social and sexual life (19). Relief of bladder-related symptoms can be obtained by palliative surgery (20), radiotherapy (21) and/or chemotherapy (22), though there is limited literature describing HRQL in palliatively treated bladder cancer patients (23). Alternative definitive treatments of muscle-invasive bladder cancer, e.g. trimodality bladder-sparing procedures, have shown similar survival times compared to cystectomy. However, the impact on HRQL has been controversial (24-29).

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13.1 Conclusions • •

There is no randomized prospective HRQL study evaluating different forms of definitive treatment for invasive bladder cancer. The overall HRQL after cystectomy remains good in most patients, whichever type of urinary diversion is used. Some data suggests that continent diversions produce a better HRQL (Level of evidence: 2b).

13.2 Recommendations • •

HRQL in patients with muscle-invasive bladder cancer should be assessed using validated questionnaires (Grade of recommendation: A). Continent urinary diversions should be offered for reasons of HRQL, whenever a patient’s age, personality, coping ability and tumour variables are suitable (Grade of recommendation: C).

13.3

References

1.

Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Bonomi A, Silberman M, Yellen SB, Winicour P, Brannon J et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol 1993;11(3):570-9. http://www.ncbi.nlm.nih.gov/pubmed/8445433 Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85(5):365-76. http://www.ncbi.nlm.nih.gov/pubmed/8433390 Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992;30(6):473-83. http://www.ncbi.nlm.nih.gov/pubmed/1593914 Ware JE Jr, Keller SD, Gandek B, Brazier JE, Sullivan M. Evaluating translations of health status questionnaires. Methods from the IQOLA project. International Quality of Life Assessment. Int J Technol Assess Health Care 1995;11(3):525-51. http://www.ncbi.nlm.nih.gov/pubmed/7591553 Ramirez A, Perrotte P, Valiquette L, Benard F, McCormack M, Saad F, Fournier C, Shariat S, Karakiewicz PI. Exploration of health-related quality of life areas that may distinguish between continent diversion and ileal conduit patients. Can J Urol 2005;12(1):2537-42. http://www.ncbi.nlm.nih.gov/pubmed/15777491 Mansson A, Caruso A, Capovilla E, Colleen S, Bassi P, Pagano F, Mansson W. Quality of life after radical cystectomy and orthotopic bladder substitution: a comparison between Italian and Swedish men. BJU Int 2000;85(1):26-31. http://www.ncbi.nlm.nih.gov/pubmed/10619940 World Health Organization (WHO) Consensus Conference on Bladder Cancer, Hautmann RE, AbolEnein H, Hafez K, Haro I, Mansson W, Mills RD, Montie JD, Sagalowsky AI, Stein JP, Stenzl A, Studer UE, Volkmer BG. Urinary diversion. Urology 2007;69(1 Suppl):17-49. http://www.ncbi.nlm.nih.gov/pubmed/17280907 Mansson A, Davidsson T, Hunt S, Mansson W. The quality of life in men after radical cystectomy with a continent cutaneous diversion or orthotopic bladder substitution: is there a difference?. BJU Int 2002;90(4):386-90. http://www.ncbi.nlm.nih.gov/pubmed/12175394 Wright JL, Porter MP. Quality-of-life assessment in patients with bladder cancer. Nat Clin Pract Urol 2007;4(3):147-54. http://www.ncbi.nlm.nih.gov/pubmed/17347659 van der Veen JH, van Andel G, Kurth KH. Quality-of-life assessment in bladder cancer. World J Urol 1999;17(4):219-24. http://www.ncbi.nlm.nih.gov/pubmed/10460404 Dutta SC, Chang SC, Coffey CS, Smith JA Jr, Jack G, Cookson MS. Health related quality of life assessment after radical cystectomy: comparison of ileal conduit with continent orthotopic neobladder. J Urol 2002;168(1):164-7. http://www.ncbi.nlm.nih.gov/pubmed/12050514 Okada Y, Oishi K, Shichiri Y, Kakehi Y, Hamaguchi A, Tomoyoshi T, Yoshida O. Quality of life survey of urinary diversion patients: comparison of continent urinary diversion versus ileal conduit. Int J Urol 1997;4(1):26-31. http://www.ncbi.nlm.nih.gov/pubmed/9179663

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29.

Gerharz EW, Weingartner K, Dopatka T, Kohl UN, Basler HD, Riedmiller HN. Quality of life after cystectomy and urinary diversion: results of a retrospective interdisciplinary study. J Urol 1997;158(3 Pt 1):778-85. http://www.ncbi.nlm.nih.gov/pubmed/9258080 Hart S, Skinner EC, Meyerowitz BE, Boyd S, Lieskovsky G, Skinner DG. Quality of life after radical cystectomy for bladder cancer in patients with an ileal conduit, cutaneous or urethral kock pouch. J Urol 1999;162(1):77-81. http://www.ncbi.nlm.nih.gov/pubmed/10379744 Hara I, Miyake H, Hara S, Gotoh A, Nakamura I, Okada H, Arakawa S, Kamidono S. Health-related quality of life after radical cystectomy for bladder cancer: a comparison of ileal conduit and orthotopic bladder replacement. BJU Int 2002;89(1):10-13. http://www.ncbi.nlm.nih.gov/pubmed/11849152 Hardt J, Filipas D, Hohenfellner R, Egle UT. Quality of life in patients with bladder carcinoma after cystectomy: first results of a prospective study. Qual Life Res 2000;9(1):1-12. http://www.ncbi.nlm.nih.gov/pubmed/10981202 Hobisch A, Tosun K, Kinzl J, Kemmler G, Bartsch G, Holtl L, Stenzl A. Life after cystectomy and orthotopic neobladder versus ileal conduit urinary diversion. Semin Urol Oncol 2001;19(1):18-23. http://www.ncbi.nlm.nih.gov/pubmed/11246729 Roychowdhury DF, Hayden A, Liepa AM. Health-related quality-of-life parameters as independent prognostic factors in advanced or metastatic bladder cancer. J Clin Oncol 2003;21(4):673-8. http://www.ncbi.nlm.nih.gov/pubmed/12586805 Fossa SD, Aaronson N, Calais da Silva F, Denis L, Newling D, Hosbach G, Kaalhus O. Quality of life in patients with muscle-infiltrating bladder cancer and hormone-resistant prostatic cancer. Eur Urol 1989;16(5):335-9. http://www.ncbi.nlm.nih.gov/pubmed/2476317 Nagele U, Anastasiadis AG, Merseburger AS, Corvin S, Hennenlotter J, Adam M, Sievert KD, Stenzl A, Kuczyk MA. The rationale for radical cystectomy as primary therapy for T4 bladder cancer. World J Urol 2007;25(4):401-5. http://www.ncbi.nlm.nih.gov/pubmed/17525849 Fokdal L, Hoyer M, von der Maase H. Radical radiotherapy for urinary bladder cancer: treatment outcomes. Expert Rev Anticancer Ther 2006;6(2):269-79. http://www.ncbi.nlm.nih.gov/pubmed/17525849 Rodel C, Weiss C and Sauer R. Organ preservation by combined modality treatment in bladder cancer: the European perspective. Semin Radiat Oncol 2005;15(1):28-35. http://www.ncbi.nlm.nih.gov/pubmed/15662604 Mommsen S, Jakobsen A, Sell A. Quality of life in patients with advanced bladder cancer. A randomized study comparing cystectomy and irradiation–the Danish Bladder Cancer Study Group (DAVECA protocol 8201). Scand J Urol Nephrol Suppl 1989;125:115-20. http://www.ncbi.nlm.nih.gov/pubmed/2699072 Rodel C, Grabenbauer GG, Kuhn R, Papadopoulos T, Dunst J, Meyer M, Schrott KM, Sauer R. Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results. J Clin Oncol 2002;20:3061-71. http://www.ncbi.nlm.nih.gov/pubmed/12118019 Merseburger AS, Kuczyk MA. The value of bladder-conserving strategies in muscle-invasive bladder carcinoma compared with radical surgery. Curr Opin Urol 2007;17(5):358-62. http://www.ncbi.nlm.nih.gov/pubmed/17762631 Milosevic M, Gospodarowicz M, Zietman A, Abbas F, Haustermans K, Moonen L, Rodel C, Schoenberg M, Shipley W. Radiotherapy for bladder cancer. Urology 2007;69(1 Suppl):80-92. http://www.ncbi.nlm.nih.gov/pubmed/17280910 Rodel C, Weiss C, Sauer R. Trimodality treatment and selective organ preservation for bladder cancer. J Clin Oncol 2006;24(35):5536-44. http://www.ncbi.nlm.nih.gov/pubmed/17158539 Zietman AL, Shipley WU, Kaufman DS. Organ-conserving approaches to muscle-invasive bladder cancer: future alternatives to radical cystectomy. Ann Med 2000;32(1):34-42. http://www.ncbi.nlm.nih.gov/pubmed/10711576 Lodde M, Palermo S, Comploj E, Signorello D, Mian C, Lusuardi L, Longhi E, Zanon P, Mian M, Pycha A. Four years experience in bladder preserving management for muscle invasive bladder cancer. Eur Urol 2005;47(6):773-8; discussion 778-9. http://www.ncbi.nlm.nih.gov/pubmed/15925072

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14. FOLLOW-UP An appropriate schedule for disease monitoring should be based on: • natural timing of recurrence • probability of disease recurrence • functional deterioration at particular sites • possibilities of treatment of a recurrence (1). Contemporary cystectomy series demonstrate a 5-15% chance of pelvic recurrence. Most recurrences manifest during the first 24 months, with many occurring within 6-18 months after surgery. However, there have been late recurrences up to 5 years after cystectomy. Variables associated with the development of a pelvic recurrence include the pathological stage (of the primary tumour) and lymph node status. Patients have a poor prognosis after pelvic recurrence; the median survival ranges from 4-8 months following diagnosis, despite treatment. Definitive therapy can sometimes provide a prolonged survival, but provides significant palliation of symptoms in most cases. Treatment is systemic chemotherapy, local surgery or radiotherapy. Distant recurrences are seen in up to 50% of patients treated with cystectomy. Most recurrences occur in the first 24 months, although progression has been observed after more than 10 years. Again, pathological stage of the primary tumour and nodal status are risk factors. The most likely sites for distant recurrences are the lungs, liver and bones (2). Upper urinary tract recurrence is rarely seen (2-7%), but when it develops, it usually does so within 22-40 months after cystectomy (1-4). Surveillance regimens often fail to detect tumours before symptoms develop. However, radical nephroureterectomy can provide prolonged survival (3). The incidence of secondary urethral tumour is 5-17% and is particularly likely to occur at 1-3 years after surgery. Prophylactic urethrectomy at the time of cystectomy is no longer justified in most patients. In men, the most important risk factor for the development of urethral recurrence is prostatic stromal invasion (21-64%) (5-7). In women, the risk factor is disease at the bladder neck (8). Multiple studies demonstrate that the risk of urethral recurrence after orthotopic diversion (0.9-4%) (5, 9-11) is significantly less than after nonorthotopic diversion (6.4-11.1%) (5,10). There is little data and agreement about the follow-up of the urethra. Some authors recommend routine surveillance urethral wash cytology and UCS (9), while others question the need for routine urethral surveillance (9, 12-14). Urethral washes and urine cytology do not appear to have any effect on survival (12, 15, 16). Treatment is influenced by the local stage and grade of a urethral occurrence: • In CIS in the urethra, BCG instillations have shown success rates of 83% (11). • In invasive disease, urethrectomy should be performed if the urethra is the only site of disease. • In distant disease, systemic chemotherapy is indicated (2).

14.1

Conclusions and recommendations according to condition

Condition Conclusion or recommendation Level of evidence or grade of recommendation Secondary Staging and treatment should be done as for primary 3 urethral tumour urethral tumour For non-invasive tumour, local organ conservative C treatment is advised In isolated invasive disease, a urethrectomy should B be performed Urethral washes and cytology are not recommended A for follow-up Pelvic recurrence The prognosis is poor 2b Treatment should be individualized depending on the local extent and symptoms Radiotherapy, chemotherapy and possibly surgery are C options for treatment, either alone or in combination Upper urinary tract Specific upper urinary tract imaging is only indicated in B recurrence case of clinical symptoms; radical nephroureterectomy can provide prolonged survival

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14.2

General recommendations for follow-up

This advice for follow-up is entirely based on expert opinion. General remarks are that follow up should be dependent on the stage of the initial tumour after cystectomy. This means that the higher the initial tumour stage, the larger the chance for subsequent tumour recurrence. A higher follow-up frequency will therefore result in identifying more recurrences. Non-oncological follow-up, for example monitoring of kidney function, seems indicated life long. After 5 years of follow-up, oncological surveillance may be stopped to be continued by functional surveillance. At every visit, the following should be performed: • History • Physical examination • Bone scan only when indicated.

14.3

References

1.

Malkowicz SB, van Poppel H, Mickisch G, Pansadoro V, Thuroff J, Soloway MS, Chang S, Benson M, Fukui I. Muscle-invasive urothelial carcinoma of the bladder. Urology 2007;69(1 Suppl):3-16. http://www.ncbi.nlm.nih.gov/pubmed/17280906 Bochner BH, Montie JE, Lee CT. Follow-up strategies and management of recurrence in urologic oncology bladder cancer: invasive bladder cancer. Urol Clin North Am 2003;30(4):777-89. http://www.ncbi.nlm.nih.gov/pubmed/14680314 Sanderson KM, Cai J, Miranda G, Skinner DG, Stein JP. Upper tract urothelial recurrence following radical cystectomy for transitional cell carcinoma of the bladder: an analysis of 1,069 patients with 10-year followup. J Urol 2007;177:2088-94. http://www.ncbi.nlm.nih.gov/pubmed/17509294 Stenzl A, Bartsch G, Rogatsch H. The remnant urothelium after reconstructive bladder surgery. Eur Urol 2002;41(2):124-31. http://www.ncbi.nlm.nih.gov/pubmed/12074398 Freeman JA, Tarter TA, Esrig D, Stein JP, Elmajian DA, Chen SC, Groshen S, Lieskovsky G, Skinner DG. Urethral recurrence in patients with orthotopic ileal neobladders. J Urol 1996;156(5):1615-9. http://www.ncbi.nlm.nih.gov/pubmed/8863551 Hardeman SW, Soloway MS. Urethral recurrence following radical cystectomy. J Urol 1990;144(3):666-9. http://www.ncbi.nlm.nih.gov/pubmed/2388323 Levinson AK, Johnson DE, Wishnow KI. Indications for urethrectomy in an era of continent urinary diversion. J Urol 1990;144(1):73-5. http://www.ncbi.nlm.nih.gov/pubmed/2359182 Stenzl A, Draxl H, Posch B, Colleselli K, Falk M, Bartsch G. The risk of urethral tumors in female bladder cancer: can the urethra be used for orthotopic reconstruction of the lower urinary tract? J Urol 1995;153(3 Pt 2):950-5. http://www.ncbi.nlm.nih.gov/pubmed/7853581 Huguet J, Palou J, Serrallach M, Sole Balcells FJ, Salvador J, Villavicencio H. Management of urethral recurrence in patients with Studer ileal neobladder. Eur Urol 2003;43(5):495-8. http://www.ncbi.nlm.nih.gov/pubmed/12705993 Nieder AM, Sved PD, Gomez P, Kim SS, Manoharan M, Soloway MS. Urethral recurrence after cystoprostatectomy: implications for urinary diversion and monitoring. Urology 2004;64(5):950-4. http://www.ncbi.nlm.nih.gov/pubmed/15533484 Varol C, Thalmann GN, Burkhard FC, Studer UE. Treatment of urethral recurrence following radical cystectomy and ileal bladder substitution. J Urol 2004;172(3):937-42. http://www.ncbi.nlm.nih.gov/pubmed/15311003 Lin DW, Herr HW, Dalbagni G. Value of urethral wash cytology in the retained male urethra after radical cystoprostatectomy. J Urol 2003;169(3):961-3. http://www.ncbi.nlm.nih.gov/pubmed/12576822 Sherwood JB, Sagalowsky AI. The diagnosis and treatment of urethral recurrence after radical cystectomy. Urol Oncol 2006;24(4):356-61. http://www.ncbi.nlm.nih.gov/pubmed/16818191 Slaton JW, Swanson DA, Grossman HB, Dinney CP. A stage specific approach to tumor surveillance after radical cystectomy for transitional cell carcinoma of the bladder. J Urol 1999;162(3 Pt 1):710-4. http://www.ncbi.nlm.nih.gov/pubmed/10458349

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

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15.

16.

52

Erckert M, Stenzl A, Falk M, Bartsch G. Incidence of urethral tumor involvement in 910 men with bladder cancer. World J Urol 1996;14(1):3-8. http://www.ncbi.nlm.nih.gov/pubmed/8646239 Clark PE, Stein JP, Groshen SG, Miranda G, Cai J, Lieskovsky G, Skinner DG. The management of urethral transitional cell carcinoma after radical cystectomy for invasive bladder cancer. J Urol 2004;172(4 Pt 1):1342-7. http://www.ncbi.nlm.nih.gov/pubmed/15371837

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15. ABBREVIATIONS USED IN THE TEXT

This list is not comprehensive for the most common abbreviations

ARCO ARCON ASCO 5-ALA BC BCG CI CIS CISCA CM CMV CT EAU EBRT ECOG EORTC FACT 5-FU GC GFR GCSF HAL HD-MVAC HRQL IARC IPD ISUP IVU MCV MDCT MiM-BC MRC MR(I) MVAC MVA(E)C NAT OS PAHs PCR PET PS PUNLMP R-biopsies SF-36 SWOG TCC TNM TUR TURBT UICC UC US UUT WHO

accelerated radiotherapy with carbogen accelerated radiotherapy with carbogen nicotinamide American Society of Clinical Oncology 5-aminolaevulinic acid bladder cancer Bacille Calmette-Guérin confidence interval carcinoma in situ cisplatin, cyclophosphamide plus adriamycin cisplatin, methotrexate cisplatin, methotrexate plus vinblastine computed tomography European Association of Urology external beam radiation therapy Eastern Cooperative Oncology Group European Organization for Research and Treatment of Cancer Functional Assessment of Cancer Therapy 5-Fluorouracil gemcitabine plus cisplatin glomerular filtration rate granulocyte colony stimulating factor hexaminolaevulinate high-dose methotrexate, vinblastine, adriamycin plus cisplatin health-related quality of life International Agency for Research on Cancer independent patient data International Society of Urological Pathology Intravenous urography methrotrexate, cisplatin and vinblastine multidetector-row CT Muscle-invasive and metastatic bladder cancer Medical Research Council (UK) magnetic resonance (imaging) methotrexate, vinblastine, adriamycin plus cisplatin methotrexate, vinblastine, adriamycine or epirubicine, and cisplatin N-acetyltransferase overall survival polycyclic aromatic hydrocarbons pathological complete remission positron emission tomography performance status papillary urothelial neoplasms of low malignant potential random biopsies Short Form-36 Southwest Oncology Group transitional cell carcinoma Tumour, Node, Metastases transurethral resection transurethral resection of bladder tumour Union International Contre le Cancer urethrocystoscopy ultrasonography upper urinary tract World Health Organization

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Conflict of interest All members of the Muscle-Invasive and Metastatic Bladder Cancer guidelines writing panel have provided disclosure statements of all relationships which they have and which may be perceived as a potential source of conflict of interest. This information is kept on file in the European Association of Urology Central Office database. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

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Guidelines on

Prostate Cancer A. Heidenreich (chairman), M. Bolla, S. Joniau, T.H. van der Kwast, V. Matveev, M.D. Mason, N. Mottet, H-P. Schmid, T. Wiegel, F. Zattoni

© European Association of Urology 2009

TABLE OF CONTENTS

page

1

BACKGROUND 1.1 Reference

7 7

2.

BACKGROUND 2.1 References

8 8

3.

CLASSIFICATION 3.1 Gleason score 3.2 References

8 9 9

4.

RISK FACTORS 4.1 References

9 10

5.

SCREENING AND EARLY DETECTION 5.1 References

10 11

6. DIAGNOSIS 6.1 Digital rectal examination (DRE) 6.2 Prostate specific antigen (PSA) 6.2.1 Free/total PSA ratio (f/t PSA) 6.2.2 PSA velocity (PSAV), PSA doubling time (PSADT) 6.2.3 PCA3 marker 6.3 Transrectal ultrasonography (TRUS) 6.4 Prostate biopsy 6.4.1 Baseline biopsy 6.4.2 Repeat biopsy 6.4.3 Saturation biopsy 6.4.4 Sampling sites and number of cores 6.4.5 Diagnostic transurethral resection of the prostate (TURP) 6.4.6 Seminal vesicle biopsy 6.4.7 Transition zone biopsy 6.4.8 Antibiotics 6.4.9 Local anaesthesia 6.4.10 Fine-needle aspiration biopsy 6.4.11 Complications 6.5 Pathology of prostate needle biopsies 6.5.1 Grossing and processing 6.5.2 Microscopy and reporting 6.6 Pathohistology of radical prostatectomy (RP) specimens 6.6.1 Processing of the RP specimen 6.6.2 RP specimen report 6.6.2.1 Gleason score 6.6.2.2 Interpreting the Gleason score 6.6.2.3 Definition of extraprostatic extension 6.6.3 Prostate cancer volume 6.6.4 Surginal margin status 6.6.5 Other factors 6.7 References

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7.

24 24 26 27 28 28

2

STAGING 7.1 T-staging 7.2 N-staging 7.3 M-staging 7.4 Guidelines for the staging of prostate cancer (PCa) 7.5 References

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8. TREATMENT: DEFERRED TREATMENT (WATCHFUL WAITING [WW] / ACTIVE MONITORING 8.1 Introduction 8.1.1 Definition 8.2 Deferred treatment of localised PCa (stage T1-T2, Nx-N0, M0) 8.2.1 Watchful waiting (WW) 8.2.2 Active surveillance 8.3 Deferred treatment for locally advanced PCa (stage T3-T4, Nx-N0, M0) 8.4 Deferred treatment for metastatic PCa (stage M1) 8.5 Summary of deferred treatment 8.5.1 Indications 8.5.2 Options 8.6 References

33 33 33 34 34 36 37 38 38 38 38 39

9. TREATMENT: RADICAL PROSTATECTOMY 9.1 Introduction 9.2 Low-risk localised PCa: cT1-T2a AND Gleason score 2-6 and PSA < 10 9.2.1 Stage T1a-T1b PCa 9.2.2 Stage T1c and T2a PCa 9.3 Intermediate-risk localised PCa: cT2b-T2c OR Gleason score = 7 or PSA 10-20 9.3.1 Oncological results of RP in low- and intermediate risk PCa 9.4 High-risk localised PCa: cT3a OR Gleason score 8-10 or PSA > 20 9.4.1 Locally-advanced PCa: cT3a 9.4.2 High-grade PCa: Gleason score 8-10 9.4.3 PCa with PSA > 20 9.5 Very high-risk localised PCa: cT3b-T4 N0 or any T, N1 9.5.1 cT3b-T4 N0 9.5.2 Any T, N1 9.5.2.1 Indication and extent of extended pelvic lymph node dissection (eLND) 9.5.2.2 Therapeutic role of eLND 9.5.2.3 Morbidity 9.5.2.4 Summary of eLND 9.6 Summary of RP in high-risk localised disease 9.7 Neoadjuvant hormonal therapy and RP 9.7.1 Summary of neoadjuvant and adjuvant hormonal treatment and RP 9.8 Complications and functional outcome 9.9 Summary of indications for nerve-sparing surgery 9.10 Guidelines and recommendations for RP 9.11 References

42 42 43 43 43 43 44 44 44 45 45 46 46 46 46 47 47 47 47 47 48 48 48 49 49

10. TREATMENT: DEFINITIVE RADIATION THERAPY 10.1 Introduction 10.2 Technical aspects: three dimensional conformal radiotherapy and intensity modulated external beam radiotherapy 10.3 Localised prostate cancer T1-2c N0, M0 10.3.1 T1a-T2a, N0, M0 and Gleason score ≤ 6 and PSA < 10 ng/mL (low-risk group) 10.3.2 T2b or PSA 10-20 ng/mL, or Gleason score 7 (intermediate-risk group) 10.3.3 T2c or Gleason score > 7 or PSA > 20 ng/mL (high-risk group) 10.3.4 Prophylactic irradiation of pelvic lymph nodes in high-risk localised prostate cancer 10.4 Innovative techniques 10.4.1 Intensity modulated radiotherapy 10.4.2 Proton beam and carbon ion beam therapy 10.5 Transperineal brachytherapy 10.6 Late toxicity 10.7 Immediate post-operative external irradiation for pathological tumour stage T3 N0 M0 10.8 Locally advanced prostate cancer: T3-4 N0, M0 10.8.1 Neoadjuvant and concomitant hormonal therapy 10.8.2 Concomitant and long-term adjuvant hormonal therapy 10.8.3 Long-term adjuvant hormonal therapy 10.8.4 Neoadjuvant, concomitant and long-term adjuvant hormonal therapy

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56 56 56 57 57 57 58 58 58 59 60 61 62 62 62 63 63

3

10.9 10.10 10.11

10.8.5 Short-term or long-term adjuvant hormonal treatment 10.8.6 Dose escalation with hormonal therapy Very high-risk prostate cancer: c or pN1 M0 Summary of definitive radiation therapy References

63 63 63 64 64

11. EXPERIMENTAL LOCAL TREATMENT OF PROSTATE CANCER 11.1 Background 11.2 Cryosurgery of the prostate (CSAP) 11.2.1 Indication for CSAP 11.2.2 Results of modern cryosurgery for PCa 11.2.3 Complications of CSAP for primary treatment of PCa 11.2.4 Summary of CSAP 11.3 High-intensity focused ultrasound (HIFU) of the prostate 11.3.1 Results of HIFU in PCa 11.3.2 Complications of HIFU 11.4 Radiofrequency interstitial tumour ablation (RITA) 11.5 Summary of experimental therapeutic options to treat clinically localized PCa 11.6 References

70 70 70 71 71 71 72 72 72 73 73 73 73

12. HORMONAL THERAPY 12.1 Introduction 12.2 Basics of hormonal control of the prostate 12.3 Different types of hormonal therapy 12.3.1 Testosterone-lowering therapy (castration) 12.3.1.1 Bilateral orchiectomy 12.3.1.2 Oestrogens 12.3.1.3 LHRH agonists 12.3.1.4 LHRH antagonists 12.3.2 Anti-androgens 12.3.2.1 Steroidal anti-androgens Cyproterone acetate (CPA) Megestrol acetate and medroxyprogesterone acetate 12.3.2.2 Non-steroidal anti-androgens Nilutamide Flutamide Bicalutamide 12.3.3 Combination therapies 12.3.3.1 Complete androgen blockade 12.3.3.2 Minimal androgen blockade (or peripheral androgen blockade) 12.3.3.3 Intermittent vs continuous androgen deprivation therapy 12.3.3.4 Immediate vs deferred ADT 12.4 Indications for hormonal therapy 12.5 Contraindications for various therapies 12.6 Outcome 12.7 Side-effects, QoL and cost of hormonal therapy 12.7.1 Side-effects 12.7.2 Quality of Life (QoL) 12.7.3 Cost-effectiveness of hormonal therapy options 12.8 Summary of hormonal therapy 12.9 References

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SUMMARY OF GUIDELINES ON PRIMARY TREATMENT OF PCa

14 FOLLOW-UP: AFTER PRIMARY TREATMENT WITH CURATIVE INTENT 14.1 Definition 14.2 Why follow-up? 14.3 How to follow-up? 14.3.1 PSA monitoring 14.3.2 Definition of PSA progression

4

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14.4 14.5 14.6

14.3.3 PSA monitoring after radical prostatectomy 14.3.4 PSA monitoring after radiation therapy 14.3.5 Digital rectal examination (DRE) 14.3.6 Transrectal ultrasonography (TRUS) and biopsy 14.3.7 Bone scintigraphy 14.3.8 Computed tomography (CT) and magnetic resonance imaging (MRI) When to follow-up? Guidelines for follow-up after treatment with curative intent References

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15. FOLLOW-UP AFTER HORMONAL TREATMENT 15.1 Introduction 15.2 Purpose of follow-up 15.3 Methods of follow-up 15.3.1 Prostate-specific antigen monitoring 15.3.2 Creatinine, haemoglobin and liver function monitoring 15.3.3 Bone scan, ultrasound and chest X-ray 15.4 When to follow-up 15.4.1 Stage M0 patients 15.4.2 Stage M1 patients 15.4.3 Hormone-refractory patients 15.5 Guidelines for follow-up after hormonal treatment 15.6 References

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16. TREATMENT OF BIOCHEMICAL FAILURE AFTER TRATMENT WITH CURATIVE INTENT 16.1 Background 16.2 Definitions 16.2.1 Definition of treatment failure 16.2.2 Definition of recurrence 16.3 Local or systemic relapse 16.3.1 Definition of local and systemic failure 16.4 Evaluation of PSA progression 16.5 Diagnostic procedures in patients with PSA relapse 16.6 Treatment of PSA-only recurrences 16.6.1 Radiation therapy for PSA-only recurrence after radical prostatectomy (RP) 16.6.2 Hormonal therapy 16.6.3 Observation 16.6.4 Management of PSA relapse after radical prostatectomy 16.7 Management of PSA failures after radiation therapy 16.7.1 Salvage cryosurgical ablation of the prostate (CSAP) for radiation failures 16.7.2 Salvage brachytherapy for radiation failures 16.7.3 Observation 16.7.4 Management of PSA-relapse after radiation therapy 16.8 Guidelines for second-line therapy after treatment with curative intent 16.9 References

106 106 106 106 106 106 107 108 109 109 109 110 111 111 111 112 112 112 113 113 113

17. HORMONE REFACTORY PROSTATE CANCER (HRPC) 17.1 Background 17.2 Definition of HRPC 17.3 Assessing treatment outcome in androgen-independent PCa 17.3.1 PSA level as marker of response 17.3.2 Other parameters 17.3.3 Trial end-points 17.4 Recommendations for assessing therapeutic response 17.5 Androgen deprivation in androgen-independent PCa 17.6 Secondary hormonal therapy 17.7 Anti-androgen withdrawal syndrome 17.8 Treatment alternatives after initial hormonal therapy 17.8.1 Bicalutamide 17.8.2 Switching to an alternative anti-androgen therapy

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17.8.3 Anti-androgen withdrawal accompanied by simultaneous ketoconazole 17.8.4 Oestogens 17.9 Non-hormonal therapy (cytotoxic agents) 17.9.1 Timing of chemotherapy in metastatic HRPC Taxanes in combination therapy Mitroxantrone combined with corticosteroids Alternative combination treatment approaches Estramustine in combination therapies Oral cyclophosphamide Suramin Salvage chemotherapy 17.10 Palliative therapeutic options 17.10.1 Painful bone metastases 17.10.2 Common complications due to bone mestatases 17.10.3 Bisphosphonates 17.11 Summary of treatment after hormonal therapy 17.12 Guidelines and recommendations for cytotoxic therapy in HRPC 17.13 Guidelines for palliative management of HRPC 17.14 Recommendations for palliative management of HRPC 17.15 References

122 122 123 123 123 124 124 124 124 124 124 125 125 125 125 126 126 126 126 126

18.

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ABBREVIATIONS USED IN THE TEXT

Update march 2009

1. BACKGROUND The European Association of Urology (EAU) Guidelines Group for Prostate Cancer have prepared this guidelines document to assist medical professionals assess the evidence-based management of prostate cancer. The multidisciplinary panel of experts include urologists, radiation oncologists, a medical oncologist and a pathologist.   The recommendations provided in the current guidelines are based on a systemic literature search using Medline, the Cochrane Central Register of Controlled Trials, and reference lists in publications and review articles. Where possible a level of evidence (LE) and/or grade of recommendation (GR) have been assigned (1). Recommendations are graded in order to provide transparency between the underlying evidence and the recommendation given (Tables 1 and 2). Prior to publication external review has taken place. It has to be emphasised that the current guidelines contain information for the treatment of an individual patient according to a standardised general approach. Publication history information: The Prostate Cancer Guidelines were first published in 2001, with partial updates in 2003 and 2007, followed by the current full text update. But for one section (Chapter 14), all topics have been revised. Additionally, a quick reference guide is available. All texts can be viewed and downloaded for personal use at the society website: http://www.uroweb.org/professional-resources/guidelines/. Table 1: Level of evidence Level Type of evidence 1a Evidence obtained from meta-analysis of randomised trials 1b Evidence obtained from at least one randomised trial 2a Evidence obtained from one well-designed controlled study without randomisation 2b Evidence obtained from at least one other type of well-designed quasi-experimental study 3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case reports 4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities Modified from Sackett et al. (1). Table 2: Grade of recommendation Grade Nature of recommendations A Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomised trial B Based on well-conducted clinical studies, but without randomised clinical trials C Made despite the absence of directly applicable clinical studies of good quality Modified from Sackett et al. (1).

1.1

REFERENCE

1.

Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998.  http://www.cebm.net/index.aspx?o=1025 [accessed February 2009].

   

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2. BACKGROUND Cancer of the prostate (PCa) is now recognized as one of the most important medical problems facing the male population. In Europe, PCa is the most common solid neoplasm, with an incidence rate of 214 cases per 1000 men, outnumbering lung and colorectal cancer (1). Furthermore, PCa is currently the second most common cause of cancer death in men (2). In addition, since 1985, there has been a slight increase in most countries in the number of deaths from PCa, even in countries or regions where PCa is not common (3). Prostate cancer affects elderly men more often than young men. It is therefore a bigger health concern in developed countries with their greater proportion of elderly men. Thus, about 15% of male cancers are PCa in developed countries compared to 4% of male cancers in undeveloped countries (4). It is worth mentioning that there are large regional differences in incidence rates of PCa. For example, in Sweden, where there is a long life expectancy and mortality from smoking-related diseases is relatively modest, PCa is the most common malignancy in males, accounting for 37% of all new cases of cancer in 2004 (5).

2.1

REFERENCES

1.

Boyle P, Ferlay J. Cancer incidence and mortality in Europe 2004. Ann Oncol 2005;16(3):481-8. http://www.ncbi.nlm.nih.gov/pubmed/15718248 Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. CA Cancer J Clin 2008;58(2):71-96. http://www.ncbi.nlm.nih.gov/pubmed/18287387 Quinn M, Babb P. Patterns and trends in prostate cancer incidence, survival, prevalence and mortality. Part I: international comparisons. BJU Int 2002;90(2):162-73. http://www.ncbi.nlm.nih.gov/pubmed/12081758 Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000: the global picture. Eur J Cancer 2001;37(Suppl 8):S4-66. http://www.ncbi.nlm.nih.gov/pubmed/11602373 Cancer incidence in Sweden 2004. The National Board of Health and Welfare: Stockholm, 2005. http://www.socialstyrelsen.se/NR/rdonlyres/A23BCC9E-23B5-4747AAA923BB9CDF4B75/4753/20054291.pdf

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3. CLASSIFICATION The 2002 TNM (Tumour Node Metastasis) classification for PCa is shown in Table 3 (1). The new TNM system is due to be published early in 2009, but was not yet available for citation. Table 3: Tumour Node Metastasis (TNM) classification of PCa*. T - Primary tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour T1 Clinically inapparent tumour not palpable or visible by imaging T1a Tumour incidental histological finding in 5% or less of tissue resected T1b Tumour incidental histological finding in more than 5% of tissue resected T1c Tumour identified by needle biopsy (e.g. because of elevated prostate-specific antigen [PSA] level) T2 Tumour confined within the prostate1 T2a Tumour involves one half of one lobe or less T2b Tumour involves more than half of one lobe, but not both lobes T2c Tumour involves both lobes T3 Tumour extends through the prostatic capsule2 T3a Extracapsular extension (unilateral or bilateral) T3b Tumour invades seminal vesicle(s) T4 Tumour is fixed or invades adjacent structures other than seminal vesicles: bladder neck, external sphincter, rectum, levator muscles, or pelvic wall N - Regional lymph nodes3 NX Regional lymph nodes cannot be assessed

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N0 No regional lymph node metastasis N1 Regional lymph node metastasis M - Distant metastasis4 MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis M1a Non-regional lymph node(s) M1b Bone(s) M1c Other site(s) 1

 umour found in one or both lobes by needle biopsy, but not palpable or visible by imaging, is classified as T1c. T Invasion into the prostatic apex, or into (but not beyond) the prostate capsule, is not classified as T3, but as T2. 3 Metastasis no larger than 0.2 cm can be designated pN1mi. 4 When more than one site of metastasis is present, the most advanced category should be used. 2

*At the time of the publication of this document the updated TNM system was not yet available for citation.

3.1 Gleason score The Gleason score is the most commonly used system for grading adenocarcinoma of the prostate (2). The Gleason score can only be assessed using biopsy material (core biopsy or operative specimens). Cytological preparations cannot be used. The Gleason score is the sum of the two most common patterns (grades 1-5) of tumour growth found. The Gleason score ranges between 2 and 10, with 2 being the least aggressive and 10 the most aggressive. In needle biopsy, it is recommended that the worst grade always should be included, even if it is present in < 5% of biopsy material (3).

3.2

REFERENCES

1.

Sobin LH and Wittekind Ch (eds). TNM Classification of Malignant Tumours. 6th edn. Wiley-Liss: New York, 2002. http://www.wiley.com/WileyCDA/WileyTitle/productCd-0471222887.html Gleason DF, Mellinger GT. Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J Urol 1974;111(1):58-64. http://www.ncbi.nlm.nih.gov/pubmed/4813554 Amin M, Boccon-Gibod L, Egevad L, Epstein JI, Humphrey PA, Mikuz G, Newling D, Nilsson S, Sakr W, Srigley JR, Wheeler TM, Montironi R. Prognostic and predictive factors and reporting of prostate carcinoma in prostate needle biopsy specimens. Scand J Urol Nephrol 2005 (Suppl);216:20-33. http://www.ncbi.nlm.nih.gov/pubmed/16019757

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4. RISK FACTORS The factors that determine the risk of developing clinical PCa are not well known, although a few have been identified. There are three well-established risk factors for PCa: increasing age, ethnical origin and heredity. If one first-line relative has PCa, the risk is at least doubled. If two or more first-line relatives are affected, the risk increases 5- to 11-fold (1, 2). A small subpopulation of individuals with PCa (about 9%) has true hereditary PCa. This is defined as three or more affected relatives or at least two relatives who have developed earlyonset disease, i.e. before age 55 (3). Patients with hereditary PCa usually have an onset 6-7 years prior to spontaneous cases, but do not differ in other ways (4). The frequency of autopsy-detected cancers is roughly the same in different parts of the world (5). This finding is in sharp contrast to the incidence of clinical PCa, which differs widely between different geographical areas, being high in the USA and Northern Europe and low in Southeast Asia (6). However, if Japanese men move from Japan to Hawaii, their risk of PCa increases; if they move to California their risk increases even more, approaching that of American men (7) (level of evidence: 2). These findings indicate that exogenous factors affect the risk of progression from so-called latent PCa to clinical PCa. Factors such as food consumption, pattern of sexual behaviour, alcohol consumption, exposure to ultraviolet radiation and occupational exposure have all been discussed as being of aetiological importance (8). Prostate cancer is an ideal candidate for exogenous preventive measures, such as dietary and pharmacological prevention, due to some specific features: high prevalence, long latency, endocrine dependency, availability of serum markers (PSA) and histological precursor lesions (PIN). Dietary/nutritional

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factors that may influence disease development include total energy intake (as reflected by body mass index), dietary fat, cooked meat, micronutrients and vitamins (carotenoids, retinoids, vitamins C, D, and E), fruit and vegetable intake, minerals (calcium, selenium), and phyto-oestrogens (isoflavonoids, flavonoids, lignans). Since most studies reported to date are case-control analyses, there remain more questions than evidence-based data available to answer them. Several ongoing large randomised trials are trying to clarify the role of such risk factors and the potential for successful prostate cancer prevention (9). In summary, hereditary factors are important in determining the risk of developing clinical PCa, while exogenous factors may have an important impact on this risk. The key question is whether there is enough evidence to recommend lifestyle changes (lowered intake of animal fat and increased intake of fruit, cereals and vegetables) in order to decrease the risk (10). There is some evidence to support such a recommendation and this information can be given to male relatives of PCa patients who ask about the impact of diet (level of evidence: 2-3).

4.1

REFERENCES

1.

Steinberg GD, Carter BS, Beaty TH, Childs B, Walsh PC. Family history and the risk of prostate cancer. Prostate 1990;17(4):337-47. http://www.ncbi.nlm.nih.gov/pubmed/2251225 Gronberg H, Damber L, Damber JE. Familial prostate cancer in Sweden. A nationwide register cohort study. Cancer 1996;77(1):138-43. http://www.ncbi.nlm.nih.gov/pubmed/8630920 Carter BS, Beaty TH, Steinberg GD, Childs B, Walsh PC. Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci USA 1992;89(8):3367-71. http://www.ncbi.nlm.nih.gov/pubmed/1565627 Bratt O. Hereditary prostate cancer: clinical aspects. J Urol 2002;168(3):906-13. http://www.ncbi.nlm.nih.gov/pubmed/12187189 Breslow N, Chan CW, Dhom G, Drury RAB, Franks LM, Gellei B, Lee YS, Lundberg S, Sparke B, Sternby NH, Tulinius H. Latent carcinoma of prostate at autopsy in seven areas. The International Agency for Research on Cancer, Lyons, France. Int J Cancer 1977;20(5):680-8. http://www.ncbi.nlm.nih.gov/pubmed/924691 Quinn M, Babb P. Patterns and trends in prostate cancer incidence, survival, prevalence and mortality. Part I: international comparisons. BJU Int 2002;90(2):162-73. http://www.ncbi.nlm.nih.gov/pubmed/12081758 Zaridze DG, Boyle P, Smans M. International trends in prostatic cancer. Int J Cancer 1984;33(2): 223-30. http://www.ncbi.nlm.nih.gov/pubmed/6693200 Kolonel LN, Altshuler D, Henderson BE. The multiethnic cohort study: exploring genes, lifestyle and cancer risk. Nat Rev Cancer 2004;4(7):519-27. http://www.ncbi.nlm.nih.gov/pubmed/15229477 Schmid H-P, Engeler DS, Pummer K, Schmitz-Dräger B J. Prevention of prostate cancer: more questions than data. Cancer Prevention. Recent Results Cancer Res 2007;174:101-7. http://www.ncbi.nlm.nih.gov/pubmed/17302190 Schulman CC, Zlotta AR, Denis L, Schroder FH, Sakr WA. Prevention of prostate cancer. Scand J Urol Nephrol 2000;205(Suppl):50-61. http://www.ncbi.nlm.nih.gov/pubmed/11144904

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5. SCREENING AND EARLY DETECTION Population or mass screening is defined as the examination of asymptomatic men (at risk). It usually takes place as part of a trial or study and is initiated by the screener. In contrast, early detection or opportunistic screening comprises individual case findings, which are initiated by the person being screened (patient) and/or his physician. The primary endpoint of both types of screening has two aspects: 1. Reduction in mortality from PCa. The goal is not to detect more and more carcinomas, nor is survival the endpoint because survival is strongly influenced by lead-time from diagnosis. 2. The quality of life is important as expressed by quality-of-life adjusted gain in life years (QUALYs). Prostate cancer mortality trends range widely from country to country in the industrialised world (1). Decreased mortality rates due to PCa have occurred in the USA, Austria, UK and France, while in Sweden, 10

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the 5-year survival rate has increased from 1960 to 1988, probably due to increased diagnostic activity and greater detection of non-lethal tumours (2). However, this trend was not confirmed in a similar study from the Netherlands (3). The reduced mortality seen recently in the USA is often attributed to the widely adopted aggressive screening policy, but there is still no absolute proof prostate-specific antigen (PSA) screening reduces mortality due to PCa (4) (level of evidence: 2). A non-randomised screening project in Tyrol (Austria) may support the hypothesis that screening can be effective in reducing mortality from PCa. An early detection programme and free treatment have been used to explain the 33% decrease in the PCa mortality rate seen in Tyrol compared to the rest of Austria (5) (level of evidence: 2b). In addition, a Canadian study has claimed lower mortality rates in men randomised to active PCa screening (6), though these results have been challenged (7). Positive findings attributed to screening have also been contradicted by a comparative study between the US city of Seattle area (highly screened population) and the US state of Connecticut (seldom screened population) (8). The study found no difference in the reduction in the rate of PCa mortality (level of evidence: 2b), even allowing for the very great diversity in PSA testing and treatment. Prospective, preferably population-based, randomised trials are needed to properly evaluate the efficacy of PCa screening. Two large trials are underway, the PLCO (Prostate, Lung, Colorectal and Ovary) trial in the USA and the ERSPC (European Randomized Screening for Prostate Cancer) in Europe (9, 10). The main endpoint of these trials is difference in PCa mortality, with first results due in 2009 (level of evidence: 1b). Thus, there is currently no evidence for introducing widespread, population-based, screening programmes for early PCa detection in all men in a given population (4) (level of evidence: 2). A less controversial programme, which is also recommended by most guidelines, is using PSA with digital rectal examination (DRE) as an aid to early diagnosis (11) (see Section 6.1) (level of evidence: 3). Nevertheless, a few conclusions about screening intervals can be deduced from the ERSPC study (12): • A screening interval of 2 or 4 years had no impact on outcome in a cohort of 17,505 men aged 55-74 years • The rate of interval cancer, especially aggressive interval cancer, was low in this study (0.43% vs 0.74%) • Although the 2-year screening interval had a higher detection rate for PCa than the 4-year interval (13.14% vs 8.42%), it did not lead to lower incidences of interval PCa (0.11%) and aggressive interval PCa (0.12%) • A screening interval of 8 years might be enough in men with initial PSA levels ≤ 1 ng/ml (13) • A total of 1703 men had a PSA level ≤ 1 ng/ml when they first presented for screening. A total of 1327 men (79.3%) attended the second screening visit during which 13 men (0.98%) had PSA levels ≥ 3.0 ng/mL and three cancers were detected (0.23%) • A total of 1017 men (76.8%) attended the third screening visit during which 34 men (3.3%) had a PSA level ≥ 3.0 ng/mL and five cancers were detected (0.49%) • The 2344 subsequent PSA determinations during an 8-year period following the initial screening visit resulted in the detection of eight cancers (0.47%) • Thus, PSA screening every 8 years for men with PSA levels ≤ 1.0 ng/mL would mean fewer screening visits (with less cost and stress), with a minimal risk of missing aggressive cancer at a curable stage. The decision to undergo early PSA testing should be a shared decision between the patient and his physician (14, 15). PSA testing and digital rectal examination should be offered from the age of 45 years to men with a life expectancy of at least 10 years. The most recent research suggests further PSA testing is unnecessary in men ≥ 75 years and a PSA level ≤ 3 ng/mL at their first screening visit. This is because these men have a very low risk of dying from PCa (16).

5.1

REFERENCES

1.

Oliver SE, May MT, Gunnell D. International trends in prostate-cancer mortality in the ‘PSA-ERA’. Int J Cancer 2001;92(6):893-8. http://www.ncbi.nlm.nih.gov/pubmed/11351313 2. Helgesen F, Holmberg L, Johansson JE, Bergstrom R, Adami HO. Trends in prostate cancer survival in Sweden, 1960 through 1988, evidence of increasing diagnosis of non-lethal tumours. J Natl Cancer Inst 1996;88(17):1216-21. http://www.ncbi.nlm.nih.gov/pubmed/8780631

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Post PN, Kil PJ, Coebergh JW. Trends in survival of prostate cancer in southeastern Netherlands 1971-1989. Int J Cancer 1999;81(4):551-4. http://www.ncbi.nlm.nih.gov/pubmed/10225443 Ilic D, O’Connor D, Green S, Wilt T. Screening for prostate cancer: a Cochrane systematic review. Cancer Causes Control 2007;18(3):279-85. http://www.ncbi.nlm.nih.gov/pubmed/17206534 Bartsch G, Horninger W, Klocker H, Reissigl A, Oberaigner W, Schönitzer D, Severi G, Robertson C, Boyle P; Tyrol Prostate Cancer Screening Group. Prostate cancer mortality after introduction of prostate specific antigen mass screening in the Federal State of Tyrol, Austria. Urology 2001;58(3):417-24. http://www.ncbi.nlm.nih.gov/pubmed/11549491 Labrie F, Candas B, Dupont A, Cusan L, Gomez JL, Suburu RE, Diamond P, Lévesque J, Belanger A. Screening decreases prostate cancer death: first analysis of the 1988 Quebec prospective randomized controlled trial. Prostate 1999;38(2):83-91. http://www.ncbi.nlm.nih.gov/pubmed/9973093 Boer R, Schroeder FH. Quebec randomized controlled trial on prostate cancer screening shows no evidence of mortality reduction. Prostate 1999;40(2):130-4. http://www.ncbi.nlm.nih.gov/pubmed/10386474 Lu-Yao G, Albertsen PC, Stamford JL, Stukel TA, Walker-Corkery ES, Barry MJ. Natural experiment examining impact of aggressive screening and treatment on prostate cancer mortality in two fixed cohorts from Seattle area and Connecticut. BMJ 2002;325(7367):740. http://www.ncbi.nlm.nih.gov/pubmed/12364300 De Koning HJ, Liem MK, Baan CA, Boer R, Schroder FH, Alexander FE. Prostate cancer mortality reduction by screening: power and time frame with complete enrolment in the European Randomized Screening for Prostate Cancer (ERSPC) trial. Int J Cancer 2002;98(2):268-73. http://www.ncbi.nlm.nih.gov/pubmed/11857418 Schröder FH, Bangma CH, Roobol MJ. Is it necessary to detect all prostate cancers in men with serum PSA levels < 3 ng/ml? A comparison of biopsy results of PCPT and outcome-related information from ERSPC. Eur Urol 2008;53(5):901-8. http://www.ncbi.nlm.nih.gov/pubmed/18262712 Schmid H-P, Riesen W, Prikler L. Update on screening for prostate cancer with prostate-specific antigen. Crit Rev Oncol Hematol 2004;50(1):71-8. http://www.ncbi.nlm.nih.gov/pubmed/15094160 Roobol MJ, Grenabo A, Schröder FH, Hugosson J. Interval cancers in prostate cancer screening: comparing 2- and 4-year screening intervals in the European Randomized Study of Screening for Prostate Cancer, Gothenburg and Rotterdam. J Natl Cancer Inst 2007;99(17):1296-303. http://www.ncbi.nlm.nih.gov/pubmed/17728218 Roobol MJ, Roobol DW, Schröder FH. Is additional testing necessary in men with prostate-specific antigen levels of 1.0 ng/mL or less in a population-based screening setting? (ERSPC, section Rotterdam). Urology 2005;65(2):343-6. http://www.ncbi.nlm.nih.gov/pubmed/15708050 Smith RA, Cokkinides V, von Eschenbach AC, Levin B, Cohen C, Runowicz CD, Sener S, Saslow D, Eyre HJ; American Cancer Society. American Cancer Society guidelines for the early detection of cancer. CA Cancer J Clin 2002;52(1):8-22. http://www.ncbi.nlm.nih.gov/pubmed/11814067 Smith RA, Cokkinides V, Brawley OW. Cancer screening in the United States 2009: a review of current American Cancer Society guidelines and issues in cancer screening. CA Cancer J Clin 2009;59:27-41. http://www.ncbi.nlm.nih.gov/pubmed/19147867 Carter HB, Kettermann AE, Ferrucci L, Landis P, Trock BJ, Metter EJ. Prostate specific antigen testing among the elderly: when to stop. J Urol 2008;179 (Suppl):600, abstract 1751.

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6. DIAGNOSIS* The main diagnostic tools used to look for evidence of PCa include DRE, serum concentration of PSA and transrectal ultrasonography (TRUS). Diagnosis depends on the presence of adenocarcinoma in operative specimens, prostate biopsy cores or aspiration needle cytology. Histopathological examination also allows grading of the tumour.

6.1

Digital rectal examination (DRE)

Most prostate cancers are located in the peripheral zone of the prostate and may be detected by DRE when the volume is about 0.2 mL or larger. A suspect DRE is an absolute indication for prostate biopsy. In about 18% of all patients, PCa is detected by a suspect DRE alone, irrespective of the PSA level (1) (level of evidence: 2a). A suspect DRE in patients with a PSA level of up to 2 ng/mL has a positive predictive value of 5-30% (2) (level of evidence: 2a).

6.2 Prostate-specific antigen (PSA) The measurement of PSA level has revolutionised the diagnosis of PCa (3). Prostate-specific antigen (PSA) is a kallikrein-like serine protease produced almost exclusively by the epithelial cells of the prostate. For practical purposes, it is organ-specific but not cancer-specific. Thus, serum levels may be elevated in the presence of benign prostatic hypertrophy (BPH), prostatitis and other non-malignant conditions. The level of PSA as an independent variable is a better predictor of cancer than suspicious findings on DRE or TRUS (4). There are many different commercial test kits for measuring PSA, but no commonly agreed international standard exists (5). The level of PSA is a continuous parameter: the higher the value, the more likely is the existence of PCa (Table 4). This means there is no universally accepted cut-off or upper limit. The finding that many men may harbour PCa, despite low levels of serum PSA, has been underscored by recent results from a US prevention study (6) (level of evidence: 2a). Table 4 gives the rate of PCa in relation to serum PSA for 2950 men in the placebo-arm and with normal PSA values. Table 4: Risk of PCa in relation to low PSA values PSA level (ng/mL) • 0-0.5 • 0.6-1 • 1.1-2 • 2.1-3 • 3.1-4

Risk of PCa 6.6% 10.1% 17.0% 23.9% 26.9%

PSA = prostate-specific antigen. These findings highlight an important issue about lowering the PSA-level threshold, which is how to avoid detecting insignificant cancers with a natural history unlikely to be life threatening (7). As yet, there is no long-term data to help determine the optimal PSA threshold value for detecting non-palpable, but clinically significant, PCa (level of evidence: 3). Several modifications of serum PSA value have been described, which may improve the specificity of PSA in the early detection of PCa. They include: PSA density, PSA density of the transition zone, age-specific reference ranges and PSA molecular forms. However, these derivatives and certain PSA isoforms (cPSA, proPSA, BPSA, iPSA) have limited usefulness in the routine clinical setting and have therefore not been considered for inclusion in these guidelines. 6.2.1 Free/total PSA ratio (f/t PSA) The free/total PSA ratio (f/t PSA) is the concept most extensively investigated and most widely used in clinical practice to discriminate BPH from PCa, and has been used to stratify the risk of PCa for men with total PSA levels between 4 and 10 ng/mL and with a negative DRE. In a prospective multicentre trial, PCa was found on biopsy in 56% of men with a f/t PSA < 0.10, but in only 8% of men with f/t PSA > 0.25 (8) (level of evidence: 2a). Nevertheless, the concept must be used with caution as several pre-analytical and clinical factors may influence the f/t PSA. For example, free PSA is unstable at both 4°C and at room temperature. In addition, * Acknowledgment: Section 6.4 is partly based on the Guidelines of the AUO Study Group Urologic Oncology of the Austrian Society of Urologists and Andrologists (W. Höltl, W. Loidl, M. Rauchenwald, M. Müller, M. Klimpfinger, A. Schratter-Sehn, C. Brössner). Update march 2009

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assay characteristics may vary and concomitant BPH in large prostates may result in a ‘dilution effect’ (9). Furthermore, f/t PSA is clinically useless in total serum PSA values > 10 ng/mL and in follow-up of patients with known PCa. 6.2.2 PSA velocity (PSAV), PSA doubling time (PSADT) There are two methods of measuring PSA over time. These are: • PSA velocity (PSAV), defined as an absolute annual increase in serum PSA (ng/mLyear) (10) (level of evidence: 1b). • PSA doubling time (PSADT), which measures the exponential increase of serum PSA over time reflecting a relative change (11). These two concepts may have a prognostic role in patients with treated PCa (12). However, they have limited use in the diagnosis of PCa because of several unresolved issues, including background noise (total volume of prostate, BPH), the interval between PSA determinations, and acceleration/deceleration of PSAV and PSADT over time. Prospective studies have not shown these measurements can provide additional information compared to PSA alone (13, 14). 6.2.3 PCA3 marker In contrast to the serum markers discussed above, PCA3 is measured in urine sediment obtained after prostatic massage (15). Determination of this PCa-specific gene is experimental. In the near future, several molecular diagnostic tests may move out of the laboratory into the clinical setting (16). So far, none of the above biomarkers can be used to counsel an individual patient on the need to perform a prostate biopsy to rule out PCa.

6.3

Transrectal ultrasonography (TRUS)

The classic picture of a hypoechoic area in the peripheral zone of the prostate will not always be seen (17). Gray-scale TRUS does not detect areas of PCa with adequate reliability. Replacing systematic biopsies by targeted biopsies of suspect areas is therefore unproductive. However, additional biopsies of suspect areas may be useful.

6.4 Prostate biopsy 6.4.1 Baseline biopsy The need for prostate biopsies should be determined on the basis of the PSA level and/or a suspicious DRE. The patient’s biological age, potential co-morbidities (ASA Index and Charlson Comorbidity Index) and the therapeutic consequences should also be considered. The first elevated PSA level should not prompt an immediate biopsy. The PSA level should be verified after a few weeks by the same assay under standardised conditions (i.e. no ejaculation and no manipulations, such as catheterisation, cystoscopy or TUR, and no urinary tract infections) in the same diagnostic laboratory, using the same methods (18, 19) (level of evidence: 2a). The ultrasound-guided perineal approach is a useful alternative in special situations, e.g. after rectal amputation. Its detection rates are comparable to those of the transrectal approach (20) (level of evidence: 1b). 6.4.2 Repeat biopsy Indications are rising and/or persistent PSA, suspicious DRE and atypical small acinar proliferation (ASAP). The optimal timing is uncertain and depends on the histological outcome of the baseline ASAP biopsy and the index of a persistent suspicion of PCa (high or dramatically rising PSA, suspect DRE, family history). The later the repeat biopsy is done, the higher the detection rate (21). High-grade prostatic intraepithelial neoplasia (PIN) is no longer considered an indication for re-biopsy (22) (level of evidence: 2a). A repeat biopsy should therefore be prompted by other clinical features, like DRE findings and PSA level. If PIN is extensive (i.e. in several biopsies) this could be a reason for early re-biopsy. 6.4.3 Saturation biopsy The incidence of PCa detected by saturation repeat biopsy is between 30% and 43% and depends on the number of cores sampled during earlier biopsies (23) (level of evidence: 2a). In special situations, saturation biopsy may be performed with the transperineal technique. This will detect an additional 38% of PCa. The high rate of urinary retention (10%) is a drawback (3D- stereotactic biopsy) (24) (level of evidence: 2b). 6.4.4 Sampling sites and number of cores On baseline biopsies, the sample sites should be as far posterior and lateral in the peripheral gland as possible. 14

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Additional cores should be obtained from suspect areas by DRE/TRUS. These should be chosen on an individual basis. Sextant biopsy is no longer considered adequate. At a glandular volume of 30-40 mL, at least eight cores should be sampled. More than 12 cores are not significantly more conclusive (25) (level of evidence: 1a). The British Prostate Testing for Cancer and Treatment Study has recommended 10-core biopsies (26) (level of evidence: 2a). 6.4.5 Diagnostic transurethral resection of the prostate (TURP) The use of diagnostic TURP instead of repeat biopsies is of minor importance. Its detection rate is no better than 8% and makes it a poor tool for cancer detection (27) (level of evidence: 2a). 6.4.6 Seminal vesicle biopsy Indications for seminal vesicle biopsies are not well defined. At PSA levels > 15-20 ng/mL, a biopsy is only useful if the outcome will have a decisive impact on treatment, i.e. if the biopsy result rules out radical removal for tumour involvement or radiotherapy with intent to cure. At PSA levels > 15-20 ng/L, the odds of tumour involvement are 20-25% (28) (level of evidence: 2a). 6.4.7 Transition zone biopsy Transition zone (TZ) sampling during baseline biopsies provides a very low detection rate and TZ sampling should therefore be confined to repeat biopsies (29) (level of evidence: 1b). 6.4.8 Antibiotics Oral or intravenous antibiotics are state-of-the-art treatment. Optimal dosing and treatment time vary. Quinolones are the drugs of choice, with ciprofloxacin superior to ofloxacin (30) (level of evidence: 1b). 6.4.9 Local anaesthesia Ultrasound-guided peri-prostatic block is state-of-the-art (31) (level of evidence: 1b). It does not make any difference whether the depot is apical or basal. Intrarectal instillation of a local anaesthetic is clearly inferior to peri-prostatic infiltration (32) (level of evidence: 1b). 6.4.10 Fine-needle aspiration biopsy Fine-needle aspiration biopsy is not as effective as TRUS-guided transrectal core biopsy because of the lack of uropathologists experienced in cytology. In addition, TRUS-guided transrectal core biopsies provide more information on the extent of the tumour. 6.4.11 Complications Complication rates are low (Table 5) (33). Minor complications include macrohaematuria and haematospermia. Severe post-procedural infections have been reported in < 1% of cases. The recent increase in the number of biopsy cores performed has not increased the rate of severe complications requiring treatment. Low-dose aspirin is no longer an absolute contraindication (34) (level of evidence: 1b). Table 5: Percentage given per biopsy session, irrespective of the number of cores* Complications • Haematospermia • Bleeding from urethra, urinary bladder (> 1 day) • Fever • Urosepsis • Rectal bleeding • Urine retention • Prostatitis • Epididymitis

% of biopsies 37.4 14.5 0.8 0.3 2.2 0.2 1.0 0.7

* Adapted from Consensus Guidelines NCCN, Version 1.2007 (33).

6.5 Pathology of prostate needle biopsies 6.5.1 Grossing and processing Prostate core biopsies taken from different sites are usually sent to the pathology laboratory in separate vials and should be processed in separate cassettes. Before processing, record the number of cores per vial and

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length of each core. There is a significant correlation between the length of prostate biopsy tissue on the histological slide and the detection rate of PCa (35). To achieve optimal flattening and alignment of individual cores, embed a maximum of three cores per cassette and use sponges or paper to keep the cores stretched and flat (36, 37). To optimise the detection of small lesions, blocks should be cut in three levels (38). It may be of help if intervening tissue sections are routinely mounted in case additional immunostaining is needed. 6.5.2 Microscopy and reporting Diagnosis of prostate cancer is based on histological examination. However, immunostaining may also be helpful (39, 40). Ancillary staining techniques (e.g. basal cell staining) and additional (deeper) sections should be considered if a suspect glandular lesion is identified (38, 40). For suspicious lesions in biopsies, diagnostic uncertainty may often be resolved by intradepartmental consultation and a second opinion from an external institution (39). Use concise clear terminology to report prostate biopsies (37) (Table 6) and avoid terms such as ’atypia‘, ’atypical glands‘ or ‘possibly malignant‘. Table 6: Diagnostic terms used to report prostate biopsy findings* • Benign/negative for malignancy. If appropriate, include a description (e.g. atrophy). Chronic inflammation may be added (optional) • Active inflammation, negative for malignancy • Atypical adenomatous hyperplasia/adenosis, no evidence of malignancy • Granulomatous inflammation, negative for malignancy • High-grade PIN, negative for adenocarcinoma • High-grade PIN with atypical glands suspicious for adenocarcinoma • Focus of atypical glands/lesion suspicious for adenocarcinoma • Adenocarcinoma *From Van der Kwast, 2003 (36). PIN = prostatic intra-epithelial neoplasia. For each biopsy site, report the proportion of biopsies positive for carcinoma and the Gleason score, using the system adopted in 2005 (41). According to current international convention, the (modified) Gleason score of cancers detected in a prostate biopsy consists of the Gleason grade of the dominant (most extensive) carcinoma component plus the highest grade, irrespective of its extent (no 5% rule). When the carcinoma largely consists of grade 4/5 carcinoma, identification of a small portion (< 5% of the carcinoma) of Gleason grade 2 or 3 glands should be ignored. A diagnosis of Gleason score 4 or lower should not be given on prostate biopsies (41). The presence of high-grade PIN and extraprostatic extension should be reported. In addition to a report of the carcinoma features for each biopsy site, provide an overall Gleason score based on findings in the individual biopsies. The presence of perineural invasion is usually reported, even though there is conflicting evidence about its usefulness as a prognosticator of unfavourable disease (42, 43). The proportion (%) or length (mm) of tumour involvement per biopsy site correlates with tumour volume, extraprostatic extension and prognosis after prostatectomy (43-45) and should therefore be recorded. The length of carcinoma (mm) and the percentage of carcinoma involvement of the biopsy have equal prognostic impact (46). The extent of a single, small focus of adenocarcinoma, which is located in only one of the biopsies, should be clearly stated (e.g. < 1 mm or < 1%), as this might be an indication for further diagnostic work-up before selecting therapy. In some studies, a finding of < 3 mm carcinoma in one biopsy with a Gleason score 5–6 has often been associated with insignificant cancer and with an increased risk of vanishing cancer (4749). A prostate biopsy that does not contain glandular prostate tissue could be reported as inadequate for diagnostics, except on staging biopsies. A recent study evaluated the concordance of pattern and change of prognostic groups for the conventional and the modified Gleason grading (50). The evaluation was based on 172 prostatic needle biopsies of patients who subsequently underwent RP. Four prognostic Gleason grading groups were considered, divided into scores of 2–4, 5–6, 7 and 8–10. To check the discriminative power of the modified Gleason grading, the time of biochemical progression-free outcome, according to prognostic groups, was compared between standard and revised grading. The greatest impact of the International Society of Urological Pathology consensus recommendations for Gleason grading was seen on the secondary pattern, which had the lowest percentage of concordance and was reflected in a change toward higher Gleason prognostic groups. Of 172 patients in whom the Gleason prognostic group was changed (to higher grades) based solely on the consensus criteria, 46 (26.7%) had a higher pre-operative PSA level, more extensive tumours and positive surgical

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margins, and a higher pathological stage. In this series, the revised Gleason grading identified more patients in the aggressive prognostic group Gleason score 8–10, who had a significantly shorter time to biochemical progression-free outcome after radical prostatectomy (log rank p = 0.011). These findings have shown that the recommendations of the International Society of Urological Pathology are a valuable refinement of the standard Gleason grading system.

6.6 Pathohistology of radical prostatectomy (RP) specimens 6.6.1 Processing of the RP specimen The histopathological examination of RP specimens aims to provide information about the actual pathological stage, grade and surgical margin status of the prostate cancer. The weight and dimensions of the specimen are recorded before embedding it for histological processing. It is generally recommended that RP specimens are totally embedded to enable the best assessment of location, multifocality and heterogeneity of the cancer. However, for cost-efficiency purposes, partial embedding using a standard method may also be considered, particularly for large-sized prostates (> 60 g). The most acceptable method includes the complete embedding of the posterior (dorsal) part of the prostate in addition to a single mid-anterior left and right section. Compared to total embedding, this method of partial embedding permitted detection of 98% of prostate cancers with a Gleason score ≥ 7 and accurate staging in 96% of cases (51). Upon receipt in the histopathology lab, the entire RP specimen is inked in order to appreciate the surgical margin status. The specimen is fixed in buffered formalin, preferably prior to incision of the sample, as incision causes distortion of the tissue. Generally, appropriate fixation is achieved by immersing the RP specimen in fixative for a few days. Fixation can be enhanced by injecting formalin using 21-gauge syringes, which provides a more homogeneous fixation and sectioning after 24 hours (52). After fixation, the apex is removed and cut with (para)sagittal or radial sections; the shave method is not recommended (53). Separate sagittal sectioning of the bladder neck is optional. The remainder of the RP specimen is generally cut in transverse sections at 3-4 mm steps, perpendicularly to the posterior surface. The resulting tissue slices can be embedded and processed either as whole-mounts or after quadrant sectioning. Whole-mount processing provides better topographic visualisation of the carcinoma and a faster histopathological examination. However, it is a more time-consuming and more expensive technique requiring specialised equipment and personnel. Although whole-mount sectioning may be necessary for research, its advantages do not outweigh its disadvantages for routine sectioning. Recommendations • Total embedding of a prostatectomy specimen is preferred, either by conventional (quadrant sectioning) or by whole-mount sectioning • The entire surface of RP specimens should be inked before cutting in order to evaluate the surgical margin status • The apex should be separately examined using the cone method with sagittal or radial sectioning.

6.6.2 RP specimen report The pathology report provides essential information on the prognostic characteristics relevant for making clinical decisions. The report includes: • typing (> 95% of PCa represent conventional (acinic) adenocarcinomas) • grading according to the Gleason score • (sub)staging and surgical margin status of the tumour • if appropriate, location and extent of extraprostatic extension, sidedness of extraprostatic extension or seminal vesicle invasion, location and extent of positive surgical margins • additional information may be provided on multifocality, diameter of the dominant tumour and the zonal location (transition zone, peripheral zone, anterior horn) of the dominant tumour. Given the complex information to be provided on each RP specimen, the use of synoptic-(like) or checklist reporting is recommended (see table 7). Synoptic reporting of surgical specimens results in more transparent and complete pathology reporting (54).

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Table 7: Example checklist - reporting of prostatectomy specimens Histologic type Type of carcinoma (e.g. conventional acinar, ductal, etc.) Histologic grade Primary (predominant) grade Secondary grade Tertiary grade (if applicable) Total / global Gleason score Approximate percentage of Gleason grade 4 or 5 (optional) Tumour quantitation (optional) Percentage of prostatic gland involved Tumour size of dominant nodule (if identified), greatest dimension in mm Pathologic staging (pTNM) Presence of extraprostatic extension (focal or extensive) If present: specify site(s) Presence of seminal vesicle invasion If applicable: Regional lymph nodes: - Location - Number of lymph nodes retrieved - Number of lymph nodes involved Surgical margins Presence of carcinoma at margin If present: specify site(s) and extra- or intraprostatic Other If identified: presence of angioinvasion Location (site, zone) of dominant tumour (optional) Perineural invasion (optional) If present: specify extra-or intra-prostatic 6.6.2.1. Gleason score Grading of conventional prostatic adenocarcinomas using the (modified) Gleason score system (41) is the single strongest prognostic factor for clinical behaviour and treatment response. The Gleason score is therefore one of the parameters incorporated in nomograms that predict the risk of recurrence after prostatectomy (55). 6.6.2.2. Interpreting the Gleason score The Gleason score is the sum of the most dominant and second most dominant (in terms of volume) Gleason grade. If only one grade is present, the primary grade is doubled. If a grade comprises ≤ 5% of the cancer volume, this grade is not incorporated in the Gleason score (5% rule). Both the primary and the secondary grade should be reported in addition to the Gleason score (e.g. Gleason score 7 [4 + 3]). A global Gleason score is given when there are multiple tumours, but a separate tumour focus with a higher Gleason score should also be mentioned. A tertiary Gleason grade 4 or 5, particularly if exceeding 5% of the prostate cancer volume, is an unfavourable prognosticator for biochemical recurrence. The presence of the tertiary grade and its approximate proportion of the cancer volume should also be reported (56), in addition to the Gleason score. 6.6.2.3 Definition of extraprostatic extension The TNM staging system of the International Union Against Cancer (UICC) is recommended for pathological staging of carcinomas of the prostate (53, 57). It measures the anatomical extension of the cancer, which may (e.g. pT3 substaging) or may not (e.g. pT2 substaging) be prognostic. Extraprostatic extension is the recommended term for the presence of tumour beyond the confines of the prostate. Extraprostatic extension is defined as carcinoma admixed with periprostatic adipose tissue, or bulging out beyond the contour of the prostate gland, e.g at the neurovascular bundle or the anterior prostate. It is useful to report not only the location, but also the extent of extraprostatic extension because the extension is related to the risk of recurrence (58, 59). There are no well-established and internationally accepted definitions of the terms ‘focal’ and ‘non-focal’ or ‘extensive extraprostatic extension’. Some authors describe focal as ‘a few glands‘ (60) or extension less than 1 high power field (59), while others measure the depth of extent in mm (61). Currently, it is considered clinically useful to measure the extent of extraprostatic extension (e.g. less or more than 1 high power field or 1 mm). At the site of the apex, there is no agreed definition on how to determine extraprostatic extension. Here,

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tumour admixed with skeletal muscle does not constitute extraprostatic extension, and it should be noted that at the apex, a diagnosis of stage pT4 is not rendered. In the bladder neck, microscopic invasion of small fibres of smooth muscle is not equated to bladder wall invasion (62). Some consider tumour invasion of large bundles of smooth muscle to be gross invasion (63), as determined by the urologist, or a positive bladder neck margin to be equivalent to pT4 (64). 6.6.3 Prostate cancer volume The prognostic value of determining the volume of PCa in RP specimens is controversial with several conflicting studies either demonstrating or refuting its independent prognostic impact (59, 65-68). Nevertheless, a prostate cancer volume cut-off of 0.5 mL continues to be an important parameter to distinguish insignificant from clinically relevant cancers (65). Furthermore, continued improvement in radio-imaging of the prostate glands has allowed more accurate measurements of cancer volume before surgery. For these reasons, it may be recommended that, if present, the greatest dimension of the dominant tumour nodule should be provided in millimeters. 6.6.4 Surgical margin status Surgical margin status is an independent risk factor for biochemical recurrence. It is usually possible to provide clear information about the surgical margin status: positive if tumour cells are in touch with the ink on the surface of the specimen, and negative if not. The margin is negative if tumour cells are very close to the inked surface of the margin (66) or when they are at the surface of the tissue lacking any ink. If the tissue has severe crush artifacts (usually at the apex), it may not be possible to assign a surgical margin status (69). Surgical margin status is independent of the pathological stage and a positive margin is not evidence of extraprostatic extension (70). There is insufficient evidence to prove a relationship between the extent of positive margin and the risk of recurrence (59). However, it is recommended that some indication is given of the (multi)-focality and extent of margin positivity (e.g. linear extent in millimeters, or number of blocks with positive margin involvement). 6.6.5 Other factors According to the College of American Pathologists consensus statement (71), additional potential biomarkers, such as perineural invasion, neuroendocrine differentiation, microvessel density, nuclear roundness, chromatin texture, other karyometric factors, proliferation markers, prostate-specific antigen derivatives, and other factors (oncogenes, tumor suppressor genes, apoptosis genes, etc) have not been sufficiently studied to demonstrate their additional prognostic value and clinical usefulness outside the standard patient care setting (category III).

6.7

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51.

Sehdev AE, Pan CC, Epstein JI. Comparative analysis of sampling methods for grossing radical prostatectomy specimens performed for nonpalpable (stage T1c) prostatic adenocarcinoma. Hum Pathol 2001;32(5):494-9. http://www.ncbi.nlm.nih.gov/pubmed/11381367 52. Ruijter ET, Miller GJ, Aalders TW, van de Kaa CA, Schalken JA, Debruyne FM, Boon ME. Rapid microwave-stimulated fixation of entire prostatectomy specimens. Biomed-II MPC Study Group. J Pathol 1997;183(3):369-75. http://www.ncbi.nlm.nih.gov/pubmed/9422995 53. Epstein JI, Allsbrook WC Jr, Amin MB, Egevad LL; ISUP grading committee. The 2005 International Society of Urologic Pathology (ISUP) Consensus Conference on Gleason grading of Prostatic Carcinoma. Am J Surg Pathol 2005;29(9):1228-42. http://www.ncbi.nlm.nih.gov/pubmed/16096414 54. Chan NG, Duggal A, Weir MM, Driman DK. Pathological reporting of colorectal cancer specimens: a retrospective survey in an academic Canadian pathology department. Can J Surg 2008;51(4):284-8. http://www.ncbi.nlm.nih.gov/pubmed/18815652 55. Partin AW, Mangold LA, Lamm DM, Walsh PC, Epstein JI, Pearson JD. Contemporary update of the prostate cancer staging nomograms (Partin tables) for the new millennium. Urology 2001;58(6):843-8. http://www.ncbi.nlm.nih.gov/pubmed/11744442 56. Harnden P, Shelley MD, Coles B, Staffurth J, Mason MD. Should the Gleason grading system for prostate cancer be modified to account for high-grade tertiary components? A systematic review and meta-analysis. Lancet Oncology 2007;8(5):411-9. http://www.ncbi.nlm.nih.gov/pubmed/17466898 57. Ohori M, Kattan M, Scardino PT, Wheeler TM. Radical prostatectomy for carcinoma of the prostate. Mod Pathol 2004;17(3):349-59. http://www.ncbi.nlm.nih.gov/pubmed/14765206 58. Wheeler TM, Dillioglugil O, Kattan MW, Arakawa A, Soh S, Suyama K, Ohori M, Scardino PT. Clinical and pathological significance of the level and extent of capsular invasion in clinical stage T1-2 prostate cancer. Hum Pathol 1998;29(8):856-62. http://www.ncbi.nlm.nih.gov/pubmed/9712429 59. Marks M, Koch, Lopez-Beltran A, Montironi R, Juliar B, Cheng L. The relationship between the extent of surgical margin positivity and prostate specific antigen recurrence in radical prostatectomy specimens.  Human Pathology 2007;38(8):1207-11. http://www.ncbi.nlm.nih.gov/pubmed/17490720 60. Epstein JI, Carmichael MJ, Pizov G, Walsh PC. Influence of capsular penetration on progression following radical prostatectomy: a study of 196 cases with long-term followup. J Urol 1993;150(1): 135-41. http://www.ncbi.nlm.nih.gov/pubmed/7685422 61. Sung MT, Lin H, Koch MO, Davidson DD, Cheng L. Radial distance of extraprostatic extension measured by ocular micrometer is an independent predictor of prostate-specific antigen recurrence: A new proposal for the substaging of pT3a prostate cancer. Am J Surg Pathol 2007;31(2):311-8. http://www.ncbi.nlm.nih.gov/pubmed/17255778 62. Aydin H, Tsuzuki T, Hernandez D, Walsh PC, Partin AW, Epstein JI. Positive proximal (bladder neck) margin at radical prostatectomy confers greater risk of biochemical progression. Urology 2004;64(3):551-5. http://www.ncbi.nlm.nih.gov/pubmed/15351591 63. Hoedemaeker RF, Vis AN, Van Der Kwast TH. Staging prostate cancer. Microsc Res Tech 2000;51(5):423-9. http://www.ncbi.nlm.nih.gov/pubmed/11074612 64. Srigley JR, Amin MB, Epstein JI, Grignon DJ, Humphrey PA, Renshaw AA, Wheeler TM; Members of the Cancer Committee, College of American Pathologists. Updated protocol for the examination of specimens from patients with carcinomas of the prostate gland. Arch Pathol Lab Med 2006;130(7):936-46. http://www.ncbi.nlm.nih.gov/pubmed/16831046 65. Stamey TA, Yemoto CM, McNeal JE, Sigal BM, Johnstone IM. Prostate cancer is highly predictable: a prognostic equation based on all morphological variables in radical prostatectomy specimens. J Urol 2000;163(4):1155-60. http://www.ncbi.nlm.nih.gov/pubmed/10737486

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66.

67.

68.

69.

70.

71.

Epstein JI, Amin M, Boccon-Gibod L, Egevad L, Humphrey PA, Mikuz G, Newling D, Nilsson S, Sakr W, Srigley JR, Wheeler TM, Montironi R Prognostic factors and reporting of prostate carcinoma in radical prostatectomy and pelvic lymphadenectomy specimens. Scand J Urol Nephrol Suppl 2005;216:34-63. http://www.ncbi.nlm.nih.gov/pubmed/16019758 Kikuchi E, Scardino PT, Wheeler TM, Slawin KM, Ohori M. Is tumor volume an independent prognostic factor in clinically localized prostate cancer? J Urol 2004;172(2):508-11. http://www.ncbi.nlm.nih.gov/pubmed/15247716 Van Oort IM, Witjes JA, Kok DE, Kiemeney LA, Hulsbergen-vandeKaa CA. Maximum tumor diameter is not an independent prognostic factor in high-risk localized prostate cancer. World J Urol 2008;26(3):237-41. http://www.ncbi.nlm.nih.gov/pubmed/18265988 Evans AJ, Henry PC, Van der Kwast TH, Tkachuk DC, Watson K, Lockwood GA, Fleshner NE, Cheung C, Belanger EC, Amin MB, Boccon-Gibod L, Bostwick DG, Egevad L, Epstein JI, Grignon DJ, Jones EC, Montironi R, Moussa M, Sweet JM, Trpkov K, Wheeler TM, Srigley JR. Interobserver variability between expert urologic pathologists for extraprostatic extension and surgical margin status in radical prostatectomy specimens. Am J Surg Pathol 2008;32(10):1503-12. http://www.ncbi.nlm.nih.gov/pubmed/18708939 Chuang AY, Epstein JI. Positive surgical margins in areas of capsular incision in otherwise organconfined disease at radical prostatectomy: histologic features and pitfalls. Am J Surg Pathol 2008;32(8):1201-6. http://www.ncbi.nlm.nih.gov/pubmed/18580493 Bostwick DG, Grignon DJ, Hammond ME, Amin MB, Cohen M, Crawford D, Gospadarowicz M, Kaplan RS, Miller DS, Montironi R, Pajak TF, Pollack A, Srigley JR, Yarbro JW. Prognostic factors in prostate cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 2000;124(7):995-1000. http://www.ncbi.nlm.nih.gov/pubmed/10888774

7. STAGING The primary extension assessment of prostate cancer (PCa) is usually made by digital rectal examination (DRE), prostate-specific antigen (PSA) measurement and bone scan, supplemented with computed tomography (CT) or magnetic resonance imaging (MRI) and chest X-ray in specific situations.

7.1

T-staging

The first level is the assessment of local tumour stage, where the distinction between intracapsular (T1-T2) and extracapsular (T3-T4) disease has the most profound impact on treatment decisions. DRE often underestimates the tumour extension; a positive correlation between DRE and pathological tumour stage was found in fewer than 50% of cases (1). However, more extensive examinations for adequate T-staging are only recommended in selected cases when more precise staging directly affects the treatment decision, i.e. when curative treatment is an option. Serum PSA levels increase with advancing stage. Nevertheless, when PSA level is measured in an individual patient, it appears to have a limited ability to predict the final pathological stage accurately. Due to the production of PSA by benign and malignant prostatic tissue, there is no direct relationship between serum PSA concentration and the clinical and pathological tumour stage (2-4). A combination of serum PSA level, Gleason score on prostate biopsy and clinical T-stage, however, has been proven to be more useful in predicting the final pathological stage than the individual parameters per se (5). The ability of the molecular forms of PSA to predict T-stage is still controversial. Percentage-free serum PSA did not appear to be able to predict organ-confined disease in the overall population: it could significantly predict favourable pathology in a subset of patients where DRE is normal and total PSA ranges from 4.1-10.0 ng/mL (6). Total PSA and PSA complexed to antichymotrypsin (PSA-ACT) may be superior to their density derivatives in the prediction of post-surgical pathological stage, but it does not seem to justify the substitution of PSA-ACT data in the Partin’s nomogram (7). Large multicentre studies are needed before any form of PSA can be used as a single modality for staging.

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The most commonly used method for viewing the prostate is transrectal ultrasound (TRUS). However, only 60% of tumours are visible with TRUS, and the remainder are not recognised due to their echogenicity. A combination of DRE and TRUS can detect T3a PCa more accurately than either method alone (8). TRUS is not able to determine tumour extension with sufficient accuracy to be recommended for routine use in staging. About 60% of pT3 tumours will not be detected pre-operatively by TRUS (9) (level of evidence: 3). Three-dimensional ultrasound (3D-US) is a non-invasive method of reproducing whole volume images of solid structures with a suggested staging accuracy of 91% (10). Several adjuncts to 3D greyscale TRUS have been investigated. A greater sensitivity for cancer detection has been achieved with the addition of power colour Doppler and contrast agents: the presence or absence of vessels crossing the capsule to determine an extracapsular extension was considered a significant predictive sign (11, 12). Unfortunately, recognition of these findings is largely operator-dependent. Thus, differentiation between T2 and T3 tumours should not be based on TRUS alone (13, 14). Furthermore, in a large multi-institutional study, TRUS was no more accurate at predicting organ-confined disease than was DRE (15). These findings were supported by another large study, which showed that there was no meaningful superiority of TRUS over DRE (16). Seminal vesicle invasion is predictive of local relapse and distant failure. Seminal vesicle biopsies may be used to increase the accuracy of pre-operative staging (17). This is not recommended as a first-line examination, but should be reserved for patients with a substantial risk of seminal vesicle invasion in whom a positive seminal vesicle biopsy would modify treatment decisions. Patients with a clinical stage greater than T2a and a serum PSA level of more than 10 ng/mL could be candidates for seminal vesicle biopsies (18, 19). Patients with any of the basal biopsies positive for cancer are more likely to have positive seminal vesicle biopsies (20). The biopsy Gleason score, serum PSA level and clinical stage are known to be independent predictors of adverse pathological features after radical prostatectomy (RP). Of the prostate needle biopsy parameters examined, the percentage of tissue with cancer was the strongest predictor for positive surgical margins, seminal vesicle invasion and non-organ-confined disease (21). An increased number of biopsies involved with tumour independently predicts extracapsular extension, margin involvement and lymph node invasion (22). In a multivariate analysis, the best risk predictors of extracapsular extension on one side were the overall average of positive biopsy cores being 15% or greater, and the average from three ipsilateral biopsies being 15% or greater. When used in combination, these two factors yielded a model with a positive predictive value of 37%, and a negative predictive value of 95%. The high negative predictive value of the side-specific model identifies patients who are good candidates for nerve-sparing surgery (23). Furthermore, it may be useful to correlate the bioptic Gleason score with the final pathological stage: about 70% of patients have localised disease when the biopsy Gleason score is ≤ 6 (24). Both CT and MRI are now of a high technical standard, but neither modality is sufficiently reliable to make their use mandatory in the assessment of local tumour invasion (25-27). Endorectal MRI (e-MRI) may allow for more accurate local staging by complementing the existing clinical variables by improvements in spatial characterisation of the prostatic zonal anatomy and molecular changes (28). Image quality and localisation improves significantly with e-MRI compared with external coil MRI (29). When compared with DRE and TRUS prostate biopsy findings, e-MRI contributes significant incremental value for local PCa staging (30), particularly in the pre-operative identification of extracapsular extension (ECE) and seminal vesicle invasion (SVI) when interpreted by dedicated genitourinary radiologists (31, 32, 33). E-MRI could impact on the decision to preserve or resect the neurovascular bundle (NVB) at the time of radical surgery (34). Similarly, e-MRI could be accurate in evaluating the presence of SVI (35). Features associated with the identification of SVI include low signal intensity within the seminal vesicle, and lack of preservation of normal seminal vesicle architecture. Combining these features with the presence both of tumour at the base of the prostate and ECE is highly predictive for the presence of SVI (35, 36). When assessed for the ability to predict organ-confined PCa, the contribution of e-MRI to staging nomograms was significant in all risk categories, but the greatest benefit was seen in the intermediate and high risk groups (37). The combination of dynamic contrast-enhanced MR imaging and T2-weighted MR imaging yields improved assessment of ECE and better results for PCa staging compared with either technique independently (38) (level of evidence: 3). Update march 2009

25

MR spectroscopic imaging (MRSI) allows for the assessment of tumour metabolism by displaying the relative concentrations of citrate, choline, creatinine and polyamines. Differences in the concentrations of these chemical metabolites between normal and malignant prostate tissues allow for better tumour localisation within the peripheral zone, increasing the accuracy of ECE detection among less-experienced readers, and decreasing interobserver variability (39). Furthermore, correlations have been demonstrated between the metabolic signal pattern and a pathological Gleason score, suggesting the potential for a non-invasive assessment of PCa aggressiveness (40). Despite the proposed accuracy and benefit of e-MRI and MRSI in PCa characterisation and localisation, e-MRI has several limitations that hamper its widespread application in PCa staging, e.g. difficulties in interpreting signal changes related to post-biopsy haemorrhage and inflammatory changes of the prostate, and the unquantifiable but significant inter- and intra-observer variability seen between both non-dedicated and dedicated radiologists that may lead to under- or overestimation of tumour presence and the local extent of disease (level of evidence: 3). The overall accuracy of 11C-choline positron emission tomography (PET) in defining local tumour stage (pT2 and pT3a-4) has been reported to be around 70%. PET tends to understage PCa, and has a limited value for making treatment decisions in patients with clinically localised PCa, especially if a nerve-sparing procedure is being considered (41) (level of evidence: 2b).

7.2

N-staging

N-staging should be performed only when the findings will directly influence a treatment decision. This is usually the case in patients for whom potentially curative treatments are planned. High PSA values, stages T2b-T3 disease, poor tumour differentiation and peri-neural tumour invasion have been associated with a higher risk of the presence of nodal metastases (5, 42, 43). The measurement of PSA level alone is unhelpful in predicting the presence of lymph node metastases for an individual patient. The nomograms could be used to define a group of patients with a low risk of nodal metastasis (< 10%, see reference number 44). In such cases, patients with a serum PSA level of less than 20 ng/mL, stage T2a or less, and a Gleason score of 6 or less may be spared N-staging procedures before potentially curative treatment (5). The extent of the Gleason 4 pattern in sextant biopsies has also been used to define the risk of N1 disease. If any core had a predominant Gleason 4 pattern, or > three cores any Gleason 4 pattern, the risk of nodal metastases was found to be 20-45%. For the remaining patients, the risk was 2.5%, supporting the idea that nodal staging is unnecessary in selected patients (45). In the current published literature, the results indicate that CT and MRI perform similarly in the detection of pelvic lymph node metastases, although CT seems to be slightly superior (46) (level of evidence: 2a). In either case, the decision about whether nodal involvement is present rests solely on whether there is enlargement of the investigated lymph nodes. The centimetre threshold used to decide whether a lymph node is pathologically involved varies between 0.5 cm and 2 cm. A threshold of 1 cm in the short axis for the oval nodes, and 0.8 cm for the round nodes, has been recommended as the criteria for the diagnosis of lymph node metastases (47). A fine-needle aspiration biopsy (FNAB) might provide a decisive answer in cases of positive imaging results. However, the lymph node can be difficult to reach because of the anatomical position. In addition, FNAB is not a highly sensitive staging procedure, and a false-negative rate of 40% has been reported (47). High-resolution MRI with lymphotrophic ultra-small super-paramagnetic iron oxide particles (USPIO) was more recently suggested in the detection of small and otherwise occult lymph node metastases in patients with PCa (48, 49). These iron nanoparticles are taken up by circulating macrophages, which travel to normal nodal tissue. The presence of the nanoparticles causes normal nodal tissue to turn black, and because malignant nodal tissue is unable to take up the agent, metastases will have a signal intensity higher than normal nodes, even in those that do not meet the standard size criteria for metastasis (50). In asymptomatic patients with newly diagnosed PCa and a serum PSA level of less than 20 ng/mL, the likelihood of positive findings on CT or MRI is approximately 1% (37). CT scanning may therefore be warranted in patients with a very high risk of harbouring lymph node metastases, as the specificity of a positive scan is high (93-96%). Patients with nodal metastases on CT can thus be spared operative lymphadenectomy (51). Radio-immunoscintigraphy and PET have been investigated in order to improve the diagnosis of metastatic disease to the lymph nodes. Both methods are still under investigation, and further evaluation is needed before they can be recommended for routine use in clinical practice, especially as negative results should

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be interpreted with caution (52). The results obtained using 18F-choline PET/CT scans for initial N-staging were discouraging, especially in terms of inability to detect small metastases/micrometastases (< 5 mm) (53). Furthermore, 11C-choline PET/CT has quite a low sensitivity for the detection of lymph node metastases, but performed better than clinical nomograms, with equal sensitivity and better specificity (54). The gold standard for N-staging is operative lymphadenectomy, either by open or laparoscopic techniques. It is worth pointing out that recent studies with more extensive lymphadenectomy have shown that the obturator fossa is not always the primary site for metastatic deposits in the lymph nodes, and pelvic lymph node dissection that is limited to the obturator fossa will therefore miss about 50% of lymph node metastases (55, 56). When deciding on pelvic lymph node dissection, extended lymphadenectomy should be considered, despite its disadvantages: it requires surgical experience; it is time-consuming; and it often leads to more complications than the limited procedures. Furthermore, it may fail to identify lymph node metastases, however present, even outside the region of extended dissection (57). The primary removal of the so-called sentinel lymph node (SLN), defined as the first lymph node that receives lymphatic drainage from PCa, has the main aim of reducing the eventual morbidity associated with an extended pelvic node dissection, while preserving maximal sensitivity for diagnosis of metastatic disease (58) (level of evidence: 3) (see section 9.5.2.1 ‘Treatment: radical prostatectomy, indication and extent of LND’).

7.3

M-staging

The axial skeleton is involved in 85% of patients who die from PCa (59). The presence and extent of bone metastases accurately reflect the prognosis for an individual patient. Elevated skeletal alkaline phosphatase levels may indicate the presence of bony metastasis in 70% of affected patients (60). Furthermore, the measurement of skeletal alkaline phosphatase and PSA at the same time increases clinical effectiveness to approximately 98% (61). In a prospective study, multiple regression analysis showed the extent of bone disease to be the only variable influencing the serum levels of skeletal alkaline phosphatase and PSA. However, in contrast to serum PSA, skeletal alkaline phosphatase demonstrated a statistical correlation with the extent of bone disease (62). Early detection of bone metastases will alert the clinician to the possible complications inherent in skeletal destruction. Bone scintigraphy remains the most sensitive method of assessing bone metastases, being superior to clinical evaluation, bone radiographs, serum alkaline phosphatase measurement and prostatic acid phosphatase (PAP) determination (63, 64). Technetium diphosphonates are the optimum radiopharmaceuticals currently available because of their extremely high bone-to-soft tissue ratio (65). A semi-quantitative grading system based on the extent of disease observed on the bone scan was found to correlate with survival (66). Increased 18F-fluoride uptake in malignant bone lesions reflects the increase in regional blood flow and bone turnover that characterise these lesions. Studies have shown that 18F-fluoride PET/CT is a highly sensitive and specific imaging modality for detection of bone metastases (67, 68). However, no definitive results have been obtained and therefore no final recommendations can be made (69). Besides bone, PCa may metastasise to any organ, but most commonly it affects distant lymph nodes, lung, liver, brain and skin. Clinical examination, chest X-ray, ultrasound, CT and MRI scans are appropriate methods of investigation, but only if symptoms suggest the possibility of soft-tissue metastasis. The need for reliable serum markers to improve the pre-treatment staging of patients with PCa has long been recognised. At present, PSA is the marker of choice. A pre-treatment serum PSA level greater than 100 ng/ mL has been found to be the single most important indicator of metastatic disease, with a positive predictive value of 100% (70). Furthermore, it has helped to reduce the number of patients with newly diagnosed PCa who require a bone scan. Patients with a low serum PSA concentration have only rarely been found to harbour detectable skeletal metastases. The correlation between serum PSA and bone scintigraphy in patients with newly diagnosed untreated PCa has been further investigated (71-75). Results suggest that a staging bone scan may be superfluous if the serum PSA concentration is less than 20 ng/mL in asymptomatic patients with well or moderately differentiated tumours. In contrast, in patients with poorly differentiated tumours and locally advanced disease, a staging bone scan should be obtained irrespective of the serum PSA value (76, 77).

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7.4 Guidelines for the staging of PCa

1.

An abnormal DRE result or elevated serum PSA measurement could indicate PCa. The exact cut-off level of what is considered to be a normal PSA value has not been determined, but values of approximately < 2-3 ng/mL are often used for younger men. 2. The diagnosis of PCa depends on histopathological (or cytological) confirmation. • Biopsy and further staging investigations are only indicated if they affect the management of the patient. 3. TRUS-guided systemic biopsy is the recommended method in most cases of suspected PCa. A minimum of 10 systemic, laterally directed, cores are recommended, with perhaps more cores in larger: • transition zone biopsies are not recommended in the first set of biopsies due to low detection rates • one set of repeat biopsies is warranted in cases with persistent indication (abnormal DRE, elevated PSA or histopathological findings suggestive of malignancy at the initial biopsy) for prostate biopsy • overall recommendations for further (three or more) sets of biopsies cannot be made; the decision must be made based on an individual patient. 4. Transrectal peri-prostatic injection with a local anaesthetic can be offered to patients as effective analgesia when undergoing prostate biopsies. 5. Local staging (T-staging) of PCa is based on findings from DRE and possibly MRI. Further information is provided by the number and sites of positive prostate biopsies, the tumour grade and the level of serum PSA. Despite its high specificity in the evaluation of ECE and SVI, TRUS is limited by poor contrast resolution, resulting in low sensitivity and tendency to understage PCa. Even with the advent of colour and power Doppler to assist in identifying tumour vascularity, the accuracy of TRUS in local staging remains inadequate. In comparison with DRE, TRUS, and CT, MRI demonstrates higher accuracy for the assessment of uni- or bilobar disease (T2), ECE and SVI (T3), as well as the invasion of adjacent structures (T4). However, the literature shows a wide range in the accuracy of T-staging by MRI, from 50-92%. The addition of dynamic contrast-enhanced MRI (DCE-MRI) can be helpful in equivocal cases. The addition of MRSI to MRI also increases accuracy and decreases interobserver variability in the evaluation of ECE. 6. Lymph node status (N-staging) is only important when potentially curative treatment is planned. Patients with stage T2 or less, PSA < 20 ng/mL and a Gleason score ≤ 6 have a lower than 10% likelihood of having node metastases and can be spared nodal evaluation. Given the significant limitations of pre-operative imaging in the detection of small metastases (< 5 mm), pelvic lymph node dissection remains the only reliable staging method in clinically localised. Currently, it seems that only methods of histological detection of lymph node metastases with high sensitivity, such as sentinel lymph node dissection or extended pelvic lymph node dissection, are suitable for lymph node staging in PCa. 7. Skeletal metastasis (M-staging) is best assessed by bone scan. This may not be indicated in asymptomatic patients if the serum PSA level is less than 20 ng/mL in the presence of well or moderately differentiated tumours. In equivocal cases, 18F-fluorodeoxyglucose-PET or PET/CT could be of value, especially to differentiate active metastases and healing bones. GR = grade of recommendation

7.5

GR C

B C B

C B

C A C

C

B

C

B

C

REFERENCES

1.

Spigelman SS, McNeal JE, Freiha FS, Stamey TA. Rectal examination in volume determination of carcinoma of the prostate: clinical and anatomical correlations. J Urol 1986;136(6):1228-30. http://www.ncbi.nlm.nih.gov/pubmed/3773095 2. Hudson MA, Bahnson RR, Catalona WJ. Clinical use of prostate-specific antigen in patients with prostate cancer. J Urol 1989;142(4):1011-7. http://www.ncbi.nlm.nih.gov/pubmed/2477559

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Lange PH, Ercole CJ, Lightner DJ, Fraley EE, Vessella R. The value of serum prostate specific antigen determinations before and after radical prostatectomy. J Urol 1989;141(4):873-9. http://www.ncbi.nlm.nih.gov/pubmed/2467013 4. Partin AW, Carter HB, Chan DW, Epstein JI, Oesterling JE, Rock RC, Weber JP, Walsh PC. Prostate specific antigen in the staging of localized prostate cancer: influence of tumour differentiation, tumour volume and benign hyperplasia. J Urol 1990;143(4):747-52. http://www.ncbi.nlm.nih.gov/pubmed/1690309 5. Partin AW, Mangold LA, Lamm DM, Walsh PC, Epstein JI, Pearson JD. Contemporary update of the prostate cancer staging nomograms (Partin tables) for the new millennium. Urology 2001;58(6):843-8. http://www.ncbi.nlm.nih.gov/pubmed/11744442 6. Morote J, Encabo G, de Torres IM. Use of percent free prostate-specific antigen as a predictor of the pathological features of clinically localized prostate cancer. Eur Urol 2000 Aug;38(2):225-9. http://www.ncbi.nlm.nih.gov/pubmed/10895016 7. Custovic Z, Kraus O, Tomaskovic I, Tarle M. Serum tPSA, cPSA, related density parameters and chromogranin A as predictors of positive margins after radical prostatectomy. Anticancer Res 2007;27(4C):2817-21. http://www.ncbi.nlm.nih.gov/pubmed/17695453 8. Hsu CY, Joniau S, Oyen R, Roskams T, Van Poppel H. Detection of clinical unilateral T3a prostate cancer – by digital rectal examination or transrectal ultrasonography? BJU Int 2006;98(5):982-5. http://www.ncbi.nlm.nih.gov/pubmed/16945120 9. Enlund A, Pedersen K, Boeryd B, Varenhorst E. Transrectal ultrasonography compared to histopathological assessment for local staging of prostatic carcinoma. Acta Radiol 1990;31(6):597600. http://www.ncbi.nlm.nih.gov/pubmed/2278785 10. Mitterberger M, Pinggera GM, Pallwein L, Gradl J, Frauscher F, Bartsch G, Strasser H, Akkad T, Horninger W The value of three-dimensional transrectal ultrasonography in staging prostate cancer. BJU Int 2007;100(1):47-50. http://www.ncbi.nlm.nih.gov/pubmed/17433033 11. Sauvain JL, Palascak P, Bourscheid D, Chabi C, Atassi A, Bremon JM, Palascak R. Value of power Doppler and 3D vascular sonography as a method for diagnosis and staging of prostate cancer. Eur Urol 2003;44(1):21-30; discussion 30-1. http://www.ncbi.nlm.nih.gov/pubmed/12814671 12. Zalesky M, Urban M, Smerhovský Z, Zachoval R, Lukes M, Heracek J. Value of power Doppler sonography with 3D reconstruction in preoperative diagnostics of extraprostatic tumor extension in clinically localized prostate cancer. Int J Urol 2008;15(1):68-75; discussion 75. http://www3.interscience.wiley.com/journal/119407751 13. Oyen RH. Imaging modalities in diagnosis and staging of carcinoma of the prostate. In: Brady LW, Heilmann HP, Petrovich Z, Baert L, Brady LW, Skinner DG (eds). Carcinoma of the Prostate. Innovations & Management, 1996, Springer Verlag, Berlin, pp. 65-96. 14. Rorvik J, Halvorsen OJ, Servoll E, Haukaas S. Transrectal ultrasonography to assess local extent of prostatic cancer before radical prostatectomy. Br J Urol 1994;73(1):65-9. http://www.ncbi.nlm.nih.gov/pubmed/8298901 15. Smith JA Jr, Scardino PT, Resnick MI, Hernandez AD, Rose SC, Egger MJ. Transrectal ultrasound versus digital rectal examination for the staging of carcinoma of the prostate: results of a prospective multi-institutional trial. J Urol 1997;157(3):902-6. http://www.ncbi.nlm.nih.gov/pubmed/9072596 16. Liebross RH, Pollack A, Lankford SP, Zagars GK, von Eshenbach AC, Geara FB. Transrectal ultrasound for staging prostate carcinoma prior to radiation therapy: an evaluation based on disease outcome. Cancer 1999;85(7):1577-85. http://www.ncbi.nlm.nih.gov/pubmed/10193949 17. Saliken JC, Gray RR, Donnelly BJ, Owen R, White LJ, Ali-Ridha N, So B, Ting PT. Extraprostatic biopsy improves the staging of localized prostate cancer. Can Assoc Radiol J 2000;51(2):114-20. http://www.ncbi.nlm.nih.gov/pubmed/10786920 18. Stone NN, Stock RG, Unger P. Indications for seminal vesicle biopsy and laparoscopic pelvic lymph node dissection in men with localized carcinoma of the prostate. J Urol 1995;154(4):1392-6. http://www.ncbi.nlm.nih.gov/pubmed/7658545 19. Allepuz Losa CA, Sans Velez JI, Gil Sanz MJ, Mas LP, Rioja Sanz LA. Seminal vesicle biopsy in prostate cancer staging. J Urol 1995;154(4):1407-11. http://www.ncbi.nlm.nih.gov/pubmed/7544842

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Guillonneau B, Debras B, Veillon B, Bougaran J, Chambon E, Vallancien G. Indications for preoperative seminal vesicle biopsies in staging of clinically localized prostatic cancer. Eur Urol 1997;32(2):160-5. http://www.ncbi.nlm.nih.gov/pubmed/9286646 21. Freedland SJ, Csathy GS, Dorey F, Aronson WJ. Percent prostate needle biopsy tissue with cancer is more predictive of biochemical failure or adverse pathology after radical prostatectomy than prostate specific antigen or Gleason score. J Urol 2002;167(2 PT 1):516-20. http://www.ncbi.nlm.nih.gov/pubmed/11792909 22. Quinn DI, Henshall SM, Brenner PC, Kooner R, Golovsky D, O’Neill GF, Turner JJ, Delprado W, Grygiel JJ, Sutherland RL, Stricker PD. Prognostic significance of preoperative factors in localized prostate carcinoma treated with radical prostatectomy: importance of percentage of biopsies that contain tumor and the presence of biopsy perineural invasion. Cancer 2003;97(8):1884-93. http://www.ncbi.nlm.nih.gov/pubmed/12673714 23. Elliott SP, Shinohara K, Logan SL, Carroll PR. Sextant prostate biopsies predict side and sextant site of extracapsular extension of prostate cancer. J Urol 2002;168(1):105-9. http://www.ncbi.nlm.nih.gov/pubmed/12050501 24. Narayan P, Gajendran V, Taylor SP, Tewari A, Presti JC Jr, Leidich R, Lo R, Palmer K, Shinohara K, Spaulding JT. The role of transrectal ultrasound-guided biopsy-based staging, preoperative serum prostate-specific antigen, and biopsy Gleason score in prediction of final pathological diagnosis in prostate cancer. Urology 1995;46(2):205-12. http://www.ncbi.nlm.nih.gov/pubmed/7542823 25. Lee N, Newhouse JH, Olsson CA, Benson MC, Petrylak DP, Schiff P, Bagiella E, Malyszko B, Ennis RD. Which patients with newly diagnosed prostate cancer need a computed tomography scan of the abdomen and pelvis? An analysis based on 588 patients. Urology 1999;54(3):490-4. http://www.ncbi.nlm.nih.gov/pubmed/10475360 26. May F, Treumann T, Dettmar P, Hartnung R, Breul J. Limited value of endorectal magnetic resonance imaging and transrectal ultrasonography in the staging of clinically localized prostate cancer. BJU Int 2001;87(1):66-9. http://www.ncbi.nlm.nih.gov/pubmed/11121995 27. Jager GJ, Severens JL, Thornbury JR, de la Rosette JJ, Ruijs SH, Barentsz JO. Prostate cancer staging: should MR imaging be used? A decision analytic approach. Radiology 2000;215(2):445-51. http://www.ncbi.nlm.nih.gov/pubmed/10796923 28. Masterson TA, Touijer K. The role of endorectal coil MRI in preoperative staging and decision-making for the treatment of clinically localized prostate cancer. MAGMA 2008;21(6):371-7. http://www.springerlink.com/content/x762r7un2ml1117k/ 29. Heijmink SW, Fütterer JJ, Hambrock T, Takahashi S, Scheenen TW, Huisman HJ, Hulsbergen-Van de Kaa CA, Knipscheer BC, Kiemeney LA, Witjes JA, Barentsz JO. Prostate cancer: body-array versus endorectal coil MR imaging at 3 T – comparison of image quality, localization, and staging performance. Radiology 2007;244(1):184-95. http://radiology.rsnajnls.org/cgi/content/full/244/1/184 30. Mullerad M, Hricak H, Kuroiwa K, Pucar D, Chen HN, Kattan MW. Comparison of endorectal magnetic resonance imaging, guided prostate biopsy and digital rectal examination in the preoperative anatomical localization of prostate cancer. J Urol 2005;174(6): 2158-63. http://www.ncbi.nlm.nih.gov/pubmed/16280755 31. Sala E, Akin O, Moskowitz CS, Eisenberg HF, Kuroiwa K, Ishill NM, Rajashanker B, Scardino PT, Hricak H. Endorectal MR imaging in the evaluation of seminal vesicle invasion: diagnostic accuracy and multivariate feature analysis. Radiology 2006;238(3):929-37. http://radiology.rsnajnls.org/cgi/content/full/238/3/929 32. Mullerad M, Hricak H, Wang L, Chen HN, Kattan MW, Scardino PT. Prostate cancer: detection of extracapsular extension by genitourinary and general body radiologists at MRI imaging. Radiology 2004;232(1):140-6. http://radiology.rsnajnls.org/cgi/content/full/232/1/140 33. Wang L, Mullerad M, Chen HN, Eberhardt Sc, Kattan MW, Scardino PT. Prostate cancer: incremental value of endorectal MRI findings for prediction of extracapsular extension. Radiology 2004;232(1): 133-9. http://radiology.rsnajnls.org/cgi/content/full/232/1/133 34. Hricak H, Wang L, Wei DC, Coakley FV, Akin O, Reuter VE. The role of preoperative endorectal MRI in the decision regarding whether to preserve or resect neurovascular bundles during radical retropubic prostatectomy. Cancer 2004;100(12):2655-63. http://www.ncbi.nlm.nih.gov/pubmed/15197809

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Sala E, Akin O, Moskowitz CS, Eisemberg HF, Kuroiwa K, Ishill NM. Endorectal MRI in the evaluation of seminal vesicle invasion: diagnostic accuracy and multivariate feature analysis. Radiology 2006;238(3):929-37. http://radiology.rsnajnls.org/cgi/content/full/238/3/929 36. Wang L, Hricak H, Kattan MW, Chen HN, Kuroiwa K, Eisemberg HF. Prediction of seminal vesicle invasion in prostate cancer: incremental value of adding endorectal MRI to the Kattan Nomogram. Radiology 2007;242(1):182-8. http://radiology.rsnajnls.org/cgi/content/full/242/1/182 37. Wang L, Hricak H, Kattan MW, Chen HN, Scardino PT, Kuroiwa K. Prediction of organ confined prostate cancer: incremental value of MRI and MRI sprectroscopic imaging to staging nomograms. Radiology 2006;238(2):597-603. http://radiology.rsnajnls.org/cgi/content/full/238/2/597 38. Fuchsjager M, Shukla-Dave A, Akin O, Barentsz, Hricak H. Prostate cancer imaging. Acta Radiol 2008;49:107-20. http://www.informaworld.com/smpp/1906288645-11741620/content~db=all?content=10.1080/02841 850701545821 39. Scheidler J, Hricak H, Vigneron DB, Yu KK, Sokolov DL, Huang LR, Zaloudek CJ, Nelson SJ, Carroll PR, Kurhanewicz J. Prostate cancer: localization with three-dimensional proton MR spectroscopic imaging – clinicopathologic study. Radiology 1999;213(2):473-80. http://radiology.rsnajnls.org/cgi/content/full/213/2/473 40. Zakian KL, Sircar K, Hricak H, Chen HN, Shukla-Dave A, Eberhardt S. Correlation of proton MR spectroscopic imaging with Gleason score based on step section pathologic analysis after radical prostatectomy. Radiology 2005;234(3):804-14. http://radiology.rsnajnls.org/cgi/content/full/234/3/804 41. Rinnab L, Blumstein NM, Mottaghy FM, Hautmann RE, Küfer R, Hohl K, Reske SN. 11C-choline positron-emission tomography/computed tomography and transrectal ultrasonography for staging localized prostate cancer. BJU Int 2007;99(6):1421-6. http://www.ncbi.nlm.nih.gov/pubmed/17355373 42. Stone NN, Stock RG, Parikh D, Yeghiayan P, Unger P. Perineural invasion and seminal vesicle involvement predict pelvic lymph node metastasis in men with localized carcinoma of the prostate. J Urol 1998;160(5):1722-6. http://www.ncbi.nlm.nih.gov/pubmed/9783940 43. Pisansky TM, Zincke H, Suman VJ, Bostwick DG, Earle JD, Oesterling JE. Correlation of pretherapy prostate cancer characteristics with histologic findings from pelvic lymphadenectomy specimens. Int J Radiat Oncol Biol Phys 1996;34(1):33-9. http://www.ncbi.nlm.nih.gov/pubmed/12118563 44. Cagiannos I, Karakiewicz P, Eastham JA, Ohori M, Rabbani F, Gerigk C, Reuter V, Graefen M, Hammerer PG, Erbersdobler A, Huland H, Kupelian P, Klein E, Quinn DI, Henshall SM, Grygiel JJ, Sutherland RL, Stricker PD, Morash CG, Scardino PT, Kattan MW. A preoperative nomogram identifying decreased risk of positive pelvic lymph nodes in patients with prostate cancer. J Urol 2003;170(5):1798-803. 45. Haese A, Epstein JI, Huland H, Partin AW. Validation of a biopsy-based pathologic algorithm for predicting lymph node metastases in patients with clinically localized prostate carcinoma. Cancer 2002;95(5):1016-21. http://www.ncbi.nlm.nih.gov/pubmed/12209685 46. Hoivels AM, Heesakkers RAM, Adang EM., Jager GJ, Strum S, Hoogeveen YL, Severens JL, Barentsz JO. The diagnostic accuracy of CT and MRI in the staging of pelvic lymph nodes in patients with prostate cancer: a meta-analysis. Clinical Radiology 2008;63:387-95. http://linkinghub.elsevier.com/retrieve/pii/S0009-9260(07)00334-0 47. GJ Jager GJ, Barentsz JO, Oosterhof GO, Witjes JA, Ruijs SJH. Pelvic adenopathy in prostatic and urinary bladder carcinoma: MR-imaging with a three-dimensional T1-weighted magnetizationprepared-rapid gradient-echo sequence. Am J Roentgenol 1996;167(6):1503-7. http://www.ncbi.nlm.nih.gov/pubmed/8956585 48. Harisinghani MG, Barentsz J, Hahn PF, Deserno WM, Tabatabaei S, van de Kaa CH, de la Rosette J, Weissleder R. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med 2003;348(25):2491-9. http://www.ncbi.nlm.nih.gov/pubmed/12815134

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49. Heesakkers RA, Fütterer JJ, Hövels AM, van den Bosch HC, Scheenen TW, Hoogeveen YL, Barentsz JO. Prostate cancer evaluated with ferumoxtran-10-enhanced T2*-weighted MR imaging at 1.5 and 3.0 T: early experience. Radiology 2006;239(2):481-7. http://www.ncbi.nlm.nih.gov/pubmed/16641354 50. Bellin MF, Roy C, Kinkel K, Thoumas D, Zaim S, Vanel D, Tuchmann C, Richard F, Jacqmin D, Delcourt A, Challier E, Lebret T, Cluzel P. Lymph node metastases: safety and effectiveness of MR imaging with ultrasmall superparamagnetic iron oxide particles – initial clinical experience. Radiology 1998;207(3):799-808. http://www.ncbi.nlm.nih.gov/pubmed/9609907 51. Wolf JS Jr, Cher M, Dall’era M, Presti JC Jr, Hricak H, Carroll PR. The use and accuracy of crosssectional imaging and fine needle aspiration cytology for detection of pelvic lymph node metastases before radical prostatectomy. J Urol 1995;153(3Pt2):993-9. http://www.ncbi.nlm.nih.gov/pubmed/7853590 52. Salminen E, Hogg A, Binns D, Frydenberg M, Hicks R. Investigations with FDG-PET scanning in prostate cancer show limited value for clinical practice. Acta Oncol 2002;41(5):425-9. http://www.ncbi.nlm.nih.gov/pubmed/12442917 53. Husarik DB, Miralbell R, Dubs M, John H, Giger OT, Gelet A, Cservenyàk T, Hany TF. Evaluation of [(18)F]-choline PET/CT for staging and restaging of prostate cancer. Eur J Nucl Med Mol Imaging 2008;35(2):253-63. http://www.ncbi.nlm.nih.gov/pubmed/17926036 54. Schiavina R, Scattoni V, Castellucci P, Picchio M, Corti B, Briganti A, Franceschelli A, Sanguedolce F, Bertaccini A, Farsad M, Giovacchini G, Fanti S, Grigioni WF, Fazio F, Montorsi F, Rigatti P, Martorana G. (11)C-choline positron emission tomography/computerized tomography for preoperative lymphnode staging in intermediate-risk and high-risk prostate cancer: comparison with clinical staging nomograms. Eur Urol 2008;54(2):392-401. http://www.ncbi.nlm.nih.gov/pubmed/18456393 55. Heidenreich A, Varga Z, Von Knobloch R. Extended pelvic lymphadenectomy in patients undergoing radical prostatectomy: high incidence of lymph node metastasis. J Urol 2002;167(4):1681-6. http://www.ncbi.nlm.nih.gov/pubmed/11912387 56. Bader P, Burkhard FC, Markwalder R, Studer UE. Is a limited lymph node dissection an adequate staging procedure for prostate cancer? J Urol 2002;168(2):514-18, discussion 518. http://www.ncbi.nlm.nih.gov/pubmed/12131300 57. Weckermann D, Dorn R, Holl G, Wagner T, Harzmann R. Limitations of radioguided surgery in highrisk prostate cancer. Eur Urol 2007;51(6):1549-56. http://www.ncbi.nlm.nih.gov/pubmed/16996201 58. Weckermann D, Dorn R, Trefz M, Wagner T, Wawroschek F, Harzmann R. Sentinel lymph node dissection for prostate cancer: experience with more than 1,000 patients. J Urol 2007;177(3): 916-20. http://www.ncbi.nlm.nih.gov/pubmed/17296375 59. Whitmore WF Jr. Natural history and staging of prostate cancer. Urol Clin North Am 1984;11(2): 205-20. http://www.ncbi.nlm.nih.gov/pubmed/6375067 60. Wolff JM, Ittel TH, Borchers H, Boekels O, Jakse G. Metastatic workup of patients with prostate cancer employing alkaline phosphatase and skeletal alkaline phosphatase. Anticancer Res 1999;19(4A):2653-5. http://www.ncbi.nlm.nih.gov/pubmed/10470213 61. Lorente JA, Morote J, Raventos C, Encabo G, Valenzuela H. Clinical efficacy of bone alkaline phosphatase and prostate specific antigen in the diagnosis of bone metastasis in prostate cancer. J Urol 1996;155(4):1348-51. http://www.ncbi.nlm.nih.gov/pubmed/8632571 62. Lorente JA, Valenzuela H, Morote J, Gelabert A. Serum bone alkaline phosphatase levels enhance the clinical utility of prostate specific antigen in the staging of newly diagnosed prostate cancer patients. Eur J Nucl Med 1999;26(6):625-32. http://www.ncbi.nlm.nih.gov/pubmed/10369948 63. McGregor B, Tulloch AG, Quinlan MF, Lovegrove F. The role of bone scanning in the assessment of prostatic carcinoma. Br J Urol 1978;50(3):178-81. http://www.ncbi.nlm.nih.gov/pubmed/753456 64. O’Donoghue EP, Constable AR, Sherwood T, Stevenson JJ, Chisholm GD. Bone scanning and plasma phosphatases in carcinoma of the prostate. Br J Urol 1978;50(3):172-7. http://www.ncbi.nlm.nih.gov/pubmed/753455

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Buell U, Kleinhans E, Zorn-Bopp E, Reuschel W, Muenzing W, Moser EA, Seiderer M. A comparison of bone imaging with Tc-99m DPD and Tc-99m MDP: concise communication. J Nucl Med 1982;23(3):214-17. http://www.ncbi.nlm.nih.gov/pubmed/6460854 Soloway MS, Hardemann SW, Hickey D, Raymond J, Todd B, Soloway S, Moinuddin M. Stratification of patients with metastatic prostate cancer based on the extent of disease on initial bone scan. Cancer 1988;61(1):195-202. http://www.ncbi.nlm.nih.gov/pubmed/3334948 Even-Sapir E, Metser U, Mishani E, Lievshitz G, Lerman H, Leibovitch I. The detection of bone metastases in patients with high-risk prostate cancer: 99mTc-MDP Planar bone scintigraphy, singleand multifield-of-view SPECT, 18F-fluoride PET/CT. J Nucl Med 2006;47(2):287-97. http://www.ncbi.nlm.nih.gov/pubmed/16455635 Beheshti M, Vali R, Langsteger W. [18F]Fluorocholine PET/CT in the assessment of bone metastases in prostate cancer. Eur J Nucl Med Mol Imaging 2007;34(8):1316-7. http://www.ncbi.nlm.nih.gov/pubmed/17476505 Bouchelouche K, Oehr P. Recent developments in urologic oncology: positron emission tomography molecular imaging. Curr Opin Oncol 2008;20(3):321-6. http://www.ncbi.nlm.nih.gov/pubmed/18391633 Rana A, Karamanis K, Lucas MG, Chisholm GD. Identification of metastatic disease by T category, Gleason score and serum PSA level in patients with carcinoma of the prostate. Br J Urol 1992;69(3):277-81. http://www.ncbi.nlm.nih.gov/pubmed/1373666 Chybowski FM, Keller JJ, Bergstrahl EJ, Oesterling JE. Predicting radionuclide bone scan findings in patients with newly diagnosed, untreated prostate cancer: prostate specific antigen is superior to all other parameters. J Urol 1991;145(2):313-8. http://www.ncbi.nlm.nih.gov/pubmed/1703240 Kemp PM, Maguire GA, Bird NJ. Which patients with prostatic carcinoma require a staging bone scan? Br J Urol 1997;79(4):611-4. http://www.ncbi.nlm.nih.gov/pubmed/9126094 Lee N, Fawaaz R, Olsson CA, Benson MC, Petrylak DP, Schiff PB, Bagiella E, Singh A, Ennis RD. Which patients with newly diagnosed prostate cancer need a radionuclide bone scan? An analysis based on 631 patients. Int J Radiat Oncol Biol Phys 2000;48(5):1443-6. http://www.ncbi.nlm.nih.gov/pubmed/11121646 O’Donoghue JM, Rogers E, Grimes H, McCarthy P, Corcoran M, Bredin H, Given HF. A reappraisal of serial isotope bone scans in prostate cancer. Br J Radiol 1993;66(788):672-6. http://www.ncbi.nlm.nih.gov/pubmed/7536607 Wolff JM, Bares R, Jung PK, Buell U, Jakse G. Prostate-specific antigen as a marker of bone metastasis in patients with prostate cancer. Urol Int 1996;56(3):169-73. http://www.ncbi.nlm.nih.gov/pubmed/8860738 Wolff JM, Zimny M, Borchers H, Wildberger J, Buell U, Jakse G. Is prostate-specific antigen a reliable marker of bone metastasis in patients with newly diagnosed cancer of the prostate? Eur Urol 1998;33(4):376-81. http://www.ncbi.nlm.nih.gov/pubmed/9612680 Bruwer G, Heyns CF, Allen FJ. Influence of local tumour stage and grade on reliability of serum prostate-specific antigen in predicting skeletal metastases in patients with adenocarcinoma of the prostate. Eur Urol 1999;35(3):223-7. http://www.ncbi.nlm.nih.gov/pubmed/10072624

8. TREATMENT: DEFERRED TREATMENT (WATCHFUL WAITING/ACTIVE MONITORING) 8.1

Introduction

8.1.1 Definition There is a great difference between the incidence of and mortality from prostate cancer (PCa): in the USA in 2007, there were 218,900 new cases with only 27,050 deaths (1).

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Several autoptic studies of people dying from different causes have shown that while 60-70% of older men have histological PCa (2, 3), a large proportion of these tumours will not progress. PCa is diagnosed in only 15-20% of men during their lifetime, with a 3% lifetime risk of death (4). The incidence of small, localised, well-differentiated PCa is increasing, mainly as a result of prostate-specific antigen (PSA) screening and ‘multi-core’ schemes of prostate biopsy. These data suggest that a lot of the men with localised PCa would not, in fact, benefit from a definitive treatment. With the aim of reducing the risk of overtreatment in this subgroup of patients, two conservative management strategies have been proposed: • Watchful waiting (WW)  Also known as ‘deferred treatment’ or ‘symptom-guided treatment’, this term was coined in the pre-PSA screening era (before 1990) and referred to the conservative management of PCa until the development of local or systemic progression, at which point the patient would be treated palliatively (transurethral resection of the prostate [TURP] or other procedures for urinary tract obstruction, and hormonal therapy or radiotherapy for the palliation of metastatic lesions). • Active surveillance (AS)  Also known as ‘active monitoring’, this is the new term for the conservative management of PCa. Introduced in the past decade, it includes an active decision not to treat the patient immediately; to follow him with close surveillance and treat at pre-defined thresholds that classify progression (short PSA doubling time and deteriorating histopathological factors on repeat biopsy). In these cases, the treatment options are intended to be curative.

8.2

Deferred treatment of localised PCa (stage T1-T2, Nx-N0, M0)

8.2.1 Watchful waiting (WW) The rationale behind WW is the observation that PCa often progresses slowly, and is diagnosed in older men in whom there is a high incidence of co-morbidity and related high competitive mortality (5). WW can be considered as an option for treating patients with localised PCa in whom life expectancy is limited, or older patients with less aggressive cancers. There have been several attempts to summarise the key papers dealing with deferred treatment in patients with presumed localised PCa (6-10). Most of them present the same results as they analyse roughly the same series, but with a somewhat different methodology. The outcome studies on WW usually include patients whose PSA readings are not always available, and in whom the lesions are predominantly palpable, which would currently be defined as intermediate-risk tumours as described by D’Amico et al. (11). These studies include patients with a follow-up of up to 25 years, having as endpoints overall survival (OS) and disease-specific survival (DSS). Several WW series show a very consistent DSS ratio at 10 years, ranging from 82-87% (6, 12-17). In three studies with data beyond 15 years, the DSS was 80%, 79% and 58%, respectively (14, 16, 17). Two of them reported a 20-year DSS of 57% and 32%, respectively (14, 16). Chodak and co-workers reported a pooled analysis of the original data from 828 patients treated by WW (6). The paper is based on patients from six non-randomised studies (10, 18-23). The results describe cancerspecific survival (CSS) and metastasis-free survival after five and 10 years of follow-up (6) (level of evidence: 2b). Tumour grade is clearly significant, with very low survival rates for grade 3 tumours. Although the 10-year CSS rate is equally good (87%) for grade 1 and 2 tumours, the latter have a significantly higher progression rate, with 42% of these patients developing metastases (Table 8). Table 8: O  utcome of deferred treatment in localised PCa in relation to tumour grade (6): percentage of patients (95% confidence interval) surviving at five and 10 years. Grade Disease-specific survival Grade 1 Grade 2 Grade 3 Metastasis-free survival Grade 1 Grade 2 Grade 3

34

5 years (%)

10 years (%)

98 (96-99) 97 (93-98) 67 (51-79)

87 (81-91) 87 (80-92) 34 (19-50)

93 (90-95) 84 (79-89) 51 (36-64)

81 (75-86) 58 (49-66) 26 (13-41)

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The importance of tumour grade on survival after conservative management of PCa was also underlined in a large register study utilising the Surveillance, Epidemiology and End Results (SEER) database of the National Cancer Institute in the USA (12) (level of evidence: 3). Patients with grade 1, 2 and 3 tumours had 10-year CSS rates of 92%, 76% and 43%, respectively, correlating with the data from the pooled analysis. The paper by Chodak and co-workers also specifically described the outcome for stage T1a patients (6), with cancer-specific 10-year survival rates of 96% and 94%, respectively, for grade 1 and 2 tumours. The metastasis-free survival rate was 92% for patients with grade 1 tumours, but 78% for those with grade 2 tumours, indicating a higher risk of progression in individuals with moderately differentiated tumours. This difference in progression rate correlates with other studies on stage T1a disease (24, 25). In order to stage patients accurately and not overlook the presence of more extensive and/or more poorly differentiated tumours, repeat examinations with PSA measurement, transrectal ultrasound (TRUS) and needle biopsy of the prostate remnant have been advocated, especially in younger males with a long life expectancy (26). The impact of grade on the risk of tumour progression and ultimately death from PCa is also described in a paper by Albertsen and co-workers (27). They re-evaluated all biopsy specimens using the more widely accepted Gleason score, and showed that the risk of PCa death was very high in Gleason 7-10 tumours, intermediate in Gleason 6 tumours, but low in Gleason 2-5 cancers (Table 9) (28, 29) (level of evidence: 3). This paper also showed that Gleason 6-10 tumours carry a continuously increasing risk of ending the patient’s life for up to 15 years of follow-up after conservative management. The CSS curves for this group of patients have been published in a recent discussion article on different methods of assessing outcome in treatment for localised PCa (28). Table 9: The 15-year risk of dying from PCa in relation to Gleason score at diagnosis in patients with localised disease aged 55-74 years (27, 28). Gleason score Risk of cancer death* (%) Cancer-specific mortality† (%) 2-4 4-7 8 5 6-11 14 6 18-30 44 7 42-70 76 8-10 60-87 93 * The figures on the risk of cancer death differ for different age groups and represent the true risk in the studied population (taking actual competing mortality from other causes into consideration). † The cancer-specific mortality compensates for differences in competing mortality and indicates the outcome if the patient actually lived for 15 years. Three randomised clinical trials have reported long-term follow-up of patients randomised to WW or radical prostatectomy (RP): the first was in the pre-PSA screening era (29); the second was at the beginning of PSA screening (30); and the third was a recent study, the results from which are not yet mature (1). The Veterans Administration Cooperative Urological Research Group between 1967 and 1975, randomised 142 patients affected by clinical localised PCa. The study was underpowered to detected treatment differences (31). Between 1989 and 1999, the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) randomised 695 patients with clinical stage T1-T2 to WW (348) or RP (347) (Table 10) (30). This study began after PSA screening was introduced into clinical practice, but only 5% of men were diagnosed by screening. After a median followup of 10.8 years, this study showed a significant decrease in cancer-specific mortality, overall mortality, metastatic risk progression and local progression in patients treated with RP vs WW (level of evidence: 1b).

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Table 10: O  utcome of Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) at 10 years of follow-up (median of 8.2 years) (30). Disease-specific mortality Overall mortality Metastatic progression Local progression

RP (n 347) % (n) 9.6 (30) 27 (83) 15.2 (50) 19.2 (64)

WW (n 348) % (n) 14.9 (50) 32 (106) 35.4 (79) 44.3 (149)

Relative risk (95% CI) 0.56 (0.36-0.88) 0.74 (0.56-0.86) 0.60 (0.42-0.44) 0.33 (0.25-0.44)

p value 0.01 0.04 0.004 < 0.001

The results of three more years of follow-up were published recently. At 12 years’ follow-up, the group of patients treated with RP presented a favourably significant difference of 5.4% in PCa-specific mortality and 6.7% in non-metastatic progression (Table 11) (32) (level of evidence: 1b). Table 11: Outcome of Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) at 12 years of follow-up (median of 10.8 years) (32). Disease-specific mortality Metastatic progression

RP (n 347) % (n) 12.5 (43) 19.3

WW (n 348) % (n) 17.9 (68) 26

Relative risk (95% CI) 0.65 (0.2-11.1) 0.65 (0.47-0.88)

p value 0.03 0.006

The Prostate Cancer Intervention Versus Observation Trial: VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT) (1) is an ongoing controlled multicentre randomised clinical trial comparing RP with WW in patients with clinical stage T1-T2 disease. Between 1994 and 2002, 731 patients with a median age of 67 years were enrolled. The median PSA was 7.8 ng/mL (mean 10.2 ng/mL). Three-quarters of the men had clinical stage T1c disease. Using previously developed tumour risk categorisations incorporating PSA levels, Gleason histological grade and tumour stage, approximately 43% had low-risk, 36% had medium-risk and 20% had high-risk PCa. Follow-up is planned for 15 years, and the primary endpoint is the overall mortality. PIVOT enrolees are more representative of men being diagnosed and treated in contemporary clinical practice than were those enrolled in SPCG-4. In summary: • Clinical stage T1c currently represents 40-50% of new cases of PCa (33). The incidence of small, localised, well-differentiated PCa is increasing, mainly as a result of PSA screening and ‘multi-core’ schemes of prostate biopsy. • The SPCG-4 study demonstrated significant advantages for RP over WW, but only 5% of those studied were PSA-screened patients. • During the past 20 years, there has apparently been a shift towards higher Gleason scoring levels (34), even in cases evaluating microscopic foci of PCa. Some tumours previously given a Gleason score of 6 (3 + 3), might be scored as 7 (3 + 4) or more today. • The lead time in PSA screening is about 10 years (35, 36). It is therefore possible that the cancer mortality from untreated, non-screen-detected PCa in patients with contemporary Gleason scores of 6 might be as low as 10% at 20-year follow-up (37). It would seem that many small, localised, well-differentiated PCas will not progress, and radical therapy may lead to substantial overtreatment with consequent problems in terms of quality of life and socio-economic costs. 8.2.2 Active surveillance AS was conceived with the aim of reducing the ratio of overtreatment in patients with clinically confined lowrisk PCa, without giving up radical treatment, as happened with the WW strategy. Only data from non-mature randomised clinical trials of AS with follow-up < 10 years are currently available. A multicentre clinical trial of AS versus immediate treatment was opened in the USA in 2006. Its results are expected in 2025. Choo, Klotz and co-workers were the first to report on a prospective AS protocol (38, 39). They enrolled 331 patients with clinical stage T1c or T2a, PSA ≤ 10 ng/mL and a Gleason score ≤ 6 (PSA ≤ 15 and Gleason score ≤ 7 [3 + 4] in patients above the age of 70 years). At a median follow-up of eight years, the overall survival was

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85%, DSS and metastasis-free survival were 99%. The median value of the PSA doubling time was 7 years; in 42% of patients it was > 10 years, and in 22% < 3 years. Thirty-three per cent of the patients subsequently underwent a radical treatment: 20% for a PSA doubling time < 3 years; 5% for Gleason score progression on repeat biopsies; and 10% because of patient preference. Soloway et al., evaluating 175 patients with a median follow-up of four years, reported no PCa deaths or metastatic disease and a ratio of only 8% having delayed treatment (40). Carter et al., looking at 407 patients with a median follow-up of 3.4 years, reported no PCa deaths (41). All these studies confirm that, in well selected patients with low-risk disease, there is a very low rate of progression and cancer-specific death, and only a few patients require delayed radical intervention. However, another five to seven more years of follow-up will be necessary in order to obtain definitive results. Different series have identified several eligibility criteria for enrollers: • clinically confined PCa (T1-T2) • Gleason score ≤ 7 • PSA < 15-20 ng/mL (5). Moreover, different criteria were applied to define cancer progression (5), although all groups used: • a PSA doubling time with a cut off ranging between ≤ 2 and ≤ 4years • Gleason score progression to ≥ 7 at re-biopsy, at intervals ranging from one to four years. These indicators are poorly validated and, currently, it is impossible to make evidence-based recommendations on when to intervene in patients with a long life expectancy. Data that include PSA and PSA changes over time are relatively sparse in the literature. In a recent review article, it was pointed out that patients with a PSA of < 3 ng/mL had no mortality from PCa within the first 10 years, and that PSA changes over time were relatively unreliable in determining the risk for tumour progression (42). The data above indicate a high risk of tumour progression after conservative treatment for some patients with apparently localised PCa. This has been supported by the results of other studies in which patients with a life expectancy exceeding 10 years have been shown to have a higher mortality rate from PCa when left without curative treatment (43-45). Long-term follow-up of the Johansson series shows the same outcome: there is a higher risk of dying from PCa in patients surviving more than 15 years with well and moderately differentiated tumours at diagnosis (46) (level of evidence: 3). For patients who choose deferred treatment, the risk of delaying hormone therapy until disease progression has occurred appears to be modest, although shorter CSS times have been reported after deferred therapy compared with immediate hormone therapy in presumed localised PCa (not utilising PSA for staging) after 15 years of follow-up (47). In contradiction of Lundgren et al. (47), the report of the Casodex Early Prostate Cancer Trialists’ Group programme showed higher mortality in a group of men with localised PCa treated with bicalutamide 150 mg than in those who received placebo (48). In summary, it seems that hormonal therapy should be withheld until there is definitive proof of disease activity (progression), but it is open to speculation whether there might be some benefit in delivering it before the patient develops metastatic disease (see below).

8.3

Deferred treatment for locally advanced PCa (stage T3-T4, Nx-N0, M0)

The literature reporting on deferred treatment for locally advanced PCa is sparse. There are no randomised studies that compare more aggressive treatments, such as radiotherapy or surgery, with or without hormones. Most patients whose disease progresses after deferred treatment of locally advanced PCa will be candidates for hormone therapy. There are reports from non-randomised studies showing that hormone treatment may safely be delayed until metastatic progression occurs, as no survival advantage was noted between patients treated with immediate orchiectomy compared with delayed treatment (49, 50). In a recent prospective randomised clinical phase III trial (EORTC 30981), 985 patients with T0-4 N0-2 M0 prostate cancer were randomly assigned to immediate androgen-deprivation therapy (ADT) or received ADT

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37

only on symptomatic disease progression or occurrence of serious complications (51, 52). After a median follow-up of 7.8 years, the overall survival hazard ratio was 1.25 (95% CI, 1.05-1.48; non-inferiority p > 0.1) favouring immediate treatment, seemingly due to fewer deaths of non-prostatic cancer causes (p = 0.06). The time from randomisation to progression of hormone refractory disease did not differ significantly, nor did prostate cancer-specific survival. The median time to the start of deferred treatment after study entry was seven years. In this group, 126 patients (25.6%) died without ever needing treatment (44% of the deaths in this arm). The conclusion drawn from this study is that immediate ADT resulted in a modest but statistically significant increase in overall survival but no significant difference in prostate cancer mortality or symptomfree survival. Furthermore, the authors identified significant risk factors associated with a significantly worse outcome: in both arms, patients with a baseline PSA > 50 ng/mL were at a > 3.5-fold higher risk of dying of PCa than patients with a baseline PSA ≤ to 8 ng/mL. If the baseline PSA was between 8 ng/mL and 50 ng/ mL, the risk of PCa death was approximately 7.5-fold higher in patients with a PSA doubling time < 12 months than in patients with a PSA doubling time > 12 months. The time to PSA relapse after response to immediate ADT correlated significantly with baseline PSA, suggesting that baseline PSA may also reflect disease aggressiveness. However, when early and delayed treatments were compared in a large randomised trial carried out by the Medical Research Council (MRC), a survival benefit for immediate hormone therapy was demonstrated (53), comparable with the results of the Lundgren et al. study mentioned above (47) (level of evidence: 1b). Also, a comparison of bicalutamide, 150 mg/day, with placebo showed that progression-free survival was better with early treatment in patients with locally advanced PCa (48) (level of evidence: 1b). Fifty selected asymptomatic patients (mean age 71 years) with highly or moderately differentiated stage T3 M0 PCa were followed up for 169 months (54). The five- and 10-year CSS rates were 90% and 74%, respectively, and the likelihood of being without treatment at five and 10 years was 40% and 30%, respectively. The authors concluded that WW might be a treatment option for selected patients with non-poorly differentiated T3 tumours and a life expectancy of less than 10 years (level of evidence: 3).

8.4

Deferred treatment for metastatic PCa (stage M1)

There are only very sparse data on this subject. The only candidates for such treatment should be asymptomatic patients with a strong wish to avoid treatment-related side-effects (level of evidence: 4). As the median survival time is about two years, the time without any treatment (before symptoms occur) is very short in most cases. The MRC trial highlighted the risk of developing symptoms (pathological fractures, spinal cord compression), and even death from PCa, without receiving the possible benefit from hormone treatment (53, 55) (level of evidence:1b). If a deferred treatment policy is chosen for a patient with advanced PCa, close follow-up must be possible.

8.5 Summary of deferred treatment 8.5.1 Indications In presumed localised PCa (Nx-N0, M0): • Stage T1a: well and moderately differentiated tumours. In younger patients with a life expectancy of > 10 years, re-evaluation with PSA, TRUS and biopsies of the prostatic remnant is recommended (level of evidence: 2a). • Stage T1b-T2b: well and moderately differentiated tumours. In asymptomatic patients with a life expectancy of < 10 years (level of evidence: 2a). 8.5.2 Options In presumed localised PCa (Nx-N0, M0): • stage T1b-T2b patients who are well informed and have well differentiated (or Gleason 2-4) PCa and a life expectancy of 10-15 years • all patients not willing to accept side-effects of active treatment • well informed, asymptomatic patients with high PSA levels for whom cure is unlikely (level of evidence: 3). In locally advanced disease (stage T3-T4): • asymptomatic patients with well or moderately differentiated cancer, PCa and a short life expectancy (level of evidence: 3) • PSA < 50 ng/mL and PSA doubling time > 12 months (level of evidence: 1).

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In metastatic disease (M1): • a very rare patient without any symptoms and the possibility of close follow-up (level of evidence: 4).

8.6

REFERENCES

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Wilt TJ, Brawer MK, Barry MJ, Jones KM, Kwon Y, Gingrich JR, Aronson WJ, Nsouli I, Iyer P, Cartagena R, Snider G, Roehrborn C, Fox S. The Prostate Cancer Intervention Versus Observation Trial: VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT): design and baseline results of a randomized controlled trial comparing radical prostatectomy to watchful waiting for men with clinically localized prostate cancer. Contemp Clin Trials 2009;30(1):81-7. http://www.ncbi.nlm.nih.gov/pubmed/18783735 Rullis I, Schaeffer JA, Lilien OM. Incidence of prostatic carcinoma in the elderly. Urology 1975;6(3):295-7. http://www.ncbi.nlm.nih.gov/pubmed/1172317 Sakr, WA, Grignon, DJ, Crissman JD, Heilbrun LK, Cassin BJ, Pontes JJ, Haas GP. High grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma between the ages of 20-69: an autopsy study of 249 cases. In Vivo 1994;8(3):439-43. http://www.ncbi.nlm.nih.gov/pubmed/7803731 Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ. Cancer statistics, 2006. CA Cancer J Clin 2006;56(2):106-30. http://caonline.amcancersoc.org/cgi/content/full/56/2/106 Adolfsson J .Watchful waiting and active surveillance: the current position. BJU Int 2008;102(1):10-4. http://www.ncbi.nlm.nih.gov/pubmed/18422774 Chodak GW, Thisted RA, Gerber GS, Johansson JE, Adolfsson J, Jones GW, Chisholm GD, Moskovitz B, Livne PM, Warner J. Results of conservative management of clinically localized prostate cancer. N Engl J Med 1994;330(4):242-8. http://www.ncbi.nlm.nih.gov/pubmed/8272085 Middleton RG, Thompson IM, Austenfeld MS, Cooner WH, Correa RJ, Gibbons RP, Miller HC, Oesterling JE, Resnick MI, Smalley SR, Wasson JH. Prostate Cancer Clinical Guidelines Panel Summary report on the management of clinically localized prostate cancer. The American Urological Association. J Urol 1995;154(6):2144-8. http://www.ncbi.nlm.nih.gov/pubmed/7500479 Thompson IM. Observation alone in the management of localized prostate cancer: the natural history of untreated disease. Urology 1994;43(2Suppl.):41-6. http://www.ncbi.nlm.nih.gov/pubmed/8272085 Schellhammer PF. Contemporary expectant therapy series: a viewpoint. Urology Symposium 1994;44(6A):47-52. Adolfsson J, Steineck G, Whitmore WF Jr. Recent results of management of palpable clinically localized prostate cancer. Cancer 1993;72(2):310-22. http://4www.ncbi.nlm.nih.gov/pubmed/8319164 D’Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA, Tomaszewski JE, Renshaw AA, Kaplan I, Beard CJ, Wein A. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280(11):969-74. http://jama.ama-assn.org/cgi/content/full/280/11/969 Lu-Yao GL, Yao SL. Population-based study of long-term survival in patients with clinically localised prostate cancer. Lancet 1997;349(9056):906-10. http://www.ncbi.nlm.nih.gov/pubmed/9093251 Sandblom G, Dufmats M, Varenhorst E. Long-term survival in a Swedish population-based cohort of men with prostate cancer. Urology 2000;56(3):442-7. http://www.ncbi.nlm.nih.gov/pubmed/10962312 Johansson JE, Adami HO, Andersson SO, Bergström R, Krusemo UB, Kraaz W. Natural history of localized prostatic cancer. A population-based study in 223 untreated patients. Lancet 1989;1(8642):799-803. http://www.ncbi.nlm.nih.gov/pubmed/2564901 Bill-Axelson A, Holmberg L, Ruutu M, Häggman M, Andersson SO, Bratell S, Spångberg A, Busch C, Nordling S, Garmo H, Palmgren J, Adami HO, Norlén BJ, Johansson JE; for the Scandinavian Prostate Cancer Group Study No. 4. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2005;352(19):1977-84. http://content.nejm.org/cgi/content/full/352/19/1977

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Adolfsson J, Tribukait B, Levitt S. The 20-yr outcome in patients with well- or moderately differentiated clinically localized prostate cancer diagnosed in the pre-PSA era: the prognostic value of tumour ploidy and comorbidity. Eur Urol 2007 Oct;52(4):1028-35. http://www.ncbi.nlm.nih.gov/pubmed/17467883 17. Jonsson E, Sigbjarnarson HP, Tomasson J, Benediktsdottir KR, Tryggvadottir L, Hrafnkelsson J, Olafsdottir EJ, Tulinius H, Jonasson JG. Adenocarcinoma of the prostate in Iceland: a populationbased study of stage, Gleason grade, treatment and long-term survival in males diagnosed between 1983 and 1987. Scand J Urol Nephrol 2006;40(4):265-71. http://www.ncbi.nlm.nih.gov/pubmed/16916765 18. Moskovitz B, Nitecki A, Richter Levin D. Cancer of the prostate: is there a need for aggressive treatment? Urol Int 1987;42(1):49-52. http://www.ncbi.nlm.nih.gov/pubmed/3590404 19. Goodman CM, Busuttil A, Chisholm GD. Age, and size and grade of tumour predict prognosis in incidentally diagnosed carcinoma of the prostate. Br J Urol 1988;62(6):576-80. http://www.ncbi.nlm.nih.gov/pubmed/3219513 20. Jones GW. Prospective, conservative management of localized prostate cancer. Cancer 1992;70(1Suppl.):307-10. http://www.ncbi.nlm.nih.gov/pubmed/1600492 21. Whitmore WF Jr, Warner JA, Thompson IM Jr. Expectant management of localized prostatic cancer. Cancer 1991;67(4):1091-6. http://www.ncbi.nlm.nih.gov/pubmed/1991257 22. Adolfsson J, Carstensen J, Löwhagen T. Deferred treatment in clinically localised prostatic carcinoma. Br J Urol 1992;69(2):183-7. http://www.ncbi.nlm.nih.gov/pubmed/1537031 23. Johansson JE, Adami HO, Andersson SO, Bergström R, Holmberg L, Krusemo UB. High 10-year survival rate in patients with early, untreated prostatic cancer. JAMA 1992;267(16):2191-6. http://www.ncbi.nlm.nih.gov/pubmed/1556796 24. Lowe BA. Management of stage T1a Prostate cancer. Semin Urol Oncol 1996;14(3):178-82. http://www.ncbi.nlm.nih.gov/pubmed/8865481 25. Loughlin KR, Renshaw AA, Kumar S. Expectant management of stage A-1 (T1a) prostate cancer utilizing serum PSA levels: a preliminary report. J Surg Oncol 1999;70(1):49-53. http://www.ncbi.nlm.nih.gov/pubmed/9989421 26. Griebling TL, Williams RD. Staging of incidentally detected prostate cancer: role of repeat resection, prostate-specific antigen, needle biopsy, and imaging. Semin Urol Oncol 1996;14(3):156-64. http://www.ncbi.nlm.nih.gov/pubmed/8865478 27. Albertsen PC, Hanley JA, Gleason DF, Barry MJ. Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA 1998;280(11): 975-80. http://www.ncbi.nlm.nih.gov/pubmed/9749479 28. Albertsen P, Hanley JA, Murphy-Setzko M. Statistical considerations when assessing outcomes following treatment for prostate cancer. J Urol 1999;162(2):439-44. http://www.ncbi.nlm.nih.gov/pubmed/10411053 29. Iversen P, Johansson JE, Lodding P, Lukkarinen O, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Carroll K; Scandinavian Prostatic Cancer Group. Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3-year median followup from the Scandinavian Prostate Cancer Group Study Number 6. J Urol 2004 Nov;172(5Pt1):1871-6. http://www.ncbi.nlm.nih.gov/pubmed/15540741 30. Holmberg L, Bill-Axelson A, Helgesen F, Salo JO, Folmerz P, Haggman M, Andersson SO, Spangberg A, Busch C, Nordling S, Palmgren J, Adami HO, Johansson JE, Norlen BJ; Scandinavian Prostatic Cancer Group Study Number 4. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med. 2002;347(11):781-9. http://www.ncbi.nlm.nih.gov/pubmed/12226148 31. Iversen P, Madsen PO, Corle DK. Radical prostatectomy versus expectant treatment for early carcinoma of the prostate. Twenty-three year follow-up of a prospective randomized study. Scand J Urol Nephrol Suppl 1995;172:65-72. http://www.ncbi.nlm.nih.gov/pubmed/8578259

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32.

Bill-Axelson A, Holmberg L, Filén F, Ruutu M, Garmo H, Busch C, Nordling S, Häggman M, Andersson SO, Bratell S, Spångberg A, Palmgren J, Adami HO, Johansson JE; Scandinavian prostate cancer Group Study Number 4. Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian prostate cancer group-4 randomized trial. J Natl Cancer Inst 2008;100(16):1144-54. http://jnci.oxfordjournals.org/cgi/content/full/100/16/1144 33. Klotz L. Active surveillance for prostate cancer: trials and tribulations. World J Urol 2008;26(5):437-42. http://www.ncbi.nlm.nih.gov/pubmed/18813934 34. Albertsen PC, Hanley JA, Barrows GH, Penson DF, Kowalczyk PD, Sanders MM, Fine J. Prostate cancer and the Will Rogers phenomenon. J Natl Cancer Inst 2005;97(17):1248-53. http://www.ncbi.nlm.nih.gov/pubmed/16145045 35. Draisma G, Boer R, Otto SJ, van der Cruijsen IW, Damhuis RA, Schröder FH, de Koning HJ. Lead times and overdetection due to prostate-specific antigen screening: estimates from the European Randomized Study of Screening for prostate cancer. J Natl Cancer Inst 2003;95(12):868-78. http://www.ncbi.nlm.nih.gov/pubmed/12813170 36. Törnblom M, Eriksson H, Franzén S, Gustafsson O, Lilja H, Norming U, Hugosson J. Lead time associated with screening for prostate cancer. Int J Cancer 2004;108(1):122-9. http://www.ncbi.nlm.nih.gov/pubmed/14618626 37. Klotz L. Active surveillance for favorable-risk prostate cancer: who, how and why? Nat Clin Pract Oncol 2007;4(12):692-8. http://www.nature.com/ncponc/journal/v4/n12/full/ncponc0966.html 38. Choo R, Klotz L, Danjoux C, Morton GC, DeBoer G, Szumacher E, Fleshner N, Bunting P, Hruby G. Feasibility study: watchful waiting for localized low to intermediate grade prostate carcinoma with selective delayed intervention based on prostate specific antigen, histological and/or clinical progression. J Urol 2002;167(4):1664-9. http://www.ncbi.nlm.nih.gov/pubmed/11912384 39. Choo R, DeBoer G, Klotz L, Danjoux C, Morton GC, Rakovitch E, Fleshner N, Bunting P, Kapusta L, Hruby G. PSA doubling time of prostate carcinoma managed with watchful observation alone. Int J Radiat Oncol Biol Phys 2001;50(3):615-20. http://www.ncbi.nlm.nih.gov/pubmed/11395227 40. Soloway MS, Soloway CT, Williams S, Ayyathurai R, Kava B, Manoharan M. Active surveillance; a reasonable management alternative for patients with prostate cancer: the Miami experience. BJU Int 2008;101(2):165-9. http://www.ncbi.nlm.nih.gov/pubmed/17850361 41. Carter HB, Kettermann A, Warlick C, Metter EJ, Landis P, Walsh PC, Epstein JI. Expectant management of prostate cancer with curative intent: an update of the Johns Hopkins experience. J Urol 2007;178(6):2359-64. http://www.ncbi.nlm.nih.gov/pubmed/17936806 42. Schmid HP, Adolfsson J, Aus G. Active monitoring (deferred treatment or watchful waiting) in the treatment of prostate cancer. A review. Eur Urol 2001;40(5):488-94. http://www.ncbi.nlm.nih.gov/pubmed/11752854 43. Aus G, Hugosson J, Norlén L. Long-term survival and mortality in prostate cancer treated with noncurative intent. J Urol 1995;154(2 PT 1):460-5. http://www.ncbi.nlm.nih.gov/pubmed/7541864 44. Hugosson J, Aus G, Bergdahl C, Bergdahl S. Prostate cancer mortality in patients surviving more than 10 years after diagnosis. J Urol 1995;154(6):2115-17. http://www.ncbi.nlm.nih.gov/pubmed/7500471 45. Brasso K, Friis S, Juel K, Jorgensen T, Iversen P. Mortality of patients with clinically localized prostate cancer treated with observation for 10 years or longer: a population based study. J Urol 1999;161(2):524-8. http://www.ncbi.nlm.nih.gov/pubmed/9915440 46. Johansson JE, Andrén O, Andersson SO, Dickman PW, Holmberg L, Magnuson A, Adami HO. Natural history of early, localized prostate cancer. JAMA 2004;291(22):2713-19. http://www.ncbi.nlm.nih.gov/pubmed/15187052 47. Lundgren R, Nordle O, Josefsson K. Immediate estrogen or estramustine phosphate therapy versus deferred endocrine treatment in nonmetastatic prostate cancer: a randomized multicentre study with 15 years of followup. The South Sweden Prostate Cancer Study Group. J Urol 1995;153(5):1580-6. http://www.ncbi.nlm.nih.gov/pubmed/7714978 48. Wirth MP, See WA, McLeod DG, Iversen P, Morris T, Carroll K; Casodex Early Prostate Cancer Trialists’ Group. Bicalutamide 150 mg in addition to standard care in patients with localized or locally advanced prostate cancer: results from the second analysis of the early prostate cancer program at

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49.

50.

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53.

54.

55.

median followup of 5.4 years. J Urol 2004;172(5Pt1):1865-70. http://www.ncbi.nlm.nih.gov/pubmed/15540740 Rana A, Chisholm GD, Khan M, Rashwan HM, Elton RA. Conservative management with symptomatic treatment and delayed hormonal manipulation is justified in men with locally advanced carcinoma of the prostate. Br J Urol 1994;74(5):637-41. http://www.ncbi.nlm.nih.gov/pubmed/7827816 Parker MC, Cook A, Riddle PR, Fryatt I, O’Sullivan J, Shearer RJ. Is delayed treatment justified in carcinoma of the prostate? Br J Urol 1985;57(6):724-8. http://www.ncbi.nlm.nih.gov/pubmed/4084734 Studer UE, Whelan P, Albrecht W, Casselman J, de Reijke T, Hauri D, Loidl W, Isorna S, Sundaram SK, Debois M, Collette L. Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer (EORTC) Trial 30891. J Clin Oncol 2006;24(12):1868-76. http://www.ncbi.nlm.nih.gov/pubmed/16622261 Studer UE, Collette L, Whelan P, Albrecht W, Casselman J, de Reijke T, Knönagel H, Loidl W, Isorna S, Sundaram SK, Debois M; EORTC Genitourinary Group. Using PSA to guide timing of androgen deprivation in patients with T0-4 N0-2 M0 prostate cancer not suitable for local curative treatment (EORTC 30891). Eur Urol 2008;53(5):941-9. http://www.ncbi.nlm.nih.gov/pubmed/18191322 The Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. Br J Urol 1997;79(2):235-46. [No authors listed.] http://www.ncbi.nlm.nih.gov/pubmed/9052476 Adolfsson J, Steineck G, Hedlund PO. Deferred treatment of locally advanced non-metastatic prostate cancer: a long-term followup. J Urol 1999;161(2):505-8. http://www.ncbi.nlm.nih.gov/pubmed/9915436 Walsh PC. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council trial. The Medical Research Council Prostate Cancer Working Party Investigators Group. J Urol 1997;158(4):1623-4. http://www.ncbi.nlm.nih.gov/pubmed/9302187

9. TREATMENT: RADICAL PROSTATECTOMY 9.1

Introduction

The surgical treatment of prostate cancer (PCa) consists of radical prostatectomy (RP), which is the removal of the entire prostate gland between the urethra and the bladder, with resection of both seminal vesicles. In men with localised PCa and a life expectancy of 10 years or more, the goal of an RP by any approach must be eradication of the disease (1). There is no age threshold for RP. A patient should not be denied this procedure on the grounds of age alone (2). In fact, increasing co-morbidity with age greatly increases the risk of dying from non-PCa related causes (3, 4). Life expectancy estimation is paramount in the counselling of a patient for surgery. Radical prostatectomy was first applied at the beginning of the 20th century by Young (5) using a perineal approach, while Memmelaar and Millin were the first to perform retropubic RP (6). In 1982, Walsh and Donker described the anatomy of the dorsal venous complex and the neurovascular bundles. This resulted in a significant reduction of blood loss and improved continence and potency rates (7). Currently, radical prostatectomy is the only treatment for localised PCa that has shown a cancer-specific survival benefit when compared with conservative management in a prospective, randomised trial (8). Surgical expertise has decreased the complication rates and improved cancer cure (9-12). The retropubic approach is more commonly performed, as it enables simultaneous pelvic lymph node assessment to be carried out, which is an advantage over the perineal approach. It has been suggested that perineal radical prostatectomy might result in positive surgical margins more often than the retropubic approach (13), but this has not been confirmed (14). In the past 5-10 years, several European centres have acquired considerable experience with laparoscopic radical prostatectomy (15-18). More recently, the robotic-assisted laparoscopic RP has been developed. It is

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likely that laparoscopic, robot-assisted and perineal prostatectomies have lower morbidity than the retropubic operation, but randomised studies are as yet unavailable. Functional and short-term oncological outcomes of laparoscopic and robot-assisted RP seem comparable with the open technique in high-volume centres. However, long-term oncological outcomes are still unavailable (19).

9.2

Low-risk, localised PCa: cT1-T2a and Gleason score 2-6 and PSA < 10

9.2.1 Stage T1a-T1b PCa Stage T1a PCa is defined as an incidental histological finding of cancer in 5% or less of resected prostatic tissue (transurethral resection of the prostate [TURP] or open adenomectomy). Stage T1b PCa is defined as > 5% cancer. A recent Swedish register-based study in 23,288 men with incidental PCa detected at TURP or open adenoma enucleation showed a 10-year PCa mortality of 26.6%. No details on prostate-specific antigen (PSA) or Gleason score were provided. Neither were details available on the numbers of cases with cT1a or cT1b PCa (20). Although the risk of disease progression of untreated T1a PCa after five years is only 5%, these cancers can progress in about 50% of cases after 10-13 years (21). Thus, in younger patients with a life-expectancy of 15 years or more, the chance of disease progression is real. An RP may also be offered when the Gleason score is > 6. In contrast, most patients with T1b tumours are expected to show disease progression after five years, and aggressive treatment is often warranted (21). Patients with T1b lesions are offered RP when they have a life expectancy of 10 years or more. It is consequently very important to distinguish between T1a and T1b tumours. Systematic prostate biopsies of the remnant prostate may be useful to detect concomitant peripheral zone cancer, or to ascertain a more correct tumour grade. RP may be very difficult after a thorough TURP, when almost no residual prostate is left behind (22). 9.2.2 Stage T1c and T2a PCa Clinically unapparent tumour identified by needle biopsy because of an elevated PSA (cT1c) has become the most prevalent PCa. In an individual patient, it is difficult to differentiate between clinically insignificant and life-threatening PCa. Most reports, however, stress that cT1c tumours are mostly significant and should not be left untreated since up to 30% of cT1c tumours are locally advanced disease at final histopathology (23). The proportion of insignificant tumours varies between 11% and 16% (24, 25). Increasing the number of biopsies might carry the risk of detecting a higher number of insignificant cancers. However, a recent study has shown that increasing the number of biopsies to 12 did not increase the number of insignificant tumours (26). The major problem is how to recognise those tumours that do not need RP. The biopsy findings and the free PSA ratio are helpful in predicting insignificant disease (27). Partin tables may be very helpful in better selecting patients requiring surgical treatment because of their ability to provide an estimation of the final pathological stage (28). Other authors have suggested the incorporation of biopsy information, such as the number of cores or the percentage of cores invaded (29). When only one or a few cores are invaded and the percentage of invasion in one core is limited, the chance of finding an insignificant PCa is more likely, certainly when the lesion is of low Gleason grade (30). It might be reasonable to follow up some patients whose tumours are most likely to be insignificant. In general, however, RP should be advocated for patients with T1c tumours, bearing in mind that significant tumours will be found in most of these individuals. T2a patients with a 10-year life expectancy should be offered RP since 35-55% of them will have disease progression after five years if not treated. If watchful waiting (WW) is proposed for low-grade T2 cancer, it should be remembered that pre-operative assessment of tumour grade by needle biopsy is often unreliable (31). As a rule of thumb, an extended pelvic lymph node dissection (eLND) is not necessary in low-risk, localised PCa, as the risk for positive lymph nodes does not exceed 7% (32). A limited lymph node dissection should no longer be performed, as this will miss at least half of the nodes involved.

9.3

Intermediate-risk, localised PCa: cT2b-T2c or Gleason score = 7 or PSA 10-20

RP is one of the recommended standard treatments for patients with intermediate-risk PCa and a life

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expectancy of more than 10 years (33). The prognosis is excellent when the tumour is confined to the prostate based on pathological examination (34, 35). A policy of WW has been proposed for some patients with intermediate-risk localised tumours (36). However, when the tumour is palpable or visible on imaging and clinically still confined to the prostate, disease progression can be expected in most long-term survivors. The median time to progression of untreated T2 disease is reported to be 6-10 years. T2b cancer still confined to the prostate but involving more than half of a lobe or both lobes will progress in more than 70% of patients within five years (37). These data have been confirmed by a large randomised trial comparing RP and WW that included mostly T2 PCa patients showing a significant reduction in disease-specific mortality in favour of RP (8). Total surgical removal is an excellent option, and, if performed by an experienced surgeon, the patient’s subsequent quality of life should be satisfactory. Lower rates of positive surgical margins for high-volume surgeons suggest that experience and careful attention to surgical details, adjusted for the characteristics of the cancer being treated, can decrease positive surgical margin rates and improve cancer control with RP (38). As a rule of thumb, an eLND should be performed if the estimated risk for positive lymph nodes exceeds 7% (32). In all other cases, an eLND can be omitted, accepting a low risk of missing positive nodes. A limited lymph node dissection should no longer be performed, as this will miss at least half of the nodes involved. 9.3.1 Oncological results of RP in low-and intermediate risk PCa The results achieved in a number of studies involving RP are shown in Table 12. Table 12: Oncological results of RP in organ-confined disease Reference (no.) Han et al. (2001) (39) Catalona and Smith (1994) (40)

2404 925

Mean follow-up (months) 75* 28

Hull et al. (2002) (41)

1000

53

–

75

601

34

69

47

3170

60

70

52

Trapasso et al. (1994) (42) Zincke et al. (1994) (43) * = 15-year, 66%.

9.4

No. of patients

5-year PSA-free survival (%) 84 78

10-year PSA-free survival (%) 74 65

High-risk localised PCa: cT3a or Gleason score 8-10 or PSA > 20

The widespread use of PSA testing has led to a significant migration of stage and grade of PCa, with > 90% of men in the current era diagnosed with clinically localised disease (44). Despite the trends towards lower risk PCa, 20-35% of patients with newly diagnosed PCa are still classified as high risk, based on either PSA > 20 ng/mL, Gleason score > 8, or an advanced clinical stage (45). There is no consensus regarding the optimal treatment of men with high-risk PCa. 9.4.1 Locally advanced PCa: cT3a T3a cancer is defined as cancer that has perforated the prostate capsule. In the past, locally advanced PCa was seen in about 40% of all clinically diagnosed tumours. This figure is lower today, although its management remains controversial. Surgical treatment of clinical stage T3 PCa has traditionally been discouraged (46), mainly because patients have an increased risk of positive surgical margins and lymph node metastases and/or distant relapse (47, 48). Several randomised studies on radiotherapy with androgen-deprivation therapy (ADT) vs radiotherapy alone showed a clear advantage for the combination treatment. However, no trial has ever shown this approach to be superior to RP (49). Another problem is ‘contamination’ by the additional use of either adjuvant radiotherapy or immediate or delayed hormonal treatment in most of the series reporting the treatment of clinical T3 PCa. In recent years, there has been renewed interest in surgery for locally advanced PCa, and several retrospective case-series have been published. Although still controversial, it is increasingly evident that surgery has a place in treating locally advanced disease (50-55). Overstaging of cT3 PCa is relatively frequent and occurs in 13-27% of cases. These pT2 patients and patients with specimen-confined pT3 disease have similarly good biochemical and clinical PFS (54, 55). In about 33.5-

44

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66% of patients, positive section margins will be present, and 7.9-49% will have positive lymph nodes (56). Thus, 56-78% of patients primarily treated by surgery eventually require adjuvant or salvage radiotherapy or hormonal therapy (54, 55). Nevertheless, excellent 5-, 10- and 15-year overall survival (OS) and cancer-specific survival (CSS) rates have been published (Table 2). These rates surpass radiotherapy-alone series and are no different from radiotherapy combined with adjuvant hormonal therapy series (49). The problem remains the selection of patients before surgery that have neither lymph node involvement nor seminal vesicle invasion. Nomograms, including PSA level, stage and Gleason score, can be useful in predicting the pathological stage of disease (28, 56). In addition, nodal imaging with computed tomography (CT), and seminal vesicle imaging with magnetic resonance imaging (MRI), or directed specific puncture biopsies of the nodes or seminal vesicles can be helpful in recognising those patients unlikely to benefit from a surgical approach (57). RP for clinical T3 cancer requires sufficient surgical expertise to keep the level of morbidity acceptable. Increased overall surgical experience must contribute to a decreased operative morbidity and to better functional results after RP for clinical T3 cancer (54, 58). Table 13: Overall and cancer-specific survival rates for prostate cancer Survival no. of Median and/ OS (%) CSS (%) BPFS (%) CPFS (%) rate patients or mean 5 y 10 y 15 y 5 y 10 y 15 y 5 y 10 y 15 y 5 y 10 y 15 y survival rate Yamada 57 Median, 5.4 y 91.2 - - 45.5 - 81.4 et al. (77.6 at 7.5 y) (PSA > 0.4) (1994) (50) Gerber 242 Mean, 39 m - 85 57 - - 72 32 et al. Median, 26 m (meta free) (1997) (51) Van den 83 Median, 52 m 75 60 - 85 72 - 29 59 31 Ouden (PSA > 0.1) et al. (1998) (52) Isorna 83 Mean, 68.7 m 97.6 94.8 - 100 - 59.8 - Martinez (cT3a only) (PSA > 0.3) de la Riva et al. (2004) (53) Ward 841 Median, 10.3 y 90 76 53 95 90 79 58 43 38 85 73 67 et al. (PSA > 0.4) (2005) (54) Hsu et al. 200 Mean, 70.6 m 95.9 77 - 98.7 91.6 - 59.5 51.1 - 95.9 85.4 (2007) (55) (cT3a only) (PSA > 0.2) BPFS = biochemical progression-free survival; CSS = cancer-specific survival; CPFS = clinical progression-free survival; OS = overall survival; PSA = prostate-specific antigen. 9.4.2 High-grade PCa: Gleason score 8-10 Although most poorly differentiated tumours extend outside the prostate, the incidence of organconfined disease is between 26% and 31%. Patients with high-grade tumours confined to the prostate at histopathological examination still have a good prognosis after RP. Furthermore, one third of patients with a biopsy Gleason score ≥ 8 may in fact have a specimen Gleason score ≤ 7 with better prognostic characteristics. PSA value and the % of positive prostate biopsies may be helpful in selecting men with highgrade prostate cancer most likely to benefit from RP (59). 9.4.3 PCa with PSA > 20 Yossepowitch et al. reported the results of RP as a monotherapy in men with PSA > 20 ng/mL in a cohort with mostly clinically organ-confined tumours, and found a PSA failure rate of 44% and 53% at five and 10 years, respectively (60). D’Amico et al. found that men with PSA levels > 20 ng/mL had a 50% risk of PSA failure at five years after RP (61). Tiguert and co-workers presented the outcome for an identical cohort of patients who had a disease-free survival of 65% at five years after RP (62). More recently, Inman and co-workers described

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the long-term outcomes of RP with multimodal adjuvant therapy in men with PSA ≥ 50. Systemic progressionfree survival rates at 10 years were 83% and 74% for PSA 50-99 and ≥ 100, respectively, while overall CSS was 87%. These results argue for aggressive management with RP as initial step (63). As a rule of thumb, an eLND should be performed in all high-risk cases, as the estimated risk for positive lymph nodes will be in the range 15-40% (32). A limited lymph node dissection should no longer be performed, as this will miss at least half of the nodes involved.

9.5

Very high-risk localised prostate cancer: cT3b-T4 N0 or any T, N1

9.5.1 cT3b-T4 N0 Men with very high-risk PCa generally have a significant risk of disease progression and cancer-related death if left untreated. Very high-risk patients present two specific challenges. There is a need for local control as well as a need to treat any microscopic metastases likely to be present but undetectable until disease progression. The optimal treatment approach will therefore often necessitate multiple modalities. The exact combinations, timing and intensity of treatment continue to be strongly debated. Management decisions should be made after all treatments have been discussed by a multidisciplinary team (including urologists, oncologists, radiologists and pathologists), and after the balance of benefits and side-effects of each therapy modality has been considered by the patient with regard to his own individual circumstances. Provided that the tumour is not fixed to the pelvic wall, or that there is no invasion of the urethral sphincter, RP may be considered a reasonable first step in a selection of patients with low tumour volume. 9.5.2 Any T, N1 The indication for RP in all previously described stages assumes the absence of nodal involvement. Lymph node-positive (N+) disease will mostly be followed by systemic disease progression, and all patients with significant N+ disease will ultimately fail treatment. Nevertheless, the combination of RP and simultaneous hormonal treatment has been shown to achieve a 10-year CSS rate of 80% (64). However, it is questionable whether or not these results could also have been obtained with hormonal treatment alone. Most urologists are reluctant to perform RP for clinical N+ disease, or will cancel surgery if a frozen section shows lymph node invasion. It should also be noted that the definitive pathological examination after RP can show microscopic lymph node invasion. The incidence of tumour progression is lower in patients with fewer positive lymph nodes and in those with microscopic invasion only (65, 66). Clinical N+ patients usually have significant nodal involvement and will be treated with hormonal manipulation only. In patients who prove to be pN+ after RP, adjuvant hormonal treatment can be advocated, but the benefits should be judged against the side-effects of long-term hormonal therapy. PSA follow-up and hormonal treatment in the case of an increase in PSA level is therefore an acceptable option in selected cases. The most accurate staging method for the assessment of lymph node involvement is eLND. This includes removal of al node-bearing tissue from the area bounded by the external iliac vein anteriorly, the lateral pelvic side wall, the bladder wall medially, the floor of the pelvis posteriorly, Cooper’s ligament distally, and the internal iliac artery proximally. During recent years, there has been increasing interest in eLND, but controversy regarding indication and extent of ELND, its therapeutic role and morbidity remain. 9.5.2.1 Indication and extent of extrended pelvic lymph node dissectiori (eLND) Although it is generally accepted that eLND provides important information for prognosis (number of nodes involved, tumour volume, capsular perforation) that cannot be matched by any other current procedures, consensus has not been reached as to when eLND is indicated and to what extent it should be performed. When making such decisions, many physicians rely on nomograms based on pre-operative biochemical markers and biopsies (28). According to these nomograms, patients with a PSA value < 10 ng/mL and a biopsy Gleason score < 7 have a low risk of lymph node metastasis and, therefore, eLND might not be beneficial. However, the fact that most of these nomograms are based on a limited eLND (obturator fossa and external iliac vein) probably results in underestimation of the incidence of patients with positive nodes (32). Lymphography studies have shown that the prostate drains not only to the obturator and external iliac but also to the internal iliac and pre-sacral lymph nodes. Performing an eLND results in removal of all lymph nodes in these particular anatomical regions, producing a higher yield of removed lymph nodes (mean of 20 nodes) compared with limited LND (mean of 8-10 nodes). In patients with a PSA value < 10 and a Gleason score ≥ 7, an incidence of 25% nodal involvement was reported (67). Different reports mention that 19-35% of positive lymph nodes are found exclusively outside the area of the traditionally limited LND (68, 69).

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Update march 2009

9.5.2.2 Therapeutic role of eLND Besides being a staging procedure, (extended) pelvic lymph node dissection might be curative, or at least beneficial, in a subset of patients with limited lymph node metastases (70-72). For an eLND to be representative, a mean of 20 lymph nodes should be removed (73). In some series, the number of nodes removed during lymphadenectomy correlated significantly with time to progression (74). At present, however, lymph node metastases are considered to be a sign of systemic disease. Whenever lymph node metastases are found, prognosis worsens and systemic therapy is advised. 9.5.2.3 Morbidity An eLND remains a surgical procedure, which adds morbidity to the treatment of PCa. When comparing limited vs extended LND, threefold higher complication rates were reported by some authors (75). Complications consist of lymphocoeles, lymphoedema, deep venous thrombosis and pulmonary embolism. Other authors, however, reported more acceptable complication rates (76, 77). 9.5.2.4 • • •

Summary of eLND eLND can play a role in the treatment of PCa for a subset of patients. The number of lymph nodes removed correlates with the time to progression. Concomitant morbidity has to be balanced against the therapeutic effects, and a decision will have to be made based on individual cases.

9.6

Summary of RP in high-risk localised disease

•

 P is a reasonable treatment option in selected patients with cT3a PCa, Gleason score 8-10 or PSA > R 20. If RP is performed, an extended pelvic lymphadenectomy must be performed, as lymph node involvement is frequent. The patient must be informed about the likelihood of a multimodal approach. In case of adverse tumour characteristics (positive section margin, extracapsular extension, seminal vesicle invasion), adjuvant RT may be reasonably used after recuperation from surgery.

• •

Recently, Thompson and colleagues reported the results of a trial enrolling 431 men with pT3N0M0 PCa treated with RP. Patients were randomised to receive 60-64 Gy adjuvant RT or observation. Metastasis-free survival and OS were significantly better with radiotherapy (78). In cases of positive lymph nodes at final histopathology, adjuvant ADT may be considered. Messing et al. examined the role of immediate ADT vs observation in patients with positive lymph nodes found at initial surgery. At a median follow-up of 11.9 years, those receiving immediate ADT had a significant improvement in OS over those managed with observation (79).

9.7

Neoadjuvant hormonal therapy and RP

Generally, neoadjuvant or up-front therapy is defined as therapy given prior to definitive local curative treatment (e.g. surgery or radiation therapy). As PCa is an androgen-dependent tumour, neoadjuvant hormonal therapy (NHT) is an appealing concept. Attempts to decrease the size of the prostate before RP were first reported by Vallett as early as 1944 (80). In a recent Cochrane review and meta-analysis, the role of neoadjuvant and adjuvant hormonal therapy and prostatectomy were studied (81). Patients had predominantly localised T1 and T2 disease, low- and intermediate-grade, with Gleason scores < 7, and PSA < 20 ng/mL in most patients. The Cochrane review made the following observations: • Neoadjuvant hormonal therapy before RP does not provide a significant OS advantage over prostatectomy alone (pooled odds ratio [OR] 1.11; 95% confidence interval [CI] 0.67-1.85). • Neoadjuvant hormonal therapy before RP does not provide a significant advantage in disease-free survival over prostatectomy alone (pooled OR 1.24; 95% CI 0.97-1.57). • Neoadjuvant hormonal therapy before RP does substantially improve local pathological variables such as organ-confined rates, pathological down-staging, positive surgical margins and rate of lymph node involvement. • Adjuvant hormonal therapy following RP: the pooled data for five-year OS showed an OR of 1.50 and 95% CI 0.79-2.84. This was not statistically significant, although there was a trend favouring adjuvant hormonal therapy. Similarly, there was no survival advantage at 10 years. • Adjuvant hormonal therapy following RP: the pooled data for disease-free survival gave an overall OR of 3.73 and 95% CI 2.3-6.03. The overall effect estimate was highly statistically significant (p < 0.00001) in favour of the hormonal arm. • It is noteworthy that the Early Prostate Cancer Trialists’ Group (EPC) trial was not included in the

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47

•

9.7.1 • • •

• •

9.8

Cochrane review. The third update from this large randomised trial of bicalutamide, 150 mg once daily, in addition to standard care in localised and locally advanced, non-metastatic PCa was published in November 2005 (82). Median follow-up was 7.2 years. There was a significant improvement in objective progression-free survival (PFS) in the RP group. This improvement was only statistically significant in the locally advanced disease group (HR 0.75; 95% CI 0.61-0.91). There was no significant improvement in OS in the RP group, both the localised and locally advanced disease groups. In the WW group, there was an OS trend in favour of WW alone in the localised disease group (HR 1.16; 95% CI 0.99-1.37). Summary of neoadjuvant and adjuvant hormonal treatment and RP Neoadjuvant hormonal therapy before RP does not provide a significant OS advantage over prostatectomy alone. Neoadjuvant hormonal therapy before RP does not provide a significant advantage in disease-free survival over prostatectomy alone. Neoadjuvant hormonal therapy before RP does substantially improve local pathological variables such as organ-confined rates, pathological down-staging, positive surgical margins and rate of lymph node involvement. Adjuvant hormonal therapy following RP shows no survival advantage at 10 years. Adjuvant hormonal therapy following RP: the overall effect estimate was highly statistically significant (p < 0.00001) in favour of the hormonal arm.

Complications and functional outcome

The post-operative complications of RP are listed in Table 14. The mortality rate is 0-1.5% (75); urinary fistulas are seen in 1.2-4% of patients (83); and urinary incontinence persists after one year in 7.7% (84). In men undergoing prostatectomy, the rates of post-operative and late urinary complications are significantly reduced if the procedure is performed in a high-volume hospital and by a surgeon who performs a large number of such procedures (85-87). Erectile dysfunction used to occur in nearly all patients, but nerve-sparing techniques can be applied in early-stage disease (88). Patients who benefit from nerve-sparing RP may have a higher chance of local disease recurrence and should therefore be selected carefully. Table 14: Complications of RP Complication • Peri-operative death • Major bleeding • Rectal injury • Deep venous thrombosis • Pulmonary embolism • Lymphocoele • Urine leak, fistula • Slight stress incontinence • Severe stress incontinence • Impotence • Bladder neck obstruction • Ureteral obstruction • Urethral stricture

Incidence (%) 0.0-2.1 1.0-11.5 0.0-5.4 0.0-8.3 0.8-7.7 1.0-3.0 0.3-15.4 4.0-50.0 0.0-15.4 29.0-100.0 0.5-14.6 0.0-0.7 2.0-9.0

9.9 Summary of indications for nerve-sparing surgery* Reference name Pre-operative selection criteria Stage > T2 PSA > 10 Biopsy Gleason score 7 Biopsy Gleason score 8-10 Partin tables Side with > 50% tumour in biopsy Side with peri-neural invasion

48

Sofer (89) Walsh (90) + +

+

Alsikafi (91) Graefen (92) +

+

Bianco (93) +

+ +

+ + +/-

+ + +

Update march 2009

Intra-operative selection criteria Side of palpable tumour + Side of positive biopsy Induration of lateral pelvic fascia + Adherent to neurovascular bundles + Positive section margins 24% 5% 11% *Clinical criteria used by different authors when NOT to perform a nerve-sparing RP.

+ + + 5%

15.9%

 erve-sparing RP can be performed safely in most men undergoing RP (94, 95). In the past decade, a dramatic N shift towards lower-stage tumours has become evident. More importantly, men are younger at the time of diagnosis and more interested in preserving sexual function. Nevertheless, clear contraindications are those patients in whom there is a high risk of extracapsular disease, such as any cT3 PCa, cT2c, any Gleason score > 7 on biopsy, or more than one biopsy > 6 at the ipsilateral side. Partin tables will help guide decision-making (28). If any doubt remains regarding residual tumour, the surgeon should remove the neurovascular bundle. Alternatively, the use of intra-operative frozen-section analysis can help guide these decisions. The patient must be informed before surgery about the risks of nerve-sparing surgery, the potency rates of the surgeon, and the possibility that, to ensure adequate cancer control, the nerves may be sacrificed despite any pre-operative optimism favouring the potential for their salvage. The early administration of intracavernous injection therapy could improve the definitive potency rates (96, 97) and the significance of sural nerve transplant needs further multicentre study (98). Finally, the early use of PDE-5 inhibitors in penile rehabilitation remains controversial. A recent study showed no benefit of daily early administration of vardenafil versus on-demand vardenafil in the postoperative period (99).

9.10 Guidelines and recommendations for RP LE Indications • In patients with low and intermediate risk localised PCa (cT1b-T2 and Gleason score 2-7 and PSA < 20) and a life expectancy > 10 years. Optional • Patients with stage T1a disease and a life expectancy > 15 years or Gleason score 7. • Selected patients with low-volume high-risk localised PCa (cT3a or Gleason score 8-10 or PSA > 20). • Highly selected patients with very high-risk localised PCa (cT3b-T4 N0 or any T N1) in the context of multimodality treatment. Recommendations • Short-term (three months) neoadjuvant therapy with gonadotrophin releasing-hormone analogues is not recommended in the treatment of stage T1-T2 disease. • Nerve-sparing surgery may be attempted in pre-operatively potent patients with low risk for extracapsular disease (T1c, Gleason score < 7 and PSA < 10 ng/mL or see Partin tables/ nomograms). • Unilateral nerve-sparing procedures are an option in stage T2a disease

1b

3 3 3

1a 3

4

LE = level of evidence

9.11

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Andrèn O, Garmo H, Mucci L, Andersson SO, Johansson JE, Fall K. Incidence and mortality of incidental prostate cancer: a Swedish register-based study. Br J Cancer 2009;100(1):170-3. http://www.ncbi.nlm.nih.gov/pubmed/19088721 Lowe BA, Listrom MB. Incidental carcinoma of the prostate: an analysis of the predictors of progression. J Urol 1988;140(6):1340-4. http://www.ncbi.nlm.nih.gov/pubmed/3193495 Van Poppel H, Ameye F, Oyen R, Van de Voorde W, Baert L. Radical prostatectomy for localized prostate cancer. Eur J Surg Oncol 1992;18(5):456-62. http://www.ncbi.nlm.nih.gov/pubmed/1426296 Elgamal AA, Van Poppel HP, Van de Voorde WM, Van Dorpe JA, Oyen RH, Baert LV. Impalpable invisible stage T1c prostate cancer: characteristics and clinical relevance in 100 radical prostatectomy specimens – a different view. J Urol 1997;157(1):244-50. http://www.ncbi.nlm.nih.gov/pubmed/8976263 Oesterling JE, Suman VJ, Zincke H, Bostwick DG. PSA-detected (clinical stage T1c or B0) prostate cancer. Pathologically significant tumours. Urol Clin North Am 1993;20(4):687-93. http://www.ncbi.nlm.nih.gov/pubmed/7505977 Epstein JI, Walsh PC, Brendler CB. Radical prostatectomy for impalpable prostate cancer: the Johns Hopkins experience with tumours found on transurethral resection (stages T1A and T1B) and on needle biopsy (stage T1C). J Urol 1994;152(5 Pt 2):1721-9. http://www.ncbi.nlm.nih.gov/pubmed/7523719 Singh H, Canto EI, Shariat SF, Kadmon D, Miles BJ, Wheeler TM, Slawin KM. Improved detection of clinically significant, curable prostate cancer with systematic 12-core biopsy. J Urol 2004;171(3): 1089-92. http://www.ncbi.nlm.nih.gov/pubmed/14767277 Epstein JI, Chan DW, Sokoll LJ, Walsh PC, Cox JL, Rittenhouse H, Wolfert R, Carter HB. Nonpalpable stage T1c prostate cancer: prediction of insignificant disease using free/total prostate specific antigen levels and needle biopsy findings. J Urol 1998;160(6 Pt 2): 2407-11. http://www.ncbi.nlm.nih.gov/pubmed/9817393 Partin AW, Mangold LA, Lamm DM, Walsh PC, Epstein JI, Pearson JD. Contemporary update of prostate cancer staging nomograms (Partin tables) for the new millennium. Urology 2001;58(6):843-8. http://www.ncbi.nlm.nih.gov/pubmed/11744442 D’Amico AV, Whittington R, Malkowicz SB, Wu YH, Chen M, Art M, Tomaszewski JE, Wein A. Combination of preoperative PSA level, biopsy Gleason score, percentage of positive biopsies and MRI T-stage to predict early failure in men with clinically localized prostate cancer. Urology 2000;55(4):572-7. http://www.ncbi.nlm.nih.gov/pubmed/10736506 Epstein JI. Gleason score 2-4 adenocarcinoma of the prostate on needle biopsy: a diagnosis that should not be made. Am J Surg Pathol 2000;24(4):477-8. http://www.ncbi.nlm.nih.gov/pubmed/10757394 Epstein JI, Steinberg GD. The significance of low grade prostate cancer on needle biopsy. A radical prostatectomy study of tumour grade, volume, and stage of the biopsied and multifocal tumour. Cancer 1990;66(9):1927-32. http://www.ncbi.nlm.nih.gov:/pubmed/1699655 Briganti A, Chun FK, Salonia A, Gallina A, Farina E, Da Pozzo LF, Rigatti P, Montorsi F, Karakiewicz PI. Validation of a nomogram predicting the probability of lymph node invasion based on the extent of pelvic lymphadenectomy in patients with clinically localized prostate cancer. BJU Int 2006;98(4): 788-93. http://www.ncbi.nlm.nih.gov/pubmed/16796698 Schroder FH, Van den Ouden D, Davidson P. The role of surgery in the cure of prostatic carcinoma. Eur Urol Update Series 1992;1:18-23. Gibbons RP. Total prostatectomy for clinically localized prostatic cancer: long-term surgical results and current morbidity. NCI Monogr 1988;(7):123-6. http://www.ncbi.nlm.nih.gov/pubmed/3173498 Pound CR, Partin AW, Epstein JI, Walsh PC. Prostate-specific antigen after anatomic radical retropubic prostatectomy. Patterns of recurrence and cancer control. Urol Clin North Am 1997;24(2):395-406. http://www.ncbi.nlm.nih.gov/pubmed/9126237 Johansson JE, Andersson SO. Deferred treatment in localized prostatic cancer. Acta Oncol 1991;30(2):221-3. http://www.ncbi.nlm.nih.gov/pubmed/2029410

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Graversen PH, Nielsen KT, Gasser TC, Corle DK, Madsen PO. Radical prostatectomy versus expectant primary treatment in stages I and II prostatic cancer. A fifteen-year follow-up. Urology 1990;36(6):493-8. http://www.ncbi.nlm.nih.gov/pubmed/2247914 38. Eastham JA, Kattan MW, Riedel E, Begg CB, Wheeler TM, Gerigk C, Gonen M, Reuter V, Scardino PT. Variations among individual surgeons in the rate of positive surgical margins in radical prostatectomy specimens. J Urol 2003;170(6 Pt 1):2292-5. http://www.ncbi.nlm.nih.gov/pubmed/14634399 39. Han M, Partin AW, Pound CR, Epstein JI, Walsh PC. Long-term biochemical disease-free and cancerspecific survival following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experience. Urol Clin North Am 2001;28(3):555-65. http://www.ncbi.nlm.nih.gov/pubmed/11590814 40. Catalona WJ, Smith DJ. 5-year tumour recurrence rates after anatomical radical retropubic prostatectomy for prostate cancer. J Urol 1994;152 (5 Pt 2):1837-42. http://www.ncbi.nlm.nih.gov/pubmed/7523731 41. Hull GW, Rabbani F, Abbas F, Wheeler TM, Kattan MW, Scardino PT. Cancer control with radical prostatectomy alone in 1,000 consecutive patients. J Urol 2002;167(2 Pt 1):528-34. http://www.ncbi.nlm.nih.gov/pubmed/11792912 42. Trapasso JG, deKernion JB, Smith RB, Dorey F. The incidence and significance of detectable levels of serum prostate specific antigen after radical prostatectomy. J Urol 1994;152(5 Pt 2):1821-5. http://www.ncbi.nlm.nih.gov/pubmed/7523728 43. Zincke H, Oesterling JE, Blute ML, Bergstralh EJ, Myers RP, Barrett DM. Long-term (15 years) results after radical prostatectomy for clinically localized (stage T2c or lower) prostate cancer. J Urol 1994;152(5Pt2):1850-7. http://www.ncbi.nlm.nih.gov/pubmed/7523733 44. Makarov DV, Trock BJ, Humphreys EB, Mangold LA, Walsh PC, Epstein JI, Partin AW. Updated nomogram to predict pathologic stage of prostate cancer given prostate-specific antigen level, clinical stage, and biopsy Gleason score (Partin tables) based on cases from 2000 to 2005. Urology 2007 Jun;69(6):1095-101. http://www.ncbi.nlm.nih.gov/pubmed/17572194 45. Cooperberg MR, Lubeck DP, Mehta SS, Carroll PR; CaPSURE. Time trends in clinical risk stratification for prostate cancer: implications for outcomes (data from CaPSURE). J Urol 2003;170(6 Pt 2): S21-S25; discussion S26-27. http://www.ncbi.nlm.nih.gov/pubmed/14610406 46. Hodgson D, Warde P, Gospodarowicz M. The management of locally advanced prostate cancer. Urol Oncol 1998;4:3-12. 47. Fallon B, Williams RD. Current options in the management of clinical stage C prostatic carcinoma. Urol Clin North Am 1990;17(4):853-66. http://www.ncbi.nlm.nih.gov/pubmed/2219582 48. Boccon-Gibod L, Bertaccini A, Bono AV, Dev Sarmah B, Höltl W, Mottet N, Tunn U, Zamboglou N. Management of locally advanced prostate cancer: a European Consensus. Int J Clin Pract 2003;57(3):187-94. http://www.ncbi.nlm.nih.gov/pubmed/12723722 49. Bolla M, Collette L, Blank L, Warde P, Dubois JB, Mirimanoff RO, Storme G, Bernier J, Kuten A, Sternberg C, Mattelaer J, Lopez Torecilla J, Pfeffer JR, Lino Cutajar C, Zurlo A, Pierart M. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002:360(9327):103-6. http://www.ncbi.nlm.nih.gov/pubmed/12126818 50. Yamada AH, Lieskovsky G, Petrovich Z, Chen SC, Groshen S, Skinner DG. Results of radical prostatectomy and adjuvant therapy in the management of locally advanced, clinical stage TC, prostate cancer. Am J Clin Oncol 1994;17(4):277-85. http://www.ncbi.nlm.nih.gov/pubmed/8048388 51. Gerber GS, Thisted RA, Chodak GW, Schroder FH, Frohmuller HG, Scardino PT, Paulson DF, Middleton AW Jr, Rukstalis DB, Smith JA Jr, Ohori M, Theiss M, Schellhammer PF. Results of radical prostatectomy in men with locally advanced prostate cancer: multi-institutional pooled analysis. Eur Urol 1997;32(4):385-90. http://www.ncbi.nlm.nih.gov/pubmed/9412793

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van den Ouden D, Hop WC, Schroder FH. Progression in and survival of patients with locally advanced prostate cancer (T3) treated with radical prostatectomy as monotherapy. J Urol 1998;160(4):1392-7. http://www.ncbi.nlm.nih.gov/pubmed/9751362 53. Isorna Martinez de la Riva S, Belón López-Tomasety J, Marrero Dominguez R, Alvarez Cruz E, Santamaria Blanco P. [Radical prostatectomy as monotherapy for locally advanced prostate cancer (T3a): 12 years follow-up]. Arch Esp Urol 2004;57(7):679-92. [article in Spanish] http://www.ncbi.nlm.nih.gov/pubmed/15536949 54. Ward JF, Slezak JM, Blute ML, Bergstralh EJ, Zincke H. Radical prostatectomy for clinically advanced (cT3) prostate cancer since the advent of prostate-specific antigen testing: 15-year outcome. BJU Int 2005;95(6):751-6. http://www.ncbi.nlm.nih.gov/pubmed/15794776 55. Hsu CY, Joniau S, Oyen R, Roskams T, Van Poppel H. Outcome of surgery for clinical unilateral T3a prostate cancer: a single-institution experience. Eur Urol 2007;51(1):121-8; discussion 128-9. http://www.ncbi.nlm.nih.gov/pubmed/16797831 56. Joniau S, Hsu CY, Lerut E, Van Baelen A, Haustermans K, Roskams T, Oyen R, Van Poppel H. A pretreatment table for the prediction of final histopathology after radical prostatectomy in clinical unilateral T3a prostate cancer. Eur Urol 2007;51(2):388-96. http://www.ncbi.nlm.nih.gov/pubmed/16901622 57. Van Poppel H, Ameye F, Oyen R, Van de Voorde W, Baert L. Accuracy of combined computerized tomography and fine needle aspiration cytology in lymph node staging of localized prostatic carcinoma. J Urol 1994;151(5):1310-14. http://www.ncbi.nlm.nih.gov/pubmed/8158777 58. Van Poppel H, Vekemans K, Da Pozzo L, Bono A, Kliment J, Montironi R, Debois M, Collette L. Radical prostatectomy for locally advanced prostate cancer: results of a feasibility study (EORTC 30001). Eur J Cancer 2006;42(8):1062-7. http://www.ncbi.nlm.nih.gov/pubmed/16624554 59. Van Poppel H, Joniau S. An analysis of radical prostatectomy in advanced stage and high-grade prostate cancer. Eur Urol 2008;53(2):253-9. http://www.ncbi.nlm.nih.gov/pubmed/17949893 60. Yossepowitch O, Eggener SE, Bianco FJ Jr, Carver BS, Serio A, Scardino PT, Eastham JA. Radical prostatectomy for clinically localized, high risk prostate cancer: critical analysis of risk assessment methods. J Urol 2007;178(2):493-9;discussion 499. http://www.ncbi.nlm.nih.gov/pubmed/17561152 61. D’Amico AV, Whittington R, Malkowicz SB, Fondurulia J, Chen MH, Kaplan I, Beard CJ, Tomaszewski JE, Renshaw AA, Wein A, Coleman CN. Pretreatment nomogram for prostate-specific antigen recurrence after radical prostatectomy or external-beam radiation therapy for clinically localized prostate cancer. J Clin Oncol 1999;17(1):168-72. http://www.ncbi.nlm.nih.gov/pubmed/10458230 62. Tiguert LL, Harrel F, Fradet Y. Disease outcome of patients with a PSA > 20 treated by radical prostatectomy: analysis of 177 patients. J Urol 2006;175:311A. 63. Inman BA, Davies JD, Rangel LJ, Bergstralh EJ, Kwon ED, Blute ML, Karnes RJ, Leibovich BC. Longterm outcomes of radical prostatectomy with multimodal adjuvant therapy in men with a preoperative serum prostate-specific antigen level > or = 50 ng/mL. Cancer 2008;113(7):1544-51. http://www.ncbi.nlm.nih.gov/pubmed/18680171 64. Ghavamian R, Bergstralh EJ, Blute ML, Slezak J, Zincke H. Radical retropubic prostatectomy plus orchiectomy versus orchiectomy alone for pTxN+ prostate cancer: a matched comparison. J Urol 1999;161(4):1223-7; discussion 1277-8. http://www.ncbi.nlm.nih.gov/pubmed/10081874 65. Briganti A, Karnes JR, Da Pozzo LF, Cozzarini C, Gallina A, Suardi N, Bianchi M, Freschi M, Doglioni C, Fazio F, Rigatti P, Montorsi F, Blute ML. Specific survival in patients with node positive prostate cancer. a new proposal based on a two-institution experience on 703 consecutive N+ patients treated with radical prostatectomy, extended pelvic lymph node dissection and adjuvant therapy. Eur Urol 2008. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/18838212 66. Schumacher MC, Burkhard FC, Thalmann GN, Fleischmann A, Studer UE. Good outcome for patients with few lymph node metastases after radical retropubic prostatectomy. Eur Urol 2008;54(2):344-52. http://www.ncbi.nlm.nih.gov/pubmed/18511183

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Schumacher MC, Burkhard FC, Thalmann GN, Fleischmann A, Studer UE. Is pelvic lymph node dissection necessary in patients with a serum PSA 300 cases. J Urol 2004;171:a312. 77. Burkhard FC, Schumacher M, Studer UE. The role of lymphadenectomy in prostate cancer. Nat Clin Pract Urol 2005;2(7):336-42. http://www.ncbi.nlm.nih.gov/pubmed/16474786 78. Thompson IM, Tangen CM, Paradelo J, Lucia MS, Miller G, Troyer D, Messing E, Forman J, Chin J, Swanson G, Canby-Hagino E, Crawford ED. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol 2009. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/19167731 79. Messing EM, Manola J, Yao J, Kiernan M, Crawford D, Wilding G, di’SantAgnese PA, Trump D; Eastern Cooperative Oncology Group study EST 3886. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol 2006;7(6):472-9. http://www.ncbi.nlm.nih.gov/pubmed/16750497 80. Vallett BS. Radical perineal prostatectomy subsequent to bilateral orchiectomy. Delaware Med J 1944;16:19-20. 81. Kumar S, Shelley M, Harrison C, Coles B, Wilt TJ, Mason MD. Neoadjuvant and adjuvant hormone therapy for localised and locally advanced prostate cancer. Cochrane Database Syst Rev 2006;(4):CD006019. http://www.ncbi.nlm.nih.gov/pubmed/17054269 82. McLeod DG, Iversen P, See WA, Morris T, Armstrong J, Wirth MP; Casodex Early Prostate Cancer Trialists’ Group. Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer. BJU Int 2006;97(2):247-54. http://www.ncbi.nlm.nih.gov/pubmed/16430622

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83. Hautmann RE, Sauter TW, Wenderoth UK. Radical retropubic prostatectomy: morbidity and urinary continence in 418 consecutive cases. Urology 1994;43(2 Suppl.):47-51. http://www.ncbi.nlm.nih.gov/pubmed/8116133 84. Murphy GP, Mettlin C, Menck H, Winchester DP, Davidson AM. National patterns of prostate cancer treatment by radical prostatectomy: results of a survey by the American College of Surgeons Commission on Cancer. J Urol 1994;152(5 Pt 2):1817-9. http://www.ncbi.nlm.nih.gov/pubmed/7523727 85. Begg CB, Riedel ER, Bach PB, Kattan MW, Schrag D, Warren JL, Scardino PT. Variations in morbidity after radical prostatectomy. N Engl J Med 2002;346(15):1138-44. http://www.ncbi.nlm.nih.gov/pubmed/11948274 86. Potosky AL, Legler J, Albertsen PC, Stanford JL, Gilliland FD, Hamilton AS, Eley JW, Stephenson RA, Harlan LC. Health outcomes after prostatectomy or radiotherapy for prostate cancer: results from the Prostate Cancer Outcome Study. J Natl Cancer Inst 2000;92(19):1582-92. http://www.ncbi.nlm.nih.gov/pubmed/11018094 87. Van Poppel H, Collette L, Kirkali Z, Brausi M, Hoekstra W, Newling DW, Decoster M, EORTC GU Group. Quality control of radical prostatectomy: a feasibility study. Eur J Cancer 2001;37(7):884-91. http://www.ncbi.nlm.nih.gov/pubmed/11313177 88. Walsh PC, Partin AW, Epstein JI. Cancer control and quality of life following anatomical radical retropubic prostatectomy: results at 10 years. J Urol 1994;152(5Pt2):1831-6. http://www.ncbi.nlm.nih.gov/pubmed/7523730 89. Sofer M, Savoie M, Kim SS, Civantos F, Soloway MS. Biochemical and pathological predictors of the recurrence of prostatic adenocarcinoma with seminal vesicle invasion. J Urol 2003;169(1):153-6. http://www.ncbi.nlm.nih.gov/pubmed/12478125 90. Walsh RM, Thompson IM. Prostate cancer screening and disease management: how screening may have an unintended effect on survival and mortality-the camel’s nose effect. J Urol 2007;177(4): 1303-6. http://www.ncbi.nlm.nih.gov/pubmed/17382719 91. Alsikafi NF, Brendler CB. Surgical modifications of radical retropubic prostatectomy to decrease incidence of positive surgical margins. J Urol 1998;159(4):1281-5. http://www.ncbi.nlm.nih.gov/pubmed/9507853 92. Graefen M. Is the open retropubic radical prostatectomy dead? Eur Urol 2007 Nov;52(5):1281-3. http://www.ncbi.nlm.nih.gov/pubmed/17764828 93. Bianco FJ Jr, Scardino PT, Eastham JA. Radical prostatectomy: long-term cancer control and recovery of sexual and urinary function (‘trifecta’). Urology 2005; 66(5 Suppl.):83-94. http://www.ncbi.nlm.nih.gov/pubmed/16194712 94. Gontero P, Kirby RS. Nerve-sparing radical retropubic prostatectomy: techniques and clinical considerations. Prostate Cancer Prostatic Dis 2005;8(2):133-9. http://www.ncbi.nlm.nih.gov/pubmed/15711608 95. Sokoloff MH, Brendler CB. Indications and contraindications for nerve-sparing radical prostatectomy. Urol Clin North Am 2001;28(3):535-43. http://www.ncbi.nlm.nih.gov/pubmed/11590812 96. Montorsi F, Guazzoni G, Strambi LF, Da Pozzo LF, Nava L, Barbieri L, Rigatti P, Pizzini G, Miani A. Recovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy with and without early intracavernous injections of alprostadil: results of a prospective, randomized trial. J Urol 1997;158(4):1408-10. http://www.ncbi.nlm.nih.gov/pubmed/9302132 97. Nandipati K, Raina R, Agarwal A, Zippe CD. Early combination therapy: intracavernosal injections and sildenafil following radical prostatectomy increases sexual activity and the return of natural erections. Int J Impot Res 2006;18(5):446-51. http://www.ncbi.nlm.nih.gov/pubmed/16482200 98. Secin FP, Koppie TM, Scardino PT, Eastham JA, Patel M, Bianco FJ, Tal R, Mulhall J, Disa JJ, Cordeiro PG, Rabbani F. Bilateral cavernous nerve interposition grafting during radical retropubic prostatectomy: Memorial Sloan-Kettering Cancer Center experience. J Urol 2007;177(2):664-8. http://www.ncbi.nlm.nih.gov/pubmed/17222654 99. Montorsi F, Brock G, Lee J, Shapiro J, Van Poppel H, Graefen M, Stief C. Effect of nightly versus on-demand vardenafil on recovery of erectile function in men following bilateral nerve-sparing radical prostatectomy. Eur Urol 2008 Oct;54(4):924-31. http://www.ncbi.nlm.nih.gov/pubmed/18640769

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10. TREATMENT: DEFINITIVE RADIATION THERAPY 10.1

Introduction

There are no randomised studies comparing radical prostatectomy with either external beam therapy or brachytherapy for localised prostate cancer, but the National Institutes of Health (NIH) consensus set up in 1988 (1) remains available: external irradiation offers the same long-term survival results as surgery; moreover, external irradiation provides a quality of life at least as good as that provided by surgery (2). Three-dimensional conformal radiotherapy (3D-CRT) is the gold standard and, at the beginning of the third millennium, intensity modulated radiotherapy (IMRT), an optimised form of 3D-CRT, is gradually gaining ground in centres of excellence. In addition to external irradiation, there has been continued and growing interest in transperineal low dose or high dose brachytherapy. In localised and locally advanced prostate cancer, several randomised phase III trials conducted by radiation therapy scientific societies, such as the Radiation Therapy Oncology Group (RTOG) and European Organisation for Research and Treatment of Cancer (EORTC), have established the indications for the combination of external irradiation and androgen deprivation treatment (ADT). Whatever the technique, the choice of treatment after the appropriate assessment of tumour extension must be based on a multidisciplinary approach taking account of: • the 2002 tumour node metastasis (TNM) classification • the Gleason score defined on a sufficient number of core biopsies (at least 12) • the baseline prostate-specific antigen (PSA) • the age of the patient • his co-morbidity, life expectancy and quality of life • d’Amico’s prognostic factor classification. Obtaining a patient’s consent is essential after giving full information regarding diagnosis, the therapeutic modalities and morbidity. Additional information on the various aspects of radiotherapy in the treatment of prostate cancer is available in a newly published extensive overview (3).

10.2

Technical aspects: three dimensional conformal radiotherapy and intensity modulated external beam radiotherapy

Anatomical data acquired by scanning the patient in a treatment position, are transferred to the 3D treatment planning system where the clinical target volume is visualised, following which a (surrounding) safety margin is added. At the time of irradiation, a multileaf collimator automatically and, in the case of IMRT, continuously, adapts to the contours of the target volume seen by each beam. Real-time verification of the irradiation field by means of portal imaging allows for comparison of the treated and simulated fields, and correction of deviations where displacement is more than 5 mm. Three-dimensional CRT improves local control through dose escalation without increasing the risk of morbidity. The use of IMRT is possible with linear accelerators equipped with the latest multileaf collimators and specific software. Movement of the leaves during the course of the irradiation allows for a more complex distribution of the dose to be delivered within the treatment field, and provides concave isodose curves, which are particularly useful as a means to spare the rectum. Whatever the techniques and their sophistication, quality assurance plays a major role in the management of radiotherapy, mandating the involvement of physicians, physicists, dosimetrists, radiographers, radiologists and computer scientists.

10.3

Localised prostate cancer T1-2c N0, M0

10.3.1 T1a-T2a, N0, M0 and Gleason score ≤ 6 and PSA < 10 ng/mL (low-risk group) Retrospective, non-randomised studies have shown that biochemical disease-free survival is significantly higher with a radiation dose ≥ 72 Gy compared with < 72 Gy (p = 0.04) (4). Two randomised trials focusing on clinical stages T1-3 N0 M0 paved the way for dose escalation: • The MD Anderson study compared 78 Gy with 70 Gy conventional radiotherapy: it included 305 stage T1-3 patients with a pre-treatment PSA level of more than 10 ng/mL and, with a median follow-up of

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8.7 years, showed a significant increase in freedom from biochemical and/or clinical failure for low-risk patients (p = 0.04) (5). The PROG 95-09 evaluated 393 T1b-T2b patients, of whom 75% had a Gleason score ≤ 6 and a PSA < 15 ng/mL. Patients were randomised to receive an initial boost to the prostate alone, using conformal protons of either 19.8 Gy or 28.8 Gy, and then 50.4 Gy to a larger volume. With a median follow-up of 5.5 years, there was a significant increase in five-year freedom from biochemical failure (p < 0.001) in favour of low-risk patients, who were given a higher dose (79.2 Gy), compared with those receiving a conventional dose (70.2 Gy) (6).

In daily practice, a minimum dose of 74 Gy is recommended. 10.3.2 T2b or PSA 10-20 ng/mL, or Gleason score 7 (intermediate-risk group) Many non-randomised studies have shown dose escalation to have a significant impact on five-year survival without biochemical relapse for patients classified as cT1c-T3, with a dose ranging from 76-81 Gy (4, 7, 8). A Dutch randomised phase III trial comparing 68 Gy with 78 Gy showed a significant increase in five-year freedom from clinical or biochemical failure for patients in an intermediate-risk group (9). The phase III trial of the French Federation of Cancer Centres compared 70 Gy with 80 Gy in 306 patients with a pelvic lymph node involvement risk of < 10% (Partin) or pN0, with no hormonal therapy allowed before, during or after radiotherapy. With a median follow-up of 59 months, high dose should provide a better five-year biological outcome in intermediate-risk patients, especially if the initial PSA > 15ng/mL (10). Patients who are reluctant to accept short-term hormonal treatment (11) can receive definitive radiotherapy alone provided that a dose escalation up to 78-80 Gy is proposed. 10.3.3 T2c or Gleason score > 7 or PSA > 20 ng/mL (high-risk group) External irradiation with dose escalation is mandatory since it improves the five-year biochemical disease-free survival, as shown in several phase III randomised trials. • The Dutch study comparing 68 Gy with 78 Gy showed a 10% increase in the five-year freedom from clinical or biochemical failure (p = 0.02) (9). • The MRC study comparing 64 Gy with 74 Gy, with neoadjuvant hormonal therapy, has shown an 11% difference in five-year biochemical disease-free survival (12). • The PROG 95-09 study, with a significant increase in five-year freedom from biochemical failure (p < 0.02) in favour of high-risk patients given a higher dose (79.2 Gy) vs those receiving a conventional dose (70.2 Gy) (9). • The MD Anderson study showed a significant increase in freedom from biochemical and/or clinical failure for high-risk patients (p = 0.004) (5). • The EORTC trial 22991, comparing 3D-CRT +/- IMRT with a choice of three levels of dose (70 Gy, 74 Gy and 78 Gy), with or without six months of neoadjuvant and concomitant hormonal therapy, was closed in April 2008 after recruiting 800 patients, and its results are awaited (13). In daily practice, a combination of external irradiation with short-term androgen deprivation is recommended, based on the results of a phase III randomised trial. This trial, which included 206 patients with a PSA of at least 10 ng/mL (maximum 40 ng/mL), a Gleason score of at least 7 (range 5-10), or radiographic evidence of extra-prostatic disease, compared 3D-CRT alone or in combination with six months of ADT. After a median follow-up of 7.6 years, intermediate- or high-risk patients without moderate or severe co-morbidity randomised to receive 3D-CRT plus ADT had a 13% improvement in overall survival rate (p < 0.001) (11). 10.3.4 Prophylactic irradiation of pelvic lymph nodes in high-risk localised prostate cancer Invasion of the pelvic lymph nodes is a poor prognostic factor and mandates systemic medical treatment because radiotherapy alone is insufficient (14). Prophylactic whole pelvis irradiation has been abandoned since randomised trials failed to show that patients benefited from prophylactic irradiation of the pelvic lymph nodes in high-risk cases (46-50 Gy). Such studies include the RTOG study with 484 T1b-T2 patients (15), the Standford study with only 91 patients (16), and the GETUG-01 trial, which included 444 T1b-T3 N0 pNx M0 patients (17). In order better to select patients who might benefit from pelvic lymph node irradiation, and to supplement the use of Partin’s tables (18) and/or the Roach formula (19), pelvic lymphadenectomy might be required, particularly for young patients, because its results will enable radiation oncologists to tailor both the planning target volume and the duration of ADT: specifically, no pelvic irradiation for pN0 patients, but pelvic irradiation for pN1 patients with long term ADT.

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10.4

Innovative techniques

10.4.1 Intensity modulated radiotherapy IMRT enables radiation oncologists to increase radiation doses homogeneously up to as much as 86 Gy within the target volume, while respecting the tolerance doses in organs at risk. Certainly, for dose escalation beyond 80 Gy, using conventional 2 Gy fraction sizes, or for dose escalation using hypofractionated radiotherapy, in which there has been renewed interest, IMRT is the only safe means of treatment delivery, although both treatment scenarios should be performed only within the confines of a properly designed clinical trial. The Memorial Sloan-Kettering Cancer Center has the largest experience with this technique, and its results have now been updated, reporting on disease control and toxicity in two cohorts of patients. In the first, 561 patients with organ-confined disease were treated with a dose of 81 Gy. The eight-year actuarial PSA relapse-free survival rates for patients in favourable, intermediate and unfavourable risk groups were 85%, 76% and 72%, respectively, according to the then-current American Society for Radiation Oncology (ASTRO) definition (20). In the second cohort, 478 patients with organ-confined disease were treated with a dose of 86.4 Gy. The fiveyear actuarial PSA relapse-free survival according to the nadir plus 2 ng/mL definition was 98%, 85% and 70% for the low-, intermediate-, and high-risk groups, respectively (21). To date, no randomised trials have been published comparing dose escalation using IMRT and 3D-CRT. However, several such trials are ongoing (UK NCRI, MD Anderson, Fox Chase, and Ottawa Health Research Institute), although one (Ottawa) is studying helical tomotherapy (see below), and two (NCRI and MD Anderson) are studying hypofractionated, doseescalated radiotherapy. With dose escalation using IMRT, organ movement becomes a critical issue, in terms of both tumour control and treatment toxicity, and evolving techniques will combine IMRT with some form of image-guided radiotherapy (IGRT), in which organ movement can be visualised and corrected for in real time, although the optimum means of achieving this is still unclear (22). Another evolving technique for the delivery of IMRT is tomotherapy, which uses a linear accelerator mounted on a ring gantry that rotates as the patient is delivered through the centre of the ring, analogous to spiral computed tomography (CT) scanning. Preliminary data suggest that this technique is feasible in prostate cancer treatment (23). 10.4.2 Proton beam and carbon ion beam therapy In theory, proton beams are an attractive alternative to photon beam radiotherapy for prostate cancer because they deposit almost all their radiation dose at the end of the particle’s path in tissue (the Bragg peak), in contrast to photons, which deposit radiation along their path. Additionally, there is a very sharp fall-off for proton beams beyond their deposition depth, meaning that critical normal tissues beyond this depth could be effectively spared, in contrast to photon beams, which will continue to deposit energy up to and including an exit dose as they leave the body. In practice, however, this has the disadvantage that dose distributions from protons are highly sensitive to changes in internal anatomy, such as might occur with bladder or rectal filling, and prostate proton therapy is usually delivered with lateral beams. It is also possible that high linear energy transfer (LET) radiation therapy using protons or carbon ions offers inherent biological advantages over photons, having more capacity for DNA damage dose-for-dose. Only one randomised trial has incorporated proton therapy in one arm: the Loma Linda/Massachusetts General Hospital trial discussed above compared standard-dose conformal radiotherapy with dose-escalated radiotherapy using protons for the boost dose (6). This trial cannot, however, be used as evidence for the superiority of proton therapy per se, as its use here could be viewed merely as a sophisticated method for dose escalation. In order to compare the efficacy of protons versus photons, a randomised trial using equivalent doses, comparing proton beam therapy with IMRT, would be needed, and such a study is under consideration by the RTOG. Two recent planning studies comparing conformal proton therapy with IMRT have yielded conflicting results, one suggesting that the two are equivalent in terms of rectal dose sparing, but IMRT is actually superior in terms of bladder sparing (24), and the other suggesting a clearer advantage to protons (25). Further studies are clearly needed, and in the interim, proton therapy must be regarded as a promising but experimental alternative to photon beam therapy. Theoretically, proton therapy might be associated with a lower risk of secondary

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cancers compared with IMRT, because of the lower integral dose of radiation, but there are no data in patients treated for prostate cancer to support this. Carbon ions offer similar theoretical advantages as protons as an alternative to photon beam therapy. In a phase II study, 175 patients with T1-3, N0-1, M0 prostate cancer were treated with carbon ions in a dose equivalent to 66 Gy in 20 fractions over five weeks (26). Treatment appeared to be well tolerated, with no RTOG grade 3 or 4 bowel or genitourinary toxicity, and an overall four-year biochemical disease-free rate of 88% (25). As with protons, a randomised trial comparing carbon ions with IMRT and using equivalent doses is required.

10.5

Transperineal brachytherapy

Transperineal brachytherapy is a safe and effective technique that generally requires fewer than two days of hospitalisation. There is consensus on the following eligibility criteria: • stage cT1b- T2a N0, M0, • a Gleason score ≤ 6 assessed on a sufficient number of random biopsies • an initial PSA level of≤ 10 ng/mL • ≤ 50% of biopsy cores involved with cancer • a prostate volume of < 50 cm3 • a good International Prostatic Symptom Score (IPSS) (27). Patients with low-risk prostate cancer are the most suitable candidates for low-dose rate (LDR) brachytherapy. Further guidelines on technical aspects of brachytherapy have been published recently, and are strongly recommended (28). In 1983, Holm et al. described the transperineal method with endorectal sonography in which the patient is positioned in a dorsal decubitus gynaecological position (29). Implantation is undertaken under general anaesthesia or spinal block, and involves a learning curve for the whole team: the surgeon for the delineation of the prostate and the placement of the needles, the physicist for real-time dosimetry, and the radiation oncologist for source loading. The sonography probe introduced into the rectum is fixed in a stable position. No randomised trials have been performed comparing brachytherapy with other curative treatment modalities, and outcomes are based on unrandomised case series. Results of permanent implants have been reported from different institutions, with a median follow-up ranging between 36 and 120 months (30). Recurrence-free survival after five and 10 years was reported to range from 71-93% and from 65-85%, respectively (31-38). A significant correlation has been shown between the implanted dose and recurrence rates (39). Patients receiving a D90 of > 140 Gy demonstrated a significantly higher biochemical control rate (PSA < 1.0 ng/mL) at four years than patients receiving less than 140 Gy (92% vs 68%). There is no benefit from adding neoadjuvant or adjuvant androgen deprivation to LDR brachytherapy (30). Some patients experience significant urinary complications following implantation, such as urinary retention (1.5-22%), post-implant transurethral resection of the prostate (TURP) (up to 8.7%), and incontinence (0-19%). A small randomised trial has suggested that prophylactic tamsulosin does not reduce the rates of acute urinary retention, but may improve urinary morbidity (40). This observation could usefully be further studied in a larger number of patients. Chronic urinary morbidity can occur in up to 20% of patients, depending on the severity of symptoms prior to brachytherapy. Previous TURP for benign prostatic hyperplasia increases the risk of postimplant incontinence and urinary morbidity. Brachytherapy-induced rectal morbidity with grade II/III proctitis occurs in 5-21% of patients. Erectile dysfunction develops in about 40% of patients after three to five years. In a recent retrospective analysis of 5621 men who had undergone LDR brachytherapy (41), urinary, bowel and erectile morbidity rates were 33.8%, 21% and 16.7%, respectively, with invasive procedure rates of 10.3%, 0.8% and 4%, respectively. In cases of permanent implants, iodine-125 in granular form is the radio-element of reference, while palladium-103 may be used for less differentiated tumours with a high doubling time. The dose delivered to the planning target volume is 160 Gy for iodine-125, and 120 Gy for palladium-103. A Gleason score of 7 remains a ‘grey area’, but patients with a Gleason score of 4 + 3 show no difference in outcome (42). A small randomised trial has suggested that, as one might expect, the use of stranded rather than loose seeds is associated with better seed retention and less seed migration, and this should be the standard choice (43).

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In cases of intermediate or high-risk localised prostate cancer, its combination with supplemental external irradiation (44) or neoadjuvant hormonal treatment (45) may be considered. The optimum dose of supplemental external beam radiation therapy (EBRT) is unclear. A randomised trial comparing 44 Gy with 20 Gy of EBRT plus palladium-103 brachytherapy closed early, showing no difference in biochemical outcomes (46). Non-permanent transperineal interstitial prostate brachytherapy using a high-dose rate iridium-192 stepping source and a remote afterloading technique can be applied with a total dose of 12-20 Gy in two to four fractions combined with fractionated external radiotherapy of 45 Gy (47). Higher doses of supplemental EBRT than this may best be delivered with IMRT, and a report from Memorial Sloan-Kettering indicates that such an approach is safe and feasible (48). Recent data suggest an equivalent outcome in terms of biochemical disease-free survival compared with high-dose EBRT (HD EBRT) (49). In a retrospective analysis of modern series (50, 51), biochemical diseasefree survival rates of 85.8%, 80.3% and 67.8% in men with low-, intermediate- and high-risk prostate cancer, respectively, are reported after a mean follow-up of 9.43 years. Quality-of-life changes are similar between HD EBRT and high-dose rate (HDR) brachytherapy in terms of diarrhoea and insomnia (52). However, the frequency of erectile dysfunction is significantly increased with HDR brachytherapy (86% vs 34%). A single randomised trial of EBRT versus EBRT plus HDR brachytherapy has been reported (53). A total of 220 patients with organ-confined prostate cancer were randomised to EBRT alone with a dose of 55 Gy in 20 fractions, or EBRT with a dose of 35.75 Gy in 13 fractions, followed by HDR brachytherapy with a dose of 17 Gy in two fractions over 24 hours. A significant improvement in biochemical relapse-free survival was seen in favour of the combined brachytherapy schedule (p = 0.03). There were no differences in the rates of late toxicity. Patients randomised to brachytherapy had significantly better quality of life as measured by their Functional Assessment of Cancer Therapy-prostate (FACT-P) score at 12 weeks (53). There is still a need to compare dose escalated EBRT plus hormone therapy, with the same plus a brachytherapy boost, in intermediate- and high-risk patients. For T1-2 N0 M0 disease, the five-year biochemical failure rates are similar for permanent seed implantation, high-dose (> 72 Gy) external radiation, combination seed/external irradiation, and radical prostatectomy. These were the results from a study that included 2991 patients diagnosed with T1-2 consecutive localised prostate cancer treated between 1990 and 1998 at the Cleveland Clinic Foundation and Memorial Sloan-Kettering Cancer Center with a minimum of one-year follow-up (49).

10.6

Late toxicity

Patients must be informed about the potential late genitourinary or gastrointestinal toxicity that may occur, as well as the impact of irradiation on erectile function. Late toxicity was analysed using a dose of 70 Gy in the prospective EORTC randomised trial 22863 (1987-1995) (54), in which 90% of patients were diagnosed as stage T3-4. A total of 377 patients (91%) out of 415 enrolled were evaluable for long-term toxicity, graded according to a modified RTOG scale. Eighty-six (22.8%) patients had grade ≥ 2 urinary or intestinal complications or leg oedema, of which 72 had grade 2 (moderate) toxicity, 10 had grade 3 (severe) toxicity, and four died due to grade 4 (fatal) toxicity. Although four (1%) late treatment-related deaths occurred, longterm toxicity was limited, with fewer than 5% grade 3 or 4 late complications being reported (Table 15). These data can be used as a baseline for comparison with irradiation techniques currently in use, such as 3D-CRT or IMRT. Table 15: Incidence of late toxicity by RTOG grade (from EORTC trial 22863) Toxicity

Grade 2

Grade 3

Grade 4

Cystitis Haematuria Urinary stricture Urinary incontinence Overall GU toxicity Proctitis

No. 18 18 18 18 47 31

No. 2 0 5 2 9 0

No. 0 0 4 0 4† 0

60

% 4.7 4.7 4.7 4.7 12.4 8.2

% 0.5 0 1.3 0.5 2.3

% 0 0 1 0 1† 0

Any significant toxicity (> grade 2) No. % 20 5.3 18 4.7 27 7.1 20 5.3 60 15.9 31 8.2

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Chronic diarrhoea Small bowel obstruction Overall GI toxicity Leg oedema Overall toxicity*

14 1 36 6 72

3.7 0.2 9.5 1.5 19.0

0 1 1 0 10

0.2 0.2 0 2.7

0 0 0 0 4

0 0 0 0 1

14 2 37 6 86

3.7 0.5 9.8 1.5 22.8

GU = genitourinary; GI = gastrointestinal. * Overall toxicity included genitourinary and gastrointestinal toxicity and leg oedema. As most patients had more than one type of toxicity, the overall toxicity does not result from simple addition. † Two of the grade 4 patients were irradiated with cobalt-60. Note: there was no other significant (≥ grade 2) toxicity among patients irradiated with cobalt-60 (n = 15) except for two patients with grade 4 genitourinary toxicity (stated above) and only one patient with grade 2 gastrointestinal toxicity. Radiotherapy affects erectile function to a lesser degree than surgery according to retrospective surveys of patients (2). A recent meta-analysis has shown that the one-year rate of probability for maintaining erectile function was 0.76 after brachytherapy, 0.60 after brachytherapy plus external irradiation, 0.55 after external irradiation, 0.34 after nerve-sparing radical prostatectomy, and 0.25 after standard radical prostatectomy. When studies with more than two years of follow-up were selected (i.e. excluding brachytherapy), the rates became 0.60, 0.52, 0.25, and 0.25, respectively, with a greater spread between the radiation techniques and surgical approaches (55). Recent studies have demonstrated a significantly increased risk of developing secondary malignancies of the rectum and bladder following EBRT (56, 57). In a retrospective evaluation of 30,552 and 55,263 men who had undergone either EBRT or radical prostatectomy, the risk of being diagnosed with rectal cancer increased 1.7fold in comparison with the surgery group (56). Another analysis (57) showed that the relative risk of developing bladder cancer increased by 2.34-fold compared with a healthy control population. Corresponding data on late toxicity has also been reported by the Memorial Sloan-Kettering Cancer Center group, from its experience in 1571 patients with T1-T3 disease treated with either 3D-CRT or IMRT in doses of between 66 Gy and 81 Gy, with a median follow-up of 10 years (58). Both acute GI and GU toxicity appeared to predict for corresponding late toxicity. The overall rates of NCIC-CTC grade 2 or more GI toxicity was 5% with IMRT, compared with 13% with 3D-CRT. The incidence of grade 2 or more late GU toxicity was 20% in patients treated with 81 Gy, compared with 12% in patients treated with lower doses. The overall incidence of grade 3 GI toxicity was 1%, and grade 3 GU toxicity was 3%. These data suggest that IMRT can successfully protect against late GI toxicity, but, interestingly, with dose escalation, GU toxicity may take over as the dominant morbidity (58).

10.7

Immediate post-operative external irradiation for pathological tumour stage T3 N0, M0

Extracapsular invasion (pT3) is associated with a risk of local recurrence, which can be as high as 30% (59). In a multifactorial analysis, the predictors of biochemical relapse are: • PSA level (p = 0.005) • Gleason score of the surgical specimen (p = 0.002) • positive surgical margins (p < 0.001) (60). Three prospective randomised trials have assessed the role of immediate post-operative radiotherapy. The EORTC study 22911, with a target sample size of 1005 patients, compared immediate post-operative radiotherapy (60 Gy) with radiotherapy delayed until local recurrence (70 Gy) in patients classified as pT3 pN0 after retropubic radical prostatectomy. Immediate post-operative radiotherapy proved to be well tolerated, with a risk of grade 3-4 urinary toxicity of less than 3.5% (61), without significant differences regarding the rate of incontinence and/or stricture of anastomosis (62). The study concludes that immediate post-operative radiotherapy after surgery significantly improves five-year clinical or biological survival: 72.2% vs 51.8% (p < 0.0001) (63). However, the EORTC study has not yet demonstrated improved metastasis-free and cancer-specific survival in this cohort of patients. The most suitable candidates for immediate radiation therapy might be those with multifocal positive surgical margins and a Gleason score > 7. The conclusions of the ARO trial 96-02 – based on a cohort of 385 patients – echoed those of EORTC since after a median follow-up of 54 months, biochemical progression-free survival was significantly improved in the radiotherapy group: 72% vs 54% (p = 0.0015) (64).

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In the same way, the SWOG 8794 trial randomised 425 pT3 patients, and the updated results (65), with a median follow-up of 11.5 years, show that adjuvant radiation significantly improved metastasis-free survival, with a 15-year metastasis-free survival of 46% vs 38% (p = 0.036) and a 15-year overall survival of 47% vs 37% (p = 0.053). Thus, for patients classified as T1-2 N0 (or T3 N0 with selected prognostic factors), pT3 pN0 with a high risk of local failure after radical prostatectomy due to capsular rupture, positive margins and/or invasion of the seminal vesicles, who present with a PSA level of < 0.1 ng/mL one month after surgery, two options can be offered within the frame of an informed consent: • either an immediate radiotherapy to the surgical bed (66) upon recovery of urinary function • or clinical and biological monitoring followed by salvage radiotherapy when the PSA exceeds 0.5 ng/ mL (67); 1.0 ng/mL seems to be a breakpoint above which the likelihood of local control is significantly reduced (68). A retrospective analysis based on 635 patients undergoing prostatectomy from 1982-2004, followed up through to December 2007, who experienced biochemical and/or local recurrence and received no salvage treatment (397) or salvage radiotherapy alone (160) within two years of biochemical recurrence has shown that salvage radiotherapy was associated with a threefold increase in prostate cancer-specific survival relative to those who received no salvage treatment (p < 0.001) (69). These two approaches, together with the efficacy of neo-adjuvant hormone therapy, are currently being compared in the UK MRC RADICALS randomised trial, and the role of short-term hormone therapy in combination with radiotherapy in the EORTC 22043 randomised trial.

10.8

Locally advanced prostate cancer: T3-4 N0, M0

The incidence of locally advanced prostate cancer has declined as a result of individual or mass screening. Pelvic lymph node irradiation is optional for N0 patients, but the results of radiotherapy alone are very poor (70). Because of the hormonal dependence of prostate cancer (71), ADT has been combined with external irradiation with the aim of: • reducing the risk of distant metastases by potentially sterilising micrometastases already present at the moment of diagnosis • decreasing the risk of non-sterilisation and/or local recurrence as a source of secondary metastases (72) through the effect of radiation-induced apoptosis (73, 74). Numerous randomised trials have confirmed the value of long-term administration. 10.8.1 Neoadjuvant and concomitant hormonal therapy The RTOG study 86-10 included 471 patients with bulky (5 x 5 cm) tumours T2-4N0-X M0. ADT was administered two months before irradiation and during irradiation, or in the case of relapse in the control arm. Thirty-two per cent of patients were diagnosed as T2, 70% as T3-4, and 91% as N0. The hormone treatment consisted of oral eulexine, 250 mg three times daily, and goserelin acetate (Zoladex), 3.6 mg every four weeks by subcutaneous injection. The pelvic target volume received 45 Gy, and the prostatic target volume received 20-25 Gy. The 10-year overall survival estimates – 43% vs 34% – favoured ADT and irradiation, but the difference was not significant (p = 0.12). There was a significant improvement in the 10-year disease-specific mortality (23% vs 36%; p = 0.01), disease-free survival (11% vs 3%; p < 0.0001), and biochemical failure (65% vs 80%; p < 0.0001), with the addition of ADT having no statistical impact on the risk of fatal cardiac events (75). 10.8.2 Concomitant and long-term adjuvant hormonal therapy The EORTC study 22863 recruited 415 patients diagnosed with T1-2 grade 3 WHO (World Health Organization), T3-4, N0 M0 and any histological grade, and compared radiotherapy plus adjuvant ADT, with radiotherapy alone. ADT was allowed in cases of relapse. A total of 82% of patients was diagnosed as T3, 10% as T4, and 89% as N0. The hormone treatment consisted of oral cyproterone acetate (CPA), 50 mg three times daily for one month, beginning one week before the start of radiotherapy, and goserelin acetate (Zoladex), 3.6 mg subcutaneously every four weeks for three years, starting on the first day of radiotherapy. The pelvic target volume received was 50 Gy, and the prostatic target volume was 20 Gy. With a median follow-up of 66 months, combination therapy compared with radiotherapy alone yielded significantly better survival (78% vs 62%, p = 0.001) (76). At a median follow-up of 9.1 years, the 10-year overall survival remained significantly higher – 58.1% vs 39.8%

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(p < 0.0001) – as did clinical progression-free survival – 47.7% vs 22.7% (p < 0.0001). The 10-year cumulative incidence of prostate cancer mortality was 11. 1% vs 31% (p < 0.0001), and the 10-year cumulative incidence of cardiovascular mortality was 11.1% vs 8.2% (p = 0.75) (77). 10.8.3 Long-term adjuvant hormonal therapy The RTOG study 85-31 recruited 977 patients diagnosed with T3-4 N0-1 M0, or pT3 after radical prostatectomy. ADT was begun in the last week of irradiation and continued up to relapse (group I) or was started at recurrence (group II). A total of 15% of patients in group I and 29% in group II had undergone radical prostatectomy, while 14% of patients in group I and 26% in group II were pN1. Goserelin acetate, 3.6 mg subcutaneously, was administered every four weeks. The pelvis received 45 Gy and the prostatic bed received 20-25 Gy. Patients diagnosed with stage pT3 received 60-65 Gy. With a median follow-up time of 7.6 years for all patients, the 10-year overall survival was significantly greater for the adjuvant arm, at 49% vs 39% (p = 0.002) (78). National Cancer Institute (NCI) of Canada /Medical Research Council intergroup PR3/PR07 study, including patients diagnosed with stage cT3-4 N0 M0, compared complete androgen blockade (CAB) (goserelin acetate 3.6 mg subcutaneously every four weeks and flutamide 750 mg/ day) alone and in combination with radiation 65-69 Gy (79, 80). The results are awaited. The SPCG-7/SFUO-3 randomised study (81) compared endocrine treatment alone, three months of CAB followed by continuous endocrine treatment using flutamide (439 patients) with the same treatment combined with radiotherapy (436 patients). After a median follow-up of 7.6 years, the 10-year cumulative incidence for prostate cancer-specific mortality was respectively 23.9% and 11.9% (difference 12%; 95% CI; 4.9-19.1%), and the 10-year cumulative incidence for overall mortality was 39.4% in the endocrine treatment alone group, and 29.6% in the endocrine plus radiotherapy group (difference 9.8%; 0.8-18%). 10.8.4 Neoadjuvant, concomitant and long-term adjuvant hormonal therapy The RTOG 92-02 trial closed in 1995 after accruing 1554 patients. Statistically significant improvements were observed in actuarial biochemical freedom from disease (bNED) control, distant metastatic failure, local control, and disease-free survival in patients receiving long-term ADT (LDAT) (before, during, and two years after radiotherapy), compared with short-term androgen deprivation (STAD) (two months before and during radiotherapy). With a median follow-up of 5.8 years, the LTAD treatment arm showed significant improvement over the STAD arm in all efficacy end-points except five-year overall survival, which was 80% vs 78.5% (p = 0.73), respectively. In a subset of patients that was not part of the original study design, with Gleason score 8-10 tumours, the LTAD arm showed significantly better overall survival after five years than the STAD arm, with 81% vs 70.7% (p = 0.04) (82). 10.8.5 Short-term or long-term adjuvant hormonal treatment Further to EORTC trial 22863, EORTC equivalence trial 22961 was set up to test whether similar survival could be achieved in patients who underwent irradiation (to 70 Gy) and six months of combined ADT without further ADT, i.e. STADT arm, compared with patients with 2.5 years of further treatment with luteinising hormonereleasing hormone analogue (LHRHa), i.e. LTADT arm. Eligible patients had T1c-2b N1-2 or pN1-2, or T2c-4 N0-2 (UICC 1992) M0 prostate cancer with PSA < 150 ng/mL. Non-inferior survival was defined as a mortality hazard ratio (HR) = 1.35 for SADT vs LADT. A total of 970 patients were randomised. With a 5.2-year median follow-up, the five-year overall survival rate was 85.3% on LADT, and 80.6% on SADT (HR = 1.43; 96.4% CI; 1.04-1.98), and failed to prove non-inferiority (83). 10.8.6 Dose escalation with hormonal therapy For bulky locally advanced prostate cancer, there might be a role for dose escalation as suggested by the excellent results of a retrospective series by the Memorial Sloan-Kettering Cancer Center devoted to 296 patients: 130 cT3a N0-X M0 and 166 cT3bN0-X M0. The prescribed doses to the prostate gland ranged from 66 Gy to 86.4 Gy; 95 patients received IMRT with dose escalation beyond 81 Gy. ADT was given for three months prior to radiotherapy to 189 patients (64%), and was continued during the course of radiotherapy for patients with high-grade disease. With a median follow-up of eight years, the five- and 10-year overall survival and cause-specific survival were respectively 91% and 65%, 95% and 83% (84).

10.9

Very high-risk prostate cancer: c or pN1, M0

Patients with a pelvic lymph node involvement lower than the iliac regional nodes, younger than 80 years old with WHO performance status 0-1 and no severe co-morbidity may be candidates for external beam irradiation plus immediate long-term hormonal manipulation. The RTOG 85-31 randomised phase III trial has shown, with

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a median follow-up of 6.5 years, that 95 patients out of the 173 pN1 patients who received pelvic radiotherapy with immediate hormonal therapy had better five and nine-year progression-free survival (PSA < 1.5 ng/mL), with 54% and 10% respectively versus 33% and 4% with radiation alone and hormonal manipulation instituted at the time of relapse (p < 0.0001). Multivariate analysis revealed this combination as having a statistically significant impact on overall survival, disease-specific failure, metastatic failure and biochemical control (85).

10.10 Summary of definitive radiation therapy

•

•

•

•

•

In localised prostate cancer T1c-T2c N0 M0, 3D-CRT with or without IMRT is recommended even for young patients who refuse surgical intervention. There is fairly strong evidence that low-, intermediate- and high-risk patients benefit from dose escalation For patients in the high-risk group, short-term ADT prior to and during radiotherapy results in increased overall survival. Transperineal interstitial brachytherapy with permanent implants is an option for patients with cT1T2a, Gleason score < 7 (or 3 + 4), PSA ≤ 10 ng/mL, prostate volume ≤ 50 mL, without a previous TURP and with a good IPSS. Immediate post-operative external irradiation after radical prostatectomy for patients with pathological tumour stage T3 N0 M0 improves biochemical and clinical disease-free survival. An alternative option is to give radiation at the time of biochemical failure, but before PSA rises above 1ng/mL. In locally advanced prostate cancer T3-4 N0 M0, overall survival is improved by concomitant and adjuvant hormonal therapy for a total duration of three years, with external irradiation for patients with a WHO 0-1 performance status. For a subset of patients with T2c-T3 N0-x and a Gleason score of 2- 6, short-term ADT before and during radiotherapy may favourably influence overall survival. In very high-risk prostate cancer, c-pN1 M0 with no severe co-morbidity, pelvic external irradiation and immediate long-term adjuvant hormonal treatment improve overall survival, disease-specific failure, metastatic failure and biochemical control.

LE 2

2a 2b

1 3 1

1b 2b

LE = level of evidence

10.11 REFERENCES 1.

2.

3.

4.

5.

6.

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Consensus statement: the management of clinically localized prostate cancer. National Institutes of Health Consensus Development Panel (no authors listed). NCI Monogr 1988;(7):3-6. http://www.ncbi.nlm.nih.gov/pubmed/3050539 Fowler FJ, Barry MJ, Lu-Yao G, Wasson JH, Bin L. Outcomes of external beam radiation therapy for prostate cancer: a study of Medicare beneficiaries in three surveillance epidemiology and end results areas. J Clin Oncol 1996;14(8):2258-65. http://www.ncbi.nlm.nih.gov/pubmed/8708715 Nilsson S, Norlen BJ, Widmarks A. A systematic overview of radiation therapy effects in prostate cancer. Acta Oncol 2004;43(4):316-81. http://www.ncbi.nlm.nih.gov/pubmed/15303499 Kupelian P, Kuban D, Thames H, Levy L, Horwitz E, Martinez A, Michalski J, Pisansky T, Sandler H, Shipley W, Zelefsky M, Zietman A. Improved biochemical relapse-free survival with increased external radiation doses in patients with localized prostate cancer: the combined experience of nine institutions in patients treated in 1994 and 1995. Int J Radiat Oncol Biol Phys 2005;61(2):415-9. http://www.ncbi.nlm.nih.gov/pubmed/15667961 Kuban DA, Tucker SL, Dong L, Starkshall G, Huang EH, Cheung MR, Lee AK, and Pollack A. Long term results of the MD Anderson randomized dose-escalation trial for prostate cancer. Int J Radiat Oncol Biol Phys 2008;70(1):67-74. http://www.ncbi.nlm.nih.gov/pubmed/17765406 Zietman AL, DeSilvio M, Slater JD, Rossi CJ, Miller DW, Adams JA, Shipley WU. Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate. A randomized controlled trial JAMA 2005;294(10):1233-9. http://www.ncbi.nlm.nih.gov/pubmed/16160131

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7.

8.

9.

10.

11.

12.

13.

14.

15.

16. 17.

18.

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Cahlon O, Zelefsky MJ, Shippy A, Chan H, Fuks Z, Yamada Y, Hunt M, Greenstein S, Amols H. Ultrahigh dose (86.4 Gy) IMRT for localized prostate cancer: toxicity and biochemical outcomes. Int J Radiat Oncol Biol Phys 2008;71(2):330-7. http://www.ncbi.nlm.nih.gov/pubmed/18164858 22. Ling CC, Yorke E, Fuks Z. From IMRT to IGRT: frontierland or neverland? Radiother Oncol 2006;78(2):119-22. http://www.ncbi.nlm.nih.gov/pubmed/16413622 23. Keiler L, Dobbins D, Kulasekere R, Einstein D. Tomotherapy for prostate adenocarcinoma: a report on acute toxicity. Radiother Oncol 2007;84(2):171-6. http://www.ncbi.nlm.nih.gov/pubmed/17692975 24. Trofimov A, Nguyen PL, Coen JJ, Doppke KP, Schneider RJ, Adams JA, Bortfeld TR, Zietman AL, Delaney TF, Shipley WU. Radiotherapy treatment of early-stage prostate cancer with IMRT and protons: a treatment planning comparison. Int J Radiat Oncol Biol Phys 69(2):444-53. http://www.ncbi.nlm.nih.gov/pubmed/17513063 25. Vargas C, Fryer A, Mahajan C, Indelicato D, Horne D, Chellini A, McKenzie C, Lawlor P, Henderson R, Li Z, Lin L, Olivier K, Keole S. Dose-volume comparison of proton therapy and intensity-modulated radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2008;70(3):744-51. http://www.ncbi.nlm.nih.gov/pubmed/17904306 26. Ishikawa H, Tsuji H, Kamada T, Yanagi T, Mizoe JE, Kanai T, Morita S, Wakatsuki M, Shimazaki J, Tsujii H; Working Group for Genitourinary Tumors. Carbon ion radiation therapy for prostate cancer: results of a prospective phase II study. Radiother Oncol 2006;81(1):57-64. http://www.ncbi.nlm.nih.gov/pubmed/16971008 27. Ash D, Flynn A, Batterman J, de Reijke T, Lavagnini P, Blank L; ESTRA/EAU Urological Brachytherapy Group; EORTC Radiotherapy Group. ESTRO/EAU/EORTC recommendations on permanent seed implantation for localized prostate cancer. Radiother Oncol 2000;57(3):315-21. http://www.ncbi.nlm.nih.gov/pubmed/11104892 28. Salembier C, Lavagnini P, Nickers P, Mangili P, Rijnders A, Polo A, Venselaar J, Hoskin P; GEC ESTRO PROBATE Group. Tumour and target volumes in permanent prostate brachytherapy: a supplement to the ESTRO/EAU/EORTC recommendations on prostate brachytherapy. Radiother Oncol 2007;83(1):3-10. http://www.ncbi.nlm.nih.gov/pubmed/17321620 29. Holm HH, Juul N, Pedersen JF, Hansen H, Stroyer I. Transperineal seed implantation in prostatic cancer guided by transrectal ultrasonography. J Urol 1983;130(2):283-6. http://www.ncbi.nlm.nih.gov/pubmed/6876274 30. Machtens S, Baumann R, Hagemann J, Warszawski A, Meyer A, Karstens JH, Jonas U. Long-term results of interstitial brachytherapy (LDR-brachytherapy) in the treatment of patients with prostate cancer. World J Urol 2006;24(3):289-95. http://www.ncbi.nlm.nih.gov/pubmed/16645877 31. Grimm PD, Blasko JC, Sylvester JE, Meier RM, Cavanagh W. 10-year biochemical (prostate-specific antigen) control of prostate cancer with (125)I brachytherapy. Int J Radiat Biol Phys 2001;51(1):31-40. http://www.ncbi.nlm.nih.gov/pubmed/11516848 32. Potters L, Klein EA, Kattan MW, Reddy CA, Ciezki JP, Reuther AM, Kupelian PA. Monotherapy for stage T1-T2 prostate cancer: radical prostatectomy, external beam radiotherapy, or permanent seed implantation. Radiother Oncol 2004;71(1):29-33. http://www.ncbi.nlm.nih.gov/pubmed/15066293 33. Sylvester JE, Blasko JC, Grimm R, Meier R, Spiegel JF, Malmgrem JA. Fifteen year follow-up of the first cohort of localized prostate cancer patients treated with brachytherapy. J Clin Oncol 2004;22(14S):4567. http://meeting.jco.org/cgi/content/abstract/22/14_suppl/4567 34. Potters L, Morgenstern C, Calugaru E, Fearn R, Jassal A, Presser J, Mullen E. 12-year outcomes following permanent prostate brachytherapy in patients with clinically localized prostate cancer. J Urol 2005;173(5):1562-6. http://www.ncbi.nlm.nih.gov/pubmed/15821486 35. Stone NN, Stock RG, Unger P. Intermediate term biochemical-free progression and local control following 125iodine brachytherapy for prostate cancer. J Urol 2005;173(3):803-7. http://www.ncbi.nlm.nih.gov/pubmed/15711273

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42.

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Zelefsky MJ, Kuban DA, Levy LB, Potters L, Beyer DC, Blasko JC, Moran BJ, Ciezki JP, Zietman AL, Pisansky TM, Elshaikh M, Horwitz EM. Multi-institutional analysis of long-term outcome for stages T1-T2 prostate cancer treated with permanent seed implantation. Int J Radiat Oncol Biol Phys 2007;67(2):327-33. http://www.ncbi.nlm.nih.gov/pubmed/17084558 Lawton CA, DeSilvio M, Lee WR, Gomelia L, Grignon D, Gillin M, Morton G, Pisansky T, Sandler H. Results of a phase II trial of transrectal ultrasound-guided permanent radioactive implantation of the prostate for definitive management of localized adenocarcinoma of the prostate (RTOG 98-05). Int J Radiat Oncol Biol Phys 2007;67(1):39-47. http://www.ncbi.nlm.nih.gov/pubmed/17084551 Potters L, Morgenstern C, Calugaru E, Fearn P, Jassal A, Presser J, Mullen E. 12-year outcomes following permanent prostate brachytherapy in patients with clinically localized prostate cancer. J Urol 2008;179(5Suppl.):S20-S24. http://www.ncbi.nlm.nih.gov/pubmed/18405743 Stock RG, Stone NN. Importance of post-implant dosimetry in permanent brachytherapy. Eur Urol 2002;41(4):434-9. http://www.ncbi.nlm.nih.gov/pubmed/12074816 Elshaikh MA, Ulchaker JC, Reddy CA, Angermeier KW, Klein EA, Chehade N, Altman A, Ciezki JP. Prophylactic tamsulosin (Flomax) in patients undergoing prostate 125I brachytherapy for prostate carcinoma: final report of a double-blind placebo-controlled randomized study. Int J Radiat Oncol Biol Phys 62(1):164-9. http://www.ncbi.nlm.nih.gov/pubmed/15850917 Chen AB, D’Amico AV, Neville BA, Earle CC. Patient and treatment factors associated with complications after prostate brachytherapy. J Clin Oncol 2006;24(33):5298-304. http://www.ncbi.nlm.nih.gov/pubmed/17114664 Merrick GS, Butler WM, Galbreath RW, Lief JH, Adamovich E. Biochemical outcome for hormone naive patients with Gleason score 3+4 versus 4+3 prostate cancer undergoing permanent prostate brachytherapy. Urology 2002;60(1):98-103. http://www.ncbi.nlm.nih.gov/pubmed/12100932 Reed DR, Wallner KE, Merrick GS, Arthurs S, Mueller A, Cavanagh W, Butler WB, Ford E, Sutlief SG. A prospective randomized comparison of stranded vs. loose 125I seeds for prostate brachytherapy. Brachytherapy 2007;6(2):129-34. http://www.ncbi.nlm.nih.gov/pubmed/17434106 Potters L, Cha C, Ashley R, Barbaris H, Leibel S. Is pelvic radiation necessary in patients undergoing prostate brachytherapy? Int J Radiat Oncol Biol Phys 1998;42:300 (abstract 2146). Lee LN, Stock RG, Stone NN. Role of hormonal therapy in the management of intermediate- to highrisk prostate cancer treated with permanent radioactive seed implantation. Int J Radiat Oncol Biol Phys 2002;52(2):444-52. http://www.ncbi.nlm.nih.gov/pubmed/11872291 Wallner K, Merrick G, True L, Sherertz T, Sutlief S, Cavanagh W, Butler W. 20 Gy versus 44 Gy supplemental beam radiation with Pd-103 prostate brachytherapy: preliminary biochemical outcomes from a prospective randomized multi-center trial. Radiother Oncol 2005;75(3):307-10. http://www.ncbi.nlm.nih.gov/pubmed/16086912 Galalae RM, Kovacs G, Schultze J, Loch T, Rzehak P, Wilhelm R, Bertermann H, Buschbeck B, Kohr P, Kimmig B. Long term outcome after elective irradiation on the pelvic lymphatics and local dose escalation using high dose rate brachytherapy for locally advanced prostate cancer. Int J Radiat Oncol Biol Phys 2002;52(1):81-90. http://www.ncbi.nlm.nih.gov/pubmed/11777625 Zelefsky MJ, Nedelka MA, Arican ZL, Yamada Y, Cohen GN, Shippy AM, Park JJ, Zaider M. Combined brachytherapy with external beam radiotherapy for localized prostate cancer: reduced morbidity with an intraoperative brachytherapy planning technique and supplemental intensity-modulated radiation therapy. Brachytherapy 2008;7(1):1-6. http://www.ncbi.nlm.nih.gov/pubmed/18299108 Kupelian PA, Potters L, Ciezki JP, Reddy CA, Reuther AM, Klein EA. Radical prostatectomy, external beam radiotherapy < 72 Gy, external radiotherapy > or = 72 Gy, permanent seed implantation or combined seeds/external beam radiotherapy for stage T1-2 prostate cancer. Int J Radiat Oncol Biol Phys 2004;58(1):25-33. http://www.ncbi.nlm.nih.gov/pubmed/14697417

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Sylvester JE, Grimm PD, Blasko JC, Millar J, Orio PF 3rd, Skoglund S, Galbreath RW, Merrick G. 15-year biochemical relapse free survival in clinical stage T1-T3 prostate cancer following combined external beam radiotherapy and brachytherapy; Seattle experience. Int J Radiat Oncol Biol Phys 2007;67(1):57-64. http://www.ncbi.nlm.nih.gov/pubmed/17084544 51. Phan TP, Syed AM, Puthawala A, Sharma A, Khan F. High dose rate brachytherapy as a boost for the treatment of localized prostate cancer. J Urol 2007;177(1):123-7. http://www.ncbi.nlm.nih.gov/pubmed/17162020 52. Vordermark D, Wulf J, Markert K, Baier K, Kolbi O, Bekcmann G, Bratengeier K, Noe M, Schon G, Flentje M. 3-D conformal treatment of prostate cancer to 74 Gy vs high dose rate brachytherapy boost: a cross-sectional quality of life survery. Acta Oncol 2006;45(6):708-16. http://www.ncbi.nlm.nih.gov/pubmed/16938814 53. Hoskin PJ, Motohashi K, Bownes P, Bryant L, Ostler P. High dose rate brachytherapy in combination with external beam radiotherapy in the radical treatment of prostate cancer: initial results of a randomised phase three trial. Radiother Oncol 2007;84(2):114-20. http://www.ncbi.nlm.nih.gov/pubmed/17531335 54. Ataman F, Zurlo A, Artignan X, van Tienhoven G, Blank LE, Warde P, Dubois JB, Jeanneret W, Keuppens F, Bernier J, Kuten A, Collette L, Pierart M, Bolla M. Late toxicity following conventional radiotherapy for prostate cancer: analysis of the EORTC trial 22863. Eur J Cancer 2004;40(11): 1674-81. http://www.ncbi.nlm.nih.gov/pubmed/15251156 55. Robinson JW, Moritz S, Fung T. Meta-analysis of rates of erectile function after treatment of localized prostate carcinoma. Int J Radiat Oncol Biol Phys 2002;54(4):1063-8. http://www.ncbi.nlm.nih.gov/pubmed/12419432 56. Baxter NN, Trepper JE, Durham SB, Rothenberger DA, Virnig BA. Increased risk of rectal cancer after prostate radiation: a population-based study. Gastroenterology 2005;128(4):819-24. http://www.ncbi.nlm.nih.gov/pubmed/15825064 57. Liauw SL, Sylvester JE, Morris CG, Blasko JC, Grimm PD. Second malignancies after prostate brachytherapy: incidence of bladder and colorectal cancers in patients with 15 years of potential follow-up. Int J Radiat Oncol Biol Phys 2006;66(3):669-73. http://www.ncbi.nlm.nih.gov/pubmed/16887293 58. Zelefsky MJ, Levin EJ, Hunt M, Yamada Y, Shippy AM, Jackson A, Amols HI. Incidence of late rectal and urinary toxicities after three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 70(4):1124-9. http://www.ncbi.nlm.nih.gov/pubmed/18313526 59. Hanks GE. External-beam radiation therapy for clinically localized prostate cancer: patterns of care studies in the United States. NCI Monogr 1988;(7):75-84. http://www.ncbi.nlm.nih.gov/pubmed/3050542 60. Kupelian PA, Katcher J, Levin HS, Klein EA. Staging T1-2 prostate cancer: a multivariate analysis of factors affecting biochemical and clinical failures after radical prostatectomy. Int J Radiat Oncol Biol Phys 1997;37(5):1043-52. http://www.ncbi.nlm.nih.gov/pubmed/9169811 61. Bolla M, van Poppel H, Van Cangh PJ et al. Acute and late toxicity of post operative external irradiation in pT3N0 prostate cancer patients treated within EORTC trial 22911. Int J Rad Oncol Biol Phys 2002;54(Suppl.2):S62(abstract 103). 62. van Cangh PJ, Richard F, Lorge F, Castille Y, Moxhon A, Opsomer R, De Visscher L, Wese FX, Scaillet P. Adjuvant therapy does not cause urinary incontinence after radical prostatectomy: results of a prospective randomized study. J Urol 1998;159(1):164-6. http://www.ncbi.nlm.nih.gov/pubmed/9400462 63. Bolla M, van Poppel H, Collette L, van Cangh P, Vekemans K, Da Pozzo L, de Reijke TM, Verbaeys A, Bosset JF, van Velthoven R, Maréchal JM, Scalliet P, Haustermans K, Piérart M; European Organization for Research and Treatment of Cancer. Postoperative radiotherapy after radical prostatectomy: a randomized controlled trial (EORTC trial 22911). Lancet 2005;366(9485):572-8. http://www.ncbi.nlm.nih.gov/pubmed/16099293 64. Wiegel T, Bottke D, Steiner U, Siegmann A, Golz R, Storkel S, et al. Post-operative adjuvant radiotherapy in patients with pT3 prostate cancer after radical prostatectomy with postoperative undetectable PSA – a randomized controlled trial. J Clin Oncol 2008;(in press).

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Swanson GP, Thompson IM, Tangen C, ParadeloJ, Cany-Hagino E, Crawford ED, Miller G, Lucia MS, Forman J, Chin J. Update of SWOG 8794: adjuvant radiotherapy for pT3 prostate cancer improves metastasis free survival. Int J Rad Oncol Biol Phys 2008;72:S31. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T7X-4T85W5M-2R&_user=10&_ coverDate=09%2F01%2F2008&_rdoc=78&_fmt=high&_orig=browse&_srch=doc-info(%23toc%23507 0%232008%23999279998.8998%23696337%23FLA%23display%23Volume)&_cdi=5070&_sort=d&_ docanchor=&_ct=1614&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=1978c19de ba133909fb143c830f625f3 66. Poortmans P, Bossi A, Vandeputte K, Bosset M, Miralbell R, Maingon P, Boehmer D, Budiharto T, Symon Z, van den Bergh A, Scrase C, Van Poppel H, Bolla M. Guidelines for target volume definition in post-operative radiotherapy for prostate cancer, on behalf of the EORTC Radition Oncology Group. Radioth Oncol 2007;84(2):121-7. http://www.ncbi.nlm.nih.gov/pubmed/17706307 67. Cox JD, Gallagher MJ, Hammond EH, Kaplan RS, Schellhammer PF. Consensus statements on radiation therapy of prostate cancer: guidelines for prostate re-biopsy after radiation and for radiation therapy with rising prostate-specific antigen levels after radical prostatectomy. American Society for Therapeutic Radiology and Oncology Consensus Panel. J Clin Oncol 1999;17(4):1155. 68. Wilder RB, Hsiang JY, Ji M, Earle JD, de Vere White R. Preliminary results of three-dimensional conformal radiotherapy as salvage treatment for a rising prostate-specific antigen level postprostatectomy. Am J Clin Oncol 2000;23(2):176-80. http://www.ncbi.nlm.nih.gov/pubmed/10776980 69. Trock BJ, Han M, Freedland SJ, Humphreys EB, DeWeese TL, Partin AW, Walsh PC. Prostate cancerspecific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA 2008;299:2760-9. http://www.ncbi.nlm.nih.gov/pubmed/18560003 70. Bagshaw MA, Cox RS, Ray GR. Status of radiation treatment of prostate cancer at Standford University. NCI Monogr 1988;(7):47-60. http://www.ncbi.nlm.nih.gov/pubmed/3173503 71. Huggins C, Hodges CV. Studies on prostate cancer I. The effects of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. J Urol 2002;168(1):9-12. http://www.ncbi.nlm.nih.gov/pubmed/12050481 72. Leibel SA, Fuks Z, Zelefsky MJ, Whitmore WF Jr. The effects of local and regional treatments on the metastatic outcome in prostatic carcinoma with pelvic lymph node involvement. Int J Radiat Oncol Biol Phys 1994;28(1):7-16. http://www.ncbi.nlm.nih.gov/pubmed/8270461 73. Zietman AL, Prince EA, Nakfoor BM, Park JJ. Androgen deprivation and radiation therapy: sequencing studies using the Shionogi in vivo tumour system. Int J Radiat Oncol Biol Phys 1997;38(5):1067-70. http://www.ncbi.nlm.nih.gov/pubmed/9276373 74. Joon DL, Hasegawa M, Sikes C, Khoo VS, Terry NHA, Zagars GK, Meistrich M, Pollack A. Supraadditive apoptotic response of R3327-G rat prostate tumours to androgen ablation and radiation. Int J Radiat Oncol Biol Phys 1997;38(5):1071-7. http://www.ncbi.nlm.nih.gov/pubmed/9276374 75. Roach M, Bae K, Speight J, Wolkov HB, Rubin P, Lee RJ, Lawton C, Valicenti R, Grignon D, Pilepich M. Short-term neodajuvant androgen deprivation therapy and external-beam radiotherapy for localy advanced prostate cancer: long term results of RTOG 8610. J Clin Oncol 2008;26(4):585-91. http://www.ncbi.nlm.nih.gov/pubmed/18172188 76. Bolla M, Collette L, Blank L, Warde P, Dubois JB, Mirimanoff RO, Storme G, Bernier J, Kuten A, Sternberg C, Mattelaer J, Lopez Torecilla J, Pfeffer JR, Lino Cutajar C, Zurlo A, Pierart M. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomized trial. Lancet 2002;360(9327):103-6. http://www.ncbi.nlm.nih.gov/pubmed/12126818 77. Bolla M, Collette L, Van Tienhoven G, Warde W, Dubois JB, Mirimanoff RO, Storme G, Bernier J, Kuten A, Piérart M. Ten year resulst of long term adjuvant androgen deprivation with goserelin in patients with locally advanced prostate cancer treated with radiotherapy; a phase III EORTC study. Int J Radiat Oncol Biol Phys 2008;72(1 Suppl 1):S30-S31. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T7X-4T85W5M-2P&_user=10&_ coverDate=09%2F01%2F2008&_rdoc=77&_fmt=high&_orig=browse&_srch=doc-info(%23toc%23507 0%232008%23999279998.8998%23696337%23FLA%23display%23Volume)&_cdi=5070&_sort=d&_ docanchor=&_ct=1614&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=4210c0390 817dc3768d6bd16561e7d68 Update march 2009

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Pilepich MV, Winter K, Lawton C, Krisch RE, Wolkov H, Movsas B, Hug E, Asbell S, Grignon D. Phase III trial of androgen suppression adjuvant to definitive radiotherapy. Long term results of RTOG study 85-31. Proc Am Society Clin Oncol 2003;22:(abstr.1530). http://pediatricca.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnex toid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=23&abst ractID=101094 79. Warde P, Intergroup (NCIC CTG, CUOG, ECOG, CALGB, SWOG). Phase III randomized trial comparing total androgen blockade versus total androgen blockade plus pelvic irradiation in clinical stage T3-4, N0, M0 adenocarcinoma of the prostate. National Cancer Institute of Canada, Clinical Trials Group, 1995. https://www.swogstat.org/ROS/ROSBooks/Spring%202002/Intergroup/NCIC/PR3-2001.pdf 80. Mason M, Warde P, Sydes M, Cowan R, James N, Kirkbride P, Langley R, Latham J, Moynihan C, Anderson J, Millet J, Nutall J, Moffat L, Parulekar W, Parmar M; The National Cancer Institute of Canada Clinical Trials Group PR3/; Medical Research Council PR07 Trial Management Group. Defining the need for local therapy in locally advanced prostate cancer: an appraisal of the MRC PR07 study. Clin Oncol (R Coll Radiol) 2005;17(4):217-8. http://www.ncbi.nlm.nih.gov/pubmed/15997913 81. Widmark A, Klepp O, Solberg A, Damber JE, Angelsen A, Fransson P, Lund JÅ, Tasdemir I, Hoyer M, Wiklund F, Fosså SD for the Scandinavian Prostate Cancer Group Study, the Swedish Association for Urological Oncology. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomized phase III trial. Lancet 2008;373(9660):301-8. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61815-2/abstract 82. Hanks GE, Pajak TF, Porter A, Grignon D, Brereton H, Venkatesan V, Horwitz EM, Lawton C, Rosenthal SA, Sandler HM, Shipley WU; Radiation Therapy Oncology Group. RTOG 92-02: Phase III trial of long term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate. J Clin Oncol 2003;21(21):3972-8. http://www.ncbi.nlm.nih.gov/pubmed/14581419 83. Bolla M, de Reijke TM, Van Tienhoven G, Van den Bergh AC, Van der Meijden AP, Poortmans PM, Gez E, Kil P, Piérart M, Collette L. Concomitant and adjuvant androgen deprivation (ADT) with external beam irradiation (RT) for locally advanced prostate cancer: 6 months versus 3 years ADT: Results of the randomized EORTC Phase III trial 22961. J Clin Oncol 2007;25:238s(abstr.5014). 84. Zelefsky MJ, Yamada Y, Kollmeier MA, Shippy AM, Nedelka MA. Long term outcome following threedimensional conformal/intensity modulated external-beam radiotherapy for clinical stage T3 prostate cancer. Eur Urol 2008;53(6):1172-9. http://www.ncbi.nlm.nih.gov/pubmed/18222596 85. Lawton CA, Winter K, Grignon D, Pilepich MV. Androgen suppression plus radiation versus radiation alone for patients with D1/pathologic node-positive adenocarcinoma of the prostate: updated results based on a national prospective randomized trial, RTOG 85-31. J Clin Oncol 2005;23(4):800-7. http://www.ncbi.nlm.nih.gov/pubmed/15681524

11. EXPERIMENTAL LOCAL TREATMENT OF PROSTATE CANCER 11.1

Background

Besides radical prostatectomy, external beam radiation and/or brachytherapy, cryosurgical ablation of the prostate (CSAP) and high-intensity focused ultrasound (HIFU) have emerged as alternative therapeutic options in patients with clinically localised prostate cancer (PCa) (1-4). Whereas HIFU is still considered to be an experimental treatment, CSAP has been recognised as a true therapeutic alternative as recommended by the guidelines of the American Urological Association. Both techniques have been developed as minimally invasive procedures that potentially have the same therapeutic efficacy as the established surgical and non-surgical options associated with reduced therapy-associated morbidity.

11.2

Cryosurgery of the prostate (CSAP)

Cryosurgery uses freezing techniques to induce cell death by:

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• • • •

dehydration resulting in protein denaturation direct rupture of cellular membranes by ice crystals vascular stasis and microthrombi, resulting in stagnation of the microcirculation with consecutive ischaemia apoptosis (1-4).

Freezing of the prostate is ensured by the placement of 12-15 17 G cryoneedles under transrectal ultrasound (TRUS) guidance, placement of thermosensors at the level of the external sphincter and the bladder neck, and insertion of a urethral warmer. Two freeze-thaw cycles are used under TRUS guidance, resulting in a temperature of -40 °C in the mid-gland and at the neurovascular bundle. 11.2.1 Indication for CSAP Patients who are ideal candidates for CSAP are those who have organ-confined PCa and those identified to have minimal extension beyond the prostate (1-3). The prostate should be ≤ 40 mL in size. Prostate glands that are > 40mL should be hormonally downsized in order to prevent technical difficulties in placing cryoprobes under the pubic arch. Prostate-specific antigen (PSA) serum levels should be < 20 ng/mL, and the biopsy Gleason score should be < 7. Since there are no, or only very few, data on the long-term outcome in terms of cancer control at 10 and 15 years, patients with a life expectancy > 10 years must be informed accordingly. 11.2.2 Results of modern cryosurgery for PCa When comparing treatment modalities, it is important to bear in mind that in modern radical prostatectomy series of patients with clinically organ-confined PCa, the risk of dying from PCa 10 years after surgery is as low as 2.4% (5). Therapeutic results have improved over time with enhanced techniques in terms of gas-driven probes and transperineal probe placement as used in third-generation cryosurgery (6-11). Objective assessment of PSA outcome is not easily performed because some institutions use PSA values < 0.1 ng/mL as an indicator of therapeutic success, whereas others use the American Society of Therapeutic Radiology and Oncology (ASTRO) criteria with three consecutive PSA increases. With regard to second-generation CSAP, if a PSA nadir < 0.5 ng/mL is used, biochemical-free survival at five years is 60% and 36% for low-risk and high-risk patients, respectively (6, 7). The seven-year biochemical-free survival, however, is 92% if ASTRO criteria are used. Long et al. (6) retrospectively analysed the multicentre pooled CSAP results of 975 patients who were stratified into three risk groups. Using PSA thresholds of 1.0 ng/mL and < 0.5 ng/mL at a mean follow-up of 24 months, the five-year actuarial biochemical progression-free rate was 76% and 60%, respectively, for the low-risk group, 71% and 45%, respectively, for the intermediate-risk group, and 61% and 36%, respectively, for the high-risk group. However, in a recent meta-analysis of 566 publications related to cryosurgery, it was demonstrated that no controlled trial was available for analysis, no survival data were presented, and no validated biochemical surrogate end-points were available (12). Cryosurgery showed a progression-free survival of 36-92% (projected one- to seven-year data), depending on risk groups and the definition of failure. Negative biopsies were seen in 72-87%, but no biopsy data were available for the currently used thirdgeneration cryotherapy machines. With regard to third-generation cryosurgery, clinical follow-up is short, with only 110/175 (63%) patients having a PSA follow-up at 12 months (6-11). Of these, 80 (73%) patients remain with a PSA nadir < 0.4 ng/mL, and 42/65 (76%) low-risk patients remain free from biochemical progression using the 0.4 ng/mL cut-off. A longer follow-up was reported by Bahn et al. (9) analysing the therapeutic results of 590 patients undergoing CSAP for clinically localised and locally advanced PCa. Using a PSA cut-off level of < 0.5 ng/mL, the sevenyear biochemical-free survival for low-, medium- and high-risk groups was 61%, 68% and 61%, respectively. Nerve-sparing cryosurgery, as reported recently (13), must still be considered to be an experimental therapeutic option. Nerve-sparing surgery was performed in nine patients with unilateral PCa confirmed on repeated biopsies, with CSAP being carried out on the side of the positive biopsy, whereas the negative biopsy side was spared from freezing. 11.2.3 Complications of CSAP for primary treatment of PCa Erectile dysfunction occurs in about 80% of patients and remains a consistent complication of the CSAP procedure, independent of the generation of the system used. The complication rates described with the third

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generation of cryosurgery include tissue sloughing in about 3%, incontinence in 4.4%, pelvic pain in 1.4% and urinary retention in about 2% (6-11). The development of fistula is usually rare, with < 0.2% in modern series. About 5% of all patients require transurethral resection of the prostate (TURP) for subvesical obstruction. Quality of life and sexuality following CSAP have been investigated in a clinical phase II trial recruiting 75 men (14). Quality-of-life analysis by the prostate-specific FACT-P questionnaire revealed that most subscales had returned to pre-treatment levels by 12 months after CSAP. Furthermore, no significant changes could be determined when comparing the 36-month with the 12-month data. With regard to sexuality, 37% of the men were able to have intercourse at three years after CSAP. 11.2.4 Summary of CSAP • Patients with low-risk PCa (PSA < 10 ng/mL, ≤ T2a, Gleason score ≤ 6) or intermediate-risk PCa (PSA > 10 ng/mL, or Gleason score ≥ 7, or stage ≥ 2b) represent potential candidates for CSAP. • Prostate size should be < 40 mL at the time of therapy. • Long-term results are lacking, and five-year biochemical progression-free rates are inferior to those achieved by radical prostatectomy in low-risk patients. Patients must be informed accordingly.

11.3

High-intensity focused ultrasound (HIFU)

HIFU consists of focused ultrasound waves emitted from a transducer to cause tissue damage by mechanical and thermal effects as well as by cavitation (15). The goal of HIFU is to heat malignant tissues above 65 °C in order to destroy them by coagulative necrosis. HIFU is performed under general or spinal anesthesia, with the patient in the lateral (Ablatherm®) or supine (Sonablate® 500) position; the procedure is time-consuming, with about 10 g prostate tissue being treated in one hour. In a recent review, 150 papers related to HIFU were identified and evaluated with regard to various oncological and functional outcome parameters (12). No controlled trial was available for analysis, and no survival data were presented. No validated biochemical, surrogate end-point was available for HIFU therapy. 11.3.1 Results of HIFU in PCa As with CSAP, it appears to be difficult to interpret oncological outcome in patients undergoing HIFU since various PSA thresholds are defined and no international consensus exists on objective response criteria. The results of HIFU are limited, with outcome data from fewer than 1000 PCa cases having been published in the literature. According to the recent review paper mentioned above (12), HIFU showed progression-free survival (based on PSA +/- biopsy data) of 63-87% (projected three- to five-year data), but median follow-up in the studies ranged from 12-24 months only. In one of the largest single-centre studies, 227 patients with clinically organ confined PCa were treated with HIFU and their outcome data were analysed after a mean follow-up of 27 months (range = 12-121 months) (16). The projected five-year biochemical disease-free survival was 66%, and or only 57% if patients had exhibited a pre-therapeutic PSA value of 4-10 ng/mL. Incontinence and bladder neck stricture decreased over time from 28% and 31% to 9% and 6%, respectively. In one of the studies (17), a significant decrease in pre-treatment PSA serum levels from 12 ng/mL to 2.4 ng/mL was observed. However, 50% of the 14 patients demonstrated positive prostate biopsies during follow-up. In another study (18), a complete response rate defined by PSA < 4 ng/mL and six negative biopsies was achieved in 56% of the patients. Summarising the efficacy results of a European multicentre study comprising the data of 559 patients with mainly low- and intermediate-risk PCa, Thüroff et al. (18) reported on a negative biopsy rate of 87.2% in 288 men with a follow-up of at least six months. A PSA nadir after six months follow-up could be determined in 212 patients, and it was as high as 1.8 ng/mL. However, it could be demonstrated that the PSA nadir might be reached at 12-18 months following the initial procedure. Blana et al. reported on 146 patients undergoing HIFU with a mean follow-up of 22.5 months (19). The mean PSA level at initiation of therapy was 7.6 ng/mL; the PSA nadir achieved after three months was 0.07 ng/mL. However, after 22 months the median PSA level was 0.15 ng/mL. Of the 137 men available for analysis, 93.4% demonstrated a negative control biopsy. The PSA nadir appears to be strongly associated with treatment failure (20) (p < 0.001). Patients with a PSA nadir of 0.0-0.2 ng/mL have a treatment failure rate of only 11%, compared with 46% in patients with a PSA nadir of 0.21-1.00 ng/mL, and 48% with a PSA nadir of >1.0 ng/mL. Recently, the group updated its results, with a total of 163 men treated for clinically organ-confined PCa. Within

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the 4.8 +/- 1.2 years of follow-up, the actuarial disease-free survival rate at five years was 66%, with salvage treatment initiated for 12% of the patients (21). 11.3.2 Complications of HIFU Urinary retention appears to be one of the most common side-effects of HIFU, developing in almost all patients, with the mean interval of catheterisation via a suprapubic tube varying between 12 and 35 days (1517). Grade I and II urinary stress incontinence occurs in about 12% of patients. Subsequent TURP or bladder neck incision to treat subvesical obstruction is common, and is sometimes even performed at the time of HIFU. Post-operative impotence will occur in approximately 55-70% of patients.

11.4

Radio-frequency interstitial tumour ablation (RITA)

Radio-frequency interstitial tumour ablation (RITA) is a recently developed minimally invasive therapeutic option delivering radio-frequency energy via a needle electrode placed inside the prostate and resulting in coagulative necrosis by heating the tissue up to 100 °C. Clinical application so far has been limited to two small studies demonstrating the feasibility and safety of the procedure (22, 23). However, there are reliable data with regard to oncological control of PCa.

11.5

Summary of experimental therapeutic options to treat clinically localised PCa

Recommendation GR • CSAP has evolved from an investigational therapy to a possible alternative treatment for PCa in C patients who are unfit for surgery or with a life expectancy < 10 years • All other minimally invasive treatment options – such as HIFU, RITA, microwave and electro- C surgery – are still experimental or investigational. For all of these procedures, a longer follow-up is mandatory to assess their true role in the management of PCa GR = grade of recommendation

11.6

REFERENCES

1.

Fahmy WE, Bissada NK. Cyrosurgery for prostate cancer. Arch Androl 2003;49(5):397-407. http://www.ncbi.nlm.nih.gov/pubmed/12893518 2. Rees J, Patel B, Macdonagh R, Persad R. Cryosurgery for prostate cancer. BJU Int 2004;93(6):710-4. http://www.ncbi.nlm.nih.gov/pubmed/15049977 3. Han KR, Belldegrun AS. Third–generation cryosurgery for primary and recurrent prostate cancer. BJU Int 2004;93(1):14-8. http://www.ncbi.nlm.nih.gov/pubmed/14678360 4. Beerlage HP, Thüroff S, Madersbacher S, Zlotta AR, Aus G, de Reijke TM, de la Rosette JJMCH. Current status of minimally invasive treatment options for localized prostate carcinoma. Eur Urol 2000;37(1):2-13. http://www.ncbi.nlm.nih.gov/pubmed/10671777 5. Hull GW, Rabbani F, Abbas F, Wheeler TM, Kattan MW, Scardino PT. Cancer control with radical prostatectomy alone in 1,000 consecutive patients. J Urol 2002;167(2 Pt 1):528-34. http://www.ncbi.nlm.nih.gov/pubmed/11792912 6. Long JP, Bahn D, Lee F, Shinohara K, Chinn DO, Macaluso JN Jr. Five-year retrospective, multiinstitutional pooled analysis of cancer-related outcomes after cryosurgical ablation of the prostate. Urology 2001;57(3):518-23. http://www.ncbi.nlm.nih.gov/pubmed/11248631 7. Donelly BJ, Saliken JC, Ernst DS, Ali-Ridha N, Brasher PMA, Robinson JW, Rewcastle JC. Prospective trial of cryosurgical ablation of the prostate: five year results. Urology 2002;60(4):645-9. http://www.ncbi.nlm.nih.gov/pubmed/12385926 8. Han K, Cohen J, Miller R, Pantuck AJ, Freitas DG, Cuevas CA, Kim HL, Lugg J, Childs SJ, Shuman B, Jayson MA, Shore ND, Moore Y, Zisman A, Lee JY, Ugarte R, Mynderse LA, Wilson TM, Sweat SD, Zincke H, Belldegrun AS. Treatment of organ confined prostate cancer with third generation cryosurgery: preliminary multicentre experience. J Urol 2003;170(4 Pt 1):1126-30. http://www.ncbi.nlm.nih.gov/pubmed/14501706 9. Bahn DK, Lee F, Baldalament R, Kumar A, Greski J, Chernick M. Targeted cryoablation of the prostate: 7-year outcomes in the primary treatment of prostate cancer. Urology 2002;60(2 Suppl 1): 3-11. http://www.ncbi.nlm.nih.gov/pubmed/12206842

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10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

Koppie TM, Shinohara K, Grossfeld GD, Presti JC Jr, Carroll PR. The efficacy of cryosurgical ablation of prostate cancer: the University of California, San Francisco experience. J Urol 1999;162(2):427-32. http://www.ncbi.nlm.nih.gov/pubmed/10411051 De La Taille A, Benson MC, Bagiella E, Burchardt M, Shabsigh A, Olsson CA, Katz AE. Cryoablation for clinically localized prostate cancer using an argon-based system: complication rates and biochemical recurrence. BJU Int 2000;85(3):281-6. http://www.ncbi.nlm.nih.gov/pubmed/10671882 Aus G. Current status of HIFU and cryotherapy in prostate cancer – a review. Eur Urol 2006;50(5): 927-34. http://www.ncbi.nlm.nih.gov/pubmed/16971038 Onik G, Narayan P, Vaughan D, Dineen M, Brunelle R. Focal ‘nerve-sparing’ cryosurgery for treatment of primary prostate cancer: a new approach to preserving potency. Urology 2002;60(1):109-14. http://www.ncbi.nlm.nih.gov/pubmed/12100934 Robinson JW, Donnelly BJ, Saliken JC, Weber BA, Ernst S, Rewcastle JC. Quality of life and sexuality of men with prostate cancer 3 years after cryosurgery. Urology 2002;60(2 Suppl 1):12-8. http://www.ncbi.nlm.nih.gov/pubmed/12206843 Madersbacher S, Marberger M. High-energy shockwaves and extracorporeal high-intensity focused ultrasound. J Endourol 2003;17(8):667-72. http://www.ncbi.nlm.nih.gov/pubmed/14622487 Poissonnier L, Chapelon JY, Rouviere O, Curiel L, Bouvier R, Martin X, Dubernard JM, Gelet A. Control of prostate cancer by transrectal HIFU in 227 patients. Eur Urol 2007;51(2):381-7. http://www.ncbi.nlm.nih.gov/pubmed/16857310 Gelet A, Chapelon JY, Bouvier R, Pangaud C, Lasne Y. Local control of prostate cancer by transrectal high intensity focused ultrasound therapy: preliminary results. J Urol 1999;161(1):156-62. http://www.ncbi.nlm.nih.gov/pubmed/10037389 Thüroff S, Chaussy C, Vallancien G, Wieland W, Kiel HJ, Le Duc A, Desgrandschamps F, de la Rosette JJMCH, Gelet A. High-intensity focused ultrasound and localized prostate cancer: efficacy from the European multicentric study. J Endourol 2003;17(8):673-7. http://www.ncbi.nlm.nih.gov/pubmed/14622488 Blana A, Walter B, Rogenhofer S, Wieland W. High-intensity focused ultrasound for the treatment of localized prostate cancer: 5-year experience. Urology 2004;63(2)297-300. http://www.ncbi.nlm.nih.gov/pubmed/14972475 Uchida T, Illing RO, Cathcart PJ, Emberton M. To what extent does the prostate-specific antigen nadir predict subsequent treatment failure after transrectal high-intensity focused ultrasound therapy for presumed localized adenocarcinoma of the prostate? BJU Int 2006;98(3):537-9. http://www.ncbi.nlm.nih.gov/pubmed/16925749 Blana A, Rogenhofer S, Ganzer R, Lunz JC, Schostak M, Wieland WF, Walter B. Eight years’ experience with high-intensity focused ultrasonography for treatment of localized prostate cancer. Urology 2008;72(6):1329-33. http://www.ncbi.nlm.nih.gov/pubmed/18829078 Zlotta AR, Djavan B, Matis C, Noel JC, Peny MO, Silverman DE, Marberger M, Schulman CC. Percutaneous transperineal radiofrequency ablation of prostate tumour: safety, feasibility and pathological effects on human prostate cancer. Br J Urol 1998;81(2):265-75. http://www.ncbi.nlm.nih.gov/pubmed/9488071 Djavan B, Zlotta AR, Susani M, Heinz G, Shariat S, Silverman DE, Schulman CC, Marberger M. Transperineal radiofrequency interstitial tumour ablation of the prostate: correlation of magnetic resonance imaging with histopathologic examination. Urology 1997;50(6):986-92. http://www.ncbi.nlm.nih.gov/pubmed/9426739

12. HORMONAL THERAPY 12.1

Introduction

In 1941, Huggins and Hodges assessed the favourable effect of surgical castration and oestrogen administration on the progression of metastatic prostate cancer (PCa), demonstrating for the first time the responsiveness of PCa to androgen deprivation (1, 2). Since their pivotal studies, androgen-suppressing strategies have become the mainstay of the management of

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advanced PCa. Recently, however, there has been an evolution towards the use increasing use of hormonal treatment in younger men with earlier (i.e. non-metastatic) stages of disease or recurrent disease after definitive treatment, either as the primary single-agent therapy or as a part of a multimodality approach (3). Even if hormonal treatment effectively palliates the symptoms of advanced disease, there is no conclusive evidence at present that it can extend life.

12.2

Basics of hormonal control of the prostate

Prostate cells are physiologically dependent on androgens to stimulate growth, function and proliferation. Testosterone, although not tumorigenic, is essential for the growth and perpetuation of tumour cells (4). The testes are the source of most of the androgens, with only 5-10% (androstenedione, dihydroepiandrosterone and dihydroepiandrosterone sulphate) being derived from adrenal biosynthesis. Testosterone secretion is regulated by the hypothalamic-pituitary-gonadal axis. The hypothalamic luteinising hormone-releasing hormone (LHRH) stimulates the anterior pituitary gland to release luteinising hormone (LH) and follicle-stimulating hormone (FSH). LH stimulates the Leydig cells of the testes to secrete testosterone. Within the prostate cells, testosterone is converted by the enzyme 5-∝-reductase into 5-∝-dihydrotestosterone (DHT), which is an androgenic stimulant approximately 10 times more powerful than the parent molecule (5). Circulating testosterone is peripherally aromatised and converted into oestrogens, which, together with circulating androgens, exert a negative feedback control on hypothalamic LH secretion. If prostate cells are deprived of androgenic stimulation, they undergo apoptosis (programmed cell death). Any treatment ultimately resulting in the suppression of androgen activity is referred to as androgen deprivation therapy (ADT).

12.3

Different types of hormonal therapy

Androgen deprivation can be achieved either by suppressing the secretion of testicular androgens by means of surgical or medical castration, or by inhibiting the action of the circulating androgens at the level of their receptor in prostate cells using competing compounds known as anti-androgens. Alternatively, these two modalities can be combined to achieve what is commonly known as complete (or maximal or total) androgen blockade (CAB). 12.3.1 Testosterone-lowering therapy (castration) 12.3.1.1 Bilateral orchiectomy Surgical castration is still considered the ‘gold standard’ for ADT against which all other treatments are rated. By removing the testicular source of androgens, a hypogonadal status with a considerable decline of testosterone concentrations is induced, although a very low level of testosterone (known as the ‘castration level’) persists. The standard castrate level is below 50 ng/dL. It was defined more than 40 years ago, when testosterone level testing was limited. Current methods, using chemiluminescence technology, have shown a mean value after surgical castration of 15 ng/dL (6). This observation has led to a revisiting of the current definition of castration, with some authors suggesting the use of a level below 20 ng/dL. Bilateral orchiectomy, either total or by means of a subcapsular technique (i.e. with preservation of tunica albuginea and epididymis), is a simple and virtually complication-free surgical procedure that can easily be performed under local anaesthesia (7). It is the quickest way to achieve a castration level, which is usually obtained in less than 12 hours. The main drawback of orchiectomy is that it may have a negative psychological effect: some men consider it to be an unacceptable assault on their manhood. In addition, it is irreversible and does not allow for intermittent treatment. The use of bilateral orchiectomy has declined recently, which can be attributed to the effects of stage migration towards earlier disease, and the introduction of equally effective pharmacological modalities of castration (8). 12.3.1.2 Oestrogens There are several mechanisms of action: • down-regulation of LHRH secretion • androgen inactivation

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• •

direct suppression of Leydig cell function direct cytotoxicity to the prostate epithelium (in vitro evidence only) (9).

The most commonly used oestrogen is diethylstilboestrol (DES). Early studies by the Veterans Administration Co-operative Urological Research Group (VACURG) (10) tested oral DES at a dosage of 5 mg/day. However, the treatment was associated with high cardiovascular morbidity and mortality due to first-pass hepatic metabolism and the formation of thrombogenic metabolites. Accordingly, subsequent studies (11) tested lower oral dosages, namely 3 mg and 1 mg. Both regimens provided a therapeutic efficacy comparable to that of bilateral orchiectomy, but the former was still associated with high cardiotoxicity. Although a 1 mg dose was associated with substantially fewer adverse cardiovascular events than the 5 mg dosage, the side-effects were still significantly greater than with castration. Because of these concerns, and the advent of LHRH agonists and anti-androgens, the use of DES had fallen out of favour until recently. There are three main reasons for the renewed interest in oestrogens. • First, as a response to the number of deleterious side-effects and high cost of long-term ADT with the widespread use of LHRH agonists: oestrogens suppress testosterone levels and do not seem to lead to bone loss and cognitive decline (12) (level of evidence: 3). • Second, in phase II trials with patients diagnosed with hormone-refractory prostate cancer (HRPC), oestrogenic compounds (DES, DES-diphosphate) have been shown to induce prostate-specific antigen (PSA) response rates as high as 86%. • Third, a new oestrogen receptor-β (ER-β), possibly involved in prostate tumorigenesis, has been discovered (9). Two different strategies have been used to try to neutralise the cardiotoxicity that is the main drawback of oestrogen therapy. These strategies use the parenteral route of administration, which avoids first-pass hepatic metabolism, plus the addition of cardiovascular protecting agents. The final analysis of the Scandinavian Prostatic Cancer Group Study 5, a prospective randomised trial of more than 900 men with metastatic PCa that compared a parenteral oestrogen (polyoestradiol phosphate) with CAB (orchiectomy or LHRH agonist plus flutamide), showed neither a significant difference in disease-specific and overall survival between the treatment arms, nor a significant increase in cardiovascular mortality in the oestrogen arm, although the occurrence of non-fatal adverse cardiovascular events was significantly higher in this group (increase in ischaemic heart and heart decompensation events) (13, for update see 14). On the other hand, three recent, though small, phase II trials of patients with advanced PCa or HRPC evaluated the combination of DES (1 mg/day or 3 mg/day), with either low dose (1 mg/day) warfarin sodium or low dose (75-100 mg/day) aspirin for the prevention of cardiovascular toxicity, and found a persistent rate of thromboembolic complications (15-17). In conclusion, DES is one of the classic forms of hormonal therapy. Although its efficacy was demonstrated many years ago and recently reconfirmed in a meta-analysis as comparable to that of bilateral orchiectomy (18) (level of evidence: 1a), the significant cardiovascular side-effects, even at lower dosages, remain a concern. Further data are needed before oestrogens will be readmitted into clinical practice as a standard first-line treatment option. 12.3.1.3 LHRH agonists Long-acting LHRH agonists (buserelin, goserelin, leuprorelin and triptorelin) have been used in advanced PCa for more than 15 years and are currently the predominant forms of ADT (3, 19). They are synthetic analogues of LHRH, generally delivered as depot injections on a one-, two-, three-, or six-monthly basis, that interfere with the hypothalamic-pituitary-gonadal axis. They initially stimulate pituitary LHRH receptors, inducing a transient rise in LH and FSH release, and consequently elevate testosterone production (known as ‘testosterone surge’ or ‘flare up’ phenomenon), which begins within approximately two or three days of the first injection and lasts through approximately the first week of therapy (20). Chronic exposure to LHRH agonists eventually results in down-regulation of LHRH-receptors, with subsequent suppression of pituitary LH and FSH secretion and testosterone production. The level of testosterone decreases to castration levels usually within two to four weeks (21, 22). However, approximately 10% of patients treated with LHRH agonists fail to achieve castration levels (23), or up to 15% if the threshold is defined as 20 ng/dL.

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In a recent meta-analysis evaluating single-therapy ADT for advanced PCa, LHRH agonists were shown to have comparable efficacy to orchiectomy and DES (18) (level of evidence: 1a). This observation questions the clinical impact of changing the castrate testosterone level definition from 50 ng/dL to 20 ng/dL. In addition, although only based on an indirect comparison, all seemed equally effective whatever their formulation (18) (level of evidence: 3). Today, LHRH agonists have become the ‘standard of care’ in hormonal therapy because they avoid the physical and psychological discomfort associated with orchiectomy, and lack the potential cardiotoxicity associated with DES. However, the main concerns associated with the administration of LHRH agonists are the potentially detrimental effects associated with the ‘flare phenomenon’ in advanced disease, namely increased bone pain, acute bladder outlet obstruction, obstructive renal failure, spinal cord compression, and fatal cardiovascular events due to hypercoagulation status. A recent review (24) addressing these issues concluded that clinical flare needs to be distinguished from the more common biochemical flare (i.e. increasing levels of PSA), and even from asymptomatic radiographic evidence of progression, and that patients at risk for clinical flare are overwhelmingly those with high volume, symptomatic, bony disease, accounting for only 4-10% of M1 patients. Concomitant therapy with an anti-androgens definitely decreases the incidence of clinical relapse, but it does not completely remove the possibility of its occurrence. Based on pharmacokinetic considerations, it is recommended that administration of anti-androgens should be started on the same day as the depot injection, and treatment should be continued for a two-week period. However, for patients with impending spinal cord compression, alternative strategies for immediately ablating testosterone levels must be considered, such as bilateral orchiectomy or LHRH-antagonists. Apart from those patients, the clinical impact of the flare up observation is unknown. Finally, some mini-flares have also been observed with the long-term use of analogues, with an unknown clinical impact. 12.3.1.4 LHRH antagonists In contrast to the agonists, LHRH antagonists bind immediately and competitively to LHRH receptors in the pituitary gland. The effect is a rapid decrease in LH, FSH and testosterone levels without any flare. This seemingly more desirable mechanism of action has made LHRH antagonists very attractive since their introduction, but practical shortcomings have limited clinical studies. Indeed, many of these compounds have been associated with serious and life-threatening histamine-mediated side-effects and, until recently, no depot formulation was available. Two recently published phase III randomised multicentre trials comparing the LHRH antagonist abarelix with the LHRH agonist leuprorelin acetate (25) and with CAB (26) in patients with metastatic or recurrent PCa showed no difference in achieving and maintaining castration levels of testosterone and in reducing serum PSA. The biochemical ‘flare up’ phenomenon was not reported in the abarelix arms, and the overall incidence of severe adverse events (including allergic reactions) was similar across all treatment groups. Data on survival end-points and long-term safety are not yet available. Abarelix has recently been licensed for clinical use by the US Food and Drug Administration, but its use is restricted to those patients with metastatic and symptomatic PCa for whom no other treatment option is available (27). Recently, another antagonist, called degarelix, has been presented with preliminary promising results. In a phase II dose-finding study of 187 men, most patients had a testosterone level below 0.5 ng/mL at day 3, with a sustained effect at one year and no testosterone surge. The median testosterone value at one year for the 78.6% of patients with a level below 0.5 ng/mL was 0.12 ng/mL. No patient reported any systemic allergic reaction (28). Overall, even if this new family appears appealing, its real advantages over LHRH agonists are far from being proven. So far its use is limited by a monthly formulation, compared with three-month and six-month depot formulations. The clinical advantage of the suppression of the initial flare up is only clinically relevant in a minority of metastatic patients, and finally antagonists must confirm their efficacy in the long-term, most available trials being limited to a one-year follow-up period.

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12.3.2 Anti-androgens Anti-androgens compete with testosterone and DHT for binding sites on their receptors in the prostate cell nucleus, thus promoting apoptosis and inhibiting PCa growth (29). These orally administered compounds are classified according to their chemical structure as steroidal (e.g. cyproterone acetate [CPA], megestrol acetate and medroxyprogesterone acetate) and non-steroidal or pure (e.g. nilutamide, flutamide and bicalutamide). Both classes compete with androgens at the receptor level, but while this is the sole action of non-steroidal anti-androgens, steroidal anti-androgens additionally have progestational properties with central inhibition of the pituitary gland. As a consequence, non-steroidal anti-androgens do not lower testosterone levels, which remain normal or, conversely, slightly elevated. 12.3.2.1 Steroidal anti-androgens These compounds are synthetic derivatives of hydroxyprogesterone. In addition to peripherally blocking androgen receptors, they have progestational properties and inhibit gonadotrophin (LH and FSH) release and suppress adrenal activity. At high doses, megestrol acetate is cytotoxic. Since steroidal anti-androgens lower testosterone levels, the main pharmacological side-effects are loss of libido and erectile dysfunction; gynaecomastia is quite rare. The non-pharmacological side-effects are cardiovascular toxicity (4-40% for CPA) and hepatotoxicity. Cyproterone acetate (CPA) CPA was the first anti-androgen to be licensed. It is the most widely used drug, but the less studied one, leaving most questions unanswered (such as the optimal dose), or unclear (e.g. comparison with standard forms of castration – surgical or with an agonist). There is only one randomised trial (30) comparing CPA with standard hormonal therapy (i.e. medical castration). Patients in arm A (no contraindications to DES) were randomly assigned to CPA, goserelin or DES, while patients in arm B (contraindications to DES) were assigned to CPA or goserelin. In arm A, treatment with CPA was associated with significantly poorer median overall survival (OS) than goserelin only; adjusting for baseline characteristics did not account for this difference. Two other studies on CPA monotherapy have been performed, but one did not report survival data (31), and the other used a non-standard treatment combination (DES and medroxyprogesterone acetate [32]). It is therefore difficult to draw any definite conclusions from these data about the relative efficacy of CPA and castration. As no dose-finding studies of CPA monotherapy have been conducted, the most effective dose is still unknown. Although CPA has a relatively long half-life (30-40 hours), it is usually administered in two or three fractionated doses of 100 mg each (33). The only comparative study on anti-androgens as monotherapy was recently published by the European Organisation for Research and Treatment of Cancer (EORTC). The final analysis of Protocol 30892 (a randomised trial of 310 patients comparing CPA with flutamide in metastatic PCa), showed no difference in cancer-specific survival (CSS) and OS at a median follow-up of 8.6 years, although the study was underpowered (34) (level of evidence: 1b). Megestrol acetate and medroxyprogesterone acetate Very limited information is available on these two compounds. Early studies with megestrol acetate demonstrated a symptomatic and partially beneficial clinical response, both in previously untreated metastatic PCa (35-37) and, to a lesser extent, in HRPC (38). No apparent dose response correlation was shown to exist in a recent trial (39). The overall poor efficacy precluded megestrol acetate and medroxyprogesterone acetate from being recommended as a primary or second-line hormonal therapy option. The only prospective randomised trial evaluating medroxyprogesterone acetate as primary therapy in advanced (M0-1) PCa is the EORTC 30761 study mentioned above (31), in which 236 patients were assigned to receive CPA, DES or medroxyprogesterone acetate. While no difference in CSS and OS was evident between CPA and DES, treatment with medroxyprogesterone acetate had a less favourable course with a shorter survival time and time to progression than either of the other two drugs tested. 12.3.2.2 Non-steroidal anti-androgens Non-steroidal anti-androgens have been promoted in monotherapy for quality of life (QoL) and compliance benefits over castration: since they do not suppress testosterone secretion, it is claimed that libido, overall physical performance and bone mineral density are preserved (40).

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Although no direct comparisons have been undertaken in a monotherapy setting, the three available drugs do not appear to differ in the severity of pharmacological side-effects, namely gynaecomastia, breast pain and hot flashes. However, there are differences in the non-pharmacological side-effects, with bicalutamide showing a more favourable safety and tolerability profile than nilutamide and flutamide (41). They all share a common liver toxicity, and liver enzymes must be checked on a regular basis when they are used. Nilutamide There are no comparative trials on nilutamide monotherapy with castration or with other anti-androgens (42). Only one non-comparative study has been carried out, including 26 patients with M1 PCa who received nilutamide 100 mg three times daily. The results showed that as few as 38.5% of patients experienced an objective response; the median progression-free survival (PFS) time was nine months and the median OS was 23 months (43). One large randomised controlled trial of 457 patients with M1, which compared orchiectomy plus nilutamide, 300 mg/day, with orchiectomy plus placebo, showed a significant benefit in CSS and OS for the combined therapy (44). Recently, nilutamide has been tested as a second-line hormonal therapy in HRPC with encouraging results (45, 46). Non-pharmacological side-effects are visual disturbances (i.e. delayed adaptation to darkness), alcohol intolerance, nausea, hepatotoxicity, and interstitial pneumonitis. The latter, even if exceptional, is potentially life-threatening and is specific to this drug. Nilutamide is not licensed for monotherapy. Flutamide Flutamide was the first non-steroidal anti-androgen available for clinical use, and has been studied as monotherapy for more than 20 years, but no dose-finding studies against a currently accepted end-point (e.g. PSA response) have been published. Flutamide is a pro-drug, and the half-life of the active metabolite is five to six hours, so it must be administered three times per day in order to maintain therapeutic serum levels. The recommended daily dosage is 750 mg (33). Early phase II trials demonstrated flutamide to be effective in the treatment of advanced PCa, albeit that the reported response rates cannot be correlated with currently recommended end-points. The main advantage shown in these studies was the preservation of sexual function, which was maintained in up to 80% of patients with no pre-treatment erectile dysfunction (47-50). This rate has not been confirmed in the above mentioned EORTC trial 30892 (34), in which as few as 20% of men treated with flutamide maintained sexual activity for up to seven years. Although several phase III studies have been conducted, the results are often difficult to evaluate because of several drawbacks, such as the use of non-standard combinations, short-term follow-up and underpowering. Of these studies, only two phase III randomised trials comparing flutamide monotherapy with standard therapy (orchiectomy [51] and CAB [52]) for advanced PCa have reported survival data; both showed no significant difference in OS for flutamide or castration for patients with a PSA < 100 ng/mL (52). At higher PSA, flutamide was inferior. Both trials were underpowered, however. Results are eagerly awaited from an ongoing Swedish study in which 700 patients with M1 PCa have been randomised to flutamide 250 mg three times daily or CAB (40). The non-pharmacological side-effects are diarrhoea and hepatotoxicity (occasionally fatal). Bicalutamide Early reports with bicalutamide monotherapy related only to the 50 mg dosage, which was that licensed for use in CAB. An overall analysis of these studies showed that, although bicalutamide 50 mg/day had clinical benefits, it was inferior to castration in terms of OS (median difference 97 days) (53). Subsequent dose-ranging studies established that bicalutamide 150 mg once daily achieved a PSA response similar to that seen with castration while maintaining a good tolerability profile (54). Accordingly, the 150 mg dosage was chosen for further evaluation as both primary and adjuvant monotherapy. As primary monotherapy, bicalutamide 150 mg/day has been compared with medical or surgical castration in two large prospective randomised trials with identical study designs, including a total of 1435 patients with locally advanced M0 or M1 PCa (55). A pooled analysis showed: • In M1 patients, an improvement in OS with castration, although the difference in median survival between the groups was only six weeks (55); a further post hoc analysis showed a survival benefit only for patients with higher PSA levels (> 400 ng/mL) at study entry (56).

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•

In M0 patients (N = 480), no significant difference was noted in OS (57) based on the Kaplan Meier test, with median survival being 63.5 months in the bicalutamide arm compared with 69.9 months in the castration one.

In two smaller randomised trials, high-dose bicalutamide was compared with CAB. In the first trial (251 patients with predominantly M1 stage), no difference in OS was apparent (58). In the second trial (220 patients with M0 and M1 stage), there was no difference in OS for well or moderately well differentiated tumours (59) (level of evidence: 1b), but both studies were underpowered, and the first one has not yet been fully published. As for the adjuvant setting, the ongoing Early Prostate Cancer Programme (EPCP), a study comprising three different clinical trials of similar design and including 8113 patients worldwide, was designated to evaluate the efficacy and tolerability of high-dose (150 mg/day) bicalutamide vs placebo given in addition to standard primary care (i.e. radical prostatectomy, radiotherapy and watchful waiting) in localised (T1-2, N0-X) or locally advanced (T3-4, any N, or any T N+) PCa. The first combined analysis of the programme showed that, after a median follow-up of three years, adjuvant bicalutamide provided a reduction of 42% in the risk of objective disease progression compared with standard care alone (60). After a median follow-up of 5.4 years, the positive effects of bicalutamide were obvious in patients with locally advanced disease (stage M0), but patients with localised disease given bicalutamide appeared to have a reduced survival compared with those given placebo (61). However, results obtained after a median follow-up of 7.4 years showed there was no benefit to PFS from the addition of bicalutamide to standard care in localised PCa, and identified a trend (hazard ratio [HR] 1.16, 95% CI 0.99-1.37, p = 0.07) towards decreased survival in patients otherwise undergoing watchful waiting (WW). However, in locally advanced disease, bicalutamide significantly improved PFS, irrespective of standard care. The same overall results were observed in the most recent arm 24 analysis (62). Bicalutamide significantly improved OS in patients receiving radiotherapy (HR 0.65, 95% CI 0.44-0.95, p = 0.03), which was driven by a lower risk of PCa-related deaths. Bicalutamide produced a trend towards improved OS in patients with locally advanced disease otherwise undergoing WW (HR 0.81, 95% CI 0.66-1.01, p = 0.06). No survival difference was evident in the prostatectomy subgroup (61). Even though the EPCP is a combination of three trials and among the largest ever conducted in prostate cancer patients, clear conclusions are difficult to present as many problems are apparent with these protocols (63). For example, three trials were grouped for analysis, but they are different in terms of patients (80% prostatectomy in trial 23 compared with 13% in trial 25). The treatment duration was two years in trial 23, but prolonged until progression in trials 24 and 25. The OS benefit claimed with radiotherapy is mainly driven by a respiratory or cardiovascular improvement, and not by a CSS benefit, which is different from other trials with LHRH agonists (64). Furthermore, the trials are underpowered for locally advanced patients, compared with oriented trials such as the Bolla (65) or Pilepich (66) trials. Finally, direct protocol analysis reveals quite different results, such as those from the EPCP 23 (80% prostatectomy, 19% radiotherapy) (67). At a median 7.7 years of follow-up, no PFS benefit was observed (HR 1.00; CI 0.84, 1.19, p = 0.991). Likewise, OS did not differ. Even after stratifying for disease stage, no PFS benefit was apparent. No QoL benefit has been demonstrated, as is claimed, as the EPCP trial did not use a QoL questionnaire. The only QoL data come from a specific questionnaire and a limited population. The observed benefit was only significant for physical capacity and sexual interest (not function!). For all other items considered (emotional well-being, vitality, social function, pain, activity limitation and bed disability), there was no difference compared with castration (68). The breast problems related to bicalutamide must also be discussed, as they might lead to a 16.4% treatment cessation (69). The clear trend (even if not statistically significant) suggesting a decreased OS in localised disease treated with WW is a clear argument against its use in such situations (61). The mechanisms remain unclear. Many questions are still debatable with this drug, such as the practical management after progression under bicalutamide, as no data are available. In conclusion, high-dose bicalutamide has emerged as an alternative to castration for patients with locally advanced (M0) if PFS is the target, and in highly selected, well-informed cases of M1 PCa with a low PSA, but should be avoided in patients with localised PCa. The QoL benefit over castration that was expected is, however, far from being proven. The survival benefit observed with an adjuvant use after radiotherapy in locally

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advanced situations must be considered with caution, as these three trials are far from having the power of any trial conducted with LHRH agonists. Non-pharmacological side-effects are mainly gynaecomastia (70%) and breast pain (68%). These might be prevented by anti-oestrogens (70, 71), prophylactic radiotherapy (72), or treatment with surgical mastectomy or radiotherapy (73). 12.3.3 Combination therapies 12.3.3.1 Complete androgen blockade Although serum testosterone levels are reduced by up to 95% by castration, the intraprostatic androgen stimulus is sustained by the conversion of circulating androgens of adrenal origin into DHT within the prostate cells. The action of these adrenal androgens is blocked by the addition of an anti-androgen to either surgical or pharmacological castration, a concept known as complete (or maximal or total) androgen blockade (CAB). A plethora of studies evaluating CAB over monotherapy have been carried out with contrasting results. From the most recent systematic reviews and meta-analyses it appears that at a follow-up of five years, CAB provides a small survival advantage (less than 5%) when compared with monotherapy (74-78, level of evidence: 1a), although some of the largest trials included are methodologically flawed (79). It remains debatable whether this small advantage, if any, can be meaningful when applied to everyday clinical practice. The benefit seems to be limited to patients taking non-steroidal anti-androgens and to appear only after five years of follow-up. Gastrointestinal, ophthalmological, and haematological side-effects are worse with combined androgen blockade. LHRH analogues and non-steroidal anti-androgens have the highest estimated quality-adjusted survival, but have an incremental cost of more than US$1 million per quality-adjusted live-year over orchiectomy alone. 12.3.3.2 Minimal androgen blockade (or peripheral androgen blockade) This derives from the combination of finasteride and a non-steroidal anti-androgen. The rationale behind the combination is that finasteride reduces intraprostatic levels of DHT by inhibiting 5-∝-reductase, while antiandrogen competes with the binding of the residual DHT to its receptor. The result is that testosterone levels are maintained within normal ranges to ensure acceptable sexual function and a reasonable QoL. In several phase II trials (80-84), the association of finasteride and flutamide, either in a concomitant or sequential regimen, has been evaluated in terms of PSA response rate in patients with advanced or biochemically recurrent PCa. Notwithstanding the small sample and short follow-up, nearly all patients experienced a substantial decline in PSA (by up to 96% compared with the level at entry). An update of one of these studies, at a long-term follow-up, reported on stronger end-points, such as castration-free survival (median: 37 months), androgen-independent PCa-free survival (median: 48.6 months) and OS rate (65% at five years). It was concluded that combination therapy can induce an overall period of hormone responsive disease exceeding four years (85). In all these trials, sexual function was reported to be preserved in between 55% and 86% of the men studied. The preliminary data make this treatment option most attractive in the management of patients for whom QoL is the primary issue. However, while awaiting the results of follow-up and larger controlled trials, this treatment is still regarded as investigational. 12.3.3.3 Intermittent vs continuous androgen deprivation therapy For reasons that as yet remain unclear, long-term CAB, which stimulates prostate cell apoptosis, fails to eliminate the entire malignant cell population, so that after a variable period (averaging 24 months) the tumour inevitably relapses, being characterised by an androgen-independent state of growth. Experimental data indicate that androgen-independent progression may begin early after the administration of hormonal therapy, coinciding with the cessation of androgen-induced differentiation of stem cells (86). It is therefore theoretically possible that if androgen deprivation is stopped prior to the progression of androgen-independent cells, any subsequent tumour growth would then be solely sustained by the proliferation of androgen-dependent stem cells, which should be susceptible once again to androgen withdrawal. In this way, cyclical ADT would delay the emergence of the androgen-independent clone. Thus, intermittent ADT may result in two other benefits: namely the preservation of QoL in the off-therapy periods and the reduction of cost. Several phase II trials have demonstrated the feasibility of intermittent androgen blockade (IAB) in metastatic

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or biochemically recurrent disease, with PSA response rates and symptom improvement similar to that of CAB, but phase III prospective, randomised controlled trials are still underway, and data on survival endpoints and QoL are not mature (87). Preliminary results of clinical phase III trials have demonstrated not significantly different efficacy for intermittent vs continuous ADT in men with PSA progression following radical prostatectomy and in advanced metastatic PCa (88-90). The South West Oncology Group (SWOG) trial 9346 randomised 1134 men with stage D2 PCa to intermittent and continuous ADT after seven months’ induction ADT with PSA reduction < 4 ng/mL. No significant differences with regard to survival in a very preliminary analysis were identified between treatment groups (88). A PSA reduction to < 0.2 ng/mL, < 4 ng/mL and > 4 ng/mL was identified as a significant prognostic factor with regard to survival, achieving 13 months, 44 months and 75 months, respectively. In some other trials, 75 patients were considered for IAD if they had achieved PSA serum levels < 4 ng/mL or at least 90% reduction of pre-treatment levels after 9 months of ADT (89). Patients went on when PSA values rose > 20 ng/mL at which the 9-month cycle of ADT was repeated. 86% of the men are alive at a median of 134 months, with a median survival of 95 months from the initial ADT cycle. A 100% and 70% survival at 5 years was calculated for those presenting with locally advanced disease and metastases at initial presentation, respectively. A prospective randomised multicentre trial including 68 patients with a mean follow-up of 31 months have been reported (90). In the intermittent androgen deprivation (IAD) group, the median cycle length was 9.5 months and the median percentage of time off therapy was 59.5%. The median three-year progression rate was significantly lower in the IAD group (7%) than in the CAD group (38.9%), suggesting that IAD maintains the androgen-dependent state of advanced PCa at least as long as does CAD. Another trial came to the same conclusions, but, once again this presented-only German study was underpowered and had too short a followup (91). The most recent and convincing data were presented during the 2007 American Society of Clinical Oncology (ASCO) meeting (92). In a prospective trial including 478 patients with M1 (40%) or N+ (N1 to 3) disease, 335 were randomised after six months of maximal androgen blockade if the PSA was below 4 ng/mL or if a decrease of more than 90% was observed. The mean initial PSA was 158 ng/mL in the intermittent arm, and 139 ng/mL in the continuous arm, respectively. In the intermittent arm, the treatment was resumed if the PSA was above 10 ng/mL and stopped when it went below 4 ng/mL. The main question was PFS. After a median follow up of 50.5 months, no significant difference was observed in the median PFS (16.6 months in the intermittent arm compared with 11.5 months in the continuous arm [p = 0.17], neither in the entire population nor in the N+ or M1 populations. In the IAD arm, 88% of patients were off treatment for more than 50% of the time, and normalised their testosterone in a mean of 70 days after stopping treatment. Recently a published randomised trial suggested a different IAD regimen, with fixed six-month periods of treatment (CAB) and surveillance (93). The PSA was not used to direct the treatment in this heterogeneous population (N = 129). After a mean of 44.8 months of follow up, no difference was observed in either OS, CSS or PFS. The QoL was also no different between the two groups, except that painkillers were required more often in the IAD arm, and the ability to get and maintain an erection was better in the IAD arm. IAD has not been shown to be associated with prolonged hormone-sensitive status. This treatment modality is well accepted by patients and increases their QoL during the periods without treatment, although still to a questionable level (94-96), and testosterone levels recover in most studies (97, 98), leading to an intermittent castration (not just an intermittent treatment delivery). Other benefits, such as a reduction in impact on the bones (99) or sexual activity (96), are also suspected. It must be acknowledged that, so far, IAD raises more questions than it has precise answers for, especially with regard to defining the best candidates, (100, 101). In addition, the threshold at which the ADT must be stopped or resumed are empirical (100). Nevertheless, several points are clear (102): • IAD is based on intermittent castration, and therefore only drugs leading to castration should be considered. • It is unclear if an LHRH agonist may be used alone, as the published experiences are based on CAB. • The initial (induction) cycle must last between six and nine months, otherwise testosterone recovery is unlikely. • The treatment is stopped only if patients have fulfilled all the following criteria: - well informed and compliant patient - no clinical progression

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•

•

• •

- a clear PSA response, empirically defined as a PSA below 4 ng/mL in metastatic patients, or 0.5 ng/mL in relapsing patients. A strict follow-up must then be applied, with clinical examination every three to six months (the more advanced the disease, the closer the follow-up), with PSA measurements at the same time and always performed in the same laboratory. The treatment is resumed when the patient reaches either a clinical progression, or a PSA value above a predetermined empirically fixed threshold (usually 4 ng/mL in non-metastatic situations, or 10-15 ng/mL in metastatic patients). The same treatment is used for at least three to six months. The next cycles are based on the same rules until the first sign of hormone refractory status.

In conclusion, IAD is currently widely offered to patients with PCa in various clinical settings, and its status should no longer be regarded as investigational (level of evidence: 2). 12.3.3.4 Immediate vs deferred ADT The most appropriate time to introduce hormonal therapy in patients with advanced PCa is still controversial, particularly whether ADT for locally advanced and asymptomatic metastatic disease delivered immediately at diagnosis favourably influences survival and QoL compared with ADT deferred while signs and symptoms of clinical progression remain a matter of debate. This point was partially discussed in section 8.3. The dispute derives from the lack of properly conducted, randomised, controlled trials, with many being methodologically flawed because of small size and underpowering, and the heterogeneity of patient enrolment with advanced PCa (i.e. locally advanced, nodal and metastatic stages of disease), as well as variability in the hormone treatments administered and of follow-up schedules and modalities used. Bearing these limitations in mind, evidence on immediate vs deferred ADT is provided by three systematic reviews of the literature (one of which is a meta-analysis). A report by the Agency for Health Care Policy and Research indicated that a possible survival advantage for early ADT existed in single studies where hormone treatment was the primary therapy, while the combined analysis showed no significant benefit. Furthermore, androgen suppression was shown to be the most cost-effective if initiated after patients had experienced symptoms from metastatic disease (74, 103). The Cochrane Library review extracted four good quality randomised controlled trials (namely VACURG I and II studies [10, 11], the MRC trial (104) and the Eastern Cooperative Oncology Group [ECOG] 7887 study [105]), which were all conducted in the pre-PSA era and included patients with advanced PCa who received early vs deferred ADT as primary therapy or adjuvant to radical prostatectomy, but not to radiotherapy. According to the analysis, early androgen suppression significantly reduces disease progression and complication rates due to the progression itself, but does not improve CSS, and provides a relatively small benefit in OS, with an absolute risk reduction of 5.5%, which does not become evident until after 10 years (106). Since 2002, the level 1 evidence suggesting immediate ADT in every pN+ patient after a prostatectomy has been questioned for several reasons. Some were discussed earlier (see section 9.7) such as the impact of a micronodal metastasis in a single node (107), which is far from being equivalent to a massive nodal involvement, as present in the Messing trial. Recently, the analysis of 719 patients from the SEER (Surveillance, Epidemiology and End Results, part of the US National Cancer Institute) database questioned the real impact of immediate ADT in pN+ patients after a radical prostatectomy (108). In the PSA era, the EORTC 30891 (109) gave the same results, namely a small benefit in OS, but no CSS benefit. Furthermore, only young patients with a high PSA might clearly benefit. Based on a systematic review of the literature, the recently published ASCO guidelines on initial hormonal treatment for androgen-sensitive metastatic, recurrent or progressive PCa concluded that no recommendation on when to start hormonal therapy in advanced asymptomatic PCa can be made until data from studies using modern diagnostic and biochemical tests and standardised follow-up schedules become available (110). Based on the meta-analysis, published treatment was most cost-effective when started after the onset of symptoms. Based on exploratory analysis, treatment with anti-androgen monotherapy does not lead to a survival benefit in men with localised PCa managed with non-definitive therapy, and the impact is still questionable after external beam therapy. This was explored in detail in section 12.3.2.2 with regard to the EPCP trials.

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For asymptomatic patients with locally or regionally advanced PCa who undergo radiotherapy, there is good evidence from several randomised controlled trials that concomitant and/or adjuvant hormonal therapy provides longer time-to-disease progression and/or longer OS than radiotherapy alone followed by androgen suppression at progression (111-114) (level of evidence: 1b).

12.4

Indications for hormonal therapy

Table 16 lists the indications for hormonal therapy. Table 16: Indications for hormonal therapy Hormonal therapy Indications for castration M1 symptomatic

M1 asymptomatic

N+

Locally advanced M0 Locally advanced symptomatic Locally advanced treated with radiotherapy

Locally advanced asymptomatic unfit for local definitive treatment Anti-androgens Short-term administration

Non-steroidal anti-androgen monotherapy

Benefits

LE

• To palliate symptoms and to reduce the risk for potentially catastrophic sequelae of advanced disease (spinal cord compression, pathological fractures, ureteral obstruction, extraskeletal metastasis) • Even without controlled randomised trail, this is the standard of care and must be applied and considered as level 1 evidence • Immediate castration to defer progression to a symptomatic stage and prevent serious disease progression-related complications (104) • An active clinical surveillance protocol might be an acceptable option in clearly informed patients if survival is the main objective • Immediate castration to prolong PFS and even OS (105) • Might be questioned in single micrometastasis after extended lymph node dissection and radical prostatectomy (115) • Immediate castration to improve cancer-free survival • (116) • High risk d’Amico: combined and prolonged ADT • Intermediate risk d’Amico: • if low dose (< 75 Gy) radiotherapy: six months of ADT • if high dose (> 75 Gy) radiotherapy: ADT questionable • Limited OS improvement not related to a CSS benefit (109)

1

1

1b

3

1b 3

1b 4 1 1b 2 1

• To reduce the risk of the ‘flare up’ phenomenon in patients 1b with advanced metastatic disease who are to receive an LHRH agonist (117, 118) 2 • Primary monotherapy as an alternative to castration in patients with locally advanced PCa (T3-4, any N, or any T N+) (57) (level of evidence: 2) • No place in localised disease as single treatment modality • Combined with radiotherapy: no clear recommendation is possible at the present time • Combined with radical prostatectomy: no place so far in an adjuvant setting

LE = level of evidence

12.5

Contraindications for various therapies (Table 17)

Table 17 lists the contraindications for various therapies. Table 17: Contraindications for various therapies Therapy Bilateral orchiectomy

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Contraindications • Psychological reluctance to undergo surgical castration

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Oestrogens LHRH agonists alone Anti-androgens

12.6

• Known cardiovascular disease • Patients with metastatic disease at high risk for clinical ‘flare up’ phenomenon • Localised PCa as primary therapy • Known hepatic dysfunction

Outcome

Outcome depends on the stage and grade of disease at diagnosis. In M1 cases, the median OS ranges between 28 and 53 months (74); only 7% of patients with metastatic cancer treated with hormonal therapy are reported to live 10 years or more (119). Survival is likely to depend on the PSA level at diagnosis, the Gleason score, the volume of metastatic disease, and the presence of bony symptoms. In locally advanced M0 patients, the median OS is frequently reported to exceed 10 years (75).

12.7

Side-effects, QoL and cost of hormonal therapy

Many patients with PCa for whom long-term ADT is indicated are still young and physically and sexually active, so QoL is an issue of paramount importance when considering the various hormonal treatment options. In view of this, in selected patients, monotherapy with a non-steroidal anti-androgen (e.g. bicalutamide) is gaining increasing popularity because of its ability to maintain normal (or even higher) serum testosterone levels and its good tolerability profile. 12.7.1 Side-effects The many deleterious side-effects of long-term ADT have been well known for years. Some of these can have a detrimental effect on QoL, especially in young men, while others may contribute to an increased risk of serious health concerns associated with age. Loss of libido and erectile dysfunction are well known side-effects. The management of erectile dysfunction is not specific. Hot flashes are probably the most common side-effect of ADT. They appear three months after starting the treatment, persist in the long term in most patients, and have a significant impact on the QoL (120). Treatment modalities include hormonal therapy and antidepressants. Oestrogen receptor modulators or lowdose oestrogen therapies (0.5-1 mg/day), such as diethylstilboestrol, reduce their frequency and severity, but both are associated with a risk of cardiovascular complications (121). Soya phytoestrogens have shown efficacy for hot flushes in breast cancer patients (122), but have not yet been evaluated in men. Progesterone-based treatments, such as megestrol acetate, medroxyprogesterone acetate and CPA, have also demonstrated efficacy, with 80% of patients having shown improvement with CPA (123) or chlormadinone (124). Antidepressants may also have some efficacy. For example, venlafaxine (a non-specific selective noradrenaline and serotonin reuptake inhibitor) has shown efficacy in breast cancer patients, while the selective serotonin reuptake inhibitor sertraline appears to be effective in men with PCa (125). Other products have also been tested, including clonidine and veralipride, and even acupuncture (126). With a placebo effect influencing up to 30% of patients (127), few treatments are approved for the control of hot flashes in men with PCa. There is a lack of large, prospective randomised controlled trials in this area. More recently, other systemic side-effects have been described and must be paid increased attention. These include: bone problems, obesity and sarcopenia, lipid alterations and insulin resistance, metabolic syndrome, diabetes, and cardiovascular disease (128). ADT increases the non-metastatic fracture risk as a result of increased bone turn-over and decreased bone mineral density (BMD) in a time-dependent manner. This leads to an increased risk of fracture of up to 45% relative risk in the long term (129). This is a significant side-effect, as hip fractures in men are associated with a significant risk of death (130). Increased exercise and calcium supplementation are protective. Recently, bisphosphonates such as pamidronate, alendronate or zoledronic acid have been shown to increase the BMD in hip and spine by up to 7% in one year. The optimal regimen for zoledronic acid is still unclear. It is recommended once every four weeks in one study (131), while a yearly injection gave similar results in another (132). The optimal regimen is a very important question because of the risk of jaw necrosis, which might be dose and time-related (133).

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Before starting long term ADT, patients should be encouraged to adopt lifestyle changes (e.g. increase physical activity, stop smoking, decrease alcohol consumption and normalise their body mass index). A precise evaluation of the BMD should be performed by dual X-ray absorptiometry before starting long term ADT. An initial low BMD (T-score above 2.5 or above 1 in conjunction with other risk factors) indicates a high risk of subsequent non-metastatic fracture, suggesting the early use of preventive bisphosphonate therapy. Obesity and sarcopenia are common and often occur early on during the first year of ADT. An increase in body fat mass by up to 10%, and a decrease in lean tissue mass by up to 3% are expected (134). Both are linked to an increased risk of fracture. Lipid alterations are also frequent, and occur as early as the first three months of treatment (135). ADT also decreases insulin sensitivity and increases fasting plasma insulin levels (135), a marker of insulin resistance. Once again, exercise must be recommended as a protective tool. Metabolic syndrome is an association of independent cardiovascular disease risk factors often associated with insulin resistance. These include: • waist circumference > 102 cm • serum triglyceride > 1.7 mmol/L • blood pressure > 130/80 mmHg • HDL cholesterol < 1 mmol/L • glycaemia > 6.1 mmol/L. Its prevalence is higher during ADT compared with untreated men (136). ADT has been associated with an increased risk of diabetes mellitus, cardiovascular disease, and myocardial infarction in one study (137), and with a 20% increased risk of new cardiovascular disease after one year of treatment in another (138). Recently the analysis of the RTOG 92-02 data confirmed this increased cardiovascular risk (139) with no relationship with the duration of the ADT. These observations have, however, been up for discussion recently, as no increased cardiovascular mortality was demonstrated in RTOG 8610 (140), EORTC 30891 (109) or EORTC 22863 (64). In summary, if even six or fewer months of ADT might be associated with increased cardiovascular morbidity, the data on cardiovascular mortality are so far inconsistent. Again, prevention is associated with non-specific measures such as loss of weight, increased exercise, better nutrition and the cessation of smoking. 12.7.2 Quality of Life (QoL) Data on QoL during hormone treatment are scant because of a lack of solid evidence. The only large, prospective, randomised study is a double-blind placebo-controlled trial including 739 patients with M1 PCa, which compared orchiectomy plus flutamide vs orchiectomy plus placebo. The QoL was assessed in the first six months of treatment. Combined therapy resulted in lower QoL, with statistically significant differences in two QoL parameters, namely more frequent diarrhoea and worse emotional functioning, than castration alone (141). A prospective, non-randomised, observational study including 144 patients with locally advanced PCa or PSA failure after definitive local treatment showed that patients who received immediate ADT (by means of bilateral orchiectomy, LHRH agonist or CAB) reported a lower overall QoL (increased fatigue, emotional distress, and decreased physical functioning) than patients in the deferred hormone treatment arm (142) (level of evidence: 2a). A retrospective, non-randomised study including 431 patients with stage PCa who received orchiectomy or LHRH agonists as their primary therapy within 12 months of initial diagnosis, assessed healthrelated quality of life (HRQoL) outcomes at 12-months follow-up. Men receiving LHRH agonists reported more worry and physical discomfort and poorer overall health, and were less likely to believe themselves free of cancer than were orchiectomised patients. The stage at diagnosis had no significant independent effect on health outcome. However, the study was insufficiently powered (143) (level of evidence: 2b). A recent, small, randomised, controlled trial evaluated the HRQoL of patients with non-localised PCa allocated to leuprorelin, goserelin, CPA or no treatment at one-year follow-up. Both sexual and cognitive function significantly declined in men on all forms of androgen suppression, while emotional distress significantly increased in those assigned to CPA and no treatment (144) (level of evidence: 1b).

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IAD might be associated with an improved overall QoL based on the normal testosterone levels during the off treatment periods. So far the results are inconclusive, showing either no or a marginal QoL benefit. As for LHRH agonists, QoL was evaluated in the previously mentioned studies of bicalutamide monotherapy by means of a specific questionnaire covering 10 domains (sexual interest, sexual function, physical capacity, emotional well-being, vitality, social function, activity limitation, pain, bed disability and overall health). Separate analyses of data for M0 and M1 patients were performed at 12-month follow-up, and in both patient categories bicalutamide showed a significant advantage over castration in the domains of physical capacity and sexual interest (not sexual function) (57) (level of evidence: 1b). A further post hoc analysis, including only patients with sexual interest at study entry, found that significantly more patients receiving bicalutamide 150 mg/day maintained their interest in sex and felt that they were still sexually attractive than did those randomised to castration (145, 146). Data on QoL are also available from the early report of the study of Boccardo et al. (147), and support the findings of the two larger combined trials in that more men in the bicalutamide group than in the castration group reported a preserved libido and erectile function. Furthermore, a recent, small, prospective, randomised trial, including 103 patients with localised or locally advanced PCa who received bicalutamide 150 mg/day or medical castration, evaluated the changes in BMD after 96 weeks of treatment and showed it to be maintained with bicalutamide therapy (148) (level of evidence: 1b). The most common side-effects during non-steroidal anti-androgen monotherapy are gynaecomastia and breast pain, which are caused by an imbalance in the androgen:oestrogen ratio within the breast tissue. In the bicalutamide studies, these events were reported by up to 66% and 73% of patients, respectively, and might lead to a 16.4% treatment cessation. 12.7.3 Cost-effectiveness of hormonal therapy options A recent formal meta-analysis and literature review evaluated the cost-effectiveness of various long-term androgen suppression options in advanced PCa (e.g. bilateral orchiectomy, DES, LHRH-agonist, non-steroidal anti-androgen monotherapy, CAB with non-steroidal anti-androgens). For the analysis, a sophisticated statistical model was generated, assuming the base case at entry to be a 65-year-old man with a clinically evident, local recurrence of PCa and no distant metastases, followed for a 20-year time horizon. The study concluded that, for men who can accept it, bilateral orchiectomy is the most cost-effective form of ADT providing a higher quality-adjusted survival, while CAB is the least economically attractive option, yielding small health benefits for a high relative cost. Furthermore, the greatest QoL gains and least costs may be obtained by starting ADT when symptoms from distant metastases have occurred (103) (level of evidence: 1a). Finally, once ADT is started, if a clear response is obtained (see section 11.3.3. above), then IAD might be a useful way to lower treatment costs.

12.8

• • • •

•

•

Summary of hormonal therapy

In advanced PCa, ADT delays progression, prevents potentially catastrophic complications, and palliates symptoms effectively, but it does not prolong survival. In advanced PCa, all forms of castration as monotherapy (e.g. orchiectomy, LHRH and DES) have equivalent therapeutic efficacy. Non-steroidal anti-androgen monotherapy (e.g. bicalutamide) is an alternative to castration in patients with locally advanced disease. In metastatic PCa, the addition of a non-steroidal anti-androgen to castration (CAB) results in a small advantage in OS over castration alone, but is associated with increased adverse events, reduced QoL, and high costs. Intermittent ADT should no longer be regarded as experimental, even though long-term data from prospective randomised clinical trials are still awaited. ‘Minimal’ ADT should, however, continue to be seen as experimental In advanced PCa, immediate ADT (given at diagnosis) significantly reduces disease progression as well as the complication rate due to progression itself compared with deferred ADT (delivered at symptomatic progression).

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LE 1b 1b 2 1a

2

1b

87

•

However, the survival benefit is at best marginal and not related to an increased CSS. Bilateral orchiectomy might be the most cost-effective form of ADT, especially if initiated after the occurrence of symptoms from metastatic disease.

1b 3

LE = level of evidence

12.9

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13. SUMMARY OF GUIDELINES ON PRIMARY TREATMENT OF PCa Stage T1a

Treatment Watchful waiting

Radical prostatectomy Radiotherapy

T1b-T2b

Hormonal Combination Watchful waiting

Radical prostatectomy Radiotherapy

Hormonal

Combination

T3-T4

Watchful waiting

Radical prostatectomy Radiotherapy

Hormonal Combination

N+, M0

Watchful waiting

M+

Radical prostatectomy Radiotherapy Hormonal Combination Watchful waiting

Radical prostatectomy Radiotherapy Hormonal

98

Comment Standard treatment for well-, and moderately, differentiated tumours and < 10-year life expectancy. In patients with > 10-year life expectancy, re-staging with TURP and biopsy is advised Optional in young patients with a long life expectancy, especially for poorly differentiated tumours Optional in younger patients with a long life expectancy, especially for poorly differentiated tumours. Higher complication risks after TURP, especially with interstitial radiation Not an option Not an option Asymptomatic patients with well-, and moderately, differentiated tumours and a life expectancy < 10 years. Patients who do not accept treatment-related complications Standard treatment for patients with life expectancy > 10 years who accept treatment-related complications Patients with a life expectancy > 10 years who accept treatment-related complications. Patients with contraindications for surgery. Unfit patients with 5-10 years of life expectancy and poorly differentiated tumours (combination therapy is recommended; see below) Symptomatic patients, who need palliation of symptoms, unfit for curative treatment Anti-androgens are associated with a poorer outcome compared to ‘watchful waiting’ and are not recommended For high-risk patients, neoadjuvant hormonal treatment (NHT) and concomitant hormonal therapy + radiotherapy results in increased overall survival. Option in asymptomatic patients with T3, well-differentiated and moderately differentiated tumours, and a life expectancy < 10 years Optional for selected patients with T3a and a life expectancy > 10 years T3 with > 5-10 years of life expectancy. Dose escalation > 70 Gy seems to be of benefit. A combination with hormonal therapy should be recommended (see below) Symptomatic patients, extensive T3-T4, high PSA level (> 25-50 ng/mL), PSA-DT < 1 year. Patient-driven, unfit patients Overall survival is improved by concomitant and adjuvant hormonal therapy (3 years) combined with external irradiation NHT + radical prostatectomy: no indication Asymptomatic patients. Patient driven (PSA < 20-50 ng/mL), PSA DT > 12 months. Requires very close follow-up No standard option No standard option Standard therapy in N > N1 No standard option. Patient-driven No standard option. May have worse survival/more complications than with immediate hormonal therapy. Requires very close follow-up Not an option Not an option (given for cure) Standard therapy. Mandatory in symptomatic patients

GR B

B B

A C B

A B

C A A

C

C A

A A B B C C A B B

C C A

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Combination

Must be otherwise systematically discussed Not an option

C

GR = grade of recommendation; TURP = transrectal urethral resection of prostate; NHT = neoadjuvant hormonal therapy; PSA = prostate-specific antigen; PSA-DT = prostate-specific doubling time.

14. FOLLOW-UP: AFTER TREATMENT WITH CURATIVE INTENT 14.1

Definition

Curative treatment is defined as radical prostatectomy or radiotherapy, either by external beam radiation or an interstitial technique, or any combination of these. Alternative treatment options that are not fully established, such f.i. HIFU, do not have a well-defined, validated PSA-cut-point to define biochemical failure but do generally follow the outlines given below.

14.2

Why follow-up?

The first question to be answered is: ‘If failure after curative treatment is so common, are follow-up efforts worthwhile?’ The answer to this question is definitely ‘Yes’. Recurrences will occur in a substantial number of patients who received treatment with intent to cure at various time points after the primary therapy. The second question to be answered is: ‘What is the reason for follow-up?’ Reasons may vary depending on the treatment given, patient age, comorbidity and the patient’s own wishes. In general, patients who receive curative therapy may be followed-up for any of the following reasons: • good responsible patient care • possibility of second-line treatment with curative intent • possibility of early hormonal therapy after failure • as part of a study protocol. Section 16 discusses treatment options after failure of primary therapy.

14.3

How to follow-up?

The procedures indicated at follow-up visits vary depending on the clinical situation. The examinations discussed below are routinely used for the detection of PCa progression or residual disease. The PSA level, and eventually DRE, are the only tests that need to be carried out routinely. A disease-specific history should be mandatory at every follow-up visit and should include psychological aspects, signs of disease progression and treatment-related complications. The examinations used for the evaluation of treatment-related complications must be individualized and are beyond the scope of these guidelines. The examinations used most often for cancer-related follow-up after curative surgery or radiation treatment are discussed below. 14.3.1 PSA monitoring The measurement of PSA level is a cornerstone in the follow-up after curative treatment. There is a difference in what can be expected after radical prostatectomy and radiotherapy, but PSA recurrence nearly always precedes clinical recurrence after either treatment, in some cases by many years (1-5). It is recommended that the finding of a single, elevated, serum PSA level should be re-confirmed before second-line therapy is started solely based on the PSA elevation. 14.3.2 Definition of PSA progression The level of PSA at which to define treatment failure differs between radical prostatectomy cases and radiation treated cases. Following radical retropubic prostatectomy, two consecutive values of 0.2 ng/mL or greater appear to represent an international consensus defining recurrent cancer (6, 7). Other authors have argued for an even higher cut-off of 0.4 ng/mL to better define patients with a high risk for clinical progression (5). It has been shown that patients with a PSA level between 0.1 ng/mL and 0.2 ng/mL after radical prostatectomy had neither clinical nor biochemical disease progression (8). Therefore, the use of an ultra-sensitive PSA assay is not justified for routine follow-up after radical prostatectomy (4). If ongoing randomized trials show that early adjuvant treatment after radical prostatectomy (given before PSA reaches > 0.2 ng/mL) improves survival, this issue should be reconsidered. Following radiation therapy, until recently, the definition of biochemical relapse was three consecutive increases according to the recommendation of ASTRO from 1996 (9). At the 2006 RTOG-ASTRO Consensus

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conference a new definition of radiation failure was established with as the main aim to establish a better correlation between the definition and clinical outcome. The new definition of radiation failure is a rise of 2 ng/mL above the post-treatment PSA-nadir (lowest value) (10). This definition is applicable for patients treated with or without hormonal therapy. After HIFU or cryotherapy, a variety of definitions for PSA-relapse have been used (11). Most of these are based on a cut-off of around 1 ng/mL, eventually combined with a negative post-treatment biopsy. As yet, none of these end-points have been validated against clinical progression or survival and therefore it is not possible to give firm recommendations on the definition of biochemical failure. 14.3.3 PSA monitoring after radical prostatectomy PSA is expected to be undetectable within 3 weeks after a successful radical prostatectomy (12). A persistently elevated PSA level means that PSA-producing tissue remains in the body. In patients treated with radical prostatectomy, this is generally thought to be residual cancer due to either micrometastases that were not detected or undetectable beforehand, or residual disease in the pelvis possibly due to positive surgical margins. A rapidly increasing PSA level (high PSA velocity, short PSA doubling time) indicates distant metastases, while a later and slowly increasing concentration of PSA is most likely to indicate local disease recurrence. The time to PSA recurrence and tumour differentiation are also important predictive factors distinguishing between local and systemic recurrence (13, 14). Both local treatment failure and distant metastases have been shown to occur with undetectable PSA levels. This is very rare and occurs almost only in patients with unfavourable pathology (undifferentiated tumours) (15, 16). This means that, in patients with a relatively favourable pathology (< pT3, pN0, Gleason score < 8), PSA measurement, together with the disease-specific history, could stand as the single test in follow-up after radical prostatectomy. 14.3.4 PSA monitoring after radiation therapy The PSA level falls slowly after radiotherapy compared with radical prostatectomy. The optimal cut-off value for a favourable PSA nadir after radiotherapy is somewhat controversial. Achieving a PSA nadir of less than 0.5 ng/mL seems to be associated with a favourable outcome (17). The interval before reaching the nadir PSA may be very long and can sometimes take up to 3 years or more. A PSA rising more than 2 ng/mL above the nadir PSA is the current definition of biochemical failure after radiotherapy (10). Also, after radiotherapy, the PSA doubling time has been shown to correlate to the site of recurrence; patients with local recurrence had a doubling time of 13 months compared to 3 months for those with distant failure (18). 14.3.5 Digital rectal examination (DRE) DRE is performed to assess whether or not there is any sign of local disease recurrence. It is very difficult to interpret the findings of DRE after curative therapy, especially after radiotherapy. A newly detected nodule should raise the suspicion of local disease recurrence. As mentioned previously, a local disease recurrence after curative treatment is possible without a concomitant rise in PSA level (15, 16). However, this has only been proven in patients with unfavourable pathology, i.e. those with undifferentiated tumours. Thus, PSA measurement and DRE comprise the most useful combination of tests as first-line examination in follow-up after radiotherapy or radical prostatectomy, but PSA measurement may well be the only test in cases with favourable pathology (19). 14.3.6 Transrectal ultrasonography (TRUS) and biopsy TRUS and biopsy have no place in the routine follow-up of asymptomatic patients and nowadays only rarely after biochemical failure. TRUS cannot stand alone as a diagnostic tool, but must usually be combined with biopsy to establish the presence of local disease recurrence. The purpose of the investigation is to confirm a histological diagnosis of local disease recurrence. It is only warranted if the finding of a local recurrence affects the treatment decision (see Section 16 for a more detailed discussion). 14.3.7 Bone scintigraphy The purpose of bone scintigraphy is to detect skeletal metastases. It is not recommended for the routine follow-up of asymptomatic patients, but may be indicated in individuals with elevated PSA levels for whom the findings will affect the treatment decision. It is also indicated in patients with symptoms arising from the skeleton, since metastatic disease may occur even if PSA is undetectable (15, 16). 14.3.8 Computed tomography (CT) or magnetic resonance imaging (MRI) CT or MRI have no place in the routine follow-up of asymptomatic patients. They may be used selectively in the evaluation after biochemical failure before treatment decisions are made (see Section 16).

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14.4

When to follow-up?

Most patients who fail treatment for PCa do so early, even if failure only becomes clinically obvious after years. The patient should therefore be followed-up more closely during the first years after treatment when the risk of failure is highest. PSA measurement, disease-specific history and DRE are recommended at the following intervals: 3, 6 and 12 months postoperatively, every 6 months thereafter until 3 years, and then annually. The purpose of the first clinic visit is mainly to detect treatment-related complications and to assist patients in coping with the new situation. Tumour or patient characteristics may allow alterations to this schedule. For example, patients with poorly differentiated and locally advanced tumours or with positive margins may be followed-up more closely than those with a well-differentiated, intracapsular or specimenconfined tumour. Obviously, advanced age or associated comorbidity may make further follow-up in asymptomatic patients superfluous.

14.5 Guidlines for follow-up after treatment with curative intent

• In asymptomatic patients, a disease-specific history and a serum PSA measurement supplemented by DRE are the recommended tests for routine follow-up. These should be performed at 3, 6 and 12 months after treatment, then every 6 months until 3 years, and then annually. • After radical prostatectomy, a serum PSA level of more than 0.2 ng/mL can be associated with residual or recurrent disease. • After radiation therapy, a rising PSA level over 2 ng/mL above the nadir PSA, rather than a specific threshold value, is the most reliable sign of persistent or recurrent disease. • Both a palpable nodule and a rising serum PSA level can be signs of local disease recurrence. • Detection of local recurrence by TRUS and biopsy is only recommended if it will affect the treatment plan. In most cases TRUS and biopsy are not necessary before second-line therapy. • Metastasis may be detected by pelvic CT/MRI or bone scan. In asymptomatic patients, these examinations may be omitted if the serum PSA level is less than 30 ng/mL but data on this topic are sparse. • Routine bone scans and other imaging studies are not recommended in asymptomatic patients. If a patient has bone pain, a bone scan should be considered irrespective of the serum PSA level.

GR B

B B B B C

B

GR = grade of recommendation

14.6

REFERENCES

1. Han M, Partin AW, Pound CR, Epstein JI, Walsh PC. Long-term biochemical disease-free and cancerspecific survival following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experience. Urol Clin North Am 2001;28(3)555-65. http://www.ncbi.nlm.nih.gov/pubmed/11590814 2. Rosser CJ, Chichakli R, Levy LB, Kuban DA, Smith LG, Pisters LL. Biochemical disease-free survival in men younger than 60 years with prostate cancer treated with external beam radiation. J Urol 2002;168(2):536-41. http://www.ncbi.nlm.nih.gov/pubmed/12131304. 3. Horwitz EM, Thames HD, Kuban DA, Levy LB, Kupelian PA, Martinez AA, Michalski JM, Pisansky TM, Sandler HM, Shipley WU, Zelefsky MJ, Hanks GE, Zietman AL. Definitions of biochemical failure that best predict clinical failure in patients with prostate cancer treated with external beam radiation alone: a multi-institutional pooled analysis. J Urol 2005;173(3):797-802. http://www.ncbi.nlm.nih.gov/pubmed/15711272. 4. Taylor JA III, Koff SG, Dauser DA, McLeod DG. The relationship of ultrasensitive measurements of prostate-specific antigen levels to prostate cancer recurrence after radical prostatectomy. BJU Int 2006;98(3):540-3. http://www.ncbi.nlm.nih.gov/pubmed/16925750.

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5.

Stephenson AJ, Kattan MW, Eastham JA, Dotan ZA, Bianco Jr FJ, Lilja H, Scardino PT. Defining biochemical recurrence of prostate cancer after radical prostatectomy: a proposal for a standardized definition. J Clin Oncol 2006;24(24):3973-8. http://www.ncbi.nlm.nih.gov/pubmed/16921049 6. Boccon-Gibod L, Djavan WB, Hammerer P, Hoeltl W, Kattan MW, Prayer-Galetti T, Teillac P, Tunn UW. Management of prostate-specific antigen relapse in prostate cancer: a European Consensus. Int J Clin Pract 2004;58(4):382-90. http://www.ncbi.nlm.nih.gov/pubmed/15161124 7. Moul JW. Prostate specific antigen only progression of prostate cancer. J Urol 2000;163(6):1632-42. http://www.ncbi.nlm.nih.gov/pubmed/10799151 8. Schild SE, Wong WW, Novicki DE, Ferrigni RG, Swanson SK. Detection of residual prostate cancer after radical prostatectomy with the Abbott Imx PSA assay. Urology 1996;47(6):878-81. http://www.ncbi.nlm.nih.gov/pubmed/8677580 9. American Society for Therapeutic Radiology and Oncology Consensus Panel. Consensus statement: guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 1997;37(5):1035-41. http://www.ncbi.nlm.nih.gov/pubmed/9169810 10. Roach III M, Hanks G, Thames jr H, Schelhammer P, Shipley WU, Sokol GE, Sandler H. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix consensus conference. Int J Radiat Oncol Biol Phys 2006;65(4):965-74. http://www.ncbi.nlm.nih.gov/pubmed/16798415 11. Aus G. Current status of HIFU and cryotherapy in prostate cancer – a review. Eur Urol 2006;50(5): 927-34. http://www.ncbi.nlm.nih.gov/pubmed/16971038 12. Stamey TA, Kabalin JN, McNeal JE, Johnstone IM, Freiha F, Redwine EA, Yang N. Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. II. Radical prostatectomy treated patients. J Urol 1989;141(5):1076-83. http://www.ncbi.nlm.nih.gov/pubmed/2468795 13. Partin AW, Pearson JD, Landis PK, Carter HB, Pound CR, Clemens JQ, Epstein JI, Walsh PC. Evaluation of serum prostate-specific antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastases. Urology 1994;43(5):649-59. http://www.ncbi.nlm.nih.gov/pubmed/7513108 14. Trapasso JG, deKernion JB, Smith RB, Dorey F. The incidence and significance of detectable levels of serum prostate specific antigen after radical prostatectomy. J Urol 1994;152(5 Pt 2):1821-5. http://www.ncbi.nlm.nih.gov/pubmed/7523728 15. Oefelein MG, Smith N, Carter M, Dalton D, Schaeffer A. The incidence of prostate cancer progression with undetectable serum prostate specific antigen in a series of 394 radical prostatectomies. J Urol 1995;154(6):2128-31. http://www.ncbi.nlm.nih.gov/pubmed/7500474 16. Leibman BD, Dilliouglugil O, Wheeler TM, Scardino PT. Distant metastasis after radical prostatectomy in patients without an elevated serum prostate specific antigen level. Cancer 1995;76(12):2530-4. http://www.ncbi.nlm.nih.gov/pubmed/8625081 17. Ray ME, Thames HD, Levy LB, Horwitz EM, Kupelian PA, Martinez AA, Michalski JM, Pisansky TM, Shipley WU, Zelefsky MJ, Zietman AL, Kuban DA. PSA nadir predicts biochemical and distant failure after external beam radiotherapy for prostate cancer: a multi-institutional analysis. Int J Radiat Oncol Biol Phys 2006;64(4):1140-50. http://www.ncbi.nlm.nih.gov/pubmed/16198506 18. Hancock SL, Cox RS, Bagshaw MA. Prostate specific antigen after radiotherapy for prostate cancer: a reevaluation of long-term biochemical control and the kinetics of recurrence in patients treated at Stanford University. J Urol 1995;154(4):1412-17. http://www.ncbi.nlm.nih.gov/pubmed/7544843 19. Chaplin BM, Wildhagen MF, Schroder FH, Kirkels WJ, Bangma CH. Digital rectal examination is no longer necessary in the routine follow-up of men with undetectable prostate specific antigen after radical prostatectomy: the implications for follow-up. Eur Urol 2005;48(6):906-10. http://www.ncbi.nlm.nih.gov/pubmed/16126322

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15. Follow-up after hormonal treatment 15.1

Introduction

A large proportion of patients treated with hormonal therapy have either metastatic or locally advanced tumours at diagnosis. This will affect the scheme of follow-up because biochemical failure is often associated with rapid symptomatic progression.

15.2 Purpose of follow-up The main objectives of following-up these patients are: • to monitor the response to treatment • to ensure compliance with treatment • to detect potential complications of endocrine therapy • to guide the modalities of palliative symptomatic treatment at the time of hormonal escape. However, the usefulness of complementary investigations at various stages of the disease must be clarified in order to avoid unnecessary examinations and excessive economic cost to the community. On the other hand, strict recommendations for follow-up procedures are only useful if effective therapeutic strategies can be offered to patients in cases of disease progression. To date, the issue of early vs late initiation of non-hormonal treatment in hormone-refractory prostate cancer (HRPC) has still not been resolved, so follow-up should be performed on an individual basis. Based on current knowledge, it is not possible to formulate strict guidelines for follow-up procedures following hormonal therapy.

15.3

Methods of follow-up

15.3.1 Prostate-specific antigen monitoring Prostate-specific antigen (PSA) is a good marker for following the course of metastatic prostate cancer (PCa). The prognostic value of PSA (the prediction of the duration of response to endocrine treatment), based on either the initial pre-treatment value or the PSA decrease during the first three to six months, has been used to monitor prostate cancer over the past few decades (1, 2). The initial PSA level can reflect the extent of metastatic disease, although some poorly differentiated tumours do not secrete PSA. The prognostic value of the pre-treatment PSA value is variably assessed in the literature and should not be used solely to predict the duration of response to treatment (3). Treatment response may be assessed utilising the change in serum PSA level as a surrogate end-point for survival in patients with newly diagnosed metastatic PCa after hormonal treatment has been initiated. Patients with the lowest absolute value of serum PSA (< 0.2 ng/mL) also had the best survival compared with those obtaining a value of 0.2-4.0 ng/mL or > 4.0 ng/mL (4). Similar results have been seen in other studies of locally advanced and metastatic PCa (5, 6). The PSA response has been shown to be equally important for patients treated with hormonal therapy because of a rising PSA after treatments with curative intent (radical prostatectomy, radiation therapy). Patients with the best response also had the best survival (7, 8). Despite its usefulness in determining treatment response in individual patients, the role of PSA as a surrogate end-point in clinical trials is more controversial (9). After the initial phase of response to endocrine treatment, patients should be regularly monitored in order to detect and treat any complications of endocrine escape, as clinical disease progression occurs after a median interval of about 12-18 months of treatment in patients with stage M1 disease. It is well established that regular PSA control in asymptomatic patients allows the earlier detection of biochemical escape, as the rise in PSA level usually precedes the onset of clinical symptoms by several months. However, it must be stressed that the PSA level is not a reliable marker of escape and cannot stand alone as a follow-up test. Clinical disease progression (usually bone pain) with normal PSA levels has been reported to occur. 15.3.2 Creatinine, haemoglobin and liver function monitoring Creatinine monitoring has some value because it can detect upper urinary tract obstruction in cases of advanced cancer that might need to be relieved by, for example, percutaneous nephrostomy or double J-stent. Haemoglobin and liver function tests could suggest disease progression and/or toxicity of hormonal treatment, which can lead to interruption of hormonal treatment (i.e. liver toxicity from non-steroidal anti-androgens). The fact that haemoglobin levels will decrease by about 20% with androgen deprivation must be taken into consideration (10).

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Alkaline phosphatase and its bone-specific isoenzymes may be used to monitor patients with stage M1b disease. These markers have the advantage of not being directly influenced by hormonal therapy compared with PSA. It should be remembered that increases in serum concentrations of alkaline phosphatase might also be due to osteoporosis induced by androgen deprivation (11). In this scenario, the determination of bonespecific alkaline phosphatase might be helpful. 15.3.3 Bone scan, ultrasound and chest X-ray In routine practice, asymptomatic patients with a normal PSA level should not have a bone scan at regular intervals as disease progression is more reliably detected by PSA monitoring, which also has a lower cost (1214). Moreover, the interpretation of bone scans is sometimes difficult, and the appearance of a new site of uptake or deterioration of pre-existing lesions in an asymptomatic patient does not modify the therapeutic approach. In cases where there is a clinical or laboratory suspicion of disease progression, a chest X-ray or renal and hepatic ultrasound may be indicated. Imaging modalities must also be guided by symptoms. However, these examinations are not recommended for routine use in asymptomatic patients. In hormone-refractory disease, follow-up examinations should be individualised with the aim of maintaining the patient’s quality of life. During long term androgen deprivation therapy (ADT), regular measurement of bone mineral density (BMD) might be recommended (level of evidence: 3) based on the initial T-score (15): every two years if the initial T-score < 1.0, or yearly if the T-score is between 1.0 and 2.5 in the absence of associated risk factors. Otherwise an active treatment should have started at the initiation of ADT.

15.4

When to follow-up

After initiation of hormonal treatment, it is recommended that patients be followed-up at three and six months. These guidelines must be individualised, and each patient should be told to contact his physician in the event of troublesome symptoms. 15.4.1 Stage M0 patients If there is a good treatment response, i.e. symptomatic improvement, good psychological coping, good treatment compliance and a serum PSA level of less than 4 ng/mL, follow-up visits are scheduled every six months. 15.4.2 Stage M1 patients If there is a good treatment response, i.e. good symptomatic improvement, good psychological coping, good treatment compliance and a serum PSA level of less than 4 ng/mL, follow-up is scheduled every three to six months. Patients should be advised of clinical symptoms that could suggest spinal cord compression and told to consult a physician immediately should they occur. 15.4.3 Hormone-refractory patients Patients whose disease progresses, or who do not respond according to the criteria mentioned above, warrant an individualised follow-up scheme.

15.5 Guidelines for follow-up after hormonal treatment Recommendation • Patients should be evaluated at three and six months after the initiation of treatment. As a minimum, tests should include serum PSA measurement, digital rectal examination (DRE), and careful evaluation of symptoms in order to assess the treatment response and the side-effects of the treatments given • Follow-up should be tailored for the individual patient, according to symptoms, prognostic factors and the treatment given • In patients with stage M0 disease with a good treatment response, follow-up is scheduled every six months, and should include as a minimum a disease-specific history, DRE and serum PSA determination

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C • In patients with stage M1 disease with a good treatment response, follow-up is scheduled for every three to six months. • As a minimum, this should include a disease-specific history, DRE and serum PSA determination, and is frequently supplemented with haemoglobin, serum creatinine and alkaline phosphatase measurements • Patients (especially if M1b status) should be advised on the clinical signs that could suggest spinal cord compression • When disease progression occurs, or if the patient does not respond to the treatment given, the C follow-up needs to be individualised • Routine imaging of stable patients is not recommended B GR = grade of recommendation

15.6

REFERENCES

1.

Ercole CJ, Lange PH, Mathisen M, Chiou RK, Reddy PK, Vessella RL. Prostatic specific antigen and prostatic acid phosphatase in the monitoring and staging of patients with prostatic cancer. J Urol 1987;138(5):1181-4. http://www.ncbi.nlm.nih.gov/pubmed/2444720 2. Mecz Y, Barak M, Lurie A. Prognostic importance of the rate of decrease in prostatic specific antigen (PSA) levels after treatment of patients with carcinoma of prostate. J Tumour Marker Oncol 1989;4:323-8. 3. Petros JA, Andriole GL. Serum PSA after antiandrogen therapy. Urol Clin North Am 1993;20(4):749-56. http://www.ncbi.nlm.nih.gov/pubmed/7505983 4. Hussain M, Tangen CM, Higano C, Schelhammer PF, Faulkner J, Crawford DE, Wilding G, Akdas A, Small EJ, Donnelly B, MacVicar G, Raghavan D. Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data from Southwest Oncology Group Trial 9346 (INT-0162). J Clin Oncol 2006;24(24):3984-90. http://www.ncbi.nlm.nih.gov/pubmed/16921051 5. Kwak C, Jeong SJ, Park MS, Lee E, Lee SE. Prognostic significance of the nadir prostate specific antigen level after hormone therapy for prostate cancer. J Urol 2002;168(3):995-1000. http://www.ncbi.nlm.nih.gov/pubmed/12187207 6. Collette L, de Reijke TM, Schröder FH; EORTC Genito-Urinary Group. Prostate specific antigen: a prognostic marker of survival in good prognosis metastatic prostate cancer? (EORTC 30892). Eur Urol 2003;44(2):182-9. http://www.ncbi.nlm.nih.gov/pubmed/12875936 7. D’Amico AV, Moul JW, Carroll PR, Cote K, Sun L, Lubeck D, Renshaw AA, Loffredo M, Chen M. Intermediate end point for prostate cancer-specific mortality following salvage hormonal therapy for prostate-specific antigen failure. J Natl Cancer Inst 2004;96(7):509-15. http://www.ncbi.nlm.nih.gov/pubmed/15069112 8. Stewart AJ, Scher HI, Chen MH, McLeod DG, Carroll PR, Moul JW, D’Amico AV. Prostate-specific antigen nadir and cancer-specific mortality following hormonal therapy for prostate-specific antigen failure. J Clin Oncol 2005;23(27):6556-60. http://www.ncbi.nlm.nih.gov/pubmed/16170163 9. Collette L, BurzyKowski T, Carroll KJ, Newling D, Morris T and Schroder FH. Is prostate antigen a valid surrogate end point for survival in hormonally treated patients with metastatic prostate cancer? Joint research of the European Organisation for Research and Treatment of Cancer, the Limburgs Universitair Centrum, and AstraZeneca Pharmaceuticals. J Clin Oncol 2005;23(25):6139-48. http://www.ncbi.nlm.nih.gov/pubmed/16135480 10. Strum SB, McDermed JE, Scholz MC, Johnson H, Tisman G. Anaemia associated with androgen deprivation in patients with prostate cancer receiving combined hormone blockade. Br J Urol 1997;79(6):933-41. http://www.ncbi.nlm.nih.gov/pubmed/9202563 11. Daniell HW. Osteoporosis due to androgen deprivation therapy in men with prostate cancer. Urology 2001;58(2 Suppl 1):101-7. http://www.ncbi.nlm.nih.gov/pubmed/11502461 12. Miller PD, Eardley I, Kirby RS. Prostate specific antigen and bone scan correlation in the staging and monitoring of patients with prostatic cancer. Br J Urol 1992;70(3):295-8. http://www.ncbi.nlm.nih.gov/pubmed/1384920 13. Oesterling JE. Prostate specific antigen: a critical assessment of the most useful tumor marker for adenocarcinoma of the prostate. J Urol 1991;145(5):907-23. http://www.ncbi.nlm.nih.gov/pubmed/1707989

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14.

Sissons GR, Clements MA, Peeling WB, Penney MD. Can serum prostate-specific antigen replace bone scintigraphy in the follow-up of metastatic prostatic cancer? Br J Radiol 1992;65(778):861-4. http://www.ncbi.nlm.nih.gov/pubmed/1384917 15. Higano CS. Bone loss and the evolving role of bisphosphonate therapy in prostate cancer. Urol Oncol 2003;21(5):392-8. http://www.ncbi.nlm.nih.gov/pubmed/14670551

16. TREATMENT OF BIOCHEMICAL FAILURE AFTER TREATMENT WITH CURATIVE INTENT 16.1

Background

Primary curative procedures such as radical prostatectomy and radiotherapy are well established therapeutic options in the management of localised prostate cancer (PCa). Technical advances in surgery and radiation therapy have improved therapeutic efficacy and decreased treatment-associated morbidity and toxicity, respectively. However, despite these improvements, there is still a significant risk of cancer recurrence after therapy, with between 27% and 53% of all patients undergoing radiation therapy or radical prostatectomy developing local or distant recurrences within 10 years of initial therapy, and 16-35% of patients receiving second-line treatment within five years of initial therapy (1-5, 6).

16.2

Definitions

16.2.1 Definition of treatment failure In previous years, treatment failure was defined as recurrence on digital rectal examination (DRE) or the development of metastatic disease. Currently, treatment failure is defined as a rising prostate-specific antigen (PSA) level based on a study of Pound et al. (7), which demonstrated that no patient followed for more than five years developed any recurrence without a concomitant rise in PSA. The level of PSA that defines treatment failure differs between radical prostatectomy cases and those treated with radiotherapy. Following radical retropubic prostatectomy, two consecutive values of PSA > 0.2 ng/mL appear to represent an international consensus defining recurrent cancer (6, 8). However, the most appropriate definition of biochemical progression after radical prostatectomy is still uncertain. In a retrospective analysis of 2782 men who had undergone radical prostatectomy for clinically localised PCa, Amling et al. (9) determined the best PSA cut-off point to be used to define biochemical recurrence. The authors demonstrated that once PSA recurrence was detected, a subsequent increase in PSA was noted in 49%, 62% and 72% of patients who had PSA levels of 0.2 ng/mL, 0.3 ng/mL and 0.4 ng/mL, respectively. These data indicate that only half the patients with a PSA of 0.2 ng/mL will progress further, and that they can therefore initially be managed by surveillance. Similar data have been presented by Stephenson et al. (10), who identified a PSA value ≥ 0.4 ng/mL as the best cut-off to explain the development of distant metastasis among 10 candidate definitions based on retrospective review of 75 patients who developed distant metastases after radical prostatectomy. Therefore, a cut-off of 0.4 ng/mL is appropriate for the definition of progression with clinical relevance necessitating salvage treatment. Following radiotherapy, a reasonable definition of biochemical relapse is three consecutive increases, according to the recommendation of the American Society for Therapeutic Radiology and Oncology (ASTRO) Consensus Panel (11). The new definition indicates a relapse if the PSA increase is ≥ 2 ng/mL higher than the PSA nadir value, independent of the serum concentration of the nadir (12). 16.2.2 Definition of recurrence Following radical prostatectomy, PSA values > 0.4 ng/mL represent recurrent cancer. Following radiotherapy, a PSA value of 2 ng/mL above the nadir after radiotherapy represents recurrent cancer.

16.3

Local or systemic relapse

With regard to further management once PSA relapse has been diagnosed, it is of major importance to determine whether the recurrence has developed at local or distant sites. About 50% of patients who underwent radical retropubic prostatectomy will have local disease, and the remainder will have either distant

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disease alone, or distant and local disease (11). Important parameters to help differentiate between local or distant relapse (Table 18) include: • the timing of the PSA increase after surgery • PSA velocity • PSA doubling time (PSADT) • the pathohistological stage • the Gleason score of the prostatectomy specimen. PSA elevations developing within the first two years following surgery are associated with distant recurrences (12). It has been shown that a median PSADT of 4.3 months is associated with distant relapse, whereas a median PSADT of 11.7 months predicts local failure (13). According to a recent study (14), PSA velocity of < 0.75 ng/mL/y was observed in 94% of patients with local recurrence, whereas 56% of patients with distant metastases demonstrated a PSA velocity of > 0.75 ng/mL/y. Table 18: Important clinical and pathohistological parameters predicting local and systemic relapse following radical prostatectomy Parameter • Interval to PSA relapse ≤ 1 year 1-2 years > 2 years > 3 years • PSA doubling time • Gleason score 2-4 5-6 7 8-10 • Pathological stage Organ confined (≤ pT2b) pT3a, R0 pT3a, R1 pT3b pTxpN1

Local recurrence

Systemic recurrence

7% 10% 61% 74% 11.7 months

93% 90% 39% 26% 4.3 months

0% 55% 39% 11%

0% 45% 61% 89%

40% 54% 48% 16% 7%

60% 46% 52% 84% 93%

With radiotherapy, any continuously rising PSA following a nadir after radiation is an indicator for local recurrence, systemic metastatic spread or a combination of both (11, 14-16). However, due to the well known PSA bounce phenomenon, biochemical recurrence is defined by three consecutive PSA rises above the nadir level according to ASTRO guidelines. After radiotherapy, a late and slowly rising PSA is a sign of local failure only. Local recurrence is defined by: • a prostatic biopsy demonstrating malignant cells 18 months or longer after initial radiotherapy • plus an associated rise in PSA • plus no evidence of metastatic spread documented by computed tomography (CT) or magnetic resonance imaging (MRI) and bone scintigraphy. 16.3.1 Definition of local and systemic failure • Local failure following radical prostatectomy is predicted with an 80% probability by PSA increase > three years after radical prostatectomy, a PSADT ≥ 11 months, a Gleason score ≤ 6, and stage ≤ pT3a pN0, pTx R1. • Systemic failure following radical prostatectomy is predicted with > 80% accuracy by a PSA increase < one year after radical prostatectomy, a PSADT of four to six months, a Gleason score of 8-10, and stage pT3b, pTxpN1. • Local failure after radiotherapy is documented by a positive prostatic biopsy and negative imaging studies.

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•

 rostatic biopsy after radiotherapy is necessary only if local procedures such as salvage P prostatectomy are indicated in an individual patient.

16.4

Evaluation of PSA progression

In recent years, most patients with PSA progression following initial therapy with curative intent underwent physical and sonographic examinations, radiographic studies or biopsies of the prostatic fossa and the vesicourethral anastomosis to confirm the recurrence identified by serological studies. For patients with asymptomatic PSA-only progression, the yield is very low, and Lange et al. (14) have shown that biochemical failure precedes clinical disease by 6-48 months. In general, DRE is not useful in men with undetectable or very low PSA levels. In a recent study by Öbek et al. (17), it was shown that only 4/72 patients (5.5%) with a PSA recurrence following radical prostatectomy had an abnormal DRE. Traditionally, bone scans and abdominal CT scans have been used to evaluate PSA elevations following primary treatment. Both imaging studies, however, are characterised by a low sensitivity and specificity and might be safely omitted in the routine work-up of relapsing patients. Recently, Cher et al. (18) studied 144 bone scans in 93 patients with PSA recurrence after radical retropubic prostatectomy, of which 122 patients had undergone radical prostatectomy without any hormone treatment, whereas 22 patients had received either neoadjuvant or adjuvant androgen-deprivation therapy (ADT). Only 4.1% and 27% of the bone scintigrams were positive for metastatic disease; the lowest PSA associated with positive findings was 46 ng/mL in the absence of adjuvant ADT, whereas the lowest PSA value was 15.47 ng/mL in patients who had received hormonal therapy. The probability of a positive bone scan remains ≤ 5% until serum PSA reaches at least 40 ng/mL. Similar data have been achieved by other groups that have demonstrated that patients with a true positive bone scan had an average PSA level of > 60 ng/mL and a PSA velocity of 22 ng/mL/y (19, 20). On logistic regression analysis, PSA and PSA velocity predicted the findings on bone scan, and PSA velocity predicted the CT scan result. The probability of a positive bone scan and a positive CT scan was 9.4% and 14%, respectively, among the 132 patients with biochemical recurrence. However, there might be a slight difference between patients after radical retropubic prostatectomy compared with patients after radiation therapy, as demonstrated by Johnstone et al. (21) in whose study 5% and 30%, respectively, of the bone scans, were positive. In summary, bone scintigraphy and CT scans are of no additional diagnostic value unless the PSA serum levels are higher than 20 ng/mL or the PSA velocity is more than 20 ng/mL/y. Endorectal coil imaging has been described as a useful technique to detect local recurrences after radical prostatectomy (22). In a series of 48 patients, local recurrence was correctly identified in 81%, with the mean PSA at time of diagnosis being 2 ng/mL. Positron emission tomography (PET) has been successfully applied in many human cancers for early identification of local or systemic recurrences. In PCa, there are few, but promising, published data on the clinical efficacy of PET in detecting local recurrences after radical prostatectomy (23, 24). However, it must be borne in mind that the uptake of 11C-choline is not specific for PCa and might also be due to inflammatory intraprostatic lesions. In a series of 31 patients with biochemical progression after radical prostatectomy, (11C)acetate-PET demonstrated a high sensitivity and specificity for the detection of local recurrences if the PSA serum level was > 1 ng/mL (23). In another recent series of 43 patients with newly diagnosed prostate cancer, there was a significant correlation between the 11C-choline uptake and the intraprostatic location of PCa as analysed in radical prostatectomy specimens (25). Similar results have been reported for the detection of locally recurrent PCa after radiation therapy (26). However, sensitivity with regard to extraprostatic extension was significantly lower for 11C-PET when compared with MRI. The most recent series to evaluate the role of 11C-choline PET/CT in patients with biochemical recurrence after radical prostatectomy identified a significant PSA relationship: the sensitivity to identify the localisation of metastases was 20-36% at PSA levels ≤ 1 ng/mL, and increased to 63-83% in men with PSA levels ≥ 3 ng/mL (27-30). The role of choline PET/CT to detect local or systemic recurrences in men with PSA relapse following radiotherapy is unclear and based on very few studies (31). Thus no final recommendations can be made. Its sensitivity and specificity with regard to the detection of lymph node metastases is less reliable, and the routine use of 11C-PET cannot therefore be recommended, especially not for PSA values < 1 ng/mL. 108

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Immunoscintigraphy using a radiolabelled monoclonal antibody based on prostate-specific membrane antigen for messenger RNA (PSMA), called 111-indium capromab pendetide, might represent an innovative diagnostic approach, with an overall accuracy of up to 81% to detect the site of relapse in PSA-only recurrences following radical retropubic prostatectomy (23, 24, 32, 33). Independent of the PSA serum concentration, a capromab pendetide scan shows a diagnostic yield of 60-80%, and may help to stratify therapy according to the location of positive sites. A recent study (33) investigating 255 patients with PSA-only recurrence < 4.0 ng/mL after radical prostatectomy, showed capromab pendetide uptake in 72% throughout the range of post-operative PSA serum levels (0.1-4.0 ng/mL). Approximately 31%, 42% and 25% of patients exhibited local uptake, locoregional uptake and distant uptake, respectively, enabling therapy to be targeted according to the differentiation of local versus systemic relapse. It has been common practice to perform transrectal ultrasound- (TRUS) guided biopsies of the prostatic fossa, the anastomosis or the prostate gland to exclude local recurrence after radical retropubic prostatectomy or radiotherapy. However, according to available studies, routine biopsy of the vesicourethral anastomosis appears not to be justified based on a verification rate of only 54% (34-38). Only in the presence of a palpable lesion or a hypoechoic lesion on TRUS can the diagnostic yield of the biopsy be improved to approximately 80%. Furthermore, there is a strong correlation between the positive biopsy rate and PSA serum concentrations (34-38); 28% and 70% of the biopsies were positive if the PSA level was, respectively, below 0.5 ng/mL or greater than 2.0 ng/mL. It is common sense, nowadays, that routine anastomotic biopsy is not indicated, and the use of PSA and PSADT is sufficient for clinical practice. In addition, PSA-free survival in biopsy-proven recurrences does not differ significantly compared with PSA-only recurrences. With regard to PSA relapses following radiation therapy, routine prostate biopsy should no longer be performed for the evaluation of PSA-only recurrences, according to an ASTRO consensus recommendation (15). However, prostate biopsy documenting local recurrence represents the main cornerstone in the decision-making process for salvage radical prostatectomy in patients with rising PSA levels following a nadir after radiation therapy (3941). It is a general recommendation to wait about 18 months and three months following radiation therapy or seeds, and cryotherapy or high-intensity focused ultrasound (HIFU), respectively.

16.5

Diagnostic procedures in patients with PSA relapse

•

 ollowing radical prostatectomy, CT scans of the pelvis and abdomen are of low sensitivity and F specificity in patients with PSA levels < 20 ng/mL or a PSA velocity of < 20 ng/mL/y Endorectal MRI or PET scans may help to detect local recurrences if PSA is > 1-2.0 ng/mL, but is not yet routine clinical practice If available, a capromab pendetide scan shows a diagnostic yield of 60-80% independent of the PSA serum level Following radiation therapy, local recurrence is documented by a positive biopsy > 18 months after the procedure.

• • •

16.6

Treatment of PSA-only recurrences

The timing and mode of treatment of PSA-only recurrence after radical prostatectomy or radiation therapy remains controversial. After radical retropubic prostatectomy observation, radiation therapy to the prostatic bed, (complete) androgen blockade, intermittent androgen deprivation (IAD), a combination of anti-androgens with 5-α-reductase inhibitors, and even early chemohormonal approaches are therapeutic options. The same therapeutic options may be applied for PSA recurrences following radiation therapy. In addition, salvage prostatectomy, cryotherapy and brachytherapy might be indicated in carefully selected patients. 16.6.1 Radiation therapy for PSA-only recurrence after radical prostatectomy Considering the numerous studies on the use of radiation therapy for PSA-only recurrence following radical retropubic prostatectomy, there is a growing body of parameters predicting outcome that might be helpful to differentiate between observation, radiation and hormonal therapy. As confirmed by various studies, the pre-radiation PSA level appears to be of critical importance for obtaining optimal treatment results (42-50). Applying a pre-radiation cut-off of < 2.5 ng/mL, Wu et al. (42) and Schild et al. (43) reported disease-free survival rates of 53% and 76%, compared with 8% and 26%, respectively, for patients with PSA serum levels > 2.5 ng/mL. Forman et al. (44) demonstrated a disease-free survival rate of 83% compared with 33% in patients with a PSA-only recurrence of less than 2.0 ng/mL and greater than 2.0 ng/mL, respectively. Nudell et al. (45) even reported progression-free survival rates of 58% and 21% in patients having undergone radiation of the prostate bed if PSA serum levels were below 1.0 ng/mL or greater than 1.0 ng/mL, respectively. Based on

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these data, ASTRO has published a consensus paper recommending a dose of at least 64 Gy when the PSA level is < 1.5 ng/mL after radical retropubic prostatectomy (15). These data of early salvage radiation therapy are corroborated by recent papers (51-53) demonstrating a significant difference with regard to the five-year biochemical-free and overall survival rates in patients being treated for PSA recurrence only or for palpable locally recurrent cancer. The analysis of patterns of treatment failure in SWOG 8974, a prospective randomised clinical trial to address whether high-risk post-prostatectomy patients benefited from immediate radiation therapy to the prostate fossa, identified a 77% freedom from PSA failure in a subgroup of patients with post-operative PSA levels ≤ 0.2 ng/mL (52). In men with PSA levels of > 0.2 ng/mL and ≤ 1.0 ng/mL, the five-year PSA recurrence-free survival was 34%, and 0% in patients post-operative PSA serum levels > 1.0 ng/mL. These data indicated that adjuvant radiation therapy is effective even in high-risk patients, and that the therapeutic benefit is most evident in the presence of minimal PSA serum levels. In another study, Stephenson et al. (53) evaluated prognostic models to predict the outcome of salvage radiation therapy on a cohort of 1603 men with PSA progression after radical prostatectomy who were operated on in 17 North American tertiary referral centres. The authors identified a significant relationship between PSA serum concentration at the time of radiation therapy and therapeutic outcome: the six-year biochemical-free survival was 48% in men with PSA < 0.5 ng/mL, whereas it was only 40%, 28% and 18% in men with PSA levels of 0.51-1 ng/mL, 1.01-1.5 ng/mL and > 1.5 ng/mL, respectively. Egewa et al. (49) reported five-year biochemical-free and overall survival rates of 69% and 96%, compared with 45% and 78%, respectively, in the group with palpable disease. However, there is still a lack of data from prospective randomised trials, and all of the studies being performed lack long-term follow-up, so the impact on survival is unknown. 16.6.2 Hormonal therapy In patients with a high pre-radical prostatectomy PSA > 20 ng/mL, a Gleason grade > 7, an extensive positive surgical margin and extensive extraprostatic tumour growth (pT3b, pTxpN1), immediate hormonal therapy might be indicated (46-50). The impact of early ADT on long-term survival is still unknown, however. In a retrospective observational multicentre study including 1352 patients with PSA recurrence following radical prostatectomy (51), early ADT resulted in a significant reduction of the development of clinical metastases compared with delayed ADT. There was, however, no significant effect on long-term survival. These recommendations are corroborated by a study (54) demonstrating that none of the patients with a Gleason score of 8, pT3b or pTxpN1 PCa remained disease-free following radiation therapy for PSA-only recurrence after radical prostatectomy. It is difficult to make recommendations for the optimal therapeutic management for PSA-only recurrences following radical prostatectomy or radiation therapy because of the lack of prospective randomised trials. There are only very few studies analysing the clinical utility of early androgen deprivation in locally advanced (M0) and metastatic PCA (54, 55). It is believed that for the M0 category of patients with pTxN1 disease who have undergone radical prostatectomy reflecting PSA-only recurrences, hormonal therapy would appear to be beneficial for some with a high probability of occult systemic metastases. There is some evidence that combined androgen blockade (CAB) has a pronounced survival benefit in patients with minimal metastatic disease, so patients with PSA-only recurrences might have a similarly improved survival with combined androgen deprivation (56, 57). Considering the speculative benefits, the sideeffects of traditional hormonal therapy – such as hot flushes, loss of libido, impotence, decreased muscle mass and osteoporosis – must not be underestimated. The use of anti-androgens alone might overcome these side-effects as demonstrated in recent studies. Although gynaecomastia and breast tenderness were the most predominant side-effects for the treatment of organ-confined and locally advanced PCa, the incidence of hot flushes, loss of libido and impotence was significantly lower than expected for luteinising hormone-releasing hormone (LHRH) agonists and CAB (58). Furthermore, the risk of objective progression of the disease was significantly reduced in patients receiving bicalutamide 150mg (59). Anti-androgens may represent a viable alternative to other modes of androgen deprivation for the management of PSA-only recurrences, especially in young and otherwise healthy men. Non-traditional ways of using hormonal therapy for PSA-only recurrence include IAD and oral therapies combining anti-androgens with 5-α-reductase inhibitors (60-67). In the setting of PSA-only recurrences, however, no prospective randomised trials and no clinical studies with sufficient data on long-term efficacy

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are available to justify a routine clinical application of IAD, despite its potential benefits. Summarising the series in which PSA-only recurrences were treated by IAD (60-64), PSA threshold levels at study-entry varied significantly, as did the PSA level at discontinuation of hormonal therapy. Only the study of 150 patients by Tunn (64) had a sufficiently appropriate study design to allow the drawing of important clinical conclusions. Patients were started on IAD for nine months when the postprostatectomy PSA serum level was greater than 3.0 ng/mL, and all patients reached a nadir of less than 0.5 ng/mL. IAD was restarted when PSA increased to more than 3.0 ng/mL. After a mean follow-up of 48 months, and a mean duration of hormonal therapy of 26.6 months, none of the patients had progressed to hormonerefractory disease. In some studies, finasteride and flutamide have been combined to manage PSA-only recurrences since both agents work additively by blocking the intraprostatic conversion of testosterone to dihydrotestosterone (DHT), and blocking the intracytoplasmic DHT receptor (65-67). In the latest report (66), including 73 patients, the application of finasteride (10 mg/day) and low-dose flutamide (250 mg/day) resulted in a mean PSA nadir of 1.35 ng/mL within six months. However, only 62% of the patients studied reached a PSA nadir of < 0.2 ng/mL. After a mean follow-up of 15 months, none of the patients had progressed to traditional hormonal therapy. However, longer follow-up of a larger patient cohort is needed, and randomised phase III trials using modern anti-androgens with fewer gastrointestinal and hepatic side-effects are mandatory. 16.6.3 Observation Observation until the development of clinically evident metastatic disease might represent a viable option for patients with a Gleason score ≤ 7, PSA recurrence longer than two years after surgery, and a PSADT longer than 10 months. In these patients, the median actuarial time for the development of metastasis will be eight years, and the median time from metastasis to death will be another five years. 16.6.4 Management of PSA relapse after radical prostatectomy Recommendations GR • Local recurrences are best treated by salvage radiation therapy with 64-66 Gy at a PSA serum B level ≤ 1.5 ng/mL • Expectant management is an option for patients with presumed local recurrence who are too B unfit or unwilling to undergo radiation therapy • PSA recurrence indicative of systemic relapse is best treated by early ADT resulting in decreased B frequency of clinical metastases • LHRH analogues/orchiectomy or bicalutamide 150 mg/day can both be used when there is A indication for hormonal therapy GR = grade of recommendation

16.7

Management of PSA failures after radiation therapy

In a recent review of the data of the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) comprising 2336 patients with PCa, Grossfeld et al. (68) demonstrated that 92% of patients initially irradiated received ADT for secondary treatment of PSA progression. In the absence of salvage procedures, the mean time interval from biochemical to clinical progression is approximately three years. Therapeutic options in these patients are ADT or local procedures, such as salvage radical prostatectomy, cryotherapy and interstitial radiation therapy (69-74). Salvage radical retropubic prostatectomy has not, however, gained widespread acceptance because of its associated morbidity, namely incontinence, local recurrences and rectal injuries. However, in well selected patients, the procedure might result in long-term disease-free survival. One has to consider that most series reporting on salvage radical prostatectomy include patients who were treated in the pre-PSA era without modern radiotherapeutic techniques, and local recurrences were usually detected at a late stage. Complications associated with the procedure were therefore quite high, with up to 65% of patients suffering from treatment-related morbidities. Up to 60% of patients in whom salvage radical prostatectomy was planned, had to undergo anterior or total exenteration for locally extensive disease associated with a high rate of local recurrences and a mean time to progression of only 1.3 years (46, 49, 52, 53). Recent reports analysing patients who were operated on during the past decade, have described far more optimistic outcomes after salvage radical prostatectomy. In the series examined by Gheiler et al. (73), 40 patients with a mean PSA of 14 ng/mL underwent salvage radical prostatectomy. When stratified by PSA less than or greater than 10 ng/mL, the three-year disease-specific survival was 68% and 26%, respectively.

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In the series reported by Garzotto and Wajsman (74), 24 patients underwent radical cystoprostatectomy or radical prostatectomy with neoadjuvant ADT. Neoadjuvant ADT was associated with a lower rate of positive surgical margins (21%) compared with patients in whom androgen deprivation failed and who exhibited a positive surgical margin rate of 80%. The authors demonstrated that disease-specific survival correlated strongly with the surgical margin status. At a mean follow-up of five years, the disease-specific survival rate was 95% and 44% for those with negative and positive surgical margins, respectively. Vaidya and Soloway (75) demonstrated a low complications rate, good post-operative continence and only one biochemical recurrence 36 months after salvage radical prostatectomy. Similar data have been achieved by Stephenson et al. (76), who reported on 100 consecutive patients undergoing radical salvage prostatectomy associated with a very low rate of peri-operative complications. The five-year progression-free rates have improved, and the results are similar to those of standard radical prostatectomy in cases of similar pathological stages. The 10-year cancer-specific and overall survival rates are in the ranges 70-75% and 60-66%, respectively, in contemporary series. In most contemporary series, organ-confined disease, negative surgical margins and the absence of seminal vesicle and/or lymph node metastases are favourable prognosticators associated with a better disease-free survival of approximately 70-80%, compared with 40-60% in patients with locally advanced PCa (77). In general, salvage radical retropubic prostatectomy should be considered only in patients with a low co-morbidity, a life expectancy of at least 10 years, an organ-confined PCa < T2, Gleason grade < 7, and presurgical PSA < 10 ng/mL. In all other patients, accurate pre-surgical staging is not easily defined after radiation therapy, increasing the risk not only for the necessity of anterior and total extirpation procedures, but also for associated complications and decreased long-term disease-specific survival. 16.7.1 Salvage cryosurgical ablation of the prostate (CSAP) for radiation failures Salvage cryosurgery has been proposed as an alternative to salvage prostatectomy as it has the potential advantage of less morbidity but equal efficacy. Only very few studies are available, and the results are not very promising. Pisters et al. (78) reported on 150 patients who had undergone CSAP for PSA recurrences following radiotherapy (n = 110) or other extensive pre-treatment (n = 40). After a mean follow-up of 13.5 months, 58% of patients exhibited biochemical failure, and only 31% demonstrated undetectable PSA serum levels. The complications associated with salvage CSAP were significant, and occurred in virtually all patients, with the main complications being urinary incontinence (73%), obstructive symptoms (67%), impotence (72%) and severe perineal pain (8%). After a one-year follow-up, incontinence resolved in the majority of patients, with persistent significant incontinence in 22% of patients (53%). According to a recent study by Cespedes et al. (79), the risk for urinary incontinence and impotence at least 12 months after CSAP are as high as 28% and 90%, respectively. In addition, 8-40% of patients complained about persistent rectal pain, and an additional 4% of men had undergone surgical procedures for the management of treatment-associated complications. With regard to oncological outcome, recent studies demonstrated that a durable PSA-response can be achieved in about 50% of patients with a pre-cryosurgery PSA of < 10 ng/mL (80). 16.7.2 Salvage brachytherapy for radiation failures The experience with salvage brachytherapy for radiation failures is very limited and there is only one study that includes a representative number of patients and a mean follow-up of 64 months (81-84). Grado et al. (83) treated 49 patients with transperineal TRUS-guided brachytherapy and reported three- and five-year disease-free survival rates of 48% and 43%, respectively. Beyer (84) reported a five-year biochemical freedom from relapse in 34-53% of patients, with local cancer control achieved in 98% of patients. However, the complication rate was quite severe, with 27% of the patients becoming incontinent, 14% needing palliative transurethral resection of the prostate (TURP) due to acute urinary retention, another 4% suffering from rectal ulcers, and 2% requiring permanent colostomy. 16.7.3 Observation Patients with signs of local recurrence only (low-risk patients with late recurrence and a slow PSA rise) who are not opting for second-line curative options are best managed by observation alone. A retrospective cohort analysis of hormonal therapy versus watchful waiting in 248 men with PSA failure after radiotherapy showed no advantage for hormonal therapy in the subgroup of men with a PSADT of > 12 months after radiotherapy. The five-year metastasis-free survival rate was 88% with hormonal therapy vs 92% with watchful waiting (p = 0.74) (85).

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16.7.4 Management of PSA relapse after radiation therapy Recommendation GR • Local recurrences may be treated by salvage radical prostatectomy in carefully selected patients C • CSAP and interstitial brachytherapy are alternative procedures in patients not suitable for surgery C • ADT is an option in patients with presumed systemic relapse B GR = grade of recommendation

16.8 Guidelines for second-line therapy after treatment with curative intent Recommendation GR • Presumed local failure Patients with presumed local failure only may be candidates for salvage B after radical radiotherapy radiotherapy. This should be given with at least 66 Gy and preferably prostatectomy before PSA has risen above 1.0 ng/mL. Other patients are best offered a period of watchful waiting (active monitoring), with possible hormonal therapy later on • Presumed local failure  Selected patients may be candidates for salvage radical prostatectomy C after radiotherapy although patients should be informed about the comparatively high risk of complications. Other patients are best offered a period of watchful waiting (active monitoring), with possible hormonal therapy later on • Presumed distant failure  There is some evidence that early hormonal therapy may be of benefit B in +/– local failure, delaying progression, and possibly achieving a survival benefit in comparison with delayed therapy. The results are not without controversy. Local therapy is not recommended except for palliative reasons GR = grade of recommendation

16.9

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Stephenson AJ, Kattan MW, Eastham JA, Dotan ZA, Bianco FJ, Lilja H, Scardino PT. Defining biochemical recurrence of prostate cancer after radical prostatectomy: a proposal for a standardized definition. J Clin Oncol 2006; 24(24): 3973 –78 http://www.ncbi.nlm.nih.gov/pubmed/16921049 11. American Society for Therapeutic Radiology and Oncology Consensus Panel. Consensus statement: guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 1997;37(5):1035-41. http://www.ncbi.nlm.nih.gov/pubmed/9169810 12.  Roach M 3rd, Hanks G, Thames H Jr, Schellhammer P, Shipley WU, Sokol GH, Sandler H. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Biol Phys 65:965–74. http://www.mdconsult.com/das/citation/body/120674870-2/jorg=journal&source=MI&sp=16362265&s id=0/N/16362265/1.html 13. Trapasso JG, deKernion JB, Smith RB, Dorey F. The incidence and significance of detectable levels of serum prostate specific antigen after radical prostatectomy. J Urol 1994;152(5 Pt 2):1821-5. http://www.ncbi.nlm.nih.gov/pubmed/7523728 14. Lange PH, Ercole CJ, Lightner DJ, Fraley EE, Vessella R. The value of serum prostate specific antigen determinations before and after radical prostatectomy. J Urol 1989;141(4):873-9. http://www.ncbi.nlm.nih.gov/pubmed/2467013 15. Cox JD, Gallagher MJ, Hammond EH, Kaplan RS, Schellhammer PF. Consensus statements on radiation therapy of prostate cancer: guidelines for prostate re-biopsy after radiation and for radiation therapy with rising prostate-specific antigen levels after radical prostatectomy. American Society for Therapeutic Radiology and Oncology Consensus Panel. J Clin Oncol 1999;17(4):1155–63. http://www.ncbi.nlm.nih.gov/pubmed/10561174 16. Taylor JM, Griffith KA, Sandler HM. Definitions of biochemical failure in prostate cancer following radiation therapy. Int J Radiat Oncol Biol Phys 2001;50(5):1212-9. http://www.ncbi.nlm.nih.gov/pubmed/11483331 17. Öbek C, Neulander E, Sadek S, Soloway MS. Is there a role for digital rectal examination in the follow up of patients after radical prostatectomy. J Urol 1999;162(3 Pt 1):762-4. http://www.ncbi.nlm.nih.gov/pubmed/10458361 18. Cher ML, Bianco FJ Jr, Lam JS, Davis LP, Grignon DJ, Sakr WA, Banerjee M, Pontes JE, Wood DP Jr. Limited role of radionuclide bone scintigraphy in patients with prostate specific antigen elevations after radical prostatectomy. J Urol 1998;160(4):1387-91. http://www.ncbi.nlm.nih.gov/pubmed/9751361 19.  Kane CJ, Amling CL, Johnstone PAS, Pak N, Lance RS, Thrasher B, Foley JP, Riffenburgh RH, Moul JW. Limited value of bone scintigraphy and computed tomography in assessing biochemical failure after radical prostatectomy. Urology 2003;61(3):607–11. http://www.ncbi.nlm.nih.gov/pubmed/12639656 20. Gomez P, Manoharan M, Kim SS, Soloway MS. Radionuclide bone scintigraphy in patients with biochemical recurrence after radical prostatectomy: when is it indicated? BJU Int 2004;94(3):299–302. http://www.ncbi.nlm.nih.gov/pubmed/15291855 21. Johnstone PAS, Tarman GJ, Riffenburgh R. Yield of imaging and scintigraphy assessing biochemical failure in prostate cancer patients. Urol Oncol 1997;3108-14. 22. Sella T, Schwartz LH, Swindle PW, Onyebuchi CN, Scardino PT, Scher HI, Hricak H. Suspected local recurrence after radical prostatectomy: endorectal coil MR imaging. Radiology 2004;231(2):279–385. http://www.ncbi.nlm.nih.gov/pubmed/15064390 23. Kotzerke J, Volkmer BG, Neumaier B, Gschwend JE, Hautmann RE, Reske SN. Carbon-11 acetate positron emission tomography can detect local recurrence of prostate cancer. Eur J Nucl Med Mol Imaging 2002;29(10):1380–4. http://www.ncbi.nlm.nih.gov/pubmed/12271422 24. Heinisch M, Dirisamer A, Loidl W, Stiober F, Gruy B, Haim S, Langsteger W (2006) Positron emission tomography/computed tomography with F-18-flourocholine for restaging of prostate cancer patients: meaningful at PSA < 5 ng/ml? Mol Imaging Biol 8:43-8. 25. Martorana G, Schiavina R, Corti B, Farsad M, Salizzoni E, Brunocilla E, Bertaccini A, Manferrari F, Castellucci P, Fanti S, Canini R, Grigioni WF, D’Errico Grigioni A. 11C-choline positron emission tomography/computerized tomography for tumor localization of primary prostate cancer in comparison with 12-core biopsy. J Urol 2006;176(3):954-60; discussion 960. http://www.ncbi.nlm.nih.gov/pubmed/16890665

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26.

Vees H, Buchegger F, Albrecht S, Khan H, Husarik D, Zaidi H, Soloviev D, Hany TF, Miralbell R. 18F-choline and/or 11C-acetate positron emission tomography: detection of residual or progressive subclinical disease at very low prostate-specific antigen values ( 2 ng/mL • Anti-androgen withdrawal for at least 4 weeks* • PSA progression, despite secondary hormonal manipulations* • Progression of osseous lesions: progression or appearance of two or more lesions on bone scan or soft tissue lesions using the RECIST criteria** and with nodes ≥ 2 cm in diameter * Either anti-androgen withdrawal or one secondary hormonal manipulation should have been done in order to fulfil the criteria for HRPC. ** From Therasse et al., 2000 (29).

17.3

Assessing treatment outcome in androgen-independent PCa

In general, the therapeutic outcome should be assessed using the guidelines for the evaluation of treatment response in solid tumours, recently published by the RECIST group (Response Evaluation Criteria In Solid Tumours) (29). However, 80-90% of patients do not have bi-dimensionally measurable disease. Patients with primarily soft tissue cancers often have a different prognosis to those with only osseous metastases. Osteoblastic bone metastases remain difficult to quantify accurately. Magnetic resonance imaging (MRI) might be an interesting tool for axial metastases (30). Because the cause of death in PCa patients is often unreliable, a more valid end-point may be an overall survival rate rather than a disease-specific one (31). 17.3.1 PSA level as marker of response Many contemporary studies use PSA as a marker of response, even though there is no consensus about the magnitude and duration of decline in PSA level. Prostate-specific antigen is being used as a rapid screening tool to test new agents for activity. However, conflicting evidence is emerging regarding the role of PSA as a marker for response. In addition, wide fluctuations have been seen in PSA values due to a transient effect of drugs on PSA production. The effects of drugs on PSA expression need to be considered when interpreting PSA response data, which must be viewed together with other clinical data (32-39). Nevertheless, it has been reproducibly shown that ≥ 50% PSA decline in pre-treatment PSA following therapy is associated with a significant survival advantage (40, 41). Kelly et al. (40) reported a statistically significant survival advantage in 110 patients with ≥ 50% PSA decline (> 25 months) compared to those who did not (8.6 months), while Smith et al. (41) showed that a PSA decline ≥ 50% for at least 8 weeks resulted in a longer mean survival time of 91 weeks versus only 38 weeks in patients with a smaller PSA reduction. An improved PSA response was also associated with prolonged survival in the TAX 327 study with a median survival of 33 months when the PSA was normalised (< 4 ng/mL) versus 15.8 months for abnormal PSA levels. However, it was clear in this trial that a PSA response was not a surrogate marker because the same PSA response rate was found in both docetaxel arms (45%), while improved survival was only apparent with the 3 weeks’ docetaxel regimen. 17.3.2 Other parameters The evaluation of molecular markers is just beginning. It includes a possible correlation between the positive findings of reverse transcriptase-polymerase chain reaction (RT-PCR) and poor survival (42); however, these data have to be corroborated in other trials before clinical recommendations can be made. In patients with symptomatic osseous lesions, pain reduction or complete pain relief may be used as parameters to assess palliative therapeutic response (43). 17.3.3 Trial end-points An increasing number of investigators advocate subjective end-points. However, investigators should currently apply the following: • use clearly defined end-points in trials, sufficiently powered to answer the hypothesis • report each response parameter individually, rather than as a complete or partial response • use PSA response, only with other clinical parameters of response • consider QoL end-points independently in symptomatic patients. However, in everyday practice, the evaluation of treatment response must be based on symptom improvement, prolonged survival, or other pre-defined targets.

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17.4

Recommendations for assessing therapeutic response

Recommendations • PSA decline ≥ 50% maintained for 8 weeks is associated with a significantly better outcome compared to a PSA decline < 50% • In non-osseous metastases from HRPC, assessment should adhere to the RECIST criteria • In patients with advanced symptomatic metastatic HRPC, therapeutic response can be assessed best by improvement of symptoms LE = level of evidence

17.5

LE 1a 1b 1b

Androgen deprivation in androgen-independent PCa

The existence of androgen-independent PCa demonstrates that disease progression occurs despite castration. The castration levels of testosterone must therefore be documented and a serum testosterone level < 50 ng/mL (1.7 nmol/L) should be documented at initial relapse on hormonal therapy (24, 44). The overall effect of continued testicular androgen suppression in HRPC is minimal. The recommendation to continue androgen deprivation with LHRH analogues, despite PSA progression, is based on the data of Manni et al. (45), which demonstrated significantly lower survival rates in patients without continuous androgen blockade. Two recent trials have challenged these data by showing only a marginal survival benefit for patients remaining on LHRH analogues during second- and third-line therapies (46, 47). However, in the absence of prospective data, the modest potential benefits outweigh the minimal risk of treatment and androgen suppression should be continued indefinitely in these patients. 17.6 Secondary hormonal therapy For the patient with progressive disease after androgen deprivation, there are many therapeutic options. They include anti-androgen withdrawal, addition of anti-androgens, anti-androgen replacement, oestrogenic compounds, adrenolytic agents and novel approaches (48). Figure 1 summarises the treatment modalities and expected responses. Figure 1: Flowsheet of the potential therapeutic options after PSA progression following initial hormonal therapy Mean Duration Metastic prostate cancer PSA ⇓ > 50% of Response LHRH-analogues

100%

Addition of antiandrogens

60-80%

Subcapsular orchiectomy

Addition of antiandrogens

CAB

36 months

Anti-androgen withdrawn

4-6 months

25-40%

Substitution of anti-androgen

4-6 months

30-40%

Anti-androgen withdrawal

5-6 months

40-60%

Secondary hormonal manipulation such as adrenal testosterone inhibitors, low-dose DES, steroids

4-8 months

50-70%

Non-hormonal therapy such as chemotherapy

10-12 months

LHRH = luteinising hormone releasing hormone; CAB = complete androgen blockade; DES = diethylstilboesterol.

17.7

Anti-androgen withdrawal syndrome

In 1993, Kelly and Scher (49) reported clinical and PSA responses in men who discontinued flutamide therapy upon development of progressive disease. The anti-androgen withdrawal syndrome was a critical discovery in Update march 2009

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terms of understanding the biology of androgen independence, interpreting clinical trials, and treating patients (50-53). Approximately one-third of patients respond to anti-androgen withdrawal, as indicated by a ≥ 50% PSA decrease, for a median duration of approximately 4 months (Table 21). Anti-androgen withdrawal responses have also been reported with bicalutamide and megestrol acetate (54-60). Recently, in the SWOG 9426 trial, the results were reported of a subgroup of 210 patients, with a tumour stage of M0 or M1, who showed PSA progression despite CAB. A PSA response was observed in 21%, even though there was no radiographic response. Median progression-free survival was 3 months, with 19% (all MO) having 12 months’ or greater progression-free survival. Factors associated with increased progression-free and overall survival were a longer period of non-steroidal use, lower PSA at baseline and M0-stage. These results were obtained with patients on CAB following androgen withdrawal treatment. No data were available on the withdrawal effect following second-line anti-androgen treatment. In conclusion, androgen withdrawal should be systematically considered as a first-line modality in relapsing patients, even if its efficacy is limited (level of evidence: 2). Table 21: Frequency and duration of PSA response following anti-androgen withdrawal Anti-androgen Flutamide Flutamide Flutamide Flutamide Bicalutamide Combined results

17.8

No. of patients 57 82 39 21 17 210

> 50% decrease in PSA No. of patients (%) 16 (28%) 12 (15%) 11 (28%) 7 (33%) 5 (29%) 44 (21%)

Duration (months) 4.0 3.5 3.7 3.7 5.0 3 (median)

Treatment alternatives after initial hormonal therapy

Except in patients with non-castration testosterone levels, it is difficult to predict which subset of patients is most likely to respond to secondary hormonal strategies (61). 17.8.1 Bicalutamide Bicalutamide is a non-steroidal anti-androgen with a dose response, with higher doses producing a greater reduction in PSA level (62). Addition of an anti-androgen, such as bicalutamide or flutamide, to gonadal suppression at the time of PSA failure appears to result in declining PSA in only a few patients (63-65). 17.8.2 Switching to an alternative anti-androgen therapy There has been recent interest in another simple modality: the alternative anti-androgen therapy (66). After CAB in 232 progressing patients (76% being M1b), a withdrawal effect was observed in 31 men (15.1%). A secondline hormonal treatment was performed by giving an alternative non-steroidal drug (i.e. initial flutamide was replaced by bicalutamide and vice versa). An overall > 50% decline in PSA was observed in 83 men (35.8%), irrespective of any previous withdrawal effect, and lasting more than 6 months. The higher the PSA at the start of second-line therapy, the shorter the efficacy. 17.8.3 Anti-androgen withdrawal accompanied by simultaneous ketoconazole The adrenal glands secrete approximately 10% of circulating androgen in humans. Some tumour cells in androgen-independent states must retain androgen sensitivity, as a clinical response is induced by a further decrease in circulating androgen levels following bilateral adrenalectomy or administration of drugs inhibiting adrenal steroidogenesis. Aminoglutethimide, ketoconazole and corticosteroids act mainly via this mechanism (67-71) to produce a PSA response in about 25% of patients for about 4 months. However, the simultaneous addition of ketoconazole to anti-androgen withdrawal, produced a significantly increased PSA response (32% vs 11%) and a longer time to PSA progression (8.6 vs 5.9 months) compared to anti-androgen withdrawal alone (71). 17.8.4 Oestrogens Prostate cancer usually expresses oestrogen receptors, which are upregulated after androgen ablation in animal models. In-vitro oestrogens can activate mutant androgen receptors isolated from androgenindependent PCa, while high-dose oestrogens have achieved objective salvage responses. This may be due to the mitotic arrest of direct cytotoxic effects on the cells, perhaps through an apoptotic mechanism (72, 73). Recently, DES (74-76) achieved a positive PSA response between 24% and 80%, with an overall estimated survival of 63% at 2 years. However, even at low doses of DES, about one-third (31%) of patients developed

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deep venous thrombosis and 7% experienced myocardial infarction. A very promising drug, the CYP17 inhibitor abiraterone acetate, has achieved more 50% PSA decrease in clinical trials in patients with HRPC (77), including patients previously treated with ketokonazole (78) or even by docetaxel (79). A large phase III trial is underway, enrolling 1158 men, with overall survival as the primary objective. This new compound raises questions about HRPC definition status, as a clear response is apparent even in highly pretreated patients initially considered to be hormone-refractory.

17.9

Non-hormonal therapy (cytotoxic agents)

Several proven chemotherapeutic options are available for metastatic disease in HRPC (Table 22). A significant improvement in median survival of about 2 months occurred with docetaxel-based chemotherapy compared to mitoxantrone + prednisone therapy (80, 81). In the SWOG 99-16 trial, pain relief was similar in both groups, though side-effects occurred significantly more often with docetaxel than with mitoxantrone. Table 22: PSA response rates, mean survival, time to progression, and pain reduction in the large prospective randomised phase III trials of chemotherapy in patients with HRPC Study n PSA decrease Decrease in Survival TTP > 50% pain Tax 327 Mitoxantrone 32% 22% 16.5 months __ Docetaxel, 75 mg/m2 45%1 35%3 18.9 months1 __ Docetaxel, 30 mg/m2 48%1 31% 17.4 months __ SWOG 99-16 Mitoxantrone 336 50%1 __ 17.5 months2 6.3 months1 Docetaxel/EMP 338 27% __ 15.6 months 3.2 months CALGB 9182 Hydrocortisone 123 38%4 __ 12.3 months 2.3 months Mitoxantrone/HC 119 22% __ 12.6 months 3.7 months4 Tannock et al. Prednisone 81 22% 12% __ 43 weeks1 2 Mitoxantrone/Pred 80 33% 29% __ 18 weeks TTP = median time to progression; EMP = estramustine; HC = hydrocortisone; Pred = prednisone. 1p < 0.000; 2p = 0.001; 3p = 0.01; 4p < 0.03. 17.9.1 Timing of chemotherapy in metastatic HRPC The timing of chemotherapy varies in metastatic HRPC. In symptomatic patients, immediate use is advisable, every 3 weeks if possible as this schedule is associated with a survival improvement. However, a weekly regimen will result in the same symptom improvement. It must be considered in patients unable to receive the optimal regimen (level of evidence: 1b), as it is more effective than the best supportive care (82). In asymptomatic patients, timing is not so clear and must be discussed individually. Several poor prognostic factors have been described, such as PSA level > 114 ng/mL, a PSA doubling time (PSA–DT) < 55 days, or the presence of visceral metastases (83). A C-reactive protein (CRP) level below 8 mg/L (HR, 2.96) has also been suggested as predicting better survival (84). if (84).Age Ageby byitself itselfisisnot not aa contraindication to docetaxel (85). Currently, the only indication for chemotherapy in HRPC non-metastatic patients is inside clinical trials and patients should be advised to participate. Taxanes in combination therapy In an effort to improve treatment results further, several phase I and phase II trials are underway combining taxanes with anti-bcl-2, calcitriol (trial stopped due to unexpected toxicity), exisulid, and thalidomide, resulting in PSA responses of about 60% (86-89). In a randomised phase II trial of docetaxel + thalidomide (86), 75 men with chemotherapy-naïve HRPC were randomised to receive either docetaxel at 30 mg/m2 for 5 of every 6 weeks or docetaxel at the same dose and schedule plus thalidomide at 200 mg orally each day. A PSA decline of ≥ 50% was higher in the combination-treated group (53%) compared to the docetaxel-alone treated group (37%) (not statistically significant). Median progression-free survival and overall survival with combination treatment were 5.9 months and 68%, respectively, at 18 months versus 3.7 months and 43% in the docetaxelalone group (not statistically significant). However, there were considerable side-effects, with thromboembolic events occurring in 28% of the combination arm compared to no such events in the docetaxel arm. A recent phase III trial in HRPC patients confirmed the potential interest of thalidomide compared to placebo in nonmetastatic patients with a progression-free survival of 15 months versus 9.6 months (p = 0.0002) (90).

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Mitoxantrone combined with corticosteroids Mitoxantrone combined with corticosteroids (37, 91) has been extensively studied primarily in patients with symptomatic osseous lesions due to HRPC. In the CALGB 9182 study (91), 244 patients with symptomatic metastatic HRPC were randomised to receive either mitoxantrone + hydrocortisone, 12 mg/m2 every 3 weeks, or hydrocortisone alone. No differences were observed with regard to survival, PSA response, and median time to progression. However, the QoL was significantly improved in the combination arm. In another trial (37), 161 men with painful osseous metastases due to HRPC were randomised to receive mitoxantrone + prednisone versus prednisone alone. There was a significant benefit in pain reduction in the combination group (29%) versus prednisone alone (12%, p = 0.01). Furthermore, the duration of palliation was longer in patients who received mitoxantrone (43 vs 18 weeks, p < 0.0001). There were no significant differences with regard to PSA response and median survival time. However, again, QoL was improved significantly due to pain reduction. Alternative combination treatment approaches Encouraging results have been seen with alternative treatments evaluated in prospective clinical phase II trials, including pegylated doxorubicin, vinorelbine, a combination of paclitaxel, carboplatin and estramustine, a combination of vinblastine, doxorubicin and radionuclides, and a combination of docetaxel and mitoxantrone (92-98). The lack of representative randomised phase III trials and unknown long-term efficacy are major problems associated with all these studies. Estramustine in combination therapies The synergy observed for estramustine combined with other drugs that target microtubule action has generated promising results in prospective clinical trials (99). Estramustine + vinblastine has been the most studied estramustine combination. Although different doses of estramustine and vinblastine have been used in prospective randomised trials, significant PSA and measurable responses have been reported in three separate studies. Although time to progression and frequency of ≥ 50% PSA decrease was significantly higher in the combination arm, median survival did not differ significantly between the estramustine and the estramustine + vinblastine arms (100). A recent meta-analysis on estramustine (101) concluded that the addition of estramustine to chemotherapy increased the time to PSA progression and overall survival. However, there was a significant increased risk of thromboembolic events, up to 7% (102), requiring systematic prevention with coumadin. Oral cyclophosphamide Intravenous cyclophosphamide has been tested in many trials. However, there is currently interest in on oral cyclophosphamide, which seems to be less toxic than intravenous cyclophosphamide and may have greater activity (103, 104). A study of the oral cyclophosphamide + oral etoposide in 20 patients was similarly encouraging (105, 106). Cisplatin and carboplatin have activity against PCa as single agents and a welldocumented synergy with etoposide or paclitaxel in vitro in the treatment of other malignancies, such as lung and ovarian cancer. As estramustine is also synergistic with these drugs, combinations of three agents are now being tested. A combination of estramustine, etoposide and cisplatin (or carboplatin) has significant activity against poorly differentiated HRPC. A combination of estramustine, etoposide and paclitaxel has produced high response rates (107). Suramin Suramin activity against HRPC is likely to be mediated through the inhibition of binding of growth factors (e.g. transforming growth factor beta) to their receptors. Recent results have renewed interest in suramin’s initial promise in the treatment of HRPC (108-110). Salvage chemotherapy Since all patients who receive docetaxel-based chemotherapy for HRPC will progress within 6 to 8 months, there have been many clinical trials investigating the role of salvage chemotherapy. The results suggest the most appropriate approaches are intermittent docetaxel chemotherapy (111, 112), molecular-targeted therapy 113, 114) and second-line satraplatin (115). Second-line intermittent docetaxel has been used by several groups in clearly responding patients to first-line docetaxel (111, 112, 116 ). In general, a PSA response can be achieved in about 60% of patients with a median time to progression of about 6 months, while treatment-associated toxicity is minimal and similar to that of first-line docetaxel. Another, recently identified approach is molecular-targeted therapy (111-117, 118), though more research is needed in larger groups of patients. Platinum-based chemotherapeutic regimes have been investigated in patients with HRPC. Although

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the platinum complex, satraplatin, has shown activity against HRPC and some promise in clinical trials (39, 41), it was rejected for HRPC by the FDA in 2008. Many new drugs, such as gefitinib, bevasusimab (phase III trial CALB 90401), oblimersen (phase III trial EORTC 30021), and also a vaccine, G-Vax (119), are being tested in phase III trials. Patients should be advised to participate.

17.10 Palliative therapeutic options 17.10.1 Painful bone metastases Most patients with HRPC have painful bone metastases. External beam radiotherapy is highly effective (120), even as single fraction (121). The two radioisotopes, strontium-89 and samarium-153, can partially or completely decrease bone pain in up to 70% of patients, but should not be given too late when the pain is intractable. Early use can give rise to myelosuppression making subsequent chemotherapy more difficult (106, 122), even though a recent phase I trial has demonstrated manageable haematological toxicity with repeated administration of docetaxel and samarium-153 (123). The use of samarium-153 as consolidation therapy, following a clear docetaxel response, may also help with initially painful bone metastases (124). Palliative treatment with another radioisotope emitter, radium-233 has shown very promising phase II results in patients with painful bone metastases in terms of palliation and overall survival, and only a mild haematological toxicity (125). 17.10.2 Common complications due to bone metastases Common complications due to skeletal metastases include bone pain, vertebral collapse or deformity pathological fractures and spinal cord compression. Osteoporosis may also cause fractures and should be prevented (see above). Cementation is an effective treatment of painful fracture, clearly improving both pain and QoL (126). However, it is still important to offer standard palliative surgery, which can be very effective at managing osteoblastic metastases (127, 128). Impending spinal cord compression is an emergency. It must be recognised early and patients educated to recognise the warning signs. Once suspected, high-dose corticosteroids must be given and an MRI performed as soon as possible. A systematic neurosurgery consultation should be planned to discuss a possible decompression (129). Otherwise, external beam radiotherapy is the treatment of choice. 17.10.3 Bisphosphonates Recently, bisphosphonates have been used to inhibit osteoclast-mediated bone resorption and osteoclast precursors in HRPC to provide effective treatment of skeletal complications and to reduce pain or provide total pain relief. In the largest single phase III trial (130), 643 patients who had HRPC with bone metastases were randomised to receive zoledronic acid, 8 mg or 4 mg every 3 weeks for 15 consecutive months, or placebo. At 15 and 24 months of follow-up, patients treated with only 4 mg of zoledronic acid had fewer skeletalrelated events compared to the placebo group (44% vs 33%, p = 0.021) and fewer pathological fractures (13.1% vs 22.1%, p = 0.015). Furthermore, the time to first skeletal-related event was longer in the zoledronate group, so improving QoL. Patients were initially randomised to 4 or 8 mg of zoledronic acid, but the 8 mg dosage was later modified to 4 mg because of toxicity. Currently, bisphosphonates could be proposed to patients with HRPC bone metastases to prevent skeletal complications, even if the best dosing interval is unclear, but at present is every 3 weeks or less. The toxicity, e.g. jaw necrosis, of these drugs, especially aminobisphosphonate, must always be kept in mind (131). Patients should have a dental examination before starting a bisphosphonate. The risk of jaw necrosis is increased by a history of trauma, dental surgery or dental infection, as well as intravenous long-term bisphosphonate administration (132). Pain due to osseous metastases is one of the most debilitating complications of HRPC. Bisphosphonates have been highly effective with a response rate of 70-80% in small, open trials, which, associated with a low frequency of side-effects, makes bisphosphonates an ideal medication for palliative therapy of advanced HRPC (43, 133). Bisphosphonates should be considered early in the management of symptomatic HRPC. Critical issues of palliation must be addressed when considering additional systemic treatment, including management of pain, constipation, anorexia, nausea, fatigue and depression, which often occur (i.e. palliative external beam radiation, cortisone, analgesics and antiemetics). Hormone-refractory PCa is usually a debilitating disease, often affecting the elderly male. A multidisciplinary approach is required with input from medical oncologists, radiation oncologists, urologists, nurses, psychologists and social workers (134).

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17.11 Summary of treatment after hormonal therapy Recommendations GR • It is recommended to stop anti-androgen therapy once PSA progression is documented B • Four to six weeks after discontinuation of flutamide or bicalutamide, an eventual anti-androgen B withdrawal effect is apparent • No clear-cut recommendation can be made for the most effective drug for secondary hormonal C manipulations because data from randomised trials are scarce GR = grade of recommendation

17.12 Guidelines and recommendations for cytotoxic therapy in HRPC Guidelines and recommendations GR • Cytotoxic therapy should only be used to treat non-metastatic HRPC in clinical trials • In patients with a PSA rise only, two consecutive increases of PSA serum levels above a previous B reference level should be documented • Prior to treatment, PSA serum levels should be > 5 2 ng/mL to assure correct interpretation of B therapeutic efficacy • Potential benefits of cytotoxic therapy and expected side-effects should be discussed with each C individual patient • In patients with metastatic HRPCA, and who are candidates for cytotoxic therapy, docetaxel at A 75 mg/m2 every 3 weeks has shown a significant survival benefit • In patients with symptomatic osseous metastases due to HRPCA, either docetaxel or A mitoxantrone with prednisone or hydrocortisone are viable therapeutic options • Second-line docetaxel should be considered in previously responding patients to docetaxel B Otherwise, treatment is tailored to the individual patient GR = grade of recommendation

17.13 Guidelines for palliative management of HRPC Recommendations • Patients with symptomatic and extensive osseous metastases cannot benefit from medical treatment with regard to prolongation of life • Management of these patients has to be directed at improvement of QoL and mainly pain reduction • Effective medical management with the highest efficacy and a low frequency of side-effects is the major goal of therapy

17.14 Recommendations for palliative management of HRPC Recommendations GR • Bisphosphonates may be offered to patients with skeletal masses (mainly zoledronic acid has A been studied) to prevent osseous complications. However, the benefits must be balanced against the toxicity of these agents, in particular jaw necrosis must be avoided • Palliative treatments such as radionuclides, external beam radiotherapy, adequate use of B analgesics should be considered early in the management of painful osseous metastases • Spine surgery or decompressive radiotherapy might be an emergency A GR = grade of recommendation

17.15 REFERENCES 1.

Isaacs JT, Coffey DS. Adaptation vs selection as the mechanism responsible for the relapse of prostatic cancer to androgen ablation therapy as studied in the Dunning R-3327-H adenocarcinoma. Cancer Res 1981;41(12 Pt 1):5070-5. http://www.ncbi.nlm.nih.gov/pubmed/7307008 2. Horoszewicz JS, Leong SS, Kawinski E, Karr JP, Rosenthal H, Chu TM, Mirand EA, Murphy GP. LNCaP model of human prostatic carcinoma. Cancer Res 1983;43(4):1809-18. http://www.ncbi.nlm.nih.gov/pubmed/6831420 3. Taplin ME, Bubley GJ, Shuster TD, Frantz ME, Spooner AE, Ogata GK, Keer HN, Balk SP. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med 1995;332(21):1393-8. http://www.ncbi.nlm.nih.gov/pubmed/7723794 4. Elo JP, Kvist L, Leinonen K, Isomaa V, Henttu P, Lukkarinen O, Vihko P. Mutated human androgen receptor gene detected in a prostatic cancer patient is also activated by estradiol. J Clin Endocr

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Savarese DM, Halabi S, Hars V, Akerley WL, Taplin ME, Godley PA, Hussain A, Small EJ, Vogelzang NJ. Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone refractory prostate cancer: a final report of CALGB 9780. Cancer and Leukemia Group B. J Clin Oncol 2001;19(9):2509-16. http://www.ncbi.nlm.nih.gov/pubmed/11331330 Smith DC, Chay CH, Dunn RL, Fardig J, Esper P, Olson K, Pienta KJ. Phase II trial of paclitaxel, estramustine, etoposide and carboplatin in the treatment of patients with hormone-refractory prostate cancer. Cancer 2003;98(2):269-76. http://www.ncbi.nlm.nih.gov/pubmed/12872344 Dawson NA, Cooper MR, Figg WD, Headlee DJ, Thibault A, Bergan RC, Steinberg SM, Sausville EA, Myers CE, Sartor O. Antitumour activity of suramin in hormone-refractory prostate cancer controlling for hydrocortisone treatment and flutamide withdrawal as potentially confounding variables. Cancer 1995;76(3):453-62. http://www.ncbi.nlm.nih.gov/pubmed/8625127 Kelly WK, Curley T, Liebretz C, Dnistrian A, Schwartz M, Scher Hl. Prospective evaluation of hydrocortisone and suramin in patients with androgen-independent prostate cancer. J Clin Oncol 1995;13(9):2208-13. http://www.ncbi.nlm.nih.gov/pubmed/7545218 Small EJ, Halabi S, Ratain MJ, Rosner G, Stadler W, Palchak D, Marshall E, Rago R, Hars V, Wilding G, Petrylak D, Vogelzang NJ. Randomized study of three different doses of suramin administered with a fixed dosing shedule in patients with advanced prostate cancer: results of intergroup 0159, cancer and leukaemia group B 9480. J Clin Oncol 2002;20(16):3369-75. http://www.ncbi.nlm.nih.gov/pubmed/12177096 Sternberg CN, Whelan P, Hetherington J, Paluchowska B, Slee PH, Vekemans K, Van Erps P, Theodore C, Koriakine O, Oliver T, Lebwohl D, Debois M, Zurlo A, Collette L; Genitourinary Tract Group of the EORTC. Phase III trial of satraplatin, an oral platinum plus prednisone vs. prednisone alone in patients with hormone-refractory prostate cancer. Oncology 2005;68(1):2-9. http://www.ncbi.nlm.nih.gov/pubmed/15741753 Oudard S, Caty A, Humblet Y, Beauduin M, Suc E, Piccart M, Rolland F, Fumoleau P, Bugat R, Houyau P, Monnier A, Sun X, Montcuquet P, Breza J, Novak J, Gil T, Chopin D. Phase II study of vinorelbine in patients with androgen-independent prostate cancer. Ann Oncol 2001;12(6):847-52. http://www.ncbi.nlm.nih.gov/pubmed/11484963 Ohlmann C, Ozgur E, Engelmann U, Heidenreich A. Molecular triggered therapy in hormone refractory prostate cancer. Eur Urol Suppl 2006;5(2):93, abstract 281. Beer TM, Garzotto M, Henner WD, Eilers KM, Wersinger EM. Multiple cycles of intermittent chemotherapy in metastatic androgen-independent prostate cancer. Br J Cancer 2004;91(8):1425-7. http://www.ncbi.nlm.nih.gov/pubmed/15467765 Fizazi K,Le Maitre A, Hudes G, Berry WR, Kelly WK, Eymard JC, Logothetis CJ, Pignon JP, Michiels S; Meta-analysis of Estramustine in Prostate Cancer (MECaP) Trialists’ Collaborative Group. Addition of estramustine to chemotherapy and survival of patients with castration-refractory prostate cancer: a meta-analysis of individual patient data. Lancet Oncol 2007;8(11):994-1000. http://www.ncbi.nlm.nih.gov/pubmed/17942366 Lubiniecki GM, Berlin JA, Weinstein RB, Konkle BA, Vaughn DJ; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; Center for Clinical Epidemiology and Biostatistics of the University of Pennsylvania, Philadelphia, PA; Presbyterian Hospital of the University of Pennsylvania, Philadelphia, PA. Risk of thromboembolic events (TE) with estramustine-based chemotherapy in hormone-refractory prostate cancer (HRPC): results of a meta-analysis. Abstract. Proc Am Soc Clin Oncol 2003;22: #1581. http://pediatricca.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnex toid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=23&inde x=y&abstractID=102825 Ohlmann C, Ozgur E, Wille S, Engelmann U, Heidenreich A. Second-line chemotherapy with docetaxel for prostate-specific antigen relapse in men with hormone refractory prostate cancer previously treated with docetaxel based chemotherapy. Eur Urol Suppl 2006;5(2):93, abstract 289. Lara PN Jr, Twardowski P, Quinn DI. Angiogenesis-targeted therapies in prostate cancer. Clin Prostate Cancer 2004;3(3):165-73. http://www.ncbi.nlm.nih.gov/pubmed/15636683

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Sternberg CN, Hetherington J, Paluchowska B, Slee PHTJ., Collette L, Debois M, Zurlo A. Randomized phase III trial of a new oral platinum, satraplatin (JM-216) plus prednisone or prednisone alone in patients with hormone refractory prostate cancer. Proc Am Soc Clin Oncol 2003;22, abstract 1586. http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=7 6f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=23&index=y&a bstractID=100833 Porter AT, McEwan AJ, Powe JE, Reid R, McGowan DG, Lukka H, Sathyanarayana JR, Yakemchuk VN, Thomas GM, Erlich LE, Crook J, Gulenchyn KY, Hong KE, Wesolowski C, Yardlye J. Results of a randomized phase III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J Radiat Oncol Biol Phys 1993;25(5):805-13. http://www.ncbi.nlm.nih.gov/pubmed/8478230 Smith DC, Chay CH, Dunn RL, Fardig J, Esper P, Olson K, Pienta KJ. Phase II trial of paclitaxel, estramustine, etoposide and carboplatin in the treatment of patients with hormone-refractory prostate cancer. Cancer 2003;98(2):269-76. http://www.ncbi.nlm.nih.gov/pubmed/12872344 Dawson NA, Cooper MR, Figg WD, Headlee DJ, Thibault A, Bergan RC, Steinberg SM, Sausville EA, Myers CE, Sartor O. Antitumour activity of suramin in hormone-refractory prostate cancer controlling for hydrocortisone treatment and flutamide withdrawal as potentially confounding variables. Cancer 1995;76(3):453-62. http://www.ncbi.nlm.nih.gov/pubmed/8625127 Kelly WK, Curley T, Liebretz C, Dnistrian A, Schwartz M, Scher Hl. Prospective evaluation of hydrocortisone and suramin in patients with androgen-independent prostate cancer. J Clin Oncol 1995;13(9):2208-13. http://www.ncbi.nlm.nih.gov/pubmed/7545218 Small EJ, Halabi S, Ratain MJ, Rosner G, Stadler W, Palchak D, Marshall E, Rago R, Hars V, Wilding G, Petrylak D, Vogelzang NJ. Randomized study of three different doses of suramin administered with a fixed dosing shedule in patients with advanced prostate cancer: results of intergroup 0159, cancer and leukaemia group B 9480. J Clin Oncol 2002;20(16):3369-75. http://www.ncbi.nlm.nih.gov/pubmed/12177096 Ohlmann C, Ozgur E, Engelmann U, Heidenreich A. Molecular triggered therapy in hormone refractory prostate cancer. Eur Urol Suppl 2006;5(2):93, abstr 281. Beer TM, Garzotto M, Henner WD, Eilers KM, Wersinger EM. Multiple cycles of intermittent chemotherapy in metastatic androgen-independent prostate cancer. Br J Cancer 2004;91(8):1425-7. http://www.ncbi.nlm.nih.gov/pubmed/15467765 Ohlmann C, Ozgur E, Wille S, Engelmann U, Heidenreich A. Second-line chemotherapy with docetaxel for prostate-specific antigen relapse in men with hormone refractory prostate cancer previously treated with docetaxel based chemotherapy. Eur Urol Suppl 2006;5(2):93, abstract 289. Lara PN Jr, Twardowski P, Quinn DI. Angiogenesis-targeted therapies in prostate cancer. Clin Prostate Cancer 2004;3(3):165-73. http://www.ncbi.nlm.nih.gov/pubmed/15636683 Sternberg CN, Hetherington J, Paluchowska B, Slee PHTJ, Collette L, Debois M, Zurlo A. Randomized phase III trial of a new oral platinum, satraplatin (JM-216) plus prednisone or prednisone alone in patients with hormone refractory prostate cancer. Proc Am Soc Clin Oncol: 2003;22, abstract 1586. http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=7 6f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=23&index=y&a bstractID=100833 Ansari J, Hussain SA, Zarkar A, Bliss J, Tanguay JD, Glaholm J. Docetaxel re-treatment for metastatic hormone refractory prostate cancer. Abstract. J Clin Oncol 2008;26(15S): #16016. http://meeting.ascopubs.org/cgi/content/abstract/26/15_suppl/16066 Lara PN Jr, Twardowski P, Quinn DI. Angiogenesis-targeted therapies in prostate cancer. Clin Prostate Cancer 2004;3(3):165-73. http://www.ncbi.nlm.nih.gov/pubmed/15636683 Periman PO, Sonpavde G, Bernold DM, Weckstein DJ, Williams AW, Zhan F, Boehm KA, Asma L, Hutson TE. Sunitinib malate for metastatic castration resistant prostate cancer following docetaxelbased chemotherapy. Abstract. J Clin Oncol 2008;26(15S): #5157. http://meeting.ascopubs.org/cgi/content/abstract/26/15_suppl/5157

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Small EJ, Schellhamme PF, Higano CS, Neumanaitis J, Valone F, Hershberg R. Results of a placebocontrolled phase III trial of immunotherapy with APC8015for patients with hormone refractory prostate Cancer (HRPC). Abstract. J Clin Oncol 2005;23(16S): #4500. http://meeting.ascopubs.org/cgi/content/abstract/23/16_suppl/4500 120. Dy SM, Asch SM, Naeim A, Sanati H, Walling A, Lorenz KA. Evidence-based standards for cancer pain management. J Clin Oncol 2008;26(23):3879-85. http://www.ncbi.nlm.nih.gov/pubmed/18688056 121. Hartsell WF, Scott CB, Bruner DW, Scarantino CW, Ivker RA, Roach M 3rd, Suh JH, Demas WF, Movsas B, Petersen IA, Konski AA, Cleeland CS, Janjan NA, DeSilvio M. Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. Natl Cancer Inst 2005;97(11):798-804. http://www.ncbi.nlm.nih.gov/pubmed/15928300 122. Heidenreich A, Sommer F, Ohlmann CH, Schrader AJ, Olbert P, Goecke J, Engelmann UH. Prospective randomized phase II trial of pegylated doxorubicin in the management of symptomatic hormone refractory prostate carcinoma. Cancer 2004;101(5):948-56. http://www.ncbi.nlm.nih.gov/pubmed/15329902 123. Morris MJ, Pandit-Taskar N, Stephenson RD, Hong C, Slovin SF, Solit D, Rathkopf DE, Carrasquillo JA, Larson SM, Scher HI. Phase I study of docetaxel (Tax) and 153Sm repetitively administered for castrate metastatic prostate cancer (CMPC). ). Abstract. J Clin Oncol 2008;26(15S): #5001. http://meeting.ascopubs.org/cgi/content/abstract/26/15_suppl/5001 124. Laplanche A, Beuzeboc P, Lumbroso J, Massard C, Plantade A, Escudier B, Di Palma M, Bouzy J, Haddad V, Fizazi K. A phase II trial of docetaxel and samarium in patients with bone metastases from castration-refractory prostate cancer (CRPC). Abstract. J Clin Oncol 2007;25(18S): #5122. http://meeting.ascopubs.org/cgi/content/abstract/25/18_suppl/5122 125. Nilsson S, Franzén L, Tyrrell C, Blom R , Tennvall JT, Lennernäs B, Johannessen DC, Sokal M, Parker C, Bruland ØS. Radium-223 in the treatment of metastatic hormone refractory prostate cancer (HRPC): Results from a randomized, placebo-controlled, phase II study. Abstract. J Clin Oncol 2007;25(18S): #5071. http://meeting.ascopubs.org/cgi/content/abstract/25/18_suppl/5071 126. Dutka J, Sosin P. Time of survival and quality of life of the patients operatively treated due to pathological fractures due to bone metastases. Ortop Traumatol Rehabil 2003;5(3):276-83. http://www.ncbi.nlm.nih.gov/pubmed/18034018 127. Frankel BM, Jones T, Wang C. Segmental polymethylmethacrylate-augmented pedicle screw fixation in patients with bone softening caused by osteoporosis and metastatic tumor involvement: a clinical evaluation. Neurosurgery 2007;61(3):531-7; discussion 537-8. http://www.ncbi.nlm.nih.gov/pubmed/17881965 128. Marco RA, Sheth DS, Boland PJ, Wunder JS, Siegel JA, Healey JH. Functional and oncological outcome of acetabular reconstruction for the treatment of metastatic disease. J Bone Joint Surg Am 2000;82(5):642-51. http://www.ncbi.nlm.nih.gov/pubmed/10819275 129. George R, Jeba J, Ramkumar G, Chacko AG, Leng M, Tharyan P. Interventions for the treatment of metastatic extradural spinal cord compression in adults. Cochrane Database Syst Rev 2008:8;(4):CD006716. http://www.ncbi.nlm.nih.gov/pubmed/18843728 130. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goad JA, Chen B. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94(19):1458-68. http://www.ncbi.nlm.nih.gov/pubmed/12359855 131. Aapro M, Abrahamsson PA, Body JJ, Coleman RE, Colomer R, Costa L, Crinò L, Dirix L, Gnant M, Gralow J, Hadji P, Hortobagyi GN, Jonat W, Lipton A, Monnier A, Paterson AH, Rizzoli R, Saad F, Thürlimann B. Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol 2008;19(3):420-32. http://www.ncbi.nlm.nih.gov/pubmed/17906299 132. Diel IJ, Fogelman I, Al-Nawas B, Hoffmeister B, Migliorati C, Gligorov J, Väänänen K, Pylkkänen L, Pecherstorfer M, Aapro MS. Pathophysiology, risk factors and management of bisphosphonateassociated osteonecrosis of the jaw: Is there a diverse relationship of amino- and nonaminobisphosphonates? Crit Rev Oncol Hematol 2007;64(3):198-207. http://www.ncbi.nlm.nih.gov/pubmed/17855108

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133. Heidenreich A, Elert A, Hofmann R. Ibandronate in the treatment of prostate cancer associated painful osseous metastases. Prostate Cancer Prostatic Dis 2002;5(3):231-5. http://www.ncbi.nlm.nih.gov/pubmed/12496987 134. Esper PS, Pienta KJ. Supportive care in the patient with hormone refractory prostate cancer. Semin Urol Oncol 1997;15(1):56-64. http://www.ncbi.nlm.nih.gov/pubmed/9050140

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18. ABBREVIATIONS USED IN THE TEXT This list is not comprehensive for the most common abbreviations 3D-US ADT AS ASCO ASTRO AUA BMD bNED CAB CaP CPA CRT CSAP CSS CT DES DRE DHT DSS EBRT ECE ECOG eLND ELND e-MRI EORTC EPC EPCP ER-β ESRPC FACT-P FNAB FSH GI GR GU HD EBRT HDR HIFU HR HRPC HRQoL IAD IGRT IMRT IPSS LDAT LDR LE LET LH LHRH LHRHa LND MRC MRI MRSI

three-dimensional ultrasound androgen-deprivation therapy active surveillance American Society of Clinical Oncology American Society for Therapeutic Radiology and Oncology American Urological Association bone mineral density actuarial biochemical freedom from disease complete (or maximal or total) androgen blockade cancer of the prostate cyproterone acetate conformal radiotherapy cryosurgical ablation of the prostate cancer-specific survival computed tomography diethylstilboestrol digital rectal anticipation dihydrostestosterone disease-specific survival electron beam radiation therapy extracapsular extension Eastern Cooperative Oncology Group extended lymph node dissection elective lymph node dissection endorectal MRI European Organisation for Research and Treatment of Cancer Early Prostate Cancer Trialists’ Group Early Prostate Cancer Programme oestrogen receptor-β European Randomized Screening for Prostate Cancer Functional Assessment of Cancer Therapy-prostate fine-needle aspiration biopsy follicle-stimulating hormone gastrointestinal grade of recommendation genitourinary high-dose EBRT high-dose rate high-intensity focused ultrasound hazard ratio hormone-refractory prostate cancer health-related quality of life intermittent androgen deprivation image-guided radiotherapy intensity modulated radiotherapy International Prostatic Symptom Score long-term ADT low-dose rate (LDR) level of evidence linear energy transfer luteinising hormone luteinising hormone-releasing hormone luteinising hormone-releasing hormone analogue lymph node dissection Medical Research Council magnetic resonance imaging magnetic resonance spectroscopy imaging

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NHT neoadjvant hormonal therapy NIH National Institutes of Health NVB neurovascular bundle OR odds ratio OS  overall survival PAP prostate acid phosphatase PCa prostate cancer PET positron emission tomography PFS progression-free survival PIN prostatic intraepithelial neoplasia PIVOT Prostate Cancer Intervention Versus Observation Trial: VA/NCI/AHRQ Cooperative Studies Program #407 PLCO Prostate, Lung, Colorectal and Ovary PSA prostate-specific antigen PSA-ACT PSA complexed to antichymotrypsin PSADT PSA doubling time PSAV PSA velocity PSMA prostate-specific membrane antigen for messenger RNA QoL quality of life QUALYs quality of life adjusted gain in life RITA radio-frequency interstitial tumour ablation RP     radical prostatectomy RTOG Radiation Therapy Oncology Group SEER Surveillance, Epidemiology, and End Results SLN sentinel lymph node SPCG-4 Scandinavian Prostate Cancer Group Study Number 4 STAD short-term androgen deprivation SVI seminal vesicle invasion SWOG South West Oncology Group TNM Tumour Node Metastasis TZ transition zone TRUS transrectal ultrasound TURP transurethral resection of the prostate UICC Union Against Cancer USPIO ultra-small super-paramagnetic iron oxide particles VACURG Veterans Administration Co-operative Urological Research Group WHO World Health Organization WW watchful waiting

Aknowledgement The Prostate Cancer guidelines panel gratefully acknowledge the assistance of the following experts in the review process: Prof.Dr. L. Egevad, Prof.Dr. R. Montironi and Prof.Dr. H. Van Poppel. Conflict of interest All members of the Prostate Cancer Guidelines writing panel have provided disclosure statements on all relationships that they have and that might be perceived to be a potential source of conflict of interest. This information is kept on file in the European Association of Urology Central Office database. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

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Guidelines on

Renal Cell Carcinoma B. Ljungberg, D.C. Hanbury, M.A. Kuczyk, A.S. Merseburger, P.F.A. Mulders, J-J. Patard, I.C. Sinescu

© European Association of Urology 2009

TABLE OF CONTENTS

page

1

INTRODUCTION 1.1 Reference

4 4

2.

EPIDEMIOLOGY AND AETIOLOGY 2.1 Conclusion 2.2 References

4 5 5

3. DIAGNOSIS AND STAGING 3.1 Symptoms 3.1.1 Physical examination 3.1.2 Laboratory findings 3.2 Radiological investigations 3.3 Conclusion 3.4 References

6 6 6 6 6 6 7

4. CLASSIFICATION AND PROGNOSTIC FACTORS 4.1 Classification 4.2 Prognostic factors 4.2.1 Anatomical factors 4.2.2 Histological factors 4.2.3 Clinical factors 4.2.4 Molecular factors 4.2.5 Prognostic systems and nomograms 4.3 Conclusion 4.4 References

8 8 9 9 9 10 10 10 10 10

5. TREATMENT OF LOCALISED DISEASE 5.1 Surgery 5.1.1 Embolisation 5.1.1.1 Conclusion 5.1.2 Nephron-sparing surgery 5.1.2.1 Conclusion 5.1.3 Laparoscopic nephrectomy 5.1.3.1 Conclusion 5.1.4 Partial laparoscopic nephrectomy 5.1.4.1 Conclusion 5.2 Alternative treatments to surgery 5.2.1 Conclusion 5.3 Adjuvant therapy 5.3.1 Conclusion 5.4 Surgical treatment of metastatic RCC (tumour nephrectomy) 5.4.1 Conclusion 5.5 Resection of metastases 5.5.1 Conclusion 5.6 Radiotherapy for metastases in RCC 5.6.1 Conclusion 5.7 References

13 13 13 13 14 14 14 14 15 15 15 15 15 16 16 16 16 16 16 16 17

6. SYSTEMIC THERAPY FOR METASTATIC RCC 6.1 Chemotherapy 6.1.1 Conclusion 6.2 Immunotherapy 6.2.1 Interferon-alpha monotherapy and combined with bevacizumab 6.2.1.1 Conclusion 6.2.2 Interleukin-2 6.2.2.1 Conclusion 6.3 Angiogenesis inhibitor drugs 6.3.1 Sorafenib 6.3.2 Sunitinib

20 20 20 21 21 21 21 21 21 21 21

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6.3.3 Bevacizumab monotherapy and combined with interferon-alpha 6.3.4 Mammalian target of rapamycin (mTOR) inhibitors 6.3.4.1 Temsirolimus 6.3.4.2 Everolimus 6.3.5 Conclusion 6.4 References

22 22 22 22 22 23

7.

SURVEILLANCE FOLLOWING RADICAL SURGERY FOR RCC 7.1 Introduction 7.2 Which investigations for which patient, and when? 7.3 Imaging modalities 7.4 Conclusion 7.5 References

24 24 25 25 26 26

8.

Summary of major amendments of the 2009 RCC guidelines update

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9. ABBREVIATIONS USED IN THE TEXT

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3

1. INTRODUCTION The EAU Guideline Group for renal cell carcinoma (RCC) have prepared these guidelines to help urologists assess the evidence-based management of RCC and to help them incorporate the guidelines recommendations into their clinical practice. Publications concerning RCC are mostly retrospective analyses, which include some larger multicentre studies and well-designed controlled studies. As only a few randomised controlled trials are available, there is a lack of data with a strong evidence base. The recommendations provided in the current guideline are based on a systemic literature search using Medline, the Cochrane Central Register of Controlled Trials, and reference lists in publications and review articles. Where possible a level of evidence (LE) and/or grade of recommendation (GR) have been assigned (1). Recommendations are graded in order to provide transparency between the underlying evidence and the recommendation given (Tables 1 and 2). There is clearly a need for continuous re-evaluation at regular intervals by the RCC Guideline Group of the information provided in these guidelines. It has to be emphasised that the current guidelines contain information for the treatment of an individual patient according to a standardised general approach. The information should be considered as providing recommendations without legal implications. A summary of major amendments of the 2009 RCC guidelines update can be found on page 27 of this document. Publication history information: The Renal Cell Cancer Guidelines were first published in 2000. A partial update was achieved in 2001, followed by a full text update in 2007. The current 2009 version presents a partial update. Additionally, a quick reference guide is available. All texts can be viewed and downloaded for personal use at the society website: http://www.uroweb.org/professional-resources/guidelines/.

Table 1: Level of evidence Level Type of evidence 1a Evidence obtained from meta-analysis of randomised trials 1b Evidence obtained from at least one randomised trial 2a Evidence obtained from one well-designed controlled study without randomisation 2b Evidence obtained from at least one other type of well-designed quasi-experimental study 3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case reports 4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities Modified from Sackett et al. (1). Table 2: Grade of recommendation Grade Nature of recommendations A Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomised trial B Based on well-conducted clinical studies, but without randomised clinical trials C Made despite the absence of directly applicable clinical studies of good quality Modified from Sackett et al. (1).

1.2

REFERENCE

1.

Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998.  http://www.cebm.net/index.aspx?o=1025 [accessed February 2009].

2. EPIDEMIOLOGY AND AETIOLOGY Renal cell carcinoma represents 2-3% of all cancers (1), with the highest incidence occurring in Western countries. There is a worldwide and European annual increase in incidence of approximately 2%, though in Denmark and Sweden a continuing decrease has been observed during the last 20 years (2). In 1998, about

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30,000 patients were diagnosed with kidney cancer within the EU and approximately 15,000 died of the disease (3). Renal cell carcinoma is the most common solid lesion within the kidney. It comprises different RCC types with specific histopathological and genetic characteristics (4). There is a 1.5:1 predominance of men over women, with peak incidence occurring between 60 and 70 years of age. Aetiological factors include lifestyle factors, such as smoking, obesity and antihypertensive therapy (2, 5, 6). The most effective prophylaxis is to avoid cigarette smoking. Due to the increased detection of tumours by imaging techniques, such as ultrasound (US) and computerised tomography (CT), the number of incidentally diagnosed RCCs has increased. These tumours are more often smaller and of lower stage (7-9). However, despite the increased incidental detection rate, after the early 1990s mortality from RCC has stabilized showing a tendency towards decline (10).

2.1

Conclusion

A number of aetiological factors have been identified including smoking, obesity and antihypertensive drugs. Cigarette smoking is a definite risk factor for RCC (level of evidence: 2a). The roles of obesity and prolonged intake of antihypertensive medication as risk factors for RCC remain to be definitively clarified (level of evidence: 2a). Recommendation GR •T  he most important primary prevention for RCC is to eliminate cigarette smoking and to avoid B obesity GR = grade of recommendation

2.2

REFERENCES

1.

European Network of Cancer Registries. Eurocim version 4.0. European incidence database V2.3, 730 entity dictionary (2001), Lyon, 2001. Lindblad P. Epidemiology of renal cell carcinoma. Scand J Surg 2004;93(2):88-96. http://www.ncbi.nlm.nih.gov/pubmed/15285559 EUCAN. http://www-dep.iarc.fr/eucan/eucan.htm Kovacs G, Akhtar M, Beckwith BJ, Bugert P, Cooper CS, Delahunt B, Eble JN, Fleming S, Ljungberg B, Medeiros LJ, Moch H, Reuter VE, Ritz E, Roos G, Schmidt D, Srigley JR, Storkel S, van den Berg E, Zbar B. The Heidelberg classification of renal cell tumours. J Pathol 1997;183(2):131-3. http://www.ncbi.nlm.nih.gov/pubmed/9390023 Bergstrom A, Hsieh CC, Lindblad P, Lu CM, Cook NR, Wolk A. Obesity and renal cell cancer - a quantitative review. Br J Cancer 2001;85(7):984-90. http://www.ncbi.nlm.nih.gov/pubmed/11592770 Pischon T, Lahmann PH, Boeing H, Tjonneland A, Halkjaer J, Overvad K, Klipstein-Grobusch K, Linseisen J, Becker N, Trichopoulou A, Benetou V, Trichopoulos D, Sieri S, Palli D, Tumino R, Vineis P, Panico S, Monninkhof E, Peeters PH, Bueno-de-Mesquita HB, Buchner FL, Ljungberg B, Hallmans G, Berglund G, Gonzalez CA, Dorronsoro M, Gurrea AB, Navarro C, Martinez C, Quiros JR, Roddam A, Allen N, Bingham S, Khaw KT, Kaaks R, Norat T, Slimani N, Riboli E. Body size and risk of renal cell carcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer 2006;118(3):728-38. http://www.ncbi.nlm.nih.gov/pubmed/16094628 Patard JJ, Rodriguez A, Rioux-Leclercq N, Guille F, Lobel B. Prognostic significance of the mode of detection in renal tumours. BJU Int. 2002;90(4):358-63. http://www.ncbi.nlm.nih.gov/pubmed/12175389 Kato M, Suzuki T, Suzuki Y, Terasawa Y, Sasano H, Arai Y. Natural history of small renal cell carcinoma: evaluation of growth rate, histological grade, cell proliferation and apoptosis. J Urol 2004;172(3):863-6. http://www.ncbi.nlm.nih.gov/pubmed/15310984 Tsui KH, Shvarts O, Smith RB, Figlin R, de Kernion JB, Belldegrun A. Renal cell carcinoma: prognostic significance of incidentally detected tumors. J Urol 2001;163(2):426-30. http://www.ncbi.nlm.nih.gov/pubmed/10647646 Levi F, Ferlay J, Galeone C, Lucchini F, Negri E, Boyle P, La Vecchia C. The changing pattern of kidney cancer incidence and mortality in Europe. BJU Int 2008;101(8):949-58 http://www.ncbi.nlm.nih.gov/pubmed/18241251

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5.

6.

7.

8.

9.

10.

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3. DIAGNOSIS AND STAGING 3.1

Symptoms

Many renal masses remain asymptomatic and non-palpable until late in the natural course of the disease (1) (level of evidence: 4). Today, more than 50% of RCCs are detected incidentally using non-invasive imaging to evaluate a variety of non-specific symptom complexes (1) (level of evidence: 4). The classic triad of flank pain, gross haematuria and palpable abdominal mass is now rare (6-10%) (2, 3) (level of evidence: 3). Paraneoplastic syndromes are found in around 30% of patients with symptomatic RCC, the most common of these being: hypertension, cachexia, weight loss, pyrexia, neuromyopathy, amyloidosis, elevated erythrocyte sedimentation rate, anaemia, abnormal liver function, hypercalcaemia, polycythaemia, etc. (1) (level of evidence: 4). A minority (25-30%) of patients are diagnosed as a result of symptoms due to metastatic disease, such as bone pain or persistent cough (1) (level of evidence: 4). 3.1.1 Physical examination Physical examination has a limited role in diagnosing RCC. However, it is valuable in some cases such as: • palpable abdominal mass • palpable cervical lymphadenopathy • non-reducing varicocele • bilateral lower extremity oedema, which suggests venous involvement. These findings should initiate radiological examinations. 3.1.2 Laboratory findings The most commonly assessed laboratory parameters are serum creatinine, haemoglobin, erythrocyte sedimentation rate, alkaline phosphatase and serum calcium (1, 4) (level of evidence: 4). The glomerular filtration rate (GFR) and separate bilateral renal function should be estimated when (5, 6) (level of evidence: 4): • renal function is of relevant clinical concern, as in patients with a solitary kidney tumour or bilateral tumours • renal function is compromised, as indicated by an increased concentration of serum creatinine, and in patients at risk for future renal impairment from intercurrent disorders such as diabetes, chronic pyelonephritis, renovascular, stone or renal polycystic disease.

3.2

Radiological investigations

Most renal tumours are diagnosed by abdominal ultrasound (US) and CT performed for various reasons (level of evidence: 4). Detection of a solid renal mass with US should be further investigated with a high-quality CT scan using contrast medium. This will confirm a diagnosis of RCC and provides information on the function and morphology of the contralateral kidney (5) (level of evidence: 3). • Abdominal CT assesses primary tumour extension with extrarenal spread and provides information on venous involvement, enlargement of locoregional lymph nodes, and condition of adrenal glands and the liver (level of evidence: 3). • Chest CT is the most accurate investigation for chest staging (6-13) (level of evidence: 3). However, at the very least, routine chest radiography, as a less accurate alternative to chest CT imaging, must be done for metastatic evaluation (level of evidence: 3). Magnetic resonance imaging (MRI) can be reserved primarily for patients with locally advanced malignancy, possible venous involvement, renal insufficiency or allergy to intravenous contrast (14-18) (level of evidence: 3). It is also an option for the evaluation of inferior vena cava tumour thrombus extension and unclassified renal masses (level of evidence: 3). Evaluation of the tumour thrombus can also be performed with Doppler US (19) (level of evidence: 3). In patients with any sign of impaired renal function, a renal scan and total renal function evaluation should be considered in order to optimise the treatment decision, e.g. the need to preserve renal function (6) (level of evidence: 2a). There is consensus that most bone and brain metastases are symptomatic at the time of diagnosis so that a routine bone scan or brain CT are not generally indicated (20, 21). However, if indicated by clinical or laboratory signs and symptoms, other diagnostic procedures may be applied, such as a bone scan, brain CT or MRI (level of evidence: 3). Renal arteriography, inferior venacavography or fine-needle biopsy (22-24) have only a limited role in the work-up of selected patients with RCC (level of evidence: 3).

3.3

Conclusion

In Europe, a large number of patients with RCC are still diagnosed due to clinical symptoms, such as palpable

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mass and haematuria, paraneoplastic and metastatic symptoms (level of evidence: 3). However, the number of incidentally detected RCCs is significantly increasing. Accurate staging of RCC with abdominal and chest CT or MRI is obligatory (level of evidence: 3). Chest CT is the most sensitive approach for chest staging. There is no role for routine bone scan or CT of the brain in the standard clinical work-up of asymptomatic patients. There is only a limited indication for fine-needle biopsy (level of evidence: 3). Recommendations GR • In a patient with one or more laboratory or physical findings, the possible presence of RCC A should be suspected • A plain chest X-ray can be sufficient for assessment of the lung in low-risk patients, but chest CT A is most sensitive • Abdominal CT and MRI are recommended for the work-up of patients with RCC and are the most A appropriate imaging modalities for TNM classification prior to surgery • In high-risk patients for bone metastases (raised alkaline phosphatase or bone pain), further A evaluation using an imaging approach should be done • Evaluation of renal function is recommended A GR = grade of recommendation

3.4

REFERENCES

1.

Novick AC, Campbell SC. Renal tumours. In: Walsh PC, Retik, AB, Vaughan ED, Wein AJ, eds. Campbell’s Urology. Philadelphia: WB Saunders, 2002, pp. 2672-2731. Lee CT, Katz J, Fearn PA, Russo P. Mode of presentation of renal cell carcinoma provides prognostic information. Urol Oncol 2002;7(4):135-40. http://www.ncbi.nlm.nih.gov/pubmed/12474528 Patard JJ, Leray E, Rodriguez A, Rioux-Leclercq N, Guille F, Lobel B. Correlation between symptom graduation, tumor characteristics and survival in renal cell carcinoma. Eur Urol 2003;44(2):226-32. http://www.ncbi.nlm.nih.gov/pubmed/12875943 Sufrin G, Chasan S, Golio A, Murphy GP. Paraneoplastic and serologic syndromes of renal adenocarcinoma. Semin Urol 1989;7(3):158-71. http://www.ncbi.nlm.nih.gov/pubmed/2690260 Song C, Bang JK, Park HK, Ahn H. Factors influencing renal function reduction after partial nephrectomy. J Urol 2009;181(1):48-53; discussion 53-4. http://www.ncbi.nlm.nih.gov/pubmed/19012914 Uzzo RG, Novick AC. Nephron sparing surgery for renal tumors: indications, techniques and outcomes. J Urol 2001;66(1):6-18. http://www.ncbi.nlm.nih.gov/pubmed/11435813 Bechtold RE, Zagoria RJ. Imaging approach to staging of renal cell carcinoma. Urol Clin North Am 1997;24(3):507-22. http://www.ncbi.nlm.nih.gov/pubmed/9275976 Heidenreich A, Ravery V; European Society of Oncological Urology. Preoperative imaging in renal cell cancer. World J Urol 2004;22(5):307-15. http://www.ncbi.nlm.nih.gov/pubmed/15290202 Sheth S, Scatarige JC, Horton KM, Corl FM, Fishman EK. Current concepts in the diagnosis and management of renal cell carcinoma: role of multidetector CT and three-dimensional CT. Radiographics 2001;21 Spec No:S237-54. http://www.ncbi.nlm.nih.gov/pubmed/11598260 Miles KA, London NJ, Lavelle JM, Messios N, Smart JG. CT staging of renal carcinoma: a prospective comparison of three dynamic computed tomography techniques. Eur J Radiol 1991;13(1):37-42. http://www.ncbi.nlm.nih.gov/pubmed/1889427 Lim DJ, Carter MF. Computerized tomography in the preoperative staging for pulmonary metastases in patients with renal cell carcinoma. J Urol 1993;150(4):1112-4. http://www.ncbi.nlm.nih.gov/pubmed/8371366 Doda SS, Mathur RK, Buxi TS. Role of computed tomography in staging of renal cell carcinoma. Comput Radiol 1986;10(4):183-8. http://www.ncbi.nlm.nih.gov/pubmed/3791984 Fritzsche PJ, Millar C. Multimodality approach to staging renal cell carcinoma. Urol Radiol 1992;14(1):3-7. http://www.ncbi.nlm.nih.gov/pubmed/1615571

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McClennan BL, Deyoe LA. The imaging evaluation of renal cell carcinoma: diagnosis and staging. Radiol Clin North Am 1994;32(1):55-69. http://www.ncbi.nlm.nih.gov/pubmed/8284361 15. Tammela TL, Leinonen AS, Kontturi MJ. Comparison of excretory urography, angiography, ultrasound and computed tomography for T category staging of renal cell carcinoma. Scand J Urol Nephrol 1991;25(4):283-6. http://www.ncbi.nlm.nih.gov/pubmed/1780704 16. Hricak H, Demas BE, Williams RD, McNamara MT, Hedgcock MW, Amparo EG, Tanagho EA. Magnetic resonance imaging in the diagnosis and staging of renal and perirenal neoplasms. Radiology 1985;154(3):709-15. http://www.ncbi.nlm.nih.gov/pubmed/3969475 17. Janus CL, Mendelson DS. Comparison of MRI and CT for study of renal and perirenal masses. Crit Rev Diagn Imaging 1991;32(2):69-118. http://www.ncbi.nlm.nih.gov/pubmed/1863349 18. Krestin GP, Gross-Fengels W, Marincek B. [The importance of magnetic resonance tomography in the diagnosis and staging of renal cell carcinoma.] Radiologe 1992;32(3):121-6. [article in German] http://www.ncbi.nlm.nih.gov/pubmed/1565792 19. Nishimura K, Hida S, Okada K, Yoshida O, Nishimuara K. Staging and differential diagnosis of renal cell carcinoma: a comparison of magnetic resonance imaging (MRI) and computed tomography (CT). Hinyokika Kiyo 1988;34(8):1323-31. http://www.ncbi.nlm.nih.gov/pubmed/3195400 20. Kabala JE, Gillatt DA, Persad RA, Penry JB, Gingell JC, Chadwick D. Magnetic resonance imaging in the staging of renal cell carcinoma. Br J Radiol 1991;64(764):683-9. http://www.ncbi.nlm.nih.gov/pubmed/1884119 21. Gupta NP, Ansari MS, Khaitan A, Sivaramakrishna MS, Hemal AK, Dogra PN, Seth A. Impact of imaging and thrombus level in management of renal cell carcinoma extending to veins. Urol Int 2004;72(2):129-34. http://www.ncbi.nlm.nih.gov/pubmed/14963353 22. Hendriksson C, Haraldsson G, Aldenborg F, Lindberg S, Pettersson S. Skeletal metastases in 102 patients evaluated before surgery for renal cell carcinoma. Scand J Urol Nephrol 1992;26(4):363-6. http://www.ncbi.nlm.nih.gov/pubmed/1292074 23. Marshall ME, Pearson T, Simpson W, Butler K, McRoberts W. Low incidence of asymptomatic brain metastases in patients with renal cell carcinoma. Urology 1990;36(4):300-2. http://www.ncbi.nlm.nih.gov/pubmed/2219605 24. Seaman E, Goluboff ET, Ross S, Sawczuk IS. Association of radionuclide bone scan and serum alkaline phosphatase in patients with metastatic renal cell carcinoma. Urol 1996;48(5):692-5. http://www.ncbi.nlm.nih.gov/pubmed/8911510 25. Brierly RD, Thomas PJ, Harrison NW, Fletcher MS, Nawrocki JD, Ashton-Key M. Evaluation of fine needle aspiration cytology for renal masses. BJU Int 2000;85(1):14-8. http://www.ncbi.nlm.nih.gov/pubmed/10619937 26. Dechet CB, Zincke H, Sebo TJ, King BF, LeRoy AJ, Farrow GM, Blute ML. Prospective analysis of computerized tomography and needle biopsy with permanent sectioning to determine the nature of solid renal masses in adults. J Urol 2003;169(1):71-4. http://www.ncbi.nlm.nih.gov/pubmed/12478106

4. CLASSIFICATION AND PROGNOSTIC FACTORS 4.1

Classification

The 2002 TNM stage classification system is generally recommended for clinical and scientific use (1). It is unclear whether the current TNM classification is optimal for the prediction of survival in patients with RCC and it may require re-classification. The pT1 substratification, introduced in 2002 (1), has been validated by several studies (2-4) (level of evidence: 3). However, refinements are needed for pT3 tumours. Firstly, it has not been established whether renal sinus fat invasion only carries the same prognosis as does perinephric fat invasion (5, 6). Secondly, many studies have suggested that adrenal invasion is a very poor prognostic factor and that RCCs with this feature should be classified as T4 tumours (7, 8). Furthermore, it is still not clear whether the stratification of RCCs with venous invasion in T3b and T3c

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is accurate. More research is needed to investigate the independent prognostic value of vena caval invasion compared to renal vein invasion (9). More recently, the accuracy of the N1-N2 subclassification has been questioned (10). For adequate M-staging of patients with RCC, accurate pre-operative imaging (currently, chest and abdominal CT) should be performed (11, 12).

4.2 Prognostic factors Factors influencing prognosis can be classified into: anatomical, histological, clinical and molecular (13). 4.2.1 Anatomical factors Anatomical factors include tumour size, venous invasion, renal capsule invasion, adrenal involvement, and lymph node and distant metastasis. These factors are commonly gathered together in the universally used 2002 TNM staging classification system (Table 3). Table 3: The 2002 TNM staging classification system T - Primary tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour T1 Tumour < 7 cm in greatest dimension, limited to the kidney T1a Tumour < 4 cm in greatest dimension, limited to the kidney T1b Tumour > 4 cm but < 7 cm in greatest dimension T2 Tumour > 7 cm in greatest dimension, limited to the kidney T3 Tumour extends into major veins or directly invades adrenal gland or perinephric tissues but not beyond Gerota’s fascia T3a Tumour directly invades adrenal gland or perinephric tissues1 but not beyond Gerota’s fascia T3b Tumour grossly extends into renal vein(s)2 or its segmental branches, or the vena cava below the diaphragm T3c Tumour grossly extends into vena cava or its wall above diaphragm T4 Tumour directly invades beyond Gerota’s fascia N- Regional lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single regional lymph node N2 Metastasis in more than 1 regional lymph node pN0 lymphadenectomy specimen ordinarily includes 8 or more lymph nodes. If the lymph nodes are negative, but the number ordinarily examined is not met, classify as pN0. M-

Distant metastasis MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis

TNM stage grouping Stage I T1 N0 M0 Stage II T2 N0 M0 Stage III T3 N0 M0 T1, T2, T3 N1 M0 Stage IV T4 N0, N1 M0 Any T N2 M0 Any T Any N M1 1 Includes renal sinus (prepelvic fat). 2 Includes segmental (muscle-containing branches). A help desk for specific questions about TNM classification is available at http://www.uicc.org/tnm. 4.2.2 Histological factors Histological factors include Fuhrman grade, histological subtype, sarcomatoid features, microvascular invasion, tumour necrosis and collecting system invasion. Fuhrman nuclear grade is the most widely accepted histological grading system in RCC (14). Although affected by intra- and inter-observer discrepancies, it is an

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9

independent prognostic factor (15) (level of evidence: 3). According to the World Health Organization (WHO) classification (16), three major histological subtypes of RCC exist (level of evidence: 4): • conventional (clear cell) (80-90%) • papillary (10-15%) • chromophobe (4-5%). Many studies have shown a trend towards a better prognosis for patients with chromophobe, papillary and conventional (clear cell) RCCs, respectively (17, 18). However, the prognostic information provided by the RCC subtype is lost when stratified to tumour stage (18). Among papillary RCCs, two subgroups with different outcomes have been identified (19): • Type I are low-grade tumours with a chromophilic cytoplasm and a favourable prognosis. • Type II are mostly high-grade tumours with an eosinophilic cytoplasm and a great propensity for developing metastases (level of evidence: 3). The RCC type subclassification has been confirmed at the molecular level by cytogenetic and genetic analyses (20-22). 4.2.3 Clinical factors Clinical factors include patient performance status, localised symptoms, cachexia, anaemia and platelet count (23-27) (level of evidence: 3). 4.2.4 Molecular factors Numerous molecular markers being investigated include: carbonic anhydrase IX (CaIX), vascular endothelial growth factor (VEGF), hypoxia inducible factor (HIF), Ki67 (proliferation), p53, PTEN (phosphatase and tensin homolog) (cell cycle), E-cadherin, and CD44 (cell adhesion) (21, 22) (level of evidence: 3). As yet, these markers are not in widespread use. Recently, gene expression profiling has identified 259 genes, which predict survival independent of clinical prognostic factors in conventional RCCs, indicating that genetic information will improve prognostication (28). 4.2.5 Prognostic systems and nomograms Post-operative prognostic systems and nomograms that combine independent prognostic factors have been developed and externally validated (29-35). These systems may be more accurate than TNM stage or Fuhrman grade alone for predicting survival (level of evidence: 3). A substantial advantage of nomograms is their ability to measure predictive accuracy (PA), which enables objective evaluation of all new predictive parameters. Recently, new pre-operative nomograms with excellent PA have been designed (36, 37).

4.3

Conclusion

In patients with RCC, TNM stage, nuclear grade according to Fuhrman and RCC subtype (WHO, 2004; 16), should be performed because they contribute important prognostic information (level of evidence: 2). There are currently no prognostic integrated systems or molecular markers recommended for routine clinical use. Prognostic systems or nomograms can be useful for the stratified inclusion of patients into clinical trials (level of evidence: 2). Recommendations GR •T  he current TNM classification system is recommended since it has consequences for prognosis B and therapy •T  he Fuhrman grading system and classification of RCC subtype should be used B •T  he use of integrated prognostic systems or nomograms is not routinely recommended, although B these systems can provide a rationale for enrolling patients into clinical trials •N  o molecular prognostic marker is currently recommended for routine clinical use B GR = grade of recommendation

4.4

REFERENCES

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Sobin LH, Wittekind CH, eds. International Union Against Cancer (UICC). TNM classification of malignant tumours. 6th edn. New York: Wiley-Liss, 2002, pp. 193-195. Frank I, Blute ML, Leibovich BC, Cheville JC, Lohse CM, Zincke H. Independent validation of the 2002 American Joint Committee on cancer primary tumor classification for renal cell carcinoma using a large, single institution cohort. J Urol 2005;173(6):1889-92. http://www.ncbi.nlm.nih.gov/pubmed/15879769

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Salama ME, Guru K, Stricker H, Peterson E, Peabody J, Menon M, Amin MB, De Peralta-Venturina M. pT1 substaging in renal cell carcinoma: validation of the 2002 TNM staging modification of malignant renal epithelial tumors. J Urol 2005;173(5):1492-5. http://www.ncbi.nlm.nih.gov/pubmed/15821466 Ficarra V, Schips L, Guille F, Li G, De La Taille A, Prayer Galetti T, Cindolo N, Novara G, Zigeuner RE, Bratti E, Tostain J, Altieri V, Abbou CC, Artibani W, Patard JJ. Multiinstitutional European validation of the 2002 TNM staging system in conventional and papillary localized renal cell carcinoma. Cancer 2005;104(5):968-74. http://www.ncbi.nlm.nih.gov/pubmed/16007683 Bonsib SM. The renal sinus is the principal invasive pathway: a prospective study of 100 renal cell carcinomas. Am J Surg Pathol 2004;28(12):1594-600. http://www.ncbi.nlm.nih.gov/pubmed/15577678 Thompson RH, Leibovich BC, Cheville JC, Webster WS, Lohse CM, Kwon ED, Frank I, Zincke H, Blute ML. Is renal sinus fat invasion the same as perinephric fat invasion for pT3a renal cell carcinoma? J Urol 2005;174(4 Pt 1):1218-21. http://www.ncbi.nlm.nih.gov/pubmed/16145373 Han KR, Bui MH, Pantuck AJ, Freitas DG, Leibovich BC, Dorey FJ, Zisman A, Janzen NK, Mukouyama H, Figlin RA, Belldegrun AS. TNM T3a renal cell carcinoma: adrenal gland involvement is not the same as renal fat invasion. J Urol 2003;169(3):899-903; discussion 903-4. http://www.ncbi.nlm.nih.gov/pubmed/12576809 Thompson RH, Leibovich BC, Cheville JC, Lohse CM, Frank I, Kwon ED, Zincke H, Blute ML. Should direct ipsilateral adrenal invasion from renal cell carcinoma be classified as pT3a? J Urol 2005;173(3):918-21. http://www.ncbi.nlm.nih.gov/pubmed/15711327 Thompson RH, Cheville JC, Lohse CM, Webster WS, Zincke H, Kwon ED, Frank I, Blute ML, Leibovich BC. Reclassification of patients with pT3 and pT4 renal cell carcinoma improves prognostic accuracy. Cancer 2005;104(1):53-60. http://www.ncbi.nlm.nih.gov/pubmed/15895375 Terrone C, Cracco F, Porpiglia F, Bollito E, Scoffone C, Poggio M, Berutti A, Ragni F, Cossu M, Scarpa RM, Rosetti SR. Reassessing the current TNM lymph node staging for renal cell carcinoma. Eur Urol 2006;49(2):324-31. http://www.ncbi.nlm.nih.gov/pubmed/16386352 Heidenreich A, Ravery V; European Society of Oncological Urology. Preoperative imaging in renal cell cancer. World J Urol 2004;22(5):307-15. http://www.ncbi.nlm.nih.gov/pubmed/15290202 Sheth S, Scatarige JC, Horton KM, Corl FM, Fishman EK. Current concepts in the diagnosis and management of renal cell carcinoma: role of multidetector CT and three-dimensional CT. Radiographics 2001;21 Spec No:S237-S254. http://www.ncbi.nlm.nih.gov/pubmed/11598260 Lam JS, Shvarts O, Leppert JT, Figlin RA, Belldegrun AS. Renal cell carcinoma 2005: new frontiers in staging, prognostication and targeted molecular therapy. J Urol 2005;173(6):1853-62. http://www.ncbi.nlm.nih.gov/pubmed/15879764 Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982;6(7):655-63. http://www.ncbi.nlm.nih.gov/pubmed/7180965 Lang H, Lindner V, de Fromont M, Molinie V, Letourneux H, Meyer N, Martin M, Jacqmin D. Multicenter determination of optimal interobserver agreement using the Fuhrman grading system for renal cell carcinoma: assessment of 241 patients with > 15-year follow-up. Cancer 2005;103(3):625-9. http://www.ncbi.nlm.nih.gov/pubmed/15611969 Eble JN, Sauter G, Epstein JI, Sesterhenn IA (eds). In: Pathology and genetics of tumours of the urinary system and male genital organs. World Health Organization Classification of Tumours. Lyons: IARC Press, 2004, p. 7. Cheville JC, Lohse CM, Zincke H, Weaver AL, Blute ML. Comparisons of outcome and prognostic features among histological subtypes of renal cell carcinoma. Am J Surg Pathol 2003;27(5):612-24. http://www.ncbi.nlm.nih.gov/pubmed/12717246 Patard JJ, Leray E, Rioux-Leclercq N, Cindolo L, Ficarra V, Zisman A, De LaTaille A, Tostain J, Artibani W, Abbou CC, Lobel B, Guille F, Chopin DK, Mulders PF, Wood CG, Swanson DA, Figlin RA, Belldegrun AS, Pantuck AJ. Prognostic value of histological subtypes in renal cell carcinoma: a multicenter experience. J Clin Oncol 2005;23(12):2763-71. http://www.ncbi.nlm.nih.gov/pubmed/15837991

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Delahunt B, Eble JN, McCredie MR, Bethwaite PB, Stewart JH, Bilous AM. Morphologic typing of papillary renal cell carcinoma: comparison of growth kinetics and patient survival in 66 cases. Hum Pathol 2001;32(6):590-5. http://www.ncbi.nlm.nih.gov/pubmed/11431713 Linehan WM, Vasselli J, Srinivasan R, Walther MM, Merino M, Choyke P, Vocke C, Schmidt L, Isaacs JS, Glenn G, Toro J, Zbar B, Bottaro D, Neckers L. Genetic basis of cancer of the kidney: diseasespecific approaches to therapy. Clin Cancer Res 2004;10(18 Pt 2):6282S-9S. http://www.ncbi.nlm.nih.gov/pubmed/15448018 Furge KA, Lucas KA, Takahashi M, Sugimura J, Kort EJ, Kanayama HO, Kagawa S, Hoekstra P, Curry J, Yang XJ, Teh BT. Robust classification of renal cell carcinoma based on gene expression data and predicted cytogenetic profiles. Cancer Res 2004;64(12):4117-21. http://www.ncbi.nlm.nih.gov/pubmed/15205321 Yang XJ, Tan MH, Kim HL, Ditlev JA, Betten MW, Png CE, Kort EJ, Futami K, Furge KA, Takahashi M, Kanayama HO, Tan PH, Teh BS, Luan C, Wang K, Pins M, Tretiakova M, Anema J, Kahnoski R, Nicol T, Stadler W, Vogelzang NG, Amato R, Seligson D, Figlin R, Belldegrun A, Rogers CG, Teh BT. A molecular classification of papillary renal cell carcinoma. Cancer Res 2005;65(13):5628-37. http://www.ncbi.nlm.nih.gov/pubmed/15994935 Kim HL, Belldegrun AS, Freitas DG, Bui MH, Han KR, Dorey FJ, Figlin RA. Paraneoplastic signs and symptoms of renal cell carcinoma: implications for prognosis. J Urol 2003;170(5):1742-6. http://www.ncbi.nlm.nih.gov/pubmed/14532767 Kim HL, Han KR, Zisman A, Figlin RA, Belldegrun AS. Cachexia-like symptoms predict a worse prognosis in localized T1 renal cell carcinoma. J Urol 2004;171(5):1810-3. http://www.ncbi.nlm.nih.gov/pubmed/15076282 Patard JJ, Leray E, Cindolo L, Ficarra V, Rodriguez A, De La Taille A, Tostain J, Artibani W, Abbou CC, Guille F, Chopin DK, Lobel B. Multi-institutional validation of a symptom based classification for renal cell carcinoma. J Urol 2004;172(3):858-62. http://www.ncbi.nlm.nih.gov/pubmed/15310983 Bensalah K, Leray E, Fergelot P, Rioux-Leclercq N, Tostain J, Guille F, Patard JJ. Prognostic value of thrombocytosis in renal cell carcinoma. J Urol 2006;175(3 Pt 1):859-63. http://www.ncbi.nlm.nih.gov/pubmed/16469566 Patard JJ, Leray E, Rodriguez A, Rioux-Leclercq N, Guille F, Lobel B. Correlation between symptom graduation, tumor characteristics and survival in renal cell carcinoma. Eur Urol 2003;44(2):226-32. http://www.ncbi.nlm.nih.gov/pubmed/12875943 Zhao H, Ljungberg B, Grankvist K, Rasmuson T, Tibshirani R, Brooks JD. Gene expression profiling predicts survival in conventional renal cell carcinoma. PLoS Med 2006;3(1):e13. http://www.ncbi.nlm.nih.gov/pubmed/16318415 Kattan MW, Reuter V, Motzer RJ, Katz J, Russo P. A postoperative prognostic nomogram for renal cell carcinoma. J Urol 2001;166(1):63-7. http://www.ncbi.nlm.nih.gov/pubmed/11435824 Zisman A, Pantuck AJ, Dorey F, Said JW, Shvarts O, Quintana D, Gitlitz BJ, deKernion JB, Figlin RA, Belldegrun AS. Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol 2001;19(6):1649-57. http://www.ncbi.nlm.nih.gov/pubmed/11250993 Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H. An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade and necrosis: the SSIGN score. J Urol 2002;168(6):2395-400. http://www.ncbi.nlm.nih.gov/pubmed/12441925 Leibovich BC, Blute ML, Cheville JC, Lohse CM, Frank I, Kwon ED, Weaver AL, Parker AS, Zincke H. Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer 2003;97(7):1663-71. http://www.ncbi.nlm.nih.gov/pubmed/12655523 Patard JJ, Kim HL, Lam JS, Dorey FJ, Pantuck AJ, Zisman A, Ficarra V, Han KR, Cindolo L, De La Taille A, Tostain J, Artibani W, Dinney CP, Wood CG, Swanson DA, Abbou CC, Lobel B, Mulders PF, Chopin DK, Figlin RA, Belldegrun AS. Use of the University of California Los Angeles integrated staging system to predict survival in renal cell carcinoma: an international multicenter study. J Clin Oncol 2004;22(16):3316-22. http://www.ncbi.nlm.nih.gov/pubmed/15310775

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36.

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Karakiewicz PI, Briganti A, Chun FK, Trinh QD, Perrotte P, Ficarra V, Cindolo L, De la Taille A, Tostain J, Mulders PF, Salomon L, Zigeuner R, Prayer-Galetti T, Chautard D, Valeri A, Lechevallier E, Descotes JL, Lang H, Mejean A, Patard JJ. Multi-institutional validation of a new renal cancer-specific survival nomogram. J Clin Oncol 2007;25(11):1316-22. http://www.ncbi.nlm.nih.gov/pubmed/17416852 Zigeuner R, Hutterer G, Chromecki T, Imamovic A, Kampel-Kettner K, Rehak P, Langner C, Pummer K. External validation of the Mayo Clinic stage, size, grade, and necrosis (SSIGN) score for clear-cell renal cell carcinoma in a single European centre applying routine pathology. Eur Urol 2008; Nov 28. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/19062157 Karakiewicz PI, Suardi N, Capitanio U, Jeldres C, Ficarra V, Cindolo L, de La Taille A, Tostain J, Mulders PF, Bensalah K, Artibani W, Salomon L, Zigeuner R, Valeri A, Descotes JL, Rambeaud JJ, Mejean A, Montorsi F, Bertini R, Patard JJ. A preoperative prognostic model for patients treated with nephrectomy for renal cell carcinoma. Eur Urol 2008; Jul 25. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/18715700 Raj GV, Thompson RH, Leibovich BC, Blute ML, Russo P and Kattan MW. Preoperative nomogram predicting 12-year probability of metastatic renal cancer. J Urol 2008;179(6):2146-51; discussion 2151. http://www.ncbi.nlm.nih.gov/pubmed/18423735

5. TREATMENT OF LOCALIsED DISEASE 5.1

Surgery

Until recently, radical nephrectomy that included the removal of the tumour-bearing kidney was the gold standard for curative therapy for localised RCC and it still offers a reasonable chance of curing the disease (1). There is no evidence to favour a specific surgical approach. The evidence also indicates that a routine adrenalectomy is not necessary during the surgical treatment of RCC, provided tumour staging is negative according to pre-operative imaging (CT, MRI). There are two exceptions to this general rule, which are: • a large upper pole tumour, which is associated with a risk of direct invasion of the adrenal gland • a tumour of > 7 cm maximum diameter, which is associated with a higher risk of intra-adrenal metastatic spread. Radical lymph node dissection does not improve survival in patients without clinically detectable lymph nodes and distant metastases (2) (level of evidence: 1a). In patients with palpable or CT-detected enlarged lymph nodes, lymph node dissection should still be performed to obtain adequate stage information. 5.1.1 Embolisation Indications for tumour embolisation include: • patients with gross haematuria who are not fit for surgical intervention • prior to surgical resection of large paravertebral metastases. There is no benefit in performing tumour embolisation before routine radical nephrectomy (level of evidence: 3) (3-9). 5.1.1.1 Conclusion Radical nephrectomy according to Robson is no longer the gold standard treatment for smaller renal tumours (level of evidence: 2b). Adrenalectomy is not recommended provided the adrenal is normal on pre-operative CT scan (level of evidence: 3). About half of adrenal metastases develop from larger upper pole tumours (level of evidence: 3). Extended lymphadenectomy does not improve survival in patients without clinically detectable lymph nodes and distant metastases and should be restricted to staging purposes in palpable and CT-detected enlarged lymph nodes (2) (level of evidence: 1b). Renal cell carcinomas with tumour thrombi have a higher stage and grade (level of evidence: 2b). Distant or lymph node metastases are twice as common (level of evidence: 3). This increased biological aggressiveness determines the clinical prognosis more than the presence or the cranial extension of intracaval thrombosis (level of evidence: 3) (10-23). Recommendations GR •S  urgical therapy is the only curative therapeutic approach for the treatment of RCC. Routine A extended lymph node dissection in patients without detectable lymph nodes does not improve survival and can be restricted to staging purposes Update march 2009

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•A  drenalectomy, together with nephrectomy, except in the case of large upper pole tumours where direct invasion of the adrenal gland is likely, can be spared in most patients . •E  mbolisation as a palliative approach can be beneficial in patients unfit for surgery with massive haematuria or profound local pain GR = grade of recommendation

B C

5.1.2 Nephron-sparing surgery Standard indications for nephron-sparing surgery are divided into the following categories: • absolute (anatomical or functional solitary kidney) • relative (functioning opposite kidney that is affected by a condition that might impair renal function in future) • elective (localised unilateral RCC with a healthy contralateral kidney). Relative indications also include patients with hereditary forms of RCC, who are at high risk of developing a tumour in the contralateral kidney in the future. 5.1.2.1 Conclusion Nephron-sparing surgery for RCC, when performed in patients with a solitary tumour < 4 cm maximum diameter, provides recurrence-free and long-term survival rates similar to those observed after a radical surgical procedure (level of evidence: 2b) (24-26). Nephron-sparing surgery carried out for absolute rather than elective indications has an increased complication rate and higher risk of developing locally recurrent disease, probably due to the larger tumour size (level of evidence: 3) (27, 28). There is some evidence that radical nephrectomy compared to nephron-sparing surgery carries an increased risk of impaired renal function, resulting in chronic renal insufficiency and proteinuria (level of evidence: 3) (29-31). In a few series, even patients with larger tumours (up to 7 cm), who have undergone nephron-sparing surgery, have shown oncological outcomes equivalent to those of radical surgery. If the tumour is completely resected, the thickness of the surgical margin does not impact on the likelihood of local recurrence (level of evidence: 3). Recommendations GR •N  ephron-sparing surgery is an established curative approach for the treatment of RCC B •N  ephron-sparing surgery for tumours > 4-7 cm maximum diameter can be performed in centres B with expertise in selected patients •A  minimal tumour-free surgical margin following partial resection of RCC appears appropriate to B avoid the increased risk of local recurrence • If tumours of larger size are treated with nephron-sparing surgery, follow-up should be intensified B due to an increased risk of intrarenal recurrence GR = grade of recommendation 5.1.3 Laparoscopic nephrectomy Since its introduction, laparoscopic nephrectomy for RCC has become an established surgical procedure worldwide. Whether done retro- or trans-peritoneally, the laparoscopic approach must duplicate established open surgical oncological principles, which are: • early control of the renal vessels before tumour manipulation • wide specimen mobilisation external to Gerota’s fascia • avoidance of specimen traumatisation or rupture • intact specimen extraction. In the hands of experienced laparoscopic urological surgeons, and adhering to these principles of open radical nephrectomy, laparoscopic radical nephrectomy may now be considered a standard of care for patients with T1-2 RCCs. Intermediate outcome data indicate equivalent cancer-free survival rates when compared with open radical nephrectomy. 5.1.3.1 Conclusion Laparoscopy for radical nephrectomy has a lower morbidity when compared with open surgery (level of evidence: 3). Tumour control rates appear equivalent for T1-2 and possible T3a tumours in experienced hands (level of evidence: 3).

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Recommendation GR • Laparoscopic tumour nephrectomy should be performed in centres with laparoscopic expertise B • Laparoscopic tumour nephrectomy is likely to become a widely distributed treatment option. B It can be promoted in specialised centres treating kidney tumours GR = grade of recommendation 5.1.4 Partial laparoscopic nephrectomy In experienced hands, laparoscopic partial nephrectomy is an alternative to open nephron-sparing surgery for selected patients (32-35). The optimal indication for laparoscopic nephron-sparing surgery is a relatively small and peripheral renal tumour. It has been suggested that the oncological outcome following laparoscopic partial nephrectomy duplicates that of open nephron-sparing surgery (36, 37). However, currently, there are no larger studies able to reveal reliable long-term equivalence. Suggested disadvantages of the laparoscopic approach are the longer warm ischaemia time and increased intra-operative and post-operative complications compared with open surgery (38-40). 5.1.4.1 Conclusion Partial nephrectomy by laparoscopic surgery is technically feasible (level of evidence: 2b). Recommendations GR • Open partial nephrectomy currently remains the standard of care C • Laparoscopic partial nephrectomy should be limited to experienced centres C GR = grade of recommendation

5.2

Alternative treatments to surgery

Suggested alternatives to the surgical treatment of RCC have included image-guided percutaneous and minimally invasive techniques, e.g. percutaneous radiofrequency (RF) ablation (41, 42), cryoablation (43), microwave ablation, laser ablation and high-intensity focused ultrasound ablation (HIFU) (level of evidence: 2b) (44). Possible advantages of these and other techniques include reduced morbidity, outpatient therapy, and the ability to treat high-risk surgical candidates (level of evidence: 2b). Indications for minimally invasive techniques, including RF ablation, are small, incidentally found, renal cortical lesions in elderly patients, patients with genetic predisposition to multiple tumours, or patients with a solitary kidney, or bilateral tumours (level of evidence: 2b). Contraindications to the above-mentioned procedures include a poor life expectancy of < 1 year, multiple metastases, or difficulty for successful treatment due to size or location of tumour. In general, tumours > 5 cm or tumours in the hilum, the proximal ureter or central collecting system are not typically recommended for RF ablation (45). Absolute contraindications include irreversible coagulopathies or severe medical instability, such as sepsis. Although, even in high-risk patients, the reported complication rates are low, greater multicentre experience is needed to define the oncological success and complications of these procedures as an alternative to open or laparoscopic surgery. 5.2.1 Conclusion The formerly mentioned, minimally invasive approaches currently have the status of experimental treatment options for kidney cancer. Their efficacy should be further evaluated within clinical trials. Their disadvantage is a lack of adequate histopathological evaluation. However, their advantage is decreased invasiveness, enabling treatment of less well patients with a poor performance status and unfit for conventional surgery (level of evidence: 3). Recommendation GR •C  urrently, patients not suitable for open or laparoscopic surgery due to a poor performance status B with smaller peripheral tumours should be considered for non-surgical alternative techniques • These techniques include image-guided percutaneous and minimally invasive techniques, e.g. B percutaneous radiofrequency ablation, cryoablation, microwave ablation, laser ablation and high-intensity focused ultrasound ablation GR = grade of recommendation

5.3

Adjuvant therapy

There is evidence that adjuvant tumour vaccination might improve the duration of the progression-free survival of selected subgroups of patients undergoing nephrectomy for T3 renal carcinomas. However, further confirmation is needed regarding the impact on overall survival (level of evidence: 1b) (46-50). Prognostic

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algorithms might identify patients likely to benefit most from adjuvant vaccination therapy. 5.3.1 Conclusion Adjuvant therapy with cytokines does not improve survival after nephrectomy (level of evidence: 1b). Recommendation GR • Outside controlled clinical trials, there is no indication for adjuvant therapy following surgery A GR = grade of recommendation

5.4

Surgical treatment of metastatic RCC (tumour nephrectomy)

Tumour nephrectomy is curative only if surgery can excise all tumour deposits. For most patients with metastatic disease, tumour nephrectomy is palliative and other systemic treatments are necessary. A meta-analysis of two randomised studies comparing nephrectomy + immunotherapy versus immunotherapy only showed that long-term survival increased in patients subjected to tumour nephrectomy (51). Nephrectomy in patients with metastatic disease is indicated for patients who are both suitable for surgery and have a good performance status (52). 5.4.1 Conclusion Tumour nephrectomy in combination with interferon-alpha (IFN-alpha) improves the survival of patients with metastatic RCC (mRCC) and a good performance status (level of evidence: 1b). Recommendation GR •T  umour nephrectomy is recommended for metastatic RCC patients with a good performance status A when combined with IFN-alpha GR = grade of recommendation

5.5

Resection of metastases

Complete removal of metastatic lesions contributes to an improvement of clinical prognosis. Immunotherapy, where there has been complete resection of metastatic lesions or isolated local recurrences, does not contribute to an improvement in clinical prognosis (level of evidence: 2b) (52-56). 5.5.1 Conclusion Metastasectomy in patients with RCC has a definite role in improving the clinical prognosis (level of evidence: 3). Recommendations GR • In patients with synchronous metastatic spread, metastasectomy should be performed when B disease is resectable and the patient has a good performance status •T  he clinical prognosis is worse in patients who have surgery for metachranous metastases B •M  etastasectomy should be performed in patients with residual and resectable metastatic lesions B previously responding to immunotherapy and/or a limited (solitary lesion) number of metachranous metastases in order to improve the patient’s prognosis GR = grade of recommendation

5.6

Radiotherapy for metastases in RCC

Radiotherapy can be used for selected symptomatic patients with non-resectable brain or osseous lesions who do not respond to other conservative treatment approaches (57, 58). 5.6.1 Conclusion Radiotherapy of metastases from RCC can induce significant relief from symptoms, e.g. reduction of pain from a single bony deposit (level of evidence: 2b). Recommendation GR • In individual cases, radiotherapy for brain metastases (whole brain irradiation or stereotactic B approach) and osseous lesions can induce relief from symptoms due to mRCC (59, 60) GR = grade of recommendation

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5.7

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50. Jocham D, Richter A, Hoffmann L, Iwig K, Fahlenkamp D, Zakrzewski G, Schmitt E, Dannenberg T, Lehmacher W, von Wietersheim J, Doehn C. Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial. Lancet 2004;363(9409):594-9. http://www.ncbi.nlm.nih.gov/pubmed/14987883 51. Flanigan RC, Mickisch G, Sylvester R, Tangen C, Van Poppel H, Crawford ED. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol 2004;171(3): 1071-6. http://www.ncbi.nlm.nih.gov/pubmed/14767273 52. Ljungberg B, Landberg G, Alamdari FI. Factors of importance for prediction of survival in patients with metastatic renal cell carcinoma, treated with or without nephrectomy. Scand J Urol Nephrol 2000;34(4):246-51. http://www.ncbi.nlm.nih.gov/pubmed/11095082 53. Pongracz N, Zimmerman R, Kotz R. Orthopaedic management of bony metastases of renal cancer. Semin Surg Oncol 1988;4(2):139-42. http://www.ncbi.nlm.nih.gov/pubmed/3393777 54. Tongaonkar HB, Kulkarni JN, Kamat MR. Solitary metastases from renal cell carcinoma: a review. J Surg Oncol 1992;49(1):45-8. http://www.ncbi.nlm.nih.gov/pubmed/1548881 55. van der Poel HG, Roukema JA, Horenblas S, van Geel AN, Debruyne FM. Metastasectomy in renal cell carcinoma: A multicenter retrospective analysis. Eur Urol 1999;35(3):197-203. http://www.ncbi.nlm.nih.gov/pubmed/10072620 56. Jackson RJ, Loh SC, Gokaslan ZL. Metastatic renal cell carcinoma of the spine: surgical treatment and results. J Neurosurg 2001;94(1 Suppl):18-24. http://www.ncbi.nlm.nih.gov/pubmed/11147860 57. Fossa SD, Kjolseth I, Lund G. Radiotherapy of metastases from renal cancer. Eur Urol 1982;8(6): 340-2. http://www.ncbi.nlm.nih.gov/pubmed/6183119 58. Gez E, Libes M, Bar-Deroma R, Rubinov R, Stein M, Kuten A. Postoperative irradiation in localized renal cell carcinoma: the Rambam Medical Center experience. Tumori 2002;88(6):500-2. http://www.ncbi.nlm.nih.gov/pubmed/12597146 59. Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC, Werner-Wasik M, Demas W, Ryj J, Bahary JP, Souhami L, Rotman M, Mehta MP, Curran WJ Jr. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 2004;363(9422):1665-72. http://www.ncbi.nlm.nih.gov/pubmed/15158627 60. Kavolius JP, Mastorakos DP, Pavlovich C, Russo P, Burt ME, Brady MS. Resection of metastatic renal cell carcinoma. J Clin Oncol 1998;16(6):2261-6. http://www.ncbi.nlm.nih.gov/pubmed/9626229

6. SYSTEMIC THERAPY FOR METASTATIC RCC 6.1

Chemotherapy

Since RCCs develop from the proximal tubules, they have high levels of expression of the multiple-drug resistance protein P-glycoprotein and are therefore resistant to most chemotherapies. Chemotherapy seems to be effective only if 5-fluorouracil (5FU) is combined with immunotherapeutic agents (1). 6.1.1 Conclusion Only 5FU in combination with immunotherapy seems to be effective in patients with mRCC (level of evidence: 3). Recommendation GR • Chemotherapy as monotherapy should not be considered effective in patients with mRCC B GR = grade of recommendation

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6.2

Immunotherapy

6.2.1 Interferon-alpha monotherapy and combined with bevacizumab In randomised studies, IFN-alpha has proven superiority for survival over hormonal therapy in patients with mRCC (2). Interferon-alpha provided a response rate of 6-15%, together with a 25% decrease in the risk for tumour progression, and a modest survival benefit of 3-5 months when compared with placebo-equivalent (3, 4). Recently, bevacizumab + IFN-alpha demonstrated increased response rates and progression-free survival in first-line therapy compared to IFN-alpha monotherapy (5, 6). All recent randomised studies comparing antiangiogenic drugs in a first-line setting to IFN-alpha monotherapy have demonstrated a superiority for either sunitinib, bevacizumab + IFN-alpha or temsirolumus (5-8). 6.2.1.1 Conclusion Interferon-alpha monotherapy is no longer recommended as first-line therapy for mRCC (level of evidence: 1b). 6.2.2 Interleukin-2 Interleukin-2 (IL-2) has been used to treat mRCC since 1985 with response rates ranging from 7-27% (8-10). The optimal IL-2 regimen is not clear, but long-term (> 10 years) complete responders have been achieved with high-dose bolus IL-2 (11). The toxicity of IL-2 is substantially higher than that of IFN-alpha. It seems that only clear cell type RCC responds to immunotherapy. Interleukin-2 has not been validated in controlled randomised studies compared with best supportive care (4). 6.2.2.1 Conclusion Interleukin-2 has more side-effects than INF-alpha. High-dose IL-2 gives durable complete responders in a limited number of patients. Interleukin-2 remains the only cytokine suitable for monotherapy in selected patients with a good prognosis profile. Recommendations GR •M  onotherapy with IFN-alpha can no longer be recommended as a first-line treatment for mRCC. A •B  evacizumab + IFN-alpha is recommended as first-line therapy in low- and intermediate-risk B patients. Only selected patients with mRCC, revealing a good risk profile, and clear cell subtype histology, show clinical benefit from immunotherapy with IL-2. • Cytokine combinations, with or without additional chemotherapy, do not improve overall survival A compared with monotherapy GR = grade of recommendation

6.3

Angiogenesis inhibitor drugs

Recent advances in molecular biology have led to the development of several novel agents for the treatment of mRCC (Table 4). In sporadic clear cell RCC, HIF accumulation due to von Hippel Landau (VHL) inactivation, results in overexpression of VEGF and PDGF (platelet-derived growth factor), both of which promote neo-angiogenesis (12-14). This process substantially contributes to the development and progression of RCC. At present, four targeting drugs have been approved both in the USA and in Europe for the treatment of mRCC: • sorafenib (Nexavar®) • sunitinib (Sutent®) • bevacizumab (Avastin®) combined with IFN-alpha • temsirolimus (Torisel®). Several other new agents targeting angiogenesis are under investigation, as well as combinations of these new agents with each other or with cytokines. 6.3.1 Sorafenib Sorafenib is an oral multikinase inhibitor with activity against Raf-1 serine/threonine kinase, B-Raf, vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor (PDGFR), FMS-like tyrosine kinase 3 (FLT-3) and c-KIT. A phase III trial comparing sorafenib and placebo after failure of a prior systemic immunotherapy reported a 3-month improvement in progression-free survival in favour of sorafenib (15). Survival seems to improve in patients crossed over from placebo to sorafenib treatment (16). 6.3.2 Sunitinib Sunitinib is an oxindol tyrosine kinase (TK) inhibitor. It selectively inhibits PDGFR, VEGFR, KIT and FLT-3 and has anti-tumour and anti-angiogenic activity. Phase II trials with sunitinib as second-line monotherapy in patients with mRCC demonstrated a partial response rate in 34-40% of patients and stable disease > 3 months in 27-29% of patients (17).

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21

In a recent phase III trial of first-line monotherapy that compared treatment with sunitinib to IFN-alpha, sunitinib achieved a longer progression-free survival than with IFN-alpha (11 vs 5 months, p < 0.000001). Results suggested monotherapy with IFN-alpha was inferior compared to sunitinib in low- and intermediaterisk patients with mRCC (18). Overall survival was 26.4 and 21.8 months in the sunitinib and IFN-alpha arms, respectively (p = 0.05) (18). In patients crossed over from IFN-alpha to sunitinib (n = 25), median survival times were 26.4 versus 20.0 months for sunitinib and IFN-alpha, respectively (p = 0.03). In patients who did not receive any post-study treatment, the median overall survival reached 28.1 months in the sunitinib group versus 14.1 months in the IFN-alpha group (p = 0.003). 6.3.3 Bevacizumab monotherapy and combined with interferon-alpha Bevacizumab is a humanised monoclonal antibody that binds isoforms of VEGF-A. Bevacizumab, 10 mg/kg every 2 weeks, in patients refractory to immunotherapy showed an increase in overall response (10%) and in progression-free survival versus placebo (19). A recent double-blind phase III trial (n = 649) in mRCC compared bevacizumab + IFN-alpha to IFN-alpha monotherapy (5).The median overall response was 31% in the bevacizumab + IFN-alpha group versus 13% in the IFN-alpha only group (p < 0.0001). Median progression-free survival increased significantly from 5.4 months with IFN-alpha to 10.2 months for bevacizumab + IFN-alpha (p  10cm Regional lymph node status pNx/pN0 pN1-pN2 Nuclear grade Grade 1-2 Grade 3 Grade 4 Tumour necrosis No necrosis Necrosis

Score 0 2 3 4 0 1 0 2 0 1 3 0 1

Risk groups can be stratified according to the Mayo Scoring System (13) into low-risk, 0-2, intermediate-risk,

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25

3-5, and high-risk, > 6. The use of scoring systems, such as the Mayo System, helps the urologist to select the use of imaging and to appropriately target those patients most in need of intensive surveillance. Table 6: A  ccumulated risk of metastases (%) after nephrectomy in patients with clear cell RCC as defined in risk groups according to the Mayo Scoring System (13). Risk group • Low • Intermediate • High

7.4

Year 1 0.5 9.6 42.3

Year 3 2.1 20.2 62.9

Year 5 2.9 26.2 68.8

Year 10 7.5 35.7 76.4

Conclusion

In cases with a very low risk for tumour recurrence or systemic tumour progression, CT scans can be omitted as routine follow-up examinations. In these patients, a CT scan is only justified in cases of possible tumourassociated symptoms. In the intermediate-risk group, an intensified follow-up that includes CT scans at regular time intervals should be performed according to a risk-stratified nomogram. In high-risk patients, the follow-up examinations should include routine CT scans (level of evidence: 4). Recommendation GR •T  he intensity of the follow-up programme for an individual patient should be adapted according to C the risk of tumour recurrence or systemic tumour progression, as determined by a risk nomogram developed for risk stratification GR = grade of recommendation

7.5

REFERENCES

1.

Lau WK, Blute ML, Weaver AL, Torres VE, Zincke H. Matched comparison of radical nephrectomy vs nephron-sparing surgery in patients with unilateral renal cell carcinoma and a normal contralateral kidney. Mayo Clin Proc 2000;75(12):1236-42. http://www.ncbi.nlm.nih.gov/pubmed/11126830 Itano NB, Blute ML, Spotts B, Zincke H. Outcome of isolated renal fossa recurrence after nephrectomy. J Urol 2000;164(2):322-5. http://www.ncbi.nlm.nih.gov/pubmed/10893575 Sandhu SS, Symes A, A’Hern R, Sohaib SA, Eisen T, Gore M, Christmas TJ. Surgical excision of isolated renal-bed recurrence after radical nephrectomy for renal cell carcinoma. BJU Int 2005;95(4):522-5. http://www.ncbi.nlm.nih.gov/pubmed/15705072 Bani-Hani AH, Leibovich BC, Lohse CM, Cheville JC, Zincke H, Blute ML. Associations with contralateral recurrence following nephrectomy for renal cell carcinoma using a cohort of 2,352 patients. J Urol 2005;173(2):391-4. http://www.ncbi.nlm.nih.gov/pubmed/15643178 Lam JS, Shvarts O, Leppert JT, Figlin RA, Belldegrun AS. Renal cell carcinoma 2005: new frontiers in staging, prognostication and targeted molecular therapy. J Urol 2005;173(6):1853-62. http://www.ncbi.nlm.nih.gov/pubmed/15879764 Patard JJ, Leray E, Rioux-Leclercq N, Cindolo L, Ficarra V, Zisman A, De La Taille A, Tostain J, Artibani W, Abbou CC, Lobel B, Guille F, Chopin DK, Mulders PF, Wood CG, Swanson DA, Figlin RA, Belldegrun AS, Pantuck AJ. Prognostic value of histological subtypes in renal cell carcinoma: a multicenter experience. J Clin Oncol 2005;23(12):2763-71. http://www.ncbi.nlm.nih.gov/pubmed/15837991 Ionising Radiation (Medical Exposures) Regulations 2000. National Radiation Protection Board 2000 www.hpa.org.uk http://www.hpa.org.uk/radiation/understand/radiation_topics/medical/diagnostic_radiology/national_ reference_doses.html http://www.hpa.org.uk/webw/HPAweb&HPAwebStandard/HPAweb_C/1195733806727?p=11589346 078298 Montie J. Follow-up after partial or total nephrectomy for renal cell carcinoma. Urol Clin North Am 1994;21(4):725-7. http://www.ncbi.nlm.nih.gov/pubmed/7974900

2.

3.

4.

5.

6.

7.

8.

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9.

10.

11.

12.

13.

Patard JJ , Shvarts O, Lam JS, Pantuck AJ, Kim HL, Ficarra V, Cindolo L, Han KR, De La Taille A, Tostain J, Artibani W, Abbou CC, Lobel B, Chopin DK, Figlin RA, Mulders PF, Belldegrun AS. Safety and efficacy of partial nephrectomy for all T1 tumors based on an international multicenter experience. J Urol 2004;171(6 Pt 1):2181-5; quiz 2435. http://www.ncbi.nlm.nih.gov/pubmed/15126781 Ljungberg B, Alamdari FI, Rasmuson T, Roos G. Follow-up guidelines for nonmetastatic renal cell carcinoma based on the occurrence of metastases after radical nephrectomy. BJU Int 1999;84(4):40511. http://www.ncbi.nlm.nih.gov/pubmed/10468753 Kattan MW, Reuter V, Motzer RJ, Katz J, Russo P. A postoperative prognostic nomogram for renal cell carcinoma. J Urol 2001;166(1):63-7. http://www.ncbi.nlm.nih.gov/pubmed/11435824 Lam JS, Shvarts O, Leppert JT, Pantuck AJ, Figlin RA, Belldegrun AS. Postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma based on a validated prognosticated nomogram and risk group stratification system. J Urol 2005;174(2):466-72; discussion 472; quiz 801. http://www.ncbi.nlm.nih.gov/pubmed/16006866 Leibovich BC, Blute ML, Cheville JC, Lohse CM, Frank I, Kwon ED, Weaver AL, Parker AS, Zincke H. Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer 2003;97(7):1663-71. http://www.ncbi.nlm.nih.gov/pubmed/126555238.

The current document provides a limited update, with a summary of the amendments provided below.  

8.

Summary of major amendments of the 2009 RCC guidelines update

Prognosis • Prognostic nomograms have been validated and one advantage of nomograms is their ability to measure predictive accuracy. Treatment • Interferon-alpha (IFN-alpha) is not recommended in a first-line setting as monotherapy in the treatment of metastatic RCC (mRCC) • Bevacizumab + IFN-alpha is recommended as first-line therapy in low- and intermediate-risk patients • Everolimus can be recommended as second-line therapy after tyrosine kinase inhibitor (TKI) failure

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9. ABBREVIATIONS USED IN THE TEXT

This list is not comprehensive for the most common abbreviations

5FU BSC CT FLT-3 HIF HIFU IFN-alpha IL-2 mRCC MRI mTOR PA PDGF PDGFR RCC RF TNM US VEGF VEGFR VHL WHO

5-fluorouracil best supportive care computerised tomography FMS-like tyrosine kinase 3 hypoxia inducible factor high-intensity focused ultrasound interferon-alpha interleukin-2 metastatic renal cell carcinoma magnetic resonance imaging mammalian target of rapamycin predictive accuracy platelet-derived growth factor platelet-derived growth factor receptor renal cell carcinoma radiofrequency Tumour Node Metastasis abdominal ultrasound vascular endothelial growth factor vascular endothelial growth factor receptor von Hippel-Lindau World Health Organization

Conflict of interest All members of the Renal Cell Cancer Guidelines writing panel have provided disclosure statements on all relationships that they have and that might be perceived to be a potential source of conflict of interest. This information is kept on file in the European Association of Urology Central Office database. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

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Update march 2009

Guidelines on

Penile Cancer G. Pizzocaro (Chairman), F. Algaba, S. Horenblas, E. Solsona, S. Tana, H. Van Der Poel, N. Watkin

© European Association of Urology 2009

TABLE OF CONTENTS

PAGE

1.

Introduction

4

2.

METHODOLOGY 2.1 References

4 4

3. DEFINITION OF PENILE CANCER

5

4.

EPIDEMIOLOGY 4.1 References

5 6

5. RISK FACTORS AND PREVENTION 5.1 References

6 7

6. TNM CLASSIFICATION AND PATHOLOGY 6.1 TNM classification 6.1.1 References 6.2 Pathology 6.2.1 Penile biopsy 6.2.2.1 Pathological categories 6.2.2.2 Histology and metastatic risk 6.2.3 References

8 8 9 9 10 10 10 10

7. DIAGNOSIS AND STAGING 7.1 Primary lesion 7.2 Regional lymph nodes 7.2.1 Lymphatic drainage of the penis 7.2.2 Non-palpable nodes 7.2.3 Risk factors 7.2.4 Palpable nodes 7.3 Distant metastases 7.4 Guidelines for the diagnosis of penile cancer 7.5 References

11 11 11 11 12 12 12 12 13 13

8. TREATMENT 8.1 Primary tumour 8.1.1 Category Tis and Ta 8.1.2 Category T1G1 8.1.3 Category T1G2-3 8.1.4 Category T2 (of the glans) 8.1.5 Category T2 (of the corpora) and T3 8.1.6 Category T4 8.1.7 Local disease recurrence 8.1.8 Technical aspects 8.1.8.1 Conservative surgery 8.1.8.2 Radical amputation 8.1.9 Radiotherapy 8.1.9.1 Recommendations for radiotherapy 8.1.10 Guidelines for treatment strategies for primary tumour 8.2 Treatment of regional lymph nodes 8.2.1 Management of patients with non-palpable inguinal nodes 8.2.1.1 Surveillance 8.2.1.2 Prognostic factors 8.2.1.3 Sentinel node biopsy (SNB) 8.2.2 Management of patients with palpable inguinal nodes 8.2.2.1 Inguinal LAD 8.2.2.2 Modified inguinal LAD 8.2.2.3 The role of pelvic LAD 8.2.2.4 Video-endoscopic inguinal and pelvic LAD

16 16 16 16 16 17 17 17 17 17 17 17 17 18 18 19 19 19 19 19 19 20 20 20 20

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8.2.3 Adjuvant chemotherapy 8.2.4 Management of patients with fixed or relapsed inguinal nodes 8.2.5 The role of radiotherapy 8.2.6 Guidelines for treatment strategies for nodal metastases 8.3 References

20 21 21 22 22

9.

27 27 27 27 27 28 28

FOLLOW-UP 9.1 How to follow-up 9.2 When to follow-up 9.3 Primary tumour 9.4 Regional recurrences 9.5 Guidelines for follow-up in penile cancer 9.6 References

10. QUALITY OF LIFE 10.1 Sexuality and fertility after penile cancer 10.1.1 Sexual activity and quality of life after penile cancer laser treatment 10.1.2 Sexual function after partial penectomy for penile cancer 10.2 Sexual mutilation, relapse and death 10.3 References

29 29 29 29 29 30

11.

31

ABBREVIATIONS USED IN THE TEXT

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1. INTRODUCTION The European Association of Urology (EAU) Guidelines Group on Penile Cancer has prepared this guidelines document to assist medical professionals in the management of penile cancer. The guidelines aim to provide detailed, up-to-date information, based on recent developments in our understanding and management of penile squamous cell carcinoma (SCC). However, it must be emphasised that these guidelines provide a standardised general approach to treating a patient and that the Guidelines provide guidance and recommendations without legal authority or implications. Publication history information: The Penile Cancer Guidelines were first published in 2001 and updated in 2004, followed by this full text update in 2009.

2. METHODOLOGY To update the last published guidelines in 2004, a meticulous PubMed literature search between October 2003 and October 2008 was carried out by all members of the Penile Cancer Consensus Group according to their field of interest (1). A total of 980 abstracts published on SCC of the penis were identified. Only one evidence-based peer-reviewed document was published during the period 2004 to 2008. This was the physician data query (PDQ) on ‘Penile Cancer Treatment’ (Health Professional Version) published by the National Cancer Institute , National Institutes of Health (Bethseda, USA) (2). No randomised controlled trials or Cochrane reviews were published. References used in the text have been assessed according to their level of scientific evidence (Table 1) and guideline recommendations have been graded (Table 2) according to the Oxford Centre for Evidence-based Medicine Levels of Evidence (3). The aim of grading recommendations is to provide transparency between the underlying evidence and the recommendation given. Publication history: The EAU Penile Cancer Guidelines were first published in 2000. Partial updates were achieved in 2001 and 2004, followed by the current version which presents a full text update. Additionally, a quick reference guide is available. All texts can be viewed and downloaded for personal use at the society website: http://www.uroweb.org/professional-resources/guidelines/. Table 1: Level of evidence Level Type of evidence 1a Evidence obtained from meta-analysis of randomised trials 1b Evidence obtained from at least one randomised trial 2a Evidence obtained from one well-designed controlled study without randomisation 2b Evidence obtained from at least one other type of well-designed quasi-experimental study 3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case reports 4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities Table 2: Grade of recommendation Grade Nature of recommendations A Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomised trial B Based on well-conducted clinical studies, but without randomised clinical trials C Made despite the absence of directly applicable clinical studies of good quality *modified from Sackett et al. (3)

2.1

REFERENCES

1.

Solsona E, Algaba F, Horenblas S, Pizzocaro G, Windahl T. EAU guidelines on penile cancer. Eur Urol 2004;46(1):1-8. http://www.ncbi.nlm.nih.gov/pubmed/15183542

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Update march 2009

2. National Cancer Institute. Penile Cancer Treatment (PDQ). Health Professional Version. US National Institutes of Health, 2008, pp. 1-13. http://www.cancer.gov/cancertopics/pdq/treatment/penile/healthprofessional/allpages 3. Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998. http://www.cebm.net/index.aspx?o=1025 [Access date February 2009]

3. DEFINITION OF PENILE CANCER Penile cancer is a relatively rare SCC. It usually originates in the epithelium of the inner prepuce and glans. It shares a similar pathology and natural history with SCC of the oropharynx, female genitalia (cervix, vagina and vulva) and anus. Phimosis, poor hygiene and smoking are the major risk factors for penile cancer. Typing has been done of the human papillomaviruses (HPV) responsible for the sexual transmission of genital warts, condyloma acuminata SCC of the penis. An improved understanding of the natural history of the disease, earlier diagnosis, better technology, research group collaboration and centralisation of patients in centres of excellence has improved the cure rate for penile cancer from 50% in the 1990s to 80% in 2008.

4. EPIDEMIOLOGY In Western countries, primary malignant penile cancer is uncommon, with an incidence of less than 1.00 per 100,000 males in Europe and the United States of America (USA) (1, 2). There are, however, important geographical variations, with several European regions (Figure 1) reporting an incidence greater than 1.00 per 100,000 males (3). Incidence is also affected by race and ethnicity in North America (1), with the highest incidence of penile cancer found in white Hispanics (1.01 per 100,000), followed by Alaskan, Native/American Indians (0.77 per 100,000), Blacks (0.62 per 100,000) and White non-Hispanics (0.51 per 100,000). In contrast, in the non-Western world, the incidence rate of penile cancer is much higher and can represent 10-20% of malignant disease in men ranging from an age-adjusted incidence of 0.7 to 3 per 100,000 people in India to 8.3 per 1000,000 men in Brazil and even higher in Uganda, where it is the most commonly diagnosed cancer. Important risk factors include social and cultural habits, hygienic and religious practices (4). Penile carcinoma is rare in communities that practise circumcision in newborns or before puberty (Jews, Muslims and the Ibos of Nigeria). Early circumcision reduces the risk of penile cancer by 3 to 5 times. Adult circumcision does not protect against penile cancer. In the USA, the overall age-adjusted incidence rate decreased considerably between 1973 and 2002 from 0.84 per 100,000 in 1973-1982 to 0.69 per 100,000 in 1983-1992 and further to 0.58 per 100,000 in 19932002 (1). In European countries, the incidence during the 1980s and 1990s was stable or increased slightly (2). The incidence rate continuously increases with age (2); however, the disease has been reported in younger men and in children.

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Figure 1: Annual incidence rate (world standardised) by European region/country* Penis: ASR (World) (per 100,000) (All ages) Spain, Albacete Malta Switzerland, Neuchatel France, Haut-Rhin Italy, Ragusa Province UK, Scotland Denmark Austria, Tyrol Norway Spain, Asturias France, Bas-Rhin *UK, England Estonia Slovakia *Switzerland, Ticino The Netherlands *Belgium Flanders (excl. Limburg) Italy, Torino Poland, Warsaw city Germany, Saarland *Portugal, Vila Nova de Gaia Slovenia Italy, Sassari 0

0.5

1.0

1.5

2.0

*From Parkin et al. (2003) (3).

4.1

REFERENCES

1.

Barnholtz-Sloan JS, Maldonado JL, Pow-sang J, Giuliano AR. Incidence trends in primary penile cancer. Urol Oncol 2007;25(5):361-7. http://www.ncbi.nlm.nih.gov/pubmed/17826651 ENCR (European Network of Cancer Registries). Eurocim version 4.0. European incidence database V2.2 (1999). Lyon, France: IARC, 2001. Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB (eds). Cancer Incidence in Five Continents. Vol. VIII. IARC Scientific Publications. No. 155. Lyon, France: IARC, 2002. http://www.iarc.fr/en/Publications/PDFs-online/Cancer-Epidemiology/IARC-Scientific-PublicationNo.-155 Misra S, Chaturvedi A, Misra NC. Penile carcinoma: a challenge for the developing world. Lancet Oncol 2004;5(4):240-7. http://www.ncbi.nlm.nih.gov/pubmed/15050955

2. 3.

4.

5. RISK FACTORS AND PREVENTION Risk factors for penile cancer were identified by the Karolinska Institute from a Medline search of published literature from 1966-2000 (1). Strong risk factors (OR > 10) identified by case-control studies included (level of evidence: 2a): • phimosis • chronic inflammatory conditions, e.g. balanoposthitis, lichen sclerosus and atrophicus (balanitis xerotica obliterans) • treatment with sporalene and ultraviolet A photochemotherapy. Sexual history (multiple partners, early age of first intercourse) and a self-reported history of condylomata were associated with a 3- to 5-fold increased risk of penile cancer. Smoking is also a risk factor. Cervical cancer in the wife was not consistently associated with penile cancer in the husband.

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Update march 2009

In many case series, HPV DNA was identified in 70-100% intraepithelial neoplasia and in 40-50% of cases with invasive penile cancer. These results were confirmed by a population-based case control study (2). Among men not circumcised in childhood, phimosis was strongly associated with the development of invasive penile cancer (OR = 11.4; 95% CI 5.0-25.9), while cigarette smoking was associated with a 4.5-fold increased risk (95% CI 2.0-10.1). Human papillomavirus DNA was detected in 80% of tumour specimens; 69% were positive for HPV-16 (level of evidence: 2a). Smegma as a carcinogen has been clearly excluded (3). The risk of cancer among patients with condyloma acuminata increased for vulva, vagina, penis and anus (4) (level of evidence: 2b). Human papillomavirus-16 and -18 have a causal role in 70% of cancers of the cervix, vagina and anus and about 30-40% of cancers of the vulva, penis and oropharynx. Other cofactors are very likely to be necessary for progression from HPV infection to cancer (5). In June 2006, the US Food and Drug Administration (FDA) licensed the first vaccine to prevent cervical cancer and other HPV-associated diseases in women (6). The vaccine protects against infection with HPV-6, HPV-11, HPV-16 and HPV-18, which together are responsible for 70% of cervical cancers and 90% of genital warts. Human papillomavirus is highly transmissible, with a peak incidence soon after the onset of sexual activity. The recommended age for vaccination in females is 11-12 years (7), with catch-up vaccination recommended in females aged 13-26 years. However, vaccination is not a substitute for routine cervical cancer screening and vaccinated females should continue to have cervical cancer screening. Vaccination against HPV has also been recommended in males (8). Although a study found that mid-adult (25 years or older) women have a high level of acceptance for HPV vaccination (9), only 33% of males wanted the HPV vaccine, 27% did not and 40% were undecided (10). Interestingly, the presence of high-risk HPV DNA in penile cancer does not compromise prognosis. An early study (11) found no difference between HPV DNA-negative and HPV DNA-positive patients in lymph node metastases and 10-year survival rate. In a more recent study (12), disease-specific 5-year survival in the high-risk HPV-negative group was 78% versus 93% in the high-risk HPV-positive group (log rank test p = 0.03). This suggests the presence of high-risk HPV confers a survival advantage in patients with penile cancer. The virus plays an important role in oncogenesis through interaction with oncogenes and tumour suppressor genes (P53 and Rb-gene) (13).

5.1

REFERENCES

1. Dillner J, von Krogh G, Horenblas S, Meijer CJ. Etiology of squamous cell carcinoma of the penis. Scand J Urol Nephrol Suppl 2000;(205):189-93. http://www.ncbi.nlm.nih.gov/pubmed/11144896 2. Daling JR, Madeleine MM, Johnson LG, Schwartz SM, Shera KA, Wurscher MA, Carter JJ, Porter PL, Galloway DA, McDougall JK, Krieger JN. Penile cancer: importance of circumcision, human papillomavirus and smoking in situ and invasive disease. Int J Cancer 2005;116(4):606-16. http://www.ncbi.nlm.nih.gov/pubmed/15825185 3. Van Howe RS, Hodges FM. The carcinogenicity of smegma: debunking a myth. Eur Acad Dermatol Venereol 2006;20(9):1046-54. http://www.ncbi.nlm.nih.gov/pubmed/16987256 4. Nordenvall C, Chang ET, Adami HO, Ye W. Cancer risk among patients with condylomata acuminata. Int J Cancer 2006;119(4):888-93. http://www.ncbi.nlm.nih.gov/pubmed/16557590 5. Munoz N, Castelisague X, de Gonzalez AB, Gissmann L. HPV in the etiology of human cancer. Vaccine 2006;24(Suppl 3):S3/1-10. http://www.ncbi.nlm.nih.gov/pubmed/16949995 6. Huang CM. Human papillomavirus and vaccination. Mayo Clin Proc 2008;83(6):701-6. http://www.ncbi.nlm.nih.gov/pubmed/18533087 7. Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER; Centers for Disease Control and Prevention (CDC); Advisory Committee on Immunization Practices (ACIP). Quadrivalent Human Papillomavirus Vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007;56(RR-2):1-24. http://www.ncbi.nlm.nih.gov/pubmed/17380109 8. Giuliano AR. Human papillomavirus vaccination in males. Gynecol Oncol 2007;107(2 Suppl 1):S24S26. http://www.ncbi.nlm.nih.gov/pubmed/17938015

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7

9.

10.

11.

12.

13.

Ferris DG, Waller JL, Owen A and Smith J. Midadult women’s attitudes about receiving the prophylactic human papillomavirus vaccine. J Low Genit Tract Dis 2007;11(3):166-72. http://www.ncbi.nlm.nih.gov/pubmed/17596762 Ferris DG, Waller JL, Miller J, Patel P, Jackson L, Price GA, Wilson C. Men’s attitudes toward receiving the human papillomavirus vaccine. J Low Genit Tract Dis 2008;12(4):276-81. http://www.ncbi.nlm.nih.gov/pubmed/18820541 Bezerra AL, Lopes A, Santiago GH, Ribeiro KC, Latorre MR, Villa LL. Human papillomavirus as a prognostic factor in carcinoma of the penis: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. Cancer 2001;15;91(12):5-21. http://www.ncbi.nlm.nih.gov/pubmed/11413520 Lont AP, Kroon BK, Horenblas S, Gallee MP, Berkhof J, Meijer CJ, Snijders PJ. Presence of high risk human papilllomavirus DNA in penile carcinoma predicts favorable outcome in survival. Int J Cancer 2006;119(5):1078-81. http://www.ncbi.nlm.nih.gov/pubmed/16570278 Kayes O, Ahmed HU, Arya M, Minhas S. Molecular and genetic pathways in penile cancer. Lancet Oncol 2007;8(5):420-9. http://www.ncbi.nlm.nih.gov/pubmed/17466899

6. TNM CLASSIFICATION AND PATHOLOGY 6.1

TNM classification

The 2002 UICC Tumour Node Metastasis (TNM) classification (1) for penile cancer is shown in Table 3. Table 3: 2002 TNM (Tumour, Node, Metastasis) classification of penile cancer T - Primary tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour Tis Carcinoma in situ Ta Non-invasive verrucous carcinoma T1 Tumour invades subepithelial connective tissue T2 Tumour invades corpus spongiosum or cavernosum T3 Tumour invades urethra or prostate T4 Tumour invades other adjacent structures N - Regional lymph nodes NX Regional lymph nodes cannot be assessed N0 No evidence of lymph node metastasis N1 Metastasis in a single inguinal lymph node N2 Metastasis in multiple or bilateral superficial lymph nodes N3 Metastasis in deep inguinal or pelvic lymph nodes, unilateral or bilateral M - Distant metastases MX Distant metastases cannot be assessed M0 No evidence of distant metastases M1 Distant metastases This classification is in need of an update, particularly the definition of T2 category, as the prognosis of patients with tumour invasion of the corpus spongiosum is much better than invasion of the corpus cavernosum (2, 3). Rees et al. (2) reported on 72 patients with T2 tumours. Both local recurrence (35% vs 17%) and mortality (30% vs 21%) rates were higher in patients with tunical or cavernosal involvement after a mean follow-up of 3 years (level of evidence: 2b). The authors proposed defining T2a patients by spongiosum-only invasion and T2b patients by involvement of tunica or corpus cavernosum. However, a deeper analysis resulted in severe criticism and a new proposal for classification (3). A retrospective analysis of the records of 513 patients treated between 1956 and 2006 confirmed the above-mentioned difference between tumour invasion of corpus spongiosum and cavernosum. It also confirmed that there were no differences in long-term survival between T2 and T3, and no

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significant differences between N1 and N2 in the 1987-2002 TNM classification (level of evidence: 2a). A new TNM classification was therefore proposed for T2, T3, T4 and N1, N2, N3 (Table 4) (3). In the new proposed classification, retroperitoneal node metastases are considered to be distant metastases as for the neck, lung and other visceral organs. The new classification is much more appropriate than the present TNM categories, but it needs to be confirmed by UICC. Table 4: Proposed modification to 1987-2002 TNM classification* T - Primary tumour TX, T0, Tis, Ta and T1 Unchanged T2 Tumour invades corpus spongiosum T3 Tumour invades corpus cavernosum T4 Tumour invades adjacent structures (e.g. urethra, prostate) N - Regional lymph nodes Nx and N0 Unchanged N1 Unilateral inguinal metastases, mobile N2 Bilateral inguinal metastases N3 Fixed inguinal metastases or metastases in pelvic lymph nodes *From Leiitje et al. (2008) (3). 6.1.1 References 1. Sobin LH, Wittekind C. TNM Classification of Malignant Tumours. Philadelphia, PA: Wiley-Liss, 2002. 2. Rees RW, Freeman A, Borley N, Ralf DJ, Minhas S. PT2 penile squamous cell carcinomas: cavernosus vs. spongiosus invasion. Eur Urol Suppl 2008;7(3):111 (abstr 163). 3. Leijte JA, Gallee M, Antonini N, Horenblas S. Evaluation of current TNM classification of penile carcinoma. J Urol 2008;180(3):933-8; discussion 938. http://www.ncbi.nlm.nih.gov/pubmed/18635216

6.2

Pathology

Squamous cell carcinoma accounts for more than 95% of cases of malignant disease of the penis. Malignant melanomas and basal cell carcinoma are much less common. It is not known how often SCC is preceded by premalignant lesions (1). Although SCC is the most common penile neoplasia, different types and varying growth patterns have been identified (2-4) (Tables 5 and 6). Table 5: Premalignant lesions Lesions sporadically associated with SCC of the penis • Cutaneous horn of the penis • Bowenoid papulosis of the penis • Balanitis xerotica obliterans (lichen sclerosus et atrophicus) Lesions at high risk of developing SCC of the penis (up to one-third transform to invasive SCC) • Penile intraepithelial neoplasia (carcinoma in situ): erythroplasia of Queyrat and Bowen’s disease LE = level of evidence; SCC = squamous cell carcinoma. Table 6: Penile SCC Types of SCC • Classic • Basaloid • Verrucous and its varieties (2): - Warty (condylomatous) carcinoma - Verrucous carcinoma - Papillary carcinoma - Hybrid verrucous carcinoma - Mixed carcinomas (warty basaloid, adenobasaloid carcinoma) • Sarcomatoid • Adenosquamous

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Growth patterns of SCC • Superficial spread • Nodular or vertical-phase growth • Verrucous Differentiation grading systems for SCC • Broders’ system (5) • Maiche’s system score (6) SCC = squamous cell carcinoma. 6.2.1 Penile biopsy There is no need for biopsy if: • There is no doubt about the diagnosis and/or • Treatment of the lymph nodes is postponed after treatment of the primary tumour and/ or after histological examinations of the sentinel node(s). There is a need for histological confirmation if: • There is doubt about the exact nature of the lesion (metastasis, melanoma, etc) • Treatment of the lymph nodes is based on pre-operative histological information (risk-adapted strategy). In these cases an adequate biopsy is advised. When performing a biopsy, it is important to consider the findings from a study of biopsy size. The study of biopsies with an average size of 1.1 cm found there was: • difficulty in evaluating the extent of depth in 91% of biopsies • discordance between the grade at biopsy and the final specimen in 30% of cases • failure to detect cancer in 3.5% (1) • Thus, although a punch biopsy may be sufficient for superficial lesions, an excisional biopsy is preferred. 6.2.2.1 Pathological categories Traditionally, squamous cell carcinomas were considered as superficial or invasive. However, Cubilla et al. (2) has divided penile carcinoma into four categories: • superficial spreading • vertical growth • verrucous • multicentric. Different types of growth have different prognoses (3) and different ways of dissemination. The limits of surgical partial resections must therefore be set according to the growth pattern at the time of evaluation of the frozen sections (4). If the margins are studied following these criteria (including urethral and periurethral tissue), only 3-4 mm of tumourfree tissue is sufficient to consider the surgical margins to be negative (7). Basaloid SSC is a cellular subtype that is better recognised than before. It is highly aggressive. (8) 6.2.2.2 Histology and metastatic risk Histological subtypes carry different risks of developing metastatic lymph nodes: • condylomatous: 18.2% • SCC: 56.7% • sarcomatoid carcinoma: 89% (9). Similarly, invasion pattern (10) and vascular invasion (10, 11) are correlated with lymph node metastases, with 23.1% of positive lymph nodes associated with a nodular pattern and 64.6% with an infiltrative pattern. 6.2.3 1.

References Velazquez EF, Barreto JE, Rodriguez I, Piris A, Cubilla AL. Limitations in the interpretation of biopsies in patients with penile squamous cell carcinoma. Int J Surg Pathol 2004;12(2):139-46. http://www.ncbi.nlm.nih.gov/pubmed/15173919 2. Cubilla AL, Barreto J, Caballero C, Ayala G, Riveros M. Pathologic features of epidermoid carcinoma of the penis. A prospective study of 66 cases. Am J Surg Pathol 1993;17(8):753-63. http://www.ncbi.nlm.nih.gov/pubmed/8338190

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3.

Villavicencio H, Rubio-Briones J, Regalado R, Chéchile G, Algaba F, Palou J. Grade, local stage and growth pattern as prognostic factors in carcinoma of the penis. Eur Urol 1997;32(4):442-7. http://www.ncbi.nlm.nih.gov/pubmed/9412803 4. Velazquez EF, Soskin A, Bock A, Codas R, Barreto JE, Cubilla AL. Positive resection margins in partial penectomies: sites of involvement and proposal of local routes of spread of penile squamous cell carcinoma. Am J Surg Pathol 2004;28(3):384-9. http://www.ncbi.nlm.nih.gov/pubmed/15104302 5. Broders AC. Squamous cell epithelioma of the skin: A study of 256 cases. Ann Surg 1921;73(2):141160. http://www.ncbi.nlm.nih.gov/pubmed/17864409 6. Maiche AG, Pyrhönen S, Karkinen M. Histological grading of squamous cell carcinoma of the penis: a new score system. Br J Urol 1991;67(5):522-526. http://www.ncbi.nlm.nih.gov/pubmed/1710163 7. Minhas S, Kayes O, Hegarty P, Kumar P, Freeman A, Ralph D. What surgical resection margins are required to achieve oncological control in men with primary penile cancer? BJU Int 2005;96(7):1040-3. http://www.ncbi.nlm.nih.gov/pubmed/16225525 8. Cubilla AL, Reuter V, Velazquez E, Piris A, Saito S, Young RH. Histologic classification of penile carcinoma and its relation to outcome in 61 patients with primary resection. Int J Surg Pathol 2001;9(2):111-20. http://www.ncbi.nlm.nih.gov/pubmed/11484498 9. Bezerra AL, Lopes A, Landman G, Alencar GN, Torloni H, Villa LL. Clinicopathologic features and human papillomavirus DNA prevalence of warty and squamous cell carcinoma of the penis. Am J Surg Pathol 2001;25(5):673-8. http://www.ncbi.nlm.nih.gov/pubmed/11342782 10. Guimarães GC, Lopes A, Campos RS, Zequi Sde C, Leal ML, Carvalho AL, da Cunha IW, Soares FA. Front pattern of invasion in squamous cell carcinoma of the penis: new prognostic factor for predicting risk of lymph node metastases. Urology 2006;68(1):148-53. http://www.ncbi.nlm.nih.gov/pubmed/16844455 11. Busby JE, Pettaway CA. What’s new in the management of penile cancer? Curr Opin Urol 2005;15(5):350-7. http://www.ncbi.nlm.nih.gov/pubmed/16093861

7. DIAGNOSIS AND STAGING The primary tumour and regional lymph nodes must be staged correctly to enable the most appropriate treatment.

7.1

Primary lesion

Physical examination of a patient with penile cancer includes: • diameter of the penile lesion(s) or suspicious areas • location of lesion(s) on the penis • number of lesions • morphology of lesion(s): papillary, nodular, ulcerous or flat • relationship of lesion(s) to other structures, e.g. submucosa, tunica albuginea, urethra, • corpus spongiosum and corpus cavernosum • colour and boundaries of lesion(s) • penis length. Accurate histological diagnosis and staging of both the primary tumour and regional nodes are necessary in making treatment decisions (1). In a small series, physical examination alone was more reliable than imaging with ultrasound and/or MRI to judge infiltration into the corpora (2). Artificial erection with prostaglandin E1 (alprostadil) in combination with magnetic resonance imaging (MRI) was helpful in identifying the depth of tumour invasion of the corpora cavernosa and whether or not conservative surgery should be used (3, 4).

7.2

Regional lymph nodes

7.2.1 Lymphatic drainage of the penis Primary lymphatic drainage of penile cancer occurs to the inguinal nodes. A recent imaging study (5) has

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shown that all sentinel nodes are located in the superior and central inguinal zones with most found in the medial superior zone. No lymphatic drainage was observed from the penis to the inferior two regions of the groin and no direct drainage to the pelvic nodes was visualised. These findings confirm earlier studies (6-8). 7.2.2 Non-palpable nodes A careful inguinal physical examination is necessary. In the absence of palpable abnormalities, an inguinal ultrasound (7.5 mHz) may reveal abnormal nodes and can be used as a guide for fine-needle aspiration biopsy (9, 10). A sentinel node biopsy (SNB) (8) is not recommended because of a high rate of false-negative results (25%, range 9-50%) (11). However, recent reports suggest that dynamic SNB (using isosulphan blue and/ or technetium-99m (99mTc)-colloid sulphur) improved survival compared to a ‘wait-and-see’ policy (level of evidence: 3) and reduced toxicity compared to inguinal lymphadenectomy (LAD) (12, 13). A prospective study found dynamic SNB had 100% specificity and 78-80% sensitivity (14-18) (level of evidence: 2a). As analysis of dynamic SNB is operator-dependent (19) and relies on experience, the procedure is only available in a few centres. Because iliac lymph node metastases do not occur in the absence of inguinal metastases (19), an abdominal computed tomography (CT) scan is not necessary in patients with no inguinal node metastases. A conventional CT or MRI scan cannot detect micrometatases (20). Large studies are required to confirm promising results reported with nanoparticle-enhanced MRI and positron emission tomography (PET) or CT imaging (21, 22). 7.2.3 Risk factors The presence of lymph node metastases may be predicted from tumour characteristics other than T and G categories. Risk factors identified from retrospective studies include pathological subtype, perineural invasion, lymphovascular invasion, tumour depth or thickness, anatomical site, size and growth pattern, front of invasion, positive margins and urethral invasion (23). Several large series have identified lymphovascular invasion alone (24), lymphovascular invasion plus absent koilocytosis (25), lymphovascular invasion plus palpable inguinal nodes (26), high histological grade plus perineural invasion (27). The most important adverse pathological prognostic factors appear to be perineural invasion, vascular invasion and high histological grade (23). Nomograms can be used to evaluate the predictive power of clinical and pathological indicators (23, 26). 7.2.4 Palpable nodes Palpable nodes should be described as follows: • node consistency • node location(s) • diameter of node(s) or mass(es) • unilateral or bilateral localisation • number of nodes identified in each inguinal area • mobile or fixed nodes or masses • relationship (e.g. infiltration, perforation, etc) to other structures, such as the skin or Cooper ligament • oedema on leg and/or scrotum. Lymph node metastases in palpable nodes can be diagnosed using a percutaneous needle aspiration biopsy (cytology and/or histology punction). At the time of diagnosis of penile cancer, as many as 50% of palpable inguinal nodes will be reactive rather than due to lymph node metastasis. In contrast, during follow-up, nearly 100% of enlarged nodes are metastatic (28-30) (level of evidence: 2a). Thus, after allowing time for inflammatory reactions to subside, regional nodes should be evaluated within a few weeks after treatment of the primary tumour. Histological diagnosis can be done using fine-needle aspiration biopsy, tissue core biopsy or open biopsy, according to the preference of the pathologist (31, 32) (level of evidence: 2b). In the case of a negative biopsy and clinically suspicious nodes, a repeat biopsy or excisional biopsy should be performed. Imaging techniques (CT, MRI) are widely used, but are only useful for staging in patients with proven lymph node metastases. So far no imaging modality can identify microspcopic invasion. Imaging using PET (33) and the use of molecular biology are under investigation (34, 35).

7.3

Distant metastases

An assessment of distant metastases should be performed in patients with proven positive inguinal nodes (36) (level of evidence: 2b). Pelvic or abdominal CT scan should be used to identify pelvic (and retroperitoneal) adenopathies in patients with inguinal metastases. While this is not a very reliable diagnostic method, the detection of pelvic masses has a considerable impact on therapy and prognosis (39). Routine blood determination and chest X-rays are usually performed, despite the fact that lung metastasis

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is exceptionally rare. The value of SCC antigen determination as a staging tool is unclear and therefore not recommended for routine use (34). Biological studies are investigational (37). A diagnostic schedule is summarised in Table 7. Table 7: Diagnostic schedule for penile cancer Lesion level Primary tumour

Regional disease

• Non-palpable nodes • Palpable node

Distant metastases

Procedures Mandatory Advisable Physical examination Cytology or histology Physical examination Dynamic sentinel Ultrasound node biopsy* Ultra-sound (FNAC)* Cytology or histology Pelvic CT, if positive Abdominal CT inguinal nodes (chest X-rays)

Optional MRI Ultrasound

Bone scan in symptomatic patients

FNAC=fine needle aspiration biopsy;MRI = magnetic resonance imaging; PGE1 = prostaglandin E1; CT = computed tomography. *Dual techmique: isosulphan blue with technetium-99m (99mTc) colloid sulphur (8, 19). Regional lymph nodes are the regional disease.

7.4

Guidelines for the diagnosis of penile cancer

Primary tumour • Physical examination is mandatory, recording morphological and physical characteristics of the lesion • Cytological or histological diagnosis is mandatory Regional lymph node disease • Physical examination is mandatory • If nodes are non-palpable, ultrasound-guided FNAB • If FNAB is tumour-negative, dynamic SNB is indicated • If nodes are palpable, it is mandatory to record nodal morphological and physical and physical characteristics and to perform FNAB for histological diagnosis

GR B B

B B B B

Distant metastasis (beside inguinal nodes) • A pelvic CT scan is indicated if metastatic inguinal nodes are present B • An abdominal CT scan and chest X-ray are advisable if pelvic CT scan is positive B • A bone scan is advisable in M1 symptomatic patients C • Biological laboratory determinations for penile cancer are investigational None GR = grade of recommendation, MRI = magnetic resonance imaging; PGE1 = prostaglandin E1; FNAB = fine-needle aspiration biopsy; DSNB = sentinel node biopsy; CT = computed tomography.

7.5

REFERENCES

1.

Solsona E, Iborra I, Rubio J, Casanova JL, Ricós JV, Calabuig C. Prospective validation of the association of local tumor stage grade as a predictive factor for occult lymph node micrometastasis in patients with penile carcinoma and clinically negative inguinal lymph nodes. J Urol 2001;165(5): 1506-9. http://www.ncbi.nlm.nih.gov/pubmed/11342906 Horenblas S. The accuracy of ultrasound in squamous cell carcinoma. In: The Management of Penile Squamous Cell Carcinoma. A Retrospective and Prospective Study. Thesis. Amsterdam Zoetermeer: BV Export drukkerij, 1993, pp. 71-83. Kayes O, Minhas S, Allen C, Harc C, Freeman A, Ralph D. The role of magnetic resonance imaging in the local staging of penile cancer. Eur Urol 2007;51(5):1313-8. http://www.ncbi.nlm.nih.gov/pubmed/17113213

2.

3.

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4.

Lont AP, Besnard AP, Gallee MP, van Tinteren H, Horenblas S. A comparison of physical examination and imaging in determining the extent of primary penile carcinoma. BJU Int 2003;91(6):493-5. http://www.ncbi.nlm.nih.gov/pubmed/12656901 5. Leijte JA, Valdés Olmos RA, Nieweg OE, Horenblas S. Anatomical mapping of lymphatic drainage in penile carcinoma with SPECT-CT: implications for the extent of inguinal lymph node dissection. Eur Urol 2008;54(4):885-90. http://www.ncbi.nlm.nih.gov/pubmed/18502024 6. Daseler EH, Anson BJ, Reimann AF. Radical excision of the inguinal and iliac lymph glands: a study based upon 450 anatomical dissections and upon supportive clinical observations. Surg Gynecol Obstet 1948;87(6):679-94. http://www.ncbi.nlm.nih.gov/pubmed/18120502 7. Cabanas RM. An approach for the treatment of penile carcinoma. Cancer 1977;39(2):456-66. http://www.ncbi.nlm.nih.gov/pubmed/837331 8. Catalona WJ. Modified inguinal lymphadenectomy for carcinoma of the penis with preservation of saphenous veins: technique and preliminary results. J Urol 1988;140(4):306-10. http://www.ncbi.nlm.nih.gov/pubmed/3418818 9. Saisorn I, Lawrentschut N, Leewansangtong S, Bolton DM. Fine-needle aspiration cytology predicts inguinal lymph node metastases without antibiotic pretreatment in penile carcinoma. BJU Int 2006;97(6):1125-8. http://www.ncbi.nlm.nih.gov/pubmed/16686716 10. Kroon BK, Horenblas S, Deurloo EE, Nieweg OE, Teertstra HJ. Ultrasonography-guided fineneedle aspiration cytology before sentinel node biopsy in patients with penile carcinoma. BJU Int 2005;95(4):517-21. http://www.ncbi.nlm.nih.gov/pubmed/15705071 11. Pettaway CA, Pisters LL, Dinney CPN, Jularbal F, Swanson DA, von Eschenbach AC, Ayala A. Sentinel lymph node dissection for penile carcinoma: the MD Anderson Cancer Center Experience. J Urol 1995;154(6):1999-2003. http://www.ncbi.nlm.nih.gov/pubmed/7500444 12. Horenblas S. Surgical management of carcinoma of the penis and scrotum. In: Petrovich Z, Baert L, Brady LW (eds). Medical Radiology. Diagnostic Imaging and Radiation Oncology. Carcinoma of the Kidney and Testis, and Rare Urologic Malignancies. Berlin: Springer-Verlag, 1999, pp. 341-54. 13. Pettaway CA, Jularbal FA, Babaian RJ, Dinney CPN, Pisters LL. Intraoperative lymphatic mapping to detect inguinal metastases in penile carcinoma: results of a pilot study. J Urol 1999;161:159 (abstr 612). 14. Akduman B, Fleshner NE, Ehrlich L, Klotz L. Early experience in intermediate-risk penile cancer with sentinel node identification using the gamma probe. Urology 2001;58(1):65-8. http://www.ncbi.nlm.nih.gov/pubmed/11445481 15. Perdonà S, Gallo L, Claudio L, Marra L, Gentile M, Gallo A. [Role of crural inguinal lymphadenectomy and dynamic sentinel lymph node biopsy in lymph node staging in squamous-cell carcinoma of the penis. Our experience.] Tumori 2003;89(4 Suppl):276-9. [article in Italian] http://www.ncbi.nlm.nih.gov/pubmed/12903620 16. Tanis PJ, Lont AP, Meinhardt W, Olmos RA, Nieweg OE, Horenblas S. Dynamic sentinel node biopsy for penile cancer: reliability of a staging technique. J Urol 2002;168(1):76-80. http://www.ncbi.nlm.nih.gov/pubmed/12050496 17. Wawroschek F, Vogt H, Bachter D, Weckermann D, Hamm M, Harzmann R. First experience with gamma probe guided sentinel lymph node surgery in penile cancer. Urol Res 2000;28(4):246-9. http://www.ncbi.nlm.nih.gov/pubmed/11011963 18. Lont AP, Horenblas S, Tanis PJ, Gallee MP, Van Tinteren H, Nieweg OE. Management of clinically node negative penile carcinoma: improved survival after the introduction of dynamic sentinel node biopsy. J Urol 2003;170(3):783-6. http://www.ncbi.nlm.nih.gov/pubmed/12913697 19. Leijte JA, Kroon BK, Valdés Olmos RA, Nieweg OE, Horenblas S. Reliability and safety of current dynamic sentinel node biopsy for penile carcinoma. Eur Urol 2007;52(1):170-7. 20. Mueller-Lisse UG, Scher B, Scherr MK, Seitz M. Functional imaging in penile cancer: PET/computed tomography, MRI, and sentinel lymph node biopsy. Curr Opin Urol 2008;18(1):105-10. http://www.ncbi.nlm.nih.gov/pubmed/18090498 21. Tabatabaei S, Harisinghani M, McDougal WS. Regional lymph node staging using lymphotropic nanoparticle enhanced magnetic resonance imaging with ferumoxtran-10 in patients with penile cancer. J Urol 2005;174:923-7; discussion 927. http://www.ncbi.nlm.nih.gov/pubmed/16093989

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22.

Scher B, Seitz M, Albinger W, Reiser M, Schlenker B, Stief C, Mueller-Lisse U, Dresel S. Value of PET and PET/CT in the diagnostics of prostate and penile cancer. Recent Results Cancer Res 2008;170:159-79. http://www.ncbi.nlm.nih.gov/pubmed/18019625 23. Cubilla AL. The role of pathologic prognostic factors in squamous cell carcinoma of the penis. World J Urol 2008 Sep 3. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/18766352 24. Lopes A, Hidalgo GS, Kowalski LP, Torloni H, Rossi BM, Fonseca FP. Prognostic factors in carcinoma of the penis: multivariate analysis of 145 patients treated with amputation and lymphadenectomy J Urol 1996;156(5):1637-42. http://www.ncbi.nlm.nih.gov/pubmed/8863559 25. Ornellas AA, Nóbrega BL, Wei Kin Chin E, Wisnescky A, da Silva PC, de Santos Schwindt AB. Prognostic factors in invasive squamous cell carcinoma of the penis: analysis of 196 patients treated at the Brazilian National Cancer Institute. J Urol 2008;180(4):1354-9. http://www.ncbi.nlm.nih.gov/pubmed/18707720 26. Ficarra V, Zattoni F, Artibani W, Cunico SC, Fandella A, Martignoni G, Novara G, Galetti TP, Zattoni F; GUONE Penile Cancer Project Members. Nomogram predictive of pathological inguinal lymph nodes involvement in patients with squamous cell carcinoma of the penis. J Urol 2006;175(6):1700-5. http://www.ncbi.nlm.nih.gov/pubmed/16697813 27. Velazquez EF, Ayala G, Liu H, Chaux A, Zanotti M, Torres J, Cho SI, Barreto JE, Soares F, Cubilla AL. Histologic grade and perineural invasion are more important than tumor thickness as predictor of nodal metastasis in penile squamous cell carcinoma invading 5 to 10 mm. Am J Surg Pathol 2008;32(7):974-9. http://www.ncbi.nlm.nih.gov/pubmed/18460979 28. Horenblas S, Van Tinteren H, Delamarre JFM, Moonen LM, Lustig V, van Waardenburg EW. Squamous cell carcinoma of the penis. III. Treatment of regional lymph nodes. J Urol 1993;149(3): 492-7. http://www.ncbi.nlm.nih.gov/pubmed/8437253 29. Ornellas AA, Seixas AL, Marota A, Wisnescky A, Campos F, de Moraes JR. Surgical treatment of invasive squamous cell carcinoma of the penis: retrospective analysis of 350 cases. J Urol 1994;151(5):1244-9. http://www.ncbi.nlm.nih.gov/pubmed/7512656 30. Pizzocaro G, Piva L, Nicolai N. Treatment of lymphatic metastasis of squamous cell carcinoma of the penis: experience at the National Tumor Institute of Milan. Arch Ital Urol Androl 1996;68(3):169-72. http://www.ncbi.nlm.nih.gov/pubmed/8767505 31. Senthil Kumar MP, Ananthakrishnan N, Prema V. Predicting regional node metastasis in carcinoma of the penis: a comparison between fine-needle aspiration cytology, sentinel lymph node biopsy and medial inguinal lymph node biopsy. Br J Urol 1998;81(3):453-7. http://www.ncbi.nlm.nih.gov/pubmed/9523669 32. Skoog L, Collins BT, Tani E, Ramos RR. Fine-needle aspiration cytology of penile tumors. Acta Cytol 1998;42(2):1336-40. http://www.ncbi.nlm.nih.gov/pubmed/9568135 33. Ravizzini GC, Wagner M, Borges-Neto S. Positron emission tomography detection of metastatic penile squamous cell carcinoma. J Urol 2001;165(5):1633-4. http://www.ncbi.nlm.nih.gov/pubmed/11342941 34. Laniado ME, Lowdell C, Mitchell H, Christsmas TJ. Squamous cell carcinoma antigen: a role in the early identification of nodal metastases in men with squamous cell carcinoma of the penis. BJU Int 2003;92(3):248-5. http://www.ncbi.nlm.nih.gov/pubmed/12887477 35. Lopez A, Bezena AL, Pinto CA, Serrano SV, de Mello CA, Villa LL. p53 as a new prognostic factor for lymph node metastasis in penile carcinoma: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. J Urol 2002;168:81-6. http://www.ncbi.nlm.nih.gov/pubmed/12050497 36. Zhu Y, Zhang SL, Ye DW, Yao XD, Jiang ZX, Zhou XY Predicting pelvic lymph node metastases in penile cancer patients: a comparison of computed tomography, Cloquet’s node, and disease burden of inguinal lymph nodes. Onkologie. 2008;31:37-41. 37. Kayes O, Ahmed HU, Arya M, Minhas S. Molecular and genetic pathways in penile cancer. Lancet Oncol 2007;8(5):420-9. http://www.ncbi.nlm.nih.gov/pubmed/17466899

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38.

Lont AP, Kroon BK, Gallee MP, van Tinteren H, Moonen LM, Horenblas S. Pelvic lymph node dissection for penile carcinoma: extent of inguinal lymph node involvement as an indicator for pelvic lymph node involvement and survival. J Urol 2007;177(3):947-52; discussion 952. http://www.ncbi.nlm.nih.gov/pubmed/17296384

8. TREATMENT The primary tumour and regional lymph nodes are usually treated separately. It is important to avoid both overtreatment, which may lead to side-effects, and undertreatment, which may impair survival.

8.1

Primary tumour

8.1.1 Category Tis and Ta Tis and Ta are superficial lesions that can be treated with several conservative techniques: • topical 5-fluorouracil for Tis (1) • imiquimod 5% cream, an immune response modifier with good cosmetic and functional results on flat lesions (2) • laser therapy with carbon dioxide (CO2) or neodymium:yttrium-aluminum-garnet (Nd:YAG) lasers (3, 4) • photodynamic therapy (5) • Mohs’ micrographic surgery for Ta lesions (6, 7). However, conservative treatment may not be suitable in cases of multifocal lesions, which are responsible for 15% of recurrences. Total treatment of the glans surface combined with concomitant circumcision is strongly recommended (4) to avoid multiple recurrences (grade of recommendation: A). Cure with secondary healing was obtained in 94% of 106 Tis patients treated with peniscopically controlled CO2 laser excision. However, five patients had multiple recurrences and two required penile amputation (7). A recent paper on photodynamic therapy reported seven responses in 10 treated patients, but only four patients were recurrence-free after a mean follow-up of 35 months (5). Non-invasive verrucous carcinoma (Ta) needs a correct pre-operative diagnosis to avoid unnecessary extensive surgery (6). Furthermore, a recent report on Mohs’ micrographic surgery demonstrated a significant local recurrence rate for Tis and verrucous carcinoma as well as invasive SCC (7). In conclusion, the best results are achieved with laser surgery (level of evidence: 2b; grade of recommendation: B). 8.1.2 Category T1G1 For lesions limited (level of evidence: 2a) to the foreskin and sulcus, wide local excision with circumcision may provide adequate treatment. Pathological assessment of the surgical margin is mandatory; a margin of 3-4 mm is sufficient (8). For T1 tumours of the glans, peniscopically controlled CO2 laser excision alone cured 86% of 78 patients with histologically superficial infiltration (≤ 1 mm) of lamina propria (4). Another 40 patients had deeper infiltration (> 1 mm) with exophytic warty-like or plaque tumours. These patients received neo-adjuvant vinblastine, bleomycin and methotrexate (VBM) chemotherapy, with cure achieved in 33 (82%) patients. Of 18 (15%) relapsed patients, only eight (7%) needed penile amputation or radiotherapy (level of evidence: 2b). An alternative treatment of glans resurfacing (9) has shown promising results for preinvasive lesions (level of evidence: 2a). 8.1.3 Category T1G2-3 For patients who can guarantee they will attend for regular follow-up, a penis-preserving strategy is strongly recommended using wide local laser excision plus reconstructive surgery (10, 11) or glansectomy (12-14) (level of evidence: 2a). Treatment choice is influenced by tumour size and position on the glans and the side-effects of treatment. Meticulous follow-up is essential to enable immediate treatment of any local disease recurrence. There is no difference in the local recurrence rate (15% or more) between external radiation therapy, interstitial brachytherapy (BRT) laser therapy and wide local excision. Glansectomy has the lowest recurrence rate of 2% (13). Pathological assessment of surgical margins is essential when using these procedures to reduce the rate of local recurrence (12, 13, 15) (level of evidence: 2b). Generally, early diagnosis of local recurrence does not have a negative impact on survival (16) (level of evidence: 3).

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8.1.4 Category T2 (of the glans) A conservative strategy of total glansectomy, with or without resurfacing of the corporeal heads, is recommended (5, 14) (level of evidence: 2a). Partial glansectomy is an alternative in very carefully selected patients with tumours that include less than half of the glans and in whom close follow-up is possible (17) (level of evidence: 2b). Consider partial amputation in patients unfit for more conservative reconstructive surgery (13). 8.1.5 Category T2 (of the corpora) and T3 For tumours involving the tips of the corpora, partial amputation is standard treatment (18, 19) (level of evidence : 2a) . Reconstructive surgery with negative margins at frozen section analysis is an alternative in carefully selected patients (level of evidence: 2b). For large tumours involving more than the distal corpora, partial or radical amputation is standard (level of evidence: 2a). Traditionally, partial amputation has required removal of 2-cm tumour-free margins. This is almost certainly more than is necessary. However, it is essential to achieve tumour-free margins with pathological confirmation. A surgical margin of 5-10 mm is safe (15, 20, 21) (level of evidence: 2b). 8.1.6 Category T4 Deeply infiltrating tumours involving adjacent structures are often associated with disseminated disease at presentation and a short life expectancy. Palliative care may be most appropriate. In selected cases, downstaging with chemotherapy may be considered prior to total penectomy. Alternatives include surgery with adjuvant external beam irradiation (level of evidence: 3). 8.1.7 Local disease recurrence For local recurrence after conservative therapy, a second conservative procedure is strongly advised if there is no corpora cavernosa invasion (22) (level of evidence: 2b). However, if there is a large or deep infiltrating recurrence, partial or total amputation is strongly recommended. The incidence of local recurrence increases with penis preservation, but can be treated in most cases. Local recurrence after penile amputation has a poor prognosis (23). Combined chemotherapy and radiotherapy as for advanced head and neck cancer has not yet been tried. 8.1.8 Technical aspects of surgery 8.1.8.1 Conservative surgery The most important factors in the choice of conservative management are simplicity, morbidity of the procedure and the surgeon’s experience. Small areas of ablated/excised epithelium can heal without grafting. For a larger area, a skin graft provides a better cosmetic result in a shorter time (level of evidence: 3). 8.1.8.2 Partial/total amputation Stenosis of the neo-meatus or perineal urethrostomy is seen in approximately 7-10% and can be prevented by a spatulated repair. Orchidectomy should not be performed routinely (level of evidence: 3). 8.1.9 Radiotherapy External beam irradiation (ERT), brachytherapy (BRT) or both techniques together can be used. The ERT treatment is delivered with high-energy photons (4-6 MV) and uses CT scanning to define the target volume and to optimise dosage distribution. Different types of BRT can be used including external isotope mould, lowdose rate BRT, pulse-dose rate BRT or high-dose rate BRT. Primary tumour radiotherapy is an alternative organ-preserving approach with excellent results in selected patients with T1-2 lesions less than 4 cm in diameter (level of evidence: 2a). There have been no prospective studies or randomised trials to evaluate the different modalities of radiation treatment. A local control rate of about 60% has been reported using ERT, while BRT has achieved better control rates ranging from 70% to 90% (24-28). However, it is difficult to compare results using ERT and BRT because patients with large volume lesions (> 4 cm) are excluded from BRT. In addition, the different dosages used in different retrospective studies, even within the same institution, make it very difficult to compare results and side-effects. Local failure rates after radiotherapy were higher than after adequate partial penectomy, but salvage surgery can restore local control (28, 29). The high doses of radiation needed to achieve local control can cause iatrogenic complications. Urethral stenosis (20-35%), glans necrosis (10-20%) and late fibrosis are the most serious types of tissue damage and can result in a non-functioning penis.

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The penile preservation rate after radiotherapy is approximately 80%. The local control rate after BRT was recently reported as 90%, with an actuarial penile preservation rate of 87% at 5 years (29). Because of postradiation changes (necrosis, scars, ulcers), it may be difficult to differentiate radiation sequelae from persistent or recurrent tumour and very close follow-up is recommended. 8.1.9.1 Recommendations for radiation therapy Radiotherapy should be considered in two groups of patients with two different aims: • Organ-preserving treatment: in men with T1-2 glans or coronal sulcus lesions (< 4 cm), who are compliant for close follow-up. Both ERT combined with a BRT boost, or BRT alone, may be used to deliver the prescribed dose (> 60 Gy). • Palliative radiotherapy: in men with advanced or metastatic disease requiring palliative local treatment, the treatment of choice is ERT (40-50 Gy). 8.1.10 Guidelines for treatment strategies in primary tumour Primary tumour Category: Tis and Ta

LE 2a

GR B

2a

B

• Multifocal lesions and HPV-16 infection

Conservative therapy: CO2 or Nd:YAG lasers surgery are recommended Total glans resurfacing and circumcision are strongly recommended to prevent multiple recurrences

Category T1G1

T1G1 tumours are suitable for conservative surgery

2a

B

For glans lesions, CO2 laser surgery or resurfacing are appropriate For lesions of foreskin and sulcus, wide local excision with circumcision are appropriate with assessment of surgical margins Deeper infiltration may need adjuvant chemotherapy Penile-preserving treatment with wide local laser excision for complying patients with follow-up, or glansectomy are indicated Assessment of surgical margins reduces rate of local recurrence In these cases early diagnosis of local recurrence does not have an adverse impact on survival Total glansectomy, with or without resurfacing of corporeal heads Partial glansectomy is an alternative in very carefully selected patients with tumours less than half the glans and suitable for follow-up Consider partial amputation in patients unfit for follow-up Moderate partial amputation for tumours involving only tips of the corpora Partial or total amputation for larger tumours involving more than the distal corpora Traditionally, partial amputation has required removal of 2-cm tumour-free margins. A surgical margin of 5-10 mm is safe with pathological confirmation Deeply infiltrating tumours involving adjacent structures are often associated with disseminated disease at presentation . For patients in poor conditions with short life expectancy, palliative radiotherapy may be most appropriate Some patients may be suitable for down-staging with chemotherapy prior to surgery. Alternatives include adjuvant external beam irradiation if surgery is not possible. Local recurrence is more likely with penis preservation but it is usually treatable

2a

B

2a

B

2a 2a

B B

2b 2b

B C

2a

B

2b

B

2b 2a

B B

2a

B

2b

B

2a

C

2a

B

2a

B

2a

B

2a

B

Category T1G2-3

Category T2 (of glans)

Category T2 (of the corpora) and T3

Category T4

Local disease recurrence after conservative therapy

Second conservative procedure is strongly advised in absence of corpora cavernosa invasion Partial or total amputation is strongly recommended for large or deep infiltrating recurrence

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Main uses of radiotherapy

8.2

Local recurrence after penile amputation has a poor prognosis Organ-preserving treatment in selected patients with T1-2 glans or coronal sulcus lesions < 4 cm Palliative in advanced or metastatic disease not responsive to chemotherapy

2a 2b

B B

2b

B

Treatment of regional lymph nodes

Lymphadenectomy is the necessary surgical procedure for patients with inguinal lymph node metastases. Bilateral LAD is often followed by prolonged lymph leakage, which can result in leg and scrotal lymphoedema. Other surgical complications include skin flap necrosis, wound infection and haemorrhage from exposed femoral vessels. The procedure requires careful skin flap management, meticulous lymph node dissection, prophylactic antibiotics, compressive stoking and early ambulation. These complications occur in 30-70% of patients. Lymphadenectomy should therefore preferably only be performed in a therapeutic setting, where removal of lymph node metastases is indisputable. 8.2.1 Management of patients with non-palpable inguinal nodes 8.2.1.1 Surveillance In the past, patients with low-stage tumours and clinically unaffected inguinal nodes have often undergone surveillance strategies. The 2004 EAU guidelines ‘strongly’ recommended surveillance only in patients with superficial and well-differentiated tumours: Tis, TaG1-2, T1G1 and T1G2 with superficial growth and no vascular invasion (30). This approach was criticised following a study that found 82% of 100 consecutive patients had undergone unnecessary prophylactic LAD (31). 8.2.1.2 Prognostic factors For a long time, urologists have been oriented to look at pathological risk factors for metastases and pT3-T4 and all G3 patients were unequivocal candidates for bilateral LAD. In an old series (32), nodal metastases were found in 100% of pT3-T4, in 82% of pT2 and 23% of pT1. In particular, 16.5% of metastases were found in pT1G1 and 60% in pT1G2-3. No metastases were found in Ta or Tis. In a very recent series (33), lymph node metastases were found in 12% of pT1G2, a category that has therefore been defined as ‘intermediate risk’. A high histological grade and perineural invasion (21) or depth of invasion (34) are significant predictors of lymph node metastases. A nomogram (34) has identified palpable groin lymph nodes and vascular and/or lymphatic invasion as the most important predictors of lymph node metastases. A new nomogram with a larger international series of patients is ongoing (level of evidence: 2b). 8.2.1.3 Sentinel node biopsy (SNB) Catalona’s SNB (35) was a failure, but dynamic SNB appears very promising (36-39). The concept behind dynamic SNB assumes there is a stepwise and orderly progression of the primary node (the so-called sentinel node) to secondary lymph nodes. There may be more than one sentinel node. To identify the sentinel node(s), 99mTc-nanocolloid is injected around the penile tumour intradermally the day before surgery. The sentinel lymph node(s) are detected intra-operatively with a gamma X-ray detection probe and patent blue dye staining before being dissected and removed. If there is a positive histology, either on frozen section or definitive histology, a formal complete inguinal LAD is performed. The technique has been extensively studied in a few specialised centres. The Netherlands Cancer Institute group initially reported a high rate of false-negative cases (36). However, following modification of the technique, they reported a markedly reduced false-negative rate of 4.8% (39). However, the technique has been criticised for its steep learning curve and the need for the surgeon to perform a minimal number of 20 procedures per year (40) (level of evidence: 2a). 8.2.2 Management of patients with palpable inguinal nodes In patients with penile cancer, moderately enlarged palpable inguinal nodes, which are not fixed, may or may not signify metastatic disease. The rate of false-positive nodes has been reported as high as 50% (41), but recently much lower figures of 30% have been reported (42). Ultrasound with fine-needle aspiration biopsy provides an excellent, rapid and easy way to detect metastatic involvement. Of course this is only reliable in tumour-positive patients. In suspected cases with tumour-negative findings, fine-needle aspiration biopsy should be repeated. Dynamic SNB is not reliable in this group of patients and should not be used (43, 44). Thus, in all tumour-positive patients, early LAD should be performed (45, 46); bilateral LAD is the standard

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procedure. In contralateral non-palpable lymph nodes, surgical staging is recommended either by dynamic SNB or lymph node dissection (level of evidence: 2a). 8.2.2.1 Inguinal LAD Significant morbidity has been described including wound infection, skin necrosis, wound dehiscence, lymphoedema and lymphocele (47, 48). Optimal skin handling and careful dissection of skin flaps are two of the most important factors in preventing complications. Skin rotation flaps and myocutaneous flaps should be used for primary wound closure in advanced cases (49) (level of evidence: 2b). 8.2.2.2 Modified inguinal LAD This procedure is associated with less morbidity than standard LAD (50, 51). The rate of early complications was 6.8% (vs 41.4%) and the rate of late complications was 3.4% (vs 43.1%) for patients with modified LAD (51). However, reducing the field of dissection increased the possibility of falsenegative cases (level of evidence: 2b). The high false-negative rate described by Lopes et al. (52) should be considered in the light of recent findings concerning lymphatic drainage to the lateral superior Daseler’s zone, which was not dissected in this approach (53, 54). Current knowledge of lymphatic drainage at the penis suggests that a contemporary modified LAD should dissect the central and both superior Daseler’s zones of the inguinal region (grade of recommendation: B). 8.2.2.3 The role of pelvic LAD There is no direct lymphatic drainage from penile cancer to the pelvic lymph nodes (54, 55). Thus, if there is no involvement of inguinal nodes, pelvic LAD is not warranted. In contrast, if the Cloquet node or other two inguinal nodes are involved on one side, a contemporary pelvic lymph node dissection must be performed through an upward muscle-splitting incision. Pathological predictors for the potential involvement of pelvic nodes in patients with involved inguinal nodes are the number of positive inguinal lymph nodes and extracapsular extent of metastatic disease (56) (level of evidence: 2a). Pelvic LAD may be necessary as a secondary procedure. If bilateral dissection is indicated, it can be performed though a midline suprapubic extraperitoneal incision. The rate of positive pelvic nodes was 23% in cases with no more than two positive inguinal nodes and 56% for more than two positive inguinal nodes or if there is extracapsular extent in at least one inguinal node (57-59). If very aggressive histological subtypes of penile cancer (i.e. basaloid) are present, or there is strong expression of p53, pelvic lymph node dissection should be considered if any inguinal node is involved (60) (grade of recommendation: B). 8.2.2.4 Video-endoscopic inguinal and pelvic LAD This recently described technique is derived from laparoscopic surgery and has been evaluated only in small pilot studies (61, 62). It seems to carry a lower risk of skin complications, but a higher risk of lymphocele formation compared to an open approach; the reported overall complication rate was 23% (63). The reliability of this technique has not yet been assessed (level of evidence: 4). Laparoscopic pelvic node dissection for bilateral pelvic lymph node removal, following positive bilateral inguinal LAD, is a rational approach, but only if the dissection can be performed with similar accuracy as open surgery. 8.2.3 Adjuvant chemotherapy Adjuvant chemotherapy after resection of nodal metastases has been reported in a few series. There has been only one study group who reported consistent results with adjuvant post-operative chemotherapy in N+ patients (64, 65). Twenty-five consecutive patients with resected lymph node metastases from SCC of the penis received 12 weekly courses of adjuvant VBM (vincristine, bleomycin, methotrexate) chemotherapy between 1979 and 1990. All patients underwent ilioinguinal lymph node dissection and received adjuvant chemotherapy. Only four (16%) patients relapsed, and the other 21 had a long-term disease-free survival of 84%. These results compared favourably with a previous series of 31 patients, who underwent ilioinguinal lymph node dissection, alone or with adjuvant radiotherapy, between 1960 and 1978. The 5-year disease-free survival was only 37%. Among these 31 patients, only the involvement of a single, intranodal inguinal node metastasis was associated with good prognosis. In contrast, in the series of 25 patients treated with adjuvant chemotherapy (VBM), only bilateral and/or pelvic node involvement were significantly associated with poor prognosis, with 4 of 8 patients dying of penile cancer (level of evidence: 2a).

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Since 1991, pN2-N3 patients have been treated with three courses of adjuvant cisplatin and 5-fluorouracil (PF) with only two relapses (6.7%) in the first 30 treated patients (65) (level of evidence: 2a). 8.2.4 Management of patients with fixed or relapsed inguinal nodes Fourteen patients were treated with locally advanced or metastatic penile cancer with cisplatin, methotrexate and bleomycin (BMP) chemotherapy on days 2 to 5 (66). Toxicity was severe. Only three of the eight partial responders underwent surgery, while another two entered complete remission. In a confirmatory study by the Southwest Oncology Group (SWOG) (67), only six of 40 evaluable patients completed chemotherapy. Five complete and eight partial remissions were achieved, but at the cost of 11% treatment-related mortality and 17% life-threatening toxicity. Another study (68) of BMP chemotherapy in 13 patients reported one death from treatment-related toxicity and no complete remissions (level of evidence: 2a). A review was performed of 20 patients who had received neo-adjuvant chemotherapy, including BMP, for unresectable lymph node metastases during the period 1972 to 2005 (69). Twelve of 19 evaluable patients showed an objective tumour response. Five different chemotherapeutic regimens were used. Nine responders underwent subsequent surgery, of whom eight became long-term survivors without evidence of recurrent disease. Chemotherapy-related toxicity was fatal in three out of 10 patients treated with BMP (level of evidence: 2b). At the MD Anderson Cancer Center (Houston, TX, USA) (70), 10 patients were treated with surgical consolidation following a stable, partial, or complete response to four to five courses of the following chemotherapeutic regimens: paclitaxel, ifosfamide and cisplatin (ITP) in five patients, paclitaxel and carboplatin (PC) in two patients, and BMP in three patients. Three of the five patients treated with ITP had a pathologically documented complete remission and two of them are long-term survivors. The two patients treated with PC became disease-free with post-chemotherapy surgery. All three patients treated with BMP suffered severe toxicity and died of the disease. Systematic use of post-chemotherapy surgery in responsive patients was of main importance in the latter two studies (69, 70) (level of evidence: 2a). In addition, a preliminary report (71) on taxol combined with PF (TPF) chemotherapy in six consecutive patients with unresectable or relapsed inguinopelvic lymph node metastases from SCC of the penis suggests that TPF could have improved activity compared to PF alone in this clinical situation (65), as has been demonstrated in SCC of the head and neck in three randomised trials (72-74). In conclusion, adjuvant chemotherapy is strongly recommended in pN2-3 patients, and neo-adjuvant chemotherapy with taxanes seems to be active in unresectable or recurrent lymph node metastases (level of evidence: 2a, grade of recommendation: B). 8.2.5 The role of radiotherapy Prophylactic radiotherapy in clinical N0 patients is not recommended for the following reasons: • radiotherapy fails to prevent the development of metastatic lymph nodes (75) • complications of radiotherapy (76) • follow-up is more difficult due to fibrotic changes. Pre-operative radiotherapy in patients with fixed nodes can make the nodes operable, but it is not known whether node fixation is an inflammatory reaction or malignant growth (75, 76). Adjuvant radiotherapy may improve loco-regional control in patients with extensive metastases and/or extranodal spread. However, severe side-effects include oedema and pain (75).

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8.2.6 Guidelines for treatment strategies for nodal metastases Regional lymph nodes No palpable inguinal nodes

Palpable inguinal nodes

Pelvic nodes

Adjuvant chemotherapy

Patients with fixed or relapsed inguinal nodes

Radiotherapy

Management of regional lymph nodes is fundamental in the treatment of penile cancer Tis, Ta G1, T1G1: surveillance > T1G2: DSNB (NB: Inguinal LAD if histology is positive.) If DSNB not available: risk factors / nomogram decision-making Ultrasound-guided FNAB (NB: DSNB is unsuitable for palpable nodes) Negative biopsy: surveillance (repeat biopsy) Positive biopsy: inguinal LAD on positive side (NB: Modified LAD must include the central zone and both superior Daseler’s zones.) Pelvic LAD if there are: extranodal metastases; Cloquet node involved; > 2 inguinal node metastases Unilateral pelvic LAD if unilateral lymph node metastases with prolonged inguinal incision Bilateral pelvic LAD if bilateral inguinal metastases In patients with > 1 intranodal metastasis (pN2 pN3) after radical LAD, survival is improved by adjuvant chemotherapy (2 or 3 courses of cisplatin, fluorouracil (PF) chemotherapy) Neo-adjuvant chemotherapy is strongly recommended in patients with unresectable or recurrent lymph node metastases. Taxanes seems to improve the efficacy of standard PF chemotherapy Curative radiotherapy may be used for primary tumours of the glans penis and sulcus < 4 cm or for palliation Prophylactic radiotherapy in clinical N0 patients is not indicated

LE

GR

2a

B

2a

B

3 2a

C B

2a

B

2b

B

2a 2b

B B

2a

B

2a

B

2a

B

LE = level of evidence; GR = grade of recommendation; LAD = lymphadenectomy; FNAB = fine-needle aspiration biopsy; DSNB = sentinel node biopsy.

8.3

REFERENCES

1.

Goette DK, Carson TE. Erythroplasia of Queyrat: treatment with topical 5-fluorouracil. Cancer 1976;38(4):1498-502. http://www.ncbi.nlm.nih.gov/pubmed/991073 2. Taliaferro SJ, Cohen GF. Bowen’s disease of the penis treated with topical imiquimod 5% cream. J Drugs Dermatol 2008;7(5):483-5. http://www.ncbi.nlm.nih.gov/pubmed/18505144 3. van Bezooijen BP, Horenblas S, Meinhardt W, Newling DW. Laser therapy for carcinoma in situ of the penis. J Urol 2001;166(5):1670-1. http://www.ncbi.nlm.nih.gov/pubmed/11586199 4. Bandieramonte G, Colecchia M, Mariani L, Lo Vullo S, Pizzocaro G, Piva L, Nicolai N, Salvioni R, Lezzi V, Stefanon B, De Palo G. Peniscopically controlled CO2 laser excision for conservative treatment of in situ and T1 penile carcinoma: report on 224 patients. Eur Urol 2008;54(4):875-84. http://www.ncbi.nlm.nih.gov/pubmed/18243513 5. Paoli J, Ternesten Bratel A, Löwhagen GB, Stenquist B, Forslund O, Wennberg AM. Penile intraepithelial neoplasia: results of photodynamic therapy. Acta Derm Venereol 2006;86(5):418-21. http://www.ncbi.nlm.nih.gov/pubmed/16955186 6. Hatzichristou DG, Apostolidis A, Tzortzis V, Hatzimouratidis K, Ioannides E, Yannakoyorgos K. Glansectomy: an alternative surgical treatment for Buschke-Löwenstein tumors of the penis. Urology 2001;57(5):966-9. http://www.ncbi.nlm.nih.gov/pubmed/11337304 7. Shindel AW, Mann MW, Lev RY, Sengelmann R, Petersen J, Hruza GJ, Brandes SB. Mohs micrographic surgery for penile cancer: management and long-term followup. J Urol 2007;178(5):1980-5. http://www.ncbi.nlm.nih.gov/pubmed/17869306

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8.

Penile Cancer Treatment (PDQ®) Health Professional Version. National Cancer Institute, US National Institutes of Health, 2008, pp. 6-7. http://www.cancer.gov/cancertopics/pdq/treatment/penile/healthprofessional/allpages/print 9. Hadway P, Corbishley CM, Watkin NA. Total glans resurfacing for premalignant lesions of the penis: initial outcome data. BJU Int 2006;98(3):532-6. http://www.ncbi.nlm.nih.gov/pubmed/16925748 10. Frimberger D, Hungerhuber E, Zaak D, Waidelich R, Hofstetter A, Schneede P. Penile carcinoma. Is Nd:YAG laser therapy radical enough?. J Urol 2002;168(6):2418-21. http://www.ncbi.nlm.nih.gov/pubmed/12441930 11. Windalh T, Andersson SO. Combined laser treatment for penile carcinoma: results after long-term follow up. J Urol 2003;169(6):2118-21. http://www.ncbi.nlm.nih.gov/pubmed/12771731 12. Bissada NK, Yakout HH, Fahmy WE, Gayed MS, Touijer AK, Greene GF, Hanash KA. Multiinstitutional long-term experience with conservative surgery for invasive penile carcinoma. J Urol 2003;169(2): 500-2. http://www.ncbi.nlm.nih.gov/pubmed/12544296 13. Smith Y, Hadway P, Biedrzycki, Perry MJA, Corbishley C, Watkin NA. Reconstructive surgery forinvasive squamous cell carcinoma of the glans penis. Eur Urol 2007;52(4):1179-85. http://www.ncbi.nlm.nih.gov/pubmed/17349734 14. Davis JW, Schellhammer PF, Schlossberg SM. Conservative surgical therapy for penile and urethralcarcinoma. Urology 1999;53(2):386-92. http://www.ncbi.nlm.nih.gov/pubmed/9933060 15. Algaba F, Arce Y, López-Beltán A, Montironi R, Mikuz G, Bono AV. Intraoperative frozen section diagnosis in Urological Oncology. Eur Urol 2005;47(2):129-36. http://www.ncbi.nlm.nih.gov/pubmed/15661406 16. Gotsadze D, Matveev, B, Zak, B, Mamaladze V. Is conservative organ-sparing treatment of penile carcinoma justified? Eur Urol 2000;38(3):306-12. http://www.ncbi.nlm.nih.gov/pubmed/10940705 17. Minhas S, Kayes O, Hegarty P, Kumar P, Freeman A, Ralph D. What surgical resection margins are required to achieve oncological control in men with primary penile cancer? BJU Int 2005;96(7):1040-3. http://www.ncbi.nlm.nih.gov/pubmed/16225525 18. Ornellas AA, Seixas ALC, Marota A, Wisnescky A, Campos F, de Moraes JR. Surgical treatment of invasive squamous cell carcinoma of the penis: retrospective analysis of 350 cases. J Urol 1994;151(5):1244-9. http://www.ncbi.nlm.nih.gov/pubmed/7512656 19. Lont AP, Gallee MP, Meinhardt W, van Tinteren H, Horenblas S. Penis conserving treatment for T1 and T2 penile carcinoma: clinical implications of a local recurrence. J Urol 2006;176(2):575-80;discussion 580. http://www.ncbi.nlm.nih.gov/pubmed/16813892 20. Velázquez EF, Soskin A, Bock A, Codas R, Barreto JE, Cubilla AL. Positive resection margins in partial penectomies. Sites of involvement and proposal of local routes of spread of penile squamous cell carcinoma. Am J Surg Pathol 2004;28(3):384-9. http://www.ncbi.nlm.nih.gov/pubmed/15104302 21. Horenblas S, Van Tinteren H, Delemarre JFM, Boon TA, Moonen LMF, Lustig V. Squamous cell carcinoma of the penis. II. Treatment of the primary tumor. J Urol 1992;147(6):1533-8. http://www.ncbi.nlm.nih.gov/pubmed/1593683 22. Koch MO, Smith JA Jr. Local recurrence of squamous cell carcinoma of the penis. Urol Clin North Am 1994;21(4):739-43. http://www.ncbi.nlm.nih.gov/pubmed/7974902 23. Gotsadze D, Matveev B, Zak B, Mamaladze V. Is conservative organ-sparing treatment of penile carcinoma justified? Eur Urol 2000;38(3):306-12. http://www.ncbi.nlm.nih.gov/pubmed/10940705 24. Sarin R, Norman AR, Steel GG. Treatment results and prognostic factors in 101 men treated for squamous carcinoma of the penis. Int J Radiat Oncol Biol Phys 1997;38(4):713-22. http://www.ncbi.nlm.nih.gov/pubmed/9240637 25. Kiltie AE, Elwell C, Close A, Ash DV. Iridium-192 implantation for node-negative carcinoma of the penis: The Cookridge Hospital Experience. Clin Oncol (R Coll Radiol) 2000;12(1):25-31. http://www.ncbi.nlm.nih.gov/pubmed/10749016

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26.

Azrif M, Logue GP, Swindell R, Cowan RA, Wylie JP, Livsey JE. External-beam radiotherapy in T1-2 N0 penile carcinoma. Clin Oncol (R Coll Radiol) 2006;18(4):320-5. http://www.ncbi.nlm.nih.gov/pubmed/16703750 27. Rozan R, Albuisson E, Giraud B, Donnarieix D, Delannes M, Pigneux J, Hoffstetter S, Gerbaulet A, Chinet-Charrot P, Goupil A, et al. Interstitial brachytherapy for penile carcinoma: a multicentric survey (259 patients). Radiother Oncol 1995;36(2):83-93. http://www.ncbi.nlm.nih.gov/pubmed/7501816 28. Zouhair A, Coucke PA, Jeanneret W, Douglas P, Do HP, Jichilinski P, Mirimanoff RO, Ozsahin M. Radiation therapy alone or combined surgery and radiation therapy in squamous-cell carcinoma of the penis? Eur J Cancer 2001;37(2):198-203. http://www.ncbi.nlm.nih.gov/pubmed/11166146 29. Crook JM, Grimard L, Esche B, Pond G. Penile brachytherapy: results for 60 patients. Brachytherapy 2007;6:82. 30. Solsona E, Algaba F, Horenblas S, Pizzocaro G, Windahl T. EAU Guidelines on Penile Cancer. Eur Urol 2004;46(1):1-8. http://www.ncbi.nlm.nih.gov/pubmed/15183542 31. Hegarty PK, Kayes O, Freeman A, Christopher N, Ralph DJ, Minhas S. A prospective study of 100 cases of penile cancer managed according to European Association of Urology guidelines. BJU Int 2006;98(3):526-31. http://www.ncbi.nlm.nih.gov/pubmed/16925747 32. Pizzocaro G, Piva L, Nicolai N. [Treatment of lymphatic metastases for squamous cell carcinoma of the penis: experience at the National Tumor Institute of Milan.] Arch Ital Urol Androl 1996:68(3):169-72. [article in Italian] http://www.ncbi.nlm.nih.gov/pubmed/8767505 33. Hughes B, Leijte J, Shabbir M, et al. Lymphnode metastassis in intermediate risk penile squamous cell cancer. A multicentre experience. Eur Urol Suppl 2008;7(3):110 (abstract 160). 34. Ficarra V, Zattoni F, Artibani W. Cunico SC, Fandella A, Martignoni G, Novara G, Galetti TP, Zattoni F; GUONE Penile Cancer Project Members. Nomogram predictive of pathological inguinal lymph nodes involvement in patients with squamous cell carcinoma of the penis. J Urol 2006;175(6):1700-5. http://www.ncbi.nlm.nih.gov/pubmed/16697813 35. Catalona WJ. Modified inguinal lymphadenectomy for carcinoma of the penis with preservation of saphenous vein: technique and preliminary results. J Urol 1988;140(2):306-10. http://www.ncbi.nlm.nih.gov/pubmed/3398125 36. Horenblas S, Jansen L, Meinhardt W, Hoefnagel CA, de Jong D, Nieweg OE. Detection of occult metastasis in squamous cell carcinoma of the penis using a dynamic sentinel node procedure. J Urol 2000;163(1):100-4. http://www.ncbi.nlm.nih.gov/pubmed/10604324 37. Perdonà S, Autorino R, Gallo L, Di Lorenzo G, Cascini GL, Lastoria F, Marra L, De Sio M, Damiano R, Gallo A. Role of dynamic sentinel node biopsy in penile cancer: our experience. J Surg Oncol 2006;93(3):181-5. http://www.ncbi.nlm.nih.gov/pubmed/16482606 38. Kroon BK, Horenblas S, Estourgie SH, Lont AP, Valdes Olmos RA, Nieweg OE. How to avoid falsenegative dynamic sentinel node procedures in penile carcinoma. J Urol 2004;171(6 Pt 1):2191-4. http://www.ncbi.nlm.nih.gov/pubmed/15126783 39. Leijte JAP, Kroon BK, Valdes Olmos RD, Nieweg OE, Horenblas S. Reliability and safety of current dynamic sentinel node biopsy for penile carcinoma. Eur Urol 2007;52(1):170-7. http://www.ncbi.nlm.nih.gov/pubmed/17316967 40. Ficarra V, Galfano A. Should the dynamic sentinel node biopsy (DSNB) be considered the gold standard in the evaluation of lymph node status in patients with penile carcinoma?. Eur Urol 2007;52(1):17-19; discussion 20-1. Epub 2007. http://www.ncbi.nlm.nih.gov/pubmed/17376585 41. Persky L, deKernion J. Carcinoma of the penis. CA Cancer J Clin 1986;36(5):258-73. http://www.ncbi.nlm.nih.gov/pubmed/3093013 42. Velasquez EF, Ayala C, Liu H, Chaux A, Zanotti M, Torres J, Cho SI, Barreto JE, Soares F, Cubilla AL. Histologic grade and perineal invasion are more important than tumor thickness as predictor of nodal metastases in penile squamous cell carcinoma invading 5 to 10 mm. Am J Surg Pathol 2008;32(7):974-9. http://www.ncbi.nlm.nih.gov/pubmed/18460979

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43.

Horenblas S. Lymphadenectomy for squamous cell carcinoma of the penis. Part 1: diagnosis of lymph node metastasis. BJU Int 2001;88:467-72. http://www.ncbi.nlm.nih.gov/pubmed/11589659 44. Preis E, Jakse G. [The significance of inguinal lymphadenectomy in carcinoma of the penis.] Urologe A 2006;45(Suppl 04):176-80. [article in German] http://www.ncbi.nlm.nih.gov/pubmed/16933120 45. Kroon BK, Horenblas S, Estourgie SH, Lont AP, Valdes Olmos RA, Nieweg OE. How to avoid falsenegative dynamic sentinel node procedures in penile carcinoma. J Urol 2004;171(6 Pt 1):2191-4. http://www.ncbi.nlm.nih.gov/pubmed/15126783 46. Hungerhuber E, Schlenker B, Frimberger D, Linke R, Karl A, Stief CG, Schneede P. Lymphoscintigraphy in penile cancer: limited value of sentinel node biopsy in patients with clinically suspicious lymph nodes. World J Urol 2006;24(3):319-24. http://www.ncbi.nlm.nih.gov/pubmed/16688459 47. Kroon BK, Horenblas S, Lont AP, Tanis PJ, Gallee MP, Nieweg OE. Patients with penile carcinoma benefit from immediate resection of clinically occult lymph node metastases. J Urol 2005;173(3):816-9 http://www.ncbi.nlm.nih.gov/pubmed/15711276 48. Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA (eds). Campbell-Walsh Urology. 9th edn. Philadelphia, PA: Saunders Elsevier, 2007. 49. Horenblas S. Lymphadenectomy for squamous cell carcinoma of the penis. Part 2: the role and technique of lymph node dissection. BJU Int 2001;88(5):473-83. http://www.ncbi.nlm.nih.gov/pubmed/11589660 50. Bevan-Thomas R, Slaton JW, Pettaway CA. Contemporary morbidity from lymphadenectomy for penile squamous cell carcinoma: the MD Anderson Cancer Center Experience. J Urol 2002;167(4):1638-42. http://www.ncbi.nlm.nih.gov/pubmed/11912379 51. Bouchot O, Rigaud J, Maillet F, Hetet JF, Karam G. Morbidity of inguinal lymphadenectomy for invasive penile carcinoma. Eur Urol 2004;45(6):761-5; discussion 765-6. http://www.ncbi.nlm.nih.gov/pubmed/15149749 52. Lopes A, Rossi BM, Fonseca FP, Morini S. Unreliability of modified inguinal lymphadenectomy for clinical staging of penile carcinoma. Cancer 1996;77(10):2099-102. http://www.ncbi.nlm.nih.gov/pubmed/8640676 53. Daseler EH, Anson BJ, Reimann AF. Radical excision of inguinal and iliac lymph glands: a study based upon 450 anatomical dissections and upon supportive clinical observations. Surg Gynecol Obstet 1948;87(6):679-94. http://www.ncbi.nlm.nih.gov/pubmed/18120502 54. Leijte JAP, Valdés Olmos RA, Nieweg OE, Horenblas S. Anatomical mapping of lymphatic drainage in penile cancer with SPECT-TC: implications for the extent of inguinal lymph node dissection. Eur Urol 2008;54(4):885-90. http://www.ncbi.nlm.nih.gov/pubmed/18502024 55. Cabanas RM. An approach for treatment of penile carcinoma. Cancer 1977;39(2):456-66. http://www.ncbi.nlm.nih.gov/pubmed/837331 56. Lont AP, Kroon BK, Gallee MP, van Tinteren H, Moonen LM, Horenblas S. Pelvic lymph node dissection for penile carcinoma: extent of inguinal lymph node involvement as an indicator for pelvic lymph node involvement and survival. J Urol 2007;177(3):947-52; discussion 952. http://www.ncbi.nlm.nih.gov/pubmed/17296384 57. Ornellas AA, Seixas AL, Marota A, Wisnescky A, Campos F, de Moraes JR. Surgical treatment of invasive squamous cell carcinoma of the penis: retrospective analysis of 350 cases. J Urol 1994;151(5):1244-9. http://www.ncbi.nlm.nih.gov/pubmed/7512656 58. Culkin DJ, Beer TM. Advanced penile carcinoma. J Urol 2003;170(2 Pt 1):359-65. http://www.ncbi.nlm.nih.gov/pubmed/12853775 59. Lopes A, Bezerra AL, Serrano SV, Hidalgo GS. Iliac nodal metastases from carcinoma of the penis treated surgically. BJU Int 2000;86(6):690-3. http://www.ncbi.nlm.nih.gov/pubmed/11069378 60. Zhu Y, Zhang SL, Ye DW, Yao XD, Jiang ZX, Zhou XY. Predicting pelvic lymph node metastases in penile cancer patients: a comparison of computed tomography, Cloquet’s node, and disease burden of inguinal lymph nodes. Onkologie 2008;31(1-2):37-41. http://www.ncbi.nlm.nih.gov/pubmed/18268397

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61. Tobias-Machado M, Tavares A, Ornellas AA, Molina WR Jr, Juliano RV, Wroclawski ER. Video endoscopic inguinal lymphadenectomy: a new minimally invasive procedure for radical management of inguinal nodes in patients with penile squamous cell carcinoma. J Urol 2007;177(3):953-7;discussion 958. http://www.ncbi.nlm.nih.gov/pubmed/17296386 62. Tobias-Machado M, Tavares A, Silva MN, Molina Jr WR, Forseto PH, Juliano RV, Wroclawski ER. Can video endoscopic inguinal lymphadenectomy achieve a lower morbidity than open lymph node dissection in penile cancer patients?. J Endourol 2008;22(8):1687-91. http://www.ncbi.nlm.nih.gov/pubmed/18657031 63. Sotelo R, Sanchez-Salas R, Carmona O, Garcia A, Mariano M, Neiva G, Trujillo G, Novoa J, Cornejo F, Finelli A. Endoscopic lymphadenectomy for penile carcinoma. J Endourol 2007;21(4):364-7;discussion 367. http://www.ncbi.nlm.nih.gov/pubmed/17451323 64. Pizzocaro G, Piva L. Adjuvant and neoadjuvant vincristine, bleomycin, and methotrexate for inguinal metastases from squamous cell carcinoma of the penis. Acta Oncol 1988;27(6b):823-4. http://www.ncbi.nlm.nih.gov/pubmed/2466471 65. Pizzocaro G, Piva L, Bandieramonte G, Tana S. Up-to-date management of carcinoma of the penis. Eur Urol 1997;32(1):5-15. http://www.ncbi.nlm.nih.gov/pubmed/9266225 66. Dexeus F, Logothetis C, Sella A, Amato R, Kilbourn R, Fitz K, Striegel A. Combination chemotherapy with methotrexate, bleomycin and cisplatin for advanced squamous cell carcinoma of the male genital tract. J Urol 1991;146(5):1284-7. http://www.ncbi.nlm.nih.gov/pubmed/1719241 67. Haas G, Blumenstein B, Gagliano R, Russell CA, Rivkin SE, Culkin DJ, Wolf M, Crawford ED. Cisplatin, methotrexate and bleomycin for the treatment of carcinoma of the penis: a Southwest Oncology Group study. J Urol 1999;161(6):1823-5. http://www.ncbi.nlm.nih.gov/pubmed/10332445 68. Hakenberg OW, Nippgen JB, Froehner M, Zastrow S, Wirth MP. Cisplatin, methotrexate and bleomycin for treating advanced penile carcinoma. BJU Int 2006;98(6):1225-7. http://www.ncbi.nlm.nih.gov/pubmed/17125480 69. Lijte JA, Kerst JM, Bais E, Antonini N, Horenblas S. Neoadjuvant chemotherapy in advanced penile carcinoma. Eur Urol 2007;52(2):488-94. http://www.ncbi.nlm.nih.gov/pubmed/17316964 70. Barmejo C, Busby JK, Spiess PE, Heller L, Pagliaro LC, Pettaway CA. Neoadjuvant chemotherapy followed by aggressive surgical consolidation for metastatic penile squamous cell carcinoma. J Urol 2007;177(4):1335-8. http://www.ncbi.nlm.nih.gov/pubmed/17382727 71. Pizzocaro G, Nicolai N, Milani A. Taxanes in combination with cisplatin and fluorouracil for advanced penile cancer: preliminary results. Eur Urol 2008 Jul 14. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/18649992 72. Hitt R, López-Pousa A, Martínez-Trufero J et al. Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol 2005;23(34):8636-45. http://jco.ascopubs.org/cgi/content/full/23/34/8636 73. Posner MR, Hershock DM, Blajman CR et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007;357(17):1705-15. http://content.nejm.org/cgi/content/abstract/357/17/1705 74. Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007;357(17):1695-704. http://content.nejm.org/cgi/content/abstract/357/17/1695 75. Kulkarni JN, Kamat MR. Prophylactic bilateral groin node dissection versus prophylactic radiotherapy and surveillance in patients with N0 and N1-2A carcinoma of the penis. Eur Urol 1994;26(2):123-8. http://www.ncbi.nlm.nih.gov/pubmed/7957466 76. Ravi R, Chaturvedi HK, Sastry DV. Role of radiation therapy in the treatment of carcinoma of the penis. Br J Urol 1994;74(5):646-51. http://www.ncbi.nlm.nih.gov/pubmed/7530129

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9. FOLLOW-UP Follow-up in penile carcinoma is important for several reasons: • It enables early detection of recurrence, which is important because most local and/or loco-regional recurrences are potentially curable • It is the only way to assess treatment and anticipate early and late complications • It is also important for patient (and physician) education. A rational follow-up scheme requires an understanding of the patterns of recurrence. Preferably, follow-up should be introduced within the framework of a randomised study. Based on a retrospective study, a follow-up schedule for penis cancer has been published (1).

9.1

How to follow-up

The aim of follow-up is to detect local and/or regional recurrences because they may be cured. In contrast, metastases at distant sites are always fatal (2). Risk stratification for recurrence is also helpful. Traditional follow-up methods have been inspection and physical evaluation. Modern ultrasound imaging is a useful adjunct, with promising results from new imaging modalities, such as PET scan and laser-directed MRI (3).

9.2

When to follow-up

The follow-up interval and strategies for patients with penile cancer are directed by the initial treatment of the primary lesion and regional lymph nodes. In the above-mentioned multicentre study (1), during the first 2 years of follow-up, the following occurred: • 74.3% of all recurrences • 66.4% of local recurrences • 86.1% of regional recurrences • 100% of distant recurrences. Of all recurrences, 92.2% occurred within the first 5 years (1). All recurrences after 5 years were local recurrences or new primaries. Thus, an intensive programme of follow-up during the first 2 years is rational with less intensive follow-up needed thereafter. In well-educated and motivated patients, follow-up can stop after 5 years, although they must continue to carry out regular self-examination.

9.3

Primary tumour

Local recurrence has been reported in up to 30% of patients treated with penile-preserving surgery, during the first 2 years following treatment. Local recurrence is more likely with all types of local therapy, i.e. local resection, laser therapy, BRT, Mohs’ procedure, and associated therapies (1, 4). However, in contrast to regional recurrences, local recurrences do not impact on survival (1, 4). Local recurrences are easily detected by the patient, his partner or doctor. Patient education is an important part of follow-up and the patient should be urged to visit a specialist if any changes are seen. Despite the fact that late local recurrences are well documented, it is reasonable to stop follow-up after 5 years, provided the patient will report local changes immediately (5). This is possible because life-threatening regional and distant metastases no longer occur, while recurrences that are local only are not life-threatening. The emphasis should be placed on patient self-examination. In patients who are unlikely to self-examine, long-term follow-up may be necessary. Following penile-preserving treatment, a follow-up visit every 3 months is advised in the first 2 years. We then advise a follow-up visit every half year, provided that the patient and partner have been well instructed to examine the penis regularly and to return if any abnormality is observed. It is important to stress that the patient must continue to carry out regular self-examination even after 5 years’ follow-up. After amputation, a less frequent time interval of every 6 months is advised. The risk of local recurrence is not more than 5% (1, 4).

9.4

Regional recurrences

Stringent follow-up is advised for the 2 years following surgery. This is because most regional recurrences occur within 2 years, whether a ‘wait-and-see’ policy has been followed or the patient has undergone SNB or inguinal LAD. Previous follow-up recommendations have relied heavily on physical examination of the inguinal regions. However, experience with ‘wait and see’ and dynamic SNB have shown that, despite intensive followup, regional recurrences have shown up unexpectedly (6). Ultrasound and immediate fine-needle aspiration

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have been encouraging in finding occult metastases (6, 7) and it seems reasonable to add ultrasound to a physical examination. Patients managed with a ‘wait-and-see’ policy have a higher risk of recurrence (9%) than patients staged surgically (2.3%), whether staging has been performed by LAD or dynamic SNB. This finding only applies to patients without histopathological evidence of lymph node metastases. Patients treated surgically because of lymph node metastases have an increased risk of recurrence (19%) (1). Based on these findings, a change in the follow-up scheme is proposed. For patients in a ‘wait-and-see’ programme and patients given LAD for proven lymph node metastases, follow-up should be every 3 months and should include ultrasound investigation of the groin. This intensive follow-up programme should be for 2 years, which is the period when recurrence is most likely. Imaging using CT has been replaced by ultrasound scanning with immediate fine-needle aspiration biopsy, although CT scans are still used in patients with a regional recurrence. So far, other imaging modalities have not proven reliable at detecting pelvic and retroperitoneal recurrences. Bone scan and other tests are only recommended in symptomatic patients. The role of PET scan is unclear and therefore not advised as a routine procedure.

9.5

Guidelines for follow-up in penile cancer

Table 8 provides a follow-up schedule for penile cancer with grades of recommendation. Table 8: Follow-up schedule for penile cancer Interval of follow-up

Examinations and Investigations

Years 1 and 2 Years 3, 4 and 5 Recommendations for follow-up of primary tumour Penile-preserving 3 months 6 months treatment Amputation

6 months

1 year

Maximum length of follow-up

Regular physician or 5 years self-examination Regular physician or 5 years self-examination

GR

C C

Recommendations for follow-up of the inguinal lymph nodes ‘Wait-and-see’

3 months

6 months

pN0

6 months

1 year

pN+

3 months

6 months

Regular physician or self-examination Ultrasound with FNAB Regular physician or self-examination Ultrasound with FNAB Regular physician or self-examination Ultrasound with FNAB

5 years

C

5 years

C

5 years

C

GR = grade of recommendation; FNAB = fine-needle aspiration biopsy.

9.6

REFERENCES

1.

Leijte JAP, Kirrander P, Antonini N, Windahl T, Horenblas S. Recurrence patterns of squamous cell carcinoma of the penis: recommendations for follow-up based on a two-centre analysis of 700 patients. Eur Urol 2008;54(1):161-8. http://www.ncbi.nlm.nih.gov/pubmed/18440124 Horenblas S, van Tinteren H, Delamarre JFM, Moonen LM, Lustig V, van Waardenburg EW. Squamous cell carcinoma of the penis. III. Treatment of regional lymph nodes. J Urol 1993;149(3):492-7. http://www.ncbi.nlm.nih.gov/pubmed/8437253. Lont AP, Gallee MP, Meinhardt W, van Tinteren H, Horenblas S. Penis conserving treatment for T1 and T2 penile carcinoma: clinical implications of a local recurrence. J Urol 2006;176(2):575-80;discussion 580. http://www.ncbi.nlm.nih.gov/pubmed/16813892

2.

3.

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4.

5.

6.

7.

Horenblas S, Newling DW. Local recurrence tumour after penis-conserving therapy. A plea for longterm follow-up. Br J Urol 1993;72(6):976-9. http://www.ncbi.nlm.nih.gov/pubmed/8306171 Kroon BK, Horenblas S, Lont AP, Tanis PJ, Gallee MP, Nieweg OE. Patients with penile carcinoma benefit from immediate resection of clinically occult lymph node metastases. J Urol 2005;173(3): 816-9. http://www.ncbi.nlm.nih.gov/pubmed/15711276 Kroon BK, Horenblas S, Deurloo EE, Nieweg OE, Teertstra HJ. Ultrasonography-guided fineneedle aspiration cytology before sentinel node biopsy in patients with penile carcinoma. BJU Int 2005;95(4):517-21. http://www.ncbi.nlm.nih.gov/pubmed/15705071 Krishna RP, Sistla SC, Smile R, Krishnan R. Sonography: An underutilized diagnostic tool in the assessment of metastatic groin nodes. Clin Ultrasound 2008;36(4):212-7. http://www.ncbi.nlm.nih.gov/pubmed/17960822

10. QUALITY OF LIFE .

10.1

Sexuality and fertility after cancer

As more people achieve long-term survival after cancer, sexual dysfunction and infertility are increasingly recognised as negative consequences affecting quality of life (1). 10.1.1 Sexual activity and quality of life after penile cancer laser treatment A retrospective, face-to-face, structured interview study was carried out on Swedish patients treated with laser for localised penile carcinoma during 1986 to 2000 (2). Sixty-seven patients were treated, with 58 of them (mean age 63 years) still alive in 2006. Forty-six (79%) agreed to participate in the interview. Nearly all patients could recall their first symptom, with 37% reporting that they delayed seeking treatment for more than 6 months. Patients had a greater lifetime number of sexual partners and a greater lifetime prevalence of sexually transmitted infections than the comparable general Swedish population. Following laser treatment, there was a marked decrease in some sexual practices, such as manual stimulation or caressing and fellatio. Patient satisfaction with life overall was similar to that of the general population. In conclusion, some patients delayed seeking treatment for a considerable period despite awareness of the first local symptoms. Men with laser-treated localised penile carcinoma resumed their sexual activities to a large extent. Except for satisfaction with somatic health, a similar (or higher) proportion of patients were satisfied with life overall and with other domains of life including sexual life. 10.1.2 Sexual function after partial penectomy for penile cancer To compare sexual function and satisfaction before and after partial penectomy, 18 Brazilian patients were given a personal interview and answered the International Index of Erectile Function (IIEF) questionnaire to determine erectile function, orgasmic function, sexual desire, intercourse satisfaction and overall satisfaction with sexual life (3). The median patient age was 52 years. The medium penile length after partial penectomy was 4 cm in the flaccid state, with 55.6% of patients reporting erectile function that allowed sexual intercourse. The main reason given for not resuming sexual intercourse in 50% of sexually abstinent patients was feeling shame because of a small penis and the absence of the glans penis. Surgical complications also compromised resumption of sexual activity after amputation in 33.3% of these patients. However, 66.7% sustained the same frequency and level of sexual desire prior to surgery and 72.2% continued to have ejaculation and orgasm every time they had sexual stimulation or intercourse. Nevertheless, only 33.3% maintained their pre-operative sexual intercourse frequency and were satisfied with their sexual relationships with their partners and their overall sex life. In conclusion, the pre-operative and post-operative scores were statistically worse for all domains of sexual function after partial penectomy.

10.2

Sexual mutilation, relapse and death

Today, nearly 80% of penile cancer patients can be cured. Experience in management of this rare tumour is helpful (4). Referral to centers with experience is recommended. Psychological support is very important for these patients. Penile-sparing surgery obviously allows a better quality of life than penile amputation and must be considered whenever feasible

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10.3

REFERENCES

1.

Schover LR. Sexuality and fertility after cancer. Hematology Am Soc Hematol Educ Program 2005;523-7. http://www.ncbi.nlm.nih.gov/pubmed/16304430 2. Skeppner E, Windahl T, Andersson S, Fugl-Meyers KS. Treatment-seeking, aspects of sexual activity and life satisfaction in men with laser-treated penile carcinoma. Eur Urol 2008;54(3):631-9. http://www.ncbi.nlm.nih.gov/pubmed/18788122 3. Romero FR, Romero KR, Mattos MA, Garcia CR, Fernandes Rde C, Perez MD. Sexual function after partial penectomy for penile cancer. Urology 2005;66(6):1292-5. http://www.ncbi.nlm.nih.gov/pubmed/16360459 4. Leijte JA, Gallee M, Antonini N, Horenblas S. Evaluation of current TNM classification of penile carcinoma. J Urol 2008;180(3):933-8. http://www.ncbi.nlm.nih.gov/pubmed/18635216

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11. ABBREVIATIONS USED IN THE TEXT This list is not comprehensive for the most common abbreviations.

BMP cisplatin, methotrexate and bleomycin BRT brachytherapy CT computed tomography DSNB dynamic sentinel node biopsy EAU European Association of Urology ERT external beam irradiation FDA [US] Food and Drug Administration FNAB fine-needle aspiration biopsy HDR high-dose rate (brachytherapy) HPV human papillomavirus IIEF International Index of Erectile Function questionnaire ITP paclitaxel, ifosfamide and cisplatin LAD lymphadenectomy LDR low-dose rate (brachytherapy) MRI magnetic resonance imaging NCI National Cancer Institute Nd-YAG neodynium:yttrium-aluminum-garnet PC paclitaxel and carboplatin PDQ physician data query PDR pulse-dose rate (brachytherapy) PET positron emission tomography PF cisplatin and fluorouracil PGE1 prostaglandin E1 (alprostadil) SCC squamous cell carcinoma SNB sentinel node biopsy SWOG Southwest Oncology Group 99mTC technetium 99m TNM tumour, node, metastasis TPF taxanes combined with PF (cisplatin and fluorouracil) VBM vinblastine, bleomycin, methotrexate

Conflict of interest All members of the Penile Cancer Guidelines writing panel have provided disclosure statements on all relationships that they have and that might be perceived to be a potential source of conflict of interest. This information is kept on file in the European Association of Urology Central Office database. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

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Guidelines on

Testicular Cancer P. Albers (chairman), W. Albrecht, F. Algaba, C. Bokemeyer, G. Cohn-Cedermark, K. Fizazi, A. Horwich, M.P. Laguna

© European Association of Urology 2009

TABLE OF CONTENTS

page

1

BACKGROUND 1.1 Methods

4 4

2

PATHOLOGICAL CLASSIFICATION

5

3

DIAGNOSIS 3.1 Clinical examination 3.2 Imaging of the testis 3.3 Serum tumour markers at diagnosis 3.4 Inguinal exploration and orchidectomy 3.5 Organ-sparing surgery 3.6 Pathological examination of the testis 3.7 Diagnosis and treatment of carcinoma in situ (Tin) 3.8 Screening

5 5 5 6 6 6 6 7 7

4

STAGING 4.1 Diagnostic tools 4.2 Serum tumour markers: post-orchidectomy half-life kinetics 4.3 Retroperitoneal, mediastinal and supraclavicular lymph nodes and viscera 4.4 Staging and prognostic classifications 4.5 Prognostic risk factors

7 7 8 8 9 11

5

IMPACT ON FERTILITY AND FERTILITY-ASSOCIATED ISSUES

11

6

GUIDELINES ON DIAGNOSIS AND STAGING OF TESTICULAR CANCER

12

7 TREATMENT: STAGE I GERM CELL TUMOURS 7.1 Stage I seminoma 7.1.1 Surveillance 7.1.2 Adjuvant chemotherapy 7.1.3 Adjuvant radiotherapy 7.1.4 Retroperitoneal lymph node dissection (RPLND) 7.1.5 Risk-adapted treatment 7.2 Guidelines for the treatment of seminoma stage I 7.3 NSGCT stage I 7.3.1 Surveillance 7.3.2 Primary chemotherapy 7.3.3 Risk-adapted treatment 7.3.4 Retroperitoneal lymph node dissection 7.4 CS1S with (persistently) elevated serum tumour markers 7.5 Guidelines for the treatment of NSGCT stage I

12 12 12 12 12 13 13 13 13 13 14 14 14 15 15

8 TREATMENT: METASTATIC GERM CELL TUMOURS 8.1 Low-volume metastatic disease (stage IIA/B) 8.1.1 Stage IIA/B seminoma 8.1.2 Stage IIA/B non-seminoma 8.2 Advanced metastatic disease 8.2.1 Primary chemotherapy 8.3 Restaging and further treatment 8.3.1 Restaging 8.3.2 Residual tumour resection 8.3.3 Consolidation chemotherapy after secondary surgery 8.4 Systemic salvage treatment for relapse or refractory disease 8.4.1 Seminoma 8.4.2 Non-seminoma 8.4.3 Late relapse (≥ 2 years after end of first-line treatment) 8.5 Salvage surgery 8.6 Treatment of brain metastases

17 17 17 17 18 18 19 19 19 19 20 20 20 21 21 21

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8.7

Guidelines for the treatment of metastatic germ cell tumours

21

9 FOLLOW-UP AFTER CURATIVE THERAPY 9.1 General considerations 9.2 Follow-up: stage I non-seminoma 9.2.1 Follow-up investigations during surveillance 9.2.2 Follow-up after nerve-sparing RPLND 9.2.3 Follow-up after adjuvant chemotherapy 9.3 Follow-up: stage I seminoma 9.3.1 Follow-up after radiotherapy 9.3.2 Follow-up during surveillance 9.3.3 Follow-up after adjuvant chemotherapy 9.4 Follow-up: stage II and advanced (metastatic) disease

22 22 22 22 23 23 23 24 24 24 24

10 TESTICULAR STROMAL TUMOURS 10.1 Background 10.2 Methods 10.3 Classification 10.4 Leydig cell tumours 10.4.1 Epidemiology 10.4.2 Pathology of Leydig cell tumours 10.4.3 Diagnosis 10.4.4 Treatment 10.4.5 Follow-up 10.5 Sertoli cell tumour 10.5.1 Epidemiology 10.5.2 Pathology of Sertoli cell tumours 10.5.2.1 Classification 10.5.3 Diagnosis 10.5.4 Treatment 10.5.5 Follow-up 10.6 Granulosa cell tumour 10.7 Thecoma/fibroma group of tumours 10.8 Other sex cord/gonadal stromal tumours 10.9 Tumours containing germ cell and sex cord/gonadal stromal (gonadoblastoma) 10.10 Miscellaneous tumours of the testis 10.10.1 Tumours of ovarian epithelial types 10.10.2 Tumours of the collecting ducts and rete testis 10.10.3 Tumours (benign and malignant) of non-specific stroma

25 25 25 25 26 26 26 26 26 27 27 27 27 27 27 28 28 28 28 28 28 28 28 28 29

11.

REFERENCES 11.1 Germ cell tumours 11.2 Non-germ cell tumours

29 29 48

12.

ABBREVIATIONS USED IN THE TEXT

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1. Background Testicular cancer represents between 1% and 1.5% of male neoplasms and 5% of urological tumours in general, with 3-6 new cases occurring per 100,000 males/per year in Western society (1, 2). An increase in the incidence of testicular cancer was detected during the 1970s and 1980s, particularly in Northern European countries, and there is a clear trend towards an increased testicular cancer incidence in the last 30 years in the majority of the industrialised countries in North America, Europe and Oceania, although surprising differences in incidence rates are seen between neighbouring countries (3). Data from the Surveillance Epidemiology and End Results Program during the years 1973 to 1998 show a continuing increased risk among Caucasian men in the USA only for seminoma (4). Only 1-2% of cases are bilateral at diagnosis. The histological type varies, although there is a clear predominance (90-95%) of germ cell tumours (1). Peak incidence is in the third decade of life for nonseminoma, and in the fourth decade for pure seminoma. Familial clustering has been observed, particularly among siblings (5). Genetic changes have been described in patients with testicular cancer. A specific genetic marker (an isochromosome of the short arm of chromosome 12 – i(12p) – has been described in all histological types of germ cell tumours (5). Intratubular germ cell neoplasia (testicular intraepithelial neoplasia, Tin) shows the same chromosomal changes, and alterations in the p53 locus have been found in 66% of cases of testicular Tin (6). A deregulation in the pluripotent programme of fetal germ cells (identified by specific markers such as M2A, C-KIT and OCT4/NANOG) is probably responsible for the development of Tin and germ cell neoplasia. There is overlap in the development to seminoma and embryonal carcinoma as shown by genome-wide expression analysis and detection of alpha-fetoprotein (AFP) mRNA in some atypical seminoma (7, 8). Epidemiological risk factors for the development of testicular tumours are: a history of cryptorchidism or undescended testis, Klinefelter’s syndrome, familial history of testicular tumours among first-grade relatives (father/brothers), the presence of a contralateral tumour or Tin, and infertility (9-14). Tallness was associated with a risk of germ cell cancer, although further confirmation is needed (15). Testicular tumours show excellent cure rates. The main factors contributing to this are: careful staging at the time of diagnosis; adequate early treatment based on chemotherapeutic combinations, with or without radiotherapy and surgery; and very strict follow-up and salvage therapies. In the past decade, a decrease in the mean time delay to diagnosis and treatment has been observed (16). In the treatment of testicular cancer, the choice of centre where this treatment is going to be administered is of utmost importance. Although early stages can be successfully treated in a non-reference centre, the relapse rate is higher (17). In poor prognosis non-seminomatous germ cell tumours, it has been shown that overall survival within a clinical trial depended on the number of patients treated at the participating centre (worse < 5 patients enrolled) (18).

1.1

Methods

These guidelines represent implementation of previously published texts: the latest EAU guidelines were formally published as a review paper in 2005 (19) and as an EAU guideline, which was distributed among EAU members, in March 2006. As in 2006, this edition contains a separate chapter on testicular stromal tumours. A multidisciplinary team of urologists, medical oncologists, radiotherapists and a pathologist were involved in producing this text, which is based on a non-structured review of the literature through to October 2007 in the case of both the germ cell tumour and non-germ cell parts. Also, data from meta-analysis studies, Cochrane evidence, and the recommendations of the European Germ Cell Cancer Collaborative Group Meeting in Amsterdam in November 2006, as well as other available guidelines, have been included (20-27). Whenever possible, references have been labelled according to the principles of evidence-based medicine (EBM) (28). The nature of the recommendations in these guidelines is labelled according to the level of evidence (28).

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2. PATHOLOGICAL CLASSIFICATION The recommended pathological classification (modified from the 2004 version of the World Health Organization [WHO] guidance) is shown below (29). 1. Germ cell tumours • Intratubular germ cell neoplasia • Seminoma (including cases with syncytiotrophoblastic cells) • Spermatocytic seminoma (mention if there is sarcomatous component) • Embryonal carcinoma • Yolk sac tumour • Choriocarcinoma • Teratoma (mature, immature, with malignant component) • Tumours with more than one histological type (specify percentage of individual components). 2. Sex cord/gonadal stromal tumours • Leydig cell tumour • Malignant Leydig cell tumour • Sertoli cell tumour - lipid-rich variant - sclerosing - large cell calcifying • Malignant Sertoli cell tumour • Granulosa cell tumour - adult type - juvenile type • Thecoma/fibroma group of tumours • Other sex cord/gonadal stromal tumours - incompletely differentiated - mixed • Tumours containing germ cell and sex cord/gonadal stromal (gonadoblastoma). 3. Miscellaneous non-specific stromal tumours • Ovarian epithelial tumours • Tumours of the collecting ducts and rete testis • Tumours (benign and malignant) of non-specific stroma

3. DIAGNOSIS 3.1

Clinical examination

Testicular cancer generally affects young men in the third or fourth decade of life. It normally appears as a painless, unilateral mass in the scrotum or the casual finding of an intrascrotal mass (30). In approximately 20% of cases, the first symptom is scrotal pain, and up to 27% of patients with testicular cancer may have local pain (1). Occasionally, trauma to the scrotum may reveal the presence of a testicular mass. Gynaecomastia appears in 7% of cases and is more common in non-seminomatous tumours. Back and flank pain are present in about 11% of cases (16). Reduction in testis size can precede a testicular tumour (31). In about 10% of cases, a testicular tumour can mimic an orchioepididymitis, with consequent delay of the correct diagnosis (1, 2). Ultrasound must be performed in any doubtful case. Physical examination reveals the features of the mass and must always be carried out in conjunction with a general examination in order to find possible (supraclavicular) distant metastases, a palpable abdominal mass or gynaecomastia. A correct diagnosis must be established in all patients with an intrascrotal mass (32).

3.2

Imaging of the testis

Currently, diagnostic ultrasound serves to confirm the presence of a testicular mass and to explore the

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contralateral testis. Its sensitivity in detecting a testicular tumour is almost 100%, and it has an important role in determining whether a mass is intra- or extratesticular (33). Ultrasound is an inexpensive test, but it is unnecessary when the presence of a testicular tumour is clinically evident (34). Ultrasound of the testis has to be performed in young men without a palpable testicular mass who have retroperitoneal or visceral masses or elevated serum human chorionic gonadotrophin (hCG) or AFP (35-38). Ultrasound is recommended in the follow-up of the contralateral testis in the follow-up of patients at risk (39). Magnetic resonance imaging (MRI) offers higher sensitivity and specificity than ultrasound for diagnosing tumours (40-42) and may be able to differentiate seminomatous from non-seminomatous tumours. MRI of the scrotum offers a sensitivity of 100% and a specificity of 95-100% (43), but its high cost does not justify its use for diagnosis.

3.3

Serum tumour markers at diagnosis

Serum tumour markers are prognostic factors and contribute to diagnosis and staging (44). The following markers should be determined: • AFP (produced by yolk sac cells) • hCG (expression of trophoblasts). Lactate dehydrogenase (LDH) (marker of tissue destruction) is recommended for patients with metastatic disease. Globally, there is an increase in these markers in 51% of cases of testicular cancer (16, 30). Alphafetoprotein increases in 50-70% of patients with non-seminomatous germ cell tumour (NSGCT), and a rise in hCG is seen in 40-60% of patients with NSGCT. About 90% of non-seminomatous tumours present with a rise in one or two of the markers. Up to 30% of seminomas can present or develop an elevated hCG level during the course of the disease (45, 46). LDH is a less specific marker, and its concentration is proportional to tumour volume. Its level may be elevated in 80% of patients with advanced testicular cancer (45). It should be noted that negative marker levels do not exclude the diagnosis of a germ cell tumour. Other markers studied include placental alkaline phosphatase (PLAP), which may be of value in monitoring patients with pure seminoma. Cytogenetic and molecular markers are available in specific centres, but at present only contribute to research studies. Measurement of serum AFP, hCG and LDH (in advanced tumours) is mandatory, while that of PLAP is optional.

3.4

Inguinal exploration and orchidectomy

Every patient with a suspected testicular mass must undergo inguinal exploration with exteriorisation of the testis within its tunics. Immediate orchidectomy with division of the spermatic cord at the internal inguinal ring must be performed if a tumour is found. If the diagnosis is not clear, a testicular biopsy is taken for frozen section histological examination. In cases of disseminated disease and life-threatening metastases, it is current practice to start with up-front chemotherapy, and orchidectomy may be delayed until clinical stabilisation has occurred.

3.5

Organ-sparing surgery

Although organ-sparing surgery is not indicated in the presence of non-tumoural contralateral testis, it can be attempted in special cases with all the necessary precautions. In synchronous bilateral testicular tumours, metachronous contralateral tumours, or in a tumour in a solitary testis with normal pre-operative testosterone levels, organ preserving surgery can be performed when the tumour volume is less than 30% of the testicular volume and surgical rules are respected. In those cases, the rate of associated Tin is high (at least up to 82%), and all patients must be treated with adjuvant radiotherapy (20 Gy) at some point (47). Infertility will result after radiotherapy and the risk of long-term Leydig cell insufficiency after radiotherapy of a solitary testis is increased (48). Radiation treatment may be delayed in fertile patients who wish to father children. The option must be carefully discussed with the patient and surgery performed in a centre with experience (49, 50).

3.6 Pathological examination of the testis Mandatory pathological requirements: • Macroscopic features: side, testis size, maximum tumour size and macroscopic features of epididymis, spermatic cord and tunica vaginalis.

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•

• • •

 ampling: a 1 cm2 section for every centimetre of maximum tumour diameter, including normal S macroscopic parenchyma (if present), albuginea and epididymis, with selection of suspected areas. At least one proximal and one distal section of spermatic cord plus any suspected area. Microscopic features and diagnosis: histological type (specify individual components and estimate amount as percentage) according to WHO 2004 (29): - presence or absence of peri-tumoural venous and/or lymphatic invasion - presence or absence of albuginea, tunica vaginalis, rete testis, epididymis or spermatic cord invasion - presence or absence of intratubular germ cell neoplasia (Tin) in non-tumour parenchyma intratubular germ cell neoplasia pT category according to Tumour Node Metastasis (TNM) 2002 Immunohistochemical studies: in seminoma and mixed germ cell tumour, AFP and hCG.

Advisable immunohistochemical markers, in cases of doubt, are: • in seminoma: cytokeratins (CAM 5.2), PLAP, c-kit • in intratubular germ cell neoplasia: PLAP, c-kit • other advisable markers: chromogranine A (Cg A), Ki-1 (MIB-1).

3.7 Diagnosis and treatment of carcinoma in situ (Tin) Contralateral biopsy has been advocated to rule out the presence of Tin (51). Although this is routine policy in some countries, the low incidence of Tin and contralateral metachronous testicular tumours (up to 9% and approximately 2.5%, respectively) (52, 53), the morbidity of Tin treatment, and the fact that most of these metachronous tumours are at a low stage at presentation make it controversial to recommend a systematic contralateral biopsy in all patients (54-56). It is still difficult to reach a consensus on whether the existence of contralateral Tin must be identified in all cases. However, biopsy of the contralateral testis should be offered to high-risk patients for contralateral Tin with a testicular volume of less than 12 mL, a history of cryptorchidism, or poor spermatogenesis (Johnson Score 1-3). A contralateral biopsy is not necessary for patients older than 40 years (57-62). A double biopsy is preferred to increase sensitivity. Once Tin is diagnosed, local radiotherapy (20 Gy in single fractions of 2 Gy) is the treatment of choice. Because this may produce infertility, the patient must be carefully counselled before treatment commences (54, 63). In addition to infertility, Leydig cell function and testosterone production may be impaired long-term following radiotherapy for Tin (49). Radiation treatment may be delayed in fertile patients who wish to father children (59).

3.8

Screening

Although there are no surveys proving the advantages of screening programmes, it has been demonstrated that stage and prognosis are directly related to early diagnosis. In the presence of clinical risk factors, selfphysical examination by the affected individual is advisable.

4. STAGING To determine the presence of metastatic or occult disease, the half-life kinetics of serum tumour markers must be assessed, the nodal pathway must be screened, and the presence of visceral metastases ruled out. Consequently, it is mandatory to assess: • the post-orchidectomy half-life kinetics of serum tumour markers • the status of retroperitoneal and supraclavicular lymph nodes, and the liver • the presence or absence of mediastinal nodal involvement and lung metastases • the status of brain and bone, if any suspicious symptoms are present.

4.1 Diagnostic tools The currently available tests include: • serial blood sampling • chest X-ray • abdominopelvic and thoracic computed tomography (CT) scan • abdominal and retroperitoneal ultrasound • MRI

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• •

positron emission tomography (PET) scan other specific examinations, depending on clinical suspicion.

4.2

Serum tumour markers: post-orchidectomy half-life kinetics

The mean serum half-life of AFP and hCG is 5-7 days and 2-3 days, respectively (45). Tumour markers have to be re-evaluated after orchidectomy to determine half-life kinetics. Marker decline in patients with clinical stage I disease should be assessed until normalisation has occurred. Post-orchidectomy markers are important to classify the patient according to the International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification. The persistence of elevated serum tumour markers after orchidectomy might indicate the presence of metastatic disease (macro- or microscopically), while the normalisation of marker levels after orchidectomy does not rule out the presence of tumour metastases. During chemotherapy, the markers should decline; persistence has an adverse prognostic value.

4.3 Retroperitoneal, mediastinal and supraclavicular lymph nodes and viscera Retroperitoneal and mediastinal lymph nodes are best assessed by means of a CT scan. The supraclavicular nodes are best assessed by physical examination. Abdominopelvic CT scanning offers a sensitivity of 70-80% in determining the state of the retroperitoneal nodes. Its accuracy depends on the size of the nodes; sensitivity and the negative predictive value increase using a 3 mm threshold to define metastatic nodes in the landing zones (62). Those figures decrease slightly in stages I and II (63, 64), with a rate of understaging of 25-30% (65). New generations of CT scans do not seem to improve the sensitivity. Magnetic resonance imaging produces similar results to CT scanning in the detection of retroperitoneal nodal enlargement (66). Again, the main objections to its routine use are its high cost and limited access to it. Nevertheless, MRI can be helpful when abdominopelvic CT or ultrasound are inconclusive (66), when CT scan is contraindicated because of allergy to contrast media, or when the physician or the patient are concerned about radiation dose. MRI is an optional test, and there are currently no indications for its systematic use in the staging of testicular cancer. Chest X-ray is the routine thorax examination. An anteroposterior and lateral chest X-ray could be considered as the only thoracic examination in seminoma when retroperitoneal and pelvic CT scans are negative (67). A chest CT scan is the most sensitive way to evaluate the thorax and mediastinal nodes. This exploration has to be recommended in patients with NSGCT because up to 10% of cases can present with small subpleural nodes that are not visible radiologically (1). The CT scan has high sensitivity but low specificity (66). A chest CT is mandatory in all patients with NSGCT, and in those patients with seminoma and a positive abdominopelvic CT scan (67). There is not enough evidence to support the use of the fluorodeoxyglucose-PET (FDG-PET) scan in the staging of testis cancer. It is recommended in the follow-up of patients with seminoma with any residual mass at least 4 weeks after chemotherapy in order to decide on watchful waiting or active treatment (68-71). Other examinations, such as brain or spinal CT, bone scan or liver ultrasound, should be performed if there is suspicion of metastases to these organs. A CT or MRI scan of the skull is advisable in patients with NSGCT and widespread lung metastases. Table I shows the recommended test at staging. Table 1: Recommended tests for staging at diagnosis Test Recommendation grade B Recommendation grade C Serum tumour markers Alpha-fetoprotein hCG LDH (for advanced tumours) Abdominopelvic CT scan All patients Slim adolescent Chest X-ray Seminoma* Chest CT scan NSGCT Testis ultrasound Clinical suspicion and normal scrotum at palpation MRI When abdominal CT is inconclusive All cases PET scan† Follow-up residual masses in seminoma Other If clinical suspicion

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Recommended further investigations Fertility investigations Total testosterone, LH, FSH, semen analysis, (should be offered) sperm banking hCG = human chorionic gonadotrophin; LDH = lactate dehydrogenase; CT = computed tomography; NSGCT = non-seminomatous germ cell tumour; MRI = magnetic resonance imaging; PET = positron emission tomography; LH = luteinising hormone; FSH = follicle-stimulating hormone. *If negative, abdominopelvic CT scan. †There is currently no indication for PET scan at diagnosis.

4.4

Staging and prognostic classifications

The staging system recommended in these guidelines is the 2002 TNM of the International Union Against Cancer (UICC) (Table 2) (72). This includes: • determination of the anatomical extent of disease • assessment of serum tumour markers, including nadir values of hCG, AFP and LDH after orchidectomy (S category) • clear definition of regional nodes • some N-category modifications related to node size. Table 2: TNM classification for testicular cancer (UICC, 2002, 6th edn [72]) pT Primary tumour1 pTX Primary tumour cannot be assessed (see note 1) pT0 No evidence of primary tumour (e.g. histological scar in testis) pTis Intratubular germ cell neoplasia (carcinoma in situ) pT1 Tumour limited to testis and epididymis without vascular/lymphatic invasion: tumour may invade tunica albuginea but not tunica vaginalis pT2 Tumour limited to testis and epididymis with vascular/lymphatic invasion, or tumour extending through tunica albuginea with involvement of tunica vaginalis pT3 Tumour invades spermatic cord with or without vascular/lymphatic invasion pT4 Tumour invades scrotum with or without vascular/lymphatic invasion N Regional lymph nodes clinical NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis with a lymph node mass 2 cm or less in greatest dimension or multiple lymph nodes, none more than 2 cm in greatest dimension N2 Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension, or multiple lymph nodes, any one mass more than 2 cm but not more than 5 cm in greatest dimension N3 Metastasis with a lymph node mass more than 5 cm in greatest dimension pN Pathological pNX Regional lymph nodes cannot be assessed pN0 No regional lymph node metastasis pN1 Metastasis with a lymph node mass 2 cm or less in greatest dimension and 5 or fewer positive nodes, none more than 2 cm in greatest dimension pN2 Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension; or more than 5 nodes positive, none more than 5 cm; or evidence or extranodal extension of tumour pN3 Metastasis with a lymph node mass more than 5 cm in greatest dimension M Distant metastasis MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis M1a Non-regional lymph node(s) or lung M1b Other sites S Serum tumour markers Sx Serum marker studies not available or not performed S0 Serum marker study levels within normal limits

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S1 S2 S3

LDH (U/l) < 1.5 x N and 1.5-10 x N or > 10 x N or

hCG (mIU/ml) < 5,000 and 5,000-50,000 or > 50,000 or

AFP (ng/ml) < 1,000 1,000-10,000 > 10,000

N indicates the upper limit of normal for the LDH assay. LDH, lactate dehydrogenase; hCG = human chorionic gonadotrophin; AFP = alpha-fetoprotein. 1Except for pTis and pT4, where radical orchidectomy is not always necessary for classification purposes, the extent of the primary tumour is classified after radical orchidectomy; see pT. In other circumstances, TX is used if no radical orchidectomy has been performed. According to the 2002 TNM classification, stage I testicular cancer includes the following substages: Stage IA Stage IB Stage IS

pT1 pT2, pT3 or pT4 Any patient/TX

N0 N0 N0

M0 M0 M0

S0 S0 S1-3

Stage IA patients have primary tumours limited to the testis and epididymis, with no evidence of microscopic vascular or lymphatic invasion by tumour cells on microscopy, no sign of metastases on clinical examination or imaging, and post-orchidectomy serum tumour marker levels within normal limits. Marker decline in patients with clinical stage I disease should be assessed until normalisation. Stage IB patients have a more locally invasive primary tumour, but no sign of metastatic disease. Stage IS patients have persistently elevated (and usually increasing) serum tumour marker levels after orchidectomy, which is evidence of subclinical metastatic disease (or possibly a second germ cell tumour in the remaining testis). If serum tumour marker levels are declining according to the expected half-life decay after orchidectomy, the patient is usually followed up until normalisation. In large population-based patient series, 75-80% of seminoma patients, and about 55% of patients with NSGCT cancer have stage I disease at diagnosis (73, 74). True stage IS (persistently elevated or increasing serum marker levels after orchidectomy) is found in about 5% of non-seminoma patients. If a staging retroperitoneal lymph node dissection (RPLND) was to be performed in stage IS patients, nearly all patients would be found to have pathological stage II disease (pN+) (1, 2, 5, 73). In 1997, the IGCCCG defined a prognostic factor-based staging system for metastatic testis tumour based on identification of some clinical independent adverse factors. This staging system has been incorporated into the TNM Classification and uses histology, location of the primary tumour, location of metastases and prechemotherapy marker levels in serum as prognostic factors to categorise patients into ‘good’, ‘intermediate’ or ‘poor’ prognosis (Table 3) (75). Table 3: Prognostic-based staging system for metastatic germ cell cancer (International Germ Cell Cancer Collaborative Group). Good-prognosis group Non-seminoma (56% of cases) 5-year PFS 89% 5-year survival 92% Seminoma (90% of cases) 5-year PFS 82% 5-year survival 86% Intermediate prognosis group Non-seminoma (28% of cases) 5 years PFS 75% 5-year survival 80%

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All of the following criteria: • Testis/retroperitoneal primary • No non-pulmonary visceral metastases • AFP < 1,000 ng/mL • hCG < 5,000 IU/L (1,000 ng/mL) • LDH < 1.5 x ULN All of the following criteria: • Any primary site • No non-pulmonary visceral metastases • Normal AFP • Any hCG • Any LDH All of the following criteria: • Testis/retroperitoneal primary • No non-pulmonary visceral metastases • AFP > 1,000 and < 10,000 ng/mL or

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• hCG > 5,000 and < 50,000 IU/L or • LDH > 1.5 and < 10 x ULN Seminoma (10% of cases) Any of the following criteria: 5-year PFS 67% • Any primary site 5-year survival 72% • Non-pulmonary visceral metastases • Normal AFP • Any hCG • Any LDH Poor prognosis group Non-seminoma (16% of cases) Any of the following criteria: 5-year PFS 41% • Mediastinal primary 5-year survival 48% • Non-pulmonary visceral metastases • AFP > 10,000 ng/mL or • hCG > 50,000 IU/L (10,000 ng/mL) or • LDH > 10 x ULN Seminoma No patients classified as poor prognosis PFS = progression-free survival; AFP = alpha-fetoprotein; hCG = human chorionic gonadotrophin; LDH = lactate dehydrogenase.

4.5 Prognostic risk factors For seminoma stage I, tumour size (> 4 cm) and invasion of the rete testis have been identified as the most important predictors for relapse in multivariate analysis (20). For non-seminoma stage I, vascular invasion of the primary tumour in blood or lymphatic vessels is the most important predictor of occult metastatic disease. The proliferation rate, as well as the percentage of embryonal carcinoma, are additional predictors that improve upon the positive and negative predictive value of vascular invasion (76, 77). The significant prognostic pathological risk factors for stage I and clinical risk factors for metastatic disease are listed in Table 4. Table 4: Prognostic factors for occult metastatic disease in testicular cancer For seminoma Pathological (for stage I) Histopathological type • Tumour size (> 4 cm) • Invasion of the rete testis Clinical (for metastatic disease) • Primary location • Elevation of tumour marker levels • Presence of non-pulmonary visceral metastasis

For non-seminoma • Vascular/lymphatic in or peri-tumoural invasion • Proliferation rate > 70% • Percentage of embryonal carcinoma > 50%

5. IMPACT ON FERTILITY AND FERTILITY- ASSOCIATED ISSUES Sperm abnormalities are frequently found in patients with testis tumours. Furthermore, chemotherapy and radiation treatment can also impair fertility. In patients in the reproductive age group, pre-treatment fertility assessment (testosterone, luteinising hormone [LH] and FSH levels) should be performed, and semen analysis and cryopreservation should be offered. If cryopreservation is desired, it should be performed before or after orchidectomy, but in any case prior to chemotherapy treatment (48, 78-84). In cases of bilateral orchidectomy or low testosterone levels after treatment of Tin, life-long testosterone supplementation is necessary (85). For more detailed information, the reader is referred to the EAU Male Infertility Guidelines.

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6. GUIDELINES ON DIAGNOSIS AND STAGING OF TESTICULAR CANCER 1. 2.

3.

4.

Testicular ultrasound is mandatory (grade of recommendation: B). Orchidectomy and pathological examination of the testis are necessary to confirm the diagnosis and to define the local extension (pT category) (grade of recommendation: B). In a life-threatening situation due to extensive metastasis, chemotherapy must be started before orchidectomy. Serum determination of tumour markers (AFP, hCG, and LDH in metastatic disease) must be performed before and after orchidectomy for staging and prognostic reasons (grade of recommendation: B). The state of the retroperitoneal, mediastinal and supraclavicular nodes and viscera must be assessed in testicular cancer. In seminoma, a chest CT scan is not necessary if the abdominal nodes are negative (grade of recommendation: B).

7. TREATMENT: STAGE I GERM CELL TUMOURS 7.1

Stage I seminoma

After modern staging procedures, about 15-20% of stage I seminoma patients have subclinical metastatic disease, usually in the retroperitoneum, and will relapse after orchidectomy alone (86). 7.1.1 Surveillance Several prospective non-randomised studies of surveillance have been conducted during the past decade, the largest study coming from Canada with > 1500 patients (87). Previous meta-analysis from four studies showed an actuarial 5 years’ relapse-free rate of 82.3%. The Princess Margaret Hospital series (n = 1559) showed an overall relapse rate in unselected patients of 16.8%. The actuarial relapse rate is in the order of 15-20% at 5 years, and most of the relapses are first detected in infra-diaphragmatic lymph nodes (86, 88-90). Chemotherapy with dosing according to IGCCCG classification is a possible treatment for seminoma relapse under surveillance. However, 70% of patients with relapse are suitable for treatment with radiotherapy alone because of small volume disease at the time of recurrence. Only about 20% of these patients relapse again after salvage radiotherapy and then need salvage chemotherapy. The overall cancer-specific survival rate reported with surveillance performed by experienced centres is 97-100% for seminoma stage I (89, 90). The main drawback of surveillance is the need for more intensive follow-up, especially with repeated imaging examinations of the retroperitoneal lymph nodes, for at least 5 years after orchidectomy. This compares with the very low risk of subdiaphragmatic relapse after adjuvant radiotherapy. There is a small but clinically significant risk of relapse more than 5 years after orchidectomy for stage I seminoma which supports the need for long term surveillance (88). Cost analyses of surveillance compared with radiotherapy indicate that it is more expensive (91), but estimates vary, mainly depending on the follow-up schedules (92, 93). 7.1.2 Adjuvant chemotherapy A joint trial by the Medical Research Council (MRC) and the European Organisation for Research and Treatment of Cancer (EORTC) (MRC TE 19 trial), which compared one cycle of carboplatin (area under curve [AUC] 7) with adjuvant radiotherapy, did not show a significant difference with regard to recurrence rate, time to recurrence and survival after a median follow-up of 4 years (94). Therefore, adjuvant carboplatin therapy is an alternative to radiotherapy or surveillance in stage I seminoma (89, 90, 94). Two courses of adjuvant carboplatin seem to further reduce the relapse rate to the order of 1-3% (95, 96), but further experience and long-term observations are needed. 7.1.3 Adjuvant radiotherapy Seminoma cells are extremely radiosensitive. Adjuvant radiotherapy to a para-aortic (PA) field or to a hockeystick field (para-aortic and ipsilateral iliac nodes), with moderate doses (total 20-24 Gy), will reduce the relapse rate to only 1-3% (97-100). After modern radiotherapy, nearly all relapses will first occur outside the irradiated

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field (supradiaphragmatic lymph nodes or in the lungs) (97, 100). Based on the results of a large randomised MRC trial, Fossa et al. (97, 98) recommended radiotherapy to a PA field as standard treatment for patients with testicular seminoma stage I, T1-T3 and with undisturbed lymphatic drainage. Acute toxicity was reduced and the sperm count within the first 18 months was significantly higher after PA irradiation than after irradiation of the traditional dog-leg field. On the other hand, the relapse rate in the iliac lymph nodes was about 2% (all of them on the right side) after PA and 0% after dog-leg irradiation. Another possible site of failure is in the left renal hilum. PA irradiation should be tailored according to the site of the primary tumour. Adjuvant irradiation of supradiaphragmatic lymph nodes is not indicated in seminoma stage I. With regard to the irradiation dose, the MRC recently finished a large randomised trial of 20 Gy versus 30 Gy PA radiation in stage I seminoma that showed equivalence for both doses in terms of recurrence rates (98). The rate of severe radiation-induced long-term toxicity is less than 2%. Moderate chronic gastrointestinal (GI) sideeffects are seen in about 5% of patients, and moderate acute GI toxicity in about 60% (97). The main concern surrounding adjuvant radiotherapy is the potentially increased risk of radiation-induced secondary non-germcell malignancies (101-104). A scrotal shield can be of benefit during adjuvant radiotherapy in order to prevent scattered radiation toxicity in the contralateral testis (104). It is currently difficult to evaluate the long-term risks after adjuvant radiotherapy for stage I seminoma because former treatment procedures included larger fields, higher doses of radiotherapy and/or the use of alkylating chemotherapy. 7.1.4 Retroperitoneal lymph node dissection (RPLND) In a prospective, non-randomised study comparing radiotherapy and RPLND in stage I seminoma, there was a trend towards a higher incidence of retroperitoneal relapses (9.5%) after RPLND as primary treatment. Therefore this policy should not be recommended in stage I seminoma (105). 7.1.5 Risk-adapted treatment Using tumour size > 4 cm and rete testis invasion, patients with seminoma stage I may be subdivided into a low-and high-risk group of occult metastatic disease. Patients with and without both risk factors have a risk of occult disease of 32% and 12%, respectively. These risk factors were introduced by a meta-analysis of retrospective trials (20). A prospective trial based on these risk factors (no risk factors: surveillance; both risk factors: two courses of carboplatin AUC 7) showed the feasibility of a risk-adapted approach. Early data with limited follow-up indicate that patients without either risk factor have a 6.0% risk of relapse at 5 years. Patients at high risk treated with carboplatin experienced a 3.3% relapse rate (106).

7.2 Guidelines for the treatment of seminoma stage I 1. Surveillance (if facilities available and patient compliant) (grade of recommendation: B). 2. Carboplatin-based chemotherapy (one course at AUC 7) can be recommended as an alternative to radiotherapy and surveillance (grade of recommendation: A). 3. Adjuvant radiotherapy to a PA or hockey-stick field, to a total dose of 20 Gy (grade of recommendation: A).

7.3

NSGCT stage I

Up to 30% of NSGCT patients with clinical stage I (CS1) disease have subclinical metastases and will relapse if surveillance alone is applied after orchidectomy. 7.3.1 Surveillance Improvements in clinical staging and follow-up methods, and the availability of effective salvage treatment with cisplatin-based chemotherapy and post-chemotherapy surgery, have led to studies of only close surveillance after orchidectomy in CS1 NSGCT patients. The largest reports of the surveillance strategy indicate a cumulative relapse rate of about 30%, with 80% of relapses occurring during the first 12 months of follow-up, 12% during the second year and 6% during the third year, decreasing to 1% during the fourth and fifth years, and occasionally even later (107-110). About 35% of relapsing patients have normal levels of serum tumour markers at relapse. About 60% of relapses are in the retroperitoneum. Despite very close follow-up, 11% of relapsing patients presented with large-volume recurrent disease. The somewhat lower relapse rates reported from surveillance studies compared with some series of patients staged by RPLND (111) can be explained by the fact that some patients (presumably at risk) are excluded once surveillance is advised. Based on the overall cancer-specific survival data, surveillance within an experienced surveillance programme may be offered to patients with non-risk stratified clinical stage I non-seminoma as long as they are compliant and informed about the expected recurrence rate as well as the salvage treatment (112).

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7.3.2 Primary chemotherapy Several studies involving two courses of chemotherapy with cisplatin, etoposide and bleomycin (PEB) as primary treatment for high-risk patients (having about 50% risk of relapse) have been reported (113-118). In these series, involving more than 200 patients, some with a median follow-up of nearly 8 years (113), a relapse rate of only 2.7% was reported, with very little long-term toxicity. Two cycles of cisplatin-based adjuvant chemotherapy do not seem to adversely affect fertility or sexual activity (119). It is important to be aware of the slow-growing retroperitoneal teratomas after primary chemotherapy and of the risk of late chemoresistant cancer relapse (120). The need for repeated and long-term follow-up with imaging of the retroperitoneum after primary chemotherapy is not yet clear. The results of cost analyses comparing surveillance, RPLND and primary chemotherapy show different results among the reported studies, possibly because of differences in intensity and costs related to follow-up procedures (121). With a low frequency of follow-up CTs (such as has been proven effective for the surveillance strategy in non-seminoma CS1), the costs of follow-up can be considerably reduced (122). 7.3.3 Risk-adapted treatment Risk-adapted treatment is currently based on the risk factor vascular invasion. Stratifying patients with CS1 NSGCT according to their presumed risk of relapse is a rational option, as several studies have reported similar survival rates and a final cure rate close to 100% with all available treatment options using the risk-stratifying approach (113-118, 123-125). Risk-adapted treatment is therefore an equally effective alternative treatment of choice in CS1 NSGCT. Patients with vascular invasion are recommended to undergo adjuvant chemotherapy with two cycles of PEB, and patients without vascular invasion are recommended to undergo surveillance. Only if patients or doctors are not willing to accept the consequent risk-adapted treatment, or if there are circumstances that militate against the risk-adapted treatment option, should the remaining treatments be considered. Thus, the decision about treatment should be based on a thorough discussion with the patients, taking into account the described advantages and disadvantages, as well as the individual situation of the patient and/or the treatment centre. The Swedish-Norwegian Testicular Cancer Project (SWENOTECA) recently showed that in a large population-based study with a risk-adapted approach within a management programme and a median follow-up of 4.7 years, the relapse rate was 3.2% for patients with vascular invasion treated with only one adjuvant PEB (126). 7.3.4 Retroperitoneal lymph node dissection If RPLND is performed, about 30% of patients are found to have retroperitoneal lymph node metastases, which corresponds to pathological stage II (PS2) disease (105, 127, 128). If no retroperitoneal metastases are found at RPLND (PS1), approximately 10% of the PS1 patients relapse at distant sites (77, 111, 129-131). The main predictor of relapse in CS1 NSGCT managed by surveillance, for having PS2 disease and for relapse in PS1 after RPLND, is histopathological evidence of vascular invasion by tumour cells in, or near, the primary tumour in the testis (77, 107, 111, 131, 132). The presence of vascular invasion seems to be a very robust parameter, and is clinically usable even without centralised review by an expert panel (123, 131). Vascular invasion was the most predictive of stage in a multifactorial analysis. The absence of vascular invasion has a negative predictive value of 77%, thus allowing for surveillance in low-risk compliant patients (77). Patients without vascular invasion constitute about 50-70% of the CS1 population, and these patients have only a 15-20% risk of relapse on surveillance, compared with a 50% relapse rate in patients with vascular invasion. The risk of relapse for PS1 patients is less than 10% for those without vascular invasion and about 30% for those with vascular invasion (123, 131, 133, 134). If CS1 patients with PS2 are followed up only after RPLND, about 30% relapse, mainly at sites outside the abdomen and pelvis. The risk of relapse depends upon the amount of retroperitoneal disease resected (135137). If two (or more) courses of cisplatin-based chemotherapy are given adjuvant to RPLND in PS2 cases, the relapse rate is reduced to less than 2%, including teratoma relapse (111, 132, 138). The risk of retroperitoneal relapse after a properly performed nerve-sparing RPLND is very low (less than 2%), as is the risk of ejaculatory disturbance or other significant side-effects (132, 135, 136). The follow-up after RPLND is much simpler and less costly than that carried out during post-orchidectomy surveillance because of the reduced need for abdominal CT scans (132). A laparoscopic RPLND may become

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a good alternative to an open staging RPLND, but cannot currently be recommended as a standard diagnostic tool (139-142). In a randomised comparison of RPLND with one course of PEB chemotherapy, adjuvant chemotherapy significantly increased the 2-year recurrence-free survival to 99.41% (confidence interval [CI] 95.87%, 99.92%) as opposed to surgery, which had a 2-year recurrence-free survival of 92.37% (CI 87.21%, 95.50%). The difference was 7.04%, CI 2.52%, 11.56%. The hazard ratio to experience a tumour recurrence with surgery as opposed to chemotherapy was 7.937, CI 1.808, 34.48. Therefore, one course of adjuvant PEB is superior to RPLND with regard to recurrence rates in patients unstratified for risk factors (143). In the SWENOTECA data mentioned in section 7.3.3 it was also found that one adjuvant PEB reduced the number of recurrences for 90% for patients, whether vascular invasion was present or not (126).

7.4

CS1S with (persistently) elevated serum tumour markers

Serum tumour markers should be followed closely until levels fall into the reference values according to the expected half-life values for AFP and hCG. If the marker level increases after orchidectomy, the patient has residual disease. If RPLND is performed, up to 87% of these patients have pathologically documented nodes in the retroperitoneum (144). An ultrasound examination of the contralateral testicle must be performed, if this was not done initially. The treatment of true CS1S patients is still controversial. They may be treated with three courses of primary PEB chemotherapy and with follow-up as for CS1B patients (high risk, see below) after primary chemotherapy (145), or by RPLND (121). The presence of vascular invasion may strengthen the indication for primary chemotherapy as most CS1S with vascular invasion will need chemotherapy sooner or later anyway.

7.5 Guidelines for the treatment of NSGCT stage I CS1 risk-adapted treatments based on vascular invasion or surveillance are recommended treatment options (grade of recommendation: B) (Table 5). Table 5: Risk-adapted treatments for CS1 based on vascular invasion or surveillance GR CS1A (pT1, no vascular invasion): low risk 1. If the patient is willing and able to comply with a surveillance policy, long-term (at least B 5 years) close follow-up should be recommended. 2. Adjuvant chemotherapy or nerve-sparing RPLND in low-risk patients remain options for A those not willing to undergo surveillance. If RPLND reveals PN+ (nodal involvement) disease, chemotherapy with two courses of PEB should be considered. CS1B (pT2-pT4): high risk 1. Primary chemotherapy with two courses of PEB should be recommended. B 2. Surveillance or nerve-sparing RPLND in high-risk patients remain options for those not A willing to undergo adjuvant chemotherapy. If pathological stage II is revealed at RPLND, further chemotherapy should be considered. GR = grade of recommendation.

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Figure 1 provides a treatment algorithm for patients with NSGCT stage I. Figure 1: T  reatment algorithm after orchidectomy according to individual risk factors in patients with non-seminoma NSGCT CS1 (22) Non-seminoma CS I

Low risk no vascular invasion

Standard option

Option if conditions against surveillance

High risk Vascular invasion present

Option if conditions against surveillance and chemotherapy

Option if conditions against chemotherapy

Standard option

OR

Surveillance

Adjuvant chemotherapy 2 cycles PEB

Nerve-sparing (NS) RPLND

Adjuvant chemotherapy 2 cycles PEB

NS RPLND

Surveillance

Relapse

Treatment according to the IGCCCCG classification (3-4 cycles PEB [or VIP] followed by resection in case of residual tumour) PEB = cisplatin, etoposide, bleomycin; CS = clinical stage; IGCCCG = International Germ Cell Cancer Collaborative Group; RLNPD = retroperitoneal lymph node dissection; VIP = etoposide, cisplatin, ifosfamide

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8. TREATMENT: METASTATIC GERM CELL TUMOURS The treatment of metastatic germ cell tumours depends on: • the histology of the primary tumour • prognostic groups as defined by the IGCCCG based on 5202 non-seminoma and 660 seminoma cases (Table 3) (146).

8.1

Low-volume metastatic disease (stage IIA/B)

8.1.1 Stage IIA/B seminoma So far, the standard treatment for stage IIA/B seminoma has been radiotherapy. The radiation dose delivered in stage IIA and IIB is approximately 30 Gy and 36 Gy, respectively. The standard radiation field compared with stage I will be extended from the PA region to the ipsilateral iliac field (the hockey-stick field). In stage IIB, the lateral borders should include the metastatic lymph nodes with a safety margin of 1.0-1.5 cm. This technique yields a relapse-free survival after 6 years for stage IIA and IIB of 95% and 89%, respectively. Overall survival is almost 100% (61, 89). In stage IIB chemotherapy (4 x etoposide and cisplatin [EP] or 3 x PEB in good prognosis) is an alternative to radiotherapy. Although more toxic in the short term, it appears that 4 x EP or 3 x PEB achieve a similar level of disease control (147). Single-agent carboplatin is not an alternative to standard PEB chemotherapy (148). 8.1.2 Stage IIA/B non-seminoma There is a general consensus that treatment should start with initial chemotherapy in all advanced cases of NSGCT except for stage II NSGCT disease without elevated tumour markers, which alternatively can be treated with primary RPLND or surveillance (149, 150). If surveillance is chosen, one follow-up after 6 weeks is indicated to document whether the lesion is growing, remaining stable or shrinking. A shrinking lesion is likely to be of non-malignant origin and should be observed further. A stable or growing lesion indicates either teratoma or an undifferentiated malignant tumour. If the lesion is growing without a corresponding increase in the tumour markers AFP or beta-hCG, RPLND should be performed by an experienced surgeon because of suspected teratoma. Patients with a growing lesion and a concomitant increase in the tumour markers AFP or beta-hCG should not undergo surgery; they require chemotherapy with PEB according to the treatment algorithm for patients with metastatic disease and IGCCCG recommendations (151-153) (Figure 2). There is no proven role for PET scans in this situation. Patients not willing to undergo primary chemotherapy have the option of primary nerve-sparing RPLND with adjuvant chemotherapy (two cycles of PEB) in case of metastatic disease (pII A/B). Primary chemotherapy and primary RPLND are comparable options in terms of outcome but side-effects and toxicity are different, allowing for involvement of the patient in selecting the treatment of choice (154). The cure rate with either approach will be close to 98% (138, 155-160).

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Figure 2: Treatment options in patients with non-seminoma clinical stage IIA (23) IIA Marker +

CS IIA, marker – either

Chemotherapy PEB X 3

Residual tumour

Follow-up after 6 weeks

NS-RPLND

PS I

PS IIA/B

either

Resection

or

Follow-up Independent of vascular invasion

Follow-up

PD

or

2 cycles PEB

+

marker

3 cycles PEB +/resection of residual tumour

NC

Regression

-

NS-RPLND or chemotherapy

NS-RPLND

Further follow-up

PEB = cisplatin, etoposide, bleomycin; NS = nerve-sparing; RPLND = retroperitoneal lymph node dissection; PS = pathological stage; PD = progressive disease; NC = no change.

8.2

Advanced metastatic disease

8.2.1 Primary chemotherapy The primary treatment of choice for advanced disease is three or four cycles of PEB combination chemotherapy (Table 6), depending on the IGCCCG risk classification (see Table 3). This regimen has proven superiority to cisplatin, vinblastine and bleomycin (PVB) in patients with advanced disease (161-163). Data support a 3-day regimen of administering combination chemotherapy to be equally effective as a 5-day regimen, but associated with increased toxicity (164). Table 6: PEB regimen (interval 21 days). Drug Dosage Duration of cycles Cisplatin 20 mg/m2 Days 1-5* Etoposide 100 mg/m2 Days 1-5 Bleomycin 30 mg (bolus) Days 1, 8, 15 *Plus hydration. PEB = cisplatin, etoposide, bleomycin For patients with a ‘good prognosis’, according to the IGCCCG Classification (146), standard treatment consists of three cycles of PEB or, in cases where bleomycin is contraindicated, four cycles of EP (146,163167). Therapy should be given without reduction of the doses at 21-day intervals; delaying the following chemotherapy cycle is justified only in cases of fever with granulocytopenia < 1000/mm3 or thrombocytopenia < 100,000/IU. There is no indication for prophylactic application of haematopoietic growth factors such as, for example, granulocyte colony-stimulating factor (G-CSF). However, if infectious complications have occurred during chemotherapy, prophylactic administration of G-CSF is recommended for the following cycles (165, 168). The ‘intermediate prognosis’ group in the IGCCCG has been defined as patients with a 5- year survival rate of about 80%. The available data support four cycles of PEB as standard treatment (146, 169). Due to the generally less favourable prognosis of patients in this group compared with those with a ‘good prognosis’, they may be treated in prospective trials such as, for example, the EORTC Genitourinary Tract Cancer Cooperative Group trial with PEB vs PEB + paclitaxel (169).

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For patients with a ‘poor prognosis’, standard treatment consists of four cycles of PEB. Four cycles of cisplatin, etoposide and ifosfamide (PEI) have the same effect, but are more toxic (170, 171). The 5-year progression-free survival is between 45% and 50%. A randomised study has shown no advantage in high-dose chemotherapy for the overall group of ‘poor prognosis’ patients. However, patients with a slow marker decline may represent a prognostically inferior subgroup (172). Since a matched-pair analysis resulted in a better survival rate (173175), poor prognosis patients should still be treated in ongoing prospective randomised trials, investigating the value of high-dose chemotherapy. Patients meeting ‘poor-prognosis’ criteria should therefore be transferred to a reference centre. There are no general recommendations for treatment modifications for patients with a poor general condition (Karnofsky < 50%), extended liver infiltration (> 50%), or extended pulmonary infiltration.

8.3 Restaging and further treatment 8.3.1 Restaging Restaging is performed by imaging investigations and re-evaluation of tumour markers. At marker decline and stable or regressive tumour manifestation, chemotherapy will be completed (three or four cycles, depending on the initial stage) (146, 176, 177). In the case of marker decline but growing metastases, resection of the tumour is obligatory after termination of induction therapy, other than in an emergency, according to local tumour growth (178). Only with documented marker growth after two courses of chemotherapy is an early crossover of therapy indicated. These patients are usually candidates for new drugs trials (173, 179). Patients with a low-level marker plateau post-treatment should be observed to see whether complete normalisation occurs. Salvage chemotherapy is indicated for documented marker rise only (180, 181). 8.3.2 Residual tumour resection A residual mass of seminoma should not be resected, irrespective of the size, but controlled by imaging investigations and tumour markers (182-188). FDG-PET has a high prognostic value in patients with residual masses after treatment of seminoma. In patients with residuals of > 3 cm, FDG-PET should be performed in order to gain more information on the viability of these residuals. In patients with residuals of < 3 cm, the use of FDG-PET is optional (189). On progression, salvage therapy is indicated (chemotherapy, salvage surgery, radiotherapy) (190-194). In the case of non-seminoma and complete remission after chemotherapy (no tumour visible), residual tumour resection is not indicated (195-200). In the case of any visible residual mass and marker normalisation, surgical resection is indicated. In patients with lesions < 1 cm, there still is an increased risk of residual cancer or teratoma (201). In persistent retroperitoneal disease, all areas of primary metastatic sites must be completely resected within 4-6 weeks of completion of chemotherapy. If technically feasible, a nerve-sparing procedure should be performed (195, 202-209). Overall, following PEB induction chemotherapy, only 10% of residual masses contain viable cancer, 50% contain mature teratoma, and 40% contain necrotic-fibrotic tissue. As yet, no imaging investigations, including PET or a prognosis model, are able to predict histological differentiation of the non-seminomatous residual tumour. Thus, residual tumour resection is mandatory (196-198, 208-218). The extent of surgery should be based on the risk of relapse of an individual patient and quality of life issues (203). If possible, all the masses should be resected, because a complete resection, in the setting of viable malignant cells, is more critical than recourse to post-operative chemotherapy (219). The histology may diverge in different organ sites (211). Resection of contralateral pulmonary lesions is not mandatory in case pathologic examination of the lesions from the first lung shows complete necrosis (220). 8.3.3 Consolidation chemotherapy after secondary surgery After resection of necrosis or mature teratoma, no further treatment is required. In the case of incomplete resection of vital carcinoma or immature teratoma, two adjuvant cycles of conventionally dosed cisplatinbased chemotherapy may be given in certain subgroups (e.g. ‘poor prognosis’ patients) (219, 221) (caution: cumulative doses of bleomycin). After complete resection of vital tumour < 10% of the total volume, adjuvant chemotherapy is not beneficial for preventing further relapse. The prognosis will definitely deteriorate if vital carcinoma is found in resection specimens after second- and third-line chemotherapy. In this latter situation, post-operative chemotherapy is not indicated and is unable to improve the prognosis (207, 212).

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8.4

Systemic salvage treatment for relapse or refractory disease

8.4.1 Seminoma Cisplatin-based combination salvage chemotherapy will result in long-term remissions for about 50% of the patients who relapse after first-line chemotherapy (222). The regimens of choice are four cycles of PEI/ VIP (etoposide, ifosfamide, cisplatin), four cycles of TIP (paclitaxel, ifosfamide, cisplatin) or four cycles of VeIP (vinblastine, ifosfamide, cisplatin). At present, it is impossible to determine whether conventionally dosed cisplatin-based combination chemotherapy is sufficient as first-salvage treatment or whether early intensification of first-salvage treatment with high-dose chemotherapy should be attempted (223). It is therefore of the utmost importance that these rare patients are treated within clinical trials and at experienced centres. 8.4.2 Non-seminoma Standard salvage treatment after first-line chemotherapy consists of either four cycles of PEI/VIP, four courses of TIP, or four cycles of VeIP, respectively (Table 7). Table 7: Standard PEI/VIP, TIP and VeIP chemotherapy (interval 21 days) Chemotherapy agents Dosage Duration of cycles PEI/VIP Cisplatin* 20 mg/m2 Days 1-5 Etoposide 75-100 mg/m2 Days 1-5 Ifosfamide† 1.2 g/m2 Days 1-5 TIP Paclitaxel Ifosfamide† Cisplatin*

250 mg/m2 1.5 g/ m2 25 mg/m2

24 hour continuous infusion day 1 Days 2-5 Days 2-5

VeIP Vinblastin 0.11 mg/kg Days 1 + 2 Ifosfamide† 1.2 g/m2 Days 1-5 Cisplatin* 20 mg/m2 Days 1-5 PEI/VIP = cisplatin, etoposide, ifosfamide; TIP = paclitaxel, ifosfamide, cisplatin; VelP = vinblastine, ifosfamide, cisplatin. *Plus hydration. †Plus mesna protection. Conventionally dosed salvage chemotherapy may achieve long-term remissions in 15-40% of patients, depending on individual risk factors (181, 224). Prognostic indicators of response to salvage therapy are (181, 224-226): • the location and histology of the primary tumour • the response to first-line treatment • the duration of remissions • the level of AFP and hCG at relapse. Salvage therapy with VeIP is probably not superior to other conventionally dosed cisplatin-based combination regimens (220-222). The use of conventionally dosed combination regimens with more than three agents will increase toxicity without improving the treatment outcome (227). Depending on the presence of adverse prognostic factors, the results of salvage therapy after first-line cisplatin based treatment are unsatisfactory (181, 228). Although some phase II trials indicate a 10% improvement in survival with early intensification of first-salvage treatment using high-dose chemotherapy, others fail to demonstrate such improvement (229-233). High dose chemotherapy offered no advantage as first salvage treatment according to the results of the randomised IT 94 trial in good prognosis patients (234). Patients with good prognostic features should therefore be offered conventional-dose first salvage treatment. Several phase II trials, as well as one retrospectively matched pair-analysis, have shown an improvement in survival in poor-prognosis patients with early intensification of first-salvage treatment using high-dose chemotherapy (225, 235-237) (EBM: 2B).

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Recently, paclitaxel and gemcitabine have proved to be active in the treatment of refractory germ cell tumours; both drugs are synergistic with cisplatin (238-240). However, all of these patients should be entered into ongoing multicentre studies to define the optimal approach to salvage treatment, and should be referred to centres experienced in caring for relapse and/or refractory patients (223). 8.4.3 Late relapse (≥ 2 years after end of first-line treatment) Late relapse is defined as any patient relapsing more than 2 years following chemotherapy for metastatic disease. If technically feasible, all patients with late relapse should undergo immediate radical surgery of all lesions, irrespective of the level of their tumour markers to resect completely all undifferentiated germ-cell tumour, mature teratoma or secondary non-germ cell cancer (120, 241). If the lesions are not completely resectable, biopsies should be obtained for histological assessment, and salvage chemotherapy should be initiated according to the histological results. If the patient responds to salvage chemotherapy, secondary surgery should be conducted whenever possible. In the case of unresectable, but localised, refractory disease, radiotherapy can be considered. To avoid excess mortality, late relapses should be treated only at centres experienced in managing such patients (242).

8.5

Salvage surgery

Residual tumours after salvage chemotherapy should be resected within 4-6 weeks after marker normalisation or when a marker plateau is reached. In the case of marker progression after salvage treatment and a lack of other chemotherapeutic options, resection of residual tumours (‘desperation surgery’) should be considered if complete resection of all tumour seems feasible (about 25% long-term survival may be achieved) (181, 205, 213, 216, 243-252).

8.6

Treatment of brain metastases

Brain metastases occur in the frame of a systemic relapse and rarely as an isolated relapse. The long-term survival of patients presenting with brain metastases at initial diagnosis is poor (30-40%), but even poorer is the development of a brain metastasis as a recurrent disease (the 5-year survival-rate is 2-5%) (253, 254). Chemotherapy is the initial treatment in this case, and some data support the use of consolidation radiotherapy, even in the case of a total response after chemotherapy (255). Surgery can be considered in the case of a persistent solitary metastasis, depending on the systemic state, the histology of the primary tumour and the location of the metastasis.

8.7 Guidelines for the treatment of metastatic germ cell tumours GR 1. L  ow volume NSGCT stage IIA/B with elevated markers should be treated like ‘good or intermediate prognosis’ advanced NSGCT, with three or four cycles of PEB. Stage IIA/B without marker elevation can be treated by RPLND or close surveillance. 2. In metastatic NSGCT (> stage IIC) with a good prognosis, three courses of PEB is the primary A treatment of choice 3. In metastatic NSGCT with an intermediate or poor prognosis, the primary treatment of choice is A four courses of standard PEB 4. S  urgical resection of residual masses after chemotherapy in NSGCT is indicated in the case of B visible residual masses and when serum levels of tumour markers are normal or normalising 5. S  eminoma CSII A/B can initially be treated with radiotherapy. When necessary, chemotherapy can A be used as a salvage treatment with the same schedule as for the corresponding prognostic groups of NSGCT 6. In stage CS IIB, chemotherapy (4 x EP or 3 x PEB, in good prognosis) is an alternative to B radiotherapy. Although more toxic in the short term, it appears that 4 x EP or 3 x PEB achieve a similar level of disease control. 7. S  eminoma stage IIC and higher should be treated with primary chemotherapy according to the A same principles used for NSGCT GR = grade of recommendation

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9. FOLLOW-UP AFTER CURATIVE THERAPY 9.1 General considerations The selection of the test to be performed in follow-up should adhere to the following principles (256). • The interval between examination and duration of testing should be consistent with the time of maximal risk of recurrence and the natural history of the tumour. • The tests should be directed at the most likely sites of recurrence and should have a high predictive value, both positive and negative. • Therapy should be available that will result in cure of the recurrence, significant prolongation of life or palliation of symptoms. The initiation of earlier therapy should improve the outcome compared with therapy given when the patient becomes symptomatic from the tumour recurrence. • The increased risk of second malignancy, both in the primary site and in other tissues that may have been exposed to the same carcinogens, or in which there is epidemiological evidence of increased risk, should also guide the ordering tests. Malignant and non-malignant complications of therapy must also be considered. Such testing should also be performed with a frequency and duration consistent with the nature of the risk, and include only tests with high positive- and negative-predictive values. The following considerations apply in a general manner for the selection of an appropriate schedule and testing in the follow-up of all stages of testis tumour. • Most recurrences after curative therapy will occur in the first 2 years; surveillance should therefore be most frequent and intensive during this time. • Late relapses can occur beyond 5 years, and therefore yearly follow-up for life may be advocated. • After RPLND, relapse in the retroperitoneum is rare, the most likely site of recurrence being the chest. • The value of chest X-ray has been recently questioned in the follow-up of patients with disseminated disease after complete remission (257, 258). • CT of the chest has a higher predictive value than chest X-ray (258). • The results of therapy are dependent on the bulk of disease; thus an intensive strategy to detect asymptomatic disease may be justifiable. • After chemotherapy or radiotherapy, there is a long-term risk of the development of secondary malignancies.

9.2

Follow-up: stage I non-seminoma

Approximately 5% of patients with CS1 NSGCT present with elevated levels of tumour markers after orchidectomy, and up to 25-30% relapse during the first 2 years (5, 113, 131, 134, 155, 259-262). The follow-up schedule will differ depending on which of the three possible treatment strategies was chosen: • surveillance • nerve-sparing RPLND • adjuvant chemotherapy. 9.2.1 Follow-up investigations during surveillance The results of a surveillance policy depend upon a careful pre-operative staging procedure and follow-up management. In a ‘wait and see’ policy, relapses will occur in 30% of cases. Of these relapses, 80% will occur in the first 12 months after orchidectomy, and approximately 12% during the second year. The median time to relapse is 6 months (range 1-62 months), but relapses after 3-5 years, and even later, can still occur, with an annual rate of 4% (108, 109). Relapse occurs mainly in the retroperitoneum: approximately 20% of patients have evident metastases in the retroperitoneum, and 10% in the mediastinum and lungs (263). Sometimes the only indication is an elevated level of tumour markers. A randomised trial of two versus five CT scans has been published by the MRC recommending the reduction of imaging during surveillance in this stage to one CT scan at 3 months after orchidectomy, and another at 12 months. The trial, with a cohort of 414 patients, was powered to exclude a 3% probability of detecting a patient during surveillance only, with a relapse presenting already-metastatic disease with ‘intermediate’ or ‘poor’ prognosis features. Relapses were detected in 15% with two CTs, and 20% with five CTs; 1.6% of these patients had ‘intermediate’ or ‘poor’ prognosis features. Only 10% of patients had high-risk features (vascular invasion). In summary, this first randomised trial yielded level 1 evidence for a minimum follow-up in patients with CS1 non-seminoma (122). The recommended follow-up schedule (Table 8) includes the minimum requirements for imaging, and adds recommendations for other surveillance tests.

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Table 8: Recommended minimum follow-up schedule in a surveillance policy: stage I non-seminoma Procedure Year 1 Physical examination 4 times Tumour markers 4 times Chest X-ray Twice Abdominopelvic CT scan Twice (at 3 and 12 months) CT= computed tomography scan.

2 3-5 4 times Twice per year 4 times Twice per year Twice

6-10 Once per year Once per year

During the initial post-treatment phase, follow-up consists of regular clinical examinations, the monitoring of serum tumour markers, and imaging investigations. The frequency and type of the examinations depend on the estimated risk of relapse, the chosen treatment strategy, and the time that has elapsed since completion of therapy, and should be modified according to these risks. However, only limited information about the optimal follow-up strategy exists, and currently recommendations can only be given for seminoma (264). For low-risk stage I non-seminoma, two abdominopelvic CT scans during the first year seem sufficient to detect relapses at an early stage (122). The significance of additional CT scans remains uncertain. No studies are available that address the optimal monitoring of such patients by serum tumour markers (AFP, beta-hCG). 9.2.2 Follow-up after nerve-sparing RPLND Retroperitoneal relapse after a properly performed nerve-sparing RPLND is rare. RPLND should eliminate the retroperitoneal nodes as a site of relapse and thus the need for repeated abdominal CT scans. The US Testicular Cancer Intergroup study data show retroperitoneal relapse in 7/264 patients with pathological stage I disease (and 20 pulmonary relapses); four of these seven had no marker elevation (265). In the Indiana series, only one relapse in 559 cases was reported (266). If a relapse occurs, it is generally in the chest, neck or at the margins of the surgical field. Pulmonary relapses occur in 10-12% of patients, and more than 90% of those relapses occur within 2 years of RPLND (74, 267). However, the low rate of retroperitoneal relapse after RPLND can only be achieved by surgery in specialised centres, as shown by the high in-field relapse rate (7/13 relapses) in the German randomised trial of RPLND versus one course of PEB (143). The recommended minimum follow-up schedule is shown in Table 9. Table 9: Recommended minimum follow-up schedule after retroperitoneal lymphadenectomy or adjuvant chemotherapy: stage I non-seminoma Procedure Year 1 Physical examination 4 times Tumour markers 4 times Chest X-ray Twice Abdominopelvic CT scan Once CT = computed tomography scan.

2 3-5 4 times Twice/year 4 times Twice/year Twice Once

6-10 Once/year Once/year

9.2.3 Follow-up after adjuvant chemotherapy Prospective reports with long-term follow-up after adjuvant chemotherapy have shown a low relapse rate (113, 114, 259, 260) of about 3%. In a randomised trial with one course of PEB versus RPLND, the relapse rate with adjuvant chemotherapy was 1% (2/174 patients, one with marker relapse, one with mature teratoma in the retroperitoneum) (143). The need for repeated and long-term assessment of the retroperitoneum is still not clear. Owing to the risk of developing a late, slow-growing teratoma in the retroperitoneum after adjuvant chemotherapy, an abdominal CT should still be performed (see Table 9).

9.3

Follow-up: stage I seminoma

The majority of patients with seminoma (70-80%) present with clinical stage I disease at diagnosis (89). In - 20% of cases, there is nodal radiological involvement at the level of the retroperitoneum, and only 5% of 15¬-20% patients present with distant metastasis (89). The relapse rate varies between 1% and 20%, depending on the post-orchidectomy therapy chosen. Only up to 30% of seminomas present with elevation of hCG at diagnosis or in the course of the disease.

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Consequently, in most cases, measurement of blood markers will not be a reliable test for follow-up (268). The treatment options post-orchidectomy in stage I seminoma are retroperitoneal radiotherapy, surveillance and adjuvant chemotherapy. Due to extreme radio- and chemosensitivity, high cure rates of almost 100% are reached with each of the approaches, even in cases of relapse. The costs of the different therapies vary, as do the expected side-effects (91, 269, 270). 9.3.1 Follow-up after radiotherapy Low doses of radiotherapy (20-24 Gy) limited to the retroperitoneal or the hockey-stick field achieve an overall survival rate of approximately 99% at 5-10 years (97-99, 271, 272). The rate of relapse is 1-2% and the most common time of presentation is within 18 months of treatment (97, 100, 270, 273, 274), although late relapses have also been described (275). The site of relapse is mainly at the supradiaphragmatic lymph nodes, mediastinum, lungs or bones. In a small proportion of cases, the tumour will relapse in the inguinal or external iliac nodes (89). The side-effects of radiotherapy include impaired spermatogenesis, GI symptoms (peptic ulceration), and induction of second malignancies (270, 276, 277). Up to 50% of patients can develop moderate toxicity grade I-II (268). The schedule of follow-up is described in Table 10. Table 10: Recommended minimum follow-up schedule for post-orchidectomy surveillance, radiotherapy or chemotherapy: stage I seminoma Procedure Year 1 2 3-4 Physical 3 times 3 times Twice/year examination Tumour markers 3 times 3 times Twice/year Chest X-ray Twice/year Twice/year Once/year Abdominopelvic CT scan Twice/year Twice/year Once/year CT = computed tomography scan.

5-10 Once/year Once/year Once/year Once/year

9.3.2 Follow-up during surveillance The actuarial risk of relapse at 5 years ranges between 6% (low risk) and 20% (106, 278-282). There is no increased risk of death. The median time to relapse ranges from 12-18 months, but up to 29% of relapses can develop later than this (87, 283). The sites of relapse are the PA lymph nodes in up to 82% of cases; the pelvic lymph nodes, inguinal nodes and lungs can also be affected (87, 284-288). Due to the high and often late rate of relapse, close and active follow-up is mandatory for at least 5 years (289) (see Table 10). 9.3.3 Follow-up after adjuvant chemotherapy One or two courses of carboplatin-based chemotherapy is an effective alternative treatment in stage I seminoma. The relapse rate is 1.9-4.5%. In general, this treatment is well tolerated, with only mild, acute and intermediate-term toxicity (289, 290). Long-term data on late relapses and survival are missing (see Table 10).

9.4

Follow-up: stage II and advanced (metastatic) disease

The more advanced the nodal stage of the disease, the higher the likelihood of recurrence (138). In general, the primary tumour bulk governs the outcome for patients with NSGCT (291). In stage II NSGCT, regardless of the treatment policy adopted, excellent survival rates of 97% are reached provided that relapse is identified as soon as possible (149, 150, 156). In advanced metastatic germ cell tumours, the extent of the disease is correlated with the response to therapy and with survival. The combination of cisplatin-based chemotherapy and surgery (aggressive multimodality) achieves cure rates of between 65% and 85%, depending on the initial extent of disease (292, 293). Complete response rates to chemotherapy are in the order of 50-60% (292); another 20-30% of patients could be rendered disease-free with post-chemotherapy surgery (294). The main reasons for failure of therapy in advanced NSGCT are (291, 295, 296): • the presence of bulky disease not responding completely to chemotherapy • unresectable residual teratoma after chemotherapy • the presence or development of chemoresistant non-germ elements, which account for 8.2% of cases.

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Table 11 gives the recommended minimum follow-up schedule in advanced NSGCT and seminoma. Table 11: Recommended minimum follow-up schedule in advanced NSGCT and seminoma Procedure Year 1 2 3-5 Thereafter Physical examination 4 times 4 times Twice per year Once per year Tumour markers 4 times 4 times Twice per year Once per year Chest X-ray 4 times 4 times Twice per year Once per year Abdominopelvic CT scan*† Twice Twice Once per year Once per year Chest CT scan†‡ As indicated As indicated As indicated As indicated Brain CT scan§ As indicated As indicated As indicated As indicated CT = computed tomography scan. *Abdominal CT scanning must be performed at least annually if teratoma is found in the retroperitoneum. †If the post-chemotherapy evaluation in a seminoma patient shows any mass > 3 cm, the appropriate CT scan should be repeated 2 and 4 months later to ensure that the mass is continuing to regress. If available, FDG-PET scanning can be performed. ‡A chest CT scan is indicated if abnormality is detected on chest X-ray and after pulmonary resection. §In patients with headaches, focal neurological findings, or any central nervous system symptoms.

10. TESTICULAR STROMAL TUMOURS 10.1

Background

Testicular stromal tumours are rare and account for only 2-4% of adult testicular tumours. However, only Leydig cell and Sertoli cell tumours are of clinical relevance. As no general recommendations have been published to date, the Testicular Cancer Working Group of the European Association of Urology (EAU) has decided to include these tumours in the EAU Germ Cell Tumour Guidelines. Recommendations for diagnosis and treatment are given only for Leydig and Sertoli cell tumours.

10.2

Methods

A Medline search for Leydig cell tumours (synonym: interstitial cell tumour) and Sertoli cell tumours (synonym: androblastoma) was performed. Approximately 850 papers were found. After excluding pure laboratory work without clinical data, female and paediatric tumours and animal cases, 371 papers and abstracts were reviewed. Double publications and papers with unclear histology or missing data on clinical course were excluded. The majority of the remaining 285 publications are case reports, with only a few papers reporting series of more than 10 cases, most of them published in the pathology literature. The true incidence of stromal tumours therefore remains uncertain, and the proportion of metastatic tumours can only be given approximately. Nevertheless, the symptoms for pre-operative suspicion of testicular stromal tumours and the characteristics of tumours at high risk for metastases are sufficiently well established (EBM: IIA and IIB) to enable recommendations to be made regarding diagnosis and surgical approach. However, no recommendations for appropriate follow-up can be given due to the absence of follow-up data in most reported cases, and the fatal outcome of metastatic tumours, irrespective of the therapy chosen. The individual publications have been rated according to EBM categories (see above). The literature research for clinical data on Leydig cell tumours resulted in 193 publications dealing with more than 480 tumours in adults, including three publications (1-3) reporting larger series on a total of 90 patients. Follow-up data of more than 2 years are available for about 80 patients. The literature research for clinical data on Sertoli cell tumours resulted in 93 publications dealing with more than 260 tumours in adults, including three publications (from the same group) (4-6) reporting on a total of 80 patients. Follow-up data of more than 2 years are available in fewer than 40 patients.

10.3

Classification

The non-germ cell tumours of the testicle include the sex cord/gonadal stromal tumours and the miscellaneous non-specific stromal tumours. The different histological subtypes of testicular tumours are defined according to the WHO classification 2004 (adapted) (7).

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10.4

Leydig cell tumours

10.4.1 Epidemiology Leydig cell tumours constitute about 1-3% of adult testicular tumours (2, 8) and 3% of testicular tumours in infants and children (8). The tumour is most common in the third to sixth decade in adults, with a similar incidence observed in every decade. Another peak incidence is seen in children aged between 3 and 9 years. Only 3% of Leydig cell tumours are bilateral (2). Occasionally, they occur in patients with Klinefelter’s syndrome (8). 10.4.2 Pathology of Leydig cell tumours Leydig cell tumours are the most common type of sex cord/gonadal stromal tumours. Histopathologically, they are well outlined and usually up to 5 cm in diameter. They are also solid, coloured yellow to tan, with haemorrhage and/or necrosis present in 30% of cases. Microscopically, the cells are polygonal, with eosinophilic cytoplasm with occasional Reinke crystals, regular nucleus, solid arrangement and capillary stroma. The cells express vimentin, inhibin, protein S-100, steroid hormones, calretinin and cytokeratin (focally) (7). About 10% of Leydig cell tumours are malignant tumours, which present with the following parameters: • large size (> 5 cm) • cytological atypia • increased mitotic activity (> 3 per 10 high-power field [HPF]) • increased MIB-1 expression (18.6% vs 1.2% in benign) • necrosis • vascular invasion (9) • infiltrative margins • extension beyond the testicular parenchyma • DNA aneuploidy (1,10). 10.4.3 Diagnosis Patients either present with a painless enlarged testis or the tumour is an incidental ultrasound finding. In up to 80% of cases, hormonal disorders with high oestrogen and oestradiol levels and low testosterone, increased levels of LH and FSH are reported (11, 12), while negative results are always obtained for the testicular germ cell tumour-markers AFP, hCG, LDH and PLAP. Approximately 30% of patients present with gynaecomastia (13, 14). Only 3% of tumours are bilateral (2). Leydig cell tumours must be distinguished from the multinodular tumour-like and often bilaterally occurring lesions of the androgenital syndrome (15). Diagnostic work-up must include markers, hormones (at least testosterone, LH and FSH; if not conclusive, additionally oestrogen, oestradiol, progesterone and cortisol), ultrasound of both testes, and CT scan of chest and abdomen. On ultrasound, it may be possible to observe well-defined, small, hypoechoic lesions with hypervascularisation, but the appearance is variable and is indistinguishable from germ cell tumours (16, 17). The proportion of metastatic tumours in all published case reports is only 10%. Within three larger series with longer follow-up, 18 metastatic tumours were found in a total of 83 cases (21.7%) (1-3). Histopathological signs of malignancy have been depicted above (see 4.2) (1, 10). In addition, patients of older age have a greater risk of harbouring a tumour of malignant potential. 10.4.4 Treatment Asymptomatic testicular tumours of small volume are often misinterpreted as germ cell tumours, and inguinal orchidectomy is performed. It is highly recommended to perform an organ-sparing procedure in every small intraparenchymal lesion in order to obtain the histological diagnosis. Especially in patients with symptoms of gynaecomastia or hormonal disorders, a non germ-cell tumour should be considered and immediate orchidectomy avoided (18). In cases of germ cell tumour in either frozen section or paraffin histology, orchidectomy is recommended as long as a contralateral normal testicle is present. In stromal tumours with histological signs of malignancy, especially in patients of older age, orchidectomy and retroperitoneal lymphadenectomy is recommended to prevent metastases (19). Without histological signs of malignancy, an individualised surveillance strategy after orchidectomy is recommended (CT follow-up may be most appropriate since specific tumour markers are not available). Tumours that have metastasised to lymph nodes, lung, liver or bone respond poorly to chemotherapy or radiation and survival is poor (19).

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10.4.5 Follow-up Recommendations for appropriate follow-up cannot be given because of the lack of follow-up data in most reported cases and the lethal outcome of metastatic tumours, irrespective of the therapy chosen.

10.5

Sertoli cell tumour

10.5.1 Epidemiology Sertoli cell tumours account for fewer than 1% of testicular tumours, and the mean age at diagnosis is around 45 years, with rare cases under 20 years of age (4, 20). On rare occasions, these tumours may develop in patients with androgen insensitivity syndrome and Peutz-Jeghers syndrome. 10.5.2 Pathology of Sertoli cell tumours The tumour is well circumscribed, yellow, tan or white, with an average diameter of 3.5 cm (4). Microscopically, the cells are eosinophilic to pale with vacuolated cytoplasm. The nuclei are regular with grooves and there may be inclusions. The arrangement of the cells is tubular or solid; a cord-like or retiform pattern is possible. The stroma is fine and capillary, but in some cases a sclerosing aspect predominates. The cells express vimentin, cytokeratins, inhibin (40%) and protein S-100 (30%) (4). The rate of malignant tumours ranges between 10% and 22%, and fewer than 50 cases have been reported (21-23). Signs of a malignant Sertoli tumour are: • large size (> 5 cm) • pleomorphic nuclei with nucleoli • increased mitotic activity (> 5 per 10 HPF) • necrosis • vascular invasion. 10.5.2.1 Classification Three subtypes have been described (20): • the classic Sertoli cell tumour (4) • the large cell calcifying form with characteristic calcifications (5, 24) • the rare sclerosing form (6, 25). 10.5.3 Diagnosis Patients present either with an enlarged testis or the tumour is an incidental ultrasound finding (26). Most classic Sertoli tumours are unilateral and unifocal. Hormonal disorders are infrequent, although gynaecomastia is sometimes seen (4). The testicular tumour-markers AFP, hCG, LDH and PLAP are always negative. Diagnostic work-up must include tumour markers, hormones (at least testosterone, LH and FSH; if not conclusive, additionally oestrogen, oestradiol, progesterone and cortisol), ultrasound of both testes and CT scan of chest and abdomen. Sertoli cell tumours are generally hypoechoic on ultrasound, but they can be of variant appearance and therefore cannot be safely distinguished from germ cell tumours (20). Only the large cell calcifying form has a characteristic image with brightly echogenic foci due to calcification (27, 28). The large cell calcifying form is diagnosed in younger men and is associated with genetic syndromes (Carney’s complex [29] and Peutz-Jeghers syndrome [30]) or, in about 40% of cases, endocrine disorders. A total of 44% of cases are bilateral, either synchronous or metachronous, and 28% show multifocality (24). The characteristics of metastatic tumours have been depicted above (24, 25). However, among patients whose tumours have been histopathologically classified as ‘malignant’ using these or similar characteristics (i.e. 18.8% of tumours in all reported cases), only 7% showed metastatic disease during follow-up. In the largest series with the longest follow-up, 7.5% of patients had been classified as ‘malignant’ at primary diagnosis and 11.7% showed metastatic disease long-term (4). In general, affected patients are of higher age, tumours are nearly always palpable, and show more than one sign of malignancy (4). Up to 20% of the large cell sclerosing form are malignant. There are some hints that discrimination between an early and late onset type may define a different risk for metastatic disease (5.5% compared with 23%) (20). Metastases in the infrequent sclerosing subtype are rare.

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10.5.4 Treatment Testicular tumours of small volume, otherwise asymptomatic, are often misinterpreted as germ cell tumours and inguinal orchidectomy is performed. It is highly recommended to proceed with an organ-sparing approach in small intraparenchymal testicular lesions until final histology is available. Especially in patients with symptoms of gynaecomastia or hormonal disorders or typical imaging on ultrasound (calcifications, small circumscribed tumours), organ-sparing surgery should be considered. Secondary orchidectomy can be performed if final pathology reveals a non-stromal (e.g. germ cell) tumour. Organ-sparing surgical approaches are justified as long as the remaining testicular parenchyma is sufficient for endocrine (and in stromal tumours also exocrine) function. In tumours with histological signs of malignancy, especially in patients of older age, orchidectomy and retroperitoneal lymphadenectomy are recommended to prevent metastases (19). Without signs of malignancy, an individualised surveillance strategy after orchidectomy is recommended (CT scans may be most appropriate since specific tumour-markers are not available). Tumours metastasising to lymph nodes, lung or bone respond poorly to chemotherapy or radiation, and survival is poor. 10.5.5 Follow-up Recommendations for appropriate follow-up cannot be given because of the lack of follow-up data in most reported cases and the lethal outcome of metastatic tumours, irrespective of the therapy chosen.

10.6 Granulosa cell tumour This is a rare tumour, with two variants: juvenile and adult. • The juvenile type is benign. It is the most frequent congenital testicle tumour and represents 6.6% of all prepubertal testicular neoplasms. The cystic appearance is characteristic of this tumour type (31). • With the adult type, the average age at presentation is 44 years. The typical morphology is of a homogeneous, yellow-grey tumour, with elongated cells with grooves in microfollicular and Call-Exner body arrangements. Malignant tumours represent around 20% of cases. They are usually > 7 cm diameter. Vascular invasion and necrosis are features suggestive of malignant biology (32).

10.7

Thecoma/fibroma group of tumours

These tumours are very rare and benign (7).

10.8

Other sex cord/gonadal stromal tumours

Sex cord/gonadal stromal tumours may be incompletely differentiated or mixed forms. There is limited experience with incompletely differentiated sex cord/gonadal stromal tumours and no cases of reported metastasis (7). In mixed tumour forms, all the histological components should be reported. However, the clinical behaviour is most likely to reflect the predominant pattern or the most aggressive component of the tumour (33)

10.9

Tumours containing germ cell and sex cord/gonadal stromal (gonadoblastoma)

If the arrangement of the germ cells are in a nested pattern and the rest of the tumour is composed of sex cord/gonadal stroma, the term gonadoblastoma is used. It is most frequent in gonadal dysgenesis with ambiguous genitalia. Bilateral tumours are present in 40% of cases. The prognosis is correlated with the invasive growth of the germinal component (34). In the case of a diffuse arrangement of the different components, there are some doubts about the neoplastic nature of the germinal cells and some authors consider them to be entrapped rather than neoplastic (35).

10.10 Miscellaneous tumours of the testis 10.10.1 Tumours of ovarian epithelial types These tumours resemble the epithelial tumours of the ovary. A cystic appearance with occasional mucinous material can be observed. Microscopically, the aspect is identical to their ovarian counterparts, and their evolution is similar to that of the different epithelial ovarian subtypes. Some Brenner types can be malignant (7). 10.10.2 Tumours of the collecting ducts and rete testis These tumours are very rare. Benign (adenoma) and malignant (adenocarcinoma) have been reported, with malignant tumours showing local growth with a mortality rate of 56% (18).

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10.10.3 Tumours (benign and malignant) of non-specific stroma These are very uncommon and have a similar criteria, prognosis and treatment as do the soft tissue sarcomas.

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Gels ME, Hoekstra HJ, Sleijfer DT, Marrink J, de Bruijn HW, Molenaar WM, Freling NJ, Droste JH, Schraffordt Koops H. Detection of recurrence in patients with clinical stage I nonseminomatous testicular germ cell tumours and consequences for further follow-up: a single-center 10-year experience. J Clin Oncol 1995;13(5):1188-94. http://www.ncbi.nlm.nih.gov/pubmed/7537802 van As NJ, Gilbert DC, Money-Kyrle J, Bloomfield D, Beesley S, Dearnaley DP, Horwich A, Huddart RA. Evidence-based pragmatic guidelines for the follow-up of testicular cancer: optimising the detection of relapse. Br J Cancer 2008:17;98(12):1894-902. http://www.ncbi.nlm.nih.gov/pubmed/18542063 McLeod DG, Weiss RB, Stablein DM, Muggia FM, Paulson DF, Ellis JH, Spaulding JT, Donohue JP. Staging relationships and outcome in early stage testicular cancer: a report from the Testicular Cancer Intergroup Study. J Urol 1991;145(6):1178-83. http://www.ncbi.nlm.nih.gov/pubmed/1851890 Donohue JP, Thornhill JA, Foster RS, Rowland RG, Bihrle R. Primary retroperitoneal lymph node dissection in clinical stage A non-seminomatous germ cell testis cancer: review of the Indiana University Experience 1965-1989. Br J Urol 1993;71(3):326-35. http://www.ncbi.nlm.nih.gov/pubmed/8386580 Schmoll HJ, Weissbach L. [Diagnostik und Therapie von Hodentumouren.] Interdisziplinäre Konsensus-Konferenz, Halle (Saale), 1996. EBM IIa, IIb, III. [Diagnosis and therapy for germ cell tumours] [article in German] McCaffrey JA, Bajorin DF, Motzer RJ. Risk assessment for metastatic testis cancer. Urol Clin North Am 1998;25(3):389-95. http://www.ncbi.nlm.nih.gov/pubmed/9728209 Buchholz TA, Walden TL, Prestidge BR. Cost-effectiveness of post-treatment surveillance after radiation therapy for early stage seminoma. Cancer 1998;82(6):1126-33. http://www.ncbi.nlm.nih.gov/pubmed/9506359 Tana S, Cerrotta A, Gardani G, Palazzi M, Pizzocaro G. Post surgical policy in stage I testicular seminoma: cost and benefit of prophylactic irradiation in a long-term experience. Tumouri 1997;83(6):918-21. http://www.ncbi.nlm.nih.gov/pubmed/9526584 Sultanem K, Souhami L, Benk V, Bahary JP, Roman T, Shenouda G, Freeman C. Para-aortic irradiation only appears to be adequate treatment for patients with stage I seminoma of the testis. Int J Radiat Oncol Biol Phys 1998;40(2):455-9. http://www.ncbi.nlm.nih.gov/pubmed/9457835 Kiricuta IC, Sauer J, Bohndorf W. Omission of the pelvic irradiation in stage I testicular seminoma: a study of postorchidectomy paraaortic radiotherapy. Int J Radiat Oncol Biol Phys 1996;35(2):293-8. http://www.ncbi.nlm.nih.gov/pubmed/9457835 Warde P, Gospodarowicz MK, Panzarella T, Catton CN, Sturgeon JF, Moore M, Goodman P, Jewett MA. Stage I testicular seminoma: results of adjuvant irradiation and surveillance. J Clin Oncol 1995;13(9):2255-62. http://www.ncbi.nlm.nih.gov/pubmed/7666083 Fossa SD, Aass N, Kaalhus O. Radiotherapy for testicular seminoma stage I: treatment results and long-term post-irradiation morbidity in 365 patients. Int J Radiat Oncol Biol Phys 1989;16(2):383-8. http://www.ncbi.nlm.nih.gov/pubmed/7666083 Baniel J, Foster RS, Einhorn LH, Donohue JP. Late relapse of clinical stage I testicular cancer. J Urol 1995;154(4):1370-2. http://www.ncbi.nlm.nih.gov/pubmed/7658541 Stein ME, Leviov M, Drumea K, Moshkovitz B, Nativ O, Milstein D, Sabo E, Kuten A. Radiationinduced tumours in irradiated stage I testicular seminoma: results of a 25-year follow-up (1968-1993). J Surg Oncol 1998;67(1):38-40. http://www.ncbi.nlm.nih.gov/pubmed/9457255 Akimoto T, Takahashi I, Takahashi M, Yamakawa M, Hayakawa K, Mitsuhashi N, Niibe H. Long-term outcome of postorchidectomy radiation therapy for stage I and II testicular seminoma. Anticancer Res 1997;17(5B):3781-5. http://www.ncbi.nlm.nih.gov/pubmed/9427780 Von der Maase H, Specht L, Jacobsen GK, Jakobsen A, Madsen EL, Pedersen M, Rorth M, Schultz H. Surveillance following orchidectomy for stage I seminoma of the testis. Eur J Cancer 1993;29A(14):1931-4. http://www.ncbi.nlm.nih.gov/pubmed/8280484

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11.2

Non-germ cell tumours

1.

Cheville JC, Sebo TJ, Lager DJ, Bostwick DG, Farrow GM. Leydig cell tumour of the testis: a clinicopathologic, DNA content, and MIB-1 comparison of nonmetastasizing and metastasizing tumours. Am J Surg Pathol 1998;22(11):1361-7. http://www.ncbi.nlm.nih.gov/pubmed/9808128 Kim I, Young RH, Scully RE. Leydig cell tumours of the testis. A clinicopathological analysis of 40 cases and review of the literature. Am J Surg Pathol 1985;9(3):177-92. http://www.ncbi.nlm.nih.gov/pubmed/3993830 Matveev BP, Gurarii LL. [Leydig-cell tumours of the testis] Urol Nefrol (Mosk) 1997;(4):34-6. [article in Russian] http://www.ncbi.nlm.nih.gov/pubmed/9381620 Young RH, Koelliker DD, Scully RE. Sertoli cell tumours of the testis, not otherwise specified: a clinicopathologic analysis of 60 cases. Am J Surg Pathol 1998;22(6):709-21. http://www.ncbi.nlm.nih.gov/pubmed/9630178 Proppe KH, Scully RE. Large-cell calcifying Sertoli cell tumour of the testis. Am J Clin Pathol 1980;74(5):607-19. http://www.ncbi.nlm.nih.gov/pubmed/7446466 Zukerberg LR, Young RH, Scully RE. Sclerosing Sertoli cell tumour of the testis. A report of 10 cases. Am J Surg Pathol 1991;15(9):829-34. http://www.ncbi.nlm.nih.gov/pubmed/1719830 WHO histological classification of testis tumours, In: Eble JN, Sauter G, Epstein JI, Sesterhenn IA (eds). Pathology & Genetics. Tumours of the urinary system and male genital organs. Lyon: IARC Press, 2004: 218, pp. 250-262. Ulbright TM, Amin MB, Young RH. Tumours of the testis, adnexia, spermatic cord and scrotum. AFIP1999. Cheville JC, Sebo TJ, Lager DJ, Bostwick DG, Farrow GM. Leydig cell tumour of the testis: a clinicopathologic, DNA content, and MIB-1 comparison of non-metastasizing and metastasizing tumours. Am J Surg Pathol 1998;22(11):1361-7. http://www.ncbi.nlm.nih.gov/pubmed/9808128 McCluggage WG, Shanks JH, Arthur K, Banerjee SS. Cellular proliferation and nuclear ploidy assessments augment established prognostic factors in predicting malignancy in testicular Leydig cell tumours. Histopathology 1998;33(4):361-8. http://www.ncbi.nlm.nih.gov/pubmed/9822927 Mineur P, de Cooman S, Hustin J, Verhoeven G, de Hertogh E. Feminizing testicular Leydig cell tumour: hormonal profile before and after unilateral orchidectomy. J Clin Endocrinol Metab 1987;64(4):686-91. http://www.ncbi.nlm.nih.gov/pubmed/3818898 Reznik Y, Rieu M, Kuhn JM, Mandard JC, Bottet P, Lemonnier D, Bekka S, Mahoudeau J. Luteinizing hormone regulation by sex steroids in men with germinal and Leydig cell tumours. Clin Endocrinol (Oxf) 1993;38(5):487-93. http://www.ncbi.nlm.nih.gov/pubmed/8392454 Bercovici JP, Nahoul K, Tater D, Charles JF, Scholler R. Hormonal profile of Leydig cell tumours with gynecomastia. J Clin Endocrinol Metab 1984;59(4):625-30. http://www.ncbi.nlm.nih.gov/pubmed/6434575 Haas GP, Pittaluga S, Gomella L, Travis WD, Sherins RJ, Doppman JL, Linehan WL, Robertson C. Clinical occult Leydig cell tumour presenting with gynecomastia. J Urol 1989;142(5):1325-7. http://www.ncbi.nlm.nih.gov/pubmed/2810523 Ruthgers JL, Young RH, Scully RE. The testicular ‘tumour’ of the adrenogenital syndrome. A report of six cases and review of the literature on testicular masses in patients with adrenocortical disorders. Am J Surg Pathol 1988;12(7):503-13. http://www.ncbi.nlm.nih.gov/pubmed/3291624 Maizlin ZV, Belenky A, Kunichezky M, Sandbank J, Strauss S. Leydig cell tumours of the testis: gray scale and color Doppler sonographic appearance. J Ultrasound Med 2004;23(7):959-64. http://www.ncbi.nlm.nih.gov/pubmed/15292565 Ponce de Leon Roca J, Algaba Arrea F, Bassas Arnau L, Villavicencio Mavrich H. [Leydig-cell tumours of the testis] Arch Esp Urol 2000;53(6):453-8. [article in Spanish] http://www.ncbi.nlm.nih.gov/pubmed/11002512 Wegner HE, Dieckmann KP, Herbst H, Andresen R, Miller K. Leydig cell tumour–comparison of results of radical and testis sparing surgery in a single center. Urol Int 1997;59(3):170-3. http://www.ncbi.nlm.nih.gov/pubmed/9428434

2.

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8. 9.

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19.

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21. 22.

23. 24.

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33.

34. 35.

Mosharafa AA, Foster RS, Bihrle R, Koch MO, Ulbright TM, Einhorn LH, Donohue JP. Does retroperitoneal lymph node dissection have a curative role for patients with sex cord-stromal testicular tumours? Cancer 2003;98(4):753-7. http://www.ncbi.nlm.nih.gov/pubmed/9428434 Giglio M, Medica M, De Rose AF, Germinale F, Ravetti JL, Carmignani G. Testicular Sertoli cell tumours and relative sub-types. Analysis of clinical and prognostic features. Urol Int 2003;70(3): 205-10. http://www.ncbi.nlm.nih.gov/pubmed/12660458 Jacobsen GK. Malignant Sertoli cell tumours of the testis. J Urol Pathol 1993;1:233-55. Kratzer SS, Ulbright TM, Talerman A, Srigley JR, Roth LM, Wahle GR, Moussa M, Stephens JK, Millos A, Young RH. Large cell calcifying Sertoli cell tumour of the testis: contrasting features of six malignant and six benign tumours and a review of the literature. Am J Surg Pathol 1997;21(11): 1271-80. http://www.ncbi.nlm.nih.gov/pubmed/9351565 Henley JD, Young RH, Ulbright TM. Malignant Sertoli cell tumours of the testis: a study of 13 examples of a neoplasm frequently misinterpreted as seminoma. Am J Surg Pathol 2002;26:541-50. Plata C, Algaba F, Andujar M, Nistal M, Stocks P, Martinez JL, Nogales FF. Large cell calcifying Sertoli cell tumour of the testis. Histopathology 1995;26(3):255-9. http://www.ncbi.nlm.nih.gov/pubmed/7541015 Anderson GA. Sclerosing Sertoli cell tumour of the testis: a distinct histological subtype. J Urol 1995;154(5):1756-8. Review. http://www.ncbi.nlm.nih.gov/pubmed/7563340 Grabrilove JL, Freiberg EK, Leiter E, Nicolis GL. Feminizing and non-feminizing Sertoli cell tumour. J Urol 1980;124(6):757-67. http://www.ncbi.nlm.nih.gov/pubmed/7003168 Gierke CL, King BF, Bostwick DG, Choyke PL, Hattery RR. Large-cell calcifying Sertoli cell tumour of the testis: appearance at sonography. AJR Am J Roentgenol 1994;163(2):373-5. http://www.ncbi.nlm.nih.gov/pubmed/8037034 Chang B, Borer JG, Tan PE, Diamond DA. Large-cell calcifying Sertoli cell tumour of the testis: case report and review of the literature. Urology 1998;52(3):520-2. http://www.ncbi.nlm.nih.gov/pubmed/9730477 Washecka R, Dresner MI, Honda SA. Testicular tumours in Carney’s complex. J Urol 2002;167(3):1299-302. http://www.ncbi.nlm.nih.gov/pubmed/11832717 Young S, Gooneratne S, Straus FH, Zeller WP, Bulun SE, Rosenthal IM. Feminizing Sertoli cell tumours in boys with Peutz-Jeghers syndrome. Am J Surg Pathol 1995;19(1):50-8. http://www.ncbi.nlm.nih.gov/pubmed/7802138 Kaplan GW, Cromie WJ, Kelalis PP, Silber I, Tank ES Jr. Gonadal stromal tumours: a report of theprepuberal testicular tumours registry. J Urol 1986;136(1Pt2):300-2. http://www.ncbi.nlm.nih.gov/pubmed/3723681 Al-Bozom IA, El-Faqih SR, Hassan SH, El-Tiraifi AE, Talic RF. Granulosa cell tumour of the adult type. A case report and review of the literature of a very rare testicular tumour. Arch Pathol Lab Med 2000;124(10):1525-8. http://www.ncbi.nlm.nih.gov/pubmed/11035589 Perito PE, Ciancio G, Civantos F, Politano VA. Sertoli-Leydig cell testicular tumour. case report and review of sex cord/gonadal stromal tumour histogenesis. J Urol 1992;148(3):883-5. http://www.ncbi.nlm.nih.gov/pubmed/1512847 Scully RE. Gonadoblastoma. A review of 74 cases. Cancer 1970;25(6):1340-56. http://www.ncbi.nlm.nih.gov/pubmed/4193741 Ulbright TM, Srigley JR, Reuter VE, Wojno K, Roth LM, Young RH. Sex-cord-stromal tumours of the testis with entrapped germ cells: a lesion mimicking unclassified mixed germ cell sex cord-stromal tumours. Am J Surg Pathol 2000;24(4):535-42. http://www.ncbi.nlm.nih.gov/pubmed/10757400

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12. ABBREVIATIONS USED IN THE TEXT

This list is not comprehensive for the most common abbreviations.

AFP AUC hCG Cg A CI CS CT EAU EBM EP EORTC FDG-PET FSH GI G-CSF GR HPF IGCCCG LE LH LDH MRC MRI NSGCT PA PEB PEI PET PFS PS PLAP PVB RPLND SWENOTECA Tin TIP TNM UICC ULN VelP WHO VIP (VP-16)

alpha-fetoprotein area under curve human chorionic gonadotrophin chromogranine A confidence interval clinical stage computed tomography European Association of Urology evidence-based medicine etoposide, cisplatin European Organisation for Research and Treatment of Cancer fluorodeoxyglucose-positron emission tomography follicle-stimulating hormone gastrointestinal granulocyte colony-stimulating factor grade of recommendation high-power field International Germ Cell Cancer Collaborative Group level of evidence luteinising hormone lactate dehydrogenase Medical Research Council magnetic resonance imaging non-seminomatous germ cell tumour para-aortic cisplatin, etoposide, bleomycin cisplatin, etoposide, ifosfamide positron emission tomography progression-free survival pathological stage placental alkaline phosphatase cisplatin, vinblastine, bleomycin retroperitoneal lymph node dissection Swedish-Norwegian Testicular Cancer Project carcinoma in situ pathological definition: undifferentiated intratubular germ cell carcinoma paclitaxel, ifosfamide, cisplatin Tumour Node Metastasis International Union Against Cancer upper limit of normal vinblastine, ifosfamide, cisplatin World Health Organization etoposide, ifosfamide, cisplatin

Conflict of interest All members of the Testicular Cancer Guidelines writing panel have provided disclosure statements on all relationships that they have and that might be perceived to be a potential source of conflict of interest. This information is kept on file in the European Association of Urology Central Office database. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

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Guidelines on

Benign Prostatic Hyperplasia J. de la Rosette, G. Alivizatos, S. Madersbacher, C. Rioja Sanz, J. Nordling, M. Emberton, S. Gravas, M.C. Michel, M. Oelke

© European Association of Urology 2009

TABLE OF CONTENTS 1. Background 1.1 Prevalence 1.2 Is BPH a progressive disorder? 1.2.1 Indicators of progression 1.2.2 Conclusions 1.2.3 References

page 5 5 5 6 7 7

2. RISK FACTORS 2.1 For developing the disease 2.2 For surgical treatment 2.3 References

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3. ASSESSMENT 3.1 Symptom scores 3.1.1 International Prostate Symptom Score (I-PPS) 3.1.2 Quality-of-life assessment 3.1.3 Symptom score as decision tool for treatment 3.1.4 Symptom score as outcome predictor 3.1.5 Conclusions 3.1.6 Recommendations 3.1.7 References 3.2 Prostate specific antigen (PSA) measurement 3.2.1 Factors influencing the serum levels of PSA 3.2.2 PSA and prediction of prostatic volume 3.2.3 PSA and probability of having prostate cancer 3.2.4 PSA and prediction of BPH-related outcomes 3.2.5 Conclusions 3.2.6 Recommendation 3.2.7 References 3.3 Creatinine measurement 3.3.1 Conclusions 3.3.2 References 3.4 Urinalysis 3.4.1 Recommendation 3.5 Digital rectal examination (DRE) 3.5.1 DRE and cancer detection 3.5.2 DRE and prostate size evaluation 3.5.3 Conclusions and recommendations 3.5.4 References 3.6 Imaging of the urinary tract 3.6.1 Upper urinary tract 3.6.2 Lower urinary tract 3.6.3 Urethra 3.6.4 Prostate 3.6.5 References 3.7 Voiding charts (diaries) 3.7.1 Conclusions 3.7.2 References 3.8 Uroflowmetry 3.8.1 References 3.9 Post-void residual volume (PVR) 3.10 Urodynamic studies 3.10.1 Outcome 3.10.2 Conclusions 3.10.3 References 3.11 Endoscopy 3.11.1 LUTS caused by bladder outlet obstruction 3.11.2 Morbidity of urethrocystoscopy

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3.11.3 Relationship between trabeculation and peak flow rate 3.11.4 Relationship between trabeculation and symptoms 3.11.5 Relationship between trabeculation and prostate size 3.11.6 Relationship between trabeculation and obstruction 3.11.7 Bladder diverticula and obstruction 3.11.8 Bladder stones and obstruction 3.11.9 Intravesical pathology 3.11.10 Conclusions 3.11.11 References 3.12 Recommendations for assessment

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4. TREATMENT 4.1 Watchful waiting (WW) 4.1.1 Patient selection 4.1.2 Education, reassurance and periodic monitoring 4.1.3 Lifestyle advice 4.1.4 Conclusions 4.1.5 References 4.2 Medical treatment 4.2.1 5-Alpha reductase inhibitors 4.2.1.1 Finasteride (type 2, 5-Alpha reductase inhibitor) 4.2.1.1.1 Efficacy and clinical endpoints 4.2.1.1.2 Haematuria and finasteride 4.2.1.1.3 Side-effects 4.2.1.1.4 Effect on PSA 4.2.1.2 Dutasteride 4.2.1.3 Combination therapy 4.2.1.4 Conclusions 4.2.1.5 References 4.2.2 Alpha-blockers 4.2.2.1 Uroselectivity 4.2.2.2 Mechanism of action 4.2.2.3 Pharmacokinetics 4.2.2.4 Assessment 4.2.2.5 Clinical efficacy 4.2.2.6 Durability 4.2.2.7 Adverse effects 4.2.2.8 Acute urinary retention 4.2.2.9 Conclusions 4.2.2.10 References 4.2.3 Phytotherapeutic agents 4.2.3.1 Conclusions 4.2.3.2 References 4.3 Surgical management 4.3.1 Indications for surgery 4.3.2 Choice of surgical technique 4.3.3 Perioperative antibiotics 4.3.4 Treatment outcome 4.3.5 Complications 4.3.6 Long-term outcome 4.3.7 Conclusions and recommendations 4.3.8 References 4.4 Lasers 4.4.1 Laser types 4.4.2 Right-angle fibres 4.4.3 Interstitial Laser Coagulation (ILC) 4.4.4 Holmium laser resection of the prostate (HoLRP) 4.4.5 Conclusions 4.4.6 References

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4.5 Transrectal high-intensity focused ultrasound (HIFU) 4.5.1 Assessment 4.5.2 Procedure 4.5.3 Morbidity/complications 4.5.4 Outcome 4.5.5 Urodynamics 4.5.6 Quality of life and sexual function 4.5.7 Durability 4.5.8 Patient selection 4.5.9 Conclusions 4.5.10 References 4.6 Transurethral needle ablation (TUNA®) 4.6.1 Assessment 4.6.2 Procedure 4.6.3 Morbidity/complications 4.6.4 Outcome 4.6.5 Randomized clinical trials 4.6.6 Impact on bladder outflow obstruction 4.6.7 Durability 4.6.8 Patient selection 4.6.9 Conclusions 4.6.10 References 4.7 Transurethral microwave therapy (TUMT) 4.7.1 Assessment 4.7.2 Procedure 4.7.3 The microwave thermotherapy principle 4.7.4 Morbidity 4.7.5 High-intensity-dose-protocol 4.7.6 Prostatic temperature feedback treatment 4.7.7 Durability 4.7.8 Patient selection 4.7.9 Conclusions 4.7.10 References 4.8 Recommendations for treatment

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5.

FOLLOW-UP 5.1 Watchful waiting 5.2 Alpha-blocker therapy 5.3 5-Alpha-reductase inhibitors 5.4 Surgical management 5.5 Alternative therapies

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6. ABBREVIATIONS USED IN THE TEXT

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1. BACKGROUND Benign prostatic hyperplasia (BPH) is a condition intimately related to ageing (1). Although it is not lifethreatening, its clinical manifestation as lower urinary tract symptoms (LUTS) reduces the patient’s quality of life (2). Troublesome LUTS can occur in up to 30% of men older than 65 years (3).

1.1 Prevalence Although many epidemiological clinical studies have been conducted worldwide over the last 20 years, the prevalence of clinical BPH remains difficult to determine. A standardized clinical definition of BPH is lacking, which makes it intrinsically difficult to perform adequate epidemiological studies. Among the published epidemiological studies, some include probability samples from an entire country, while others represent agestratified random samples or enroll participants from general practice, hospital populations or responders to selective screening programmes. There is also a lack of homogeneity among these studies in the way in which BPH is assessed, with different questionnaires and methods of administration. Barry et al. have provided the histological prevalence of BPH, based on a review of five studies relating age to histological findings in human male prostate glands (4). Histological BPH was not found in men under the age of 30 years but its incidence rose with age, reaching a peak in the ninth decade. At that age, BPH was found in 88% of histological samples (4). A palpable enlargement of the prostate has been found in up to 20% of males in their 60s and in 43% in their 80s (5); however, prostate enlargement is not always related to clinical symptoms (2). Clinical BPH is a highly prevalent disease. By the age of 60 years, nearly 60% of the cohort of the Baltimore Longitudinal Study of Aging had some degree of clinical BPH (6). In the USA, results of the Olmstead County survey, in a sample of unselected Caucasian men aged 40-79 years, showed that moderate-to-severe symptoms can occur among 13% of men aged 40-49 years and among 28% of those older than 70 years (1). In Canada, 23% of the cohort studied presented with moderate-to-severe symptoms (7). The findings for prevalence of LUTS in Europe are similar to those in the USA. In Scotland and in the area of Maastricht, the Netherlands, the prevalence of symptoms increased from 14% of men in their 40s to 43% in their 60s (8,9). Depending on the sample, the prevalence of moderate-to-severe symptoms varies from 14% in France to 30% in the Netherlands (10,11). The proportion of men with moderate-to-severe symptoms doubles with each decade of life (10). Preliminary results of one of the most recent European epidemiological studies on the prevalence of LUTS show that approximately 30% of German males aged 50-80 years present with moderateto-severe symptoms according to the International Prostate Symptom Score (i.e. I-PSS > 7) (12). A multicentre study performed in different countries in Asia showed that the age-specific percentages of men with moderate-to-severe symptoms were higher than those in America (13,14). The prevalence increases from 18% for men in their 40s to 56% for those in their 70s (13). Curiously, the average weight of Japanese glands seemed to be smaller than those of their American counterparts (15). Despite methodological differences, some conclusions can be drawn from the studies mentioned above: • Mild urinary symptoms are very common among men aged 50 years and older • Mild symptoms are associated with little bother, while moderate and severe symptoms are associated with increasingly higher levels of inconvenience and interference with living activities (16) • The same symptoms can cause different troublesome and daily living interference (17) • The correlation between symptoms, prostate size and urinary flow rate is relatively low (18). It must be stressed that there is still a need for an epidemiological definition of BPH and its true incidence has yet to be determined (19).

1.2

Is BPH a progressive disorder?

As it is almost impossible to obtain agreement on what it is that defines a man with LUTS/BPH, it seems logical to say that progression cannot be defined in terms of a transition from non-cases to cases. Instead, progression must be measured by documenting deterioration in any number of physiological variables that we associate with the LUTS/BPH syndrome. Traditionally these have included the following: • decrease in maximum flow rate • increase in residual volume • increase in prostate size • deterioration (increase) in symptom score. In addition, definable events, such as the occurrence of acute urinary retention or prostate surgery, have been used. Less commonly, changes in urodynamic variables and deterioration in disease-specific quality of life have been advocated. Considerable interest currently rests with PSA. It appears to be as good a predictor of progression as any of the variables mentioned above.

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1.2.1 Indicators of progression The strongest evidence to support progression comes from the Olmsted County (20) community-based study and the PLESS placebo group (21). The strength of evidence for individual parameters as indicators of progression is summarised in Table 1 and is categorised as strong, weak, or none. The actual rates of progression of the individual parameters as determined from the papers reviewed is shown in Table 2. These parameters could potentially be used in decisions about treatment management. Patients who show signs of more pronounced disease progression could be targeted for preventative strategies. The same strategy could be applied to patients who are at increased risk of progression based on recognised risk factors. Risk factors for progression were found to be age (Olmsted County), PSA (PLESS) and prostate volume (combined 2-year placebo analysis). Other baseline risk factors can be identified, such as symptom severity and decreased urinary flow rate, but current data are not as convincing as those for age, PSA level and prostate volume. Several other complications, such as renal impairment and bladder dysfunction, have been associated with progression of BPH. Although these are important, they are very rare and therefore could not be evaluated accurately in community-based and clinical studies. The evidence for the progression of BPH has been summarised previously (22). Table 1: Strength of evidence for specific parameters as indicators of progression of benign prostatic hyperplasia (BPH) Parameter Community- based studies Clinical trials LUTS I-PSS S N/W* BII S N/N QoL N W/S* BPE DRE N N TRUS S S MRI N S/S* BOO Qmax S W/S* BPH Histology N/A N/A Miscellaneous AUR S S/S* Surgery S W/S* Crossover/treatment S N *Conditional risk factors: age and prostate-specific antigen (PSA); S = strong; W = weak; N = no evidence; N/A = not available. AUR = acute urinary retention; BOO = bladder outlet obstruction; BPE = benign prostatic enlargement; BII = BPH Impact Index; DRE = digital rectal examination; I-PSS = International Prostate Symptom Score; LUTS = lower urinary tract symptoms; MRI = magnetic resonance imaging; Qmax = maximum flow rate; QoL = quality of life; TRUS = transrectal ultrasonography. Table 2: Rates of progression of individual parameters in BPH Study Rate of progression LUTS Flow rate Prostate Acute urinary retentiona Surgerya (points) size (Incidence/1000 (Incidence/1000 person years) person years) 40-49 > 70 40-49 > 70 years years years years Olmsted 0.18 -2% 1.9% 3.0 34.7 0.3 10.9 (20, 23-26) per year per year per year Health Pro- NR NR NR 3.3 11.3 NR NR fessional (27) PLESS (28) -1.3 in +0.2 mL/s +14% 7% over 4 years 10% over 4 years 4 yearsb in 4 yearsb in 4 years 2-year studies NR NR NR 1.6-4.2%c NR (22, 29-32) 0.5-3.9%d North Ame- NR NR NR NR 10-39%e rican (33) a Men with moderate to severe symptoms. b Flow rate and LUTS responded to placebo treatment by showing an initial improvement, which deteriorated

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baseline during the course of the placebo-controlled trial. According to baseline prostate volume. d According to baseline prostate-specific antigen (PSA) level. LUTS = lower urinary tract symptoms; NR = not reported. c

1.2.2 Conclusions Based on published data on consequences and complications of the disease, BPH can be considered a progressive disease. There are limited published data on longitudinal studies and the key pieces of evidence that support this notion are the Olmsted County and PLESS studies. A group of patients at increased risk of progression can be identified based on specific risk factors, i.e. age, PSA level and prostate volume. It might be appropriate to identify these patients at risk of progression and initiate early preventative treatment. 1.2.3 References 1. Chute CG, Panser LA, Girman CJ, Oesterling JE, Guess HA, Jacobsen SJ, Lieber MM. The prevalence of prostatism: a population based survey of urinary symptoms. J Urol 1993;150(1):85-9. http://www.ncbi.nlm.nih.gov/pubmed/7685427 2. Donovan JL, Kay HE, Peters TJ, Abrama P, Coast J, Matos-Ferreira A, Rentzhog L, Bosch JL, Nordling J, Gajewski JB, Barbalias G, Schick E, Silva MM, Nissenkorn I, de la Rosette JJ. Using the ICSQoL to measure the impact of lower urinary tract symptoms on quality of life: evidence from the ICS-‘BPH’ study. International Continence Society - Benign Prostatic Hyperplasia. Br J Urol 1997;80(5):712-21. http://www.ncbi.nlm.nih.gov/pubmed/9393291 3. Chapple CR. BPH disease management. Eur Urol 1999; 36(Suppl 3):1-6. http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowAbstract&ArtikelNr=52342&Ausgab e=227835&ProduktNr=224083 4. Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human benign prostatic hyperplasia with age. J Urol 1984;132(3):474-9. http://www.ncbi.nlm.nih.gov/pubmed/6206240 5. Lytton B, Emery JM, Harvard BM. The incidence of benign prostatic obstruction. J Urol 1968;99(5):639-45. http://www.ncbi.nlm.nih.gov/pubmed/4171950 6. Arrighi HM, Metter EJ, Guess HA, Fozzard JL. Natural history of benign prostatic hyperplasia and risk of prostatectomy, the Baltimore Longitudinal Study of Aging. Urology 1991;35(Suppl):4-8. http://www.ncbi.nlm.nih.gov/pubmed/1714657 7. Norman RW, Nickel JC, Fish D, Pickett SN. Prostate-related symptoms in Canadian men 50 years of age or older: prevalence and relationships among symptoms. Br J Urol 1994;74(5):542-50. http://www.ncbi.nlm.nih.gov/pubmed/7530115 8. Garraway WM, Collins GN, Lee RJ. High prevalence of benign prostatic hypertrophy in the community. Lancet 1991;338(8765):469-71. http://www.ncbi.nlm.nih.gov/pubmed/1714529 9. Wolfs GG, Knottnerus JA, Janknegt RA. Prevalence and detection of micturition problems among 2,734 elderly men. J Urol 1994;152(5 Pt 1):1467-70. http://www.ncbi.nlm.nih.gov/pubmed/7933185 10. Sagnier PP, McFarlane G, Teillac P, Botto H, Richard F, Boyle P. Impact of symptoms of prostatism on level of bother and quality of life of men in the French community. J Urol 1995;153(3 Pt 1):669-73. http://www.ncbi.nlm.nih.gov/pubmed/7532230 11. Bosch JL, Hop WC, Kirkels WJ, Schröder FH. The international prostate symptom score in a community-based sample of men between fifty-five and seventy-four years of age. Prevalence and correlation of symptoms with age, prostate volume, flow rate and residual urine volume. Br J Urol 1995;75(5):622-30. http://www.ncbi.nlm.nih.gov/pubmed/7542132 12. Berges RR, Pientka L. Management of the BPH syndrome in Germany: who is treated and how? Eur Urol 1999; 36(Suppl 3):21-7. http://www.ncbi.nlm.nih.gov/pubmed/10559627 13. Homma Y, Kawabe K, Tsukamoto T, Yamanaka H, Okada K, Okajima E, Yoshida O, Kumazawa J, Gu FL, Lee C, Hsu TC, dela Cruz RC, Tantiwang A, Lim PH, Sheikh MA, Bapat SD, Marshall VR, Tajima K, Aso Y. Epidemiologic survey of lower urinary tract symptoms in Asia and Australia using the International Prostate Symptom Score. Int Urol 1997;4(4):40-6. http://www.ncbi.nlm.nih.gov/pubmed/9179665

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14.

Tsukamoto T, Kumamoto Y, Masumori N, Miyakr H, Rhodes T, Girman GJ, Guess HA, Jacobsen SJ, Lieber MM. Prevalence of prostatism in Japanese men in a community-based study with comparison to a similar American study. J Urol 1995;154(2 Pt 1):391-5. http://www.ncbi.nlm.nih.gov/pubmed/7541852 15. Masumori N, Tsukamoto T, Kumamoto Y, Miyake H, Rhodes T, Girman CJ, Guess HA, Jacobsen SJ, Lieber MM. Japanese men have smaller prostate volumes but comparable urinary flow rates relative to American men: results of community based studies in 2 countries. J Urol 1996;155(4):1324-7. http://www.ncbi.nlm.nih.gov/pubmed/8632564 16. Guess HA. Population-based studies of benign prostatic hyperplasia. In: Kirby R et al. eds. Textbook of Benign Prostatic Hyperplasia. Oxford: Isis Medical Media,1996, pp. 117-124. http://www.isismedical.com/ 17. Guess HA, Chute CG, Garraway WM, Girman CJ, Panser LA, Lee RJ, Jacobsen SJ, McKelvie GB, Oesterling JE, Lieber MM. Similar levels of urological symptoms have similar impact on Scottish and American men although Scots report less symptoms. J Urol 1993;150(5 Pt 2):1701-5. http://www.ncbi.nlm.nih.gov/pubmed/7692105 18. Girman CJ, Jacobsen SJ, Guess HA, Oesterling JE, Chute CG, Panser LA, Lieber MM. Natural history of prostatism: relationship among symptoms, prostate volume and peak urinary flow. J Urol 1995;153(5):1510-5. http://www.ncbi.nlm.nih.gov/pubmed/7536258 19. Oishi K, Boyle P, Barry JM, et al. Epidemiology and natural history of benign prostatic hyperplasia. In: Denis L, Griffiths K, Khoury S et al, eds. Fourth International Consultation on BPH, Paris, July 1997. Plymouth: Health Publications, 1998, pp. 25-59. http://www.congress-urology.org/ 20. Jacobsen SJ, Girman CJ, Guess HA, Rhodes T, Oesterling JE, Lieber MM. Natural history of prostatism: longitudinal changes in voiding symptoms in community dwelling men. J Urol 1996;155(2):595-600. http://www.ncbi.nlm.nih.gov/pubmed/8558668 21. McConnell JD, Bruskewitz R, Walsh P, Andriole G, Lieber M, Holtgrewe HL, Albertsen P, Roehrborn CG, Nickel JC, Wang DZ, Taylor AM, Waldstreicher J. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. New Engl J Med 1998;338(9):557-63. http://www.ncbi.nlm.nih.gov/pubmed/9475762 22. Anderson JB, Roehrborn CG, Schalken JA, Emberton M. The progression of benign prostatic hyperplasia: examining the evidence and determining the risk. Eur Urol 2001; 39(4):390-9. http://www.ncbi.nlm.nih.gov/pubmed/11306876 23. Jacobsen SJ, Jacobson DJ, Girman CJ, Roberts RO, Rhodes T, Guess HA, Lieber MM. Natural history of prostatism: risk factors for acute urinary retention. J Urol 1997;158(2):481-7. http://www.ncbi.nlm.nih.gov/pubmed/9224329 24. Jacobsen SJ, Jacobson DJ, Girman CJ, Roberts RO, Rhodes T, Guess HA, Lieber MM. Treatment for benign prostatic hyperplasia among community dwelling men: the Olmsted County Study of urinary symptoms and health status. J Urol 1999;162(4):1301-6. http://www.ncbi.nlm.nih.gov/pubmed/10492184 25. Rhodes T, Girman CJ, Jacobsen DJ, Roberts RO, Lieber MM, Jacobsen SJ. Longitudinal prostate volume in a community-based sample: 7 year followup in the Olmsted County Study of urinary symptoms and health status among men. J Urol 2000;163(Suppl 4):249 abstr 1105. 26. Roberts RO, Jacobsen SJ, Jacobson DJ, Rhodes T, Girman CJ, Lieber MM. Longitudinal changes in peak urinary flow rates in a community-based cohort. J Urol 2000;163(1):107-13. http://www.ncbi.nlm.nih.gov/pubmed/10604326 27. Meigs JB, Barry MJ, Giovannucci E, Rimm EB, Stampfer MJ, Kawachi I. Incidence rates and risk factors for acute urinary retention: the Health Professional Followup Study. J Urol 1999;162(2):376-82. http://www.ncbi.nlm.nih.gov/pubmed/10411042 28. McConnell JD, Bruskewitz R, Walsh P, Andriole G, Lieber M, Holtgrewe HL, Albertsen P, Roehrborn CG, Nickel JC, Wang DZ, Taylor AM, Waldstreicher J. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-Term Efficacy and Safety Study Group. New Engl J Med 1998;338(9):557-63. http://www.ncbi.nlm.nih.gov/pubmed/9475762 29. Arrighi HM, Guess HA, Metter EJ, Fozard JL. Symptoms and signs of prostatism as risk factors for prostatectomy. Prostate 1990;16(3):253-61. http://www.ncbi.nlm.nih.gov/pubmed/1691843

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30. Roehrborn CG, Boyle P, Bergner D, Gray T, Gittelman M, Shown T, Melman A, Bracken RB, deVere White R, Taylor A, Wang D, Waldstreicher J. PLESS Study Group. Serum prostate-specific antigen and prostate volume predict long-term changes in symptoms and flow rate: results of a fouryear, randomized trial comparing finasteride versus placebo. PLESS Study Group. Urology 1999;54(4): 662-9. http://www.ncbi.nlm.nih.gov/pubmed/10510925 31. Roehrborn CG, McConnell JD, Lieber M, Kaplan S, Geller J, Malek GH, Castellanos R, Coffield S, Saltzman B, Resnick M, Cook TJ, Waldstreicher J. PLESS Study Group. Serum prostate-specific antigen is a powerful predictor of acute urinary retention and the need for surgery in men with clinical benign prostatic hyperplasia. PLESS Study Group. Urology 1999;53(3):473-80. http://www.ncbi.nlm.nih.gov/pubmed/10096369 32. Roehrborn CG, McConnell JD, Bonilla J Rosenblatt S, Hudson PB, Malek GH, Schellhammer PF, Bruskewitz R, Matsumoto AM, Harrison LH, Fuselier HA, Walsh P, Roy J, Andriole G, Resnick M, Waldstreicher J. PROSCAR long term efficacy and safety group. Serum prostate-specific antigen is a strong predictor of future prostate growth in men with benign prostatic hyperplasia. PROSCAR longterm efficacy and safety study. J Urol 2000;163(1):13-20. http://www.ncbi.nlm.nih.gov/pubmed/10604304 33. Gormley GJ, Stoner E, Bruskowitz RC, Imperato-McKinley J, Walsh PC, McConnell JD, Adriole GL, Geller J, Bracken BR, Tenover JS et al. The effect of finasteride in men with benign prostatic hyperplasia. The Finasteride Study Group. New Engl J Med 1992 Oct 22;327(17):1185-91. http://www.ncbi.nlm.nih.gov/pubmed/1383816

2. RISK FACTORS 2.1

For developing the disease

The aetiology of BPH is multifactorial. Currently, there is no strong evidence that smoking, vasectomy, obesity or high alcohol intake are risk factors in the development of clinical BPH. Results of the different epidemiolo­ gical studies are controversial, probably because of differences in sampling and methods of analysis. In most cases only insufficient marginal differences can be established (1). Chronic conditions, such as hypertension or diabetes, have been related to clinical BPH, but given the frequent occurrence of these conditions in ageing men a large proportion of patients can be expected to suffer from such an association (2,3). Recently, it has been stated that diabetes and clinical BPH are associated more frequently than would be expected based on chance alone. Although more severe BPH symptoms (increased I-PSS and post-void residual) seem to be found in diabetic males even after age adjustment, the fact that both conditions increase with age and can cause partially similar voiding symptoms, produces a considerable bias (3). The only true factors related to the development of the disease are age and hormonal status (4). The crucial role of the testis has been recognized for more than a century and current research has extended into the field of molecular biology (5). Both of these risk factors are currently beyond prevention.

2.2

For surgical treatment

Although the number of surgical procedures for BPH has declined in the USA and Europe over the last decade (6), they still represent the second most common major operation in aged men (7). Ultimately, three in 10 men may undergo surgery for this condition (2). Surgical risk depends on age and the presence of clinical symptoms. In the absence of clinical symptoms, the likelihood of being treated surgically is about 3% (8,9). The need for surgery increases with symptoms and is twice as high in men with a high baseline-symptom score than for those with a low score (10). For men presenting with urinary retention, the cumulative incidence for prostatectomy is 60% at 1 year and 80% at 7 years (11). Multivariate analysis carried out on a sample of 16,219 men, aged at least 40 years, with a mean follow-up of 12 years, showed a positive association with surgery for age, low body mass index, nonsmokers, urine pH greater than 5, and a history of kidney X-ray and/or tuberculosis, for each of the five clinical urinary symptoms studied (12). In the Veterans Normative Aging Study, in a cohort of 2,280 men, the main predictor for surgery was the presence of urinary symptoms. The risk of requiring subsequent surgery also varied with age, the odds ratio being 1.8 for nocturia and 4.3 for hesitancy in young men (aged < 65 years). Among older men, only nocturia (odds ratio 2.4) was predictive of surgery (13). In the Baltimore study, the three predictive symptoms for surgery were change in size and force of the urinary stream, sensation of incomplete voiding and digital rectal

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enlargement of the prostate. Men with one factor had a cumulative incidence of surgery of 9%, those with two factors of 16%, and those with three factors of 37%. Nevertheless, the same study showed that increasing age was the predominant risk factor for surgery (8). From the above, it can be concluded that the risk of needing surgery for BPH increases with age and with the degree of clinical symptoms at baseline. Nocturia and changes in urinary stream seem to be the most important predictive symptoms.

2.3

REFERENCES

1. Oishi K, Boyle P, Barry JM et al. Epidemiology and natural history of benign prostatic hyperplasia. In: Denis L, Griffiths K, Khoury S et al. eds. Fourth International Consultation on BPH, Paris, July 1997. Plymouth: Health Publications, 1998, pp. 25-59. http://www.congress-urology.org/ 2. Boyle P. Epidemiology of benign prostatic hyperplasia: risk factors and concomitance with hypertension. Br J Clin Pract Suppl 1994;74:18-22. http://www.ncbi.nlm.nih.gov/pubmed/7519437 3. Michel MC, Mehlburger L, Schumacher H, Bressel HU, Goepel M. Effect of diabetes on lower urinary tract symptoms in patients with benign prostatic hyperplasia. J Urol 2000;163(6):1725-9. http://www.ncbi.nlm.nih.gov/pubmed/10799169 4. Isaacs JT, Coffey DS. Etiology and disease process of benign prostatic hyperplasia. Prostate 1989;(Suppl 2):33-50. http://www.ncbi.nlm.nih.gov/pubmed/2482772 5. Voller MC, Schalken JA. Molecular genetics of benign prostatic hyperplasia. In: Kirby R et al, eds. Textbook of Benign Prostatic Hyperplasia. Oxford: Isis Medical Media, 1996, pp. 109-113. http://www.isismedical.com/ 6. Holtgrewe HL, Ackermann R, Bay-Nielsen H et al. Report from the Committee on the Economics of BPH. In: Cockett ATK et al, eds. Third international consultation on benign prostatic hyperplasia (BPH). Jersey: Scientific Communication International, 1996, pp. 51-70. http://www.congress-urology.org/ 7. Meigs JB, Barry MJ. Natural history of benign prostatic hyperplasia. In: Kirby R et al, eds. Textbook of benign prostatic hyperplasia. Oxford: Isis Medical Media, 1996, pp. 125-135. http://www.isismedical.com/ 8. Arrighi HM, Metter EJ, Guess HA, Fozzard JL. Natural history of benign prostatic hyperplasia and risk of prostatectomy, the Baltimore Longitudinal Study of Aging. Urology 1991;38(1 Suppl):4-8. http://www.ncbi.nlm.nih.gov/pubmed/1714657 9. Diokno AC, Brown MB, Goldstein N, Herzog AR. Epidemiology of bladder emptying symptoms in elderly men. J Urol 1992;148(6):1817-21. http://www.ncbi.nlm.nih.gov/pubmed/1279223 10. Wasson JH, Reda DJ, Bruskewitz RC, Elinson J, Keller AM, Henderson WG. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. The Veterans Affairs Cooperative Study Group on Transurethral Resection of the Prostate. N Engl J Med 1995;332(2):75-9. http://www.ncbi.nlm.nih.gov/pubmed/7527493 11. Craigen AA, Hickling JD, Saunders CR, Carpenter RS. Natural history of prostatic obstruction: a prospective survey. J R Coll Gen Pract 1969;18(87):226-32. http://www.ncbi.nlm.nih.gov/pubmed/4186545 12. Sidney S, Quesenberry C Jr, Sadler MC, Lydick EG, Guess HA, Cattolica EV. Risk factors for surgically treated benign prostatic hyperplasia in a prepaid health care plan. Urology 1991;38(Suppl 1):13-9. http://www.ncbi.nlm.nih.gov/pubmed/1714653 13. Epstein RS, Lydick E, deLabry L, Vokonas PS. Age-related differences in risk factors for prostatectomy for benign prostatic hyperplasia: the VA Normative Aging Study. Urology 1991; 38(Suppl 1):9-12. http://www.ncbi.nlm.nih.gov/pubmed/1714659

3. ASSESSMENT Diagnostic investigations have been classified as: • recommended: there is evidence to support the use of this test

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• •

optional: this test is done at the discretion of the clinician not recommended: there is no evidence to support the use of this test.

3.1

Symptom scores

Probably the best way to assess symptom severity is with a validated symptom score. A number of instruments exist that can measure symptom severity, bother and quality of life (Table 3) (1). Most instruments in current use conform to acceptable standards of validity, reliability and responsiveness; in other words they measure what they purport to measure, are stable over time and are able to reflect clinically important changes (2). 3.1.1 International Prostate Symptom Score (I-PSS) The I-PSS has become the international standard. It is derived from the American Urological Association (AUA) 7 score described by Barry and his colleagues in the early 1990s (3). By adding the scores (with equal weighting) to its constituent questions, a summary or index score is generated which has been shown to be an accurate reflection of a man’s overall symptoms over the preceding month (4). The extent to which the self-reported scores reflect actual events has been questioned. Men report nocturia with accuracy but tend to overstate daytime frequency. Correlation of the self-reported score to intermittency or to the strength of stream was poor (5). Age and cultural factors may be important. The I-PSS appears less reliable in men over 65 years old (6) and careful linguistic validation needs to be undertaken prior to its use in non-North American cultures (7). Numerous authors have reported and commented upon the poor correlations between I-PSS and other physiological variables. For example, there are numerous reports of symptom severity (as expressed by I-PSS) correlating poorly with peak urinary flow rate, average flow rate, post-void residual volume, prostate size or pressure-flow relationships (1, 8-10). This lack of correlation has troubled many investigators and has led to some questions raised about the validity of the I-PSS. Correlations of similar magnitude have been seen in many other disease areas, e.g. peak respiratory flow correlates poorly with patient’s own reports of the severity of their asthma. The lack of correlation can be explained in two ways. Firstly, I-PSS and physiological measures measure different things. Secondly, there are statistical issues related to the clustering of values or data points, which will also result in poor correlation. A validated symptom score assesses symptom severity. It can be used to monitor change in symptoms over time or following an intervention. 3.1.2 Quality-of-life assessment The impact of urinary symptoms on the quality of life is generally evaluated by means of question 8 of the I-PSS. However, this question measures the extent to which patients tolerate their symptoms rather than evaluating their quality of life. A number of health-related, quality-of-life instruments have been used for clinical research. One of the best known is the generic measure, the Medical Outcomes Study, a 36-item short-form health survey (SF36) (14). It is a self-completed questionnaire used to measure general health status and quality of life. It has been used in a number of studies addressing men with lower urinary tract symptoms. Using this score, a postal population survey among 217 men aged 55 years and over with LUTS showed that, depending on the respondent’s activity, 9-49% of those with moderate or severe urinary symptoms reported interference with some of their daily activities. Increasing symptom severity was associated with worsening physical condition, social functioning, vitality, mental health and perception of general health. Increasing ‘bothersome­ ness’ was associated with a worsening of all dimensions of general health status and quality of life. The association between the outcome of this population survey and the degree of ‘bothersomeness’ was stronger than that with the I-PSS symptom score. 3.1.3 Symptom score as decision tool for treatment Can symptom severity alone be used to allocate treatment? The US Agency for Health Care Policy and Research Guidelines (1) tried to do this. Three categories of symptom severity were described: mild (0-7), moderate (8-19) and severe (20-35). The authors suggested that patients with mild symptoms were most appropriately managed by a watchful waiting approach. Patient with moderate symptoms might benefit from pharmacotherapy, while patients with severe symptoms may derive most benefit from prostatectomy. Although notions of appropriateness have not been well-studied, the proposed policy appears to hold true for patients with mild symptoms but is less reliable for men with moderate or severe symptoms (15). 3.1.4 Symptom score as outcome predictor Symptom score may be one of the more powerful predictors of symptomatic outcome (16). As men with mild symptoms have little room for improvement it is of little surprise that they do not experience high levels of symptom reduction following surgery. A man with a pre-operative I-PSS of 17, or more, has an 87% chance of experiencing a substantial symptom reduction (17). There is little evidence that physiological measures improve

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the chances of predicting a favourable symptomatic outcome. 3.1.5 Conclusions Evaluating symptom severity with a symptom score is an important part of the initial assessment of a man. It is helpful in allocating treatment, and in both predicting and monitoring the response to therapy. 3.1.6 Recommendations Recommended investigations: • Clinical history • Symptom assessment • Physical examination • Validated symptom score, e.g. I-PSS.

3.2 Prostate-specific antigen (PSA) measurement Before selecting the proper treatment for men with LUTS, every urologist will perform a DRE and most will measure the serum value of PSA. 3.2.1 Factors influencing the serum levels of PSA In cases where the architecture of the prostatic gland is disrupted, PSA will ‘leak’ into the circulation. This occurs when prostatic carcinoma is present but also in BPH, prostatitis and after urinary retention. This is why PSA is not considered as being cancer-specific, but organ-specific. Other known causes of PSA serum elevations are biopsy of the prostate gland and ejaculation (1). In addition, small and clinically insignificant changes occur after DRE. Two other important factors, age and race, must also be considered when evaluating PSA values in men with LUTS (2,3). African-Americans with no evidence of prostate carcinoma have higher PSA values after their fourth decade of life, and therefore age-specific reference ranges must be adapted and interpreted according to race and ethnicity (4). A recent community-based study of African-American men contradicts the beliefs of racial PSA differences, since only minor variations in PSA reference ranges were found (5). 3.2.2 PSA and prediction of prostatic volume Stamey et al. were the first to correlate PSA serum values and volume of prostatic tissue (6). In their studies in the late 1980s, they found that the serum PSA contribution from BPH was 0.30 ng/mL per gram of tissue and 3.5 ng/mL per cm3 of cancer tissue. Roehrborn et al, have shown that PSA and prostate volume have an agedependent, log-linear relationship and that PSA has a good predictive value for assessing prostatic volume (7). Vesely et al, also found that prostate volume and serum PSA are significantly correlated and increase with advanced age (8). Prediction of prostate volume can also be based on total and free PSA. Both PSA forms were found to be able to predict the TRUS prostate volume (± 20%) in more than 90% of the cases (9). 3.2.3 PSA and probability of having prostate cancer The chance of having prostate cancer is strongly related with the serum value of PSA. For many years the value of 4ng/mL was considered as the upper normal limit of PSA (10) but lately a lower threshold of PSA for recommending prostate biopsy in younger men has shown to improve the clinical value of this test (11). In order to avoid unnecessary biopsies, Potter et al, (12) have used three clinical parameters - age, PSA and DRE - and have calculated the likelihood of detecting prostate cancer on sextant TRUS-guided biopsies among 2,054 men. At the same time, predictive nomograms have been developed by various groups. These nomograms are being constructed from variables such as age, race, family history, DRE, PSA, PSA density and TRUS findings (13,14). 3.2.4 PSA and prediction of BPH-related outcomes In a series of studies, Roehrborn et al. (15,16) have shown that PSA and prostatic volume can be used to evaluate the risks of either needing surgery or developing acute urinary retention. These parameters were also related with long-term changes in symptom scores and flow rates. In a recent epidemiological study, elevated free PSA levels could predict clinical BPH, independent of total PSA levels (17). 3.2.5 • • • •

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Conclusions various factors (cancer, BPH, infection, trauma, age, may influence serum PSA levels the level of PSA correlates with the volume of the prostate gland the higher the PSA level, the greater is the probability of having prostate cancer the PSA level might predict the natural history of BPH.

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3.2.6 Recommendation The measurement of PSA is recommended when a diagnosis of prostatic carcinoma will change the decision made about which therapeutic option to use. 3.2.7 1.

References Herschman JD, Smith DS, Catalona WJ. Effect of ejaculation on serum total and free prostate specific antigen concentrations. Urology 1997;50(2):239-43. http://www.ncbi.nlm.nih.gov/pubmed/9255295 2. Oesterling JE, Jacobsen SJ, Chute CG, Guess HA, Girman CJ, Panser LA, Lieber MM. Serum prostate specific antigen in a community-based population of healthy men: establishment of age-specific reference ranges. JAMA 1993;270:860-4. http://www.ncbi.nlm.nih.gov/pubmed/7688054 3. Laguna P, Alivizatos G. Prostate specific antigen and benign prostatic hyperplasia. Curr Opin Urol 2000;10(1):3-8. http://www.ncbi.nlm.nih.gov/pubmed/10650506 4. Eastham JA, Sartor O, Richey W, Moparty B, Sullivan J. Racial variation in prostate specific antigen in a large cohort of men without prostate cancer. J La State Med Soc 2001;153(4):184-9. http://www.ncbi.nlm.nih.gov/pubmed/11394329 5. Cooney KA, Strawderman MS, Wojno KJ, Doerr KM, Taylor A, Alcser KH, Heeringa SG, Taylor JM, Wei JT, Montie JE, Schottenfeld D. Age-specific distribution of serum prostate-specific antigen in a community-based study of African-American men. Urology 2001;57(1):91-6. http://www.ncbi.nlm.nih.gov/pubmed/11164150 6. Stamey TA, Yang N, Hay AR, McNeal JE, Freiha FS, Redwine E. Prostate specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 1987;317(15):909-16. http://www.ncbi.nlm.nih.gov/pubmed/2442609 7. Roehrborn CG, Boyle P, Gould AL, Waldstreicher J. Serum prostate specific antigen as a predictor of prostate volume in men with benign prostatic hyperplasia. Urology 1999;53(3):581-9. http://www.ncbi.nlm.nih.gov/pubmed/10096388 8. Vesely S, Knutson T, Damber JE, Dicuio M, Dahlstrand C. Relationship between age, prostate volume, prostate-specific antigen, symptom score and uroflowmetry in men with lower urinary tract symptoms. Scand J Urol Nephrol. 2003,37(4):322-8. http://www.ncbi.nlm.nih.gov/pubmed/12944191 9. Morote J, Encabo G, López M, de Torres IM. Prediction of prostate volume based on total and free serum prostate specific antigen: is it reliable? Eur Urol 2000;38(1):91-5. http://www.ncbi.nlm.nih.gov/pubmed/10859448 10. Barry MJ. Clinical practice. Prostate-specific-antigen testing for early diagnosis of prostate cancer. N Engl J Med 2001;344(18):1373-7. http://www.ncbi.nlm.nih.gov/pubmed/11333995 11. Punglia RS, D’ Amico AV, Catalona WJ, Roehl KA, Kuntz KM. Effect of verification bias on screening for prostate cancer by measurement of prostate-specific antigen. N Engl J Med. 2003,349(3):335-42. http://www.ncbi.nlm.nih.gov/pubmed/12878740 12. Potter SR, Horniger W, Tinzl M, Bartsch G, Partin AW. Age, prostate specific antigen and digital rectal examination as determinants of the probability of having prostate cancer. Urology 2001;157(6):1100-4. http://www.ncbi.nlm.nih.gov/pubmed/11377318 13. Kalra P, Togami J, Bansal BSG, Partin AW, Brawer MK, Babaian RJ, Ross LS, Niederberger CS. A neurocomputational model for prostate carcinoma detection. Cancer 2003;98(9):1849-54. http://www.ncbi.nlm.nih.gov/pubmed/14584066 14. Garzotto M, Hudson RG, Peters L, Hsieh YC, Barrera E, Mori M, Beer TM, Klein T. Predictive modelling for the presence of prostate carcinoma using clinical, laboratory, and ultrasound parameters in patients with prostate specific antigen levels 200-300 mL) may indicate bladder dysfunction and predict a less favourable response to treatment. Still, residual urine is not a contraindication to watchful waiting or medical therapy. Because of large test-retest variability and lack of outcome studies, it is not possible to establish a PVR “cut-point” for treatment decision.

3.10

Urodynamic studies

Pressure-flow studies are regarded as an additional diagnostic test and are considered optional by both the AUA guideline panel on management of benign prostatic hyperplasia (2003) (1) and the Fifth International Consultation on BPH (2). Flow rates only determine the probability of obstruction, whereas pressure-flow studies can categorize the degree of obstruction and identify patients in whom a low flow rate may be due to a low-pressure detrusor contraction. Flow rates may be particularly limited in predicting obstruction in specific situations, such as in elderly patients, individuals with low voided volumes, or men with a Qmax of more than 10mL/s, as well as in the presence of neurological disease. Although pressure-flow studies are the only means of diagnosing obstruction accurately, debate continues as to their role in predicting treatment outcomes. Recent methodological studies looking on intra-individual variation in pressure-flow results as well as intra- und and inter-individual observer accuracy in interpretation of pressure-flow curves have demonstrated a considerable methodological variation (3-6). This makes it more difficult to judge the influence of infravesical obstruction on lower urinary tract symptoms in patients with BPH. For this reason, and because pressure-flow studies are regarded as invasive, they remain optional. In specific patient subgroups, the case for pressure-flow studies is stronger. The methodology for performing pressure-flow studies is now standardized (7) and requires simultaneous recording of both intravesical and intra-abdominal pressure. Detrusor pressure at the point of maximum flow must be recorded in order to diagnose obstruction. Different nomograms exist with which to classify patients into categories of obstruction. Those developed by Schafer (8), Abrams and Griffiths (9) and Rollema and Van Mastrigt (URA – Urethral Resistance Index) (10) are most commonly used, and they all correlate closely. The ICS (International Continence Society) nomogram (11) has now been adopted as the standard nomogram to aid comparison of different data sets, and should be used in clinical practice. 3.10.1 Outcome Pressure-flow studies do not predict the response to medical therapy and have no role in this setting. However, it is known that patients with high-pressure and low-flow urodynamics have the best outcome from prostatectomy. Patients with low-pressure and low-flow urodynamics may also have a successful outcome following prostatectomy, but the probability is lower. Most work in relation to pressure-flow studies and treatment of LUTS due to BPO relates to TURP. Studies reported by Neal et al. (12,13), Abrams et al. (14), Jensen (15), Robertson et al. (16) and Langen et al. (17) all report improved outcomes in patients who are obstructed prior to surgery, based on pressure-flow studies.

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3.10.2 Conclusions Pressure-flow studies remain optional tests in straightforward cases presenting for the first time with LUTS. These studies are the most useful investigations available for the purpose of counselling patients regarding the outcome of surgical therapies for BPH. The ICS nomogram should be used for the diagnosis of obstruction in order to standardize data for comparative purposes. 3.10.3 References 1. AUA practice guideline committee. AUA guidelines on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol 2003;170(2 Pt 1):530-47. http://www.ncbi.nlm.nih.gov/pubmed/12853821 2. Chatelain C, Denis L, Foo KT, Khoury S, McConnell J eds. Proceedings of the Fifth International Consultation on BPH, Paris, July 2000. Plymouth: Health Publications, 2001, p. 524. http://www.congress-urology.org/ 3. Hansen F, Olsen L, Atan A, Nordling J. Pressure-flow studies: Short-time repeatability. Neurourol Urodyn 1999;18(3):205-14. http://www.ncbi.nlm.nih.gov/pubmed/10338441 4. Sonke GS, Kortmann BB, Verbeek AL, Kiemeney LA, Debruyne FM, de La Rossette JJ. Variability of pressure-flow studies in men with lower urinary tract symptoms. Neurourol Urodyn 2000;19(6):637-51. http://www.ncbi.nlm.nih.gov/pubmed/11071695 5. Eri LM, Wessel N, Berge V. Test-retest variation of pressure flow parameters in men with bladder outlet obstruction. J Urol 2001;165(4):1188-92. http://www.ncbi.nlm.nih.gov/pubmed/11257668 6. Kortmann BB, Sonke GS, Wijkstra H, Nordling J, Kallestrup E, Holm NR, de La Rosette JJ. Intra- and Inter-investigator variation in the analysis of pressure-flow studies in men with lower urinary tract symptoms. Neurourol Urodyn 2000;19(3):221-32. http://www.ncbi.nlm.nih.gov/pubmed/10797579 7. Rowan D, James ED, Kramer AE, Sterling AM, Suhel PF. Urodynamic equipment: technical aspects. Produced by the International Continence Society Working Party on Urodynamic Equipment. J Med Eng Technol 1987;11(2):57-64. http://www.ncbi.nlm.nih.gov/pubmed/2956425 8. Schafer W. A new concept for simple but specific grading of bladder outflow condition independent from detrusor function. J Urol 1993;149(2):574-7. 9. Abrams PH, Griffiths DJ. The assessment of prostatic obstruction from urodynamic measurements and from residual urine. Br J Urol 1979;51(2):129-34. http://www.ncbi.nlm.nih.gov/pubmed/465971 10. Rollema HJ, van Mastrigt R. Improved indication and follow-up in transurethral resection of the prostate using the computer program CLIM: a prospective study. J Urol 1992;148(1):111-5. http://www.ncbi.nlm.nih.gov/pubmed/1377287 11. Griffiths D, Hofner K, van Mastrigt R, Rollema HJ, Spångberg A, Gleason D. Standardization of terminology of lower urinary tract function: pressure-flow studies of voiding, urethral resistance and urethral obstruction. International Continence Society Subcommittee on Standardization of Terminology of Pressure-Flow Studies. Neurourol Urodyn 1997;16(1):1-18. http://www.ncbi.nlm.nih.gov/pubmed/9021786 12. Neal DE, Styles RA, Powell PH, Thong J, Ramsden PD. Relationship between voiding pressure, symptoms and urodynamic findings in 253 men undergoing prostatectomy. Br J Urol 1987;60(6): 554-9. http://www.ncbi.nlm.nih.gov/pubmed/3427341 13. Neal DE, Ramsden PD, Sharples L, Smith A, Powell PH, Styles RA, Webb RJ. Outcome of elective prostatectomy. BMJ 1989;299(6702):762-7. http://www.ncbi.nlm.nih.gov/pubmed/2508914 14. Abrams PH, Farrar DJ, Turner-Warwick RT, Whiteside CG, Feneley RC. The results of prostatectomy: a symptomatic and urodynamic analysis of 152 patients. J Urol 1979;121(5):640-2. http://www.ncbi.nlm.nih.gov/pubmed/86617 15. Jensen KM-E. Clinical evaluation of routine urodynamic investigations in prostatism. Neurourol Urodynam 1989;8:545-78. 16. Robertson AS, Griffiths C, Neal DE. Conventional urodynamics and ambulatory monitoring in the definition and management of bladder outflow obstruction. J Urol 1996;155(2):506-11. http://www.ncbi.nlm.nih.gov/pubmed/8558647

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17.

Langen PH, Schafer W, Jakse G. Urodynamic assessment in patients undergoing transurethral resection of the prostate: a prospective study. In: Jakse G, et al, eds. Benign Prostatic Hyperplasia. New York: Springer-Verlag, 1992, pp. 75-84

3.11

Endoscopy

The standard endoscopic procedure for diagnostic evaluation of the lower urinary tract (urethra, prostate, bladder neck and bladder) is a urethrocystoscopy. This investigation can confirm causes of outflow obstruction while eliminating intravesical abnormalities. 3.11.1 LUTS caused by bladder outlet obstruction Voiding complaints in elderly men are most frequently caused by BPH resulting in benign prostatic obstruction. This obstruction has a critical role in altering voiding, resulting in significant (pathological) changes in the urinary tract of some patients and symptoms alone in others. However, the role of BPH in the voiding dysfunction experienced by elderly men is often unclear (1). Hyperplasia may be associated with striking lateral lobe enlargement, but symptoms may be negligible if the degree of obstruction is not severe. Conversely, BPH may be associated with a relatively small prostate and marked obstructive symptoms if the obstructing tissue originates exclusively within the central zone of the peri-urethral gland area (2). It is generally accepted that therapies aimed at removing obstruction will relieve LUTS in most men. Patients with BPH or other forms of bladder outlet obstruction may develop certain signs seen by urethrocystoscopy, indicating the presence of such obstruction. These signs may include: • enlargement of the prostate gland with visual obstruction of the urethra and the bladder neck • obstruction of the bladder neck by a high posterior lip of the bladder neck • muscular hypertrophy of the detrusor muscle, indicated by the presence of muscular trabeculation and the formation of cellules as well as diverticula • formation of bladder stones • retention of (post-void residual) urine. Thus, urethrocystoscopy may provide information about the cause, size and severity of obstruction, patency of the bladder neck, prostatic occlusion of the urethra and estimated prostate size (3). Several studies have addressed these issues. 3.11.2 Morbidity of urethrocystoscopy Berge et al. (4) studied 85 patients and found that the risk of acquiring clinically significant urinary tract infection was 2.4% after urethral instrumentation alone. 3.11.3 Relationship between trabeculation and peak flow rate Shoukry et al. (5) evaluated 122 patients of mean age 64 years with LUTS using three post-operative uroflowmetry tests and symptom evaluation. Urethrocystoscopy was also performed in these patients. The pre-operative peak flow rate was normal in 25% of 60 patients who had no bladder trabeculation, 21% of 73 patients with mild trabeculation and 12% of 40 patients with marked trabeculation on cystoscopy. All 21 patients who presented with diverticula had an ‘obstructive’ peak flow rate prior to surgery. Anikwe (6) showed that there was no significant correlation (p > 0.5) between the degree of trabeculation, as graded from I to IV, and the peak pre-operative flow rate in 39 men aged 53-83 years with LUTS. There appeared to be a trend towards lower peak flow rates in men with higher degrees of trabeculation. 3.11.4 Relationship between trabeculation and symptoms Simonsen et al. (7) found a correlation between the presence of trabeculation and the number of obstructive symptoms. When patients were grouped by age, it was noted that trabeculation significantly increased with increasing age (p < 0.5). In another study, none of the trabeculation ratings were predictive of symptom severity, while moderate-to-severe trabeculation was predictive of larger prostate size and reduced flow rate (8). 3.11.5 Relationship between trabeculation and prostate size Anderson and Nordling (9) examined the correlation between cystoscopic findings and the presence of trabeculation. While the cystoscopically estimated weight correlated with the presence of trabeculation (p = 0.003), the bladder neck to verumontanum distance and the cystoscopic appearance of occlusion did not correlate significantly (p > 0.5). Homma et al. (10) showed that patients had a high likelihood of outlet obstruction when their prostate size was greater than 30 mL or if their posterior urethra was severely obstructed on endoscopy. 3.11.6 Relationship between trabeculation and obstruction El Din et al. (11) evaluated urethroscopic findings and the results of urodynamic studies in 492 elderly men

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with LUTS. They noted a clear correlation between cystoscopic appearance (grade of trabeculation and grade of urethral obstruction) and urodynamic indices, detrusor instability and low compliance. It should be noted, however, that bladder outlet obstruction is present in approximately 15% of patients with normal cystoscopic findings, while approximately 8% of patients have no obstruction at all even if severe trabeculation is present, suggesting the inadvisability of drawing the same conclusion in all patients. They believe that the value of urethrocystoscopy is limited and advise against its use in the diagnosis of bladder outlet obstruction. Instead, it should be used primarily to exclude bladder pathology and to decide between interventional approaches. 3.11.7 Bladder diverticula and obstruction The detection of large bladder diverticula might be of therapeutic importance. For example, the presence of a large bladder diverticulum might dictate the type of intervention. It is, however, evident that other diagnostic modalities, such as cystography, intravenous pyelography (IVP) or transabdominal sonography, are equally sensitive, or more sensitive, at detecting large bladder diverticula, without carrying the risks of invasive urethrocystoscopy. No data are available to document the sensitivity or specificity of cystography, IVP, cystoscopy or transabdominal sonography for evaluating large bladder diverticula. Quirinia and Hoffmann (12) reported on 104 patients with BPH of whom 51% had diverticula by cystography. Although the presence of diverticula was related to age, upper tract dilation, increasing amounts of residual urine and bladder instability, there was no relationship with bladder capacity, peak flow rate or prostate size. At present, no final decision about the value of cystoscopy in the assessment of bladder diverticula can be made. Equally poorly documented is the impact that the presence or absence of bladder diverticula might have on outcome after prostate surgery. 3.11.8 Bladder stones and obstruction There is no doubt that the presence of bladder stones can be assessed accurately by urethrocystoscopy. Bladder stones are a clear indicator of bladder outlet obstruction. While it is not always clear whether the obstruction is of an organic, anatomical or neurogenic nature, the presence of stones in the bladder indicates an abnormality in the bladder-emptying mechanism and is usually preceded by the presence of residual urine or recurrent urinary tract infections. However, there is also no doubt that bladder stones are detected equally well by IVP or by the non-invasive method of transabdominal sonography. In fact, stones composed of poorly radio-opaque or radiolucent material are seen very well by transabdominal sonography, while being missed on a renal ultrasound. The crux of the matter has to be whether or not the detection of bladder stones dictates the surgical procedure of choice. It is obvious that the presence of a large bladder stone should guide the surgeon towards an open procedure rather than a lengthy electrohydraulic lithotripsy. However, the majority of all bladder stones are rather small, and can be removed during TURP through the sheath of the resectoscope, or by destroying them with endoscopic instruments prior to washing them out. It is therefore questionable whether or not urethrocystoscopy should be performed to assess the presence or absence of bladder stones prior to surgery for BPH, particularly as most patients with bladder stones will have microscopic haematuria that will have been detected during the standard basic evaluation. 3.11.9 Intravesical pathology The detection of other pathology (urethral or intravesical) is advantageous and can be accomplished by endoscopy better than with most other modalities. In a study by Ezz El Din et al. (13), urinalysis and a cystoscopy were performed in 750 consecutive patients with BPH. Only three patients had a bladder tumour while 49 had urinary calculi. There was no correlation between any clinical parameter and the finding of microscopic haematuria. It was concluded that haematuria is a frequent finding in the assessment of BPH patients and that additional tests should only be performed if indicated (e.g. in the case of abnormal urine cytology). 3.11.10 Conclusions Diagnostic endoscopy of the lower urinary tract should be considered an optional test for the following reasons: • the outcomes of the intervention are unknown • the benefits do not outweigh the harm of the invasive study • patients’ preferences are expected to be divided. 3.11.11 References 1. Grayhack JT. Benign prostatic hyperplasia. The scope of the problem. Cancer 1992;70(Suppl 1): 275-9. http://www.ncbi.nlm.nih.gov/pubmed/1376196

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Bostwick DG. Pathology of benign prostatic hyperplasia. In: Textbook of Benign Prostatic Hyperplasia. Kirby R et al, eds. Oxford: Isis Medical Media, 1996, pp. 91-104. http://www.isismedical.com/ 3. Larsen EH, Bruskewitz RC. Urodynamic evaluation of male outflow obstruction. Krane RJ, Siroky B, eds. Clinical Neurourol. New York 1991, pp 427-443. 4. Berge V, Eri LM, Tveter KJ. Complications of invasive, urodynamic examinations and prostate biopsies in patients with benign prostatic hyperplasia. Scand J Urol Nephrol Suppl 1995;172:95-8. http://www.ncbi.nlm.nih.gov/pubmed/8578262 5. Shoukry I, Susset JG, Elhilali MM, Dutartre D. Role of uroflowmetry in the assessment of lower urinary tract obstruction in adult males. Br J Urol 1975;47(5):559-66. http://www.ncbi.nlm.nih.gov/pubmed/1191927 6. Anikwe RM. Correlations between clinical findings and urinary flow rate in benign prostatic hypertrophy. Int Surg 1976;61(8):392-4. http://www.ncbi.nlm.nih.gov/pubmed/61184 7. Simonsen O, Møller-Madsen B, Dørflinger T, Nørgaard JP, Jørgensen HS, Lundhus E. The significance of age on symptoms and urodynamic and cystoscopic findings in benign prostatic hypertrophy. Urol Res 1987;15(6):355-8. http://www.ncbi.nlm.nih.gov/pubmed/2448939 8. Barry MJ, Cockett AT, Holtgrewe HL, McConnell JD, Sihelnik SA, Winfield HN. Relationship of symptoms of prostatism to commonly used physiological and anatomical measures of the severity of benign prostatic hyperplasia. J Urol 1993;150(2 Pt 1):351-8. http://www.ncbi.nlm.nih.gov/pubmed/7686980 9. Andersen JT, Nordling J. Prostatism. II. The correlation between cysto-urethroscopic, cystometric and urodynamic findings. Scand J Urol Nephrol 1980;14(1):23-7. http://www.ncbi.nlm.nih.gov/pubmed/7375838 10. Homma Y, Gotoh M, Takei M, Kawabe K, Yamaguchi T. Predictability of conventional tests for the assessment of bladder outlet obstruction in benign prostatic hyperplasia. Int J Urol 1998;5(1):61-6. http://www.ncbi.nlm.nih.gov/pubmed/9535603 11. El Din KE, de Wildt MJ, Rosier PF, Wijkstra H, Debruyne FM, de la Rosette JJ. The correlation between urodynamic and cystoscopic findings in elderly men with voiding complaints. J Urol 1996;155(3):1018-22. http://www.ncbi.nlm.nih.gov/pubmed/8583551 12. Quirinia A, Hoffmann AL. Bladder diverticula in patients with prostatism. Int Urol Nephrol 1993;25(3):243-7. http://www.ncbi.nlm.nih.gov/pubmed/7693606 13. Ezz el Din K, Koch WF, de Wildt MJ, Debruyne FM, de la Rosette JJ. The predictive value of microscopic haematuria in patients with lower urinary tract symptoms and benign prostatic hyperplasia. Eur Urol 1996;30(4):409-13. http://www.ncbi.nlm.nih.gov/pubmed/8977059 2.

3.12 RECOMMENDATIONS FOR ASSESSMENT 1. Among all the different urinary symptom score systems currently available, the use of I-PSS is recommended because of its worldwide distribution and use. 2. In patients undergoing investigation for LUTS, the minimal requirement is to assess the upper urinary tract function with a creatinine measurement and/or an ultrasonographic examination. Urinalysis may be included in the primary evaluation. However, it should be noted that there is little evidence in the literature to support this conclusion. 3. DRE is a minimal requirement in patients undergoing investigation for LUTS. 4. There is a consensus that if imaging of the upper urinary tract is performed, ultrasonography is the method of choice. 5. Imaging of the upper urinary tract is recommended in patients with LUTS and one of the following: • History of, or a current, urinary tract infection • History of urolithiasis • History of urinary tract surgery • History of urothelial tumour (including IVU) • Haematuria (including IVU) • Urinary retention. 6. CT and MRI currently have no place in the routine imaging of the upper urinary tract in elderly men with LUTS. 7. Routine imaging of the urinary bladder cannot be recommended as a diagnostic test in the work-

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up of patients with LUTS. Ultrasound of the bladder, however, is a valuable diagnostic tool for the detection of bladder diverticula or bladder stones. 8. Routine imaging of the urethra is not recommended in the diagnostic work-up of patients with LUTS. 9. The method of choice for the determination of prostate volume is ultrasonography, preferably via the transrectal route. However, imaging of the prostate by transabdominal ultrasound and TRUS is optional. 10. Prostate size should be assessed when considering open prostatectomy and TUIP, and prior to finasteride therapy. 11. If the voided volume is less than 150 mL or Qmax is greater than 10 mL/s, pressure-flow studies should be considered before surgical intervention, particularly in elderly men. 12. Measurement of residual urine volume is a recommended test in the assessment of patients with LUTS suggestive of benign prostatic obstruction. 13. Uroflowmetry is recommended as a diagnostic assessment in the work-up of patients with LUTS and is an obligatory test prior to surgical intervention. 14. Post-void residual urine measurement is recommended during initial assessment. 15. Endoscopy is recommended as a guideline at the time of surgical treatment to rule out other pathology and to assess the shape and size of the prostate, which may have an impact on the treatment modality chosen. 16. Pressure-flow studies should be considered for patients prior to surgical treatment in the following subgroups: • younger men (e.g. < 50 years of age) • elderly patients (i.e. > 80 years of age) • post-void residual urine volume over 300 mL • Qmax more than 15 mL/s • suspicion of neurogenic bladder dysfunction • after radical pelvic surgery • previous unsuccessful invasive treatment. In straightforward cases presenting for the first time with LUTS, pressure-flow studies remain optional tests.

4. TREATMENT 4.1

Watchful waiting (WW)

Many men with LUTS do not complain of high levels of bother and so are suitable for non-medical non-surgical management - a policy of care that has been called watchful waiting (WW). It is customary for this type of management to include the following components: education, reassurance, periodic monitoring and lifestyle advice. In many men it is regarded as the first tier in the therapeutic cascade and therefore the majority of men will be offered watchful waiting at some point. WW is a viable option to many men as few, if left untreated, will progress to acute urinary retention and complications such as renal insufficiency and stones (1,2). Similarly some men’s symptoms may improve spontaneously whilst others remain stable for many years (3). 4.1.1 Patient selection All men with LUTS should be formally assessed prior to starting any form of management in order to identify those with complications that may benefit from intervention therapy. Men with mild to moderate uncomplicated LUTS (causing no serious health threat) who are not too bothered by their symptoms are suitable for a trial of WW. A large study comparing WW and TURP in men with moderate symptoms showed that those who had surgery had improved bladder function over the WW group (flow rates and post void residual volumes) with the best results being in those with high levels of bother. 36% crossed over to surgery in 5 years leaving 64% doing well in the WW group (4). Approximately 85% of men will be stable on WW at 1 year, deteriorating progressively to 65% at 5 years (5,6). The reason why some men deteriorate with WW and others do not is not well understood; increasing symptom bothersomeness and post-void residual volumes appeared to be strongest predictors of failure. 4.1.2 Education, reassurance and periodic monitoring Although there is little high quality evidence to support this (the studies have not been done) it seems rational to provide the following for men who are candidates for WW: • prostate, BPH and LUTS education with the help of written information

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• •

•

reassurance that LUTS does not progress in everyone. Reassurance that serious complications are unlikely to occur. information about prostate cancer is nearly always required. Anxiety regarding prostate cancer can be the principal reason why a man consults his doctor about his urinary symptoms. Most men over 50 will note changes in their urinary function with or without high levels of bother. If these men harbour an anxiety about prostate cancer, this may focus their attention on specific symptoms and reinforce their fear. At least three high-quality studies have shown that men with LUTS are at no greater risk of prostate cancer than asymptomatic men of the same age (7-9). It is however not possible to guarantee against early undetectable prostate cancer. WW does not imply no activity; men should be periodically seen by either a urologist, general practitioner or specialist nurse. Symptom scores, symptom bothersomeness, flow rates and postvoid residual volume measurements are useful in determining whether a patient’s condition has deteriorated.

4.1.3 Lifestyle advice Optimization of WW can be achieved with lifestyle modifications. Minor changes in lifestyle and behaviour can have a beneficial effect on symptoms and may prevent deterioration requiring medical or surgical treatment. Lifestyle advice should include: • reduction of fluid intake at specific times aimed at reducing urinary frequency when most inconvenient, for example at night or when going out in public. The recommended total daily fluid intake of 1500 mL should not be reduced. • avoidance or moderation of caffeine and alcohol which may have a diuretic and irritant effect, thereby increasing fluid output and enhancing frequency, urgency and nocturia. - use of relaxed and double-voiding techniques - urethral stripping to prevent postmicturition dribble. • distraction techniques, such as penile squeeze, breathing exercises, perineal pressure and mental ‘tricks’ to take the mind off the bladder and toilet in the control of irritative symptoms. • bladder re-training, by which men are encouraged to ‘hold on’ when they have sensory urgency to increase their bladder capacity (to around 400 mL) and the time between voids. • reviewing a man’s medication and optimising the time of administration or substituting drugs for others that have fewer urinary effects. • providing necessary assistance when there is impairment of dexterity, mobility or mental state. • treatment of constipation. Again it must be stated that there is little high-quality evidence that provides reliable information on any of these lifestyle activities. Research in this area is required so that lifestyle advice to men with LUTS can be refined. 4.1.4 Conclusions Men with mild to moderate LUTS with low levels of bother are suitable for WW. Reassurance, periodic monitoring and lifestyle modifications can be used to optimise WW. Further research in this area is required.

4.1.5 1.

References Ball AJ, Feneley RC, Abrams PH. The natural history of untreated ‘prostatism’. Br J Urol 1981;53(6):613-6. http://www.ncbi.nlm.nih.gov/pubmed/6172172 2. Kirby RS. The natural history of benign prostatic hyperplasia: what have we learned in the last decade?. Urology 2000;56(5 Suppl 1):3-6. http://www.ncbi.nlm.nih.gov/pubmed/11074195 3. Isaacs JT. Importance of the natural history of benign prostatic hyperplasia in the evaluation of pharmacologic intervention. Prostate Suppl. 1990;3:1-7. http://www.ncbi.nlm.nih.gov/pubmed/1689166 4. Flanigan RC, Reda DJ, Wasson JH Anderson RJ, Abdellatif M, Bruskewitz RC. 5-year outcome of surgical resection and watchful waiting for men with moderately symptomatic BPH: a department of Veterans Affairs cooperative study. J Urol 1998;160(1):12-6;discussion 16-7. http://www.ncbi.nlm.nih.gov/pubmed/9628595

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5.

Wasson JH, Reda DJ, Bruskewitz RC, Elinson J, Keller AM, Henderson WG. A comparison of Transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. The Veterans Affairs Cooperative Study Group on Transurethral Resection of the Prostate. New Engl J Med 1995;332(2):75-9. http://www.ncbi.nlm.nih.gov/pubmed/7527493 6. Netto NR Jr, de Lima ML, Netto MR, D’Ancona CA. Evaluation of patients with bladder outlet obstruction and mild international prostate symptom score followed up by watchful waiting. Urol 1999;53(2):314-6. http://www.ncbi.nlm.nih.gov/pubmed/9933046 7. Catalona WJ, Richie JP, Ahmann FR, Hudson MA, Scardino PT, Flanigan RC, deKernion JB, Ratliff TL, Kavoussi LR, Dalkin BL et al. Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicentre clinical trial of 6,630 men. J Urol 1994;15(5):1283-90. http://www.ncbi.nlm.nih.gov/pubmed/7512659 8. Mettlin C, Murphy GP, Babaian RJ, Chesley A, Kane RA, Littrup RJ, Mostofi FK, Ray PS, Shanberg AM, Toi A. American Cancer Society National Prostate Cancer Detection Project. The results of a five-year early prostate cancer detection intervention. Investigators of the American Cancer Society National Prostate Cancer Detection Project. Cancer 1996;77(1):150-9. http://www.ncbi.nlm.nih.gov/pubmed/8630923 9. Rietbergen JB, Kranse R, Boeken Kruger AE, et al. Additional value of the AUA 7 symptoms score in prostate cancer (PC) detection. J Urol 1997;157:467.

4.2

Medical treatment

4.2.1 5-alpha reductase inhibitors 4.2.1.1 Finasteride (type 2, 5-alpha reductase inhibitor) 4.2.1.1.1 Efficacy and clinical endpoints Today, after the completion of many trials, the efficacy of 5-alpha reductase inhibitors is unquestionable and has been demonstrated over large clinical trials. It can reduce the size of the prostate gland by 20-30%; it improves symptom scores by approximately 15% and can also cause a moderate improvement in the urinary flow rate of 1.3-1.6 mL/s (1-4). A meta-analysis of six randomized clinical trials showed that baseline prostate volume was a key predictor of various treatment outcomes and that finasteride was more effective in prostates larger than 40 mL (5). Various trials have concluded that finasteride significantly reduced acute urinary retention and the need for surgical treatment in men with BPH (6-8). In a major placebo controlled trial including 3,040 men, finasteride-treated patients had significantly less bother, activity interference and worry due to urinary symptoms. Baseline PSA levels of 1.4 ng/mL, or enlarged prostate glands, could predict the best long-term response to finasteride (9). Data from three multinational, multicentre, placebo-controlled finasteride trials, in 4,222 men, showed that patients with larger prostate volumes or higher PSA levels have an increased risk of developing acute urinary retention and therefore derive the greatest benefit from finasteride therapy (10). The long-term effects of finasteride have also been examined. The North American Finasteride Study Group reported that patients treated with finasteride maintained a reduction of prostate volume and an improvement in symptom score and maximal urinary flow rate over a period of 5 years (11). In addition, the Scandinavian Finasteride Study Group has verified an earlier observation that the maximum efficacy of finasteride action is obtained after 6 months, and has shown that this improvement could be maintained for at least 6 years (12). A recent North American study has also verified that long term (10 year) treatment is well tolerated and results in durable symptom relief (13). 4.2.1.1.2 Haematuria and finasteride Another important benefit of finasteride in common clinical urological practice is that it can be used to treat haematuria associated with BPH. Various studies have confirmed this alternative for patients with haematuria due to BPH who, at the same time, had no significant obstruction or adenocarcinoma of the prostate (14-16). 4.2.1.1.3 Side-effects These are mainly related to sexual function. In the PLESS study the side effects reported were decreased libido (6,4%), impotence (8,1%), decreased ejaculate (3,7%) and in less than 1% of the patients other disorders such as rash, breast enlargement and breast tenderness (9). All these figures were higher than those observed for placebo. Such side-effects are considered ‘minimal’ since they did not increase over time and did not cause many patients to discontinue their treatment. In a recent publication from the PLESS study group it was shown that the finasteride-related sexual adverse experiences occurred mainly during the first year of therapy (17). Another conclusion from the PLESS study was that in both older and younger men with symptomatic BPH,

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finasteride had the same safety profile and no drug interactions of clinical importance were observed (18). Finally it has also been shown that the four year inhibition of type 2 5alpha-reductase with finasteride does not adversely affect bone mineral density (19). 4.2.1.1.4 Effect on PSA It is known that finasteride lowers serum PSA levels. Thus, the question of whether or not it masks the early detection of localized prostatic adenocarcinomas has been raised. It has been agreed that 12 months of finasteride, 5 mg/day, reduces serum PSA levels by 50%. Two major studies (20,21) verified earlier reports, and concluded that doubling the PSA level allowed appropriate interpretation of PSA values and that finasteride treatment did not mask the detection of prostatic adenocarcinomas. It was also shown, at the histopathological level, that finasteride did not cause problems in the diagnosis of cancer from needle specimens as cancer tissue remained unaltered (22). The results of papers dealing with the impact of finasteride on free PSA level are confusing. In one paper, finasteride seemed to lower total and free PSA levels equally, so that the ratio of free PSA to total PSA remained unchanged (23). In another report, the percentage of free PSA did not change significantly (24). 4.2.1.2 Dutasteride It is known that finasteride suppresses dihydrotestosterone (DHT) by about 70% in the serum and by 90% in the prostate. The remaining DHT is the result of type 1 5-alpha reductase activity. Dutasteride is a new drug that has the ability to suppress both type 1 and type 2 isoenzymes and as a consequence serum DHT decreases by about 90% (25). A phase II study including 399 patients showed that dutasteride can cause greater suppression of DHT than finasteride (26). The results of four large randomized, double-blind clinical trials have been presented (27, 28). Three of these studies were placebo controlled studies and they showed that dutasteride can reduce prostatic volume by almost 26%, improve symptoms and urinary flow rate and reduces also the incidence of acute urinary retention and BPH related surgery. The fourth compared dutasteride with finasteride for one year which showed that drug related adverse events were similar for both compounds. Pooled data from the patients enrolled in all four studies proved that dutasteride is well tolerated and adverse events included erectile dysfunction, ejaculatory disorders and gynecomastia (27). In a recently published study it was also shown that dutasteride is associated with clinically significant improvement in BPH specific health status as measured by the BPH Impact Index (BII) (29). Dutasteride shows similar efficacy and tolerability as finasteride in suppressing both type 1 and type 2 isoenzymes but further randomized studies are needed. 4.2.1.3 Combination therapy The combination of finasteride with an alpha-blocker was examined earlier in two clinical trials (30,31). No additional benefit from combining these two drugs was observed in either study. The lack of finasteride efficacy in these two trials may be due to smaller baseline prostate volumes. Recently the results of a multicentre randomized, placebo-controlled double-blinded trial (MTOPS trial), have shown that the combination of finasteride to doxazocin was beneficial (32).The combination therapy was superior to either drug alone in reducing AUA symptom scores, in increasing median maximal flow rates, and in reducing the likelihood of acute urinary retention and surgery. The follow-up period of the MTOPS trial was 4.5 years and another conclusion drawn from this study was that finasteride needs time to reveal its beneficial therapeutic capacity. In another study examining combination therapy, it was shown that patients with lower urinary tract symptoms and moderately enlarged prostates initially receiving combination therapy with finasteride and an alpha-blocker were likely to experience no significant symptom deterioration after discontinuing the alphablocker following 9 to 12 months of combination therapy (33). A multicentre, placebo-controled study, SMART Study C (Symptom Management After Reducing Therapy), on the short term combination of dutasteride and tamsulosin involving 327 patients confirmed compatible results (34). 4.2.1.4 Conclusions • It has been shown in numerous randomized, placebo-controlled clinical trials that 5-alpha reductase inhibitors are capable of reducing prostate volume and improving symptom scores and flow rates. Maximum benefits are seen at a mean period after 6 months. • Men with small prostates (< 40 mL) are less likely to benefit from finasteride. • 5-alpha reductase inhibitors can alter the natural history of symptomatic BPH by influencing prostatectomy and acute urinary retention rates. The costs of such protocols, however, should be further evaluated. • The long-term (up to 10 years) effects of 5- alpha reductase inhibitors are substantial.

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• • •

The combination of a 5-alpha reductase inhibitor with an alpha-blocker seems beneficial according to the data currently available. Side-effects of 5-alpha reductase inhibitors are minimal Treatment with 5-alpha reductase inhibitors does not mask the detection of prostate carcinoma. By doubling PSA serum levels, an accurate estimation can be expected.

4.2.1.5 References 1. Andersen JT, Ekman P, Wolf H, Beisland HO, Johansson JE, Kontturi M, Lehtonen T, Tveter K. Can finasteride reverse the progress of benign prostatic hyperplasia? A two year placebo-controlled study. The Scandinavian BPH study group. Urology 1995;46(5):631-7. http://www.ncbi.nlm.nih.gov/pubmed/7495111 2. Gormley GJ, Stoner E, Bruskewitz RC, Imperato-McGinley J, Walsh PC, McConnell JD, Andriole GL, Geller J, Bracken BR, Tenover JS, et al. The effect of finasteride in men with benign prostatic hyperplasia. The Finasteride Study Group. N Engl J Med 1992;327(17):1185-91. http://www.ncbi.nlm.nih.gov/pubmed/1383816 3. Nickel JC, Fradet Y, Boake RC, Pommerville PJ, Perreault JP, Afridi SK, Elhilali MM. Efficacy and safety of finasteride therapy for benign prostatic hyperplasia: results of a 2-year randomised controlled trial (the PROSPECT Study). CMAJ 1996;155(9):1251-9. http://www.ncbi.nlm.nih.gov/pubmed/8911291 4. Vaughan D, Imperato-McGinley J, McConnell J, Matsumoto AM, Bracken B, Roy J, Sullivan M, Pappas F, Cook T, Daurio C, Meeha A, Stoner E, Waldstreicher J. Long-term (7 to 8-year) experience with finasteride in men with benign prostatic hyperplasia. Urology 2002,60(6):1040-4. http://www.ncbi.nlm.nih.gov/pubmed/12475666 5. Boyle P, Gould AL, Roehrborn CG. Prostate volume predicts the outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomized clinical trials. Urology 1996;48(3):398-405. http://www.ncbi.nlm.nih.gov/pubmed/8804493 6. Andersen JT, Nickel JC, Marshall VR, Schulman CC, Boyle P. Finasteride significantly reduces acute urinary retention and need for surgery in patients with sympomatic benign prostatic hyperplasia. Urology 1997;49(6):839-45. http://www.ncbi.nlm.nih.gov/pubmed/9187688 7. McConnell JD, Bruskewitz R, Walsh P, Andriole G, Lieber M, Holtgrewe HL, Albertsen P, Roehrborn CG, Nickel JC, Wang DZ, Taylor AM, Waldstreicher J. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-term Efficacy and Safety Study Group. N Engl J Med 1998;338(9):557-63. http://www.ncbi.nlm.nih.gov/pubmed/9475762 8. Roehrborn CG, Bruskewitz R, Nickel GC, Glickman S, Cox C, Anderson R, Kandzari S, Herlihy R, Kornitzer G, Brown BT, Holtgrewe HL, Taylor A, Wang D, Waldstreicher J. Urinary retention in patients with BPH treated with finasteride or placebo over 4 years. Characterization of patients and ultimate outcomes. The PLESS Study Group. Eur Urol 2000;37(5):528-36. http://www.ncbi.nlm.nih.gov/pubmed/10765090 9. Bruskewitz R, Girman CJ, Fowler J, Rigby OF, Sullivan M, Bracken RB Fusilier HA, Kozlowski D, Kantor SD, Johnson EL, Wang DZ, Waldstreicher J. Effect of finasteride on bother and other healthrelated quality of life aspects associated with benign prostatic hyperplasia. PLESS Study Group. Proscar Long-term Efficacy and Safety Study. Urology 1999;54(4):670-8. http://www.ncbi.nlm.nih.gov/pubmed/10510926 10. Marberger MJ, Andersen JT, Nickel JC, Malice MP, Gabriel M, Pappas F, Meehan A, Stoner E, Waldstreicher J. Prostate volume and serum prostate-specific antigen as predictors of acute urinary retention. Combined experience from three large multinational placebo-controlled trials. Eur Urology 2000;38(5):563-8. http://www.ncbi.nlm.nih.gov/pubmed/11096237 11. Hudson PB, Boake R, Trachtenberg J, Romas NA, Rosenblatt S, Narayan P, Geller J, Lieber MM, Elhilali M, Norman R, Patterson L, Perreault JP, Malek GH, Bruskewitz RC, Roy JB, Ko A, Jacobsen CA, Stoner E. Efficacy of finasteride is maintained in patients with benign prostatic hyperplasia treated for 5 years. The North American Finasteride Study Group. Urology 1999;53(4):690-5. http://www.ncbi.nlm.nih.gov/pubmed/10197842

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12.

Ekman P. Maximum efficacy of finasteride is obtained within 6 months and maintained over 6 years. Follow-up of the Scandinavian Open-extension Study. The Scandinavian Finasteride Study Group. Eur Urol 1998;33(3):312-7. http://www.ncbi.nlm.nih.gov/pubmed/9555559 13. Lam JS, Romas NA, Lowe FC. Long-term treatment with finasteride in men with symptomatic benign prostatic hyperplasia: 10-year follow-up. Urology 2003;61(2):354-8. http://www.ncbi.nlm.nih.gov/pubmed/12597947 14. Foley SJ, Soloman LZ, Wedderburn AW, Kashif KM, Summerton D, Basketter V, Holmes SA. A prospective study of the natural history of hematuria associated with benign prostatic hyperplasia and the effect of finasteride. J Urol 2000;163(2):496-8. http://www.ncbi.nlm.nih.gov/pubmed/10647664 15. Kearney MC, Bingham JB, Bergland R, Meade-D’Alisera P, Puchmer PJ. Clinical predictors in the use of finasteride for control of gross hematuria due to benign prostatic hyperplasia. J Urol 2002;167(6):2489-91. http://www.ncbi.nlm.nih.gov/pubmed/11992064 16. Perimenis P, Gyftopoulos K, Markou S, Barbalias G. Effects of finasteride and cyproterone acetate on hematuria associated with benign prostatic hyperplasia: a prospective, randomized, controlled study. Urology 2002;59(3):373-7. http://www.ncbi.nlm.nih.gov/pubmed/11880073 17. Wessells H, Roy J, Bannow J, Grayhack J, Matsumoto AM, Tenover L, Herlihy R, Fitch W, Labasky R, Auerbach S, Parra R, Rajfer J, Culbertson J, Lee M, Bach MA, Waldstreicher J; PLESS Study Group. Incidence and severity of sexual adverse experiences in finasterides and placebo-treated men with benign prostatic hyperplasia. Urology 2003;61(3):579-84. http://www.ncbi.nlm.nih.gov/pubmed/12639651 18. Kaplan SA, Holtgrewe HL, Bruskewitz R, Saltzman B, Mobley D, Narayan P, Lund RH, Weiner S, Wells G, Cook TJ, Meehan A, Waldstreicher J. Comparison of the efficacy and safety of finasteride in older versus younger men with benign prostatic hyperplasia. Urology 2001;57(6):1073-7. http://www.ncbi.nlm.nih.gov/pubmed/11377309 19. Matsumoto AM, Tenover L, McClung M, Mobley D, Geller J, Sullivan M, Grayhack J, Wessells H, Kadmon D, Flanagan M, Zhang GK, Schmidt J, Taylor AM, Lee M, Waldstreicher J. PLESS Study Group. The long-term effect of specific type II 5alpha-reductase inhibition with finasteride on bone mineral density in men: results of a 4-year placebo controlled trial. J Urol 2002;167(5):2105-8. http://www.ncbi.nlm.nih.gov/pubmed/11956450 20. Oesterling JE, Roy J, Agha A, Shown T, Krarup T, Johansen T, Lagerkvist M, Gormley G, Bach M, Waldstreicher J. Biologic variability of prostate specific antigen and its usefulness as a marker for prostate cancer: effects of finasteride. The Finasteride PSA Study Group. Urology 1997;50(1):13-8. http://www.ncbi.nlm.nih.gov/pubmed/9218012 21. Andriole GL, Guess HA, Epstein JL, Wise H, Kadmon D, Crawford ED, Hudson P, Jackson CL, Romas NA, Patterson L, Cook TJ, Waldstreicher J. Treatment with finasteride preserves usefulness of prostate specific antigen in the detection of prostate cancer: results of a randomized, double-blind, placebo-controlled clinical trial. PLESS Study Group. Proscar Long-term Efficacy and Safety Study. Urology 1998;52(2):195-201. http://www.ncbi.nlm.nih.gov/pubmed/9697781 22. Yang XJ, Lecksell K, Short K, Gottesman J, Peterson L, Bannow J, Schellhammer PF, Fitch WP, Hodge GB, Parra R, Rouse S, Waldstreicher J, Epstein JI. Does long-term finasteride therapy affect the histologic features of benign prostatic tissue and prostate cancer on needle biopsy?. PLESS Study Group. Proscar Long-term Efficacy and Safety Study. Urology 1999;53(4):696-700. http://www.ncbi.nlm.nih.gov/pubmed/10197843 23. Keetch DW, Andriole GL, Ratliff TL, Catalona WJ. Comparison of percent free prostate specific antigen levels in men with benign prostatic hyperplasia treated with finasteride, terazosin or watchful waiting. Urology 1997;50(6):901-5. http://www.ncbi.nlm.nih.gov/pubmed/9426721 24. Pannek J, Marks LS, Pearson JD, Rittenhouse HG, Chan DW, Shery ED, Gormley GJ, Subong EN, Kelley CA, Stoner E, Partin AW. Influence of finasteride on free and total serum prostate specific antigen levels in men with benign prostatic hyperplasia. J Urol 1998;159(2):449-53. http://www.ncbi.nlm.nih.gov/pubmed/9649261 25. Bartsch G, Rittmaster RS, Klocker H. Dihydrotestosterone and the concept of 5 alpha – reductase inhibition in human benign prostatic hyperplasia. World J Urol 2002,19(6):413-25. http://www.ncbi.nlm.nih.gov/pubmed/12022710

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26. Clarke R, Hermann D, Gabriel H, Wilson T, Morril B, Hobbs S. Effective suppression of dihydrotestosterone (DHT) by GI 198745, a novel, dual 5-alpha reductase inhibitor. J Urol 1999;161:1037. 27. Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G; ARIA3001, ARIA3002 and ARIA3003 study investigators. Efficacy and safety of a dual inhibitor or 5-alphareductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 2002;60(3):434-41. http://www.ncbi.nlm.nih.gov/pubmed/12350480 28. Andriole GL, Kirby R Safety and tolerability of the Dual 5 alpha-Reductase Inhibitor dutasteride in the treatment of benign prostatic hyperplasia. Eur Urol 2003;44(1):82-8. http://www.ncbi.nlm.nih.gov/pubmed/12814679 29. O’Leary MP, Roehrborn C, Andriole G, Nickel C, Boyle P, Höfner K. Improvements in benign prostatic hyperplasia-specific quality of life with dutasteride, the novel dual 5 alpha-reductase inhibitor. BJU Inter 2003;92(3):262-5. http://www.ncbi.nlm.nih.gov/pubmed/12887480 30. Lepor H, Williford WO, Barry MJ, Brawer MK, Dixon CM, Gormley G, Haakenson C, Machi M, Narayan P, Padley RJ. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. Veterans Affairs Cooperative Studies, Benign Prostatic Hyperplasia Study Group. N Engl J Med 1996;335(8):533-9. http://www.ncbi.nlm.nih.gov/pubmed/8684407 31. Debruyne FM, Jardin A, Colloi D, Resel L, Witjes WP, Delauche-Cavallier MC, McCarthy C, GeffriaudRicouard C. Sustained-release alfuzosin, finasteride and the combination of both in the treatment of benign prostatic hyperplasia. European ALFIN Study Group. Eur Urol 1998;34(3):169-75. http://www.ncbi.nlm.nih.gov/pubmed/9732187 32. Mc Connell JD. The long term effects of medical therapy on the progression of BPH: Results from the MTOPS trial. J Urol 2002;167:265, abstr 1042. 33. Baldwin KC, Ginsberg PC, Roehrborn CG, Harkaway RC. Discontinuation of alpha-blockade after initial treatment with finasteride and doxazosin in men with lower urinary tract symptoms and clinical evidence of benign prostatic hyperplasia. Urology 2001;58(2):203-9. http://www.ncbi.nlm.nih.gov/pubmed/11489700 34. Barkin J, Guimaraes M, Jacobi G, Pushkar D, Taylor S, van Vierssen Trip OB. Alpha-blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5alphareductase inhibitor dutasteride. Eur Urol 2003;44(4):461-6. http://www.ncbi.nlm.nih.gov/pubmed/14499682 4.2.2 Alpha-blockers Over the past 10 years, the prescribing of alpha-blockers has steadily increased. This increase has been driven partly by patients wishing to achieve symptomatic relief without undergoing surgical treatments and partly by the marketing of these drugs by pharmaceutical companies. In view of the very real placebo effect seen in the treatment of patients with LUTS secondary to BPH, this review will focus on the results of randomized, prospective, placebo-controlled clinical studies. 4.2.2.1 Uroselectivity Alpha-blockers were first introduced into clinical practice for the treatment of LUTS secondary to BPH in 1978, following experimental work demonstrating the predominance of adrenoceptors in human prostate smooth muscle (1). Initially, the non-selective alpha-blocker, phenoxybenzamine, was investigated. However, the side-effect profile, due to its unselective nature, was unacceptable to patients (2,3). Subsequently, alpha1adrenoceptors were identified and selective, better-tolerated, alpha-blockers were developed. A large number of alpha1-selective, alpha-blockers are available (tamsulosin, alfuzosin, doxazosin, indoramin, prazosin, terazosin). Broadly speaking, they all have a similar efficacy and side-effect profile. 4.2.2.2 Mechanism of action Alpha-blockers are thought to act by reducing the dynamic element of prostatic obstruction by antagonizing the adrenergic receptors responsible for smooth muscle tone within the prostate and bladder neck. This is implied from in-vitro experiments and the predominant distribution of alpha1-receptors within the prostate and bladder neck. However, the exact contributions of alpha1-receptor subtypes and the potential central effects in vivo remain unclear. Urodynamic studies measuring voiding pressures do not reveal any significant relief of obstruction, although flow rates do improve with these agents relative to placebo.

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4.2.2.3 Pharmacokinetics Alpha-blockers are taken orally and the dosage depends on the half-life of the relevant drug. Tamsulosin, alfuzosin, terazosin and doxazosin have the advantage of being long-acting, once-daily preparations. 4.2.2.4 Assessment It is not unreasonable to offer a trial of alpha-blockers to all men with uncomplicated LUTS. The optimal duration of the trial of therapy has been debated. Symptoms can improve within 48 hours. An I-PSS assessment requires at least one month of therapy. There is no justification in prolonging therapy beyond one month in men who do not respond. One-third of men will not experience significant symptom reduction. Currently there is no method of predicting which men will show a response (4). 4.2.2.5 Clinical efficacy The interpretation of existing literature regarding the efficacy of alpha-blocker therapy is clouded by the wide dis­ cre­pancy in methodology and reporting of clinical studies. Because of this, secondary publications that have com­ pared outcomes between these studies have been useful (5-7). Djavan and Marberger’s meta-analysis estimated that overall symptoms improved by 30-40% and that flow rates improved by 16-25%, compared with placebo (6). Predicting response for any individual is more difficult and therefore a trial of therapy is required. The various types of alpha-blockers cannot be distinguished by their ability to relieve symptoms or improve flow. 4.2.2.6 Durability Good data on long-term efficacy and the effect on natural history are currently not available. Long-term studies tend to be open-label extensions or increasingly ‘real life practice’ studies which do not conform to an experimental design. Nevertheless, in this context these types of design are informative. Patients may choose to stop taking medication for a number of reasons. Studies have concentrated on two important reasons, namely, the occurrence of adverse effects and lack of efficacy (8). In general, the symptom status of men did not predict whether they were likely to stop therapy. Drop-outs occurred at the same rate, irrespective of whether symptoms were moderate or severe. The rate of drop-out in men on alphablockers appears to be between 0.01 and 1.6 per month. There is no evidence that efficacy diminishes with time. 4.2.2.7 Adverse effects The most commonly reported side-effects with alpha-blocker therapy are headaches, dizziness, postural hypotension, asthenia, drowsiness, nasal congestion and retrograde ejaculation (6). In general, the rate of sideeffects in studies looking at tamsulosin and alfuzosin were equivalent to placebo (4-10%). Tamsulosin resulted in less orthostatic hypotension than alfuzosin under test conditions. Whether this translates into a reduction in clinical side-effects remains to be seen. 4.2.2.8 Acute urinary retention Early trials comparing alpha-blockers to placebo showed an increased likelihood of a successful trial, without catheter, following an episode of acute urinary retention. As a result, a large number of urologists have adopted this practice. The effect seems to be independent of the type of alpha-blocker studied. Two trials have looked at alfuzosin (11), and one at terazosin (12). None of these trials continued therapy beyond the period of catheterization. Most men experience re-retention within the first two months (13). Studies are underway which address the question of whether men do benefit from alpha-blockade in the six months following acute urinary retention. 4.2.2.9 Conclusions • Alpha-blocker therapy can result in a rapid improvement in symptoms by a factor of 20-50% and an improvement in the flow rate of 20-30%. These changes have been shown to be significant in randomized, placebo-controlled studies. • Long-term data are limited but suggest that the benefits of treatment are sustained. If a patient does not experience an improvement in symptoms after an 8-week trial, treatment should be discontinued. • Patients should be informed about the side-effects of alpha-blocker therapy and the need for longterm use. • There is no difference between different alpha-blockers in terms of efficacy. Although the side-effect profiles for some drugs are reported to be more favourable, supportive data are weak.

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4.2.2.10 References 1. Caine M, Raz S, Zeigler M. Adrenergic and cholinergic receptors in the human prostate, prostatic capsule and bladder neck. Br J Urol 1975;47(2):193-202. http://www.ncbi.nlm.nih.gov/pubmed/1148621 2. Caine M, Perlberg S, Meretyk S. A placebo controlled double blind study of the effect of phenoxybenzamine in benign prostatic obstruction. Br J Urol 1978;50(7):551-4. http://www.ncbi.nlm.nih.gov/pubmed/88984 3. Abrams PH, Shah PJ, Stone R, Choa RG. Bladder outflow obstruction treated with phenoxybenzamine. Br J Urol 1982;54(5):527-30. http://www.ncbi.nlm.nih.gov/pubmed/6184106 4. Witjes WP, Rosier PF, Caris CT, Debruyne FM, de la Rosette JJ. Urodynamic and clinical effects of terazosin therapy in symptomatic patients with and without bladder outlet obstruction. A stratified analysis. Urology 1997;49(2):197-205. http://www.ncbi.nlm.nih.gov/pubmed/9037281 5. Chapple CR, Andersson KF, Bono VA et al. a-blockers clinical results. In: Denis L, Griffiths K, Khoury S, et al. eds. Proceedings of the Fourth International Consultation on BPH, Paris, July 1997. Plymouth:Health Publications, 1998, pp. 610-632. http://www.congress-urology.org/ 6. Djavan B, Marberger M. Meta-analysis on the efficacy and tolerability of alpha1-adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol 1999;36(1):1-13. http://www.ncbi.nlm.nih.gov/pubmed/10364649 7. Debruyne FM. Alpha blockers: are all created equal? Urology. 2000;56(5 Suppl 1):20-2. http://www.ncbi.nlm.nih.gov/pubmed/11074198 8. Lukacs B, McCarthy C, Grange JC. Long-term quality of life in patients with benign prostatic hypertrophy: preliminary results of a cohort survey of 7093 patients treated with alpha-1 adrenergic blocker, alfuzosin. QOL BPH Study Group in General Practice. Eur Urol 1993;24 Suppl 1:34-40. http://www.ncbi.nlm.nih.gov/pubmed/7687557 9. Lepor H. Long-term evaluation of tamsulosin in benign prostatic hyperplasia: placebo-controlled, double-blind extension of phase III trial. Tamsulosin Investigator Group. Urology 1998;51(6):901-6. http://www.ncbi.nlm.nih.gov/pubmed/9609624 10. Debruyne FM, Jardin A, Colloi D, Resel L, Witjes WP, Delauche-Cavallier MC, McCarthy C, GeffriaudRicouard C. Sustained-release alfuzosin, finasteride and the combination of both in the treatment of benign prostatic hyperplasia. European ALFIN Study Group. Eur Urol 1998;34(3):169-75. http://www.ncbi.nlm.nih.gov/pubmed/9732187 11. McNeil SA, Daruwala PD, Mitchel ID, Shearer MG, Hargreave TB. Sustained-release alfuzosin and trial without catheter after acute urinary retention: a prospective placebo-controlled. BJU Int 1999;84(6):622-7. http://www.ncbi.nlm.nih.gov/pubmed/10510105 12. Chan PSF, Wong WS, Chan LW, Cheng CW. Can terazosin (alpha blocker) relieve acute urinary retention and obviate the need for an indwelling urethral catheter?. Br J Urol 1996;77:Suppl.1:27. 13. McNeill SA, Hargreave TB, Gallagher H, Daruwala PD, Mitchell I-DC, Rizvi S. Long term follow-up following presentation with first episode of acute urinary retention. J Urol 2000;163:307. 4.2.3 Phytotherapeutic agents The use of phytotherapy in treating lower urinary tract symptoms and benign prostatic hyperplasia has been popular in Europe for many years and has recently spread in the USA. These agents are composed of various plant extracts and it is always difficult to identify which component has the major biological activity. A few short term randomized trials and some meta-analyses show clinical efficacy without major side effects for compounds such as Pygeum africanum and Serenoa repens (1-4). In some studies the efficacy of these compounds was found to be equivalent to finasteride and α-blockers (5,6). Many questions concerning the composition, the extraction and the mechanism of action of these compounds still remain unanswered and therefore additional randomized, placebo controlled trials are needed (7). 4.2.3.1 Conclusions The mode of action of phytotherapeutic agents is unknown. The biological effects in unclear although a few randomized clinical trials show encouraging results.

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4.2.3.2 References 1. Wilt T, Ishani A, Mac Donald R, Rutks I, Stark G. Pygeum africanum for benign prostatic hyperplasia. Cochrane Database Syst Rev 2002;(1):CD001044. http://www.ncbi.nlm.nih.gov/pubmed/11869585 2. Wilt T, Ishani A, Stark G, Mac Donald R, Mulrow C, Lau J. Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev 2000;(2):CD001423. http://www.ncbi.nlm.nih.gov/pubmed/10796790 3. Fagelman E, Lowe FC. Herbal medications in the treatment of benign prostatic hyperplasia (BPH). Urol Clin North Am 2002;29(1):23-9, vii. http://www.ncbi.nlm.nih.gov/pubmed/12109350 4. Lowe FC, Fagelman E. Phytotherapy in the treatment of benign prostatic hyperplasia. Curr Opin Urol 2002;12(1):15-8. http://www.ncbi.nlm.nih.gov/pubmed/11753128 5. Lowe FC. Phytotherapy in the management of benign prostatic hyperplasia. Urology 2001; 58(6 Suppl 1):71-6; discussion 79-7. http://www.ncbi.nlm.nih.gov/pubmed/11750257 6. Debruyne F, Koch G, Boyle P, Da Silva FC, Gillenwater JG, Hamdy FC, Perrin P, Teillac P, VelaNavarrete R, Raynaud JP. Comparison of a phytotherapeutic agent (Permixon) with an alphablocker (Tamsulosin) in the treatment of benign prostatic hyperplasia: a 1-year randomized international study. Eur Urol 2002;41(5):497-506. http://www.ncbi.nlm.nih.gov/pubmed/12074791 7. Dreikorn K. The role of phytotherapy in treating lower urinary tract symptoms and benign prostatic hyperplasia. World J Urol 2002;19(6):426-35. http://www.ncbi.nlm.nih.gov/pubmed/12022711

4.3

Surgical management

Transurethral resection of the prostate (TURP), transurethral incision of the prostate (TUIP) and open prostatectomy are the conventional surgical options. Transurethral vaporisation, an electrosurgical modification of the TURP-technique, is also included to this chapter. Two randomized controlled trials (RCTs) are available for open prostatectomy, while TURP, TUIP and TUVP have been subjected to a number of RCTs. 4.3.1 Indications for surgery The most frequent indication for surgical management is bothersome LUTS refractory to medical management (1,2). The following complications of BPH/BPE are considered strong indications for surgery: • refractory urinary retention • recurrent urinary retention • recurrent haematuria refractory to medical treatment with 5-alpha reductase inhibitors • renal insufficiency • bladder stones. Increased post-void residual volume may also be used as an indication for surgery. However, there is a great intra-individual variability and an upper limit requiring intervention has not been requiring intervention has not been defined. Variables that most likely predict the outcome of prostatectomy are severity of LUTS, the degree of bother and the presence of BPO (see above) (3,4). 4.3.2 Choice of surgical treatment Ten RCT comparing TUIP to TURP are available (5-7). They showed similar improvements of LUTS in patients with small prostates (< 20-30 mL) and no middle lobe (5-7). TUIP has several advantages has several advantages over TURP, such as a lower incidence of complications, minimal risk of bleeding and blood transfusion, decreased risk of retrograde ejaculation and shorter operating time and hospital stay, yet a higher long-term failure rate. TURP comprises 95% of all surgical procedures and is the treatment of choice for prostates sized 30-80mL. Intra- and postoperative complications are correlated with the size of the prostate and the length of the procedure. Open prostatectomy is the treatment of choice for large glands (> 80-100 mL), associated complications such as large bladder stones, or if resection of bladder diverticula is indicated (8-10). A recent RCT has shown that Holmium-laser enucleation leads to similar outcome as open prostatectomy for men with large glands (> 100 mL) at a significantly lower complication rate (11). TUVP is considered an alternative to TUIP and TURP, particularly for patients with bleeding disorders and small prostates. Coagulating intermittent cutting, rotoresection and bipolar electrocautery are electrosurgical modifications of the conventional technique (12-14). Encouraging data are available for all these techniques, the data of large scale RCT are awaited with interest (12-14). As RCT-data are not yet available, these methods are not described in more detail below.

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4.3.3 Perioperative antibiotics A known urinary tract infection should be treated before surgery (15,16). The routine use of prophylactic antibiotics remains controversial. However, antibiotics are recommended in patients on catheterisation prior to surgery. 4.3.4 Treatment outcome LUTS All four surgical procedures (TURP, TUIP, TUVP and open prostatectomy) result in an improvement of LUTS exceeding 70%, with open prostatectomy leading to slightly superior results (4-11). Mean improvement of LUTS in a meta-analysis of 29 RCT with a TURP-arm was 71% (range: 66-76%) (6). In the 10 RCTs comparing TURP to TUIP, both procedures resulted in a similar improvement in symptoms after 12 months (5-7). The RCTs comparing TURP to TUVP also revealed similar improvements of LUTS in both study arms (6). Uroflowmetry The mean increase of Qmax following TURP is 115% (range: 80-150%) (6); in absolute terms + 9.7 mL/s (range: 4-11.6 mL/s) (6). Following TUVP, the Qmax increased by 155% (range: 128-182%) (6). The highest Qmax improvement (+175%) is seen after open prostatectomy (absolute numbers: 8.2-22.6 mL/s) (6,8-10). Post-void residual volume All four surgical procedures allow a reduction of the post-void residual volume of more than 50%: -65% after open prostatectomy; -60% after TUVP; -60% after TURP; and –55% after TUIP (4-11). 4.3.5 Complications Intra-/peri-operative Mortality following prostatectomy has decreased significantly within the past two decades and is less than < 0.25% in contemporary series (6,17-19). The risk of a TUR-syndrome (fluid intoxication, serum Na+ < 130 nmol/L) is in the range of 2%. Risk factors for the development of the TUR-syndrome are excessive bleeding with opening of venous sinuses, prolonged operation time, large glands and past or present smoking (20). The estimated need for blood transfusion following TURP is in the range of 2-5%. Higher percentages have been reported following open prostatectomy (6,8-10). The risk of bleeding following TUIP and TUVP is negligible (6). Long-term complications Incontinence: Median probability for developing stress incontinence ranges is 1.8% following TUIP, 2.2% following TURP, and up to 10% following open prostatectomy (4-11). Limited information on this issue is available for TUVP; one RCT reported an incontinence rate of 5% (6,21). Bladder neck contracture and urethral stricture: The risk of developing an urethral stricture is 2.6% after open prostatectomy, 3.8% after TURP and 1.7% after TUIP (4-11). The risk of bladder neck contracture is 1.8% after open surgery, 4% after TURP and 0,4% after TUIP (4-11). The respective figures for TUVP are in the range of TURP (6). Sexual function: Retrograde ejaculation results from the destruction of the bladder neck and is reported in 80% after open prostatectomy, 65-70% after TURP and 40% after TUIP (4-11). There is a long-standing controversy on the impact of prostatectomy, particularly TURP, on erectile function. The only RCT that compared TURP to a “wait and see” policy reported identical rates of erectile dysfunction in both arms (4). In the 29 RCTs recently reviewed, the incidence of erectile dysfunction following TURP was 6.5% (95% Cl: 0.2-12.7%) (6). The frequently reported rise of erectile dysfunction after TURP is therefore most likely not a direct consequence of TURP but rather caused by confounding factors, such as age. 4.3.6 Long-term outcome Retreatment rate Favourable long-term outcome is common after open prostatectomy, TURP and TUIP. A secondary prostatic operation is reported at a constant rate of approximately 1-2% per year (4-11). Few data are available on the long-term outcome following TUVP. Long-term risk of mortality The possibility of an increased long-term risk of mortality after TURP compared to open surgery has been raised by Roos et al. (18). These findings have not been replicated by others (17,19,22).

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4.3.7 Conclusions Surgery should be considered for those men: • who are moderately/severely bothered by LUTS, yet who do not improve after non-surgical (including medical) treatment. • with bothersome LUTS, who not want medical treatment but who request active intervention. • with a strong indication for surgery. In addition: • Surgical prostatectomy (open, TURP, TUIP, TUVP) results in significant subjective and objective improvements superior to medical or minimally invasive treatment. All four surgical procedures have been evaluated in randomised controlled trials. • TUIP is the surgical therapy of choice for men with prostates < 30 mL and no middle lobes. 4.3.8 1.

References Borboroglu PG, Kane CJ, Ward JF, Roberts JL, Sands JP. Immediate and postoperative complications of transurethral prostatectomy in the 1990s. J Urol 1999;162(4):1307-10. http://www.ncbi.nlm.nih.gov/pubmed/10492185 2. Pickard R, Emberton M, Neal DE. The management of men with acute urinary retention. National Prostatectomy Audit Steering Group. Br J Urol 1998;81(5):712-20. http://www.ncbi.nlm.nih.gov/pubmed/9634047 3. Bruskewitz RC, Reda DJ, Wasson JH, Barrett L, Phelan M. Testing to predict outcome after transurethral resection of the prostate. J Urol 1997;157(4):1304-8. http://www.ncbi.nlm.nih.gov/pubmed/9120927 4. Wasson JH, Reda DJ, Bruskewitz RC, Elinson J, Keller AM, Henderson WG. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. The Veterans Affairs Cooperative Study Group on Transurethral Resection of the Prostate. New Engl J Med 1995;332(2):75-9. http://www.ncbi.nlm.nih.gov/pubmed/7527493 5. Yang Q, Peters TJ, Donovan JL, Wilt TJ, Abrams P. Transurethral incision compared with transurethral resection of the prostate for bladder outlet obstruction: a systematic review and meta-analysis of randomised controlled trials. J Urol 2001;165(5):1526-32. http://www.ncbi.nlm.nih.gov/pubmed/11342911 6. Madersbacher S, Marberger M. Is transurethral resection of the prostate still justified? Br J Urol 1999;83(3):227-37. http://www.ncbi.nlm.nih.gov/pubmed/10233485 7. Tkocz M, Prajsner A. Comparison of long-term results of transurethral incision of the prostate with transurethral resection of the prostate, in patients with benign prostatic hypertrophy. Neurourol Urody 2002;21(2):112-6. http://www.ncbi.nlm.nih.gov/pubmed/11857663 8. Tubaro A, Carter S, Hind A, Vicentini C, Miano L. A prospective study of the safety and efficacy of suprapubic transvesical prostatectomy in patients with benign prostatic hyperplasia. J Urol 2001;166(1):172-6. http://www.ncbi.nlm.nih.gov/pubmed/11435849 9. Mearini E, Marzi M, Mearini L, Zucchi A, Porena M. Open prostatectomy in benign prostatic hyperplasia: 10-year experience in Italy. Eur Urol 1998;34(6):480-5. http://www.ncbi.nlm.nih.gov/pubmed/9831789 10. Serretta V, Morgia G, Fondacaro L, Curto G, Lo bianco A, Pirritano D, Melloni D, Orestano F, Motta M, Pavone-Macaluso M for the members of the Sicilian-Calabrian Society of Urology. Open prostatectomy for benign prostatic enlargement in southern Europe in the late 1990s: a contemporary series of 1800 interventions. Urology 2002;60(4):623-7. http://www.ncbi.nlm.nih.gov/pubmed/12385922 11. Kuntz RM, Lehrich K. Transurethral holmium laser enucleation versus transvesical open enucleation for prostate adenoma greater than 100gm: a randomised prospective trial of 120 patients. J Urol 2002;168(4 Pt 1):1465-9. http://www.ncbi.nlm.nih.gov/pubmed/12352419 12. Hartung R, Leyh H, Liapi C, Fastenmeier K, Barba M. Coagulating intermittent cutting. Improved highfrequency surgery in transurethral prostatectomy. Eur Urol 2001;39(6):676-81. http://www.ncbi.nlm.nih.gov/pubmed/11464057 13. Michel MS, Knoll T, Trojan L, Kohrmann KU, Alken P. Rotoresect for bloodless transurethral resection of the prostate: a 4-year follow-up. BJU Int 2003;91(1):65-8. http://www.ncbi.nlm.nih.gov/pubmed/12614253

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14.

Eaton AC, Francis RN. The provision of transurethral prostatectomy on a day-case basis using bipolar plasma kinetic technology. BJU Int 2002;89(6):534-7. http://www.ncbi.nlm.nih.gov/pubmed/11942959 15. Elmalik EM, Ibrahim AI, Gahli AM, Saad MS, Bahar YM. Risk factors in prostatectomy bleeding: preoperative urinary tract infection is the only reversible factor. Eur Urol 2000;37(2):199-204. http://www.ncbi.nlm.nih.gov/pubmed/10705199 16. Scholz M, Luftenegger W, Harmuth H, Wolf D, Holtl W. Single-dose antibiotic prophylaxis in transurethral resection of the prostate: a prospective randomized trial. Br J Urol 1998;81(6):827-9. http://www.ncbi.nlm.nih.gov/pubmed/9666765 17. Holman CD, Wisniewski ZS, Semmens JB, Rouse IL, Bass AJ. Mortality and prostate cancer risk in 19,598 men after surgery for benign prostatic hyperplasia. BJU Int 1999;84(1):37-42. http://www.ncbi.nlm.nih.gov/pubmed/10444122 18. Roos NP, Wennberg JE, Malenka DJ, Fisher ES, McPherson K, Andersen TF, Cohen MM, Ramsey E. Mortality and reoperation after open and transurethral resection of the prostate for benignprostatic hyperplasia. N Engl J Med 1989;320(17):1120-4. http://www.ncbi.nlm.nih.gov/pubmed/2469015 19. Hahn RG, Farahmand BY, Hallin A, Hammar N, Persson PG. Incidence of acute myocardial infarction and cause-specific mortality after transurethral treatments of prostatic hypertrophy. Urology 2000;55(2):236-40. http://www.ncbi.nlm.nih.gov/pubmed/10688086 20. Hahn RG. Smoking increases the risk of large scale fluid absorption during transurethral prostatic resection. J Urol 2001;166(1):162-5. http://www.ncbi.nlm.nih.gov/pubmed/11435847 21. Gallucci M, Puppo P, Perachino M, Fortunato P, Muto G, Breda G, Mandressi A, Comeri G, Boccafoschi C, Francesca F, Guazzieri S, Pappagallo GL. Transurethral electrovaporization of the prostate vs. transurethral resection. Resection of a multicentric, randomised clinical study on 150 patients. Eur Urol 1998;33(4):359-64. http://www.ncbi.nlm.nih.gov/pubmed/9612677 22. Shalev M, Richter S, Kessler O, Shpitz B, Fredman B, Nissenkorn I. Long-term incidence of acute myocardial infarction after open and transurethral resection of the prostate for benign prostatic hyperplasia. J Urol 1999;161(2):491-3. http://www.ncbi.nlm.nih.gov/pubmed/9915433

4.4

Lasers

The use of lasers to treat BPH has been contemplated since 1986 but was anecdotal until the early 1990s (1,2), when Shanberg et al. (3) reported the use of the Nd:YAG laser to perform prostatectomy in 10 patients with BPH, resulting in marked improvement in their voiding symptoms. With the development of the right-angle fibre and the refinement of both equipment and technique, the results of many studies have been published. However, as far as durability is concerned, long-term follow-up results are only available from initial studies. 4.4.1 Laser types Four types of laser have been used to treat the prostate: Nd:YAG, Holmium:YAG, KTP:YAG and diode. Energy can be delivered through a bare fibre, right-angle fibre or interstitial fibre. The use of contact lasers using a bare fibre has been abandoned. In addition, energy levels can be varied to achieve coagulation or vaporization. The difference between coagulation and vaporization is that coagulation causes little vaporization and depends on temperature changes to achieve permanent tissue damage. There is also secondary tissue slough, which is associated with tissue oedema. Vaporization depends upon temperature changes of over 100oC, which cause the tissue to be dehydrated (4,5). This effect decreases forward scatter into tissue and may cause less tissue oedema. Interstitial treatments depend on inserting the fibre into the prostatic tissue and the use of coagulation techniques (6). 4.4.2 Right-angle fibres From 1991 onward, reports describing a TRUS-guided, side-firing Nd:YAG laser instrument (the TULIPTM device) for BPH therapy appeared in the urological literature (7,8). These, and other, reports documented the fact that prostatic tissue ablation could be achieved using the Nd:YAG laser. In subsequent years, the TULIPTM device was abandoned and other authors experimented with even greater prostatic tissue ablation using a much simpler side-firing Nd:YAG laser delivery system. This consisted of a gold-plated mirror affixed to the distal end of a standard, flexible, silica-glass, laser transmission fibre (UrolaseTM fibre) (9).

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Operative technique Side-firing laser prostatectomy is performed using Nd:YAG laser light at 1064 nm and relatively high power settings (typically between 40 and 80 W), delivered via an optical fibre equipped with a distal reflecting mechanism. This fibre fits through standard cystoscopes and all laser applications are performed transurethrally under the direct visual control of the surgeon. The operation may be performed under general or regional anaesthesia, or under local peri-prostatic block as described by Leach et al. (10). The operating time is approximately 45 minutes or less. Optimal tissue ablation is achieved using long-duration (60-90 seconds) Nd:YAG laser applications to fixed spots along the prostatic urethra. These laser applications are repeated systematically and with considerable overlap until all visible obstructing prostatic tissue has been coagulated (11). Outcome, morbidity, durability and limitations There have been many studies comparing side-fire laser to TURP. If randomized studies are considered, the results are quite similar, showing an equivalent improvement in symptom scores and increases in uroflow rates in both groups, although they are higher in the TURP arms (12-17). An improvement in voiding produced by side-firing Nd:YAG laser prostatectomy has been extensively documented in the urological literature. Kabalin et al. (18) reported that 85% of men undergoing laser prostatectomy could expect at least a 50% improvement in either prostate symptom score or peak urinary flow rate. As far as complex urodynamic evaluation is concerned, several studies have demonstrated the ability of side-firing laser prostatectomy to produce a significant improvement in bladder outflow obstruction. Results of pressure-flow studies have been reported by several authors (8,19-21). These authors reported that 78.6-95% of men undergoing laser treatment were rendered unobstructed at 3- or 6-months of post-operative follow-up. Catheter irrigation is generally not required and blood loss is statistically lower with Nd:YAG laser coagulation than with TURP because of the excellent haemostasis produced. Both the US and UK multicentre trials documented dramatic differences in serious treatment-related complications, favouring laser prostatectomy as a much safer procedure than TURP (12,13). Disadvantages are the delayed time to normal voiding and severe dysuria (8,12,22). In a single-institution, randomized, prospective evaluation, Costello et al. (14) found equivalent voiding outcomes for the two procedures, but again documented differences in morbidity between these operations. During the 3-year post-operative follow-up, serious treatment-related complications occurred in 11.8% of laser prostatectomy patients and 35.1% of TURP patients. No study has reported any occurrence of impotence or sustained incontinence. Retrograde ejaculation has been reported in up to 22% of patients. With regard to durability, the observed retreatment rates following laser prostatectomy - approximately 2% per year of followup - seem comparable to documented reoperation rates after TURP (18). Conversely, an Italian retrospective study of 36 patients submitted to side-fire Nd:YAG laser prostatectomy with a minimum follow-up of 5 years reported striking results (23). All patients had undergone pressure-flow studies at 3 months after laser treatment: 32 previously obstructed patients were unobstructed. After 5 years, 43.8% of these patients underwent TURP because of recurring obstruction. Such a retreatment rate is definitely greater than that observed after TURP and even after TUIP. These data therefore suggest caution in giving indications to laser treatment, particularly in patients who are candidates for TURP or TUIP. In fact, these techniques, TURP and TUIP, offer better long-term results and comparable (if not superior) efficacy than laser prostatectomy. Further long-term follow-up studies are needed. The major limitation of the laser technique compared with conventional TURP is the lack of immediate effect and requirement for urinary catheter drainage for several post-operative days. Some patients may require catheterization for 3-4 weeks or more (24). Even after catheter removal, an improvement in voiding occurs only gradually, and most patients do not notice significant benefits until approximately 3-4 weeks post-operatively. The best results are obtained if the weight of the gland is below 50-60 g; in larger glands significant amounts of obstructive prostatic tissue can be left behind (17). Moreover, men with chronic urinary tract infections and chronic bacterial prostatitis are not good candidates for Nd:YAG laser coagulation of the prostate (18) because of the possibility of infection of the necrotic tissue that remains in situ for several weeks after the operation; emergent TURP has been reported to solve this problem (8). 4.4.3 Interstitial Laser Coagulation (ILC) ILC as a therapy for BPH was first mentioned by Hofstetter in 1991 (25). Since then, several variations and technical and procedural developments have been introduced and tested in clinical trials (26). The objective of ILC of BPH is to achieve marked volume reduction and to decrease urethral obstruction and symptoms. Coagulation necrosis is generated within the adenoma, sparing its urethral surface. As the applicator can be inserted as deeply and as often as necessary, it is possible to coagulate any amount of tissue at any desired location. Post-procedure, the intraprostatic lesions result in secondary atrophy and regression of the prostate lobes rather than sloughing of necrotic tissue (27).

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Operative technique Fibres employed for ILC must emit laser radiation at a relatively low power density. The most commonly used fibres are ITT Light GuideTM, Dornier, and the Diffusor-TipTM, Indigo. Nd:YAG lasers or diode lasers are used for ILC. ILC can be carried out using the transurethral approach, with local, regional or systemic anaesthesia. The laser fibre is introduced from a cystoscope within the urethra. The total number of fibre placements is dictated by the total prostate volume and configuration. As a general guideline, one or two placements are used for each estimated 5-10 cm3 of prostate volume. In general, the sites for fibre placement are chosen according to where the bulk of hyperplastic tissue is found (26). Outcome, morbidity, durability and limitations Studies were performed to compare the results with ILC with those of other laser techniques, primarily TURP. The results of several studies indicated the effectiveness of ILC in treating BPH with regard to symptoms, obstruction and enlargement. All studies reported marked improvements in symptom score, peak flow rate, residual urine volume and prostate volume (26-31). Urodynamic parameters were also measured before and after ILC treatment (32,33). Pressure-flow studies demonstrated a sufficient decrease of the intravesical pressure, urethral opening pressure and urethral resistance. Prospective and randomized studies were also performed to compare the results achieved with ILC with those of other laser techniques (33) and TURP (30,34,35). Muschter et al. reported on a series of 97 patients with severely symptomatic BPH; 48 patients received ILC and 49 underwent TURP (34). Within 12 months, there were no statistical differences between groups for all the considered parameters. However, four ILC patients (8.3%) were considered to be treatment failures and underwent TURP. As for morbidity, there is a temporary increase of obstruction after ILC, which can result in urinary retention and temporary irritative symptoms, such as urgency (25). Post-operative irritative symptoms have been observed in 5-15% of patients (28,31,34). Post-operative catheterization was required for an average of up to 18 days, although the catheter was removed within 10 days in more than 70% of cases. No study has reported any occurrence of impotence or sustained incontinence, though retrograde ejaculation was occasionally reported, with an incidence ranging from 0-11.9%. Urethral strictures or bladder neck strictures are not common, and have been reported in approximately 5% of patients. The retreatment rate is up to 15.4% with a maximum follow-up of 12 months; although as follow-up becomes longer, the retreatment rate is expected to be higher. Currently, the results of only one long-term follow-up study are available (36). In 394 patients followed for up to 3 years, the retreatment rate was 3.1% per year in the first year, rising to 9.6% thereafter (36). ILC can be performed in small prostates and also seems to be suitable to debulk larger prostates or to treat highly obstructed patients (26). This procedure can be seen as a true alternative to TURP in selected patients with some advantages, such as almost no serious morbidity, and certain disadvantages, such as the need for longer post-operative catheterization and the lack of tissue for biopsy. However, further comparative randomized studies with longer follow-up are needed to assess the durability of this procedure. 4.4.4 Holmium laser resection of the prostate (HoLRP) The Holmium laser (2140 nm) is a pulsed, solid-state laser that has been used in urology for a variety of endourological applications in soft tissues and for the disintegration of urinary calculi (37). Prostatectomy using this energy source is a relatively new technique with the first patient reports appearing in 1995 (37, 38). The Ho:YAG wavelength is strongly absorbed by water and the zone of coagulation necrosis in tissue is limited to 3-4 mm, sufficient to obtain adequate haemostasis (38). The peak power achieved results in intense tissue vaporization and in precise and efficient cutting ability in the prostatic tissue. Operative technique Instrumentation for this technique includes a 550-µm end-firing quartz fibre and an 80-W Ho:YAG laser. A continuous flow resectoscope is required with a working element; normal saline is used as the irrigant. The basic principle of the technique consists of retrograde enucleation of the prostate and fragmentation of the enucleated tissue to allow its elimination through the operating channel of the resectoscope (38,39). Outcome, morbidity, durability and limitations As this technique is relatively new, only a few studies with a short follow-up have been published to date. Gilling et al. (40) presented the results of a prospective, randomized trial comparing TURP with HoLRP; so far, 120 patients with urodynamic obstruction have been enrolled with prostates less than 100 g in size (Schafer grade 2). Preliminary analysis has revealed a longer mean resection time (42.1 vs. 25.8 minutes; p < 0.0001) for HoLRP patients, but a shorter mean catheter time (20.0 vs. 37.2 hours; p < 0.0001) and length of hospital stay (26.4 vs. 47.4 hours; p < 0.0001). Symptomatic and urodynamic improvement were equivalent in the two groups.

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Comparative studies of Nd:YAG versus prostatectomy have been conducted, clearly demonstrating that HoLRP is associated with significantly shorter catheter time and a lower incidence of post-operative dysuria (41). Unfortunately, the longest available follow-up is only 12 months, which has confirmed the shortterm durability of the procedure (36). Post-operative dysuria is the most common complication, with an incidence of approximately 10% (38,40,42). No major complication has been described; however, the technique is a surgical procedure that requires significant endoscopic skill and cannot be considered easy to learn. Conversely, there are no specific limitations to the procedure; the size of the prostate that can be treated depends on the experience and patience of the urologist, although the presence of a prostate gland over 100 mL is a relative contraindication in urologists’ early experience (38). Patients on anticoagulant medication and those with urinary retention can be safely treated (43). Retrograde ejaculation occurs in 75-80% of patients; no post-operative impotence has been reported (38). 4.4.5 Conclusions Laser prostatectomy should be advised for patients who are: • receiving anticoagulant medication • unfit for TURP (side-fire or ILC) • wanting to maintain ejaculation (side-fire or ILC) • holmium laser prostatectomy is a viable alternative to TURP and irrespective of any anatomical configuration. 4.4.6 References 1. Kandel LB, Harrison LH, McCullough DL. Transurethral laser prostatectomy: Creation of a technique for using the Neodymium-Yttrium-Aluminium-Garnet (YAG) laser in the canine model. J Urol 1986;133:110A. 2. Johnson DE, Levinson AK, Greskovich FJ. Transurethral laser prostatectomy using a right-angle delivery system. SPIE Proceedings 1991;1421:36. 3. Shanberg AM, Tansey LA, Baghdassarian R. The use of the neodymium YAG laser in prostatotomy. J Urol 1985;133:331A. 4. Stein BS. Laser-tissue interaction. In: Smith JA et al. eds. Lasers in Urologic Surgery. St Louis, USA: Mosby, 1994, p. 10. 5. Johnson DE, Price RE, Cromeens DM. Pathologic changes occurring in the prostate following transurethral laser prostatectomy. Lasers Surg Med 1992;12(3):254-63. http://www.ncbi.nlm.nih.gov/pubmed/1508019 6. Muschter R, Hofstetter A, Hessel S. Interstitial laser prostatectomy - experimental and first clinical results. J Urol 1992;147:346A. 7. Assimos DG, McCullough DL, Woodruff RD, et al. Canine transurethral laser-induced prostatectomy. J Endourol 1991;5:145-9. 8. Puppo P, Perachino M, Ricciotti G, Scannapieco G. Transurethral ultrasound-guided laser-induced prostatectomy: objective and subjective assessment of its efficacy for treating benign prostatic hyperplasia. Eur Urol 1994;25(3):220-5. http://www.ncbi.nlm.nih.gov/pubmed/7515349 9. Costello AJ, Bowsher WG, Bolton DM, Braslis KG, Burt J. Laser ablation of the prostate in patients with benign prostatic hypertrophy. Br J Urol 1992;69(6):603-8. http://www.ncbi.nlm.nih.gov/pubmed/1379101 10. Leach GE, Sirls L, Ganabathi K, Roskamp D, Dmochowski R. Outpatient visual laser-assisted prostatectomy under local anesthesia. Urology 1994;43(2):149-53. http://www.ncbi.nlm.nih.gov/pubmed/7509525 11. Muschter R, Perlmutter AP. The optimisation of laser prostatectomy. Part II. Other lasing techniques. Urology 1994;44(6):856–61. http://www.ncbi.nlm.nih.gov/pubmed/7985315 12. Cowles RS 3rd, Kabalin JN, Childs S, Lepor H, Dixon C, Stein B, Zabbo A. A prospective randomized comparison of transurethral resection to visual laser ablation of the prostate for the treatment of benign prostatic hyperplasia. Urology 1995;46(2):155-60. http://www.ncbi.nlm.nih.gov/pubmed/7542818 13. Anson K, Nawrocki J, Buckley J, Fowler C, Kirby R, Lawrence W, Paterson P, Watson G. A multicenter, randomized, prospective study of endoscopic laser ablation versus transurethral resection of the prostate. Urology 1995;46(3):305-10. http://www.ncbi.nlm.nih.gov/pubmed/7544932

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14. Costello AJ, Crowe HR, Asopa R. Long-term results of randomized laser prostatectomy vs. TURP: modification of laser prostatectomy technique with biodegradable stent insertion. J Urol 1996;155:316A. 15. Oswald M, Schmidlin F, Jichilinski P, et al. Combination of thermocoagulation and vaporisation using a Nd:YAG/KTP laser versus TURP in BPH treatment: preliminary results of a multicenter prospective randomized study. J Urol 1997;157:42A. 16. Kabalin JN. Neodymium: YAG laser coagulation prostatectomy for patients in urinary retention. J Endourol 1997;11(3):207-9. http://www.ncbi.nlm.nih.gov/pubmed/9181452 17. Costello AJ, Kabalin JN. Side-firing neodymium:YAG laser prostatectomy. Eur Urol 1999;35(2):138-46. http://www.ncbi.nlm.nih.gov/pubmed/9933807 18. Kabalin JN, Bite G, Doll S. Neodymium:YAG laser coagulation prostatectomy: 3 years of experience with 227 patients. J Urol 1996;155(1):181-5. http://www.ncbi.nlm.nih.gov/pubmed/7490827 19. Te Slaa E, De Wildt MJ, Rosier PF, Wijkstra H, Debruyne FM, de la Rosette JJ. Urodynamic assessment in the laser treatment of benign prostatic enlargement. Br J Urol 1995;76(5):604-10. http://www.ncbi.nlm.nih.gov/pubmed/8535680 20. Cannon A, De Wildt M, Abrams PH, De la Rosette JJ. Urodynamics and laser prostatectomy. World J Urol 1995;13(2):134-6. http://www.ncbi.nlm.nih.gov/pubmed/7542968 21. Choe JM, Sirls LT. High-energy visual laser ablation of the prostate in men with urinary retention: pressure flow analysis. Urology 1996;48(4):584-8. http://www.ncbi.nlm.nih.gov/pubmed/8886064 22. Stein BS, Altwein JE, Bruschter R et al. Laser prostatectomy. In: Denis L, Griffiths K, Khoury S, et al, eds. Proceedings of the Fourth International Consultation on BPH, Paris, July 1997. Plymouth: Health Publications, 1998, pp. 529-540. http://www.congress-urology.org/ 23. Perachino M, Puppo P. [Prostatectomia laser con metodica side-fire: risultati a distanza di 5 anni.] Acta Urol Ital 1998;12(Suppl 1):44. [article in Italian] 24. Kabalin JN, Bite G. Laser prostatectomy performed with right angle firing neodymium: YAG laser fiber at 40 watt power settings. J Urol 1997;158(5):1923. http://www.ncbi.nlm.nih.gov/pubmed/9334638 25. Hofstetter A. Interstitielle Thermokoagulation (ITK) von Prostatatumoren. Lasermedizin 1991;7:179-80. [article in German][Interstitial laser coagulation treatment for benign prostatic hyperplasia] http://www.freepatentsonline.com/5312392.html 26. Muschter R, Whitfield H. Interstitial laser therapy of benign prostatic hyperplasia. Eur Urol 1999;35(2):147-54. http://www.ncbi.nlm.nih.gov/pubmed/9933808 27. Muschter R, Hofstetter A. Technique and results of interstitial laser coagulation. World J Urol 1995;13(2):109-14. http://www.ncbi.nlm.nih.gov/pubmed/7542962 28. Bhatta KM, Perlmutter A, Cho G, et al. A new technique of subsurface and interstitial laser therapy using a diode laser (wavelength = 1000 nm) and a catheter delivery device. J Urol 1996;155:310A. 29. Schettini M, Diana M, Fortunato P et al. Results of interstitial laser coagulation of the prostate. J. Endourol 1996;10 (Suppl 1):S191. 30. Whitfield HN. A randomized prospective multicenter study evaluating the efficacy of interstitial laser coagulation. J Urol 1996;155:318A. 31. Fay R, Chan SL, Kahn R, et al. Initial results of a randomized trial comparing interstitial laser coagulation therapy to transurethral resection of the prostate. J Urol 1997;157(Suppl 1):41. 32. Henkel TO, Greschner M, Luppold T, Alken P. Transurethral and transperineal interstitial laser therapy of BPH. In: Muller G, et al, eds. Laser-induced Interstitial Thermotherapy. Bellingham: SPIE Press, 1995, pp. 416-423. http://bookstore.spie.org/index.cfm?fuseaction=SearchResultsVolume&keywords=Laser-induced%20 Interstitial%20&searchtype=SearchResultsVolume&quicksearch=1&CFID=353971&CFTOKEN=68929120 33. Horninger W, Janetschek G, Watson G, Reissigl A, Strasser H, Bartsch G. Are contact laser, interstitial laser, and transurethral ultrasound-guided laser-induced prostatectomy superior to transurethral prostatectomy?. Prostate 1997;31(4):255-63. http://www.ncbi.nlm.nih.gov/pubmed/9180936

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Muschter R, Sroka R, Perlmutter AP, et al. High power interstitial laser coagulation of benign prostatic hyperplasia. J Endourol 1996;10(Suppl 1):S197. 35. Whitfield HN. The use of an interstitial diode laser (Indigo) in laser prostatectomy. A randomized, controlled, prospective study. J Endourol 1995;9(Suppl 1):S149. 36. Muschter R, Hofstetter A. [Laser thermocoagulation of adenoma of the prostate using an interstitial approach]. Ann Urol (Paris) 1997;31(1):27-37. [article in French] http://www.ncbi.nlm.nih.gov/pubmed/9157819 37. Le Duc A, Gilling PJ. Holmium laser resection of the prostate. Eur Urol 1999;35(2):155-60. http://www.ncbi.nlm.nih.gov/pubmed/9933809 38. Gilling PJ, Cass CB, Malcolm AR, Fraundorfer MR. Combination Holmium and Nd: YAG laser ablation of the prostate: initial clinical experience. J Endourol 1995;9(2):151-53. http://www.ncbi.nlm.nih.gov/pubmed/7633476 39. Chun SS, Razvi HA, Denstedt JD. Laser prostatectomy with the holmium:YAG laser. Tech Urol 1995;1(4):217-21. http://www.ncbi.nlm.nih.gov/pubmed/9118394 40. Gilling PJ, Fraundorfer MR, Kabalin JB. Holmium: YAG laser resection of the prostate (HoLRP) versus transurethral electrocautery resection of the prostate (TURP): a prospective randomized, urodynamicbased clinical trial. J Urol 1997;157:149A. 41. Gilling PJ, Cass CB, Malcolm A, Cresswell M, Fraundorfer MR, Kabalin JN. Holmium laser resection of the prostate versus neodymium: neodymium:yttrium-aluminum-garnet visual laser ablation of the prostate (VLAP): a randomized prospective comparison of two techniques for laser prostatectomy. Urology 1998; 51(4): 573-7. http://www.ncbi.nlm.nih.gov/pubmed/9586609 42. Le Duc A, Anidjar M, Teillac P, Desgrandchamps F. The Holmium YAG laser in the transurethral resection of prostate. Br J Urol 1997;80(Suppl 2):A773. 43. Kabalin JN, Mackey MJ, Cresswell MD, Fraundorfer MR, Gilling PJ. Holmium: YAG laser resection of the prostate (HoLRP) for patients in urinary retention. J Endourol 1997;11(4):291-3. http://www.ncbi.nlm.nih.gov/pubmed/9376851

4.5

Transrectal high-intensity focused ultrasound (HIFU)

4.5.1 Assessment No specific diagnostic work-up prior to transrectal HIFU therapy is necessary. However, the following parameters should be obtained: • I-PSS, including quality of life • Free uroflowmetry, including post-void residual urine volume • Serum PSA • TRUS • Pressure-flow study advisable. 4.5.2 Procedure A beam of ultrasound can be brought to a tight focus at a selected depth within the body, thus producing a region of high energy density within which tissue can be destroyed without damage to the overlying or intervening structures (1-3). If the site-intensity is set below the tissue cavitation threshold, the predominant therapeutic effect is the induction of heat. This technique is known as high-intensity focused ultrasound (HIFU). The source for HIFU is a piezoceramic transducer, which has the property of changing its thickness in response to an applied voltage (1-3). Theoretically the prostate can be ablated by HIFU via a transabdominal or transrectal route. In clinical use, however, only transrectal HIFU devices are applied for the indication of BPH. Clinical data are only available for one device, the Sonablate® (1-4). This system uses the same 4.0 MHz transrectal transducer for imaging and therapy. The focal length (2.5-4.0 cm) is dependent upon the crystal used. The site intensity can be varied from 1.260 to 2.200 W/cm2. Within the HIFU beam focus, an ellipsoidal tissue volume approximately 2 mm in diameter and 10 mm in length is destroyed (1-3). In order to create a clinically useful volume of necrosis, a multiplicity of laterally or axially displaced individual lesions is generated by physical movement of the sound-head. The histological effect of transrectal HIFU therapy using the Sonablate® on the canine and human prostate has been studied in detail (1-3,5,6). 4.5.3 Morbidity/complications In general, transrectal HIFU is well-tolerated but requires general anaesthesia or heavy intravenous sedation. The most prominent side-effect is prolonged urinary retention, lasting for 3-6 days. Haematospermia for 4-6 weeks is observed in up to 80% of sexually active men, and patients frequently discharge two to three drops of blood prior to micturition for several weeks. Urinary tract infection occurs in around 7% of patients. No cases

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of urethral strictures, incontinence or the need for blood transfusion have been reported in the literature. Two severe complications have been reported. In one patient, perforation of the descending colon approximately 50-60 cm above the treatment zone occurred. It was caused by inadvertent overfilling to 500 mL and subsequent rupture of the condom that covered the ultrasound probe. This complication led to reconstruction of the filling apparatus and the probe such that the problem can now be reliably avoided. The second severe complication was a thermolesion of the rectum requiring surgical intervention. This was most likely caused by using an inappropriately high-site intensity exceeding 2.300 W/cm2. As a consequence, the maximum site intensity was set at 2.000 W/cm2. 4.5.4 Outcome In June 1992, an international Phase II clinical trial was initiated to evaluate the safety and efficacy of transrectal HIFU therapy for patients with LUTS due to BPH. To date, several hundred patients have been treated with the Sonablate® at various sites. In the initial US series, Bihrle et al. (7) reported on experience with 15 patients and a follow-up of 90 days. The Qmax increased from 9.3 mL/s to 14.0 mL/s and the post-void residual urine volume decreased from 154 mL to 123 mL (7). Ebert et al. (8) treated 35 patients, eight of whom had urinary retention. The Qmax increased from 7.6 mL/s to 15.2 mL/s after 3 months. Within the same time period, the post-void residual urine volume decreased from 182 mL to 50 mL and the I-PSS from 17.9 to 7.1. The initial report of the study included 50 patients, 20 of whom were followed up for 12 months (5). The Qmax increased from 8.9 (± 4.1) to 12.4 (± 5.6) mL/s (6 months, n = 33) and 13.1 (± 6.5) mL/s (12 months, n = 20). In the same time period, the post-void residual urine volume decreased from 131 (± 120) mL to 48 (± 41) mL at 6 months and to 35 (± 30) mL at 12 months. The AUA symptom score reduced from 24.5 (± 4.7) to 13.4 (± 4.7) at 6 months and to 10.8 (± 2.5) at 12 months (5). Several other sites have confirmed these data (9-11). 4.5.5 Urodynamics The urodynamic effect of transrectal HIFU therapy has been studied by Madersbacher et al. (12). Thirty patients underwent urodynamic investigations (pressure-flow study) before and after a mean of 4.5 months following HIFU therapy. Pre-operatively, 80% of patients were obstructed and a further 20% were in the intermediate zone according to the Abrams-Griffith nomogram. After therapy, a statistically significant decrease in maximum detrusor pressure, detrusor pressure at Qmax and linear passive urethral resistance relation was observed. After HIFU, half of the patients were in the equivocal zone and 13% were clearly unobstructed, yet 37% were still obstructed according to the Abrams-Griffith nomogram. The authors concluded that the capability of transrectal HIFU to reduce bladder outlet obstruction was moderate (12). As a consequence, transrectal HIFU should not be considered for severely obstructed patients or those with an absolute indication for surgery. 4.5.6 Quality of life and sexual function There are no reliable data on quality of life after transrectal HIFU except from a study by Schatzl et al. (13), who studied in detail the early post-operative morbidity of several less invasive procedures. Similarly, there is little data on sexual function. Haematospermia lasting for a maximum of 4-6 weeks is seen in the majority of sexually active patients. Retrograde ejaculation and erectile dysfunction can be safely avoided, although some patients report a decreased ejaculate volume. 4.5.7 Durability The long-term outcome of 80 patients with a follow-up of up to 4 years and a minimum follow-up of 2 years has been studied (14). The mean follow-up of the study population (excluding patients who crossed over to TURP due to insufficient therapeutic response) was 41.3 months (range: 13-48 months). Thirty-five men (43.8%) underwent TURP due to an insufficient therapeutic response during the 4-year study period. The retreatment-free period was significantly longer for patients with a pre-treatment average flow rate of more than 5 mL/s (p = 0.05) and lower grades of urodynamically documented bladder outlet obstruction (p = 0.03) (14). A similar trend, which did not reach statistical significance, was noted for individuals with a higher Qmax and lower post-void residual urine volume. 4.5.8 Patient selection The fact that only a handful of clinical studies with a limited number of patients have been published, hinders a reliable statement concerning patient selection, yet a few selection criteria have been identified. Patients with one or more of the following criteria are unsuitable for transrectal HIFU therapy: • Prostates with dense calcifications (possibility of tissue cavitation) • Large prostates (> 75 mL) • Rectum to bladder neck distance over 40 mm • Large middle lobes • Higher grades of bladder outlet obstruction (BOO) - (higher treatment failure rate)

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•

Absolute indication for surgery.

4.5.9 Conclusions Transrectal HIFU therapy is the only technique that provides non-invasive tissue ablation; however, general anaesthesia or at least heavy intravenous sedation is required. Improvement of urinary symptoms is in the range 50-60% and Qmax increases by a mean of 40-50%. Long-term efficacy is limited, with a treatment failure rate of approximately 10% per year. No data are yet available from randomized, controlled trials. 4.5.10 References 1. Madersbacher S, Marberger M. Urological applications of high-intensity focused ultrasound. Curr Opinion Urol 1995;5:147-9. http://www.co-urology.com/pt/re/courology/toc.00042307-199505000-00000.htm;jsessionid=J8nV74 ghYvQhNTcxnsT218WhR3x7QhpQX91Xw7T13Bq0p1kvcMKL!-1854079795!181195628!8091!-1 2. Madersbacher S, Marberger M. Therapeutic applications of ultrasound in urology. In: Marberger M ed. Application of Newer Forms of Therapeutic Energy in Urology. Oxford: Isis Medical Media, 1995, pp. 115-136. http://www.isismedical.com/ 3. Madersbacher S, Marberger M. High-intensity focused ultrasound for prostatic tissue ablation. Curr Opinion Urol 1996;6:28-32. http://www.co-urology.com/pt/re/courology/toc.00042307-199601000-00000.htm;jsessionid=J8sNzh QhhhCvtwGFJPv9Pnz7LymxQJFQ73J3q51p31kTzLhQxBLh!97158217!181195629!8091!-1 4. Madersbacher S, Djavan B, Marberger M. Minimally invasive therapy in BPH. Curr Opinion Urol 1998;8:17-26. http://www.ncbi.nlm.nih.gov/pubmed/17035837 5. Madersbacher S, Kratzik C, Susani M, Marberger M. Tissue ablation in benign prostatic hyperplasia with high intensity focused ultrasound. J Urol 1994;152(6 Pt 1):1956-60. http://www.ncbi.nlm.nih.gov/pubmed/7525992 6. Madersbacher S, Pedevilla M, Vingers L, Susani M, Marberger M. Effect of high-intensity focused ultrasound on human prostate cancer in vivo. Cancer Res 1995;55(15):3346-51. http://www.ncbi.nlm.nih.gov/pubmed/7542168 7. Bihrle R, Foster RS, Sanghvi NT, Donohue JP, Hood JP. High intensity focused ultrasound for the treatment of benign prostatic hyperplasia: early United States clinical experience. J Urol 1994;151(5):1271-5. http://www.ncbi.nlm.nih.gov/pubmed/7512658 8. Ebert T, Graefen M, Miller S, Saddeler D, Schmitz-Dräger B, Ackermann R. High-intensity focused ultrasound (HIFU) in the treatment of benign prostatic hyperplasia (BPH). Keio J Med 1995;44(4): 146-9. http://www.ncbi.nlm.nih.gov/pubmed/8587227 9. Mulligan ED, Lynch TH, Mulvin D, Greene D, Smith JM, Fitzpatrick JM. High-intensity focused ultrasound in the treatment of benign prostatic hyperplasia. Br J Urol 1997;79(2):177-80. http://www.ncbi.nlm.nih.gov/pubmed/9052466 10. Nakamura K, Baba S, Saito S, Tachibana M, Murai M. High-intensity focused ultrasound energy for benign prostatic hyperplasia: clinical response at 6 months to treatment using Sonablate 200. J Endourol 1997;11(3):197-201. http://www.ncbi.nlm.nih.gov/pubmed/9181450 11. Sullivan LD, McLoughlin MG, Goldenberg LG, Gleave ME, Marich KW. Early experience with high-intensity focused ultrasound for the treatment of benign prostatic hypertrophy. Br J Urol 1997;79(2):172-6. http://www.ncbi.nlm.nih.gov/pubmed/9052465 12. Madersbacher S, Klingler CH, Schatzl G, Schmidbauer CP, Marberger M. The urodynamic impact of transrectal high intensity focused ultrasound on bladder outflow obstruction. Eur Urol 1996;30(4): 437-45. http://www.ncbi.nlm.nih.gov/pubmed/8977064 13. Schatzl G, Madersbacher S, Lang T, Marberger M. The early postoperative morbidity of transurethral resection of the prostate and of 4 minimally invasive treatment alternatives. J Urol 1997;158(1):105-11. http://www.ncbi.nlm.nih.gov/pubmed/9186334

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14.

Madersbacher S, Schatzl G, Djavan B, Stulnig T, Marberger M. Long-term outcome of transrectal high-intensity focused ultrasound therapy for benign prostatic hyperplasia. Eur Urol 2000;37(6): 687-94. http://www.ncbi.nlm.nih.gov/pubmed/10828669

4.6

Transurethral needle ablation (TUNA®)

4.6.1 Assessment No specific diagnostic work-up prior to TUNA® is necessary. 4.6.2 Procedure The TUNA® device delivers low-level, radio-frequency energy to the prostate via needles inserted transurethrally (1). 4.6.3 Morbidity/complications Is usually performed as an out-patient procedure under local anaesthesia, although intravenous sedation is required in some patients (1). Post-operative urinary retention is seen in 13.3-41.6% of patients and lasts for a mean of 1-3 days; within 1 week, 90-95% of patients are catheter-free (1). Irritative voiding symptoms lasting up to 4-6 weeks are frequently present (2). Continence status is not affected. 4.6.4 Outcome Several non-randomized clinical trials have documented the clinical efficacy of this procedure with a fairly consistent outcome (3-7). The symptomatic improvement reported ranged from 40-70%. These data are statistically significantly better than at baseline and surpass the expected placebo effect. Improvements in Qmax vary widely from 26-121% in non-retention patients. A recent report with 5 years follow up in 188 patients demonstrated a symptomatic improvement of 58% and an improvement in flow rate of 41%, 21.2% required additional treatment (8). There is no convincing evidence that prostate size is significantly reduced following TUNA® (7-9). 4.6.5 Randomized clinical trials TUNA® has been compared with TURP in one trial (8) with 12-month follow-up data. In both treatment arms, there was a significant decrease in AUA symptom score and bother score, although improvements were slightly higher in the TURP arm. Improvement in Qmax was significantly higher after TURP than after TUNA®. Adverse events, such as bleeding, dysuria, erectile dysfunction, urinary tract infection or strictures, were more frequent in the TURP arm. 4.6.6 Impact on bladder outflow obstruction The impact of TUNA® on bladder outflow obstruction as assessed by pressure-flow studies was determined in seven clinical studies (7-13). In all studies, a statistically significant decrease in maximum detrusor pressure or detrusor pressure at Qmax was demonstrable, yet a number of patients remained in the obstructed range after TUNA® therapy. 4.6.7 Durability Several authors have reported on the long-term efficacy of the TUNA® procedure. Within 1 year, positive results can be translated into percentages ranging from 5-42% (1). Schulman et al. (14) recently presented 3-year follow-up data on 49 patients after TUNA®. Improvement in Qmax exceeding 50% was seen in 53% of patients after 36 months. Ten patients (20%) underwent TURP because of an insufficient therapeutic response (1). Long-term follow-up data exceeding this time period are not yet available. 4.6.8 Patient selection Few selection criteria have been identified. TUNA® is not suitable for patients with prostate volumes exceeding 75 mL or isolated bladder neck obstruction. 4.6.9 Conclusions TUNA® is a simple and safe technique and can be performed under local anaesthesia in a significant number of patients. It results in an improvement of urinary symptoms in the range 50-60% and Qmax increases by a mean of 50-70%. Clinical efficacy has been proven in only one randomized controlled trial, and there is limited evidence of long-term efficacy.

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4.6.10 References 1. Chapple CR, Issa MM, Woo H. Transurethral needle ablation (TUNA). A critical review of radiofrequency thermal therapy in the management of benign prostatic hyperplasia. Eur Urol 1999;35(2):119-28. http://www.ncbi.nlm.nih.gov/pubmed/9933805 2. Schatzl G, Madersbacher S, Lang T, Marberger M. The early postoperative morbidity of transurethral resection of the prostate and of four minimally invasive treatment alternatives. J Urol 1997;158(1):10510. http://www.ncbi.nlm.nih.gov/pubmed/9186334 3. Ramon J, Lynch TH, Eardley I, Ekman P, Frick J, Jungwirth A, Pillai M, Wiklund P, Goldwasser B, Fitzpatrick JM. Transurethral needle ablation of the prostate for the treatment of benign prostatic hyperplasia: a collaborative multicentre study. Br J Urol 1997;80(1):128-34. http://www.ncbi.nlm.nih.gov/pubmed/9240192 4. Roehrborn CG, Issa MM, Bruskewitz RC, Naslund MJ, Oesterling JE, Perez-Marrero R, Shumaker BP, Narayan P. Transurethral needle ablation for benign prostatic hyperplasia: 12-month results of a prospective, multicenter US study. Urology 1998;51(1):415-21. http://www.ncbi.nlm.nih.gov/pubmed/9510346 5. Schulman CC, Zlotta AR. Transurethral needle ablation (TUNA) of the prostate: clinical experience with two years’ follow-up in patients with benign prostatic hyperplasia (BPH). J Urol 1997;157:98-102. 6. Minardi D, Garafolo F, Yehia M, Cristalli AF, Giammarco L, Galosi AB, Muzzonigro G. Pressure-flow studies in men with benign prostatic hypertrophy before and after treatment with transurethral needle ablation. Urol Int 2001;66(2):89-93. http://www.ncbi.nlm.nih.gov/pubmed/11223750 7. Bruskewitz R, Issa MM, Roehrborn CG, Naslund MJ, Perez-Marrero R, Shumaker BP, Oesterling JE. A prospective randomized 1-year clinical trial comparing transurethral needle ablation to transurethral resection of the prostate for the treatment of symptomatic benign prostatic hyperplasia. J Urol 1998;159(5):1588-93. http://www.ncbi.nlm.nih.gov/pubmed/9554360 8 Zlotta AR, Giannakopoulos X, Maehlum O, Ostrem T, Schulman CC. Long-term evaluation of transurethral needle ablation of the prostate (TUNA) for treatment of symptomatic benign prostatic hyperplasia: clinical outcome up to five years from three centers. Eur Urol. 2003;44(1):89-93. http://www.ncbi.nlm.nih.gov/pubmed/12814680 9. Rosario DJ, Woo H, Potts KL, Cutinha PE, Hastie KJ, Chapple CR. Safety and efficacy of transurethral needle ablation of the prostate for symptomatic outlet obstruction. Br J Urol 1997;80(4):579-86. http://www.ncbi.nlm.nih.gov/pubmed/9352697 10. Issa MM. Transurethral needle ablation of the prostate: report of initial United States experience. J Urol 1996;156(2 Pt 1):413-9. http://www.ncbi.nlm.nih.gov/pubmed/8683692 11. Millard RJ, Harewood LM, Tamaddon K. A study of the efficacy and safety of transurethral needle ablation (TUNA) treatment for benign prostatic hyperplasia. Neurourol Urodyn 1996;15(6):619-28. http://www.ncbi.nlm.nih.gov/pubmed/8916114 12. Campo B, Bergamaschi F, Corrada P, Ordesi G. Transurethral needle ablation (TUNA) of the prostate: a clinical and urodynamic evaluation. Urology 1997;49(6):847-50. http://www.ncbi.nlm.nih.gov/pubmed/9187689 13. Steele GS, Sleep DJ. Transurethral needle ablation of the prostate: a urodynamic based study with 2-year follow-up. J Urol 1997;158(5):1834-8. http://www.ncbi.nlm.nih.gov/pubmed/9334612 14. Schulman CC, Zlotta AR. Transurethral needle ablation (TUNA™) of the prostate: clinical experience with three years follow-up in patients with benign prostatic hyperplasia (BPH). Eur Urol 1998;33(Suppl 1):148.

4.7

Transurethral microwave therapy (TUMT)

4.7.1 Assessment Diagnostic endoscopy is essential because it is important to identify the presence of an isolated enlarged middle lobe or an insufficient length of the prostatic urethra. 4.7.2 Procedure TUMT is a registered trademark of Technomed Medical Systems (France), a company considered to be the pioneer of microwave thermotherapy. To date, tens of thousands of patients worldwide have been treated with the Prostatron® device. Other thermotherapy devices have also been developed: Prostcare®

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(Brucker, France); ProstaLund® (Lund Systems, Sweden); and Targis® (Urologix, USA). On a conceptional basis, they are all similar in delivering microwave energy to the prostate with some type of feedback system. The majority of data in the literature on thermotherapy has been based on the Prostatron® device. Initial experience focused on low-energy protocols, but subsequently higher energy levels were used to improve treatment outcomes and response rates. 4.7.3 The microwave thermotherapy principle Microwave thermotherapy devices consist of a treatment module that contains the microwave generator with a temperature measurement system and a cooling system. A treatment catheter is connected to the module and inserted into the prostatic urethra. The main difference between the devices available is the design of the urethral applicator. Apart from differences in the construction of the catheter, the characteristics of the applicators differ, significantly affecting the heating profile (1,2). The similarity in catheter construction consists of the presence of a microwave antenna positioned in the tip of the catheter just below the balloon. Fluid channels surrounding the catheter provide urethral cooling. Also incorporated in the catheter are one or more temperature sensors that differ in the way in which they measure temperature. 4.7.4 Morbidity Morbidity following TUMT is an important issue. Low-energy TUMT is well-tolerated by patients. Most patients experience perineal discomfort and urinary urgency for several days after treatment, but not usually for longer. Occasionally, haematuria is noticed. No tissue sloughing occurs and urinary retention is expected in up to 25% of patients (2-6). In these cases, a catheter may be necessary for an average of 7 days. High-energy treatment is also well-tolerated, although pain medication needs to be administered to most patients prior to or during therapy. In contrast to the low-energy protocol, urinary retention is usual in patients treated with high-energy TUMT; the average catheterization time is 2 weeks. Only two papers mention erectile dysfunction following thermotherapy (incidence 0.8-5%) (7,8). For patients treated with low-energy protocols, the retrograde ejaculation rate ranges from 0-11%, while for high-energy protocols, this figure increases up to 44%. Outcome: objective, subjective and urodynamics Low-energy protocols: The standard operating software for the Prostatron® is version 2.0, and remarkably similar clinical results have been reported worldwide from several centres (2-4,7,9-13). The clinical efficacy of TUMT has been confirmed in several randomized, SHAM-(placebo) controlled studies (4,5,14,15). Symptomatic improvement is significant, with a decrease in Madsen symptom score from around 13 to 4. Changes in objective parameters are less pronounced. The mean increase in Qmax is 3-4 mL/s, representing a mean improvement of approximately 35% over baseline. These improvements are noted from 6 weeks and persist over a period of 5 years (16,17). A randomized study comparing TUMT with TURP was performed by Dahlstrand et al. (3). This study showed significant improvement after both TUMT and TURP in symptom score, Qmax, post-void residual urine volume and grade of bladder outlet obstruction. Although the decrease in symptom score was more pronounced after TURP (92%) than after TUMT (78%). High-energy protocol: The first reports on the application of high-energy levels using Prostasoft® 2.5 were published by de la Rosette et al. (18) and Devonec et al. (19) and demonstrated clinically significant improvements. More recently, the European BPH Study Group performed a multicentre study of 116 patients using high-energy TUMT (20). In this study, the mean Madsen score improved from 13.6 at baseline to 5.5 at 26 weeks. Qmax improved from 9.6 mL/s at baseline to 14.1 mL/s at 26 weeks of follow-up. These objective and subjective improvements were sustained at 52 weeks. At 3-months of follow-up TRUS identified a prostatic cavity in almost 40% of patients. There appeared to be a good correlation between the presence of a cavity and uroflowmetry improvement (21). The best candidates for this treatment protocol appeared to be patients with moderate-to-severe bladder outlet obstruction, as measured by pressure-flow studies, and those with larger prostates (22). One-year follow-up results of a prospective randomized study comparing high-energy TUMT with TURP were reported recently (23). After TURP and thermotherapy, there was a significant improvement in all clinical para­ meters. At 1 year of follow-up, the symptomatic improvement was 78% in the TURP group versus 68% in the TUMT group, with improvements in free flow being 100% and 69%, respectively. Both groups had showed significant relief of bladder outlet symptoms. No serious complications occurred in either group, but one patient in each group required another treatment. It was concluded that satisfactory results were obtained after both treatments, with improvements observed following high-energy TUMT being in the same range as those seen after TURP.

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4.7.5 High-intensity-dose protocol Although the results following high-energy TUMT are good, changes to the Prostasoft® software have recently been reported. It was concluded from clinical experience that a shorter duration of treatment did not alter efficacy or decrease morbidity (22). On a conceptual basis, the so-called Prostasoft® 3.5 protocol differed significantly from former protocols. Firstly, the principle of stepwise energy increments was abandoned and the treatment was initiated at an 80 W energy level. Secondly, the urethral temperature feedback system was also abandoned. Energy delivery is now guided by the rectal temperature sensor via a feedback loop. Third, the cooling temperature starts at a lower value (8oC) and is also linked to rectal temperature. Finally, the total treatment duration is shortened to only 30 minutes. This Prostasoft® 3.5 protocol can therefore be considered to be high-intensity-dose TUMT. Pace et al. (24) found in 56 patients, at six months, a decrease in I-PSS from 18.1 to 5.1, an increase in maximum flow from 9.1 mL/s to 17.8 mL/s and cavities within the prostatic tissue of 54 of the 56 patients (95%). De La Rosette et al. (26) found in 167 patients, at 12 months, a decrease in I-PSS from 19.2 to 7.9 and an increase in maximum flow rate from 8.9 to 16.4. 4.7.6 Prostatic temperature feedback treatment A treatment protocol with calculated tissue necrosis based on simultaneous intraprostatic tissue temperature has been introduced with the Prostalund Micowave apparatus (PLFT, ProstaLund Feedback Treatment) (27). In a prospective, randomized, international, multicentre study against TURP, there was no statistically significant differences between the 2 treatments in decrease in symptom score (66% vs 65%), quality of life (I-PSS) (69% vs. 64%), increase in flow rate (74% vs. 94%) or decrease in detrusor pressure at max. flow rate (34% vs. 47%). Only decrease in prostate volume was higher in the TURP group (51%) than in the PLFT group (30%) (28). 4.7.7 Durability Several studies using low-energy thermotherapy report on surgical retreatment rates for up to 1 year of 11% (25) and 10% (20). On the other hand, Van Cauwelaert et al. (11) reported only low retreatment rates with significant subjective and objective improvements. Recently Tsai et al. (29) reported a 5-year retreatment rate in 45 patients of 84.4% with medication (46.7%) or endoscopic surgery ( 37.7%), while Daehlin et al. (30) found a retreatment rate after 5 years in 71 patients of 68%. When applying higher energy levels, the outcome seems improved and may eventually result in a more durable response. In a study by de la Rosette et al. (5,18) additional TURP was performed in only three out of 116 patients. De Wildt et al. (31) confirmed these findings, documenting five surgical interventions at 1-year follow-up in 85 patients treated. 4.7.8 Patient selection As the morbidity is relatively low and the treatment can be performed without anaesthesia, patients in poor health are particularly good candidates for thermotherapy. In particular, such patients with retention can benefit from this treatment. Good results with regard to catheter release have been obtained, with a success rate of 72% after 6 months in 29 patients (32). In a larger study of 200 patients, with a follow up of 2 years in 155 patients, only 7% failed to respond (33). 4.7.9 Conclusions • High-energy TUMT produces significant subjective and objective improvement, with sustained and durable long-term results. • Morbidity after TUMT consists mainly of the need for catheter drainage after treatment due to urinary retention. • High-energy TUMT is associated with improved objective results compared with low-energy TUMT, but with increased morbidity. 4.7.10 References 1. Bolmsjö M, Wagrell L, Hallin A, Eliasson T, Erlandsson BE, Mattiasson A. The heat is on – but how? A comparison of TUMT devices. Br J Urol 1996;78(4):564-72. http://www.ncbi.nlm.nih.gov/pubmed/8944513 2. Blute ML, Tomera KM, Hellerstein DK, McKiel CF Jr, Lynch JH, Regan JB, Sankey NE. Transurethral microwave thermotherapy for management of benign prostatic hyperplasia: results of the United States Prostatron Cooperative Study. J Urol 1993;150(5 Pt 2):1591-6. http://www.ncbi.nlm.nih.gov/pubmed/7692092

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3. Dahlstrand C, Waldén M, Deirsson G, Pettersson S. Transurethral microwave thermotherapy versus transurethral resection for symptomatic benign prostatic obstruction: a prospective randomized study with a 2-year follow-up. Br J Urol 1995;76(5):614-8. http://www.ncbi.nlm.nih.gov/pubmed/8535682 4. Ogden CW, Reddy P, Johnson H, Ramsay JW, Carter SS. Sham versus transurethral microwave thermotherapy in patients with symptoms of benign prostatic bladder outflow obstruction. Lancet 1993;341(8836):14-7. http://www.ncbi.nlm.nih.gov/pubmed/7678047 5. De la Rosette JJ, de Wildt MJ, Alivizatos G, Froeling FM, Debruyne FM. Transurethral microwave thermotherapy (TUMT) in benign prostatic hyperplasia: placebo versus TUMT. Urology 1994;44(1): 58-63. http://www.ncbi.nlm.nih.gov/pubmed/7518982 6. Servadio C. Ten years of clinical experience in transurethral hyperthermia to the prostate. In: Non surgical treatment of BPH. Fitzpatrick JM ed. SIU report 3. Edinburgh: Churchill-Livingstone, 1992, pp. 175-186. 7. Rodrigues Netto N, Claro Jde A, Cortado PL. Ejaculatory dysfunction after transurethral microwave thermotherapy for treatment of benign prostatic hyperplasia. J Endourol 1994;8(3):217–9. http://www.ncbi.nlm.nih.gov/pubmed/7524916 8. Francisca EA, d’Ancona FC, Hendriks JC, Kiemeney LA, Debruyne FM, de la Rosette JJ. Quality of life assessment in patients treated with lower energy thermotherapy (Prostasoft 2.0): results of a randomized transurethral microwave thermotherapy versus sham study. J Urol 1997;158(5):1839-44. http://www.ncbi.nlm.nih.gov/pubmed/9334613 9. Marteinsson VT, Due J. Transurethral microwave thermotherapy for uncomplicated benign prostatic hyperplasia. Scand J Urol Nephrol 1994;28(1):83-9. http://www.ncbi.nlm.nih.gov/pubmed/7516577 10. Kirby RS, Williams G, Witherow R, Milroy EJ, Philip T. The Prostatron transurethral microwave device in the treatment of bladder outflow obstruction due to benign prostatic hyperplasia. Br J Urol 1993;72(2):190-4. http://www.ncbi.nlm.nih.gov/pubmed/7691371 11. Van Cauwelaert RR, Castillo OC, Aquirre CA, Azocar GH, Medina FI. Transurethral microwave thermotherapy for the treatment of benign prostatic hyperplasia: preliminary experience. Eur Urol 1993;23(2):282-4. http://www.ncbi.nlm.nih.gov/pubmed/7683987 12. Terai A, Arai Y, Onishi H, Oishi K, Takeuchi H, Yoshida O. Transurethral microwave thermotherapy for benign prostatic hyperplasia: clinical results after a 1-year follow-up. Int J Urol 1995;2(1):24-8. http://www.ncbi.nlm.nih.gov/pubmed/7542159 13. Devonec M, Tomera K, Perrin P. Review: transurethral microwave thermotherapy in benign prostatic hyperplasia. J Endourol 1993;7(3):255-9. http://www.ncbi.nlm.nih.gov/pubmed/7689386 14. Devonec M, Houdelette P, Colombeau P, et al. A multicenter study of SHAM versus thermotherapy in benign prostatic hypertrophy. J Urol 1994;151:415A (abstr). 15. Blute ML, Patterson DE, Segura JW, Tomera KM, Hellerstein DK. Transurethral microwave thermotherapy vs. SHAM: double-blind randomized study. J Endourol. 1996;10(6):565-73. http://www.ncbi.nlm.nih.gov/pubmed/8972794 16. De Wildt MJ, d’Ancona FC, Hubregtse M, Carter SS, Debruyne FM, de la Rosette JJ. Three year follow-up of patients treated with lower energy thermotherapy. J Urol 1996;156(6):1959-63. http://www.ncbi.nlm.nih.gov/pubmed/8911365 17. Keijzers GB, Francisca EA, d’Ancona FC, Kiemeney LA, Debruyne FM, de la Rosette JJ. Long-term results of lower energy transurethral microwave thermotherapy. J Urol 1998;159(6):1966-72. http://www.ncbi.nlm.nih.gov/pubmed/9598499 18. De la Rosette JJ, de Wildt MJ, Hofner K, Carter SS, Debruyne FM, Tubaro A. High energy thermotherapy in the treatment of benign prostatic hyperplasia: results of the European Benign Prostatic Hyperplasia Study Group. J Urol 1996;156(1):97-101. http://www.ncbi.nlm.nih.gov/pubmed/8648849 19. Devonec M, Carter SS, Tubaro A et al. Microwave thermotherapy. Curr Opinion Urol 1995;5:3-9. 20. De Wildt MJ, Tubaro A, Höfner K, Carter SS. Debruyne FM, de la Rosette JJ. Responders and nonresponders to transurethral microwave thermotherapy: a multicenter retrospective analysis. J Urol 1995;154(5):1775-8. http://www.ncbi.nlm.nih.gov/pubmed/7563344

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21. De la Rosette JJ, de Wildt MJ, Höfner K, Carter SS, Debruyne FM, Tubaro A. Pressure/flow study analyses in patients treated with high-energy thermotherapy (Prostasoft 2.5). J Urol 1996;156(4): 1428-33. http://www.ncbi.nlm.nih.gov/pubmed/8808890 22. De la Rosette JJ, d’Ancona FC, Francisca EA et al. Clinical results of strategies to reduce morbidity in high energy transurethral microwave thermotherapy (HE-TUMT). (Congress report). AFU, 1997. 23. D’Ancona FC, Francisca EA, Witjes WP, Welling L, Debruyne FM, de la Rosette JJ. High energy thermotherapy versus transurethral resection in the treatment of benign prostatic hyperplasia (BPH): results of a prospective randomized study with 1 year follow up. J Urol 1997;158(1):120-5. http://www.ncbi.nlm.nih.gov/pubmed/9186336 24. Pace G, Selvaggio O, Palumbo F, Selvaggi FP. Initial experience with a new transurethral microwave thermotherapy treatment protocol ‘30-minute TUMT’. Eur Urol 2001;39(4):405-11. http://www.ncbi.nlm.nih.gov/pubmed/11306878 25. Carter SStC, Ogden CW, Patel A. Long term results of transurethral microwave thermotherapy for benign prostatic obstruction. In: Urology 1992. Guliani L, et al, eds. Bologna, 1992, pp. 257-261. 26. De la Rossette JJ, Laguna MP, Pace G, Kortmann BB, Selvaggio O, Debruyne FM, Selvaggi FP. Efficacy and safety of the new high-energy 30-minute transurethral microwave thermotherapy: results of 1-year follow-up in a multicenter study. Tech Urol 2000;6(4):271-5. http://www.ncbi.nlm.nih.gov/pubmed/11108564 27. Wagrell L, Schelin S, Bolmsjö M, Brudin L. Intraprostatic temperature monitoring during transurethral microwave thermotherapy for the treatment of benign prostatic hyperplasia. J Urol 1998;159(5): 1583-7. http://www.ncbi.nlm.nih.gov/pubmed/9554359 28. Wagrell L, Schelin S, Nordling J, Richthoff J, Magnusson B, Schain M, Larson T, Boyle E, Duelund J, Kroyer K, Ageheim H, Mattiasson A. Feedback microwave thermotherapy versus TURP for clinical BPH - a randomized controlled multicenter study. Urology. 2002;60(2):292-9. http://www.ncbi.nlm.nih.gov/pubmed/12137829 29. Tsai YS, Lin JS, Tong YC, Tzai TS, Yang WH, Chang CC, Cheng HL, Lin YM, Jou YC. Transurethral microwave thermotherapy for symptomatic benign prostatic hyperplasia: long-term durability with Prostcare. Eur Urol 2001;39(6):688-92. http://www.ncbi.nlm.nih.gov/pubmed/11464059 30. Daehlin L, Frugård J. Transurethral microwave thermotherapy in the management of lower urinary tract symptoms from benign prostatic obstruction: follow-up after five years. Scand J Urol Nephrol 2000;34(5):304-8. http://www.ncbi.nlm.nih.gov/pubmed/11186468 31. De Wildt MJ, Debruyne FM, de la Rosette JJ. High-energy transurethral microwave thermotherapy: a thermoablative treatment for benign prostatic obstruction. Urology 1996;48(3):416-23. http://www.ncbi.nlm.nih.gov/pubmed/8804495 32. Djavan B, Wammack R, Ghawidel K, Alavi S, Hasenzagel C, Dobronski P, Stoklosa A, Jakubcky T, Borkowski A, Marberger M. Microwave thermotherapy in patients with chronic urinary retention. Tech Urol 2000;6(4):278-81. http://www.ncbi.nlm.nih.gov/pubmed/11108566 33. Naqvi SA, Rizvi SA, Hasan AS. High-energy microwave thermotherapy in patients in urinary retention. J Endourol 2000;14(8):677-81. http://www.ncbi.nlm.nih.gov/pubmed/11083411

4.8

RECOMMENDATIONS FOR TREATMENT

1.

The WW policy should be recommended to patients with mild symptoms that have minimal or no impact on their quality of life. 2. 5 ARI’s are an acceptable treatment option for patients with bothersome LUTS and an enlarged prostate (> 40 mL) and can be used when there is no absolute indication for surgical treatment. 3. Alpha-blocker therapy is a treatment option for patients with bothersome LUTS who do not have an absolute indication for surgical treatment. 4. Surgical management (TURP, TUIP, open prostatectomy) is recommended as first-line treatment for patients with complications due to BPH with (an absolute indication for treatment of) LUTS. 5. Significant post-operative morbidity, disappointing long-term data and higher costs have resulted in a substantial decline in the clinical use of lasers. It is not recommended as a first-line surgical treatment for patients with LUTS, but may have a role in the treatment of high-risk patient subgroups. 6. HoLRP is a promising new technique with outcomes in the same range as those of TURP.

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7. 8. 9.

Transrectal HIFU therapy is currently not recommended as a therapeutic option for elderly men with LUTS and is considered an investigational therapy. TUNA® is an encouraging technology as an alternative with acceptable results. TUMT is an acceptable alternative to TURP and for those who prefer to avoid surgery or who no longer respond favourably to medication.

5. FOLLOW-UP All patients who receive treatment require follow-up, which will depend on the type of treatment modality undertaken. Patients who subsequently develop chronic retention will require evaluation of their upper tract by serum creatinine measurement and/or renal ultrasound. These patients may be candidates for urodynamic assessment and surgical treatment.

5.1

Watchful waiting

Patients who elect to pursue a WW policy should be reviewed at 6 months and then annually, provided there is no deterioration of symptoms or development of absolute indications for surgical treatment. The following are recommended: • I-PSS • Uro-flowmetry and post-void residual urine volume.

5.2

Alpha-blocker therapy

Patients should be reviewed after the first 6 weeks of therapy in order to determine their response. If patients gain symptomatic relief in the absence of troublesome side-effects, alpha-blocker therapy may be continued. Patients should be reviewed at 6 months and then annually, provided there is no deterioration of symptoms or development of absolute indications for surgical treatment. The following are recommended: • I-PSS • Uro-flowmetry and post-void residual urine volume.

5.3

5-alpha-reductase inhibitors

Patients should be reviewed after 12 weeks and at 6 months to determine their response. Subsequent review is as for alpha-blocker therapy. The following are recommended: • I-PSS • Uro-flowmetry and post-void residual urine volume.

5.4

Surgical management

Following surgical treatment, patients may be seen within 6 weeks to discuss the histological findings and to identify early post-operative morbidity. Long-term follow-up should be scheduled at 3 months to determine the final outcome. Patients who fail treatment should have urodynamic studies with pressure-flow analysis. Assessment includes: • I-PSS: recommended • Uro-flowmetry and post-void residual urine volume: recommended • Urine culture: optional • Histology: mandatory.

5.5

Alternative therapies

Long-term follow-up is recommended because of concerns about the efficacy and durability of alternative therapies. The intervals for follow-up will depend on the treatment modality employed. The following time schedule is appropriate for the majority of minimally invasive therapies: within 6 weeks, at 3 months, at 6 months, and then annually. Assessment includes: • I-PSS: recommended • Uroflowmetry and post-void residual urine volume: recommended • Urine culture: optional • Histology where available: mandatory.

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6. ABBREVIATIONS USED IN THE TEXT

This list is not comprehensive for the most common abbreviations.

AHCPR Agency for Health Care Policy and Research ALFIN study European multicenter double-blind study to assess the efficacy and safety of Alfuzosin (5 mg twice daily) versus finasteride (5mg once daily) and the combination of both in patients with symptomatic BPH ARI alpha reductase inhibitor AUA American Urological Association AUR Acute urinary retention BII BPH Impact Index BOO bladder outlet obstruction BPE benign prostatic enlargement BPH benign prostatic hyperplasia BUN blood urea/nitrogen CT computed tomography DAN-PSS Danish Prostate Symptom Score dL/dt 40 velocity of detrusor contraction at 40 mL volume DHT dihydrotestosterone DRE digital rectal examination EPCDS European Prostate Cancer Detection Study ERSPC European Randomized Study of Screening for Prostate Cancer HE-TUMT high-energy thermotherapy HIFU high-intensity focused ultrasound HoLRP Holmium laser resection of the prostate ICS International Continence Society I-PSS International Prostate Symptom Score ILC interstitial laser coagulation IVP intravenous pyelography IVU intravenous urography LOCM low-osmolar contrast material LinPURR Linear Passive Urethral Resistance Relation LUTS lower urinary tract symptoms MRI magnetic resonance imaging PCAR presumed circle area ratio PLESS Proscar Long-term efficacy and safety study PLCO Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial pQs pressure flow study PPV predictive positive value PQSF Prostate weight, Quality of life, Symptoms, Maximum flow rate PSA prostate-specific antigen PVR post-void residual volume Qav average flow Qmax maximum flow Qm90 mean flow for middle 90% of voided volume RCT randomized controlled trial ROC Receiver Operating Characteristics QoL Quality of Life VLAP visual laser ablation Tdesc time from Qmax until 95% of volume voided TRUS transrectal ultrasonography TUIP transurethral incision of the prostate TUMT transurethral microwave therapy TUNA® transurethral needle ablation TURP transurethral resection of the prostate TUVP transurethral electrovaporization URA Urethral Resistance Index VLAP visual laser ablation WW watchful waiting (deferred treatment)

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Conflict of interest All members of the Male LUTS Guidelines writing panel have provided disclosure statements of all relationships which they have and which may be perceived as a potential source of conflict of interest. This information is kept on file in the European Association of Urology Central Office database. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel - and meeting expenses. No honoraria or other reimbursements have been provided.”

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Guidelines on

Male Sexual Dysfunction: Erectile dysfunction and premature ejaculation E. Wespes, E. Amar, I. Eardley, F. Giuliano, D. Hatzichristou, K. Hatzimouratidis, F. Montorsi, Y. Vardi

© European Association of Urology 2009

TABLE OF CONTENTS 1.

page

BACKGROUND 1.1 Introduction 1.2 References

4 4 4

2. ERECTILE DYSFUNCTION (ED) 2.1 Epidemiology and risk factors 2.1.1 Epidemiology 2.1.2 Risk factors 2.1.3 Post-radical prostatectomy ED 2.2 Managing ED: implications for everyday clinical practice 2.3 Conclusions 2.4 References 2.5 Diagnosis 2.5.1 Basic work-up 2.5.1.1 Sexual history 2.5.1.2 Physical examination 2.5.1.3 Laboratory testing 2.5.2 Cardiovascular system and sexual activity: the patient at risk 2.5.2.1 Low-risk category 2.5.2.2 Intermediate-risk or indeterminate-risk category 2.5.2.3 High-risk category 2.5.3 Specialized diagnostic tests 2.5.3.1 Nocturnal penile tumescence and rigidity (NPTR) 2.5.3.2 Intracavernous injection test 2.5.3.3 Duplex ultrasound of penile arteries 2.5.3.4 Arteriography and dynamic infusion cavernosometry or cavernosography 2.5.3.5 Psychiatric assessment 2.5.3.6 Penile abnormalities 2.5.4 Patient education – consultation and referrals 2.5.5 Guidelines on the diagnosis of ED 2.5.6 References

4 4 4 4 5 5 5 5 7 7 8 8 8 9 10 10 11 11 11 11 11 11

3. TREATMENT OF ED 3.1 Treatment options 3.2 Lifestyle management in ED with concomitant risk factors 3.3 ED after radical prostatectomy (RP) 3.4 ‘Curable’ causes of ED 3.4.1 Hormonal causes 3.4.2 Post-traumatic arteriogenic ED in young patients 3.4.3 Psychosexual counselling and therapy 3.5 First-line therapy 3.5.1 Oral pharmacotherapy 3.5.1.1 Sildenafil 3.5.1.2 Tadalafil 3.5.1.3 Vardenafil 3.5.1.4 Choice or preference between the different PDE5 inhibitors 3.5.1.5 On-demand or chronic use of PDE5 inhibitors 3.5.1.6 Safety issues for PDE5 inhibitors Cardiovascular safety Nitrates are totally contraindicated with PDE5 inhibitors Antihypertensive drugs Alpha-blocker interactions Dosage adjustment 3.5.1.7 Management of non-responders to PDE5 inhibitors Check that the patient has been using a licensed medication Check that the medication has been properly prescribed and correctly used

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2

11 11 11 12 12

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Possible manoeuvres in patients correctly using a PDE5 inhibitor 3.5.1.8 Apomorphine sublingual 3.5.1.9 Other oral agents 3.6 Topical pharmacotherapy 3.7 Vacuum constriction devices 3.8 Second-line therapy 3.8.1 Intracavernous injections 3.8.1.1 Alprostadil Action to be taken with a prolonged erection 3.8.1.2 Combination therapy 3.8.1.3 Intraurethral alprostadil 3.9 Third-line therapy (penile prostheses) 3.9.1 Complications 3.9.2 Conclusion 3.10 Guideline recommendations for the treatment of ED 3.11 References

20 20 21 21 21 21 22 22 22 22 23 23 23 23 23 24

4. PREMATURE EJACULATION (PE) 4.1 Introduction 4.2 Definition of PE 4.2.1 Overview 4.2.2 Classifications 4.3 Epidemiology of PE 4.3.1 Prevalence 4.3.2 Pathophysiology and risk factors 4.4 Impact of PE on QoL 4.5 Diagnosis of PE 4.5.1 Intravaginal ejaculatory latency time (IELT) 4.5.2 PE assessment questionnaires 4.5.3 Physical examination and investigations 4.6 Guidelines on diagnosis of PE 4.7 References 4.8 Treatment 4.8.1 Psychological/behavioural strategies 4.8.2 Topical anaesthetic agents 4.8.2.1 Lidocaine-prilocaine cream 4.8.2.2 SS-cream 4.8.2.3 Guideline recommendation 4.8.3 Selective serotonin reuptake inhibitors 4.8.3.1 Dapoxetine 4.8.3.2 Guideline recommendation 4.8.4 Phosphodiesterase type 5 inhibitors 4.8.5 Other drugs 4.8.6 Guidelines on the treatment of PE 4.9 References 5. CONCLUSION

33 33 33 33 33 34 34 34 34 35 35 35 35 36 36 39 39 40 40 40 40 40 41 41 41 42 42 44

6.

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ABBREVIATIONS USED IN THE TEXT

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46

3

1. BACKGROUND 1.1

Introduction

Erectile dysfunction (ED, impotence) and premature ejaculation (PE) are the two main complaints in male sexual medicine. New oral therapies have completely changed the diagnostic and therapeutic approach to ED and the Guidelines Office of The European Association of Urology (EAU) has appointed an Expert Panel to update previously published EAU guidelines for ED or impotence (1). The update is based on a review of available scientific information, current research and clinical practice in the field (1, 2). The Expert Panel has also identified critical problems and knowledge gaps, setting priorities for future clinical research. Level of evidence and grade of recommendation have been included in these guidelines when possible. The aim of this practice is to provide transparency between the underlying evidence and the recommendation made (3).

1.2

References

1.

Wespes E, Amar E, Hatzichristou DG, Montorsi F, Pryor J, Vardi Y. EAU guidelines on erectile dysfunction. Update March 2004. Eur Urol 2002;41(1):1-5. http://www.ncbi.nlm.nih.gov/pubmed/11999460 Rosenberg MT, Sadovsky R. Identification and diagnosis of premature ejaculation. Int J Clin Pract 2007;61(6):903-8. http://www.ncbi.nlm.nih.gov/pubmed/17504352 Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998. http://www.cebm.net/index.aspx?o=1025 [access date Oct 24, 2008].

2.

3.

2. DIAGNOSIS 2.1

Epidemiology and risk factors

Erection is a neurovascular phenomenon under hormonal control. It includes arterial dilatation, trabecular smooth muscle relaxation and activation of the corporeal veno-occlusive mechanism (1). Erectile dysfunction has been defined as the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance. Although ED is a benign disorder, it affects physical and psychosocial health and has a significant impact on the quality of life (QoL) of sufferers and their partners and families (2). 2.1.1 Epidemiology Recent epidemiological data have shown a high prevalence and incidence of ED worldwide. The first largescale, community-based study of ED was the Massachusetts Male Aging Study (MMAS). The study reported an overall prevalence of 52% ED in non-institutionalized 40- to 70-year-old men in the Boston area in the USA (3); specific prevalences for minimal, moderate and complete ED were 17.2%, 25.2% and 9.6%, respectively. In the Cologne study of men aged 30-80 years old, the prevalence of ED was 19.2%, with a steep age-related increase from 2.3% to 53.4% (4). In the National Health and Social Life Survey (NHSLS), the prevalence of sexual dysfunctions (not specific ED) was 31% (5). The incidence rate of ED (new cases per 1000 men annually) was 26 in the MMAS study (6), 65.6 (mean follow-up of 2 years) in a Brazilian study (7) and 19.2 (mean followup of 4.2 years) in a Dutch study (8). Differences between these studies can be explained by differences in methodology and in the ages and socio-economic status of the populations studied. 2.1.2 Risk factors Erectile dysfunction shares common risk factors with cardiovascular disease (e.g. lack of exercise, obesity, smoking, hypercholesterolaemia, metabolic syndrome), some of which can be modified. In the MMAS, men who began exercising in midlife had a 70% reduced risk for ED compared to sedentary men and a significantly lower incidence of ED over an 8-year follow-up period of regular exercise (9). A multicentre, randomised, openlabel study in obese men with moderate ED compared 2 years of intensive exercise and weight loss with a control group given general information about healthy food choices and exercise (10). Significant improvements in body mass index (BMI) and physical activity scores, as well as in erectile function, were observed in the

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lifestyle intervention group. These changes were highly correlated with both weight loss and activity levels. However, it should be emphasized that controlled prospective studies are necessary to determine the effects of exercise or other lifestyle changes in prevention or treatment of ED. 2.1.3 Post-radical prostatectomy ED Radical prostatectomy (RP) in any form (open, laparoscopic, or robotic) is a widely performed procedure for patients with clinically localized prostate cancer (PCa) and a life expectancy of at least 10 years. This procedure may lead to treatment-specific sequelae affecting health-related QoL. This outcome has become increasingly important with the more frequent diagnosis of PCa in younger patients (11-13). Research has shown that about 25-75% of men experience post-operative ED (14). Post-RP ED is multifactorial. Cavernosal nerve injury induces pro-apoptotic (loss of smooth muscle) and pro-fibrotic (increase in collagen) factors within the corpora cavernosa. These changes may also be caused by poor oxygenation due to changes in the blood supply to the cavernosa. Because pre-operative potency is a major factor associated with the recovery of erectile function after surgery, patients being considered for a nerve-sparing radical prostatectomy (NSRP) should ideally be potent (15). It is also clear that cavernosal nerves must be preserved to ensure erectile function recovers after RP. In addition, the role of vascular insufficiency is of increasing interest in post-operative ED (16, 17).

2.2

Managing ED: implications for everyday clinical practice

Advances in basic and clinical research in ED during the past 15 years have led to the development of several new treatment options for ED, including new pharmacological agents for intracavernous, intraurethral, and, more recently, oral use (18-20). Treatment strategies have also changed following the poor outcomes seen in long-term follow-up of reconstructive vascular surgery (21, 22). An increasing number of men are seeking help for ED due to the great media interest in ED and the availability of effective and safe oral drug therapy. However, there are many physicians evaluating and treating ED without appropriate background knowledge and clinical experience. Thus, some men with ED may receive little or no evaluation before treatment and will therefore not receive treatment for any underlying disease that may be causing their ED. Other men without ED may be requesting treatment simply to enhance their sexual performance. Given this situation, these EAU guidelines for the diagnosis and treatment of ED are a necessity.

2.3

Conclusions

Conclusion LE GR • Erection is a neurovascular phenomenon under hormonal control in a 2b C psychological environment physiologenic environment • ED is common worldwide 3 B • ED shares several risk factors with cardiovascular disease 3 B • Lifestyle modification (intensive exercise and a decrease in body mass index) 1b A can improve erectile function • ED is a symptom, not a disease. Some men may not be properly evaluated or 4 C receive treatment for an underlying disease or condition that may be causing ED. • Radical prostatectomy is a common cause of ED 3 B LE = level of evidence; GR = grade of recommendation; ED = erectile dysfunction.

2.4

References

1.

Lue TF, Tanagho EA. Physiology of erection and pharmacological management of impotence. J Urol 1987;137(5):829-36. http://www.ncbi.nlm.nih.gov/pubmed/3553617 Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994;151(1):54-61. http://www.ncbi.nlm.nih.gov/pubmed/8254833 Wespes E. Ejaculation et ses troubles. Editions techniques EMC (Encyclopédie Médico-chirurgicale) (Paris) Nephrologie-Urologie, 18-710-A-10, 1992. [article in French] [Ejaculation and its disorders] Braun M, Wassmer G, Klotz T, Reifenrath B, Mathers M, Engelmann U. Epidemiology of erectile dysfunction: results of the ‘Cologne Male Survey’. Int J Impot Res 2000;12(6):305-11. http://www.ncbi.nlm.nih.gov/pubmed/11416833 Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA 1999;281(6):537-44. http://www.ncbi.nlm.nih.gov/pubmed/10022110

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21.

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Johannes CB, Araujo AB, Feldman HA, Derby CA, Kleinman KP, McKinlay JB. Incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the Massachusetts male aging study [see comments]. J Urol 2000;163(2):460-3. http://www.ncbi.nlm.nih.gov/pubmed/10647654 Moreira ED Jr, Lbo CF, Diament A, Nicolosi A, Glasser DB. Incidence of erectile dysfunction in men 40 to 69 years old: results from a population-based cohort study in Brazil. Urology 2003;61(2):431-6. http://www.ncbi.nlm.nih.gov/pubmed/12597962 Schouten BW, Bosch JL, Bernsen RM, Blanker MH, Thomas S, Bohnen AM. Incidence rates of erectile dysfunction in the Dutch general population. Effects of definition, clinical relevance and duration of follow-up in the Krimpen Study. Int J Impot Res 2005 Jan-Feb;17(1):58-62. http://www.ncbi.nlm.nih.gov/pubmed/15510192 Derby CA, Mohr BA, Goldstein I, Feldman HA, Johannes CB, McKinlay JB. Modifiable risk factors and erectile dysfunction: can lifestyle changes modify risk? Urology 2000;56(2):302-6. http://www.ncbi.nlm.nih.gov/pubmed/10925098 Esposito K, Giugliano F, Di Palo C, Giugliano G, Marfella R, D’Andrea F, D’Armiento M, Giugliano D. Effect of lifestyle changes on erectile dysfunction in obese men: a randomized controlled trial. JAMA 2004;291(24):2978-84. http://www.ncbi.nlm.nih.gov/pubmed/15213209 Cooperberg MR, Broering JM, Litwin MS, Lubeck DP, Mehta SS, Henning JM, Carroll PR, CaPSURE Investigators. The contemporary management of prostate cancer in the United States: lessons from the cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE), a national disease registry. J Urol 2004;171(4):1393-401. http://www.ncbi.nlm.nih.gov/pubmed/15017184 Stanford JL, Feng Z, Hamilton AS, Gilliland FD, Stephenson RA, Eley JW, Albertsen PC, Harlan LC, Potosky AL. Urinary and sexual function after radical prostatectomy for clinically localized prostate cancer: The Prostate Cancer Outcomes Study. JAMA 2000;283(3):354-60. http://www.ncbi.nlm.nih.gov/pubmed/10647798 Heidenreich A. Radical prostatectomy in 2007: oncologic control and preservation of functional integrity. Eur Urol 2008;53(5):877-9. http://www.ncbi.nlm.nih.gov/pubmed/18243495 Sanda MG, Dunn RL, Michalski J, Sandler HM, Northouse L, Hembroff L, Lin X, Greenfield TK, Litwin MS, Saigal CS, Mahadevan A, Klein E, Kibel A, Pisters LL, Kuban D, Kaplan I, Wood D, Ciezki J, Shah N, Wei JT. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 2008;358(12):1250-61. http://www.ncbi.nlm.nih.gov/pubmed/18354103 Montorsi F, Briganti A, Salonia A, Rigatti P, Burnett AL. Current and future strategies for preventing and managing erectile dysfunction following radical prostatectomy. Eur Urol 2004;45:123-33. http://www.ncbi.nlm.nih.gov/pubmed/14733995 Mulhall JP, Slovick R, Hotaling J, Aviv N, Valenzuela R, Waters WB, Flanigan RC. Erectile dysfunction after radical prostatectomy: hemodynamic profiles and their correlation with the recovery of erectile function. J Urol 2002;167(3):1371-5. http://www.ncbi.nlm.nih.gov/pubmed/11832735 Secin FP, Touijer K, Mulhall J, Guillonneau B. Anatomy and preservation of accessory pudendal arteries in laparoscopic radical prostatectomy. Eur Urol 2007;51(5):1229-35. http://www.ncbi.nlm.nih.gov/pubmed/16989942 Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA; Sildenafil Study Group. Oral sildenafil in the treatment of erectile dysfunction. 1998. J Urol 2002;167(2 Pt 2):1197-203. http://www.ncbi.nlm.nih.gov/pubmed/11905901 Hellstrom WJ, Gittelman M, Karlin G, Segerson T, Thibonnier M, Taylor T, Padma-Nathan H; Vardenafil Study Group. Sustained efficacy and tolerability of vardenafil, a highly potent selective phosphodiesterase type 5 inhibitor, in men with erectile dysfunction: results of a randomized, doubleblind, 26-week placebo-controlled pivotal trial. Urology 2003;61(4 Suppl 1):8-14. http://www.ncbi.nlm.nih.gov/pubmed/12657355 Brock GB, McMahon CG, Chen KK, Costigan T, Shen W, Watkins V, Anglin G, Whitaker S. Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses. J Urol 2002;168(4 Pt 1):1332-6. http://www.ncbi.nlm.nih.gov/pubmed/12352386 Wespes E, Schulman CC. Venous impotence: pathophysiology, diagnosis and treatment. J Urol 1993;149(5 Pt 2):1238-45. http://www.ncbi.nlm.nih.gov/pubmed/8479008

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22.

Rao DS, Donatucci CF. Vasculogenic impotence. Arterial and venous surgery. Urol Clin North Am 2001;28(2):309-19. http://www.ncbi.nlm.nih.gov/pubmed/11402583

2.5

Diagnosis

2.5.1 Basic work-up The first step in evaluating ED is always a detailed medical and psychological history of patients and partners (1, 2). Often it is not possible to include the partner on the patient’s first visit, but an effort should be made to include the partner at the second visit. The pathophysiology of ED may be vasculogenic, neurogenic, hormonal, anatomical, drug-induced or psychogenic (Table 1) (3) and taking a medical history may reveal one of the many common disorders associated with ED It is important to establish a relaxed atmosphere during history-taking. This will make it easier to ask questions about erectile function and other aspects of sexual history, particularly when patients do not find it easy to talk about their problem. It will also make it easier to explain the diagnosis and therapeutic approach to the patient and his partner. Table 1: Pathophysiology of ED Vasculogenic • Cardiovascular disease • Hypertension • Diabetes mellitus • Hyperlipidaemia • Smoking • Major surgery (radical prostatectomy) or radiotherapy (pelvis or retroperitoneum) Neurogenic Central causes • Multiple sclerosis • Multiple atrophy • Parkinson’s disease • Tumours • Stroke • Disk disease • Spinal cord disorders Peripheral causes • Diabetes mellitus • Alcoholism • Uraemia • Polyneuropathy • Surgery (pelvis or retroperitoneum, radical prostatectomy) Anatomical or structural • Peyronie’s disease • Penile fracture • Congenital curvature of the penis • Micropenis • Hypospadias, epispadias Hormonal • Hypogonadism • Hyperprolactinemia • Hyper- and hypo-thyroidism • Cushing’s disease Drug-induced • Antihypertensives (diuretics and beta-blockers are the most common causes) • Antidepressants • Antipsychotics • Antiandrogens • Antihistamines • Recreational drugs (heroin, cocaine, methadone) Psychogenic • Generalized type (e.g. lack of arousability and disorders of sexual intimacy)

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•

Situational type (e.g. partner-related, performance-related issues or due to distress)

2.5.1.1 Sexual history The sexual history may include information about previous and current sexual relationships, current emotional status, onset and duration of the erectile problem, and previous consultations and treatments. A detailed description should be made of the rigidity and duration of both erotic and morning erections and of problems with arousal, ejaculation and orgasm. Validated questionnaires, such as the International Index for Erectile Function (IIEF), help to assess all sexual function domains (erectile function, orgasmic function, sexual desire, ejaculation, intercourse and overall satisfaction), as well as the impact of a specific treatment modality (4). 2.5.1.2 Physical examination Every patient must be given a physical examination focused on the genitourinary, endocrine, vascular and neurological systems (1). A physical examination may reveal unsuspected diagnoses, such as Peyronie’s disease, prostatic enlargement or cancer, or signs and symptoms suggesting hypogonadism (small testes, alterations in secondary sexual characteristics, diminished sexual desire and changes in mood) (2). A rectal examination should be performed in every patient older than 50 years. Blood pressure and heart rate should be measured if they have not been assessed in the previous 3-6 months. Particular attention must be given to patients with cardiovascular disease (see Section 2.5.2). 2.5.1.3 Laboratory testing Laboratory testing must be tailored to the patient’s complaints and risk factors. All patients must undergo a fasting glucose and lipid profile if not assessed in the previous 12 months. Hormonal tests must include a morning sample of total testosterone. Tests that measure bioavailable or calculated-free testosterone are preferred to total testosterone tests because they are better at establishing hypogonadism. Additional laboratory tests must be considered only in selected patients, e.g. prostate-specific antigen (PSA) for detection of prostate cancer. Additional hormonal tests, e.g. prolactin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), must be carried out when low testosterone levels are detected. If any abnormality is observed, referral to another specialist may be necessary (5, 6). Figure 1 gives the minimal diagnostic evaluation (basic work-up) in patients with ED.

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Figure 1: Minimal diagnostic evaluation (basic work-up) in patients with ED

Patient with erectile dysfunction (self-reported)

Medical and psychosexual history (use of validated instruments, e.g. IIEF)

Identify other than ED sexual problems

Identify common causes of ED

Identify reversible risk factors for ED

Assess psychosocial status

Focused physical examination

Penile deformities

Prostatic disease

Signs of hypogonadism

Cardiovascular and neurological status

Laboratory tests

Glucose-lipid profile (if not assessed in the last 12 months)

Total testosterone (morning sample) If available: bio-available or free testosterone (instead of total)

2.5.2 Cardiovascular system and sexual activity: the patient at risk Patients who seek treatment for sexual dysfunction have a high prevalence of cardiovascular disease. The cardiac risks associated with sexual activity are well established. Recent epidemiological studies have emphasized the association between cardiovascular and metabolic risk factors and sexual dysfunction in both men and women (7). There has been an intensive investigation of the pharmacological properties of phosphodiesterase type 5 (PDE5) inhibitors, including their effects on cardiac smooth muscle activity and overall cardiovascular safety. The EAU Guidelines recommendations given here for using PDE5 inhibitors in PE have been adapted from previously published recommendations from consensus conferences on sexual dysfunction and cardiac risk (8, 9). Patients with ED can be stratified into three cardiovascular risk categories (Table 2), which can be used as the basis for a treatment algorithm for initiating or resuming sexual activity (Figure 2). It is also possible for the clinician to estimate the risk of sexual activity in most patients from their level of exercise tolerance, determined when taking the patient’s history.

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Table 2: Cardiac risk stratification Low-risk category Intermediate-risk category High-risk category Asymptomatic, < 3 risk factors for ≥ 3 risk factors for CAD High-risk arrhythmias CAD (excluding gender) (excluding gender) Mild, stable angina Moderate, stable angina Unstable or refractory angina (evaluated and/or being treated) Uncomplicated previous MI Recent MI (> 2, < 6 weeks) Recent MI (< 2 weeks) LVD/CHF (NYHA class I) LVD/CHF (NYHA class II) LVD/CHF (NYHA class III/IV) Post-successful coronary Non-cardiac sequelae of Hypertrophic obstructive and other revascularization atherosclerotic disease (e.g. stroke, cardiomyopathies peripheral vascular disease) Controlled hypertension Uncontrolled hypertension Mild valvular disease Moderate-to-severe valvular disease CAD = coronary artery disease; CHF = congestive heart failure; LVD = left ventricular dysfunction; MI = myocardial infarction; NYHA = New York Heart Association.

Figure 2: Treatment algorithm for determining level of sexual activity according to cardiac risk in ED

Sexual inquiry

Clinical evaluation

Low risk

Intermediate risk

Initiate or resume sexual activity or Treatment for sexual dysfunction

Cardiovascular assessment and restratification

High risk

Sexual activity deferred until stabilization of cardiac condition

Risk factors and coronary heart disease evaluation, treatment and follow-up for all patients with erectile dysfunction

2.5.2.1 Low-risk category The low-risk category includes patients who do not have any significant cardiac risk associated with sexual activity. Low risk is typically implied by the ability to perform exercise of modest intensity, which is defined as six or more ‘metabolic equivalents of energy expenditure in the resting state’ (METs) without symptoms. According to current knowledge of the exercise demand or emotional stress associated with sexual activity, low-risk patients do not need cardiac testing or evaluation before the initiation or resumption of sexual activity or therapy for sexual dysfunction. 2.5.2.2 Intermediate-risk or indeterminate-risk category The intermediate- or indeterminate-risk category consists of patients with an uncertain cardiac condition or patients whose risk profile requires testing or evaluation before the resumption of sexual activity. Based upon the results of testing, these patients may be moved to either the high- or low-risk group. A cardiology

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consultation may be needed in some patients to help the primary physician determine the safety of sexual activity. 2.5.2.3 High-risk category High-risk patients have a cardiac condition that is sufficiently severe and/or unstable for sexual activity to carry a significant risk. Most high-risk patients have moderately to severely symptomatic heart disease. High-risk individuals should be referred for cardiac assessment and treatment. Sexual activity should be stopped until the patient’s cardiac condition has been stabilized by treatment or a decision made by the cardiologist and/or internist that it is safe to resume sexual activity. 2.5.3 Specialized diagnostic tests Most patients with ED can be managed within the sexual care setting, but some patients may need specific diagnostic tests (Tables 3 and 4). 2.5.3.1 Nocturnal penile tumescence and rigidity (NPTR) The nocturnal penile tumescence and rigidity (NPTR) assessment should be done on at least two nights. A functional erectile mechanism is indicated by an erectile event of at least 60% rigidity recorded on the tip of the penis that lasts for 10 min or more (10). 2.5.3.2 Intracavernous injection test The intracavernous injection test gives limited information about vascular status. A positive test is a rigid erectile response (unable to bend the penis) that appears within 10 min after the intracavernous injection and lasts for 30 min (11). This response indicates a functional, but not necessarily normal, erection, as the erection may co-exist with arterial insufficiency or veno-occlusive dysfunction (12). A positive test shows that a patient will respond to the intracavernous injection programme. The test is inconclusive as a diagnostic procedure and Duplex ultrasound of the penile arteries should be requested. 2.5.3.3 Duplex ultrasound of penile arteries A peak systolic blood flow higher than 30 cm/s and a resistance index higher than 0.8 are generally considered normal (10). Further vascular investigation is unnecessary when a Duplex examination is normal. 2.5.3.4 Arteriography and dynamic infusion cavernosometry or cavernosography Arteriography and dynamic infusion cavernosometry or cavernosography (DICC) should be performed only in patients who are being considered for vascular reconstructive surgery (13). 2.5.3.5 Psychiatric assessment Patients with psychiatric disorders must be referred to a psychiatrist who is particularly interested in ED. In younger patients (< 40 years) with long-term primary ED, psychiatric assessment may be helpful before any organic assessment is carried out. 2.5.3.6 Penile abnormalities Surgical correction may be needed for patients with ED due to penile abnormalities, e.g. hypospadias, congenital curvature, or Peyronie’s disease with preserved rigidity. Success rates are high. 2.5.4 Patient education – consultation and referrals The consultation with the patient should include a discussion of the expectations and needs of both the patient and his partner. It should also review both the patient’s and partner’s understanding of ED and results of the diagnostic tests, and provide a rational selection of treatment options. Patient and partner education are an essential part of ED management (14, 15). Table 3: Indications for specific diagnostic tests Indications for specific diagnostic tests • Primary erectile disorder (not caused by organic disease or psychogenic disorder) • Young patients with a history of pelvic or perineal trauma who could benefit from potentially curative vascular surgery • Patients with penile deformities that might require surgical correction, e.g. Peyronie’s disease, congenital curvature • Patients with complex psychiatric or psychosexual disorders • Patients with complex endocrine disorders

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• •

Specific tests may be indicated at the request of the patient or his partner Medicolegal reasons, e.g. implantation of penile prosthesis, sexual abuse

Table 4: Specific diagnostic tests Diagnostic test • Nocturnal penile tumescence and rigidity (NTPR) using Rigiscan® • Vascular studies - Intracavernous vasoactive drug injection - Duplex ultrasound of the cavernous arteries - Dynamic infusion cavernosometry or cavernosography (DICC) - Internal pudendal arteriography • Neurological studies, e.g. bulbocavernosus reflex latency, nerve conduction studies • Endocrinological studies • Specialized psychodiagnostic evaluation

2.5.5

Guidelines on the diagnosis of ED

Diagnostice guideline • Clinical use of validated questionnaire related to ED may help to assess all sexual function domains and the effect of a specific treatment modality • Physical examination is needed in the initial assessment of men with ED to identify underlying medical conditions that may be associated with ED • Routine laboratory tests, including glucid-lipid profile and total testosterone, are required to identify and treat any reversible risk factors and lifestyle factors that can be modified • Specific diagnostic tests are indicated by only a few conditions LE = level of evidence; GR = grade of recommendation.

LE GR 3 B 4

B

4

B

4

B

2.5.6

References

1.

Davis-Joseph B, Tiefer L, Melman A. Accuracy of the initial history and physical examination to establish the etiology of erectile dysfunction. Urology 1995;45(3):498-502. http://www.ncbi.nlm.nih.gov/pubmed/7879338 Hatzichristou D, Hatzimouratidis K, Bekas M, Apostolidis A, Tzortzis V, Yannakoyorgos K. Diagnostic steps in the evaluation of patients with erectile dysfunction. J Urol 2002;168(2):615-20. http://www.ncbi.nlm.nih.gov/pubmed/12131320 Lewis RW. Epidemiology of erectile dysfunction. Urol Clin North Am 2001;28(2):209-16, vii. http://www.ncbi.nlm.nih.gov/pubmed/11402575 Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997;49(6):822-30. http://www.ncbi.nlm.nih.gov/pubmed/9187685 Morales A, Heaton JP. Hormonal erectile dysfunction. Evaluation and management. Urol Clin North Am 2001;28(2):279-88. http://www.ncbi.nlm.nih.gov/pubmed/11402581 Lue TF, Giuliano F, Montorsi F, Rosen RC, Andersson KE, Althof S, Christ G, Hatzichristou D, Hirsch M, Kimoto Y, Lewis R, McKenna K, MacMahon C, Morales A, Mulcahy J, Padma-Nathan H, Pryor J, de Tejada IS, Shabsigh R, Wagner G. Summary of the recommendations on sexual dysfunctions in men. J Sex Med 2004;1(1):6-23. http://www.ncbi.nlm.nih.gov/pubmed/16422979 Laumann EO, Paik A, Rosen RC. The epidemiology of erectile dysfunction: results from the National Health and Social Life Survey. Int J Impot Res 1999;11(Suppl 1):S60-S64. http://www.ncbi.nlm.nih.gov/pubmed/10554933

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3. 4.

5.

6.

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9.

10.

11.

12.

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15.

DeBusk R, Drory Y, Goldstein I, Jackson G, Kaul S, Kimmel SE, Kostis JB, Kloner RA, Lakin M, Meston CM, Mittleman M, Muller JE, Padma-Nathan H, Rosen RC, Stein RA, Zusman R. Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton Consensus Panel. Am J Cardiol 2000;86(6):62F-68F. http://www.ncbi.nlm.nih.gov/pubmed/10554933 Kostis J, Jackson G, Rosen R, Barrett-Connor E, Billups K, Burnett A, Carson C, Cheitlin M, Debusk R, Fonseca V, Ganz P, Goldstein I, Guay A, Hatzichristou D, Hollander JE, Hutter A, Katz S, Kloner RA, Mittleman M, Montorsi F, Montorsi P, Nehra A, Sadovsky R, Shabsigh R. Sexual dysfunction and cardiac risk (the Second Princeton Consensus Conference). Am J Cardiol 2005;96(B):313-21. http://www.ncbi.nlm.nih.gov/pubmed/16018863 Hatzichristou DG, Hatzimouratidis K, Ioannides E, Yannakoyorgos K, Dimitriadis G, Kalinderis A. Nocturnal penile tumescence and rigidity monitoring in young potent volunteers: reproducibility, evaluation criteria and the effect of sexual intercourse. J Urol 1998;159(6):1921-6. http://www.ncbi.nlm.nih.gov/pubmed/9598488 Meuleman EJ, Diemont WL. Investigation of erectile dysfunction. Diagnostic testing for vascular factors in erectile dysfunction. Urol Clin North Am 1995;22(4):803-19. http://www.ncbi.nlm.nih.gov/pubmed/7483130 Hatzichristou DG, Hatzimouratidis K, Apostolidis A, Ioannidis E, Yannakoyorgos K, Kalinderis A. Hemodynamic characterization of a functional erection. Arterial and corporeal veno-occlusive function in patients with a positive intracavernosal injection test. Eur Urol 1999;36(1):60-7. http://www.ncbi.nlm.nih.gov/pubmed/10364657 Wespes E, Schulman C. Venous impotence: pathophysiology, diagnosis and treatment. J Urol 1993;149(5 Pt 2):1238-45. http://www.ncbi.nlm.nih.gov/pubmed/8479008 Rosen RC, Leiblum SR, Spector IP. Psychologically based treatment for male erectile disorder: a cognitive-interpersonal model. J Sex Marital Ther 1994;20(2):67-85. http://www.ncbi.nlm.nih.gov/pubmed/8035472 Hatzichristou D, Rosen RC, Broderick G, Clayton A, Cuzin B, Derogatis L, Litwin M, Meuleman E, O’Leary M, Quirk F, Sadovsky R, Seftel A. Clinical evaluation and management strategy for sexual dysfunction in men and women. J Sex Med 2004 Jul;1(1):49-57. http://www.ncbi.nlm.nih.gov/pubmed/16422983

3. TREATMENT of ed 3.1

Treatment options

The primary goal in the management strategy of a patient with ED is to determine the aetiology of the disease and treat it when possible, and not to treat the symptom alone. Erectile dysfunction may be associated with modifiable or reversible factors, including lifestyle or drug-related factors. These factors may be modified either before, or at the same time as, specific therapies are used. As a rule, ED can be treated successfully with current treatment options, but cannot be cured. The only exceptions are psychogenic ED, post-traumatic arteriogenic ED in young patients and hormonal causes (e.g. hypogonadism, hyperprolactinaemia), which can be potentially cured with specific treatment. Most men with ED will be treated with treatment options that are not cause-specific. This results in a structured treatment strategy that depends on efficacy, safety, invasiveness and cost, as well as patient preference (1). To counsel patients properly with ED, physicians must be fully informed of all treatment options. The assessment of treatment options must consider the effects on patient and partner satisfaction and other QoL factors as well as efficacy and safety. A treatment algorithm for ED is given in Figure 3.

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Figure 3: Treatment algorithm for ED Treatment of erectile dysfunction

Identify and treat ‘curable’ causes of ED

Lifestyle changes and risk factor modification

Provide education and counselling to patients and partners

Identify patient needs and expectations Shared decision-making Offer conjoint psychosocial and medical treatment

Apomorphine SL Intracavernous injections Intraurethral alprostadil Vacuum devices

PDE5 inhibitors

Assess therapeutic outcome: • Erectile response • Side-effects • Satisfaction with treatment

Inadequate treatment outcome

Assess adequate use of treatment options Provide new instructions and counselling Re-trial Consider alternative or combination therapy

Inadequate treatment outcome

Consider penile prosthesis implantation

PDE5 inhibitor = phosphodiesterase type 5 inhibitor

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3.2

Lifestyle management in ED with concomitant risk factors

The basic work-up of the patient must identify reversible risk factors for ED. Lifestyle changes and risk factor modification must precede or accompany ED treatment. The potential benefits of lifestyle changes may be particularly important in individuals with ED and specific comorbid cardiovascular or metabolic diseases, such as diabetes or hypertension (2-4). Besides improving erectile function, aggressive lifestyle changes may also benefit overall cardiovascular and metabolic health, with recent studies supporting the potential of lifestyle intervention to benefit both ED and overall health (5). Although further studies are needed to make clear the role of lifestyle changes in the management of ED and related cardiovascular disease, lifestyle changes can be recommended alone or combined with PDE5 therapy. Some studies have suggested that the therapeutic effects of PDE5 inhibitors may be enhanced when other comorbidities or risk factors are aggressively managed (6). However, these results have yet to be confirmed in well-controlled, long-term studies. Because of the success of pharmacological therapy for ED, clinicians need to provide specific evidence for the benefits of lifestyle change and hopefully future research will show this.

3.3

Erectile dysfunction after radical prostatectomy (RP)

Use of pro-erectile drugs following RP is very important in achieving erectile function following surgery. Several trials have shown higher rates of erectile function recovery after RP in patients receiving any drug (therapeutic or prophylactic) for ED. Historically, the treatment options for post-operative ED included intracavernous injections (7), urethral microsuppository (8), vacuum device therapy (9) and penile implants (10). Intracavernous injections and penile implants are still suggested as second- and third-line treatments, respectively, when oral compounds are not adequately effective or contraindicated for post-operative patients (see Sections 3.8 and 3.9). The management of post-RP ED has been revolutionized by the advent of PDE5 inhibitors, with their demonstrated efficacy, ease of use, good tolerability, excellent safety, and positive impact on QoL. At present, PDE5 inhibitors are the first-line choice of oral pharmacotherapy for post-RP ED in patients who have undergone a nerve-sparing (NS) surgical approach. The choice of PDE5 inhibitors as first-line treatment is controversial because the experience (surgical volume) of the surgeon is a key factor in preserving postoperative erectile function in addition to patient age and NS technique (11-13). In fact, PDE5 inhibitors are most effective in patients who have undergone a rigorous NS procedure, which is more commonly performed by the largest-volume surgeons (12, 13). The early use of a high dose of sildenafil after RP is associated with the preservation of smooth muscle within the human corpora cavernosa (14). Daily sildenafil also resulted in a greater return of spontaneous normal erectile function post RP compared to placebo following bilateral nerve-sparing RP (NSRP) in patients who were fully potent before surgery (15, 16). The response rate to sildenafil treatment for ED after RP in different trials ranged from 35% to 75% among those who underwent NSRP and from 0% to 15% among those who underwent non-NSRP (15-18). The effectiveness of both tadalafil and vardenafil as on-demand treatment has also been evaluated in post-RP ED: • A large multicentre trial in Europe and USA studied tadalafil in patients with ED following a bilateral NS procedure. Erectile function was improved in 71% of patients treated with tadalafil 20 mg versus 24% treated with placebo, while the rate of successful intercourse attempts was 52% with tadalafil 20 mg versus 26% with placebo (19). • Similarly, vardenafil has been tested in patients treated with ED following either an unilateral or bilateral NS procedure in a multicentre, prospective, placebo-controlled, randomised North American study (20). Following bilateral NSRP, erectile function improved by 71% and 60% with vardenafil, 20 mg and 10 mg, respectively. An extended analysis of the same patients undergoing NSRP has underlined the benefit of vardenafil compared to placebo regarding intercourse satisfaction, hardness of erection, orgasmic function and overall satisfaction with sexual experience (21). A randomized, double-blind, double-dummy, multicentre, parallel-group study in 87 centres across Europe, Canada, South Africa and the USA, compared on- demand and nightly dosing of vardenafil in men with ED following bilateral NSRP. In patients whose IIEF erectile function domain (IIEF-EF) score was ≥ 26 before surgery, vardenafil was efficacious when used on demand, supporting a paradigm shift towards on-demand dosing with PDE5 inhibitors in post-RP ED (22). Patients who do not respond to oral PDE5 inhibitors after NSRP should be treated with prophylactic intracorporeal alprostadil (23). A penile prosthesis remains a very satisfactory approach for patients who do not respond to either oral or intracavernous pharmacotherapy or to a vacuum device (24).

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3.4

‘Curable’ causes of ED

3.4.1 Hormonal causes An endocrinologist’s advice is essential for managing patients with hormonal abnormalities. Testosterone deficiency is either a result of primary testicular failure or secondary to pituitary/hypothalamic causes, including a functional pituitary tumour resulting in hyperprolactinaemia. Testosterone replacement therapy (intramuscular, oral or transdermal) is effective, but should only be used after other endocrinological causes for testicular failure have been excluded (25). Testosterone replacement is contraindicated in men with a history of prostate carcinoma or with symptoms of prostatism. Before initiating testosterone replacement, a digital rectal examination (DRE) and serum PSA test should be performed. Patients given androgen therapy should be monitored for clinical response and the development of hepatic or prostatic disease. There is no contraindication for testosterone therapy in men with coronary artery disease who have been properly diagnosed with hypogonadism and/or ED. However, the haematocrit level should be monitored and a dose adjustment of testosterone may be necessary, especially in congestive heart failure. Hormonal treatment is not always effective in the management of ED associated with hypogonadism (26). 3.4.2 Post-traumatic arteriogenic ED in young patients In young patients with pelvic or perineal trauma, surgical penile revascularization has a 60-70% long-term success rate (27). The lesion must be demonstrated by Duplex ultrasound and confirmed by penile pharmacoarteriography. Corporeal veno-occlusive dysfunction is a contraindication to revascularization and must be excluded by DICC (9, 10). Vascular surgery for veno-occlusive dysfunction is no longer recommended because of poor long-term results (28). 3.4.3 Psychosexual counselling and therapy For patients with a significant psychological problem, psychosexual therapy may be given either alone or with another therapeutic approach. Psychosexual therapy takes time and has had variable results (29).

3.5

First-line therapy

3.5.1 Oral pharmacotherapy The PDE5 enzyme hydrolyzes cyclic guanosine monophosphate (cGMP) in the cavernosum tissue of the penis. Inhibition of PDE5 results in increased arterial blood flow leading to smooth muscle relaxation, vasodilatation and penile erection (30). Three potent selective PDE5 inhibitors have been approved by the European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA) for treatment of ED. They are not initiators of erection and require sexual stimulation to facilitate an erection. 3.5.1.1 Sildenafil Sildenafil, launched in 1998, was the first PDE5 inhibitor available on the market. Efficacy is defined as an erection with rigidity sufficient for vaginal penetration. Sildenafil is effective from 30 to 60 min after administration. Its efficacy is reduced after a heavy fatty meal due to prolonged absorption. It is administered in 25, 50 and 100 mg doses. The recommended starting dose is 50 mg and should be adapted according to the patient’s response and side-effects. Efficacy may be maintained for up to 12 h (31). The pharmacokinetic data of sildenafil are presented in Table 5. Adverse events (Table 6) are generally mild in nature and self-limited by continuous use. The drop-out rate due to adverse events is similar to placebo (32). After 24 weeks in a dose-response study, improved erections were reported by 56%, 77% and 84% of men taking 25, 50 and 100 mg of sildenafil, respectively, compared to 25% of men taking placebo (33). Sildenafil statistically improved patient scores in IIEF, sexual encounter profile 2 (SEP2), SEP3 and general assessment question (GAQ) and treatment satisfaction. The efficacy of sildenafil in almost every subgroup of patients with ED has been successfully established. In diabetic patients, 66.6% reported improved erections (GAQ) and 63% successful intercourse attempts compared to 28.6% and 33% of men taking placebo, respectively (34). 3.5.1.2 Tadalafil Tadalafil, licenced for the treatment of ED as of February 2003, is effective from 30 min after administration, with peak efficacy after about 2 h. Efficacy is maintained for up to 36 h (35) and is not affected by food. It is administered in 10 and 20 mg doses. The recommended starting dose is 10 mg and should be adapted according to the patient’s response and side-effects. Pharmacokinetic data of tadalafil are presented in Table 5. Adverse events (Table 6) are generally mild in nature, self-limited by continuous use. The drop-out rate due to adverse events is similar to placebo (36).

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In pre-marketing studies, after 12 weeks of treatment and in a dose-response study, improved erections were reported by 67% and 81% of men taking 10 mg and 20 mg of tadalafil compared to 35% of men in the control placebo group (36). Tadalafil statistically improved patient scores in IIEF, SEP2, SEP3 and GAQ and treatment satisfaction. These results were confirmed in post-marketing studies (37). Tadalafil also improved erections in difficult-to-treat subgroups. In diabetic patients, 64% reported improved erections (i.e. improved GAQ) versus 25% of patients in the control group and the change in the final score for IIEF-EF was 7.3 compared to 0.1 for placebo (38). 3.5.1.3 Vardenafil Vardenafil, commercially available as of March 2003, is effective from 30 min after administration. Its effect is reduced by a heavy fatty meal (> 57% fat). It is administered in 5, 10 and 20 mg doses. The recommended starting dose is 10 mg and should be adapted according to the patient’s response and side-effects. In vitro, it is 10-fold more potent than sildenafil, though this does not necessarily mean greater clinical efficacy (39). Pharmacokinetic data of vardenafil are presented in Table 5. Adverse events (Table 6) are generally mild in nature and self-limited by continuous use, with a drop-out rate similar to placebo (40). After 12 weeks in a dose-response study, improved erections were reported by 66%, 76% and 80% of men taking 5 mg, 10 mg and 20 mg of vardenafil, respectively, compared with 30% of men taking placebo (41). Vardenafil statistically improved patient scores for IIEF, SEP2, SEP3 and GAQ and treatment satisfaction. Efficacy was confirmed in post-marketing studies (42). Vardenafil improved erections in difficult-to-treat subgroups. In diabetic patients, 72% reported improved erections (i.e. improved GAQ) compared to 13% of patients taking placebo and the final IIEF-EF score was 19 compared to 12.6 for placebo (43). 3.5.1.4 Choice or preference between the different PDE5 inhibitors To date, no data are available from double- or triple-blind multicentre studies comparing the efficacy and/ or patient preference for sildenafil, tadalafil and vardenafil. Choice of drug will depend on the frequency of intercourse (occasional use or regular therapy, 3-4 times weekly) and the patient’s personal experience. Patients need to know whether a drug is short- or long-acting, possible disadvantages and how to use it. 3.5.1.5 On-demand or chronic use of PDE5 inhibitors Animal studies have shown that chronic use of PDE5 inhibitors improves or prevents significantly the intracavernous structure alterations due to age, diabetes or surgical damage (44-50). In humans, a randomised study (n = 145) showed that daily tadalafil led to a significantly higher IIEFEF score and higher completion of successful intercourse attempts compared to on-demand tadalafil (51). Two major double-blind randomised studies, using daily 5 and 10 mg tadalafil for 12 weeks (n = 268) (52) and daily 2.5 and 5 mg tadalafil for 24 weeks (n = 286) (53), showed that daily dosing was well tolerated and significantly improved erectile function. However, these studies lacked an on-demand treatment arm. An openlabel extension was carried out of both studies in 234 patients for 1 year and 238 patients for 2 years. Tadalafil, 5 mg once daily, was shown to be well tolerated and effective (54). Tadafil, 5 mg once daily, therefore provides an alternative to on-demand dosing of tadalafil for couples who prefer spontaneous rather than scheduled sexual activities or who anticipate frequent sexual activity, with the advantage that dosing and sexual activity no longer need to be temporally linked. Nevertheless, in the 1-year open-label 5 mg tadalafil extension study followed by 4 weeks of wash-out, erectile function was not maintained after discontinuation of therapy in most patients (about 75%). A double-blind, placebo-controlled, multicentre, parallel-group study was conducted in 236 men with mild-to-moderate ED randomised to receive once-daily vardenafil 10 mg plus on-demand placebo for 12 or 24 weeks, or once-daily placebo plus on-demand vardenafil 10 mg for 24 weeks, followed by 4 weeks of wash-out (55). Despite preclinical evidence, the results suggested that once-daily dosing of vardenafil 10 mg does not offer any sustainable effect after cessation of treatment compared to on-demand administration in patients with mild-to-moderate ED. Other studies (open-label, randomised, cross-over studies with limited patient numbers) showed that chronic, but not on-demand, tadalafil treatment improved endothelial function with sustained effect after its discontinuation (56, 57). This was confirmed in another study of chronic sildenafil in men with type 2 diabetes (58). Recently, in the first double-blind placebo-controlled study, enrolling 298 men with diabetes and ED for 12 weeks, once-daily tadalafil 2.5 mg and 5 mg was efficacious and well tolerated. This regimen provides an alternative to on-demand treatment for some diabetic men (59). However, when patients have the choice, it seems that they prefer on-demand rather than continuous therapy (60).

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Table 5: Summary of the key pharmacokinetic data for the three PDE5 inhibitors used to treat ED* Parameter Sildenafil, 100 mg Tadalafil, 20mg Vardenafil, 20 mg Cmax 560 µg/L 378 µg/L 18.7 µg/L Tmax 0.8-1 h 2 h 0.9 h T1/2 2.6-3.7 h 17.5 3.9 h AUC 1685 µg/h/L 8066 µg.h/L 56.8 µg.h/L Protein binding 96% 94% 94% Bioavailability 41% NA 15% Cmax: maximal concentration, Tmax: time-to-maximum plasma concentration; T1/2: plasma elimination halftime; AUC: area under curve or serum concentration time curve. * Fasted state, higher recommended dose. Data adapted from EMEA statements on product characteristics. Sildenafil: http://www.emea.europa.eu/humandocs/Humans/EPAR/viagra/viagra.htm Tadalafil: http://www.emea.europa.eu/humandocs/Humans/EPAR/cialis/cialis.htm Vardenafil: http://www.emea.europa.eu/humandocs/Humans/EPAR/levitra/levitra.htm Table 6: Common adverse events of the three PDE5 inhibitors used to treat ED* Adverse event Sildenafil Tadalafil Headache 12.8% 14.5% Flushing 10.4% 4.1% Dyspepsia 4.6% 12.3% Nasal congestion 1.1% 4.3% Dizziness 1.2% 2.3% Abnormal vision 1.9% Back pain 6.5% Myalgia 5.7% * Adapted from EMEA statements on product characteristics. Sildenafil: http://www.emea.europa.eu/humandocs/Humans/EPAR/viagra/viagra.htm Tadalafil: http://www.emea.europa.eu/humandocs/Humans/EPAR/cialis/cialis.htm Vardenafil: http://www.emea.europa.eu/humandocs/Humans/EPAR/levitra/levitra.htm

Vardenafil 16% 12% 4% 10% 2% 14% of normal shape and form** • Viability > 50% of spermatozoa • Leukocytes < 1 million/mL • Immunobead test (IBT) < 50% spermatozoa with adherent particles • MAR test** < 50% spermatozoa with adherent particles * From WHO (2000) (1). ** Assessment according to Kruger and Menkfeld criteria. † IBT = Immunobead test ‡ MAR = Mixed antiglobulin reaction 2.1.1 Frequency of semen analysis If the results of semen analysis are normal according to WHO criteria, one test should be sufficient. If the results are abnormal in at least two tests, further andrological investigation is indicated. It is important to distinguish between the following: • oligozoospermia: < 20 million spermatozoa/mL • asthenozoospermia: < 50% motile spermatozoa

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• teratozoospermia: < 14% normal forms. Quite often, all three pathologies occur simultaneously as OAT syndrome. In extreme cases of OAT syndrome (< 1 million spermatozoa/mL), as in azoospermia, there is an increased incidence of obstruction of the male genital tract and genetic abnormalities.

2.2

RECOMMENDATIONS

Recommendations • Andrological investigations are indicated if semen analysis is abnormal, according to WHO criteria, in at least two tests. • Assessment of andrological status must consider the suggestions made by the WHO for the standardised investigation, diagnosis and management of infertile men; this will result in implementation of evidence-based medicine in this interdisciplinary field of reproductive medicine (2). • Semen analysis must follow the guidelines of the WHO Laboratory Manual for Human Semen and Sperm-Cervical Mucus Interaction (4th edition) (1). GR = grade of recommendation; WHO = World Health Organization

2.3

REFERENCES

1.

World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction. 4th edn. Cambridge: Cambridge University Press, 1999. World Health Organization. WHO Manual for the Standardised Investigation, Diagnosis and Management of the Infertile Male. Cambridge: Cambridge University Press, 2000.

2.

GR C C

C

3. PRIMARY SPERMATOGENIC FAILURE 3.1

Definition

Primary spermatogenic (testicular) failure is any spermatogenic alteration caused by conditions other than hypothalamic-pituitary disease. Severe forms of primary spermatogenic failure have different aetiologies but present clinically as non-obstructive azoospermia (NOA). The prevalence of azoospermia in the general population is approximately 2%; the incidence at a male infertility clinic 10-20% (1).

3.2

Aetiology

The causes of spermatogenic failure are summarized in Table 3. Table 3: Causes of spermatogenic failure • Anorchia • Congenital factors (testicular dysgenesis) • Acquired factors (trauma, testicular torsion, tumour, surgery) • Maldescended testes • Klinefelter’s syndrome* • Other chromosomal alterations* • Germ cell aplasia • Complete and focal germ cell aplasia (Sertoli cell-only syndrome), either congenital or acquired: maldescended testes, irradiation, cytostatic drugs • Spermatogenic arrest • Post-inflammatory (orchitis) • Exogenous factors (medications, toxins, irradiation, heat) • Systemic diseases (liver cirrhosis, renal failure) • Testicular tumour • Varicocele • Surgeries that can damage vascularization of the testes • Idiopathic * See section 4 Genetic disorders in infertility.

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UPDATE MARCH 2007

3.3

History and physical examination

Typical findings from the history and physical examination of a patient with spermatogenic failure are: • • • • • • • • • • • • • •

cryptorchidism testicular torsion genito-urinary infection testicular trauma exposure to environmental toxin(s) gonadotoxic medication exposure to radiation or chemical(s) testicular cancer absence of testes abnormal secondary sexual characteristics gynaecomastia cryptorchidism abnormal testicular volume and/or consistency varicocele.

3.4

Investigations

Routine investigations include semen analysis and hormonal determinations. Other investigations may be required depending on the individual situation. 3.4.1 Semen analysis In NOA, semen analysis shows normal ejaculate volume and azoospermia after several centrifugations. A recommended method is semen centrifugation at 600 g for 10 min and thorough microscopic examination of the pellet (x 600). The upper fluid is then re-centrifuged (8000 g) for an additional 10 minutes and then examined. All samples can be stained and re-examined microscopically (2). 3.4.2 Hormonal determinations Generally, the levels of follicle-stimulating hormone (FSH) correlate with the number of spermatogonia: • When spermatogonia are absent or markedly diminished, FSH values are usually elevated. • When the number of spermatogonia is normal, but spermatocyte or spermatid blockage is complete, FSH values are within normal range. However, for an individual patient, FSH levels do not accurately predict the spermatogenesis status (3-5). Preliminary data indicate a stronger correlation between low inhibin B level and spermatogenic damage (6). 3.4.3 Testicular biopsy Testicular biopsy is usually part of an ICSI treatment in patients with clinical evidence of NOA: part of the specimen is used for pathological examination and part is cryopreserved for future ICSI cycles if spermatozoa are present (7, 8). Spermatogenesis may be focal: in about 50-60% of men with NOA, only some seminiferous tubules have spermatozoa that can be used for ICSI. Most authors therefore recommend taking several testicular samples (9, 10). A good correlation is seen between diagnostic biopsy histology and the likelihood of finding mature sperm cells during testicular sperm retrieval and ICSI (11, 12). No clear relationship has been found between successful sperm harvesting and FSH, Inhibin B or testicular volume. In case of AZFa and AZFb microdeletions, no spermatozoa can be retrieved (18, 19). Testicular sperm extraction and Microsurgical testicular sperm extraction (MicroTESE) are the techniques of choice and show excellent repeatability (20); TESE results in sperm retrievals in 50-60% of cases (21, 22). Microsurgical testicular sperm extraction may increase retrieval rates (21, 23, 24). After opening the testis, fluid from large calibre tubules is aspirated with the aid of the operating microscope: complications appear to be lower with MicroTESE than with classical TESE (25). Positive retrievals are reported even in conditions such as Sertoli cell only syndrome (21). Testicular fine-needle aspiration (TEFNA) results in lower retrieval rates and does not allow histological examination to detect carcinoma in situ (CIS) and testicular malignancies (26, 27). TEFNA may also result in more tubular and vascular damage than TESE (28). The results of ICSI are worse when sperm retrieved from men with NOA are used compared to sperm from men with obstructive azoospermia (OA) (29-31):

UPDATE MARCH 2007

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• fertilisation, implantation and birth rates are lower in NOA vs OA (19% vs 28%) (32,33) • miscarriage rates are higher in NOA vs OA (11.5% vs 2.5%) (34). In OA, no significant difference in ICSI results was found between testicular or epididymal sperm (35). Also, no significant differences have been reported in ICSI results between the use of fresh and frozen-thawed sperm (32, 35-39).

3.5

CONCLUSIONS

• •

Impaired spermatogenesis is often associated with elevated FSH concentration. Testicular biopsy is the best procedure to define the histological diagnosis and the possibility of finding sperm. Spermatozoa should be cryopreserved for future ICSI. Spermatozoa are found in about 60% of patients with NOA. Men who are candidates for sperm retrieval must receive appropriate genetic advice. For patients with NOA who have spermatozoa in their testicular biopsy, ICSI with fresh or cryopreserved spermatozoa is the only therapeutic option. Pregnancies and life births are achieved in 30-50% of couples with NOA, when spermatozoa are found in the testicular biopsy.

• • • •

3.6

RECOMMENDATIONS

Recommendations • Men with non-obstructive azoospermia (NOA) can be offered a testicular sperm extraction with cryopreservation of the spermatozoa to be used for intracytoplasmic sperm injection (40-42). Part of the specimen can be used for pathological examination. • To increase the chances of positive sperm retrievals in men with NOA, testicular sperm extraction (single, multiple or microsurgical) should be used rather than testicular fine-needle extraction. GR = grade of recommendation; NOA = non-obstructive azoospermia

3.7

GR B

B

REFERENCES

World Health Organization. WHO Manual for the Standardised Investigation, Diagnosis and Management of the Infertile Male. Cambridge: Cambridge University Press, 2000. 2. World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Spermcervical Mucus Interaction. 4th edn. Cambridge: Cambridge University Press, 1999. 3. Hauser R, Temple-Smith PD, Southwick GJ, de Kretser DM. Fertility in cases of hypergonadotropic azoospermia. Fertil Steril 1995;63(3):631-6. http://www.ncbi.nlm.nih.gov/pubmed/7851598 4. Martin-du Pan RC, Bischof P. Increased follicle stimulating hormone in infertile men. Is increased plasma FSH always due to damaged germinal epithelium? Hum Reprod 1995;10(8):1940-5. http://www.ncbi.nlm.nih.gov/pubmed/8567817 5. De Kretser DM, Burger HG, Hudson B. The relationship between germinal cells and serum FSH in males with infertility. J Clin Endocrinol Metab 1974;38(5):787-93. http://www.ncbi.nlm.nih.gov/pubmed/4823921 6. Pierik FH, Vreeburg JT, Stijnen T, De Jong FH, Weber RF. Serum inhibin B as a marker of spermatogenesis. J Clin Endocrinol Metab 1998;83(9):3110-4. http://www.ncbi.nlm.nih.gov/pubmed/9745412 7. Turek PJ, Kim M, Gilbaugh JH 3rd, Lipshultz LI. The clinical characteristics of 82 patients with Sertoli cell-only testis histology. Fertil Steril 1995;64(6):1197-200. http://www.ncbi.nlm.nih.gov/pubmed/7589676 8. Silber SJ, Nagy Z, Devroey P, Tournaye H, Van Steirteghem AC. Distribution of spermatogenesis in the testicles of azoospermic men: the presence or absence of spermatids in the testes of men with germinal failure. Hum Reprod 1997;12(11):2422-8. Erratum in Hum Reprod 1998;13(3):780. http://www.ncbi.nlm.nih.gov/pubmed/9436677 9. Gottschalk-Sabag S, Weiss DB, Folb-Zacharow N, Zukerman Z. Is one testicular specimen sufficient for quantitative evaluation of spermatogenesis? Fertil Steril 1995;64(2):399-402. http://www.ncbi.nlm.nih.gov/pubmed/7615120 10. Turek PJ, Cha I, Ljung BM. Systematic fine-needle aspiration of the testis: correlation to biopsy and results of organ ‘mapping’ for mature sperm in azoospermic men. Urology 1997;49(5):743-8. http://www.ncbi.nlm.nih.gov/pubmed/9145981 1.

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11.

Schulze W, Rehder U. Organization and morphogenesis of the human seminiferous epithelium. Cell Tissue Res 1984;237(3):395-407. http://www.ncbi.nlm.nih.gov/pubmed/6488283 12. Kim ED, Gilbaugh JH 3rd, Patel VR, Turek PJ, Lipshultz LI. Testis biopsies frequently demonstrate sperm in men with azoospermia and significantly elevated follicle-stimulating hormone levels. J Urol 1997;157(1):144-6. http://www.ncbi.nlm.nih.gov/pubmed/8976237 13. Schoysman R, Vanderzwalmen P, Nijs M, Segal L, Segal-Bertin G, Geerts L, van Roosendaal E, Schoysman D. Pregnancy after fertilization with human testicular spermatozoa. Lancet 1993;342(8881):1237. http://www.ncbi.nlm.nih.gov/pubmed/7901551 14. Devroey P, Liu J, Nagy Z, Tournaye H, Silber SJ, Van Steirteghem AC. Normal fertilization of human oocytes after testicular sperm extraction and intracytoplasmic sperm injection. Fertil Steril 1994;62(2):639-41. http://www.ncbi.nlm.nih.gov/pubmed/8062963 15. Silber SJ, Van Steirteghem AC, Liu J, Nagy Z, Tournaye H, Devroey P. High fertilization and pregnancy rate after intracytoplasmic sperm injection with spermatozoa obtained from testicle biopsy. Hum Reprod 1995;10(1):148-52. http://www.ncbi.nlm.nih.gov/pubmed/7745045 16. Devroey P, Nagy P, Tournaye H, Liu J, Silber S, Van Steirteghem A. Outcome of intracytoplasmic sperm injection with testicular spermatozoa in obstructive and non-obstructive azoospermia. Hum Reprod 1996;11(5):1015-8. http://www.ncbi.nlm.nih.gov/pubmed/8671382 17. Zheng J, Huang X, Li C. Predictive factors for successful sperm recovery in azoospermia patients. Zhonghua Wai Ke Za Zhi 2000;38(5):366-8. [article in Chinese] http://www.ncbi.nlm.nih.gov/pubmed/11832060 18. Foresta C, Ferlin A, Rossi A, Salata E, Tessari A. [Alteration of spermatogenesis and Y chromosome microdeletions. Analysis of the DAZ gene family. ] Minerva Endocrinol. 2002;27(3): 193-207. [article in Italian] http://www.ncbi.nlm.nih.gov/pubmed/12091794 19. Hopps CV, Mielnik A, Goldstein M, Palermo GD, Rosenwaks Z, Schlegel PN. Detection of sperm in men with Y chromosome microdeletions of the AZFa, AZFb, and AZFc regions. Hum Reprod 2003;18(8):1660-5. http://www.ncbi.nlm.nih.gov/pubmed/12871878 20. Amer M, Haggar SE, Moustafa T, Abd El-Naser, Zohdy W. Testicular sperm extraction: impact to testicular histology on outcome, number of biopsies to be performed and optional time for repetition. Hum Reprod 1999;14(12):3030-4. http://www.ncbi.nlm.nih.gov/pubmed/10601092 21. Colpi GM, Piediferro G, Nerva F, Giacchetta D, Colpi EM, Piatti E. Sperm retrieval for intra-cytoplasmic sperm injection in non-obstructive azoospermia. Minerva Urol Nefrol 2005(2); 57:99-107. http://www.ncbi.nlm.nih.gov/pubmed/15951734 22. Vernaeve V, Verheyen G, Goossens A, Van Steirteghem A, Devroey P, Tournaye H. How successful is repeat testicular sperm extraction in patients with azoospermia? Hum Reprod 2006; 21(6):1551-4. http://www.ncbi.nlm.nih.gov/pubmed/16473930 23. Schlegel PN. Testicular sperm extraction: microdissection improves sperm yield with minimal tissue excision. Hum Reprod 1999:14(1):131-5. http://www.ncbi.nlm.nih.gov/pubmed/10374109 24. Okada H, Dobashi M, Yamazaki T, Hara I, Fujisawa M, Arakawa S, Kamidono S. Conventional versus microdissection testicular sperm extraction for non obstructive azoospermia. J Urol 2002;168(3): 1063-7. http://www.ncbi.nlm.nih.gov/pubmed/12187223 25. Dardashti K, Williams RH, Goldstein M. Microsurgical testis biopsy: a novel technique for retrieval of testicular tissue. J Urol 2000;163(4):1206-7. http://www.ncbi.nlm.nih.gov/pubmed/10737497 26. Shulze W, Thoms F, Knuth UA. Testicular sperm extraction: comprehensive analysis with simultaneously performed histology in 1418 biopsies from 766 subfertile men. Hum Reprod 1999;14(1):82-96. http://www.ncbi.nlm.nih.gov/pubmed/10573026

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42.

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Piediferro G, Contalbi GF, Nerva F, Colpi GM. Carcinoma in situ in azoospermia non-ostruttiva sfuggito alla TEFNA e diagnosticato con TESE: Case report. Arch Ital Urol Androl 2004;11:123. Shufaro Y, Prus D, Laufer N, Simon A. Impact of repeated fine needle aspiration (TEFNA) and testicular sperm extraction (TESE) on the microscopic morphology of the testis: an animal model. Hum Reprod 2002;17(7):1795-9. http://www.ncbi.nlm.nih.gov/pubmed/12093842 Monzo A, Kondylis F, Lynch D, Mayer J, Jones E, Nehchiri F, Morshedi M, Schuffner , Muasher S, Gibbons W, Oehninger S. Outcome of intracytoplasmic sperm injection in azoospermic patients: stressing the liaison between the urologist and reproductive medicine specialist. Urology 2001;58(1):69-75. http://www.ncbi.nlm.nih.gov/pubmed/11445482 Vernaeve V, Tournaye H, Osmanagaoglu K, Verheyen G, Van Steirteghem A, Devroey P. Intracytoplasmic sperm injection with testicular spermatozoa is less successful in men with nonobstructive azoospermia than in men with obstructive azoospermia. Fertil Steril 2003;79(3):529-33. http://www.ncbi.nlm.nih.gov/pubmed/12620435 Silber S, Munné S. Chromosomal abnormalities in embryos derived from testicular sperm extraction (tese) in men with non-obstructive azoospermia. Proceedings EAA International Symposium ‘Genetics of Male Infertility: from Research to Clinic’. Florence, Italy, October 2-4, 2003. Schwarzer J, Fiedler K, Hertwig I, Krusmann G, Wurfel W, Schleyer M, Muhlen B, Pickl U, LochnerErnst D. Sperm retrieval procedures and intracytoplasmatic spermatozoa injection with epididymal and testicular sperms. Urol Int 2003;70(2):119-23. http://www.ncbi.nlm.nih.gov/pubmed/12592040 Ghanem M, Bakr NI, Elgayaar MA, El Mongy S, Fathy H, Ibrahim AH. Comparison of the outcome of intracytoplasmic sperm injection in obstructive and non-obstructive azoospermia in the first cycle: a report of case series and meta-analysis. Int J Androl 2005;28(1):16-21. http://www.ncbi.nlm.nih.gov/pubmed/15679616 Borges E Jr, Rossi-Ferragut LM, Pasqualotto FF, dos Santos DR, Rocha CC, Iaconelli A Jr. Testicular sperm results in elevated miscarriage rates compared to epididymal sperm in azoospermic patients. Sao Paulo Med J 2002;120(4):122-6. http://www.ncbi.nlm.nih.gov/pubmed/12436160 Gil Salom M. [Spermatic recovery techniques for intracytoplasmic spermatozoid injection (ICSI) in male infertility. ]Arch Esp Urol 2004;57(9):1035-46. [article in Spanish] http://www.ncbi.nlm.nih.gov/pubmed/15624403 Ben-Yosef D, Yogev L, Hauser R, Yavetz H, Azem F, Yovel I, Lessing JB, Amit A. Testicular sperm retrieval and cryopreservation prior to initiating ovarian stimulation as the first line approach in patients with non-obstructive azoospermia. Hum Reprod 1999;14(7):1794-801. http://www.ncbi.nlm.nih.gov/pubmed/10402392 Gil-Salom M, Romero J, Rubio C, Ruiz A, Remohi J, Pellicer A. Intracytoplasmic sperm injection with cryopreserved testicular spermatozoa. Mol Cell Endocrinol 2000;169(1-2):15-9. http://www.ncbi.nlm.nih.gov/pubmed/11155947 Sousa M, Cremades N, Silva J, Oliveira C, Ferraz L, Teixeira da Silva J, Viana P, Barros A. Predictive value of testicular histology in secretory azoospermic subgroups and clinical outcomes after microinjection of fresh and frozen-thawed sperm and spermatids. Hum Reprod 2002;17(7):1800-10. http://www.ncbi.nlm.nih.gov/pubmed/12093843 Hauser R, Yogev L, Amit A, Yavetz H, Botchan A, Azem F, Lessing JB, Ben-Yosef D. Severe hypospermatogenesis in cases of nonobstructive azoospermia: should we use fresh or frozen testicular spermatozoa? J Androl 2005;26(6):772-8. http://www.ncbi.nlm.nih.gov/pubmed/16291973 Friedler S, Raziel A, Soffer Y, Strassburger D, Komarovsky D, Ron-El R. Intracytoplasmic injection of fresh and cryopreserved testicular spermatozoa in patients with nonobstructive azoospermia-a comparative study. Fertil Steril 1997;68(5):892-7. http://www.ncbi.nlm.nih.gov/pubmed/9389822 Ghazzawi IM, Sarraf MG, Taher MR, Khalifa FA. Comparison of the fertilizing capability of spermatozoa from ejaculates, epididymal aspirates and testicular biopsies using intracytoplasmic sperm injection. Hum Reprod 1998;13(2):348-52. http://www.ncbi.nlm.nih.gov/pubmed/9557836 Palermo GD, Schlegel PN, Hariprashad JJ, Ergun B, Mielnik A, Zaninovic N, Veeck LL, Rosenwaks Z. Fertilization and pregnancy outcome with intracytoplasmic sperm injection for azoospermic men. Hum Reprod 1999;14(3):741-8. http://www.ncbi.nlm.nih.gov/pubmed/10221707

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4. GENETIC DISORDERS IN INFERTILITY 4.1

Introduction

All urologists working in andrology must have a knowledge of genetic abnormalities in infertility so that they can provide correct advice to couples seeking fertility treatment. Men with very low sperm counts can be given a reasonable chance of paternity using in vitro fertilisation (IVF), ICSI and TESE. However, the sperm of infertile men show an increase in aneuploidy, other genetic abnormalities and DNA damage and therefore the possibility of passing genetic abnormalities to the next generation. Although there are prospects for screening of sperm (1), current routine clinical practice is based on screening peripheral blood samples.

4.2

Chromosomal abnormalities

Chromosome abnormalities can be numerical (e.g. trisomy) or structural (e.g. inversions or translocations) (2, 3). In a survey of pooled data from 11 publications including 9,766 infertile men, the incidence of chromosomal abnormalities was 5.8% (2). Of these, sex chromosome abnormalities accounted for 4.2% and autosomal abnormalities for 1.5%. For comparison, the incidence of abnormalities in pooled data from three series totalling 94,465 newborn male infants was 0.38%, of which 131 (0.14%) were sex chromosome abnormalities and 232 (0.25%) autosomal abnormalities (3). Standard karyotype analysis should be offered to all men with damaged spermatogenesis who are seeking fertility treatment by IVF/ICSI. 4.2.1 Sperm chromosomal abnormalities Using multicolour fluorescent in situ hybridisation (FISH) analysis sperm can be examined for chromosomal normality. Aneuploidy in sperm, in particular sex chromosome aneuploidy, is associated with severe damage to spermatogenesis (2, 4, 5, 7-11) and is also seen in men with translocations (6). FISH analysis of spermatozoa is a research investigation but should be used, particularly to assess spermatozoa from men with defined andrological conditions. Techniques are needed to separate populations of genetically abnormal sperm from normal sperm or to safely safe screen individual spermatozoa before IVF and ICSI. 4.2.2 Sex chromosome abnormalities (Klinefelter’s syndrome and variants [47,XXY; 46,XY; 47,XXY mosaicism]) Klinefelter’s syndrome is the most frequent sex chromosome abnormality (3). Adult men with Klinefelter’s syndrome have small firm testicles. The phenotype can vary from a normally virilised man to one with stigmata of androgen deficiency, including female hair distribution, scanty body hair and long arms and legs because of late epiphyseal closure. Leydig cell function is commonly impaired in men with Klinefelter’s syndrome (12). Testosterone levels may be normal or low, oestradiol levels normal or elevated and FSH levels increased. Libido is often normal despite low testosterone levels, but androgen replacement may be needed as the patient ages. Germ cell presence and sperm production are variable in men with Klinefelter’s mosaicism, 46,XY, 47,XXY. Preimplantation genetic diagnosis using FISH analysis of cells from embryos can be used to confirm normality (13). The production of 24,XY sperm has been reported in 0.9% and 7.0% of men with Klinefelter’s mosaicism (14-16) and in 1.36-25% of men with somatic karyotype 47,XXY (17-21). There is one case report of declining spermatogenesis in a man with Klinefelter’s syndrome, with the recommendation that early sperm retrieval sperm should be considered (22). Haploid sperm in men with Klinefelter’s syndrome may be the result of a clone of normal cells in a mosaic population, and in certain circumstances some 47,XXY male germ cells may be viable and capable of producing haploid sperm (23). Klinefelter’s syndrome patients have an increased chance of producing 47,XXY spermatozoa. When IVF/ICSI carried out, pre-implantation diagnosis or amniocentesis and karyotype analysis should undertaken. Embryos with known Klinefelter’s karyotype should probably not be implanted. Men with Klinefelter’s syndrome might require androgen replacement therapy as they get older. All men with Klinefelter’s syndrome who undergo testicular biopsy procedures for sperm retrieval need long-term endocrine follow-up. 4.2.3 Autosomal abnormalities Genetic counselling should be offered to all couples seeking fertility treatment (including IVF/ICSI) where the male partner is known, or found to have, autosomal karyotype abnormality. 4.2.4 Translocations Reciprocal balanced translocations occur in 1 in 500 people. An individual with a balanced translocation has a complete set of genetic information and a normal phenotype. However, when this individual has children,

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the child receives unbalanced genetic information (either too much or too little genetic material). A parental balanced translocation involving chromosome 21 is one cause of Down’s syndrome. When IVF/ICSI is carried out for men with translocations, pre-implantation genetic diagnosis or, amniocentesis and karyotype analysis should be used. Embryos with known unbalanced translocation should probably not be implanted.

4.3

Genetic defects

4.3.1 X-linked genetic disorders and male fertility Each man has only one X-chromosome. An X-linked recessive disorder manifests in males, and the defect will be transmitted to daughters but not to sons. 4.3.2 Kallmann’s syndrome The most common X-linked disorder in infertility practice is Kallmann’s syndrome. The predominant form is an X-linked recessive disorder caused by a mutation in the KALIG-1 gene on Xp22.3 (24). Rarer forms of Kallmann’s syndrome include an autosomal-dominant form (25). Patients with Kallmann’s syndrome have hypogonadotropic hypogonadism and might have other clinical features, including anosmia, facial asymmetry, cleft palate, colour blindness, deafness, maldescended testes and renal abnormalities. Some men with Kallmann’s syndrome have an isolated gonadotrophin deficiency without any other phenotypic abnormalities and might present de novo with infertility. It is often possible to stimulate spermatogenesis with replacement therapy (26). 4.3.3 Androgen insensitivity: Reifenstein’s syndrome Androgen insensitivity is a rare disorder and might first present with infertility. The condition has X-linked recessive inheritance as a result of a defect in the androgen receptor gene located on Xq 11-12. The phenotype varies widely, from complete testicular feminisation to an apparently normal man with infertility, although the latter is rare. Disorders of the androgen receptor causing infertility in the absence of any genital abnormality are rare (27), although some cases have been identified (28). 4.3.4 Other X-disorders A case has been reported of an azoospermic man with biopsy-proven spermatogenetic arrest, who was found to have a submicroscopic interstitial deletion on the Xp pseudo-autosomal region in peripheral blood and skin fibroblast samples. Other genetic and chromosome examinations were entirely normal, including probing of the Yq region (29). There is also a report about two men with azoospermia and X pseudo-autosomal deletions (30).

4.4

Y genes and male infertility

4.4.1 Introduction The first cases of Y microdeletions and male infertility were reported in 1992 (31) and many case series have subsequently been published. Microdeletions may occur in fertile men, but they are more prevalent in infertile men (32). Microdeletions have been found in three non-overlapping regions of the Y chromosome, AZF a-b-c (33). A fourth region AZFd overlaps with AZFc and is considered by some to be a separate area (34, 35). The most common microdeletion is in the AZFc region, encompassing the DAZ gene. However, there is a poor correlation between AZFc microdeletions or DAZ gene deletion and spermatogenesis; men with apparently similar microdeletions can have different degrees of damage to their spermatogenesis (32, 36). TESE can be used for men with AZFc Y microdeletions (37). AZFa and AZFb microdeletions are much rarer. If the AZFa microdeletion is large enough to remove both the USP9Y (DFFRY) and the DDX3Y (DBY) genes, azoospermia occurs (38-40). There is no recorded case of sperm recovery by micro-TESE (37). Azoospermia also occurs in men with larger AZFb Y microdeletions (37). Microdeletions are a subset of rearrangments of the long arm of the Y chromosome, others include duplications and inversions. The biological significance of these haplotypes has yet to be determined (41), but some of them might be associated with reduced fertility (42). 4.4.2 Clinical implications of Y microdeletions Men with Y microdeletions are unlikely to have phenotypic abnormalities other than abnormalities of the male reproductive system. Y microdeletions are associated with varying degrees of derangement of spermatogenesis (33, 35, 36, 39, 43). The AZFc microdeletion 51gr/51gr, which is associated with male infertility, (44) is a rare low penetrance allele that confers susceptibility to testicular germ cell tumour (TGCT) (45). This finding has implications when ICSI is used for a man with a gr/gr microdeletion. More information is needed about Y genes and Y microdeletions and diseases of the male reproductive system. There is also one report of a higher frequency of AZFc microdeletions in the husbands of women with recurrent pregnancy loss (46). Y microdeletions can be transmitted to male offspring, although this is rare in the normal population

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because, without ICSI treatment, men with very low sperm counts are unlikely to father children (32, 33, 47-53). In most cases, the microdeletion in the son is the same as in the father, but there have been reports that the size of the microdeletion is greater in the son (49, 53). When ICSI is used in the presence of a Y microdeletion, long-term follow up of any male children is needed with respect to their fertility status and, in the case of gr/gr microdeletions, their risk of developing germ cell tumours. 4.4.2.1 Testing for Y microdeletions Testing for microdeletions is now widespread, and methodology is being standardised (33, 54, 55). The following genes are located in the AZF regions and specifically expressed in the testis, RBMY1A1, DAZ, VCY, XKRY, CDY1, DY2, HSFY, PRY, and BPY2. Other genes, including RPS4Y2, USP9Y, DDX3Y, UTY, JARIDID, and EIF1AY, are expressed in more than one tissue. Studies are needed to correlate testis histopathology with different combinations of loss of one or more of these genes. (For complete listings of Y genes, see the NCBI web site http://www.ncbi.nlm.nih. gov). The best test is to use selected sequence tagged sites (STS) probes chosen to define the most likely microdeletions. In future, gene array analysis may replace testing for Y microdeletions. Direct testing for genes is a research procedure. 4.4.2.2 Conclusions • For men with severely damaged spermatogenesis, testing for microdeletions before intracytoplasmic sperm injection (ICSI) is desirable. However, it is reasonable to consider the cost and availability of testing and to discuss this with the couple. • If AZFa or AZFb Y microdeletions are detected, testicular sperm extraction is not worthwhile because the chance of finding sperm is extremely low. • Microdeletions will be passed to sons, but not to daughters. • A son who inherits a microdeletion will probably have a fertility problem. 4.4.3 Autosomal defects with severe phenotypic abnormalities as well as infertility Several inherited disorders are associated with severe or considerable generalised abnormalities and infertility (Table 4). Patients with these defects will be well known to doctors, often from childhood, and any fertility problem must be managed in the context of the care of the man as a whole and with consideration of the couple’s ability to care for a child. Table 4: Less common inherited disorders associated with infertility and other alterations to phenotype Disorder Phenotype Genetic basis Prader–Willi Obesity, mental retardation Deletion of 15q12 on paternally inherited chromosome Bardet–Biedle Obesity, mental retardation, Autosomal recessive retinitis pigmentosa, polydactyly 16q21 Cerebellar ataxia and Eunuchoidism, disturbances of Autosomal recessive hypogonadotropic hypogonadism gait and speech Noonan’s syndrome Short stature, webbed neck, Autosomal dominant cardiac and pulmonary abnormalities, cryptorchidism Myotonic dystrophy Muscle wasting, cataract testicular Autosomal dominant atrophy 19q13.3 Dominant polycystic Renal cysts, obstruction from Autosomal dominant kidney disease epididymal cysts 16p13.3 and 4q 5-alpha reductase deficiency Perineal or scrotal hypospadias, Autosomal recessive vaginal pouch, immature female phenotype

4.5

Cystic fibrosis mutations and male infertility

Cystic fibrosis (CF), a fatal autosomal-recessive disorder, is the most common genetic disease of Caucasians; 4% are carriers of gene mutations involving the CF transmembrane conductance regulator (CFTR) gene. This gene is located on the short arm of chromosome 7. It encodes a membrane protein that functions as an ion channel and also influences the formation of the ejaculatory duct, seminal vesicle, vas deferens and distal twothirds of the epididymis. Congenital bilateral absence of the vas deferens (CBAVD) is associated with CFTR mutations and was found in approximately 2% of men with OA attending a clinic in Edinburgh (56). The incidence in men with OA

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varies between different countries. The clinical diagnosis of absent vasa is easy to miss and all men with azoospermia should be very carefully examined to exclude CBAVD, particularly those with a semen volume of < 1.5 mL and pH less than 7.0. Approximately 1500 mutations are listed on the CFTR database (http://www.genet.sickkids.on.ca/ cftr/). Many series of men with CBAVD, who were tested for varying numbers of mutations, have been published. In general, the more mutations tested for, the higher the percentage of men found to have them. In a review of published series of 449 men with CBAVD, the Delta F508 mutation was detected in 244 men, the R117H mutation in 54 men and the W1282X mutation in 37; 63 other mutations were found in 1-9 men, but not all mutations were tested for in all case series (57). As more mutations are defined and tested for, almost all men with CBAVD will probably be found to have mutations. It is not practical to test for all known mutations, as many have a very low prevalence in a particular population. Testing is usually restricted to mutations that occur most commonly in a particular community. Mutations may be found in both copies of the CFTR gene; however, in most men with CBAVD, mutation is found in only one copy. In some of these supposedly heterozygous cases, there may be an unknown second mutation, but there is also another mechanism. In two-thirds of men with CBAVD a DNA variant (the 5th allele) can be detected in a non-coding region of CFTR (58). Men with CBAVD often have mild clinical stigmata of CF (e.g. history of chest infections). Children born after ICSI, where the father has CBAVD and is either hetero- or homozygous, must be followed up. When a man has CBAVD, it is important to test him and his partner for CF mutations. If the female partner is found to be a carrier of CFTR, the couple must consider very carefully whether to proceed with ICSI using the husband’s sperm, as the chance of a having a baby with CF will be 25% if the man is heterozygous and 50% if the man is homozygous. If the female partner is negative for known mutations, her chance of being a carrier of unknown mutations is about 0.4%. In these circumstances, the possibility of her heterozygous partner fathering a child with CF is approximately 1:410.

4.6

Unilateral or bilateral absence/abnormality of the vas and renal anomalies

Unilateral absence of the vas deferens is usually associated with ipsilateral absence of the kidney (59) and probably has a different genetic causation. Men with unilateral absence of the vas deferens are usually fertile, and the condition is most commonly encountered as an incidental finding in the vasectomy clinic. Nevertheless, men with unilateral absence of the vas deferens and CF mutations may have the same underlying genetic diseases as men with true CBAVD. Men with bilateral absence of vas deferens and renal abnormalities do not have CFTR abnormalities (60). Men who have unilateral absence of the vas and normal kidneys or bilateral absence or bilateral abnormality, should be tested for CF mutations. If the results are negative and renal anatomy has not been defined, an abdominal ultrasound should be undertaken. Findings may range from unilateral absence of the vas with ipsilateral absence of the kidney to bilateral vessel abnormalities and renal abnormalities, such as pelvic kidney.

4.7

Other single gene disorders

There is intense research into genes that control spermatogenesis, and in particular unique Y genes as their products may be targets for non-hormonal contraception. Many research publications discuss candidate genes for spermatogenesis, for example: • ubiquitin protease 26 gene (61, 62) • polymorphisms in the oestrogen receptor gene (63, 64) • polymorphisms of the gonadotrophin-regulated testicular helicase gene (65) • UTP14c (66) • SPAG16L (67) • BGR-like gene (68) • SPO11, EIF5A2, ACT (69) • N372H variant of the BRCA2 gene (70) • heat shock transcription factor in AZFb (71). Clinical application of these findings is limited; single gene mutations of these various genes probably account for only a small proportion of male infertility. The practicality of testing is limited by expense and availability of testing techniques; however, the advent of cheap gene array testing techniques, with the capacity to screen all or most of the known single gene defects with one test, might change the approach to testing.

4.8

Unknown genetic disorders

ICSI is used to enable men with severely damaged spermatogenesis to father children in situations formerly considered hopeless and where very few spermatozoa can be obtained. This has led to worries that children

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may be born with a fetal abnormality, because ICSI may enable defective sperm to bypass the selective processes of the female genital tract and egg covering. Alternatively, eggs may be fertilised that would otherwise not be fertilised. Fetal abnormality statistics from ICSI centres do not, however, indicate any increase in congenital malformations compared with the general population. Indications for ICSI are constantly being extended to include fertilisation with immature sperm forms, and it is therefore particularly important to continue to monitor fetal abnormality rates, using detailed subgroup analysis according to the clinical and molecular diagnosis of the father.

4.9

Genetic and DNA abnormalities in sperm

The DNA damage in spermatozoa from men with oligozoospermia is increased. This increase is associated with reduced chances of natural conception and, to a lesser extent, conception after IVF/ICSI (72) and with an increase in early pregnancy loss (73). DNA damage may improve after varicocele ligation (74).

4.10

Genetic counselling and ICSI

The best management is to agree treatment with the couple and provide them with complete details of the genetic risk. Initially, the couple should be given full information about the risks to the child to help them decide whether to proceed with ICSI. Where there is conflict between the wishes of the couple and the interests of the future child, it may be ethically correct to withhold therapy. When both partners are known to carry defects (e.g. CF mutations), the chance of the child developing a clinical condition and dying early after a number of years of morbidity can be up to 50%. Many clinicians and infertility clinic personnel may consider it is unethical to proceed on the basis that the duty of care to the future child and the interests of society outweigh the wishes of the individual couple. If there is a conflict that cannot be resolved by agreement, the interests of a future child probably take precedence over the interests of a couple. The couple also need to give consideration to pre-implantation diagnosis and replacement only of normal embryos.

4.11 CONCLUSIONS • •

4.12

 ew insights into the genetic basis of infertility and the advent of ICSI require a good understanding N of genetics by clinicians and the general public. Diagnostic advances will allow us to identify the genetic basis of more disorders and diagnose known disorders at a lower cost. For some of these disorders, gene therapy might be practical.

RECOMMENDATIONS

Recommendations • Standard karyotype analysis should be offered to all men with damaged spermatogenesis who are seeking fertility treatment by in vitro fertilisation/intracytoplasmic sperm injection (ICSI) (2). • For men with severely damaged spermatogenesis, testing for Yq microdeletions before ICSI is desirable. • When a man has structural abnormalities of the vas deferens (congenital bilateral absence of the vas deferens [CBAVD]), it is important to test him and his partner for cystic fibrosis gene mutations (57). • Genetic counselling is mandatory in couples with a genetic abnormality found in clinical or genetic investigation and in patients who carry a (potential) inheritable disease (1). GR = grade of recommendation

4.13

GR A

B

A

REFERENCES

1.

Griffin DK, Finch KA. The genetic and cytogenetic basis of male infertility. Human Fertil 2005;8(1); 19-26. http://www.ncbi.nlm.nih.gov/pubmed/15823847 2. Johnson MD. Genetic risks of intracytoplasmic sperm injection in the treatment of male infertility: recommendations for genetic counseling and screening. Fertil Steril 1998;70(3):397-411. http://www.ncbi.nlm.nih.gov/pubmed/9757865 3. van Assche EV, Bonduelle M, Tournaye H, Joris H, Verheyen G, Devroey P, Van Steirteghem A, Liebaers I. Cytogenetics of infertile men. Hum Reprod 1996;11(Suppl 4):1-24. http://www.ncbi.nlm.nih.gov/pubmed/9147109 4. Chandley AC. Chromosomes. In: Hargreave TB (ed). Male Infertility. Berlin: Springer-Verlag, 1994, pp. 149-164.

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5. Clementini E, Palka C, Iezzi I, Stuppia L, Guanciali-Franchi P, Tiboni GM. Prevalence of chromosomal abnormalities in 2078 inferitle couples referred for assisted reproduction technologies. Hum Reprod 2005;20(2):437-42. http://www.ncbi.nlm.nih.gov/pubmed/15567875 6. Baccetti B, Collodel G, Marzella R, Moretti E, Piomboni P, Scapigliati G, Serafini F. Ultrastructural studies of spermatozoa from infertile males with Robertsonian translocations and 18, X, Y aneuploidies. Hum Reprod 2005;20(8):2295-300. http://www.ncbi.nlm.nih.gov/pubmed/15878922 7. Martin RH. The risk of chromosomal abnormalities following ICSI. Hum Reprod 1996;11(5):924-5. http://www.ncbi.nlm.nih.gov/pubmed/8671360 8. Gianaroli L, Magli MC, Cavallini G, Grippa A, Nadalini M, Bernardini L, Menchini Fabris GF, Voliani S, Ferraretti AP. Frequency of aneuploidy in sperm from patients with extremely severe male factor infertility. Hum Reprod 2005;20(8):2140-52. http://www.ncbi.nlm.nih.gov/pubmed/15845594 9. Pang MG, Kim YJ, Lee SH, Kim CK. The high incidence of meiotic errors increases with decreased sperm count in severe male factor infertilities. Hum Reprod 2005;20(6):1688-94. http://www.ncbi.nlm.nih.gov/pubmed/15734753 10. Machev N, Gosset P, Viville S. Chromosome abnormalities in sperm from infertile men with normal somatic karyotypes: teratozoospermia. Cytogenet Genome Res 2005;111(3-4):352-7. http://www.ncbi.nlm.nih.gov/pubmed/16192715 11. Miharu N. Chromosome abnormalities in sperm from infertile men with normal somatic karyotypes: oligozoospermia. Cytogenet Genome Res 2005;111(3-4):347-51. http://www.ncbi.nlm.nih.gov/pubmed/16192714 12. Wang C, Baker HW, Burger HG, De Kretser DM, Hudson B. Hormonal studies in men with Klinefelter’s syndrome. Clin Endocrinol (Oxf) 1975;4(4):399-411. http://www.ncbi.nlm.nih.gov/pubmed/1157343 13. Tournaye H, Staessen C, Liebaers I, Van Assche E, Devroey P, Bonduelle M, Van Steirteghem A. Testicular sperm recovery in nine 47,XXY Klinefelter patients. Hum Reprod 1996;11(8):1644-9. http://www.ncbi.nlm.nih.gov/pubmed/8921109 14. Chevret E, Rousseaux S, Monteil M, Usson Y, Cozzi J, Pelletier R, Sele B. Increased incidence of hyperhaploid 24 XY spermatozoa detected by three-colour FISH in a 46,XY/47,XXY male. Hum Genet 1996;97(2):171-5. http://www.ncbi.nlm.nih.gov/pubmed/8566948 15. Martini E, Geraedts JPM, Liebaers I, Land JA, Capitanio GL, Ramaekers FC, Hopman AH. Constitution of semen samples from XYY and XXY males as analysed by in-situ hybridization. Hum Reprod 1996;11(8):1638-43. http://www.ncbi.nlm.nih.gov/pubmed/8921108 16. Lenz P, Luetjens CM, Kamischke A, Kuhnert B, Kennerknecht I, Nieschlag E. Mosaic status in lymphocytes of infertile men with or without Klinefelter syndrome. Hum Reprod 2005;20(5):1248-55. http://www.ncbi.nlm.nih.gov/pubmed/15665007 17. Cozzi J, Chevret E, Rousseaux S, Pelletier R, Benitz V, Jalbert H, Sele B. Achievement of meiosis in XXY germ cells: study of 543 sperm karyotypes from an XY/XXY mosaic patient. Hum Genet 1994;93(1):32-4. http://www.ncbi.nlm.nih.gov/pubmed/8270252 18. Guttenbach M, Michelmann HW, Hinney B, Engel W, Schmid M. Segregation of sex chromosomes into sperm nuclei in a man with 47,XXY Klinefelter’s karyotype: a FISH analysis. Hum Genet 1997;99(4):474-7. http://www.ncbi.nlm.nih.gov/pubmed/9099836 19. Estop AM, Munne S, Cieply KM, Vandermark KK, Lamb AN, Fisch H. Meiotic products of a Klinefelter 47,XXY male as determined by sperm fluorescence in-situ hybridization analysis. Hum Reprod 1998;13(1):124-7. http://www.ncbi.nlm.nih.gov/pubmed/9512242 20. Foresta C, Galeazzi C, Bettella A, Stella M, Scandellari C. High incidence of sperm sex chromosomes aneuploidies in two patients with Klinefelter’s syndrome. J Clin Endocrinol Metab 1998;83(1):203-5. http://www.ncbi.nlm.nih.gov/pubmed/9435442 21. Hennebicq S, Pelletier R, Rousseaux S, Sèle B. Segregation of sex chromosomes in a Klinefelter patient (47,XXY). Hum Reprod (Abstract Book 1) 1999;14:66. 22. Ichioka K, Utsunomiya N, Kohei N, Ueda N, Inoue K, Terai A. Adult onset of declining spermatogenesis in a man with nonmosaic Klinefelter’s syndrome. Fertil Steril 2006;85(5):1511.e1-e2. http://www.ncbi.nlm.nih.gov/pubmed/16616747

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23.

Gonsalves J, Turek PJ, Schlegel PN, Hopps CV, Weier JF, Pera RA. Recombination in men with Klinefelter syndrome. Reproduction 2005;130(2):223-9. http://www.ncbi.nlm.nih.gov/pubmed/16049160 24. Franco B, Guioli S, Pragliola A, Incerti B, Bardoni B, Tonlorenzi R, Carrozzo R, Maestrini E, Pieretti M, Taillon-Miller P, et al. A gene deleted in Kallmann’s syndrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature 1991;353(6344):529-36. http://www.ncbi.nlm.nih.gov/pubmed/1922361 25. Santen RJ, Paulsen CA. Hypogonadotropic eunuchoidism. I. Clinical study of the mode of inheritance. J Clin Endocrinol Metab 1973;36(1):47-54. http://www.ncbi.nlm.nih.gov/pubmed/4404632 26. Miyagawa Y, Tsujimura A, Matsumiya K, Takao T, Tohda A, Koga M, Takeyama M, Fujioka H, Takada S, Koide T, Okuyama A. Outcome of gonadotropin therapy for male hypogonadotropic hypogonadism at university affiliated male infertility centers: a 30-year retrospective study. J Urol 2005;173(6):2072-5. http://www.ncbi.nlm.nih.gov/pubmed/15879837 27. Tincello DG, Saunders PT, Hargreave TB. Preliminary investigations on androgen receptor gene mutations in infertile men. Mol Hum Reprod 1997;3(11):941-3. http://www.ncbi.nlm.nih.gov/pubmed/9433918 28. Gottlieb B, Lombroso R, Beitel LK, Trifiro MA. Molecular pathology of the androgen receptor in male (in)fertility. Reprod Biomed Online 2005;10(1):42-8. http://www.ncbi.nlm.nih.gov/pubmed/15705293 29. Gonialves J, McElreavey K, Carreiro H, et al. An azoospermic man with a submicroscopic interstitial deletion on the Xp pseudoautosomal region. Hum Reprod (Abstract Book 1)1996;11:pp. 158-159. 30. Gabriel-Robez O, Rumpler Y, Ratomponirina C, Petit C, Levilliers J, Croquette MF, Couturier J. Deletion of the pseudoautosomal region and lack of sex-chromosome pairing at pachytene in two infertile men carrying an X,Y translocation. Cytogenet Cell Genet 1990;54(1-2):38-42. http://www.ncbi.nlm.nih.gov/pubmed/2249473 31. Ma K, Sharkey, A, Kirsch S, Vogt P, Keil R, Hargreave TB, McBeath S, Chandley AC. Towards the molecular localisation of the AZF locus: mapping of microdeletions in azoospermic men within 14 subintervals of interval 6 of the human Y chromosome. Hum Mol Genet 1992;1(1):29-33. http://www.ncbi.nlm.nih.gov/pubmed/1301132 32. Pryor JL, Kent-First M, Muallem A, van Bergen AH, Nolten WE, Meisner L, Roberts KP. Microdeletions in the Y chromosome of infertile men. New Engl J Med 1997;336(8):534-9. http://www.ncbi.nlm.nih.gov/pubmed/9023089 33. Vogt P, Edelmann A, Kirsch S, Henegariu O, Hirschmann P, Kiesewetter F, Kohn FM, Schill WB, Farah S, Ramos C, Hartmann M, Hartschuh W, Meschede D, Behre HM, Castel A, Nieschlag E, Weidner W, Grone HJ, Jung A, Engel W, Haidl G. Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Hum Mol Genet 1996;5(7):933-43. http://www.ncbi.nlm.nih.gov/pubmed/8817327 34. Muslumanoglu MH, Turgut M, Cilingir O, Can C, Ozyurek Y, Artan S. Role of the AZFd locus in spermatogenesis. Fertil Steril 2005;84(2):519-22. http://www.ncbi.nlm.nih.gov/pubmed/16084901 35. Kent-First M, Muallem A, Shultz J, Pryor J, Roberts K, Nolten W, Meisner L, Chandley A, Gouchy G, Jorgensen L, Havighurst T, Grosch J. Defining regions of the Y-chromosome responsible for male infertility and identification of a fourth AZF region (AZFd) by Y-chromosome microdeletion detection. Mol Reprod Dev 1999;53(1):27-41. http://www.ncbi.nlm.nih.gov/pubmed/10230814 36. Hsu CC, Kuo PL, Chuang L, Lin YH, Teng YN, Lin YM. Uniform deletion junctions of complete azoospermia factor region c deletion in infertile men in Taiwan. Asian J Androl 2006;8(2):205-11. http://www.ncbi.nlm.nih.gov/pubmed/16491273 37. Hopps CV, Mielnik A, Goldstein M, Palermo GD, Rosenwaks Z, Schlegel PN. Detection of sperm in men with Y chromosome microdeletions of the AZFa, AZFb and AZFc regions. Hum Reprod 2003;18(8):1660-5. http://www.ncbi.nlm.nih.gov/pubmed/12871878 38. Sargent CA, Boucher CA, Kirsch S, Brown G, Weiss B, Trundley A, Burgoyne P, Saut N, Durand C, Levy N, Terriou P, Hargreave T, Cooke H, Mitchell M, Rappold GA, Affara NA. The critical region of overlap defining the AZFa male infertility interval of proximal Yq contains three transcribed sequences. J Med Genet 1999;36(9):670-7. http://www.ncbi.nlm.nih.gov/pubmed/10507722

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Foresta C, Moro E, Rossi A, Rossato M, Garolla A, Ferlin A. Role of the AZFa candidate genes in male infertility. J Endocrinol Invest 2000;23(10):646-51. http://www.ncbi.nlm.nih.gov/pubmed/11097428 40. Kamp C, Huellen K, Fernandes S, Sousa M, Schlegel PN, Mielnik A, Kleiman S, Yavetz H, Krause W, Kupker W, Johannisson R, Schulze W, Weidner W, Barros A, Vogt PH. High deletion frequency of the complete AZFa sequence in men with Sertoli-cell-only syndrome. Mol Hum Reprod 2001;7(10): 987-94. http://www.ncbi.nlm.nih.gov/pubmed/11574668 41. Vogt PH. AZF deletions and Y chromosomal haplogroups: history and update based on sequence. Hum Reprod Update 2005;11(4):319-36. http://www.ncbi.nlm.nih.gov/pubmed/15890785 42. Teng YN, Lin YM, Sun HF, Hsu PY, Chung CL, Kuo PL. Association of DAZL haplotypes with spermatogenic failure in infertile men. Fertil Steril 2006;86(1):129-35. http://www.ncbi.nlm.nih.gov/pubmed/16730721 43. Reijo R, Lee TY, Salo P, Alagappan R, Brown LG, Rosenberg M, Rozen S, Jaffe T, Straus D, Hovatta O et al. Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nat Genet 1995;10(4):383-93. http://www.ncbi.nlm.nih.gov/pubmed/7670487 44. Lynch M, Cram DS, Reilly A, O’Bryan MK, Baker HW, de Kretser DM, McLachlan RI. The Y chromosome gr/gr subdeletion is associated with male infertility. Mol Hum Reprod 2005;11(7):507-12. http://www.ncbi.nlm.nih.gov/pubmed/16123079 45. Nathanson KL, Kanetsky PA, Hawes R, Vaughn DJ, Letrero R, Tucker K, Friedlander M, Phillips KA, Hogg D, Jewett MA, Lohynska R, Daugaard G, Richard S, Chompret A, Bonaiti-Pellie C, Heidenreich A, Olah E, Geczi L, Bodrogi I, Ormiston WJ, Daly PA, Oosterhuis JW, Gillis AJ, Looijenga LH, Guilford P, Fossa SD, Heimdal K, Tjulandin SA, Liubchenko L, Stoll H, Weber W. Rudd M, Huddart R, Crockford GP, Forman D, Oliver DT, Einhorn L, Weber BL, Kramer J, McMaster M, Greene MH, Pike M, Cortessis V, Chen C, Schwartz SM, Bishop DT, Easton DF, Stratton MR, Rapley EA. The Y deletion gr/gr and susceptibility to testicular germ cell tumor. Am J Hum Genet 2005;77(6):1034-43. http://www.ncbi.nlm.nih.gov/pubmed/16380914 46. Dewan S, Puscheck EE, Coulam CB, Wilcox AJ, Jeyendran RS. Y-chromosome microdeletions and recurrent pregnancy loss. Fertil Steril 2006;85(2):441-5. http://www.ncbi.nlm.nih.gov/pubmed/16595224 47. Kobayashi K, Mizuno K, Hida A, Komaki R, Tomita K, Matsushita I, Namiki M, Iwamoto T, Tamura S, Minowada S, et al. PCR analysis of the Y chromosome long arm in azoospermic patients: evidence for a second locus required for spermatogenesis. Hum Mol Genet 1994;3(11):1965-7. http://www.ncbi.nlm.nih.gov/pubmed/7661932 48. Kent-First MG, Kol S, Muallem A, Blazer S, Itskovitz-Eldor J. Infertility in intracytoplasmic sperm injection-derived sons. Lancet 1996;348(9023):332. http://www.ncbi.nlm.nih.gov/pubmed/8709700 49. Stuppia L, Gatta V, Calabrese G, Guanciali Franchi P, Morizio E, Bombieri C, Mingarelli R, Sforza V, Frajese G, Tenaglia R, Palka G. A quarter of men with idiopathic oligo-azospermia display chromosomal abnormalities and microdeletions of different types in interval 6 of Yq11. Hum Genet 1998;102(5):566-70. http://www.ncbi.nlm.nih.gov/pubmed/9654206 50. Mulhall JP, Reijo R, Alagappan R, Brown L, Page D, Carson R, Oates RD. Azoospermic men with deletion of the DAZ gene cluster are capable of completing spermatogenesis: fertilization, normal embryonic development and pregnancy occur when retrieved testicular spermatozoa are used for intracytoplasmic sperm injection. Hum Reprod 1997;12(3):503-8. http://www.ncbi.nlm.nih.gov/pubmed/9130751 51. Silber SJ, Alagappan R, Brown LG, Page DC. Y chromosome deletions in azoospermic and severely oligozoospermic men undergoing intracytoplasmic sperm injection after testicular sperm extraction. Hum Reprod 1998;13(12):3332-7. http://www.ncbi.nlm.nih.gov/pubmed/9886509 52. Kamischke A, Gromoll J, Simoni M, Behre HM, Nieschlag E. Transmisson of a Y chromosomal deletion involving the deleted in azoospermia (DAZ) and chromodomain (CDYI) genes from father to son through intracytoplasmic sperm injection: case report. Hum Reprod 1999;14(9):2320-2. http://www.ncbi.nlm.nih.gov/pubmed/10469702

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Lee SH, Ahn SY, Lee KW, Kwack K, Jun HS, Cha KY. Intracytoplasmic sperm injection may lead to vertical transmission, expansion, and de novo occurrence of Y-chromosome microdeletions in male fetuses. Fertil Steril 2006;85(5):1512-5. http://www.ncbi.nlm.nih.gov/pubmed/16566932 54. Kent-First M, Muallem A. Development of a large highly diagnostic panel of multiplexed sequence tagged sites (STSs) which cover key regions on human Yq: its application in fertile and infertile zoospermic and oligozoospermic) populations. Proceedings of the Second International Workshop on the Y Chromosome. Organized by the National Institutes of Health USA and Human genome organization, Medical Research Council, UK. Asilomar Conference Centre, Pacific Grove, California, Sept 17-20, 1995, pp. 24-25. 55. Simoni M, Nieschlag E. Molecular diagnostics of Y chromosomal microdeletions: the international quality control programme of the European Academy of Andrology. Hum Reprod (Abstract Book 1) 1999;14:92-3. 56. Donat R, McNeill AS, Fitzpatrick DR, Hargreave TB. The incidence of cystic fibrosis gene mutations in patients with congenital bilateral absence of the vas deferens in Scotland. Br J Urol 1997;79(1):74-7. http://www.ncbi.nlm.nih.gov/pubmed/9043501 57. De Braekeleer M, Ferec C. Mutations in the cystic fibrosis gene in men with congenital bilateral absence of the vas deferens. Mol Hum Reprod 1996;2(9):669-77. http://www.ncbi.nlm.nih.gov/pubmed/9239681 58. Chillon M, Casals T, Mercier B, Bassas L, Lissens W, Silber S, Romey MC, Ruiz-Romero J, Verlingue C, Claustres M et al. Mutations in cystic fibrosis gene in patients with congenital absence of the vas deferens. New Engl J Med 1995;332(22):1475-80. http://www.ncbi.nlm.nih.gov/pubmed/7739684 59. Drake MJ, Quinn FM. Absent vas deferens and ipsilateral multicystic dysplastic kidney in a child. Br J Urol 1996;77(5):756-7. http://www.ncbi.nlm.nih.gov/pubmed/8689131 60. Augarten A, Yahav Y, Kerem BS, Halle D, Laufer J, Szeinberg A, Dor J, Mashiach S, Gazit E, Madgar I. Congenital bilateral absence of the vas deferens in the absence of cystic fibrosis. Lancet 1994;344(8935):1473-4. http://www.ncbi.nlm.nih.gov/pubmed/7968122 61. Paduch DA, Mielnik A, Schlegel PN. Novel mutations in testis-specific ubiquitin protease 26 gene may cause male infertility and hypogonadism. Reprod Biomed Online (2005 Jun);10(6):747-54. http://www.ncbi.nlm.nih.gov/pubmed/15970005 62. Stouffs K, Lissens W, Tournaye H, Van Steirteghem A, Liebaers I. Possible role of USP26 in patients with severely impaired spermatogenesis. Eur J Hum Genet 2005;13(3):336-40. http://www.ncbi.nlm.nih.gov/pubmed/15562280 63. Aschim EL, Giwercman A, Stahl O, Eberhard J, Cwikiel M, Nordenskjold A, Haugen TB, Grotmol T, Giwercman YL. The RsaI polymorphism in the estrogen receptor-beta gene is associated with male infertility. J Clin Endocrinol Metab 2005;90(9):5343-8. http://www.ncbi.nlm.nih.gov/pubmed/15998774 64. Guarducci E, Nuti F, Becherini L, Rotondi M, Balercia G, Forti G, Krausz C. Estrogen receptor alpha promoter polymorphism: stronger estrogen action is coupled with lower sperm count. Hum Reprod 2006;21(4):994-1001. http://www.ncbi.nlm.nih.gov/pubmed/16396937 65. A Z, Zhang S, Yang Y, Ma Y, Lin L, Zhang W. Single nucleotide polymorphisms of the gonadotrophinregulated testicular helicase (GRTH) gene may be associated with the human spermatogenesis impairment. Hum Reprod 2006; 21(3):755-9. http://www.ncbi.nlm.nih.gov/pubmed/16293649 66. Rohozinski J, Lamb DJ, Bishop CE. UTP14c is a recently acquired retrogene associated with spermatogenesis and fertility in man. Biol Reprod 2006;74(4):644-51. http://www.ncbi.nlm.nih.gov/pubmed/16354793 67. Zhang Z, Kostetskii I, Tang W, Haig-Ladewig L, Sapiro R, Wei Z, Patel AM, Bennett J, Gerton GL, Moss SB, Radice GL, Strauss JF 3rd. Deficiency of SPAG16L causes male infertility associated with impaired sperm motility. Biol Reprod 2006;74(4):751-9. http://www.ncbi.nlm.nih.gov/pubmed/16382026 68. Zheng Y, Zhou ZM, Min X, Li JM, Sha JH. Identification and characterization of the BGR-like gene with a potential role in human testicular development/spermatogenesis. Asian J Androl 2005;7(1):21-32. http://www.ncbi.nlm.nih.gov/pubmed/15685348

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69. Carrell DT, De Jonge C, Lamb DJ. The genetics of male infertility: a field of study whose time is now. Arch Androl 2006;52(4):269-74. http://www.ncbi.nlm.nih.gov/pubmed/16728342 70. Zhoucun A, Zhang S, Yang Y, Ma Y, Zhang W, Lin L. The common variant N372H in BRCA2 gene may be associated with idiopathic male infertility with azoospermia or severe oligozoospermia. Eur J Obstet Gynecol Reprod Biol 2006;124(1):61-4. http://www.ncbi.nlm.nih.gov/pubmed/16257105 71. Tessari A, Salata E, Ferlin A, Bartoloni L, Slongo ML, Foresta C. Characterization of HSFY, a novel AZFb gene on the Y chromosome with a possible role in human spermatogenesis. Mol Hum Reprod 2004;10(4):253-8. http://www.ncbi.nlm.nih.gov/pubmed/14985478 72. Greco E, Romano S, Iacobelli M, Ferrero S, Baroni E, Minasi MG, Ubaldi F, Rienzi L, Tesarik J. ICSI in cases of sperm DNA damage: beneficial effect or oral antioxidant treatment. Hum Reprod 2005;20(9):2590-4. http://www.ncbi.nlm.nih.gov/pubmed/15932912 73. Zini A, Meriano J, Kader K, Jarvi K, Laskin CA, Cadesky K. Potential adverse effect of sperm DNA damage on embryo quality after ICSI. Hum Reprod 2005;20(12);3476-80. http://www.ncbi.nlm.nih.gov/pubmed/16123087 74. Zini A, Blumenfeld A, Libman J, Willlis J. Beneficial effect of microsurgical varicocelectomy on human sperm DNA integrity. Hum Reprod 2005;20(4):1018-21. http://www.ncbi.nlm.nih.gov/pubmed/15608026

5. OBSTRUCTIVE AZOOSPERMIA 5.1

Definition

OA is the absence of both spermatozoa and spermatogenetic cells in semen and post-ejaculate urine due to bilateral obstruction of the seminal ducts. OA is less common than NOA and occurs in 15-20% of men with azoospermia. Common causes of OA are summarised in Table 5. Table 5: Classification of OA on the basis of ductal obstruction due to congenital and acquired causes. Conditions Congenital • Epididymal Idiopathic epididymal obstruction obstruction Post-surgical (epididymal cysts) • Vas deferens Congenital absence of vas deferens obstruction Post-surgical (hernia, scrotal surgery) • Ejaculatory duct Prostatic cysts (Müllerian cysts) obstruction

Acquired Post-infective (epididymitis) Post-vasectomy Post-surgical (bladder neck surgery) Post-infective

Men with OA present with normal size testes and normal FSH. On examination, enlargement of the epididymis can be found. Sometimes, the vas deferens is absent due to congenital factors or previous inguinal or scrotal surgery. Obstructions in primary infertile men are often present at the epididymal level; other sites of obstruction are the ejaculatory ducts and the vas deferens. In 25% of men with a suspected obstruction, no spermatozoa are found in the epididymis during scrotal exploration, indicating an intratesticular obstruction.

5.2

Classification

5.2.1 Intratesticular obstruction Intratesticular obstruction occurs in 15% of OA (1). Congenital forms (dysjunction between rete testis and efferent ductules) are less common than acquired forms, (i.e. post-inflammatory or post-traumatic obstructions). Acquired forms are often associated with an obstruction of epididymis and vas deferens. 5.2.2 Epididymal obstruction Epididymal obstruction is the most common cause of OB, affecting 30-67% of azoospermic men with a serum FSH less than twice the upper limit of normal (1-4). Congenital epididymal obstruction usually manifests as CBAVD, which is associated with at least one mutation of the CF gene in 82% of cases (5). This form is often accompanied by absence of the distal part of

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the epididymis and seminal vesicle agenesis (see Section 4 Genetic disorders in infertility). Other congenital forms of obstruction (e.g. dysjunction between efferent ductules and corpus epididymis, agenesis/atresia of a short part of the epididymis) are rare. Congenital forms of epididymal obstruction include chronic sino-pulmonary infections (Young’s syndrome) (6), in which obstruction results from a mechanical blockage due to debris within the proximal epididymal lumen. Acquired forms secondary to acute (e.g. gonococcal) and subclinical (e.g. chlamydial) epididymitis are most frequent (7, 8) (see Section 11 Male accessory gland infections)Acute or chronic traumas can result in epididymal damage (9). Azoospermia caused by surgery might occur after epididymal cyst removal. Epididymal obstruction secondary to long-lasting distal obstruction must be considered when repairing seminal ducts (10). 5.2.3 Vas deferens obstruction Vas deferens obstruction is the most common cause of acquired obstruction following vasectomy for sterilisation, with possible subsequent germ cell impairment and fibrosis (11, 12). Approximately 2-6% of these men request vasectomy reversal. Of those undergoing vaso-vasostomy, 5-10% have epididymal blockage as a result of tubule rupture, making epididymo-vasostomy mandatory (see Section 10 Male contraception). Vasal obstruction may also occur after herniotomy (13). Polypropylene mesh herniorrhaphy seems to induce a fibroblastic response able to entrap, or obliterate, the vas deferens (14). The most common congenital vasal obstruction is CBAVD, often accompanied by CF. Unilateral agenesis or a partial defect is associated with contralateral seminal duct anomalies or renal agenesis in 80% and 26% of cases, respectively (15) (see Section 4 Genetic disorders in infertility). Distal vas deferens obstruction includes CBAVD and accidental injury to the vas deferens during hernia surgery (16). 5.2.4 Ejaculatory duct obstruction Ejaculatory duct obstruction is found in about 1-3% of OA (1). These obstructions can be classified as cystic or post-inflammatory. Cystic obstructions are usually congenital (i.e. Müllerian duct cyst or urogenital sinus/ejaculatory duct cysts) and are medially located in the prostate between the ejaculatory ducts. In urogenital sinus abnormalitiesone or both ejaculatory ducts empty into the cyst (17), while in Müllerian duct anomalies, ejaculatory ducts are laterally displaced and compressed by the cyst (18). Paramedian or lateral intraprostatic cysts are Wolffian in origin and seldom found in clinical practice (19). Post-inflammatory obstructions of the ejaculatory duct are usually secondary to acute, non-acute or chronic urethro-prostatitis (20). Congenital or acquired complete obstructions of the ejaculatory ducts are commonly associated with low semen volume, decreased or absent seminal fructose and acid pH. The seminal vesicles are usually dilated (anterior-posterior diameter > 15 mm) (20, 21). 5.2.5 Functional obstruction of the distal seminal ducts Functional obstruction of the distal seminal ducts might be attributed to local neuropathy (22). This abnormality is often associated with urodynamic dysfunctions because of the vasographic patterns of ampullo-vesicular atony or of ejaculatory duct hypertony. Functional obstruction of the distal seminal ducts has been seen in juvenile diabetes and polycystic kidney disease (23); however, no relevant pathology has been found in most cases. Results of semen analysis vary between azoospermia, cryptozoospermia and severe OAT syndrome.

5.3

Diagnosis

5.3.1 Clinical history Clinical history taking should follow the suggestions for investigation of infertile men (see section 2 Investigations), ask about: • haematospermia • post-ejaculatory pain • previous or present urethritis or prostatitis • obstructive or irritative urinary symptoms • previous scrotal enlargement or pain or surgery • previous inguinal herniorrhaphy or traumas • chronic sino-pulmonary infections. 5.3.2 Clinical examination Clinical examination should follow suggestions for investigation of the infertile man. The following findings indicate OA:

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• • • • • •

 t least one testis > 15 mL volume (although a smaller testicular volume may be found in some a patients with OA and concomitant partial testicular failure) enlarged and hardened epididymis nodules in the epididymis or vas deferens absence or partial atresia of the vas signs of urethritis prostatic abnormalities.

5.3.3 Semen analysis At least two examinations must be carried out at an interval of 2-3 months, according to the WHO (see section 2 Investigations). Azoospermia means absence of spermatozoa after centrifugation at x400 magnification. Careful repeat observation of several smears after semen liquefaction is needed. If no spermatozoa are found in wet preparation, aliquots or the whole semen sample should be centrifuged (600 rpm for 15 min). The pellet must be examined for spermatozoa. A semen volume 2500 g and < 2500 g group, respectively (3).

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8.3

Testicular descent and maldescent

The process of testicular descent has two distinct phases: a) transabdominal and b) inguinal. During ‘transabdominal descence’, development of the gubernaculum and genito-inguinal ligament plays an important role. The antiMüllerian hormone regulates the transabdominal descence of the testis. Induction of the gubernaculum depends on functional Insl3 gene in mice (4). This gene is expressed in Leydig cells, and its targeted deletion causes bilateral cryptorchidism with free-moving testes and genital ducts (5). Other gene families (e.g. the homeobox (HOX) genes, GREAT gene), are important for the development of genital organs and may be associated with testicular maldescence (6, 7).

8.4

Hormonal control of testicular descent

Maldescence can be caused by two hormonal factors: hypogonadism and androgen insensitivity. The increasing incidence of reproductive abnormalities in human males might be explained by an increased oestrogen exposure during gestation (8). Some pesticides and synthetic chemicals act as hormonal modulators, often possessing oestrogenic activity (xeno-oestrogens) (9). The oestrogenic and anti-androgenic properties of these chemicals might cause hypospadia, cryptorchidism, reduction of sperm density, and an increase in the incidence of testicular tumours in animal models by receptor-mediated mechanisms or direct toxic effects (10).

8.5

Pathophysiological effects in maldescended testes

8.5.1 Degeneration of germ cells Degeneration of germ cells in maldescended testes is apparent after the first year. The degenerative changes vary, depending on the position of the testis (11). During the second year of life, the number of germ cells declines. In 10-45% of affected patients, complete loss of germ cells can be detected. Early treatment is therefore recommended to conserve spermatogenesis, especially in bilateral cases. Surgical treatment is the most effective and reliable method of bringing testes into the scrotum, but hormone treatment with either hCG or GnRH analogues can be considered, particularly in cases where testes are located in the high scrotal position (12). 8.5.2 Relationship with fertility Semen parameters are often impaired in men with a history of cryptorchidism (13). Surgical treatment during the first or second year of life might have a positive effect on subsequent fertility (14). However, there is no definitive proof of the protective effect of early orchidopexy. In men with a history of unilateral cryptorchidism, paternity is almost equal (89.7%) to paternity in men without cryptorchidism (93.7%). In men with unilateral cryptorchidism, paternity is independent of the age at orchidopexy, preoperative testicular location and testicular size (15) However, a history of unilateral cryptorchidism may result in reduced fertility potential (i.e. causing a prolonged time to achieve pregnancy). In men with bilateral cryptorchidism, oligozoospermia can be found in 31% and azoospermia in 42%. In cases of bilateral cryptorchidism, the rate of paternity is only 35-53%. 8.5.3 Germ cell tumours Cryptorchidism is a risk factor for testicular cancer and is associated with testicular microcalcification and CIS of the testis. In about 5-10% of testicular cancers, there is a history of cryptorchidism (16). The risk of a germ cell tumour is 3.6-7.4 times higher than in the general population, and 2-6% of men with a history of cryptorchidism will develop a testicular tumour (16). There is no evidence for a protective effect of early orchidopexy (17).

8.6

Treatment of undescended testes

8.6.1 Hormonal treatment In randomised, controlled trials investigating the efficacy and safety of hCG and GnRH treatment, a large variation in success rates has been reported. The corresponding figures in a multicenter randomised trial were 21%, 19% and 4% for GnRH, hCG and placebo, respectively (12) A meta-analysis of 33 studies showed that the success rate was highest in pre-scrotal and high scrotal testes (18). Non-palpable testes rarely descend as a result of hormonal treatment. The current hormonal protocol used for high scrotal testes is three hCG injections given once per week. The dosage is 1500 IU per injection for children aged 1-3 years, 3000 IU at age 4-6 years, and 5000 IU at age 6-15 years. The recommended age for treatment using hCG is 12-18 months. In a patient with bilateral impalpable testes, an hCG stimulation test can be carried out; a rise in testosterone level confirms the presence of testes. Inhibin B is produced by the Sertoli cells of the testis and can be a good indicator of testicular function in children (19). Hormonal treatment is generally considered safe, with few side-effects. However, some studies have

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indicated an increased risk of interstitial fibrosis and germ cell apoptosis following hCG treatment (20). Early adverse effects include penile growth, pain in the genital region, pain at the site of injection and psychological changes as a result of androgen effects. 8.6.2 Surgical treatment The success rate of surgical treatment for undescended testes is 70-90% (21). When the spermatic cord or vessels are too short to allow proper mobilisation of the testis into the scrotum, a staged orchidopexy (FowlerStephenson procedure) can be used. The applied techniques are open surgery, laparoscopy, or microsurgery. A biopsy at the time of orchidopexy (see page 51, sections 12.1-12.2) can reveal a CIS, which can be removed, thus preventing development of a malignant tumour. If not corrected by adulthood, an undescended testis should not be removed. Following orchidopexy, vascular damage is the most severe complication and can cause testicular atrophy in 1-2% of cases. In non-palpable testes, the post-operative atrophy rate was 12% in cases where the vascular pedicles were long enough to allow scrotal positioning. Up to 40% post-operative atrophy was reported in cases of staged orchidopexy.

8.7

CONCLUSIONS

•

Cryptorchidism is multi-factorial in origin and may be caused by genetic factors and endocrine disruption early in pregnancy. Cryptorchidism can be associated with testicular dysgenesis and is a risk factor for infertility and germ cell tumours. Paternity in men with unilateral cryptorchidism in almost equal to paternity in men without cryptorchidism. Bilateral cryptorchidism, significantly reduces the likelihood of paternity.

• • •

8.8

RECOMMENDATIONS

Recommendations • Early surgical treatment of undescended testis may prevent germ cell loss. • If undescended testes are corrected in adulthood, a testicular biopsy for detection of carcinoma in situ is recommended at the time of the orchidopexy (16). GR = grade of recommendation

8.9

GR C B

REFERENCES

1.

Skakkebaek NS, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod 2001;16(5):972-8. http://www.ncbi.nlm.nih.gov/pubmed/11331648 2. Boisen KA, Kaleva M, Main KM, Virtanen HE, Haavisto AM, Schmidt IM, Chellakooty M, Damgaard IN, Mau C, Reunanen M, Skakkebaek NE, Toppari J. Difference in prevalence of congenital cryptorchidism in infants between two Nordic countries. Lancet 2004;363(9417):1264-9. http://www.ncbi.nlm.nih.gov/pubmed/15094270 3. Heyns CF, Hutson JM. Historical review of theories on testicular descent. J Urol 1995;153(3 Pt 1): 754-67. http://www.ncbi.nlm.nih.gov/pubmed/7861531 4. Scorer CG. The descent of the testis. Arch Dis Child 1964;39:605-9. http://www.ncbi.nlm.nih.gov/pubmed/14230757 5. Nguyen MT, Showalter PR, Timmons CF, Nef S, Parada LF, Baker LA. Effects of orchiopexy on congenitally cryptorchid insulin-3 knockout mice. J Urol 2002;168(4 Pt 2):1779-83; discussion 1783. http://www.ncbi.nlm.nih.gov/pubmed/12352358 6. Lewis AG, Pecha BR, Smith EP, Gardner BJ, Hsieh-Li HM, Potter SS, Sheldon CA. Early orchidopexy restores fertility in Hoxa 11 gene knockout mouse. J Urol 2003;170:302-5. http://www.ncbi.nlm.nih.gov/pubmed/12796710 7. Gorlov IP, Kamat A, Bogatcheva NV, Jones E, Lamb DJ, Truong A, Bishop CE, McElreavey K, Agoulnik AI. Mutations of the GREAT gene cause cryptorchidism. Hum Mol Genet 2002;11(19): 2309-18. http://www.ncbi.nlm.nih.gov/pubmed/12217959

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8.

Hadziselimovic F, Geneto R, Emmons LR. Elevated placental estradiol: a possible etiological factor of human cryptorchidism. J Urol 2000;164(5):1694-5. http://www.ncbi.nlm.nih.gov/pubmed/11025750 9. Hosi S, Loff S, Witt K, Niessen K, Waag KL. Is there a correlation between organochlorine compounds and undescended testes? Eur J Pediatr Surg 2000;10(5):304-9. http://www.ncbi.nlm.nih.gov/pubmed/11194541 10. Toppari J, Larsen JC, Christiansen P, Giwercman A, Grandjean P, Guillette LJ Jr, Jegou B, Jensen TK, Jouannet P, Keiding N, Leffers H, McLachlan JA, Meyer O, Muller J, Rajpert-De Meyts E, Scheike T, Sharpe R, Sumpter J, Skakkebaek NE. Male reproductive health and environmental xenoestrogens. Environ Health Perspect 1996;104(Suppl 4):741-803. http://www.ncbi.nlm.nih.gov/pubmed/8880001 11. Garcia J, González N, Gómez ME, Plaza L, Sanchez J, Alba J. Clinical and anatomopathological study of 2000 cryptorchid testes. Br J Urol 1995(6);75:697-701. http://www.ncbi.nlm.nih.gov/pubmed/7613821 12. Christiansen P, Muller J, Buhl S, Hansen OR, Hobolth N, Jacobsen BB, Jorgensen PH, Kastrup KW, Nielsen K, Nielsen LB. Hormonal treatment of cryptorchidism - hCG or GnRH - a multicentre study. Acta Paediatr 1992;81(8):605-8. http://www.ncbi.nlm.nih.gov/pubmed/1356527 13. Yavetz H, Harash B, Paz G, Yogev L, Jaffa AJ, Lessing JB, Homonnai ZT. Cryptorchidism: incidence and sperm quality in infertile men. Andrologia 1992;24(5):293-97. http://www.ncbi.nlm.nih.gov/pubmed/1356318 14. Wilkerson ML, Bartone FF, Fox L, Hadziselimovic F. Fertility potential: a comparison of intraabdominal and intracanalicular testes by age groups in children. Horm Res 2001;55(1):18-20. http://www.ncbi.nlm.nih.gov/pubmed/11423737 15. Miller KD, Coughlin MT, Lee PA. Fertility after unilateral cryptorchidism: paternity, time to conception, pretreatment testicular location and size, hormone and sperm parameters. Horm Res 2001; 55(5): 249-53. http://www.ncbi.nlm.nih.gov/pubmed/11740148 16. Giwercman A, Bruun E, Frimodt-Moller C, Skakkebaek NE. Prevalence of carcinoma in situ and other histopathological abnormalities in testes of men with a history of cryptorchidism. J Urol 1989;142(4):998-1001. http://www.ncbi.nlm.nih.gov/pubmed/2571738 17. Pike MC, Chilvers C, Peckham MJ. Effect of age at orchidopexy on risk of testicular cancer. Lancet 1986;1(8492):1246-8. http://www.ncbi.nlm.nih.gov/pubmed/2872394 18. Pyorala S, Huttunen NP, Uhari M. A review and meta-analysis of hormonal treatment of cryptorchidism. J Clin Endocrinol Metab 1995;80(9):2795-9. http://www.ncbi.nlm.nih.gov/pubmed/7673426 19. Andersson AM. Inhibin B in the assessment of seminiferous tubular function. Baillieres Best Pract Res Clin Endocrinol Metab 2000;14(3):389-97. http://www.ncbi.nlm.nih.gov/pubmed/11517906 20. Kaleva M, Arsalo A, Louhimo I, Rapola J, Perheentupa J, Henriksen K, Toppari J. Treatment with human chorionic gonadotrophin for cryptorchidism: clinical and histological effects. Int J Androl 1996;19(5):293-8. http://www.ncbi.nlm.nih.gov/pubmed/8985778 21. Jones PF. Approaches to orchidopexy. Br J Urol 1995;75(6):693-6. http://www.ncbi.nlm.nih.gov/pubmed/7613820

9. IDIOPATHIC MALE INFERTILITY 9.1

Introduction

No demonstrable cause of male infertility, other than idiopathic OAT syndrome, is found in at least 44% of infertile men (1).

9.2

Empirical treatments

A wide variety of empirical drug approaches for the treatment of idiopathic male infertility have been used; however, there is little scientific evidence for an empirical approach (2).

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Androgens, hCG/hMG, bromocriptine, alpha-blockers, systemic corticosteroids and magnesium supplementation are not effective in the treatment of OAT syndrome. FSH (3) and anti-oestrogens in combination with testosterone (4) might be beneficial in a selection of patients; however, further evaluation in multicenter studies of these agents is required (3, 4).

9.3

RECOMMENDATIONS

Recommendation • Medical treatment of male infertility is recommended only for cases of hypogonadotropic hypogonadism (1). GR = grade of recommendation

GR A

9.4

REFERENCES

1.

Pierik FH, Van Ginneken AM, Dohle GR, Vreeburg JT, Weber RF. The advantages of standardized evaluation of male infertility. Int J Androl 2000 23(6):340-6. http://www.ncbi.nlm.nih.gov/pubmed/11114979 Foresta C, Bettella A, Spolaore D, Merico M, Rossato M, Ferlin A. Suppression of the high endogenous levels of plasma FSH in infertile men are associated with improved Sertoli cell function as reflected by elevated levels of plasma inhibin B. Hum Reprod 2004;19(6):1431-7. http://www.ncbi.nlm.nih.gov/pubmed/15117900 Paradisi R, Busacchi P, Seracchioli R, Porcu E, Venturoli S. Effects of high doses of recombinant human follicle-stimulating hormone in the treatment of male factor infertility: results of a pilot study. Fertil Steril 2006;86(3):728-31. http://www.ncbi.nlm.nih.gov/pubmed/16782097 Adamopoulos DA, Pappa A, Billa E, Nicopoulou S, Koukkou E, Michopoulos J. Effectiveness of combined tamoxifen citrate and testosterone undecanoate treatment in men with idiopathic oligozoospermia. Fertil Steril 2003;80(4):914-20. http://www.ncbi.nlm.nih.gov/pubmed/14556812

2.

3.

4.

10. MALE CONTRACEPTION 10.1

Introduction

‘Male contribution to contraception’ is a more accurate phrase than ‘male contraception’, as men do not conceive. Development of male contraceptive methods is important because up to 40% of women have an unmet need for family planning; approximately 80 million women every year having unintended or unwanted pregnancies. (1). Three of the four methods of male contraception have been in use for hundreds of years (i.e. condoms, periodic abstinence and withdrawal). The typical first-year failure rates of traditional male methods are high (withdrawal 19%, periodic abstinence 20%, and condoms between 3-14%) compared to the failure rates of 0.1-3% for modern reversible female methods (2). For men to take more responsibility for family planning, male contraceptive methods must be acceptable, cheap, reversible, and effective. Research is attempting to (3): • prevent sperm production, by using androgens, progestogen and GnRH in various combinations) • interfere with the ability of sperm to mature and fertilise by using an epididymal approach to create a hostile environment for sperm • produce better barrier methods; polyurethane condoms can be used by those with latex allergy, although they have higher breakage rates (4) • produce an antisperm contraceptive vaccine (5) • inhibit sperm-egg interactions. These approaches remain experimental. The method nearest to being generally available clinically is hormonal male contraception, which is based on suppression of gonadotrophins and the use of testosterone substitution to maintain male sexual function and bone mineralisation and to prevent muscle wasting (6). Various contraceptive regimens have been developed and tested, including testosterone monotherapy, androgen/progestin combinations, testosterone with GnRH analogues, and selective androgen- and progestinreceptor modulators. There are racial differences in the response to androgens alone. However, a combination

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of testosterone with progestin has resulted in complete suppression of spermatogenesis in all races and provided contraceptive efficacy equivalent to female hormonal methods (7). Phase III clinical trials of depot preparations of androgen/progestin combinations are in progress.

10.2

Vasectomy

Vasectomy is an effective method of permanent male surgical sterilisation (8). Before the vasectomy, the couple should be given accurate information about the benefits and risks. An Australian telephone survey found that 9.2% of respondents said they regretted having a vasectomy (9). 10.2.1 Surgical techniques Various techniques are available for vasectomy. The least invasive approach is the no-scalpel vasectomy (10); this is associated with a low rate of complications (11). The most effective occlusion technique is cauterisation of the lumen of the vas and fascial interposition (12-14). Most techniques can be carried out safely under local anaesthesia in the out-patient clinic. 10.2.2 Complications Vasectomy does not significantly alter spermatogenesis and Leydig cell function. The volume of ejaculate remains unchanged. Potential systemic effects of vasectomy, including atherosclerosis, have not been proven, and there is no evidence of a significant increase of any systemic disease after vasectomy. An increased rate of prostate cancer in men who underwent vasectomy has not been detected (17). Acute local complications associated with vasectomy include haematoma, wound infection and epididymitis in up to 5% of cases (15). The potential long-term complications (e.g. chronic testicular pain) (16), must be discussed with the patient before the procedure. Epididymal tubal damage is common, and is associated with consequent development of sperm granuloma and time-dependent secondary epididymal obstruction, which limits vasectomy reversal. 10.2.3 Vasectomy failure If an effective occlusion technique is used, the risk of recanalisation after vasectomy should be 1 x 106 WBC/mL have been defined as leukospermia. Only two studies have analysed alterations of WBC in the ejaculate of patients with proven prostatitis (23, 24); both studies found more leukocytes in men with prostatitis compared to men without inflammation (CPPS, type NIH IIIb). 11.3.6 Sperm quality The deleterious effects of chronic prostatitis on sperm density, motility and morphology are under debate (1). All investigations have given contradictory results, and have not confirmed that chronic prostatitis has a decisive role in altering conventional semen parameters (25-27). 11.3.7 Seminal plasma alterations Seminal plasma elastase is a biochemical indicator of polymorphonuclear lymphocyte activity in the ejaculate (1, 28, 29), with a suggested cut-off level of approximately 600 ng/mL (1). Various cytokines are involved in inflammation and may influence sperm function. Several studies have investigated the association between

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interleukin concentration, leukocytes and sperm function (30-32): no correlations were found. The prostate is the main site of origin of interleukin-6 (IL-6) in the seminal plasma. Cytokines, especially IL-6, must play an important role in the male accessory gland inflammatory process (33). However, elevated cytokine levels do not depend on the number of leukocytes in EPS (34). 11.3.8 Glandular secretory dysfunction Infections of the sex glands can impair their excretory function. Decreased quantities of citric acid, phosphatase, fructose, zinc and alpha-glutamyl-transferase activity are indicators of disturbed prostatic secretory parameters (1). Reduced fructose concentration indicates impaired vesicular function (20, 35). 11.3.9 Sperm antibodies Serum antibodies to sperm antigens are not useful in the diagnosis of immune infertility. Early reports stated an association between increased levels of sperm antibodies in serum and NBP (36, 37). However, except suspected chlamydial infections (38), only a history of vasectomy is predictive of sperm antibody formation (39). 11.3.10 Reactive oxygen species Reactive oxygen species might be increased in chronic urogenital infections associated with increased leukocyte numbers (40). However, the biological significance in prostatitis remains unclear (1). 11.3.11 Therapy Treatment of chronic prostatitis is usually targeted at relieving symptoms (10, 41). Andrologically, therapy for altered semen composition in male adnexitis (acute and chronic infections of the male urogenital tract) is aimed at: • reduction or eradication of micro-organisms in prostatic secretions and semen • normalisation of inflammatory (e.g. leukocytes) and secretory parameters • improvement of sperm parameters to counteract fertility impairment (42). Treatment includes antibiotics, anti-inflammatory drugs, surgical procedures, normalisation of urine flow, physical therapy and alterations in general and sexual behaviour. Only antibiotic therapy of CBP (NIH II) has provided symptomatic relief, eradication of microorganisms and a decrease in cellular and humoral inflammatory parameters in urogenital secretions. The use of alpha-blockers for symptom relief is controversial. Although antibiotics might improve sperm quality (42), there is no evidence that treatment of chronic prostatitis increases the probability of conception (1, 43).

11.4

Orchitis and epididymo-orchitis

11.4.1 Introduction Orchitis is an inflammatory lesion of the testis associated with a predominantly WBC exudate inside and outside the seminiferous tubules, potentially resulting in tubular sclerosis. The inflammation causes pain and swelling. Chronic inflammatory alterations in the seminiferous tubules disrupt the normal process of spermatogenesis and alter sperm number and quality (44). Orchitis might also be an important cause of spermatogenetic arrest (45), which might be reversible in most cases. Testicular atrophy can develop as a result of tubular sclerosis (45). 11.4.2 Diagnosis Epididymo-orchitis usually presents with unilateral scrotal pain (46). Diagnosis is based on past medical history and palpation. Ultrasonography usually indicates a swollen, enlarged testis. The sonographic feature of the tissue does not allow any differential diagnosis (47). 11.4.3 Ejaculate analysis Ejaculate analysis, including leukocyte analysis, indicates persistent inflammatory activity. In many cases, especially in acute epididymo-orchitis, transiently decreased sperm counts and reduced forward motility occur (44, 46). Obstructive azoospermia due to complete obstruction is a rare complication. Mumps orchitis may result in bilateral testicular atrophy (45) and testicular azoospermia. When granulomatous orchitis is suspected, sperm-bound auto-antibodies occur. 11.4.4 Therapy Only therapy of acute bacterial epididymo-orchitis and of specific granulomatous orchitis is standardised (45) (Table 11). Several regimens improve the inflammatory lesion. Unfortunately, therapies using corticosteroids and non-steroidal antiphlogistic substances (e.g. diclofenac, indomethacin, and acetylsalicylic acid) have not

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been evaluated for their andrological outcome (47). In mumps orchitis, systemic interferon alpha-2b therapy prevents testicular atrophy and azoospermia (48). In idiopathic granulomatous orchitis, surgical removal of the testis is the therapy of choice. Table 12: Treatment of epididymo-orchitis Condition and pathogen Treatment • Acute bacterial epididymo-orchitis N. gonorrhoeae Tetracyclines C. trachomatis Tetracyclines E. coli, Enterobacteriaceae Fluoroquinolones • Mumps orchitis Interferon alpha-2b • Non-specific chronic epididymo-orchitis Steroidal and non-steroidal antiphlogistic agents • Granulomatous (idiopathic) orchitis Semi-castration • Specific orchitis According to therapy of underlying diseases

11.5

Epididymitis

11.5.1 Introduction Inflammation of the epididymis causes unilateral pain and swelling, usually with acute onset. Among sexually active men < 35 years of age, epididymitis is most often caused by C. trachomatis or N. gonorrhoea (Table 11) (49, 50). Sexually transmitted epididymitis is usually accompanied by urethritis. Non-sexually transmitted epididymitis is associated with UTI and occurs more often in men aged > 35 years, those who have recently undergone urinary tract instrumentation or surgery, and those who have anatomical abnormalities (50). 11.5.2 Diagnosis In acute epididymitis, inflammation and swelling usually begin in the tail of the epididymis, and can spread to involve the rest of the epididymis and testicular tissue (46). Although men with epididymitis caused by sexually transmitted micro-organisms always have a history of sexual activity, exposure may have occurred several months before onset. The microbial aetiology of epididymitis is usually easy to determine by Gramstained examination of both a urethral smear for urethritis and of a mid-stream urine specimen for Gramnegative bacteriuria (49, 50). Intracellular Gram-negative diplococci on the smear indicate presence of N. gonorrhoea. Only WBCs on urethral smear indicate non-gonorrhoeal urethritis; C. trachomatis will be isolated in approximately two-thirds of these patients (51). 11.5.3 Ejaculate analysis Ejaculate analysis according to WHO criteria, including leukocyte analysis, might indicate persistent inflammatory activity. In many cases, transiently decreased sperm counts and forward motility are observed (46, 49, 52). Ipsilateral low-grade orchitis (53, 54) might be the cause of this slight impairment in sperm quality (Table 12) (55). Development of stenosis in the epididymal duct, reduction of sperm count and azoospermia are more important in the follow-up of bilateral epididymitis (see Section 5 Obstructive azoospermia). The extent of azoospermia after epididymitis is unclear. Table 13: Acute epididymitis and impact on sperm parameters Author

Density

Negative influence on: Motility Morphology

Comment

Ludwig & Haselberger (56) + + + Pyospermia in 19 of 22 cases Berger et al. (49) + Weidner et al. (47) + + + Azoospermia in 3 of 70 men Haidl (57) + Chronic infections; macrophages elevated Cooper et al. (58) Decrease in epididymal markers: alpha-glucosidase, L-carnitine 11.5.4 Treatment Antibiotic therapy is indicated before culture results are available (Table 11). Treatment of epididymitis will result in:

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• • • • •

microbiological cure of infection improvement of clinical signs and symptoms prevention of potential testicular damage prevention of transmission decrease of potential complications (e.g. infertility or chronic pain).

Patients with epididymitis that is known or suspected to be caused by N. gonorrhoea or C. trachomatis must be told to refer their sexual partners for evaluation and treatment (59).

11.6 CONCLUSIONS • •

11.7

Urethritis and prostatitis are not clearly associated with male infertility. Antibiotic treatment often only eradicates micro-organisms; it has no positive effect on inflammatory alterations and/or cannot reverse functional deficits and anatomical dysfunctions.

RECOMMENDATIONS

Recommendations • In most cases, the aetiology of acute urethritis is unknown at the time of diagnosis; empirical therapy is therefore suggested using a single dose of a fluoroquinolone, followed by a 2-week regimen of doxycycline. Treatment is effective both for gonococcal and (co-existing) chlamydial/ureaplasmal infections (9) • Patients with epididymitis that is known or suspected to be caused by N. gonorrhoea or C. trachomatis must be instructed to refer their sexual partners for evaluation and treatment (59). GR = grade of recommendation

11.8

GR B

B

REFERENCES

1.

Weidner W, Krause W, Ludwig M. Relevance of male accessory gland infection for subsequent fertility with special focus on prostatitis. Hum Reprod Update 1999;5(5):421-32. http://www.ncbi.nlm.nih.gov/pubmed/10582781 2. World Health Organization. WHO Manual for the Standardized Investigation, Diagnosis and Management of the Infertile Male. Cambridge: Cambridge University Press, 2000. 3. Purvis K, Christiansen E. Infection in the male reproductive tract. Impact, diagnosis and treatment in relation to male infertility. Int J Androl 1993;16(1):1-13. http://www.ncbi.nlm.nih.gov/pubmed/8468091 4. Schiefer HG. Microbiology of male urethroadnexitis: diagnostic procedures and criteria for aetiologic classification. Andrologia 1998;30(Suppl 1):7-13. http://www.ncbi.nlm.nih.gov/pubmed/9629437 5. Chambers RM. The mechanism of infection in the urethra, prostate and epididymis. In: Keith LG, Berger GS, Edelmann DA, (eds). Infections in Reproductive Health: Common Infections. Lancaster: MTP Press, pp. 283-296. 6. Ness RB, Markovic N, Carlson CL, Coughlin MT. Do men become infertile after having sexually transmitted urethritis? An epidemiologic examination. Fertil Steril 1997;68(2):205-13. http://www.ncbi.nlm.nih.gov/pubmed/9240243 7. Trum JW, Mol BW, Pannekoek Y, Spanjaard L, Wertheim P, Bleker OP, van der Veen F. Value of detecting leukocytospermia in the diagnosis of genital tract infection in subfertile men. Fertil Steril 1998;70(2):315-9. http://www.ncbi.nlm.nih.gov/pubmed/9696227 8. Purvis K, Christiansen E. The impact of infection on sperm quality. J Br Fertil Soc 1995;1:31-41. 9. Krieger JN. New sexually transmitted diseases treatment guidelines. J Urol 1995;154(1):209-13. http://www.ncbi.nlm.nih.gov/pubmed/7776428 10. Wagenlehner FM, Diemer T, Naber KG, Weidner W. Chronic bacterial prostatitis (NIH type II): diagnosis, therapy and influence on the fertility status. Andrologia 2008:;40(2):100-4. http://www.ncbi.nlm.nih.gov/pubmed/18336459 11. Naber KG, Weidner W. Chronic prostatitis–an infectious disease? J Antimicrob Chemother 2000;46(2):157-61. http://www.ncbi.nlm.nih.gov/pubmed/10933636

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12.

Weidner W, Schiefer HG, Krauss H, Jantos C, Friedrich HJ, Altmannsberger M. Chronic prostatitis: a thorough search for etiologically involved microorganisms in 1,461 patients. Infection 1991;19(3): S119-S125. http://www.ncbi.nlm.nih.gov/pubmed/2055646 13. Bruce AW, Reid G. Prostatitis associated with Chlamydia trachomatis in 6 patients. J Urol 1989;142(4):1006-7. http://www.ncbi.nlm.nih.gov/pubmed/2677408 14. Taylor-Robinson D. Evaluation and comparison of tests to diagnose Chlamydia trachomatis genital infections. Hum Reprod 1997;12(11 Suppl):113-20. http://www.ncbi.nlm.nih.gov/pubmed/9433967 15. Taylor-Robinson D. Infections due to species of Mycoplasma and Ureaplasma: an update. Clin Infect Dis 1996;23(4):671-84; quiz 683-4. http://www.ncbi.nlm.nih.gov/pubmed/8909826 16. Krieger JN, Riley DE, Roberts MC, Berger RE. Prokaryotic DNA sequences in patients with chronic idiopathic prostatitis. J Clin Microbiol 1996;34(12):3120-8. http://www.ncbi.nlm.nih.gov/pubmed/8940458 17. Litwin MS, McNaughton-Collins M, Fowler FJ Jr, Nickel JC, Calhourn EA, Pontari MA, Alexander RB, Farrar JT, O’Leary MP. The National Institutes of Health chronic prostatitis symptom index: development and validation of a new outcome measure. Chronic Prostatitis Collaboration Research Network. J Urol 1999;162(2):369-75. http://www.ncbi.nlm.nih.gov/pubmed/10411041 18. Ludwig M, Schroeder-Printzen I, Ludecke G, Weidner W. Comparison of expressed prostatic secretions with urine after prostatic massage–a means to diagnose chronic prostatitis/inflammatory chronic pelvic pain syndrome. Urology 2000;55(2):175-7. http://www.ncbi.nlm.nih.gov/pubmed/10688073 19. Liversedge NH, Jenkins JM, Keay SD, LcLaughlin EA, Al-Sufyan H, Maile LA, Joels LA, Hull MG. Antibiotic treatment based on seminal cultures from asymptomatic male partners in in-vitro fertilization is unnecessary and may be detrimental. Hum Reprod 1996;11(6):1227-31. http://www.ncbi.nlm.nih.gov/pubmed/8671429 20. Weidner W, Krause W, Schiefer HG, Brunner H, Friedrich HJ. Ureaplasmal infections of the male urogenital tract, in particular prostatitis, and semen quality. Urol Int 1985;40(1):5-9. http://www.ncbi.nlm.nih.gov/pubmed/3883615 21. Aitken RJ, Baker HW. Seminal leukocytes: passengers, terrorists or good samaritans? Hum Reprod1995;10(7):1736-9. http://www.ncbi.nlm.nih.gov/pubmed/8582971 22. Tomlinson MJ, Barratt CLR, Cooke ID. Prospective study of leukocytes and leukocyte subpopulations in semen suggests they are not a cause of male infertility. Fertil Steril 1993;60(6):1069-75. http://www.ncbi.nlm.nih.gov/pubmed/8243688 23. Krieger JN, Berger RE, Ross SO, Rothman I, Muller CH. Seminal fluid findings in men with nonbacterial prostatitis and prostatodynia. J Androl 1996;17(3):310-8. http://www.ncbi.nlm.nih.gov/pubmed/8243688 24. Weidner W, Jantos C, Schiefer HG, Haidl G, Friedrich HJ. Semen parameters in men with and without proven chronic prostatitis. Arch Androl 1991;26(3):173-83. http://www.ncbi.nlm.nih.gov/pubmed/1872650 25. Giamarellou H, Tympanidis K, Bitos NA, Leonidas E, Daikos GK. Infertility and chronic prostatitis. Andrologia 1984;16(5):417-22. http://www.ncbi.nlm.nih.gov/pubmed/6496959 26. Christiansen E, Tollefsrud A, Purvis K. Sperm quality in men with chronic abacterial prostatovesiculitis verified by rectal ultrasonography. Urology 1991;38(6):545-9. http://www.ncbi.nlm.nih.gov/pubmed/1746084 27. Leib Z, Bartoov B, Eltes F, Servadio C. Reduced semen quality caused by chronic abacterial prostatitis: an enigma or reality? Fertil Steril 1994;61(6):1109-16. http://www.ncbi.nlm.nih.gov/pubmed/8194626 28. Wolff H, Bezold G, Zebhauser M, Meurer M. Impact of clinically silent inflammation on male genital tract organs as reflected by biochemical markers in semen. J Androl 1991;12(5):331-4. http://www.ncbi.nlm.nih.gov/pubmed/1765569 29. Wolff H. The biologic significance of white blood cells in semen. Fertil Steril 1995;63(6):1143-57. http://www.ncbi.nlm.nih.gov/pubmed/7750580

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30. Dousset B, Hussenet F, Daudin M, Bujan L, Foliguet B, Nabet P. Seminal cytokine concentrations (IL-1beta, IL-2, IL-6, sR IL-2, sR IL-6), semen parameters and blood hormonal status in male infertility. Hum Reprod 1997;12(7):1476-9. http://www.ncbi.nlm.nih.gov/pubmed/9262280 31. Huleihel M, Lunenfeld E, Levy A, Potashnik G, Glezerman M. Distinct expression levels of cytokines and soluble cytokine receptors in seminal plasma of fertile and infertile men. Fertil Steril 1996;66(1):135-9. http://www.ncbi.nlm.nih.gov/pubmed/8752625 32. Shimonovitz S, Barak V, Zacut D, Ever-Hadani P, Ben Chetrit A, Ron M. High concentration of soluble interleukin-2 receptors in ejaculate with low sperm motility. Hum Reprod 1994;9(4):653-5. http://www.ncbi.nlm.nih.gov/pubmed/8046017 33. Zalata A, Hafez T, van Hoecke MJ, Comhaire F. Evaluation of beta-endorphin and interleukin-6 in seminal plasma of patients with certain andrological diseases. Hum Reprod 1995;10(12):3161-5. http://www.ncbi.nlm.nih.gov/pubmed/8822435 34. Alexander RB, Ponniah S, Hasday J, Hebel JR. Elevated levels of proinflammatory cytokines in the semen of patients with chronic prostatitis/chronic pelvic pain syndrome. Urology 1998;52(5):744-9. http://www.ncbi.nlm.nih.gov/pubmed/9801092 35. Comhaire F, Verschraegen G, Vermeulen L. Diagnosis of accessory gland infection and its possible role in male infertility. Int J Androl 1980;3(1):32-45. http://www.ncbi.nlm.nih.gov/pubmed/7409893 36. Jarow JP, Kirkland JA Jr, Assimos DG. Association of antisperm antibodies with chronic nonbacterial prostatitis. Urology 1990;36(2):154-6. http://www.ncbi.nlm.nih.gov/pubmed/2385884 37. Witkin SS, Zelikovsky G. Immunosuppression and sperm antibody formation in men with prostatitis. J Clin Lab Immunol 1986;21(1):7-10. http://www.ncbi.nlm.nih.gov/pubmed/3543373 38. Munoz MG, Witkin SS. Autoimmunity to spermatozoa, asymptomatic Chlamydia trachomatis genital tract infection and gamma delta T lymphocytes in seminal fluid from the male partners of couples with unexplained infertility. Hum Reprod 1995;10(5):1070-4. http://www.ncbi.nlm.nih.gov/pubmed/7657743 39. Jarow JP, Sanzone JJ. Risk factors for male partner antisperm antibodies. J Urol 1992;148(6):1805-7. http://www.ncbi.nlm.nih.gov/pubmed/1433613 40. Depuydt CE, Bosmans E, Zalata A, Schoonjans F, Comhaire FH. The relation between reactive oxygen species and cytokines in andrological patients with or without male accessory gland infection. J Androl 1996;17(6):699-707. http://www.ncbi.nlm.nih.gov/pubmed/9016401 41. Schaeffer AJ. Clinical practice. Chronic prostatitis and chronic pelvic pain syndrome. N Engl J Med 2006;355(16):1690-8. http://www.ncbi.nlm.nih.gov/pubmed/17050893 42. Weidner W, Ludwig M, Miller J. Therapy in male accessory gland infection–what is fact, what is fiction? Andrologia 1998;30(Suppl 1):87-90. http://www.ncbi.nlm.nih.gov/pubmed/9629448 43. Comhaire FH, Rowe PJ, Farley TM. The effect of doxycycline in infertile couples with male accessory gland infection: a double blind prospective study. Int J Androl 1986;9(2):91-8. http://www.ncbi.nlm.nih.gov/pubmed/3539821 44. Purvis K, Christiansen E. Infection in the male reproductive tract. Impact, diagnosis and treatment in relation to male infertility. Int J Androl 1993;16(1):1-13. http://www.ncbi.nlm.nih.gov/pubmed/8468091 45. Diemer T, Desjardins C. Disorders of Spermatogenesis. In: Knobil E, Neill JD, eds. Encyclopedia of Reproduction. Vol 4. San Diego: Academic Press, 1999, pp. 546-556. 46. [No authors listed.] Association of Genitourinary Medicine and the Medical Society for the Study of Venereal Diseases: National guideline for the management of epididymo-orchitis. Sex Transm Infect 1999;75(Suppl 1): S51-S53. http://www.ncbi.nlm.nih.gov/pubmed/10616385 47. Weidner W, Garbe C, Weissbach L, Harbrecht J, Kleinschmidt K, Schiefer HG, Friedrich HJ. [Initial therapy of acute unilateral epididymitis using ofloxacin. II. Andrological findings.] Urologe A 1990;29(5):277-80. [article in German] http://www.ncbi.nlm.nih.gov/pubmed/2120839

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48. Ruther U, Stilz S, Rohl E, Nunnensiek C, Rassweiler J, Dorr U, Jipp P. Successful interferon-alpha 2, a therapy for a patient with acute mumps orchitis. Eur Urol 1995;27(2):174-6. http://www.ncbi.nlm.nih.gov/pubmed/7744163 49. Berger RE, Alexander RE, Harnisch JP, Paulsen CA, Monda GD, Ansell J, Holmes KK. Etiology, manifestations and therapy of acute epididymitis: prospective study of 50 cases. J Urol 1979;121(6):750-4. http://www.ncbi.nlm.nih.gov/pubmed/7744163 50. Berger RE. Epididymitis. In: Holmes KK, Mardh PA, Sparling PF et al. (eds). Sexually Transmitted Diseases. New York: McGraw-Hill, 1984, pp. 650-662. 51. Weidner W, Schiefer HG, Garbe C. Acute nongonococcal epididymitis. Aetiological and therapeutic aspects. Drugs 1987;34(Suppl 1):111-17. http://www.ncbi.nlm.nih.gov/pubmed/3481311 52. Weidner W, Krause W. Orchitis. In: Knobil E, Neill JD, eds. Encyclopedia of Reproduction. Vol. 3. San Diego: Academic Press, 1999, pp. 92-95. 53. Nilsson S, Obrant KO, Persson PS. Changes in the testis parenchyma caused by acute non-specific epididymitis. Fertil Steril 1968;19:748-57. http://www.ncbi.nlm.nih.gov/pubmed/5676481 54. Osegbe DN. Testicular function after unilateral bacterial epididymo-orchitis. Eur Urol 1991;19(3):204-8. http://www.ncbi.nlm.nih.gov/pubmed/1855525 55. Weidner W, Krause W, Ludwig M. Relevance of male accessory gland infection for subsequent fertility with special focus on prostatitis. Hum Reprod Update 1999;5(5):421-32. http://www.ncbi.nlm.nih.gov/pubmed/10582781 56. Ludwig G, Haselberger J. [Epididymitis and fertility. Treatment results in acute unspecific epididymitis.] Fortschr Med 1977;95(7):397-9. [article in German] http://www.ncbi.nlm.nih.gov/pubmed/849851 57. Haidl G. Macrophages in semen are indicative of chronic epididymal infection. Arch Androl 1990;25(1):5-11. http://www.ncbi.nlm.nih.gov/pubmed/2389992 58. Cooper TG, Weidner W, Nieschlag E. The influence of inflammation of the human genital tract on secretion of the seminal markers alpha-glucosidase, glycerophosphocholine, carnitine, fructose and citric acid. Int J Androl 1990;13(5):329-36. http://www.ncbi.nlm.nih.gov/pubmed/2283178 59. Robinson AJ, Grant JB, Spencer RC, Potter C, Kinghorn GR. Acute epididymitis: why patient and consort must be investigated. Br J Urol 1990;66(6):642-5. http://www.ncbi.nlm.nih.gov/pubmed/2265337

12. GERM CELL MALIGNANCIES AND TESTICULAR MICROCALCIFICATIONS 12.1

Germ cell malignancies and male infertility

Testicular germ cell tumour is the most common malignancy in Caucasian males aged 15-40 years and affects approximately 1% of subfertile men. The lifetime risk of TGCT varies between ethnic groups and from country to country. The highest annual incidence of TGCT occurs in Caucasians, and varies from 10/100,000 (e.g. in Denmark and Norway) to 2/100,000 (e.g. in Finland and the Baltic countries). Generally seminomas and nonseminomas are always preceded by CIS, and untreated CIS will eventually progress to an invasive cancer (1, 2). The most convincing evidence for a general decline in male reproductive health is the increase in testicular cancer seen in Western countries (3). In almost all countries that have reliable cancer registers, the incidence of testicular cancer has increased (4). Both cryptorchidism and hypospadias are associated with an increased risk of testicular cancer; men with cryptorchidism and/or hypospadias are over-represented among patients with testicular cancer. Males with dysgenic testes have an increased risk of developing testicular cancer in adulthood. These cancers arise from pre-malignant gonocytes or CIS cells (5). Testicular microlithiasis can be associated with both germ cell tumours and CIS of the testis.

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12.2

Testicular germ cell cancer and reproductive function.

Men with TGCT have decreased semen quality, even before cancer is diagnosed (6). Orchidectomy implies a risk of azoospermia in these men, with sperm found in the ejaculate before the tumour-bearing testis has been removed. Semen cryopreservation before orchidectomy should therefore be considered (see Section 14 Semen cryopreservation) Treatment of TGCT can result in additional impairment of semen quality (7). In addition to spermatogenic failure, patients with TGCT have Leydig cell dysfunction, even in the contralateral testis (8). The risk of hypogonadism may therefore be increased in men treated for TGCT. Obtaining pre-treatment levels of testosterone, SHBG, LH and oestradiol, might help to anticipate posttreatment hypogonadism. Men who have had TGCT and have low normal androgen levels should be followed up long term because they are at risk of developing hypogonadism as a result of age-related decrease in testosterone production (9).

12.3

Testicular microlithiasis

Microcalcifications inside the testicular parenchyma can be found in 0.6-9% of men referred for testicular ultrasound (10-13). Although the true incidence of microcalcifications in the general population is unknown, it is probably rare. However, ultrasound findings of testicular microlithiasis are common in men with TGCT, cryptorchidism, testicular dysgenesis, male infertility, testicular torsion and atrophy, Klinefelter’s syndrome, hypogonadism, male pseudo-hermaphroditism, varicocele, epididymal cysts, pulmonary microlithiasis and non-Hodgkin’s lymphoma. The incidence reported seems to be higher with high-frequency ultrasound machines (14). The relationship between testicular microlithiasis (TM) and infertility is unclear, but probably relates to dysgenesis of the testis, with degenerate cells being sloughed inside an obstructed seminiferous tubule and failure of the Sertoli cells to phagocytose the debris. Subsequently, calcification occurs. Testicular microcalcification is a condition found in testes at risk of malignant development. The reported incidence of TM in men with TGCT is 6-46% (15-17); TM should therefore be considered premalignant. However, it has not been established whether TM is present before development of invasive TGCT, or whether TM might be an indicator for the preinvasive stage of TGCTs (i.e. CIS). Testicular biopsies from men with TM have found a higher prevalence of CIS, especially in men with bilateral microlithiasis (18). However, TM is found most often in men with a benign testicular condition and the microcalcifications themselves are not malignant. Further investigation of the association between TM and CIS will require testicular biopsies in large series of men without signs of a TGCT. Available data indicate high-risk patients (e.g. patients referred for infertility and/or cryptorchidism) in whom TM is found, should be followed-up by repeated ultrasound and/or testicular biopsy for detection of CIS.

12.4

RECOMMENDATIONS

Recommendations • In men with testicular microlithiasis (TM) and a history of male infertility, cryptorchidism or testicular cancer and in men with atrophic testis, a testicular biopsy or a follow-up scrotal ultrasound is recommended to rule out carcinoma in situ of the testis (17, 18). • It is important to encourage and educate these patients about self-examination, as this may result in early detection of testicular germ cell tumour (TGCT). • If there are suspicious findings on physical examination or ultrasound in patients with TM and associated lesions, a surgical exploration with testicular biopsy or orchidectomy should be considered. • Testicular biopsy, follow-up scrotal ultrasound or routine use of biochemical tumour markers, abdominal and pelvic computed tomography scanning is not justified for men with isolated TM without associated risk factors (e.g. male infertility, cryptorchidism, testicular cancer, atrophic testis) (11). • Men with TGCT are at increased risk of developing hypogonadism and should therefore be followed up (9). GR = grade of recommendation

GR B

B

B

B

12.5

REFERENCES

1.

Skakkebaek NE. Carcinoma in situ of the testis: frequency and relationship to invasive germ cell tumours in infertile men. Histopathology 1978;2(3):157-70. http://www.ncbi.nlm.nih.gov/pubmed/27442

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2.

von der Maase H, Rorth M, Walbom-Jorgensen S, Sorensen BL, Christophersen IS, Hald T, Jacobsen GK, Berthelsen JG, Skakkebaek NE. Carcinoma in situ of contralateral testis in patients with testicular germ cell cancer: study of 27 cases in 500 patients. Br Med J 1986;293(6559):1398-401. http://www.ncbi.nlm.nih.gov/pubmed/3026550 3. Jacobsen R, Bostofte E, Engholm G, Hansen J, Olsen JH, Skakkebaek NE, Moller H. Risk of testicular cancer in men with abnormal semen characteristics: cohort study. BMJ 2000;321(7264):789-92. http://www.ncbi.nlm.nih.gov/pubmed/11009515 4. Huyghe E, Matsuda T, Thonneau P. Increasing incidence of testicular cancer worldwide: a review. J Urol 2003;170(1):5-11. http://www.ncbi.nlm.nih.gov/pubmed/12796635 5. Giwercman A, Muller J, Skakkebaek NE. Carcinoma in situ of the undescended testis. Semin Urol 1988;6(2):110-9. http://www.ncbi.nlm.nih.gov/pubmed/2903524 6. Petersen PM, Skakkebaek NE, Vistisen K, Rorth M, Giwercman A. Semen quality and reproductive hormones before orchiectomy in men with testicular cancer. J Clin Oncol 1999;17(3):941-7. http://www.ncbi.nlm.nih.gov/pubmed/10071288 7. Eberhard J, Stahl O, Giwercman Y, Cwikiel M, Cavallin-Stahl E, Lundin KB, Flodgren P, Giwercman A. Impact of therapy and androgen receptor polymorphism on sperm concentration in men treated for testicular germ cell cancer: a longitudinal study. Hum Reprod 2004;19(6):1418-25. http://www.ncbi.nlm.nih.gov/pubmed/15105386 8. Willemse PH, Sleijfer DT, Sluiter WJ, Schraffordt Koops H, Doorenbos H. Altered Leydig cell function in patients with testicular cancer: evidence for bilateral testicular defect. Acta Endocrinol (Copenh) 1983;102(4):616-24. http://www.ncbi.nlm.nih.gov/pubmed/6133401 9. Nord C, Bjoro T, Ellingsen D, Mykletun A, Dahl O, Klepp O, Bremnes RM, Wist E, Fossa SD. Gonadal hormones in long-term survivors 10 years after treatment for unilateral testicular cancer. Eur Urol 2003;44(3):322-8. http://www.ncbi.nlm.nih.gov/pubmed/12932930 10. Parra BL, Venable DD, Gonzalez E, Eastham JA. Testicular microlithiasis as a predictor of intratubular germ cell neoplasia. Urology 1996;48(5):797-9. http://www.ncbi.nlm.nih.gov/pubmed/8911532 11. Peterson AC, Bauman JM, Light DE, McMann LP, Costabile RA. The prevalence of testicular microlithiasis in an asymptomatic population of men 18 to 35 years old. J Urol 2001;166(6):2061-4. http://www.ncbi.nlm.nih.gov/pubmed/11696707 12. von Eckardstein S, Tsakmakidis G, Kamischke A, Rolf C, Nieschlag E. Sonographic testicular microlithiasis as an indicator of premalignant conditions in normal and infertile men. J Androl 2001;22(5):818-24. http://www.ncbi.nlm.nih.gov/pubmed/11545295 13. Thomas K, Wood SJ, Thompson AJ, Pilling D, Lewis-Jones DI. The incidence and significance of testicular microlithiasis in a subfertile population. Br J Radiol 2000;73(869):494-7. http://www.ncbi.nlm.nih.gov/pubmed/10884745 14. Pierik FH, Dohle GR, van Muiswinkel JM, Vreeburg JT, Weber RF. Is routine scrotal ultrasound advantageous in infertile men? J Urol 1999;162(5):1618-20. http://www.ncbi.nlm.nih.gov/pubmed/10524881 15. Derogee M, Bevers RF, Prins HJ, Jonges TG, Elbers FH, Boon TA. Testicular microlithiasis, a premalignant condition: prevalence, histopathologic findings, and relation to testicular tumor. Urology 2001;57(6):1133-7. http://www.ncbi.nlm.nih.gov/pubmed/11377326 16. Miller FN, Sidhu PS. Does testicular microlithiasis matter? A review. Clin Radiol 2002;57(10):883-90. http://www.ncbi.nlm.nih.gov/pubmed/12413911 17. Giwercman A, Muller J, Skakkebaek NE. Prevalence of carcinoma in situ and other histopathological abnormalities in testes from 399 men who died suddenly and unexpectedly. J Urol 1991;145(1):77-80. http://www.ncbi.nlm.nih.gov/pubmed/1984105 18. de Gouveia Brazao CA, Pierik FH, Oosterhuis JW, Dohle GR, Looijenga LH, Weber RF. Bilateral testicular microlithiasis predicts the presence of the precursor of testicular germ cell tumors in subfertile men. J Urol 2004;171(1):158-60. http://www.ncbi.nlm.nih.gov/pubmed/14665866

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13. DISORDERS OF EJACULATION 13.1

Definition

Disorders of ejaculation are uncommon, but important, causes of male infertility. This group includes several heterogeneous dysfunctions, which can be either organic or functional.

13.2

Classification and aetiology

13.2.1 Anejaculation Anejaculation involves complete absence of an antegrade or retrograde ejaculation and is caused by a failure of emission of semen from the seminal vesicles, the prostate and the ejaculatory ducts into the urethra (1). True anejaculation is usually associated with a normal orgasmic sensation. Occasionally (e.g. in incomplete spinal cord injuries), this sensation may be altered or decreased. True anejaculation is always associated with central or peripheral nervous system dysfunctions or with drugs (2) (Table 13). Table 14: Aetiologies of anejaculation Neurogenic causes • Spinal cord injury • Cauda equina lesion • Retroperitoneal lymphadenectomy • Aortoiliac or horseshoe-kidney surgery • Colorectal surgery • Multiple sclerosis • Parkinson’s disease • Autonomic neuropathy (diabetes mellitus)

Drug-related causes • Antihypertensives • Antipsychotics • Antidepressants • Alcohol

13.2.2 Anorgasmia Anorgasmia is the inability to reach orgasm and may give rise to anejaculation. Anorgasmia is often a primary condition and its cause is usually psychological. Some patients report sporadic events of nocturnal emission or of ejaculation occurring during great emotional excitement unrelated to sexual activity (3). 13.2.3 Delayed ejaculation In delayed ejaculation, abnormal stimulation of the erect penis is needed to achieve orgasm with ejaculation (1). Delayed ejaculation can be considered a mild form of anorgasmia; both conditions can be found alternately in the same patient. The causes of delayed ejaculation may be psychological or organic, e.g. incomplete spinal cord lesion (3), iatrogenic penile nerve damage (4) or pharmacological (antidepressants, antihypertensives, antipsychotics) (5). 13.2.4 Retrograde ejaculation Retrograde ejaculation is the total, or sometimes partial, absence of an antegrade ejaculation as a result of semen passing backwards through the bladder neck into the bladder. Patients experience a normal or decreased orgasmic sensation, except in paraplegia Partial antegrade ejaculation must not be confused with the secretion of bulbo-urethral glands. The causes of retrograde ejaculation can be divided into neurogenic, pharmacological urethral, or bladder neck incompetence (Table 14). Table 15: Aetiology of retrograde ejaculation Neurogenic causes • Spinal cord injury • Cauda equina lesions • Multiple sclerosis • Autonomic neuropathy (juvenile diabetes) • Retroperitoneal lymphadenectomy • Sympathectomy • Colorectal and anal surgery Urethral causes • Ectopic ureterocele • Urethral stricture • Urethral valves or verumontaneum

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Pharmacological causes • Antihypertensives • Alpha1-adrenoceptor antagonists • Antipsychotics • Antidepressants Bladder neck incompetence • Congenital defects/dysfunction of hemitrigone • Bladder extrophy • Bladder neck resection

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•

hyperplasia Congenital dopamine beta-hydroxylase deficiency

•

Prostatectomy

13.2.5 Asthenic ejaculation Asthenic ejaculation, also defined as partial ejaculatory incompetence or ‘ejaculation baveuse’ (6), is characterised by an altered propulsive phase with a normal emission phase. The orgasmic sensation is reduced and the typically rhythmical contractions associated with ejaculation are missing, while in asthenic ejaculation due to urethral obstruction, these contractions are present. Asthenic ejaculation is generally due to the neurogenic or urethral pathologies already listed in Table 14. Asthenic ejaculation does not usually alter semen quality. 13.2.6 Premature ejaculation Premature ejaculation is the inability to control ejaculation for a ‘sufficient’ length of time during vaginal penetration. Although a universally accepted definition of ‘sufficient’ length of time does not exist, some patients are unable to delay ejaculation beyond a few coital thrusts, or even after vaginal penetration. Premature ejaculation may be strictly organic (e.g. prostatitis-related) or ‘psychogenic’ (i.e. neurobiologically based), primary or acquired, partner-related or non-selective, and can be associated with erectile dysfunction. Premature ejaculation does not impair fertility, provided intravaginal ejaculation occurs. For more extensive discussion on this topic, the EAU Male Sexual Dysfunction guidelines may be consulted (http://www.uroweb. org/nc/professional-resources/guidelines/online/). 13.2.7 Painful ejaculation Painful ejaculation is usually an acquired condition, often related to lower urinary tract symptoms (7). It sometimes causes moderate sexual dysfunction. The painful sensation may be felt in the perineum, or urethra and urethral meatus (8). It can be caused by ejaculatory duct obstruction, all types of chronic prostatitis/ chronic pelvic pain syndrome, urethritis, urethrocele, antidepressant drugs and psychological problems.

13.3

Diagnosis

Diagnostic management includes the following recommended procedures. 13.3.1 Clinical history The patient must be carefully checked for diabetes, neuropathies, traumas, urogenital infections, previous surgery and medications. Particular attention must be paid to the characteristics of micturition and ejaculation (presence of nocturnal emission, ejaculatory ability in given circumstances, primary or acquired disorder), as well as to psychosexual aspects (education, features of affective relationship, pre-existent psychological traumas, previous psychological therapies). 13.3.2 Physical examination Genital and rectal examinations are conducted, including evaluation of the prostate, bulbo-cavernosus reflex and anal sphincter tone. Minimal neurological tests include: • sensitivity of scrotum, testes and perineum • cremasteric and abdominal cutaneous reflex • leg osteotendinous and plantar reflexes. 13.3.3 Post-ejaculatory urinalysis Post-ejaculatory urinalysis will determine if there is total or partial retrograde ejaculation. 13.3.4 Microbiological examinations Initial, mid-stream urine, EPS and/or urine after prostatic massage are cultured for evidence of prostatic infection. In cases of increased leukocytes in semen, semen culture is also suggested (9). 13.3.5 Optional diagnostic work up This diagnostic workup can include: • neurophysiological tests (bulbocavernosus evoked response and dorsal nerve somatosensory evoked potentials) • tests for autonomic neuropathies (i.e. appreciation of temperature regulation in the feet) • psychosexual evaluation • video-cystometry

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• • • •

cystoscopy transrectal ultrasonography uroflowmetry vibratory stimulation of the penis

13.4

Treatment

Infertility caused by disorders of ejaculation is seldom treated on the basis of aetiology. Treatment usually involves retrieving spermatozoa for use in assisted reproduction techniques (ART). The following aspects must be considered when selecting treatment: • age of patient and his partner • psychological problems of the patient and his partner • couple’s willingness and acceptance of different fertility procedures • associated pathologies • psychosexual counselling.

13.5

Aetiological treatments

If possible, stop any pharmacological treatments that are interfering with ejaculation. Tamsulosin can be administered during antidepressant treatment (10). Treatment should be given for urogenital infections (i.e. in cases of painful ejaculation) (9). Selective serotonin re-uptake inhibitors (SSRIs) should be given for premature ejaculation, which appears to be related to serotonin levels (11). If possible, any underlying urethral pathology or metabolic disorder (e.g. diabetes) should be corrected. Psychotherapy is not usually very effective.

13.6

Symptomatic treatments

13.6.1 Premature ejaculation This can be treated with topical anaesthetic agents to increase intravaginal ejaculation latency time or the offlabel use of SSRIs (e.g. paroxetine, fluoxetine), behavioural therapy and/or psychotherapy. 13.6.2 Retrograde ejaculation In the absence of spinal cord injury, anatomical anomalies of the urethra, or pharmacological agents, drug treatment must be used to induce antegrade ejaculation (Table 15). Alternatively, the patient can be encouraged to ejaculate when his bladder is full to increase bladder neck closure (12). Table 16: Drug therapy for retrograde ejaculation • • • • •

Ephedrine sulphate, 10-15 mg four times daily (13) Midodrin, 5 mg three times daily (14) Brompheniramine maleate, 8 mg twice daily(15) Imipramine, 25-75 mg three times daily (16) Desipramine, 50 mg every second day (17)

Sperm collection from post-orgasmic urine for use in ART is recommended if: • drug treatment is ineffective or intolerable as a result of side-effects • the patient has a spinal cord injury • drug therapy inducing retrograde ejaculation cannot be interrupted. Sperm retrieval is timed to coincide with the partner’s ovulation. Urine must be alkalinised (pH 7.2-7.8) and osmolarity must be 200-300 mOsmol/kg. The patient is asked to have intercourse or to masturbate. Within 10 minutes after ejaculation, urine must be voided and centrifuged, and the pellet resuspended in 0.5 mL Tyrode’s or Ham’s F-10 medium and immediately inseminated (18). Alternatively, a catheter may be applied to the bladder and 10-50 mL Tyrode’s or Ham’s F-10 medium instilled into the bladder. The patient must ejaculate, and a second catheterisation is carried out immediately to retrieve spermatozoa. The latter treatment minimises contact between spermatozoa and urine (19). If the biological sperm preparation is not of sufficient quality for intrauterine insemination, the couple must undergo in vitro reproductive procedures (i.e. ICSI) with fresh or cryopreserved spermatozoa. 13.6.3 Anejaculation Drug treatment for anejaculation caused by lymphadenectomy and neuropathy or psychosexual therapy in anorgasmic men is not very effective. In all these cases and in men who have a spinal cord injury, vibrostimulation (i.e. the application of a vibrator to the penis) is first-line therapy. In anejaculation, vibro-stimulation evokes the ejaculation reflex (20), which requires an intact

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lumbosacral spinal cord segment. Complete spinal injuries and injuries above T10 show a better response to vibro-stimulation. Once the safety and efficacy of this procedure has been assessed, patients can manage the process in their own home. Intravaginal insemination using a 10 mL syringe during ovulation can be carried out. If the quality of semen is poor, or ejaculation is retrograde, the couple may enter an IVF programme. If vibro-stimulation has failed, electro-ejaculation is the therapy of choice (21). Electro-ejaculation involves electric stimulation of the periprostatic nerves via a probe inserted into the rectum, which seems unaffected by reflex arc integrity. Anaesthesia is required except in cases of complete spinal cord injury. In 90% of patients, electro-stimulation induces ejaculation, which is retrograde in one-third of cases. Semen quality is often poor and most couples will need to enter an IVF programme (22). When electro-ejaculation fails or cannot be carried out, sperm can be retrieved from the seminal ducts by aspiration from the vas deferens (23) (see Section 5 Obstructive azoospermia) or seminal tract washout (24). When sperm cannot be retrieved, epididymal obstruction or testicular failure must be suspected. TESE can then be used (9, 25). Anejaculation following either surgery for testicular cancer or total mesorectal excision can be prevented using monolateral lymphadenectomy or autosomic nerve preservation (25), respectively.

13.7 CONCLUSIONS •

13.8

Ejaculation disorders can be treated using a wide range of drugs and physical stimulation trials with a high level of efficacy.

RECOMMENDATIONS

Recommendations GR • Aetiological treatments for ejaculatory disorders should be offered before sperm collection and ART is performed. • Premature ejaculation can be treated successfully with either topical anaesthetic creams or SSRIs (23). • In men with spinal cord injury, vibro-stimulation and electro-ejaculation are effective methods of sperm retrieval. GR = grade of recommendation

13.9

REFERENCES

Buvat J. Glossaire. [Ejaculation and its Disruptions] In: Buvat J, Jouannet P (eds). [L’éjaculation et ses Perturbations.] Lyon-Villeurbanne: SIMEP, 1984, p. 9. [Book in French] 2. Wang R, Monga M, Hellstrom WJG. Ejaculatory dysfunction. In: Comhaire FH (ed). Male Infertility: Clinical Investigation. Cause, Evaluation and Treatment. London: Chapman Hall, 1996, pp. 205-221. 3. Pryor JP. Erectile and ejaculatory problems in infertility. In: Hargreave TB (ed). Male Infertility. Berlin: Springer-Verlag, 1997, pp. 319-336. 4. Yachia D. Our experience with penile deformations: incidence, operative techniques, and results. J Androl 1994;15(Suppl):63S-68S. http://www.ncbi.nlm.nih.gov/pubmed/7721682 5. Rudkin L, Taylor MJ, Hawton K. Strategies for managing sexual dysfunction induced by antidepressant medication. Cochrane Database Syst Rev. 2004 18;(4):CD003382. http://www.ncbi.nlm.nih.gov/pubmed/15495050 6. Chapelle PA. [[Séquelles génito-sexuelles du paraplégique ] 2-Neuro-physiologie. Tempo Medical 1982;103:67-70. [article in French] 7. Vallancien G, Emberton M, Harving N, van Moorselaar RJ; Alf-One Study Group. Sexual dysfunction in 1,274 European men suffering from lower urinary tract symptoms. J Urol 2003;169(6):2257-61. http://www.ncbi.nlm.nih.gov/pubmed/12771764 8. Hermabessiere J, Bouquet de la Joliniere J, Buvat J. [Painful ejaculation. Researching organic causes.] In: Buvat J, Jouannet P (eds). [Ejaculation and its Disruptions.] Lyon-Villeurbanne: SIMEP, 1984, pp. 129-134. [book in French] 9. Abdel-Hamid IA, El Naggar EA, El Gilany AH. Assessment of as needed use of pharmacotherapy and the pause-squeeze technique in premature ejaculation. Int J Impot Res 2001;13(1):41-5. http://www.ncbi.nlm.nih.gov/pubmed/11313839 10. Perimenis P, Gyftopoulos K, Ravazoula P, Athanassopoulos A, Barbalias G. Excessive verumontanum hyperplasia causing infertility. Urol Int 2001;67(2):184-5. http://www.ncbi.nlm.nih.gov/pubmed/11490221 1.

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11. Demyttenaere K, Huygens R. Painful ejaculation and urinary hesitancy in association with antidepressant therapy: relief with tamsulosin. Eur Neuropsychopharmacol 2002;12(4):337-41. http://www.ncbi.nlm.nih.gov/pubmed/12126873 12. Crich JP, Jequier AM. Infertility in men with retrograde ejaculation: the action of urine on sperm motility, and a simple method for achieving antegrade ejaculation. Fertil Steril 1978;30(5):572-6. http://www.ncbi.nlm.nih.gov/pubmed/720646 13. Gilja I, Parazajder J, Radej M, Cvitkovic P, Kovacic M. Retrograde ejaculation and loss of emission: possibilities of conservative treatment. Eur Urol 1994;25(3):226-8. http://www.ncbi.nlm.nih.gov/pubmed/8200405 14. Jonas D, Linzbach P, Weber W. The use of midodrin in the treatment of ejaculation disorders following retroperitoneal lymphadenectomy. Eur Urol 1979;5(3):184-7. http://www.ncbi.nlm.nih.gov/pubmed/87324 15. Schill WB. Pregnancy after brompheniramine treatment of a diabetic with incomplete emission failure. Arch Androl 1990;25(1):101-4. http://www.ncbi.nlm.nih.gov/pubmed/2389987 16. Brooks ME, Berezin M, Braf Z. Treatment of retrograde ejaculation with imipramine. Urology 1980;15(4):353-5. http://www.ncbi.nlm.nih.gov/pubmed/7190335 17. Hendry WF. Disorders of ejaculation: congenital, acquired and functional. Br J Urol 1998;82(3):331-41. http://www.ncbi.nlm.nih.gov/pubmed/9772867 18. Schill WB. Diagnosis and treatment of ejaculatory sterility. In: Paulson JD, Nigro-Vilar A, Lucena E, Martini L (eds). Andrology. Male Fertility and Sterility. Orlando: Academic Press, 1986, pp. 599-617. 19. Hotchkiss RS, Pinto AB, Kleegman S. Artificial insemination with semen recovered from the bladder. Fertil Steril 1954;6(1):37-42. http://www.ncbi.nlm.nih.gov/pubmed/13220644 20. Brindley GS. Reflex ejaculation under vibratory stimulation in paraplegic men. Paraplegia 1981;19(5):299-302. http://www.ncbi.nlm.nih.gov/pubmed/7279433 21. Elliott S, Rainsbury PA. Treatment of anejaculation. In: Colpi GM, Balerna M (eds). Treating Male Infertility: New Possibilities. Basel: Karger AG, 1994, pp. 240-254. 22. Denil J, Kuczyk MA, Schultheiss D, Jibril S, Kupker W, Fischer R, Jonas U, Schlosser HW, Diedrich K. Use of assisted reproductive techniques for treatment of ejaculatory disorders. Andrologia 1996;28(Suppl 1):43-51. http://www.ncbi.nlm.nih.gov/pubmed/9082877 23. Waldinger MD. The neurobiological approach to premature ejaculation. J Urol 2002;168(6):2359-67. http://www.ncbi.nlm.nih.gov/pubmed/12441918 24. Jankowicz E, Drozdowski W, Pogumirski J. [Idiopathic autonomic neuropathy (pandysautonomia)]. Neurol Neurochir Pol 2001;35(3):439-52. [article in Polish] http://www.ncbi.nlm.nih.gov/pubmed/11732267 25. Maurer CA, Z’Graggen K, Renzulli P, Schilling MK, Netzer P, Buchler MW. Total mesorectal excision preserves male genital function c0ompared with conventional rectal cancer surgery. Br J Surg 2001;88(11):1501-5. http://www.ncbi.nlm.nih.gov/pubmed/11683749

14. SEMEN CRYOPRESERVATION 14.1

Definition

Cryopreservation is the storage of biological material at subzero temperatures (e.g. -80°C or -196°C [the boiling point of liquid nitrogen]), at which biochemical processes of cell metabolism are slowed or interrupted. At -196°C, the biochemical reactions that lead to cell death are effectively stopped.

14.2

Introduction

Cryopreservation was first developed in the 1940s by veterinarians and adapted for human sperm in the 1950s. The first pregnancy that involved the use of cryopreservation techniques was in 1954 (1). In fertility practice, clinical indications for cyropreservation include storage of sperm, testicular and ovarian tissue and early embryos.

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14.3

Indications for storage

Storage of sperm is available in many clinics for the following indications: • before potentially sterilising chemotherapy or radiotherapy for cancer (2) or for non-malignant disease (e.g. Behçet’s disease) • before surgery that might interfere with fertility (e.g. bladder neck surgery in a younger man or removal of the second testicle in a man with bilateral testicular malignancy) • for men with progressive decrease in semen quality as a result of diseases carrying an associated risk of subsequent azoospermia (i.e. pituitary macro-adenomas, cranio-pharyngiomas, empty sella syndrome, chronic nephropathies, uncontrolled diabetes mellitus, multiple sclerosis). • for men with paraplegia when sperm have been obtained by electro-ejaculation • for men with psychogenic anejaculation, after sperm have been obtained either by electro-ejaculation or a sperm retrieving procedure • after gonadotrophin treatment has induced spermatogenesis in men with hypogonadotropic hypogonadism • for men with NOA, the chance of finding sperm using micro-TESE is approximately 60-70%; cryopreservation can be used to separate sperm collection from ICSI, thus avoiding unnecessary hyper-stimulation of the female partner. It may also be used to avoid repeated sperm retrieval procedures. • in any situation where sperm have been obtained by a sperm retrieving procedure (e.g. after failed vasectomy reversal, or in some cases of epididymal obstruction not amenable to surgery) • for storage of sperm before vasectomy; this service is offered by a few clinics as an insurance policy against change of mind or circumstances • for storage of donor sperm; cryopreservation and a 3-6 months quarantine period reduce the risk of transmission of infection from sperm donors; in most countries, fresh sperm are no longer used.

14.4

Precautions and techniques

14.4.1 Freezing and thawing process The cryopreservation techniques currently in use are not yet optimal as damage occurs to cells during cyropreservation and during prolonged storage. Most damage occurs during freezing and thawing. Major causes of damage during freezing are ice crystal formation and cell dehydration causing disruption of the cell wall and intracellular organelle .Sperm morphology, motility and vitality decrease significantly after thawing, and cryopreservation increases the damage done to sperm DNA (3-5, 6). Further damage may be caused by contamination of samples with micro-organisms and high levels of superoxide radicals (7, 8). To reduce ice crystal formation, a cryopreservation solution is added before freezing. Various cryopreservation solutions are available commercially, most of which contain varying proportions of glycerol and albumen. After freezing, the tissues are immersed in liquid nitrogen. Several techniques have been developed to try to reduce damage caused by freezing and thawing. • Rapid method (9, 10): sample is held in the vapour phase for 10 min before being plunged into liquid nitrogen. • Slow method (11): sample is gradually cooled in the vapour phase for approximately 40 min. • A programmable automatic freezing machine, which is pre-set to cool at a rate of 1-10°C/min, is used. The method available depends on the laboratory’s resources. Whichever freezing technique is employed, it should be tested using donor sperm and post-thaw examination, and should regularly undergo a qualitycontrol programme. The likelihood of sperm survival decreases with increased storage time and repeated freezing and thawing. The maximum viable storage time for human sperm is not known. Many laboratory or regulatory authorities apply a storage time limit of up to 10 years (12); however, longer storage times are sometimes needed (e.g. for a 17-year-old male who has had sperm stored before undergoing chemotherapy for testicular cancer). 14.4.2 Cryopreservation of very small numbers of sperm Standard cryopreservation in straws is an efficient way of storing large number of sperm (e.g. for a donor insemination programme). However, in micro-TESE, very few sperm might be obtained, and the choice is either to freeze testicular tissue and find sperm after thawing the tissue, or to freeze very small numbers of sperm. If sperm are frozen in straws, it can be very difficult to find any sperm after thawing. Instead, the sperm should be frozen in the form of a pellet (13) or in a container (14). 14.4.3 Testing for infections and preventing cross-contamination Sperm storage in straws is used extensively. Large numbers of straws are stored in canisters, and the straws are bathed in a pool of liquid nitrogen. Micro-organism contamination of the pool of liquid nitrogen results

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in contamination of the outside of all the straws. The most widely used safeguard is to accept samples for storage only from patients whose semen samples have been tested for infection and confirmed as safe. Donor samples should be tested for viral (hepatitis B and C, HIV) and sexually transmitted infections (C. trachomatis, gonorrhoea, syphilis). Until the test results are known, samples must be stored in an individual quarantine vessel (15) (http://www.hfea.gov.uk/cps/rde/xchg/SID-3F57D79B-1F88B22E/hfea/hs.xsl/576.html). Some laboratories use the additional safeguard of double-wrapping the straws before freezing, although this is more costly and can interfere with the freezing process, reducing sample quality upon thawing. Some centres carry out cytomegalovirus (CMV) testing and store CMV-negative and CMV-positive samples separately. Considerable ethical issues surround the storage of samples before cancer chemotherapy for a man who is hepatitis- or HIV-positive. Very few clinics have separate storage facilities for HIV-positive samples. However, the success of antiretroviral treatment is increasing the number of HIV-positive men who may wish to store sperm. There is also concern about HIV transmission to children conceived using HIV-positive sperm, as sperm-washing techniques fail in about 5%. 14.4.4 Fail-safe precautions to prevent loss of stored materials Any laboratory undertaking long-term storage of human biological materials should have procedures that guard against accidental loss of material caused by storage vessel failure. This is particularly important for sperm stored before potentially sterilising cancer chemotherapy because these patients may not be able to obtain further sperm. The level of precaution will depend on the cost and resources available to the laboratory, but if possible the following safeguards should be in place. • All in-use storage vessels should be fitted with an alarm system activated by a rising temperature or liquid nitrogen leakage • The alarm system should alert a laboratory staff member, according to a 24-hour 365-day rota • Ideally, there should be a spare storage container into which samples can be transferred following a vessel failure. 14.4.5 ‘Orphan’ samples In malignancy and some other situations, years may pass before stored samples are required. Inevitably, during this time, the owners of some samples might disappear or die, leaving behind ‘orphan’ samples for which the owner is no longer contactable. The duty of the laboratory and the legal ownership of these samples can create considerable problems. It is best to obtain instructions from the owner of the sample at the time of, or very shortly after, storage, about what to do with the sample in the event of death or untraceability. In some countries, owners are legally required to provide instructions/consent. Choices available for the owner of the sample, depend on the laws of the country, might or might not be appropriate in all situations, and include: • a request that the sample should be destroyed • use of the sample by their wife or partner • use of the sample in research • donation of the sample to help another infertile couple.

14.5

Biological aspects

Cryopreservation induces deterioration of the seminal quality. After the sample has been thawed, motility (16) and morphology (17, 18) are worsened, including mitochondrial acrosomal and sperm tail damage (19). Sperm freezing decreases motility by 31%, morphology by 37%, and mitochondrial activity by 36% (9). Motility is correlated best with IVF capacity of the thawed sample. Further improvement can be achieved by selecting the subpopulation of sperm with the best motility and DNA integrity and freezing these sperm in seminal plasma (13).

14.6 CONCLUSIONS • •

The purpose of sperm cryopreservation is to secure future pregnancies using ART. Cryopreservation techniques are not optima, and future efforts are needed to improve the outcome of sperm banking.



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14.7

RECOMMENDATIONS

Recommendations • Cryopreservation of semen should be offered to all men who are candidates for chemotherapy, radiation or surgical interventions that might interfere with spermatogenesis or cause ejaculatory disorders. • If cryopreservation is not available locally, patients should be advised about the possibility of visiting, or transferring to, the nearest cryopreservation unit before therapy starts. • Precautions should be taken to prevent transmission of viral, sexually transmitted or any other infection by cryostored materials from donor to recipient and also to prevent contamination of stored samples.

14.8

REFERENCES

1.

Bunge RG, Keettel WC, Sherman JK. Clinical use of frozen semen; report of four cases. Fertil Steril. 1954;5(6):520-9. http://www.ncbi.nlm.nih.gov/pubmed/13210484 2. Saito K, Suzuki K, Iwasaki A, Yumura Y, Kubota Y. Sperm cryopreservation before cancer chemotherapy helps in the emotional battle against cancer. Cancer 2005;104(3):521-4. http://www.ncbi.nlm.nih.gov/pubmed/15968690 3. Desrosiers P, Legare C, Leclerc P, Sullivan R. Membranous and structural damage that occur during cryopreservation of human sperm may be time-related events. Fertil Steril 2006;85(6):1744-52. http://www.ncbi.nlm.nih.gov/pubmed/16643911 4. Donnelly ET, McClure N, Lewis SE. Cryopreservation of human semen and prepared sperm: effects on motility parameters and DNA integrity. Fertil Steril 2001;76(5):892-900. http://www.ncbi.nlm.nih.gov/pubmed/11704107 5. Chohan KR, Griffin JT, Carrell DT. Evaluation of chromatin integrity in human sperm using acridine orange staining with different fixatives and after cryopreservation. Andrologia 2004;36(5):321-6. http://www.ncbi.nlm.nih.gov/pubmed/15458552 6. Askari HA, Check JH, Peymer N, Bollendorf A. Effect of natural antioxidants tocopherol and ascorbic acids in maintenance of sperm activity during freeze-thaw process. Arch Androl 1994;33(1):11-5. http://www.ncbi.nlm.nih.gov/pubmed/7979804 7. Smith KD, Steinberger E. Survival of spermatozoa in a human sperm bank. Effects of long-term storage in liquid nitrogen. J Am Med Assoc 1973;223(7):774-7. http://www.ncbi.nlm.nih.gov/pubmed/4739258 8. Agarwal A, Said TM. Oxidative stress, DNA damage and apoptosis in male infertility: a clinical approach. BJU Int 2005;95(4):503-7. http://www.ncbi.nlm.nih.gov/pubmed/15705068 9. Grischenko VI, Dunaevskaya AV, Babenko VI. Cryopreservation of human sperm using rapid cooling rates. Cryo Letters 2003;24(2):67-76. http://www.ncbi.nlm.nih.gov/pubmed/12819827 10. Sherman JK, Bunge RG. Observations on preservation of human spermatozoa at low temperatures. Proc Soc Exp Biol Med 1953;82(4):686-8. http://www.ncbi.nlm.nih.gov/pubmed/13055973 11. Sawada Y, Ackerman D, Behrman SJ. Motility and respiration of human spermatozoa after cooling to various low temperatures. Fertil Steril 1967;18(6):775-81. http://www.ncbi.nlm.nih.gov/pubmed/13055973 12. Henry MA, Noiles EE, Gao D, Mazur P, Critser JK. Cryopreservation of human spermatozoa. IV. The effects of cooling rate and warming rate on the maintenance of motility, plasma membrane integrity, and mitochondrial function. Fertil Steril 1993;60(5):911-8. http://www.ncbi.nlm.nih.gov/pubmed/8224279 13. Bahadur G, Ling KL, Hart R, Ralph D, Wafa R, Ashraf A, Jaman N, Mahmud S, Oyede AW. Semen quality and cryopreservation in adolescent cancer patients. Hum Reprod 2002;17(12):3157-61. http://www.ncbi.nlm.nih.gov/pubmed/12456617 14. Hallak J, Hendin BN, Thomas AJ Jr, Agarwal A. Investigation of fertilizing capacity of cryopreserved spermatozoa from patients with cancer. J Urol 1998;159(4):1217-20. http://www.ncbi.nlm.nih.gov/pubmed/9507838 15. Clarke GN. Sperm cryopreservation: is there a significant risk of cross-contamination? Hum Reprod 1999;14(12):2941-3. http://www.ncbi.nlm.nih.gov/pubmed/10601075

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16. O’Connell M, McClure N, Lewis SE. The effects of cryopreservation on sperm morphology, motility and mitochondrial function. Hum Reprod 2002;17(3):704-9. http://www.ncbi.nlm.nih.gov/pubmed/11870124 17. Woolley DM, Richardson DW. Ultrastructural injury to human spermatozoa after freezing and thawing. J Reprod Fertil 1978;53(2):389-94. http://www.ncbi.nlm.nih.gov/pubmed/567693 18. Watson PF. Recent developments and concepts in the cryopreservation of spermatozoa and the assessment of their post-thawing function. Reprod Fertil Dev 1995;7(4):871-91. http://www.ncbi.nlm.nih.gov/pubmed/8711221 19. Donnelly ET, McClure N, Lewis SE. Cryopreservation of human semen and prepared sperm: effects on motility parameters and DNA integrity. Fertil Steril 2001;76(5):892-900. http://www.ncbi.nlm.nih.gov/pubmed/11704107

15. LEVELS OF EVIDENCE AND GRADES OF GUIDELINE RECOMMENDATIONS Table 17: Levels of evidence.* Level Type of evidence 1a Evidence obtained from meta-analysis of randomised trials 1b Evidence obtained from at least one randomised trial 2a Evidence obtained from one well-designed controlled study without randomisation 2b Evidence obtained from at least one other type of well-designed quasi-experimental study 3 Evidence obtained from well-designed non-experimental studies (e.g. comparative studies, correlation studies and case reports) 4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities * Modified from Sacket et al. (1). Table 18: Grades of guideline recommendations.* Grade Nature of recommendations A Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomised trial B Based on well-conducted clinical studies, but without randomised clinical trials C Made despite the absence of directly applicable clinical studies of good quality * Modified from Sacket et al. (1).

15.1

REFERENCES

1.

Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998. http://www.cebm.net/index.aspx?o=1025 [access date Oct 24, 2008].

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16. ABBREVIATIONS USED IN THE TEXT This list is not comprehensive for the most common abbreviations

ABP acute bacterial prostatitis ART assisted reproduction techniques CBAVD congenital bilateral absence of the vas deferens CBP chronic bacterial prostatitis CF cystic fibrosis CFTR cystic fibrosis transmembrane conductance regulator gene CIS carcinoma in situ CMV cytomegalovirus CPPS chronic pelvic pain syndrome CFTR cystic fibrosis transmembrane conductance regulator EPS espressed prostatic excretion FISH (multicolour) fluorescent in situ hybridisation HIV human immunodeficiency virus FSH follicle-stimulating hormone GnRH gonadotrophin-releasing hormone hCG human chorionic gonadotrophin hMG human menopausal gonadotrophin IBT immunobead test ICSI intracytoplasmic sperm injection IL-6 interleukin-6 IVF in vitro fertilisation LH luteinising hormone MAGI male accessory gland infection MAR mixed antiglobulin reaction MESA microsurgical epididymal sperm aspiration NBP non- or abacterial prostatitis NIDDK National Institute of Diabetes and Digestive and Kidney Diseases NIH National Institute of Health NOA non-obstructive azoospermia OA obstructive azoospermia OAT oligo-astheno-teratozoospermia [syndrome] SHBG sex hormone binding globulin SSRIs selective serotonin reuptake inhibitors STS sequence tagged sites TESE testicular sperm extraction TEFNA testicular fine-needle aspiration TGCT testicular germ cell tumour TM testicular microlithiasis TRUS transurethral ultrasound TURED transurethral resection of the ejaculatory ducts WBC white blood cells VB1 first-voided urine

Conflict of interest All members of the Male Infertility guidelines writing panel have provided disclosure statements of all relationships which they have and which may be perceived as a potential source of conflict of interest. This information is kept on file in the European Association of Urology Central Office database. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

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Guidelines on

Urinary Incontinence A. Schröder, P. Abrams (Co-Chairman), K-E. Andersson, W. Artibani, C.R. Chapple, M.J. Drake, C. Hampel, A. Neisius, A. Tubaro, J.W. Thüroff (Chairman)

© European Association of Urology 2009

TABLE OF CONTENTS 1.

page

Introduction 1.1 References

4 5

2. Epidemiology 2.1 Introduction 2.2 Risk factors in women 2.2.1. Risk factors in pelvic organ prolapse (POP) 2.3 Risk factors in men 2.4 Overactive bladder (OAB) 2.5 Disease progression 2.5.1 Longitudinal studies 2.5.2 Genetic epidemiology 2.5.3 Twin studies 2.5.4 Worldwide estimates of current and future LUTS including urinary incontinence (UI) and OAB in individuals > 20 yrs 2.5.5 Conclusions 2.6 References

5 5 5 5 5 6 6 6 6 6 6 6 6

3. Pharmacotherapy 3.1 Introduction 3.2 Drugs used in the treatment of OAB/detrusor overactivity (DO) 3.3 Drugs used in the treatment of stress urinary incontinence (SIU) 3.4 Drugs used for the treatment of ‘overflow incontinence’ 3.5 Hormonal treatment of UI 3.5.1 Oestrogen 3.5.2 Other steroid hormones/receptor ligands 3.5.3 Desmopressin 3.6 References

7 7 7 8 9 9 9 9 9 10

4. Incontinence in men 4.1 Initial assessment 4.2 Initial treatment 4.2.1 General management 4.2.2 Post-radical prostatectomy (RP) incontinence 4.2.3 Conclusions 4.3 Specialised management 4.3.1 Assessment 4.3.2 Interventions 4.3.3 Sphincter incompetence 4.3.3.1 Detrusor overactivity (DO) 4.3.3.2 Poor bladder emptying 4.3.3.3 Bladder outlet obstruction (BOO) 4.4 Surgical treatment 4.4.1 Incontinence after surgery for benign prostatic obstruction (BPO) or prostate cancer (CaP) 4.4.1.1 Incontinence after surgery for BPO or prostate cancer (CaP) 4.4.1.2 Incontinence after surgery for prostate cancer (CaP 4.4.1.3 Definitions of post-RP continence 4.4.1.4 Incontinence risk factors 4.4.1.5 Interventional treatment for post-RP incontinence 4.4.1.6 Age 4.4.1.7 Post-RP incontinence with bladder neck stricture 4.4.2 Incontinence after external beam radiotherapy for CaP 4.4.2.1 Artificial urinary sphincter (AUS) after radiotherapy 4.4.2.2 Conclusion 4.4.2.3 Other treatments for SIU after radiotherapy 4.4.3 Incontinence after other treatment for CaP 4.4.3.1 Brachytherapy

11 11 11 11 12 12 13 13 13 13 13 13 14 14

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4.4.3.2 Cryotherapy 4.4.3.3 High-intensity focused ultrasound (HIFU) 4.4.3.4 Recommendation 4.4.4 Treatment of incontinence after neobladder 4.4.5 Urethral and pelvic floor injuries 4.4.5.1 Recommendation 4.4.6 Incontinence in adult epispadias-exstrophy complex 4.4.7. Refractory UUI and idiopathic DO 4.4.8 Incontinence and reduced capacity bladder 4.4.9 Urethro-cuteneous fistula and recto-urethral fistula 4.4.10 Management of AUS complications 4.5 References

16 16 16 16 16 17 17 17 17 17 17 17

5. INCONTINENCE IN WOMEN 5.1 Initial Assessment 5.2 Initial treatment of UI in women 5.2.1 Pelvic floor muscle training (PFMT) under special circumstances 5.3 Specialised management of UI in women 5.3.1 Assessment 5.3.2 Treatment 5.4 Surgery for UI in women 5.4.1 Outcome measures 5.5 Outcome measures 5.6 References

28 28 28 30 31 31 31 32 34 34 34

6. URINARY INCONTINENCE IN FRAIL / OLDER MEN AND WOMEN 6.1 History and symptom assessment 6.1.1 General principles 6.1.2 Nocturia 6.1.3 Post-void residual (PVR) volume 6.2 Clinical diagnosis 6.3 Initial management 6.3.1 Drug therapy 6.4 Ongoing management and reassessment 6.5 Specialised management 6.5.1 Surgical approaches to UI in the frail / older men and women 6.6 References

44 44 44 44 45 45 45 45 45 46 46 47

7.

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Abbreviations used in the text

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3

1. Introduction In the first International Consultation on Incontinence in 1998, a structure of ‘Clinical Guidelines for Management of Incontinence’ was developed (1). This included a summary and overview, which were presented in flow sheets (‘algorithms’), with recommendations for ‘Initial Management’ and ‘Specialised Management’ of urinary incontinence (UI) in children, men, women, patients with neuropathic bladder and elderly patients. These algorithms have already been presented in the previous EAU Guidelines on Incontinence and continue to be the skeleton of the guidelines. The algorithms are uniformly constructed to follow from top to bottom a chronological pathway from patient’s history and symptoms assessment, clinical assessment using appropriate studies and tests so that the condition of the underlying pathophysiology can be defined as a basis for rational treatment decisions. To limit the number of diagnostic pathways in the algorithms, clinical presentations that require a similar complexity of diagnostic evaluation have been grouped together by history and symptoms. Again, for simplification, treatment options have been grouped under a few diagnoses (‘conditions’) and their underlying pathophysiology, for which the terminology as standardised by the International Continence Society (ICS) is used. As a rule, the least invasive treatment option is recommended first, proceeding in a stepwise escalation to a more invasive treatment option, when the former fails. Depth and intensity of diagnostic evaluation and therapeutic interventions are grouped into two levels, ‘Initial Management’ and ‘Specialised Management’. The level of ‘Initial Management’ comprises measures generally needed at the first patient contact with a health professional. Depending on the healthcare system and local or general service restrictions, this first contact maybe with an incontinence nurse, a primary care physician or a specialist. The primary information about the patient’s condition is established by medical history, physical examination and applying basic diagnostic tests, which are readily available. If treatment is at all installed at this level of care, it will be mostly of an empirical nature. The level of ‘Specialised Management’ appeals to patients in whom a diagnosis could not be established at the ‘Initial Management’, in whom primary treatment failed, or in whom history and symptoms suggest a more complex or serious condition requiring more elaborate diagnostic evaluation and/or specific treatment options. For instance, at this level urodynamic studies are usually required for establishing a diagnosis on the grounds of pathophysiology, and treatment options at this level include invasive interventions and surgery. The principles of ‘evidence-based medicine’ (EBM) apply for analysis and rating of the relevant papers published in the literature, for which a modified Oxford system has been developed (2, 3). This approach applies ‘levels of evidence’ (LE) to the body of analysed literature and, from there, derives ‘grades of recommendation’ (GR) (Tables 1 and 2). This document presents a synthesis of the findings of the 4th International Consultation on Incontinence held in July 2008 (4). References have been included in the text, with a focus on new publications covering the time span 2005 to the present. An exhaustive reference list is available for consultation on line at the society website (http://www.uroweb.org/professional-resources/guidelines/) and on the CD-rom version. Additionally, an ultra short document is available. Table 1: Level of evidence* Level Type of evidence 1a Evidence obtained from meta-analysis of randomised trials 1b Evidence obtained from at least one randomised trial 2a Evidence obtained from one well-designed controlled study without randomisation 2b Evidence obtained from at least one other type of well-designed quasi-experimental study 3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case reports 4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities Modified from Sackett et al. (2, 3).

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Table 2: Grade of recommendation* Grade Nature of recommendations A Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomised trial B Based on well-conducted clinical studies, but without randomised clinical trials C Made despite the absence of directly applicable clinical studies of good quality Modified from Sackett et al. (2, 3).

1.1 REFERENCES 1. Thüroff JW, Abrams P, Artibani W, Haab F, Khoury S, Madersbacher H, Nijman R, Norton P. Clinical guidelines for the management of incontinence. In: Abrams P, Khoury S, Wein A, (eds). Incontinence. Plymouth: Health Publications Ltd, 1999, pp. 933-943. 2. Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998.  http://www.cebm.net/index.aspx?o=1025 [accessed February 2009]. 3. Abrams P, Khoury S, Grant A. Evidence-based medicine overview of the main steps for developing and grading guideline recommendations. In: Abrams P, Cardozo L, Khoury S, Wein A, (eds). Incontinence. Paris: Health Publications Ltd, 2005, pp. 10-11. 4. Abrams P, Cardozo L, Wein A, Khoury S. 4th International Consultation on Incontinence. Paris, July 5-8, 2008. Publication due in the course of 2009.

2. EPIDEMIOLOGY* 2.1

Introduction

There is a large variation in the estimated prevalence of urinary incontinence (UI), even after taking into account differences in definitions, epidemiological methodology and demographic characteristics. However, recent prospective studies have provided much data on the incidence of UI and the natural history (progression, regression and resolution) of UI (1-4). Urinary incontinence, or urine loss occurring at least once during the last 12 months, has been estimated as occurring in 5-69% of women and 1-39% of men. In general, UI is twice as common in women as in men. Limited data from twin studies suggest there is a substantial genetic component to UI, especially stress urinary incontinence (SUI) (5, 6).

2.2 Risk factors in women Pregnancy and vaginal delivery are significant risk factors, but become less important with age. Contrary to previous popular belief, menopause per se does not appear to be a risk factor for UI and there is conflicting evidence regarding hysterectomy. Diabetes mellitus is a risk factor in most studies. Research also suggests that oral oestrogen substitution and body mass index are important modifiable risk factors for UI. Although mild loss of cognitive function is not a risk factor for UI, it increases the impact of UI. Smoking, diet, depression, urinary tract infections (UTIs) and exercise are not risk factors. 2.2.1 Risk factors in pelvic organ prolapse (POP) Pelvic organ prolapse (POP) has a prevalence of 5-10% based on the finding of a mass bulging in the vagina. Childbirth carries an increased risk for POP later in life, with the risk increasing with the number of children. It is unclear whether Caesarean section (CS) prevents the development of POP though most studies indicate CS carries less risk than vaginal delivery for subsequent pelvic floor morbidity. Several studies suggest hysterectomy and other pelvic surgery increase the risk of POP. Further research is needed.

2.3 Risk factors in men Risk factors for UI in men include increasing age, lower urinary tract symptoms (LUTS), infections, functional and cognitive impairment, neurological disorders and prostatectomy. *This section of the guidelines is based on the recommendations of the ICI committee chaired by Ian Milsom (Committee 1: Epidemiology).

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2.4

Overactive bladder (OAB)

The prevalence of OAB in adult males varies from 10% to 26% and in adult females from 8% to 42%. It increases with age and often occurs with other LUTS. Several common chronic conditions, such as depression, constipation, neurological conditions and erectile dysfunction, have been significantly associated with OAB, even after adjusting for important covariates, such as age, gender and country (7).

2.5 Disease progression 2.5.1 Longitudinal studies The literature on incidence and remission of UI is still scarce, particularly among men. However, the annual incidence rates of UI in women ranges from 2% to 11%, with the highest incidence occurring during pregnancy. Rates of complete remission of UI range from 0% to 13%, with the highest remission rate after pregnancy. The annual incidence rates of OAB range from 4% to 6%, while annual remission rates of OAB range from 2% to 3%. The annual incidence of prolapse surgery ranges from 0.16% to 0.2%. The estimated life-time cumulative risk for prolapse surgery is estimated to be 7-11%. 2.5.2 Genetic epidemiology The familial transmission of UI is well documented. However, it is often difficult to differentiate between heritability and non-inherited transmission (environmental factors) in the family environment. Ethnic and racial differences for UI and POP are also well documented. 2.5.3 Twin studies It is possible to estimate the relative proportions of phenotypic variance caused by genetic and environmental factors by comparing monozygotic female twins (who have an identical genotype) with dizygotic female twins (who share an average of 50% of their segregating genes). A genetic influence is suggested when monozygotic twins are more concordant for the disease than dizygotic twins. Suggested candidate genes include, for example, a polymorphism of the gene for collagen type I. In contrast, an environmental effect is suggested when monozygotic twins are discordant for the disease 2.5.4 Worldwide estimates of current and future LUTS including UI and OAB in individuals > 20 years old The EPIC study is a population-based study estimating the prevalence of UI, OAB and other LUTS among men and women from five countries using the 2002 ICS definitions. The age- and gender-specific prevalence rates from the EPIC study were used to estimate the current and future worldwide number of individuals with LUTS, OAB and UI (8). This was done by extrapolating prevalence rates to the worldwide population aged 20 years and older (4.2 billion). Males and females from the age of 20 to 80+ years were stratified into five-year age groups (e.g. 20-24 years) to estimate the current and future worldwide number of individuals with LUTS, OAB and UI, and the age- and gender-specific prevalence rates. Projected population estimates for all worldwide regions are based on information from the United States (US) Census Bureau International Database (IDB) (9). 2.5.5 Conclusions As the population ages, the prevalence of LUTS is also expected to increase. LUTS are burdensome to individuals. The projected increase in the number of individuals experiencing LUTS has implications for healthcare resources and overall health burden. The estimated number of individuals with LUTS has been based on a conservative prevalence rate. Thus, the future number of those with LUTS may be much higher.

2.6 REFERENCES* 1. Offermans MP, Du Moulin MF, Hamers JP, Dassen T, Halfens RJ. Prevalence of urinary incontinence and associated risk factors in nursing home residents: A systematic review. Neurourol Urodyn 2009 Feb 3. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/19191259 2. Botlero R, Davis SR, Urquhart DM, Shortreed S, Bell RJ. Age-specific prevalence of, and factors associated with, different types of urinary incontinence in community-dwelling Australian women assessed with a validated questionnaire. Maturitas 2009 Jan 30. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/19181467 3. Wennberg AL, Molander U, Fall M, Edlund C, Peeker R, Milsom I. A Longitudinal Population-based Survey of Urinary Incontinence, Overactive Bladder, and Other Lower Urinary Tract Symptoms in

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Women. Eur Urol 2009 Jan 13. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/19157689 4. Long RM, Giri SK, Flood HD. Current concepts in female stress urinary incontinence. Surgeon 2008;6(6):366-72. http://www.ncbi.nlm.nih.gov/pubmed/19110826 5. Altman D, Forsman M, Falconer C, Lichtenstein P. Genetic influence on stress urinary incontinence and pelvic organ prolapse. Eur Urol 2008;54(4):918-22. Epub 2007 Dec 17. http://www.ncbi.nlm.nih.gov/pubmed/18155350 6. Rohr G, Kragstrup J, Gaist D, Christensen K. Genetic and environmental influences on urinary incontinence: a Danish population-based twin study of middle-aged and elderly women. Acta Obstet Gynecol Scand 2004;83(10):978-82. http://www.ncbi.nlm.nih.gov/pubmed/15453898 7. Irwin DE, Milsom I, Reilly K, Hunskaar S, Kopp Z, Herschorn S, Coyne KS, Kelleher CJ, Artibani W, Abrams P. Overactive bladder is associated with erectile dysfunction and reduced sexual quality of life in men. J Sex Med 2008;5(12):2904-10. http://www.ncbi.nlm.nih.gov/pubmed/19090944 8. Irwin DE, Milsom I, Hunskaar S, Reilly K, Kopp Z, Herschorn S, Coyne K, Kelleher C, Hampel C, Artibani W, Abrams P. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 2006;50(6):1306-14; discussion 1314-5. Epub 2006 Oct 2. http://www.ncbi.nlm.nih.gov/pubmed/17049716 9. US Census Bureau, International Data Base http://www.census.gov/ipc/www/idb/index.html [accessed February 2009] *An exhaustive reference list is available for consultation on line at the society website (http://www.uroweb.org/ professional-resources/guidelines/) and on the guidelines CD-rom version.

3. PHARMACOTHERAPY* 3.1

Introduction

More than 50 million people in the developed world are affected by UI and many drugs have been used for treatment (Table 3). Although drugs may be efficacious in some patients, side-effects mean they are often discontinued after short periods of time and they are best used as an adjuvant to conservative and surgical therapy (1).

3.2 Drugs used in the treatment of overactive bladder (OAB)/detrusor overactivity (DO) The clinical relevance of efficacy of antimuscarinic drugs relative to placebo has been widely discussed (2). However, recent large meta-analyses of the most widely used antimuscarinic drugs have clearly shown these drugs provide a significant clinical benefit (3, 4). More research is needed to decide the best drugs for first-, second-, or third-line treatment (4). None of the commonly used antimuscarinic drugs (darifenacin, fesoterodine, oxybutynin, propiverine, solifenacin, tolterodine and trospium) is an ideal first-line treatment for all OAB/DO patients. Optimal treatment should be individualised, considering the patient’s co-morbidities, concomitant medications and the pharmacological profiles of the different drugs (5).

Table 3: Drugs used in the treatment of OAB/DO* Drugs Antimuscarinic drugs • Tolterodine • Trospium • Solifenacin • Darifenacin • Propantheline • Atropine, hyoscyamine

LE

GR

1 1 1 1 2 3

A A A A B C

*This section of the guidelines is based on the recommendations of the ICI committee chaired by Karl-Erik Andersson (Committee 8: Drug Treatment).

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Drugs acting on membrane channels • Calcium antagonists • K+-channel openers Drugs with mixed actions • Oxybutynin • Propiverine • Dicyclomine • Flavoxate Antidepressants • Imipramine • Duloxetine Alpha-adrenoreceptor antagonists • Alfuzosin • Doxazosin • Prazosin • Terazosin • Tamsulosin Beta-adrenoreceptor antagonists • Terbutaline (beta-2) • Salbutamol (beta-2) • YM-178 (beta-3) PDE-5 inhibitors (for male LUTS/OAB) • Sildenafil, taladafil, vardenafil • COX inhibitors • Indomethacin • Flurbiprofen Toxins • Botulinum toxin (neurogenic), injected into bladder wall • Botulinum toxin (idiopathic), injected into bladder wall • Capsaicin (neurogenic), intravesical • Resiniferatoxin (neurogenic), intravesical Other drugs • Baclofen, intrathecal Hormones • Oestrogen • Desmopressin, for nocturia (nocturnal polyuria), but care should be taken because of the risk of hyponatraemia, especially in the elderly

2 2 1 1 3 2

A A C

3 2

C C

3 3 3 3 3

C C C C C

3 3 2

C C B

2

B

2 2

C C

2 3 2 2

A B C C

3

C

2 1

C A

Assessments have been done according to the Oxford modified system, see Tables 1 and 2 LE = level of evidence; GR = grade or recommendation; PDE-5 inhibitor = phosphodiesterase-type 5 inhibitor; COX inhibitor = cyclo-oxygenase inhibitor.

3.3 Drugs used in the treatment of stress urinary incontinence (SUI) Factors that may contribute to urethral closure include: • the tone of urethral smooth and striated muscle • the passive properties of the urethral lamina propria, particularly its vasculature. The relative contribution of these factors to intraurethral pressure is still debated. However, evidence shows that a substantial part of urethral tone is mediated through stimulation of alpha-adrenoreceptors in the urethral smooth muscle by released noradrenaline (6, 7). A contributory factor to SUI, mainly in elderly women with a lack of oestrogen, may be a deterioration in the mucosal co-adaptation function. Pharmacological treatment of SUI aims to increase the force of intraurethral closure by increasing tone in the urethral smooth and striated muscles. Several drugs may contribute to such an increase (8, 9). Their clinical use is limited by low efficacy and/or side-effects (Table 4).

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Table 4: Drugs used in the treatment of stress urinary incontinence Drug LE GR • Duloxetine 1 B • Imipramine 3 NR • Clenbuterol 3 C • Methoxamine 2 NR • Midodrine 2 C • Ephedrine 3 NR • Norephedrine (phenylpropanolamine) 3 NR • Oestrogen 2 NR GR = grade of recommendation; NR = no recommendation possible.

3.4 Drugs used for the treatment of ‘overflow incontinence’ Incontinence may occur when there are large quantities of residual urine with a markedly distended bladder (chronic urinary retention). The ICS no longer approves of the term, ‘overflow incontinence’ (10). Various medical approaches to overflow incontinence have been suggested (11, 12) based upon theoretical reasoning, animal studies (13, 14) and reports of drugs associated with poor bladder emptying (15). These include direct or indirect muscarinic receptor agonists and alpha-1-adrenoreceptor antagonists. However, a recent review of controlled clinical studies on direct and indirect parasympathetic agonists in patients with an underactive detrusor found these drugs were not consistently beneficial and may even be harmful (16). In contrast, alpha-1-adrenoreceptor antagonists have been consistently beneficial in patients with acute urinary retention (17). A recent Medline search using the keyword ‘overflow incontinence’ did not find any randomised controlled trials (RCT) for treatment using parasympathomimetic drugs or alpha-1-adrenoreceptor antagonists nor even a case series with a meaningful number of patients. This indicates that medical treatments currently used to treat overflow incontinence are being used on the basis of empirical evidence. Any previous recommendations for the medical treatment of overflow incontinence can be considered as ‘expert opinion’ at best. In addition, it is important to make sure any medical treatment for overflow incontinence is likely to reduce or eliminate residual urine better than the alternatives of catheterisation or surgery.

3.5

Hormonal treatment of UI

3.5.1 Oestrogen Oestrogen deficiency is an aetiological factor in the pathogenesis of several conditions. However, oestrogen treatment, either alone or combined with progestogen, has achieved only poor results in UI. The current evidence (level of evidence: 1) against the treatment of UI with oestrogen is based on studies originally designed to assess oestrogen for preventing cardiovascular events. In fact, the evidence is derived from secondary analyses of these studies using subjective, self-reported symptoms of urinary leakage. Nevertheless, these large RCTs showed a worsening of pre-existing UI (stress and urgency) and an increased new incidence of UI, with either oestrogen monotherapy or oestrogen combined with progestogen. It should be noted, however, that most patients were taking combined equine oestrogen, which may not be representative of all oestrogens taken by all routes of administration. A systematic review of the effects of oestrogen on symptoms suggestive of OAB concluded that oestrogen therapy may be effective in alleviating OAB symptoms and local administration may be the most beneficial route of administration (18). It is possible that urinary urgency, frequency and urgency incontinence are symptoms of urogenital atrophy in older post-menopausal women (19). There is good evidence that low-dose (local) vaginal oestrogen therapy may reverse the symptoms and cytological changes of urogenital atrophy. However, oestrogens (with or without progestogens) should not be used to treat UI, as there is no evidence to show they have a direct effect on the lower urinary tract. 3.5.2 Other steroid hormones/receptor ligands There are no reported clinical trials evaluating the effect of androgens, particularly testosterone, on UI in women. 3.5.3 Desmopressin Desmopressin (DDVAP) was found to be well tolerated and resulted in a significant improvement in UI

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compared to placebo in reducing nocturnal voids and increasing the hours of undisturbed sleep. Quality of life (QOL) also improved. However, hyponatraemia is one of the main, clinically important, side-effects of DDVAP administration. Hyponatraemia can lead to a range of adverse events from mild headache, anorexia, nausea, and vomiting to loss of consciousness, seizures and death. The risk of hyponatraemia has been reported in a meta-analysis as about 7.6% (20) and seems to increase with age, cardiac disease and a high 24-hour urine volume (21).

3.6 REFERENCES* 1.

Andersson K-E, Appell R, Cardozo L et al. Pharmacological treatment of urinary incontinence, in Abrams P, Khoury S, Wein A (Eds), Incontinence, 3rd International Consultation on Incontinence. Plymouth, Plymbridge Distributors Ltd, UK, Plymouth, 2005, p 811. 2. Herbison P, Hay-Smith J, Ellis G, Moore K. Effectiveness of anticholinergic drugs compared with placebo in the treatment of overactive bladder: systematic review. Br Med J 2003;326(7394):841-4. http://www.ncbi.nlm.nih.gov/pubmed/12702614 3. Chapple CR, Martinez-Garcia R, Selvaggi L, Toozs-Hobson P, Warnack W, Drogendijk T, Wright DM, Bolodeoku J; for the STAR study group. A comparison of the efficacy and tolerability of solifenacin succinate and extended release tolterodine at treating overactive bladder syndrome: results of the STAR trial. Eur Urol 2005;48(3):464-70. http://www.ncbi.nlm.nih.gov/pubmed/15990220 4. Novara G, Galfano A, Secco S, D’Elia C, Cavalleri S, Ficarra V, Artibani W.. Systematic Review and Meta-Analysis of Randomized Controlled Trials with Antimuscarinic Drugs for Overactive Bladder. Eur Urol 2008;54(4):740-63. http://www.ncbi.nlm.nih.gov/pubmed/18632201 5. Chapple CR, Van Kerrebroeck PE, Jünemann KP, Wang JT, Brodsky M. Comparison of fesoterodine and tolterodine in patients with overactive bladder. BJU Int 2008;102(9):1128-32. http://www.ncbi.nlm.nih.gov/pubmed/18647298 6. Andersson KE. Pharmacology of lower urinary tract smooth muscles and penile erectile tissues. Pharmacol Rev 1993;45(3):253-308. http://www.ncbi.nlm.nih.gov/pubmed/8248281 7. Andersson KE, Wein AJ. Pharmacology of the lower urinary tract–basis for current and future treatments of urinary incontinence. Pharmacol Rev 2004;56(4):581-631. http://www.ncbi.nlm.nih.gov/pubmed/15602011 8. Andersson KE. Current concepts in the treatment of disorders of micturition. Drugs 1988;35(4):477-94. http://www.ncbi.nlm.nih.gov/pubmed/3292211 9. Zinner N, Gittelman M, Harris R, Susset J, Kanelos A, Auerbach S;Trospium Study Group.Trospium chloride improves overactive bladder symptoms: a multicenter phase III trial. J Urol 2004;171(6 Pt 1):2311-5. http://www.ncbi.nlm.nih.gov/pubmed/15126811 10. Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, van Kerrebroeck P, Victor A, Wein A; Standardisation Sub-committee of the International Continence Society. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002;21(2):167-78. http://www.ncbi.nlm.nih.gov/pubmed/11857671 11. Chutka DS, Takahashi PY. Urinary incontinence in the elderly. Drug treatment options. Drugs 1998;56(4):587-95. http://www.ncbi.nlm.nih.gov/pubmed/9806105 12. Hampel C, Gillitzer R, Pahernik S, Melchior SW, Thüroff JW. [Drug therapy of female urinary incontinence] Urologe A 2005;44(3):244-55. [article in German] http://www.ncbi.nlm.nih.gov/pubmed/15711814 13. Kamo I, Chancellor MB, De Groat WC, Yoshimura A. Differential effects of activation of peripheral and spinal tachykinin neurokinin3 receptors on the micturition reflex in rats. J Urol 2005;174(2):776-81. http://www.ncbi.nlm.nih.gov/pubmed/16006975 14. Gu B, Fraser MO, Thor KB, Dolber PC. Induction of bladder sphincter dyssynergia by kappa-2 opioid receptor agonists in the female rat. J Urol 2004 Jan;171(1):472-7. http://www.ncbi.nlm.nih.gov/pubmed/14665958 15. Anders RJ, Wang E, Radhakrishnan J, Sharifi R, Lee M. Overflow urinary incontinence due to carbamazepine. J Urol 1985 Oct;134(4):758-9. http://www.ncbi.nlm.nih.gov/pubmed/4032590

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16.

Barendrecht MM, Oelke M, Laguna MP, Michel C. Is the use of parasympathomimetics for treating an underactive urinary bladder evidence-based? BJU Int 2007;99(4):749-52. http://www.ncbi.nlm.nih.gov/pubmed/17233798 17. McNeill SA, Hargreave TB; Members of the Alfaur Study Group. Alfuzosin once daily facilitates return to voiding in patients in acute urinary retention. J Urol 2004;171(6 Pt 1):2316-20. http://www.ncbi.nlm.nih.gov/pubmed/15126812 18. Cardozo L, Lisec M, Millard R, van Vierssen Trip O, Kuzmin I, Drogendijk TE, Huang M, Ridder AM. Randomized, double-blind placebo controlled trial of the once daily antimuscarinic agent solifenacin succinate in patients with overactive bladder. J Urol 2004;172(5 Pt 1):1919-24. http://www.ncbi.nlm.nih.gov/pubmed/15540755 19. Robinson D, Cardozo L, Terpstra G, Bolodeoku J; Tamsulosin Study Group. A randomized doubleblind placebo-controlled multicentre study to explore the efficacy and safety of tamsulosin and tolterodine in women with overactive bladder syndrome. BJU Int 2007;100(4):840-5. http://www.ncbi.nlm.nih.gov/pubmed/17822465 21. Weatherall M. The risk of hyponatremia in older adults using desmopressin for nocturia: a systematic review and meta-analysis. Neurourol Urodyn 2004;23(4):302-5. http://www.ncbi.nlm.nih.gov/pubmed/15227644 21. Rembratt A, Norgaard JP, Andersson KE. Desmopressin in elderly patients with nocturia: short-term safety and effects on urine output, sleep and voiding patterns. BJU Int 2003;91(7):642-6. http://www.ncbi.nlm.nih.gov/pubmed/12699476 *An exhaustive reference list is available for consultation on line at the society website (http://www.uroweb.org/ professional-resources/guidelines/) and on the guidelines CD-rom version.

4. INCONTINENCE IN MEN* 4.1

Initial assessment

Initial assessment in men should triage patients with a ‘complicated’ incontinence, who need to be referred for specialist management, from the remainder who are suitable for general assessment. The ‘complicated’ incontinence group comprises patients with: • pain • haematuria • recurrent infection • previous failed incontinence surgery • total incontinence • voiding dysfunction (e.g. due to bladder outlet obstruction). Poor bladder emptying may be suspected from symptoms, physical examination or if imaging has been performed by ultrasound or X-ray after voiding • previous pelvic radiotherapy. The group of remaining patients, with a history of UI identified by initial assessment, can be stratified into four main symptomatic groups of men suitable for initial management: • post-micturition dribble alone • OAB symptoms: urgency (with or without urge incontinence), frequency, and nocturia • stress incontinence, most often after prostatectomy • mixed urgency and stress incontinence, most often after prostatectomy.

4.2

Initial treatment

4.2.1 General management Conservative management is the main approach to UI in men at the primary care level (Figure 1), and is often considered to be simple and low cost. The term ‘conservative management’ describes any treatment that does not involve pharmacological or surgical intervention. However, for conditions, such as OAB, conservative strategies are often combined with drug treatment. *

This section of the guidelines is based on the recommendations of the ICI committees chaired by Jean Hay-Smith and Sender Herschorn. 4.1 (Initial assessment of UI) and 4.2 (Initial treatment of UI) provide the management algorithms and the explanatory notes; 4.4 (Surgical treatment of UI) provides additional evidence from the chapters.

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Many conservative management interventions require a change of behaviour, which is neither easy to initiate nor to maintain. Most patients with minor-to-moderate symptoms wish to try less invasive treatments first. However, patients with complicated or severe symptoms may need to be referred directly for specialised management. For men with post-micturition dribble, no further assessment is generally required. However, the patient should be told how to exert a strong pelvic floor muscle contraction after voiding or to manually compress the bulbous urethra directly after micturition (grade of recommendation: B). For men with stress incontinence, urgency or mixed stress/urgency incontinence, initial treatment should include appropriate lifestyle advice, physical therapies, scheduled voiding regimes, behavioural therapies and medication. In summary, these initial treatments carry lower grades of recommendation. Recommendations for initial treatments for UI in men Recommendations

GR

• Lifestyle intervention

NR

• Supervised pelvic floor muscle training for post prostatectomy SUI

B

• Scheduled voiding regimes for OAB

C

• When there is no evidence of significant post-void residual urine, antimuscarinic drugs for OAB symptoms, with or without urgency incontinence • Alpha-adrenergic antagonists (alpha-blockers) can be added if there is also bladder outlet obstruction GR = grade of recommendation; NR = no recommendation possible.

C C

4.2.2 Post-radical prostatectomy RP incontinence Despite the prevalence of UI and LUTS in older men, the only group to have been researched properly is men who have had RP. Overall, the effect of conservative treatment (lifestyle interventions, physical therapies, scheduled voiding regimes, complementary therapies) has been much less researched in men compared to women. There is generally insufficient level 1 or 2 evidence and most recommendations are essentially hypotheses requiring further research. Recommendations for conservative treatment of UI in men Recommendations Lifestyle interventions • It seems reasonable for health professionals to offer men advice on healthy lifestyle choices that may reduce or delay the onset of continence problems Pelvic floor muscle training (PFMT) • Some pre-operative or immediate post-operative instructions in PFMT for men undergoing radical prostatectomy may be helpful • It is not clear whether PFMT taught by digital rectal examination (DRE) has more benefit than verbal or written instruction in PFMT • The use of biofeedback to assist PFMT is currently a therapist/patient decision based on economics and preference Electrical stimulation • For men with post-prostatectomy incontinence, adding electrical stimulation to a PFMT programme does not appear to be of benefit

GR NR

B B B

B

GR = grade of recommendation; NR = no recommendation possible 4.2.3 Conclusions • There is generally insufficient level 1 or 2 evidence for these initial treatments. Most ‘recommendations’ are hypotheses needing further testing in high-quality research studies. • If initial treatment is unsuccessful after a reasonable period of time (e.g. 8-12 weeks), specialist’s advice is highly recommended.

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Figure 1: Algorithm for initial management of UI in men.

 

   

 

  

  

 

  

  

   

 



     s         



   

   

  

   

     

     

  



   s       s   



4.3

Specialised management of UI in men

The specialist may first decide to re-institute initial management if previous therapy might have been inadequate. Specialised management of UI in men is summarised in Figure 2. 4.3.1 Assessment Patients with ‘complicated’ incontinence referred directly to specialised management will probably need additional testing to exclude any other underlying pathology, i.e. cytology, cystourethroscopy and urinary tract imaging. If these tests are normal, patients can be treated for incontinence by initial or specialised management options as appropriate. If symptoms suggestive of detrusor overactivity or of sphincter incompetence persist, urodynamic studies are recommended to establish a diagnosis based on pathophysiological findings (urodynamic diagnosis). 4.3.2 Interventions If initial management has failed and the patient’s incontinence is affecting quality of life, invasive therapies may be considered. 4.3.3 Sphincter incompetence For sphincter incompetence, the recommended option is surgical implantation of an artificial urinary sphincter (AUS) (grade of recommendation: B). An alternative option is a male sling. 4.3.3.1 Detrusor overactivity (DO) For idiopathic DO (with intractable OAB symptoms), the recommended therapies are: • surgical bladder augmentation with intestinal segments (grade of recommendation: C) • implantation of a neuromodulator (grade of recommendation: B). Detrusor injections with botulinum toxin continue to show promise in the treatment of symptomatic detrusor overactivity unresponsive to other therapies. 4.3.3.2 Poor bladder emptying If incontinence is associated with poor bladder emptying due to detrusor underactivity, effective means should be used to ensure bladder emptying, e.g. CIC (grade of recommendation: B-C).

Update march 2009

13

4.3.3.3 Bladder outlet obstruction (BOO) If incontinence is due to bladder outlet obstruction, then the obstruction should be relieved (grade of recommendation: B-C). Pharmacological treatment options for UI and proven outlet obstruction are alphablockers or 5-alpha-reductase inhibitors (grade of recommendation: C-D). There is increasing evidence for the safety of antimuscarinic agents for OAB symptoms in men with outlet obstruction, when combined with an alpha-blocker (grade of recommendation: B). Currently, botulinum toxin injections into the detrusor muscle are being used ‘off-label’ for this indication. Figure 2: Algorithm for specialised management of UI in men

     



 

  

      

   

 

     

   

   



4.4

           

      

       

   

 



 

       

    

    

Surgical treatment

Urinary incontinence in men suitable for surgical correction can be classified by cause into sphincter-related incontinence (post-operative, post-traumatic, and congenital), bladder-related incontinence and fistulae (Table 5). Initial routine assessment and further evaluations are described in Table 6. Table 5: Aetiological classification of surgically correctable UI in men Sphincter-related • Postoperative - Post-prostatectomy for benign disease - Post-prostatectomy for prostate cancer - Post radiotherapy, brachytherapy, cryosurgery, HIFU for prostate cancer - Post cystectomy and neobladder for bladder cancer • Post-traumatic - After prostato-membranous disruption and urethral reconstruction - Pelvic floor trauma • Unresolved paediatric UI - Exstrophy and incontinent epispadias Bladder-related • Refractory UUI (overactive bladder) • Reduced capacity bladder Fistulae • Urethro-cutaneous • Recto-urethral HIFU = high-intensity focused ultrasound; UI = urinary incontinence; UUI = urge urinary incontinence.

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Update march 2009

Table 6: Initial assessment prior to surgical therapy Routine assessment • Medical history and physical examination, urinalysis, post void residual urine, frequency/volume chart, pad test, and serum creatinine if renal disease is suspected Further evaluation as required (level of evidence: 2-4, grade of recommendation: A-C) • Cysto-urethroscopy to assess urethral integrity, sphincter appearance, stricture, bladder pathology and imaging of the upper and lower urinary tract (ultrasound, cysto-urethrography, intravenous pyelogram) • Urodynamic studies to assess sphincter and/or detrusor function • Valsalva leak point pressure to measure sphincter weakness • Urethral pressure profile (UPP) or retrograde perfusion sphincterometry may be performed if AUS or slings are to be implanted • Sphincter electromyography to investigate suspected neuropathy • Multichannel pressure/flow video-urodynamic evaluation to assess detrusor function and characterise the underlying pathophysiology 4.4.1 Incontinence after surgery for BPO or prostate cancer (CaP) 4.4.1.1 Incontinence after surgery for benign prostatic obstruction (BPO) Incidence of UI is similar after open surgery, transurethral resection of the prostate (TURP), transurethral incision of the prostate (TUIP) and Holium laser enucleation. 4.4.1.2 Incontinence after surgery for prostate cancer (CaP) Generally, the incidence of UI after RP has decreased, but it is still a significant problem. Overall, the reported incidences range between 5% and 48%. Generally, patients report higher degrees of UI than do their physicians. The degree of UI varies and is often estimated by the numbers of pads and their wetness, social impairment and bothersomeness, which are usually assessed by non-standardised instruments. 4.4.1.3 Definitions of post-RP continence The definitions of post-RP continence are: • total control without any pad or leakage • no pad but loss of few drops of urine (‘underwear staining’) • none or 1 pad (‘safety pad’) per day. 4.4.1.4 Incontinence risk factors Reported risk factors for incontinence after RP include age at surgery, prostate size, co-morbidities, nervesparing surgery, bladder neck stenosis, tumour stage (possibly related to surgical technique), and preoperative bladder and sphincter dysfunction. The risk is unrelated to the technique of prostatectomy (radical vs non-radical vs robotic: these reports are entirely from centres of excellence). 4.4.1.5 Interventional treatment for post-RP incontinence After a period of conservative management of at least 6-12 months, the artificial urinary sphincter (AUS) is the treatment of choice for patients with moderate-to-severe UI. In studies that report treatment results of UI after surgery of BPO and CaP together, the success rates for AUS range between 59% and 90% (0-1 pad/ day). Long-term success rates and high patient satisfaction seem to outweigh the need for periodic revisions in some patients. Until similar experience is seen with newer, less invasive treatments, the AUS remains the reference standard to which all other treatments must be compared (level of evidence: 2) (grade of recommendation: B). Male slings are an alternative for men with mild-to-moderate UI (radiotherapy is an adverse risk factor). The overall minimum success is 58%, with best results achieved in patients with low-to-moderate leakage of urine, who had not undergone radiotherapy (level of evidence: 3) (grade of recommendation: C). Bulking agents are a less effective option for some men with mild-to-moderate UI. The early failure rate is about 50% and any beneficial effects decrease with time (level of evidence: 3) (grade of recommendation: C). The implantation of compressive adjustable balloons is a new treatment option. Early high complication rates appear to have been resolved. However, more evidence is required before specific recommendations can be made (level of evidence: 3) (grade of recommendation: D).

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4.4.1.6 Age Age is not a restriction for surgical treatment of post-prostatectomy incontinence. However, cognitive impairment and a lack of normal dexterity may restrict use of an AUS and must be assessed pre-operatively (level of evidence: 3-4) (grade of recommendation: C). 4.4.1.7 Post-RP incontinence with bladder neck stricture Treatment options for incontinence following RP with concomitant bladder neck stricture and other types of surgical stricture are visual internal urethrotomy, followed by implantation of an AUS once the urethra has been stabilised. 4.4.2 Incontinence after external beam radiotherapy for CaP The risk of incontinence after external beam radiotherapy ranges between 0 and 18.9%, but it may increase over time. There is a higher earlier risk in patients, who have had either a pre- or post-treatment TURP of 5-11%. Adjuvant radiotherapy may increase the risk of incontinence after RP. Also salvage RP after radiotherapy has an increased risk of incontinence. 4.4.2.1 AUS after radiotherapy There is a variably higher revision rate after radiotherapy than without radiotherapy, due to a higher incidence of erosion and infection, possibly caused by urethral atrophy from radiation-induced vasculitis. Detrusor overactivity and bladder neck contractures may also occur. Prolonged and/or intermittent de-activation of the sphincter is recommended; the cuff of the sphincter must be placed outside the radiotherapy field. 4.4.2.2 Conclusion An artificial sphincter is the most widely used treatment. Radiotherapy is a risk factor for an increase in complications (level of evidence: 3, grade of recommendation: C) 4.4.2.3 Other treatments for SUI after radiotherapy Limited evidence suggests that perineal compression slings can be an alternative therapy. However, injectable agents have not been successful (level of evidence 3; grade of recommendation: C). 4.4.3 Incontinence after other treatment for CaP 4.4.3.1 Brachytherapy After brachytherapy, incontinence occurs in 0-45% of the cases. TURP after brachytherapy carries a high risk of incontinence. 4.4.3.2 Cryotherapy Radiotherapy prior to cryotherapy is a risk factor for incontinence, fistulae occur in 0-5%. 4.4.3.3 High-intensity focused ultrasound (HIFU) The rate of incontinence decreases with surgical experience. 4.4.3.4 Recommendation The artificial sphincter is most widely used (grade of recommendation: C). Injectable agents have not been successful (grade of recommendation: C). 4.4.4 Treatment of incontinence after neobladder Continence rates achieved 2 years after orthotopic urinary diversion are 85-100% during the day and 55-100% at night. Treatment includes conservative management, intermittent catheterisation and artificial sphincter implantation (grade of recommendation: C). 4.4.5 Urethral and pelvic floor injuries Incontinence following injuries of the posterior urethra occurs in 0-20% of patients. The most commonly published surgical therapy is the AUS (level of evidence: 2) (grade of recommendation: B). Depending on the individual case, additional procedures are needed, i.e. urethral or bladder neck reconstruction. If reconstruction is impossible, one treatment option is bladder neck closure and construction of a Mitrofanoff catheterisable abdominal stoma (level of evidence: 3) (grade of recommendation: C). For patients with severe bladder neck stricture and incontinence, an intra-urethral stent may be used together with an AUS (level of evidence: 3) (grade of recommendation: C).

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4.4.5.1 Recommendation Recommendation • Although other treatments are possible, the AUS provides a reasonable outcome in appropriate cases. 4.4.6 Incontinence in adult epispadias-exstrophy complex Patients should be treated in centres of excellence using a patient-directed approach. Treatment choices include: • bladder neck reconstructive surgery • bladder neck closure • bladder reconstruction • urinary diversion. There is not enough data to provide a specific recommendation. The patient’s transition is important between the paediatric and adult urologist. Life-long follow-up is mandatory, particularly for continence, voiding efficiency, upper tract status and other urological complications (level of evidence: 3) (grade of recommendation: C). 4.4.7 Refractory UUI and idiopathic DO Botulinum toxin A detrusor injection is a minimally invasive treatment with some efficacy that is currently used as an ‘off-label detrusor injection for this indication. Other treatment options include neuromodulation or detrusor myectomy, which have both been successful in a few male patients. Augmentation cystoplasty with intestinal segments is potentially successful in controlling symptoms but may have side-effects. Urinary diversion is a final option (level of evidence: 3) (grade of recommendation: C). 4.4.8 Incontinence and reduced capacity bladder Augmentation cystoplasty has been successful in helping with reduced capacity bladder due to most aetiologies except radiotherapy cystitis (level of evidence: 3) (grade of recommendation: C). 4.4.9 Urethro-cutaneous fistula and recto-urethral fistula The aetiology of acquired fistulae can be iatrogenic, trauma, inflammation, and tumour. Fistulae in men are most often iatrogenic (surgery, radiotherapy, cryotherapy, HIFU) or inflammatory (diverticulitis). The localisation and size of acquired urethro-cutaneous fistulae are demonstrated by clinical, endoscopic and imaging studies. Surgical reconstruction is performed as required. Similar diagnostic manoeuvres are applied to recto-urethral fistulas. Surgical reconstruction may be carried out in fistulae that do not close, with or without temporary urinary and faecal diversion. Most repairs are carried out after prior faecal diversion. Various techniques are available for closure and can be done in collaboration with colorectal surgeons (level of evidence: 3) (grade of recommendation: C). 4.4.10 Management of AUS complications Recurrent incontinence after AUS implantation may result from alteration in bladder function, urethral atrophy, or mechanical malfunction. All or part of the prosthesis must be surgically removed if there is infection and/ or erosion of components. Risk factors are surgery, radiotherapy, catheterisation and endoscopy (level of evidence: 3) (grade of recommendation: C).

4.5 REFERENCES* •

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Galli S, Simonato A, Bozzola A, Gregori A, Lissiani A, Scaburri A, Gaboardi F. Oncologic outcome and continence recovery after laparoscopic radical prostatectomy: 3 years’ follow-up in a ‘second generation center’. Eur Urol 2006;49(5):859-65. http://www.ncbi.nlm.nih.gov/pubmed/16519991 Colombo R, Naspro R, Salonia A, Montorsi F, Raber M, Suardi N, Saccà A, Rigatti P. Radical prostatectomy after previous prostate surgery: clinical and functional outcomes. J Urol 2006;176(6Pt1):2459-63; discussion 2463. http://www.ncbi.nlm.nih.gov/pubmed/17085129 Schneider T, Sperling H, Rossi R, Schmidt S, Rübben H. Do early injections of bulking agents following radical prostatectomy improve early continence? World J Urol 2005;23(5):338-42. http://www.ncbi.nlm.nih.gov/pubmed/16261366 Jones JS, Vasavada SP, Abdelmalak JB, Liou L, Ahmed ES, Zippe CD, Rackley RR. Sling may hasten return of continence after radical prostatectomy. Urology 2005;65(6):1163-7. http://www.ncbi.nlm.nih.gov/pubmed/15922423 Wendt-Nordahl G, Bucher B, Häcker A, Knoll T, Alken P, Michel MS. Improvement in mortality and morbidity in transurethral resection of the prostate over 17 years in a single center. J Endourol 2007;21(9):1081-7. http://www.ncbi.nlm.nih.gov/pubmed/17941791 Roehrborn CG, McConnell JD, Barry MJ, Benaim E, Bruskewitz R, Blute M,HL Holtgrewe, Kaplan S, Lange J, Lowe F, Roberts R, Stein B. Guideline on the Management of Benign Prostatic Hyerplasia (BPH), 2006. American Urological Association. http://www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines.cfm?sub=bph Tan A, Liao C, Mo Z, Cao Y. Meta-analysis of holmium laser enucleation versus transurethral resection of the prostate for symptomatic prostatic obstruction. Br J Surg 2007;94(10):1201-8. http://www.ncbi.nlm.nih.gov/pubmed/17729384 Gupta N, Sivaramakrishna, Kumar R, Dogra PN, Seth A. Comparison of standard transurethral resection, transurethral vapour resection and holmium laser enucleation of the prostate for managing benign prostatic hyperplasia of >40 g. BJU Int 2006;97(1):85-9. http://www.ncbi.nlm.nih.gov/pubmed/16336334 Westney OL, Bevan-Thomas R, Palmer JL, Cespedes RD, McGuire EJ. Transurethral collagen injections for male intrinsic sphincter deficiency: the University of Texas-Houston experience. J Urol 2005;174(3):994-7. http://www.ncbi.nlm.nih.gov/pubmed/16094021 Dylewski DA, Jamison MG, Borawski KM, Sherman ND, Amundsen CL, Webster GD. A statistical comparison of pad numbers versus pad weights in the quantification of urinary incontinence. Neurourol Urodyn 2007;26(1):3-7. http://www.ncbi.nlm.nih.gov/pubmed/17080415 O’Connor RC, Nanigian DK, Patel BN, Guralnick ML, Ellision LM, Stone AR. Artificial urinary sphincter placement in elderly men. Urology 2007;69(1):126-8. http://www.ncbi.nlm.nih.gov/pubmed/17270633 Ponholzer A, Brössner C, Struhal G, Marszalek M, Madersbacher S. Lower urinary tract symptoms, urinary incontinence, sexual function and quality of life after radical prostatectomy and external beam radiation therapy: real life experience in Austria. World J Urol 2006;24(3):325-30. http://www.ncbi.nlm.nih.gov/pubmed/16688458 Miller DC, Sanda MG, Dunn RL, Montie JE, Pimentel H, Sandler HM, McLaughlin WP, Wei JT. Longterm outcomes among localized prostate cancer survivors: health-related quality-of-life changes after radical prostatectomy, external radiation, and brachytherapy. J Clin Oncol 2005;23(12):2772-80. http://www.ncbi.nlm.nih.gov/pubmed/15837992 Nguyen PL, D’Amico AV, Lee AK, Suh WW. Patient selection, cancer control, and complications after salvage local therapy for postradiation prostate-specific antigen failure: a systematic review of the literature. Cancer 2007;110(7):1417-28. http://www.ncbi.nlm.nih.gov/pubmed/17694553 Raj GV, Peterson AC, Webster GD. Outcomes following erosions of the artificial urinary sphincter. J Urol 2006;175(6):2186-90; discussion 2190. http://www.ncbi.nlm.nih.gov/pubmed/16697836 Bottomley D, Ash D, Al-Qaisieh B, Carey B, Joseph J, St Clair S, Gould K. Side effects of permanent I125 prostate seed implants in 667 patients treated in Leeds. Radiother Oncol 2007;82(1):46-9. http://www.ncbi.nlm.nih.gov/pubmed/17161481

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Petit JH, Gluck C, Kiger WS 3rd, Laury Henry D, Karasiewicz C, Talcott JA, Berg S, Holupka EJ, Kaplan ID. Androgen deprivation-mediated cytoreduction before interstitial brachytherapy for prostate cancer does not abrogate the elevated risk of urinary morbidity associated with larger initial prostate volume. Brachytherapy 2007;6(4):267-71. http://www.ncbi.nlm.nih.gov/pubmed/17959423 Robinson JW, Donnelly BJ, Coupland K, Siever JE, Saliken JC, Scott C, Brasher PM, Ernst DS. Quality of life 2 years after salvage cryosurgery for the treatment of local recurrence of prostate cancer after radiotherapy. Urol Oncol 2006;24(6):472-86. http://www.ncbi.nlm.nih.gov/pubmed/17138127 Rebillard X, Soulié M, Chartier-Kastler E, Davin JL, Mignard JP, Moreau JL, Coulange C; Association Francaise d’Urologie. High-intensity focused ultrasound in prostate cancer; a systematic literature review of the French Association of Urology. BJU Int 2008;101(10):1205-13. http://www.ncbi.nlm.nih.gov/pubmed/18325057 Nieuwenhuijzen JA, de Vries RR, Bex A, van der Poel HG, Meinhardt W, Antonini N, Horenblas S. Urinary diversions after cystectomy: the association of clinical factors, complications and functional results of four different diversions. Eur Urol 2008;53(4):834-42; discussion 842-34. http://www.ncbi.nlm.nih.gov/pubmed/17904276 Cerqueira M, Xambre L, Silva V, Santos R, Lages R, Prisco R, Carreira F. [Bulbourethral sling. The experience of our service]. Actas Urol Esp 2005;29(4):401-7. http://www.ncbi.nlm.nih.gov/pubmed/15981429 Raj GV, Peterson AC, Toh KL, Webster GD. Outcomes following revisions and secondary implantation of the artificial urinary sphincter. J Urol 2005;173(4):1242-5. http://www.ncbi.nlm.nih.gov/pubmed/16697836 Simonato A, Gregori A, Lissiani A, Carmignani G. Two-stage transperineal management of posterior urethral strictures or bladder neck contractures associated with urinary incontinence after prostate surgery and endoscopic treatment failures. Eur Urol 2007;52(5):1499-504. http://www.ncbi.nlm.nih.gov/pubmed/17418481 Woodhouse CR, North AC, Gearhart JP. Standing the test of time: long-term outcome of reconstruction of the exstrophy bladder. World J Urol 2006;24(3):244-9. http://www.ncbi.nlm.nih.gov/pubmed/16518662 Lee C, Reutter HM, Grasser MF, Fisch M, Noeker M. Gender-associated differences in the psychosocial and developmental outcome in patients affected with the bladder exstrophy-epispadias complex. BJU Int 2006;97(2):349-53. http://www.ncbi.nlm.nih.gov/pubmed/16430645 Burki T, Hamid R, Duffy P, Ransley P, Wilcox D, Mushtaq I. Long-term followup of patients after redo bladder neck reconstruction for bladder exstrophy complex. J Urol 2006;176(3):1138-41; discussion 1141-2. http://www.ncbi.nlm.nih.gov/pubmed/16890709 Baird AD, Frimberger D, Gearhart JP. Reconstructive lower urinary tract surgery in incontinent adolescents with exstrophy/epispadias complex. Urology 2005;66(3):636-40. http://www.ncbi.nlm.nih.gov/pubmed/16140093 Burki T, Hamid R, Ransley PG, Mushtaq I, Duffy PG. Injectable polydimethylsiloxane for treating incontinence in children with the exstrophy-epispadias complex: long-term results. BJU Int 2006;98(4):849-53. http://www.ncbi.nlm.nih.gov/pubmed/16978283 Lottmann HB, Margaryan M, Lortat-Jacob S, Bernuy M, Lackgren G. Long-term effects of dextranomer endoscopic injections for the treatment of urinary incontinence: an update of a prospective study of 61 patients. J Urol 2006;176(4Pt2):1762-6. http://www.ncbi.nlm.nih.gov/pubmed/16945642 Quek P. A critical review on magnetic stimulation: what is its role in the management of pelvic floor disorders? Curr Opin Urol 2005;15(4):231-5. http://www.ncbi.nlm.nih.gov/pubmed/15928511 Kuo HC. Multiple intravesical instillation of low-dose resiniferatoxin is effective in the treatment of detrusor overactivity refractory to anticholinergics. BJU Int 2005;95(7):1023-7. http://www.ncbi.nlm.nih.gov/pubmed/15839924 Kuo HC, Liu HT, Yang WC. Therapeutic effect of multiple resiniferatoxin intravesical instillations in patients with refractory detrusor overactivity: a randomized, double-blind, placebo controlled study. J Urol 2006;176(2):641-5. http://www.ncbi.nlm.nih.gov/pubmed/16813911

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Rios LA, Panhoca R, Mattos D Jr, Srugi M, Bruschini H. Intravesical resiniferatoxin for the treatment of women with idiopathic detrusor overactivity and urgency incontinence: a single dose, 4 weeks, double-blind, randomized, placebo controlled trial. Neurourol Urodyn 2007;26(6):773-8. http://www.ncbi.nlm.nih.gov/pubmed/17638305 Cruz F, Dinis P. Resiniferatoxin and botulinum toxin type A for treatment of lower urinary tract symptoms. Neurourol Urodyn 2007;26(6Suppl.):920-7. http://www.ncbi.nlm.nih.gov/pubmed/17705161 Liu HT, Kuo HC. Increased expression of transient receptor potential vanilloid subfamily 1 in the bladder predicts the response to intravesical instillations of resiniferatoxin in patients with refractory idiopathic detrusor overactivity. BJU Int 2007;100(5):1086-90. http://www.ncbi.nlm.nih.gov/pubmed/17711510 Silva C, Silva J, Castro H, Reis F, Dinis P, Avelino A, Cruz F. Bladder sensory desensitization decreases urinary urgency. BMC Urol 2007;7:9. http://www.ncbi.nlm.nih.gov/pubmed/17561998 Apostolidis A, Gonzales GE, Fowler CJ. Effect of intravesical Resiniferatoxin (RTX) on lower urinary tract symptoms, urodynamic parameters, and quality of life of patients with urodynamic increased bladder sensation. Eur Urol 2006;50(6):1299-1305. http://www.ncbi.nlm.nih.gov/pubmed/16697519 Jeffery S, Fynes M, Lee F, Wang K, Williams L, Morley R. Efficacy and complications of intradetrusor injection with botulinum toxin A in patients with refractory idiopathic detrusor overactivity. BJU Int 2007;100(6):1302-6. http://www.ncbi.nlm.nih.gov/pubmed/17979928 Kuschel S, Werner M, Schmid DM, Faust E, Schuessler B. Botulinum toxin-A for idiopathic overactivity of the vesical detrusor: a 2-year follow-up. Int Urogynecol J Pelvic Floor Dysfunct 2008;19(7):905-9. http://www.ncbi.nlm.nih.gov/pubmed/18204796 Schmid DM, Sauermann P, Werner M, Schuessler B, Blick N, Muentener M, Strebel RT, Perucchini D, Scheiner D, Schaer G, John H, Reitz A, Hauri D, Schurch B. Experience with 100 cases treated with botulinum-A toxin injections in the detrusor muscle for idiopathic overactive bladder syndrome refractory to anticholinergics. J Urol 2006;176(1):177-85. http://www.ncbi.nlm.nih.gov/pubmed/16753396 Lee JC, Yokoyama T, Hwang HJ, Arimitsu H, Yamamoto Y, Kawasaki M, Takigawa T, Takeshi K, Nishikawa A, Kumon H, Oguma K. Clinical application of Clostridium botulinum type A neurotoxin purified by a simple procedure for patients with urinary incontinence caused by refractory destrusor overactivity. FEMS Immunol Med Microbiol 2007;51(1):201-11. http://www.ncbi.nlm.nih.gov/pubmed/17692094 Popat R, Apostolidis A, Kalsi V, Gonzales G, Fowler CJ, Dasgupta P. A comparison between the response of patients with idiopathic detrusor overactivity and neurogenic detrusor overactivity to the first intradetrusor injection of botulinum-A toxin. J Urol 2005;174(3):984-9. http://www.ncbi.nlm.nih.gov/pubmed/16094019 Rajkumar GN, Small DR, Mustafa AW, Conn G. A prospective study to evaluate the safety, tolerability, efficacy and durability of response of intravesical injection of botulinum toxin type A into detrusor muscle in patients with refractory idiopathic detrusor overactivity. BJU Int 2005;96(6):848-52. http://www.ncbi.nlm.nih.gov/pubmed/16153215 Kuo HC. Comparison of effectiveness of detrusor, suburothelial and bladder base injections of botulinum toxin A for idiopathic detrusor overactivity. J Urol 2007;178(4Pt1):1359-63. http://www.ncbi.nlm.nih.gov/pubmed/17706718 Ghalayini IF, Al-Ghazo MA. Intradetrusor injection of botulinum-A toxin in patients with idiopathic and neurogenic detrusor overactivity: urodynamic outcome and patient satisfaction. Neurourol Urodyn 2007;26(4):531-6. http://www.ncbi.nlm.nih.gov/pubmed/17330289 Sahai A, Khan MS, Dasgupta P. Efficacy of botulinum toxin-A for treating idiopathic detrusor overactivity: results from a single center, randomized, double-blind, placebo controlled trial. J Urol 2007;177(6):2231-6. http://www.ncbi.nlm.nih.gov/pubmed/17509328 Kessler TM, Danuser H, Schumacher M, Studer UE, Burkhard FC. Botulinum A toxin injections into the detrusor: an effective treatment in idiopathic and neurogenic detrusor overactivity? Neurourol Urodyn 2005;24(3):231-6. http://www.ncbi.nlm.nih.gov/pubmed/15747344

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Apostolidis A, Popat R, Yiangou Y, Cockayne D, Ford AP, Davis JB, Dasgupta P, Fowler CJ, Anand P. Decreased sensory receptors P2X3 and TRPV1 in suburothelial nerve fibers following intradetrusor injections of botulinum toxin for human detrusor overactivity. J Urol 2005;174(3):977-82; discussion 982-3. http://www.ncbi.nlm.nih.gov/pubmed/16094018 Sinha D, Karri K, Arunkalaivanan AS. Applications of Botulinum toxin in urogynaecology. Eur J Obstet Gynecol Reprod Biol 2007;133(1):4-11. http://www.ncbi.nlm.nih.gov/pubmed/17275980 De Laet K, Wyndaele JJ. Adverse events after botulinum A toxin injection for neurogenic voiding disorders. Spinal Cord 2005;43(7):397-9. http://www.ncbi.nlm.nih.gov/pubmed/15741978 Early communication about an ongoing safety review Botox and Botox Cosmetic (botulinum toxin type A) and Myobloc (botulinum toxin type B). [accessed 8 February 2008]. http://www.fda.gov/cder/drug/early_comm/botulinium_toxins.htm Schurch B, Corcos J. Botulinum toxin injections for paediatric incontinence. Curr Opin Urol 2005;15(4):264-7. http://www.ncbi.nlm.nih.gov/pubmed/15928517 Kalsi V, Apostolidis A, Popat R, Gonzales G, Fowler CJ, Dasgupta P. Quality of life changes in patients with neurogenic versus idiopathic detrusor overactivity after intradetrusor injections of botulinum neurotoxin type A and correlations with lower urinary tract symptoms and urodynamic changes. Eur Urol 2006;49(3):528-35. http://www.ncbi.nlm.nih.gov/pubmed/16426735 Kalsi V, Popat RB, Apostolidis A, Kavia R, Odeyemi IA, Dakin HA, Warner J, Elneil S, Fowler CJ, Dasgupta P. Cost-consequence analysis evaluating the use of botulinum neurotoxin-A in patients with detrusor overactivity based on clinical outcomes observed at a single UK centre. Eur Urol 2006;49(3):519-27. http://www.ncbi.nlm.nih.gov/pubmed/16413656 Hirst GR, Watkins AJ, Guerrero K, Wareham K, Emery SJ, Jones DR, Lucas MG. Botulinum toxin B is not an effective treatment of refractory overactive bladder. Urology 2007;69(1):69-73. http://www.ncbi.nlm.nih.gov/pubmed/17270619 Karsenty G, Elzayat E, Delapparent T, St-Denis B, Lemieux MC, Corcos J. Botulinum toxin type a injections into the trigone to treat idiopathic overactive bladder do not induce vesicoureteral reflux. J Urol 2007;177(3):1011-14. http://www.ncbi.nlm.nih.gov/pubmed/17296399 Apostolidis A, Dasgupta P, Fowler CJ. Proposed mechanism for the efficacy of injected botulinum toxin in the treatment of human detrusor overactivity. Eur Urol 2006;49(4):644-50. http://www.ncbi.nlm.nih.gov/pubmed/16426734 Sahai A, Dowson C, Khan MS, Dasgupta P. Re: Efficacy and complications of intradetrusor injection with botulinum toxin A in patients with refractory idiopathic detrusor overactivity. BJU Int 2008;101(4):515-16; author reply 516-17. http://www.ncbi.nlm.nih.gov/pubmed/18234066 Smaldone MC, Chancellor MB. Neuromodulation versus neurotoxin for the treatment of refractory detrusor overactivity: for neurotoxin. Nat Clin Pract Urol 2008;5(3):120-1. http://www.ncbi.nlm.nih.gov/pubmed/18195722 Sahai A. A prospective study to evaluate the safety, tolerability, efficacy and durability of response of intravesical injection of botulinum toxin type A into detrusor muscle in patients with refractory idiopathic detrusor overactivity. BJU Int 2006;97(2):413. http://www.ncbi.nlm.nih.gov/pubmed/16430657 Nitti VW. Botulinum toxin for the treatment of idiopathic and neurogenic overactive bladder: state of the art. Rev Urol 2006;8(4):198-208. http://www.ncbi.nlm.nih.gov/pubmed/17192799 Patel AK, Patterson JM, Chapple CR. The emerging role of intravesical botulinum toxin therapy in idiopathic detrusor overactivity. Int J Clin Pract Suppl 2006;(151):27-32. http://www.ncbi.nlm.nih.gov/pubmed/17169008 Casanova N, McGuire E, Fenner DE. Botulinum toxin: a potential alternative to current treatment of neurogenic and idiopathic urinary incontinence due to detrusor overactivity. Int J Gynaecol Obstet 2006;95(3):305-11. http://www.ncbi.nlm.nih.gov/pubmed/17070528

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Patel AK, Patterson JM, Chapple CR. Botulinum toxin injections for neurogenic and idiopathic detrusor overactivity: A critical analysis of results. Eur Urol 2006;50(4):684-709; discussion 709-10. http://www.ncbi.nlm.nih.gov/pubmed/16934391 Patterson JM, Chapple CR. Botulinum toxin in urinary incontinence. Curr Opin Urol 2006;16(4):255-60. http://www.ncbi.nlm.nih.gov/pubmed/16770124 Dmochowski R, Sand PK. Botulinum toxin A in the overactive bladder: current status and future directions. BJU Int 2007;99(2):247-62. http://www.ncbi.nlm.nih.gov/pubmed/17313422 Apostolidis A, Fowler CJ. The use of botulinum neurotoxin type A (BoNTA) in urology. J Neural Transm 2008;115(4):593-605. http://www.ncbi.nlm.nih.gov/pubmed/18322639 Ho MH, Lin LL, Haessler AL, Bhatia NN. Intravesical injection of botulinum toxin for the treatment of overactive bladder. Curr Opin Obstet Gynecol 2005;17(5):512-18. http://www.ncbi.nlm.nih.gov/pubmed/18322639 Kim DK, Thomas CA, Smith C, Chancellor MB. The case for bladder botulinum toxin application. Urol Clin North Am 2006;33(4):503-10, ix. http://www.ncbi.nlm.nih.gov/pubmed/17011386 MacDonald R, Fink HA, Huckabay C, Monga M, Wilt TJ. Botulinum toxin for treatment of urinary incontinence due to detrusor overactivity: a systematic review of effectiveness and adverse effects. Spinal Cord 2007;45(8):535-41. http://www.ncbi.nlm.nih.gov/pubmed/17453012 Schmidt RA. Treatment of unstable bladder. Urology 1991;37(1):28-32. http://www.ncbi.nlm.nih.gov/pubmed/1986470 van der Pal F, Heesakkers JP, Bemelmans BL. Current opinion on the working mechanisms of neuromodulation in the treatment of lower urinary tract dysfunction. Curr Opin Urol 2006;16(4):261-7. http://www.ncbi.nlm.nih.gov/pubmed/16770125 Daneshgari F, Moy ML. Current indications for neuromodulation. Urol Clin North Am 2005;32(1):37-40, vi. http://www.ncbi.nlm.nih.gov/pubmed/15698874 Leng WW, Chancellor MB. How sacral nerve stimulation neuromodulation works. Urol Clin North Am 2005;32(1):11-18. http://www.ncbi.nlm.nih.gov/pubmed/15698871 Keppene V, Mozer P, Chartier-Kastler E, Ruffion A. [Neuromodulation in the management of neurogenic lower urinary tract dysfunction]. Prog Urol 2007;17(3):609-15. http://www.ncbi.nlm.nih.gov/pubmed/17622098 Nakib N, Siegel S. Neuromodulation versus neurotoxin for the treatment of refractory detrusor overactivity: for neuromodulation. Nat Clin Pract Urol 2008;5(3):118-19. http://www.ncbi.nlm.nih.gov/pubmed/18195723 van Kerrebroeck PE, van Voskuilen AC, Heesakkers JP, et al. Results of sacral neuromodulation therapy for urinary voiding dysfunction: outcomes of a prospective, worldwide clinical study. J Urol 2007;178(5):2029-34. http://www.ncbi.nlm.nih.gov/pubmed/17869298 Groen J, Ruud Bosch JL, van Mastrigt R. Sacral neuromodulation in women with idiopathic detrusor overactivity incontinence: decreased overactivity but unchanged bladder contraction strength and urethral resistance during voiding. J Urol 2006;175(3 Pt 1):1005-9; discussion 1009. http://www.ncbi.nlm.nih.gov/pubmed/16469603 Groenendijk PM, Lycklama a Nyeholt AA, Heesakkers JP, et al. Urodynamic evaluation of sacral neuromodulation for urge urinary incontinence. BJU Int 2008;101(3):325-9. http://www.ncbi.nlm.nih.gov/pubmed/18070199 South MM, Romero AA, Jamison MG, Webster GD, Amundsen CL. Detrusor overactivity does not predict outcome of sacral neuromodulation test stimulation. Int Urogynecol J Pelvic Floor Dysfunct 2007;18(12):1395-8. http://www.ncbi.nlm.nih.gov/pubmed/17364132 Groenendijk PM, Heesakkers JP, Lycklama ANAA. Urethral instability and sacral nerve stimulation-a better parameter to predict efficacy? J Urol 2007;178(2):568-2; discussion 572. http://www.ncbi.nlm.nih.gov/pubmed/17570438 Humphreys MR, Vandersteen DR, Slezak JM, et al. Preliminary results of sacral neuromodulation in 23 children. J Urol 2006;176(5):2227-31. http://www.ncbi.nlm.nih.gov/pubmed/17070300?

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McAchran SE, Daneshgari F. Sacral neuromodulation in the older woman. Clin Obstet Gynecol 2007;50(3):735-44. http://www.ncbi.nlm.nih.gov/pubmed/17762421 Hussain Z, Harrison SC. Neuromodulation for lower urinary tract dysfunction--an update. ScientificWorldJournal 2007;7:1036-45. http://www.ncbi.nlm.nih.gov/pubmed/17619785 Oerlemans DJ, van Kerrebroeck PE. Sacral nerve stimulation for neuromodulation of the lower urinary tract. Neurourol Urodyn 2008;27(1):28-33. http://www.ncbi.nlm.nih.gov/pubmed/17563110 Spinelli M, Malaguti S, Giardiello G, Lazzeri M, Tarantola J, Van Den Hombergh U. A new minimally invasive procedure for pudendal nerve stimulation to treat neurogenic bladder: description of the method and preliminary data. Neurourol Urodyn 2005;24(4):305-309. http://www.ncbi.nlm.nih.gov/pubmed/15977260 Brazzelli M, Murray A, Fraser C. Efficacy and safety of sacral nerve stimulation for urinary urge incontinence: a systematic review. J Urol 2006;175(3 Pt 1):835-41. http://www.ncbi.nlm.nih.gov/pubmed/16469561 Kumar SP, Abrams PH. Detrusor myectomy: long-term results with a minimum follow-up of 2 years. BJU Int 2005;96(3):341-4. http://www.ncbi.nlm.nih.gov/pubmed/16042727 Blaivas JG, Weiss JP, Desai P, Flisser AJ, Stember DS, Stahl PJ. Long-term followup of augmentation enterocystoplasty and continent diversion in patients with benign disease. J Urol 2005;173(5):1631-4. http://www.ncbi.nlm.nih.gov/pubmed/15821519 de Figueiredo AA, Lucon AM, Srougi M. Bladder augmentation for the treatment of chronic tuberculous cystitis. Clinical and urodynamic evaluation of 25 patients after long term follow-up. Neurourol Urodyn 2006;25(5):433-40. http://www.ncbi.nlm.nih.gov/pubmed/16791845 Lima SV, Araujo LA, Vilar Fde O, Lima RS, Lima RF. Nonsecretory intestinocystoplasty: a 15-year prospective study of 183 patients. J Urol 2008;179(3):1113-6; discussion 1116-7. http://www.ncbi.nlm.nih.gov/pubmed/18206934 Shakespeare D, Mitchell DM, Carey BM, et al. Recto-urethral fistula following brachytherapy for localized prostate cancer. Colorectal Dis 2007;9(4):328-31. http://www.ncbi.nlm.nih.gov/pubmed/17432984 Ismail M, Ahmed S, Kastner C, Davies J. Salvage cryotherapy for recurrent prostate cancer after radiation failure: a prospective case series of the first 100 patients. BJU Int 2007;100(4):760-4. http://www.ncbi.nlm.nih.gov/pubmed/17662081 Larson DW, Chrouser K, Young-Fadok T, Nelson H. Rectal complications after modern radiation for prostate cancer: a colorectal surgical challenge. J Gastrointest Surg 2005;9(4):461-6. http://www.ncbi.nlm.nih.gov/pubmed/15797224 Lane BR, Stein DE, Remzi FH, Strong SA, Fazio VW, Angermeier KW. Management of radiotherapy induced rectourethral fistula. J Urol 2006;175(4):1382-1387; discussion 1387-8. http://www.ncbi.nlm.nih.gov/pubmed/16516003 Chrouser KL, Leibovich BC, Sweat SD, et al. Urinary fistulas following external radiation or permanent brachytherapy for the treatment of prostate cancer. J Urol 2005;173(6):1953-7. http://www.ncbi.nlm.nih.gov/pubmed/15879789 Marguet C, Raj GV, Brashears JH, Ludwig K, Mouraviev V, Robertson CN, Polascik TJ. Rectourethral fistula after combination radiotherapy for prostate cancer. Urology 2007;69(5):898-901. http://www.ncbi.nlm.nih.gov/pubmed/17482930 Rivera R, Barboglio PG, Hellinger M, Gousse AE. Staging rectourinary fistulas to guide surgical treatment. J Urol 2007;177(2):586-8. http://www.ncbi.nlm.nih.gov/pubmed/17222638 Elliott SP, McAninch JW, Chi T, Doyle SM, Master VA. Management of severe urethral complications of prostate cancer therapy. J Urol 2006;176(6 Pt 1):2508-13. http://www.ncbi.nlm.nih.gov/pubmed/17085144 Singh I, Mittal G, Kumar P, Gangas R. Delayed post-traumatic prostatic-urethrorectal fistula: transperineal rectal sparing repair - point of technique. Int J Urol 2006;13(1):92-4. http://www.ncbi.nlm.nih.gov/pubmed/16448443 Pratap A, Agrawal CS, Pandit RK, Sapkota G, Anchal N. Factors contributing to a successful outcome of combined abdominal transpubic perineal urethroplasty for complex posterior urethral disruptions. J Urol 2006;176(6 Pt 1):2514-7; discussion 2517. http://www.ncbi.nlm.nih.gov/pubmed/17085145

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Dal Moro F, Mancini M, Pinto F, Zanovello N, Bassi PF, Pagano F. Successful repair of iatrogenic rectourinary fistulas using the posterior sagittal transrectal approach (York-Mason): 15-year experience. World J Surg 2006;30(1):107-13. http://www.ncbi.nlm.nih.gov/pubmed/16369708 Erickson BA, Dumanian GA, Sisco M, Jang TL, Halverson AL, Gonzalez CM. Rectourethral fistula associated with two short segment urethral strictures in the anterior and posterior urethra: singlestage reconstruction using buccal mucosa and a radial forearm fasciocutaneous free flap. Urology 2006;67(1):195-8. http://www.ncbi.nlm.nih.gov/pubmed/16413364 Castillo OA, Bodden E, Vitagliano G. Management of rectal injury during laparoscopic radical prostatectomy. Int Braz J Urol 2006;32(4):428-33. http://www.ncbi.nlm.nih.gov/pubmed/16953909 Quinlan M, Cahill R, Keane F, Grainger R, Butler M. Transanal endoscopic microsurgical repair of iatrogenic recto-urethral fistula. Surgeon 2005;3(6):416-7. http://www.ncbi.nlm.nih.gov/pubmed/16353863 Bochove-Overgaauw DM, Beerlage HP, Bosscha K, Gelderman WA. Transanal endoscopic microsurgery for correction of rectourethral fistulae. J Endourol 2006;20(12):1087-90. http://www.ncbi.nlm.nih.gov/pubmed/17206908 Varma MG, Wang JY, Garcia-Aguilar J, Shelton AA, McAninch JW, Goldberg SM. Dartos muscle interposition flap for the treatment of rectourethral fistulas. Dis Colon Rectum 2007;50(11):1849-55. http://www.ncbi.nlm.nih.gov/pubmed/17828402 Chirica M, Parc Y, Tiret E, Dehni N, McNamara D, Parc R. Coloanal sleeve anastomosis (Soave procedure): the ultimate treatment option for complex rectourinary fistulas. Dis Colon Rectum 2006;49(9):1379-83. http://www.ncbi.nlm.nih.gov/pubmed/16819570 Reynolds WS, Patel R, Msezane L, Lucioni A, Rapp DE, Bales GT. Current use of artificial urinary sphincters in the United States. J Urol 2007;178(2):578-83. http://www.ncbi.nlm.nih.gov/pubmed/17570407 Catto JW, Natarajan V, Tophill PR. Simultaneous augmentation cystoplasty is associated with earlier rather than increased artificial urinary sphincter infection. J Urol 2005;173(4):1237-41. http://www.ncbi.nlm.nih.gov/pubmed/15758760 Henry GD, Graham SM, Cleves MA, Simmons CJ, Flynn B. Perineal approach for artificial urinary sphincter implantation appears to control male stress incontinence better than the transscrotal approach. J Urol 2008;179(4):1475-9; discussion 1479. http://www.ncbi.nlm.nih.gov/pubmed/18295275 Kendirci M, Gupta S, Shaw K, et al. Synchronous prosthetic implantation through a transscrotal incision: an outcome analysis. J Urol 2006;175(6):2218-22. http://www.ncbi.nlm.nih.gov/pubmed/16697843 Sellers CL, Morey AF, Jones LA. Cost and time benefits of dual implantation of inflatable penile and artificial urinary sphincter prosthetics by single incision. Urology 2005;65(5):852-3. http://www.ncbi.nlm.nih.gov/pubmed/15882709 van der Horst C, Naumann CM, Wilson SK, Wefer B, Braun PM, Junemann KP. [Dysfunctions of artificial urinary sphincters (AMS 800) and their management via a transscrotal access. Optimum procedure illustrated by reference to clinical examples]. Urologe A 2007;46(12):1704-9. http://www.ncbi.nlm.nih.gov/pubmed/17932644 Hussain M, Greenwell TJ, Venn SN, Mundy AR. The current role of the artificial urinary sphincter for the treatment of urinary incontinence. J Urol 2005;174(2):418-24. http://www.ncbi.nlm.nih.gov/pubmed/16006857 Petrou SP, Thiel DD, Elliot DS, Broderick GA, Wehle MJ, Young PR. Does indigo carmine prevent early artificial urinary sphincter cuff erosion? Can J Urol 2006;13(4):3195-8. http://www.ncbi.nlm.nih.gov/pubmed/16952328 Webster GD, Sherman ND. Management of male incontinence following artificial urinary sphincter failure. Curr Opin Urol 2005;15(6):386-90. http://www.ncbi.nlm.nih.gov/pubmed/16205488 Lopez Pereira P, Somoza Ariba I, Martinez Urrutia MJ, Lobato Romero R, Jaureguizar Monroe E. Artificial urinary sphincter: 11-year experience in adolescents with congenital neuropathic bladder. Eur Urol 2006;50(5):1096-101; discussion 101. http://www.ncbi.nlm.nih.gov/pubmed/16530321

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Ruiz E, Puigdevall J, Moldes J, et al. 14 years of experience with the artificial urinary sphincter in children and adolescents without spina bifida. J Urol 2006;176(4 Pt 2):1821-5. http://www.ncbi.nlm.nih.gov/pubmed/16945659 Patki P, Hamid R, Shah PJ, Craggs M. Long-term efficacy of AMS 800 artificial urinary sphincter in male patients with urodynamic stress incontinence due to spinal cord lesion. Spinal Cord 2006;44(5):297-300. http://www.ncbi.nlm.nih.gov/pubmed/16249789 Magera JS, Jr., Elliott DS. Tandem transcorporal artificial urinary sphincter cuff salvage technique: surgical description and results. J Urol 2007;177(3):1015-19; discussion 1019-20. http://www.ncbi.nlm.nih.gov/pubmed/17296400 Rahman NU, Minor TX, Deng D, Lue TF. Combined external urethral bulking and artificial urinary sphincter for urethral atrophy and stress urinary incontinence. BJU Int 2005;95(6):824-6. http://www.ncbi.nlm.nih.gov/pubmed/15794791 Werner M, Schmid DM, Schussler B. Efficacy of botulinum-A toxin in the treatment of detrusor overactivity incontinence: a prospective nonrandomized study. Am J Obstet Gynecol 2005;192(5):1735-40. http://www.ncbi.nlm.nih.gov/pubmed/15902187

An exhaustive reference list is available for consultation on line at the society website (http://www.uroweb.org/ professional-resources/guidelines/) and on the guidelines CD-rom version.

5. INCONTINENCE IN WOMEN* 5.1

Initial assessment

Initial assessment should triage patients into those with a ‘complicated’ incontinence, who require referral for specialised management and those suitable for general assessment. The ‘complicated’ incontinence group comprises patients with: • Pain • Haematuria • Recurrent infections • Voiding dysfunction • Significant pelvic organ prolapse • Failed previous incontinence surgery • Previous pelvic radiotherapy • Previous pelvic surgery • Suspected fistula. The remaining patients, with a history of UI identified by initial assessment, can be stratified into three main symptomatic groups of women suitable for initial primary care management: • Stress incontinence • Overactive bladder (OAB) symptoms: urgency with or without urgency incontinence, frequency and nocturia • Mixed urgency and stress incontinence. Routine physical examination includes abdominal, pelvic and perineal examinations. Women should perform a ‘stress test’ (cough and strain) to detect leakage secondary to sphincter incompetence. Any POP or urogenital atrophy must be assessed. It is also important to assess voluntary pelvic floor muscle function by vaginal or rectal examination before teaching pelvic floor muscle training (PFMT).

5.2

Initial treatment of UI in women

For women with stress, urgency or mixed urinary incontinence, initial treatment includes appropriate lifestyle advice, physical therapy, a scheduled voiding regime, behavioural therapy and medication (Table 7, Figure 3). Some recommendations are based on good and consistent evidence of effect. However, many other recommendations are based on insufficient level 1 or 2 evidence and are essentially hypotheses requiring better evidence of their benefit. * This section of the guidelines is based on the recommendations of the ICI committees chaired by Jean Hay-Smith (Committee 12: Adult Conservative Management), Tony Smith (Committee 14: Surgery for Urinary Incontinence in Women) and Linda Brubaker (Committee 15: Surgery for Pelvic Organ Prolapse).

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Update march 2009

Table 7: Initial treatment for UI in women Treatment Lifestyle interventions • For morbidly and moderately obese women, weight loss helps to reduce UI prevalence • Caffeine intake reduction may benefit UI symptoms •A  decrease in fluid intake should only be tried in patients with abnormally high fluid intakes, as a decrease in fluids may lead to UTIs, constipation, or dehydration •C  rossing the legs and bending forward can help to reduce leakage during coughing or other provocations Pelvic floor muscle training: general considerations •P  FMT should be offered as first-line conservative therapy to women with stress, urgency, or mixed UI •P  rovide the most intensive PFMT programme possible (i.e. amount of exercise and of health professional supervision) within service constraints, as health-professional or supervised programmes are more effective than self-directed programmes. In addition, greater health professional contact is better than less •T  he addition of biofeedback to the PFMT programme does not appear to be of benefit: - clinic biofeedback - home-based biofeedback Vaginal cones • VC may be offered to women with SUI or MUI •V  C can be offered as first-line conservative therapy to those who can, and are prepared to use them • VC may not be helpful because of side-effects and discomfort •V  C and EStim seem equally effective in SUI and MUI, but the usefulness of VC and EStim is limited because of side-effects and discomfort Electrical stimulation • EStim may be offered to women with SUI, UUI or MUI •F  or treating SUI, 6 months of EStim, 50 Hz twice daily at home, may be better than no treatment •L  ow-intensity home-based EStim daily for 6 months may be better than 16 sessions of maximal clinic-based EStim •F  or treating UUI secondary to DO, 9 weeks of EStim, 4-10 Hz twice daily at home, might be better than no treatment •A  ddition of EStim to a biofeedback-assisted PFMT programme does not appear to add benefit •E  Stim may have limited usefulness, because some women cannot use it (due to contraindications), have difficulty using it, or dislike it Magnetic stimulation (MStim) • MStim should only be used as part of a clinical trial as its benefit has not been established Bladder training • BT is an appropriate first-line treatment for UUI in women • Either BT or antimuscarinic drugs may be effective for treating UUI •S  ome patients may prefer BT because it does not produce the adverse events associated with drug therapy • Addition of a brief written instruction for BT, in addition to drug therapy, has no benefit •F  or women with symptoms of SUI or MUI, a combination of PFMT/BT may be better than PFMT alone in the short-term •C  linicians and researchers should refer to the operant conditioning and educational literature to explain their choice of training parameters or approach •C  linicians should provide the most intensive BT supervision possible within service constraints Timed voiding •T  imed voiding with a 2-hour voiding interval may be beneficial as a sole intervention for women with mild UI and infrequent voiding patterns

Update march 2009

GR A B C C

A A

A B

B

B

C C C C

NR A B

B B NR B

C

29

GR = grade of recommendation; UI = urinary incontinence; UTI = urinary tract infection; PFMT = pelvic floor muscle training; VC = vaginal cone; SUI = stress urinary incontinence; MUI = mixed urinary incontinence; EStim = electrical stimulation; MStim = magnetic stimulation; UUI = urge urinary incontinence; DO = detrusor overactivity; NR = no recommendation possible; BT = bladder training. 5.2.1 Pelvic floor muscle training (PFMT) under special circumstances The following recommendations may help with decision-making for specific groups. However, most of these are essentially hypotheses that need further testing. Since empirical evidence is lacking the recommendations presented below are supported by expert opinion. Recommendations for PFMT in special circumstances Recommendations Pregnant women expecting their first baby • Offer an intensive strengthening ante-partum PFMT • Provide regular health professional contact to supervise PFMT training to prevent postpartum UI: - women continent at 18 weeks -p  opulation approaches, i.e. intervention offered whether or not women are continent at 20 weeks’ gestation Post-partum women, immediately after delivery • After vaginal delivery of a large baby (> 4000 g) or a forceps delivery an individually-taught PFMT programme, which includes advice on how to keep to the programme, will be beneficial Post-partum women with persistent symptoms of UI at 3 months after delivery • PFMT is offered as first-line conservative therapy • ‘Intensive’ programmes, i.e. highly supervised and high amount of exercise Women with SUI • PFMT is more effective than EStim as first-line conservative therapy, particularly if PFMT is intensively supervised • PFMT is more effective than BT as first-line conservative therapy • PFMT and duloxetine are both effective. Clinicians and women may choose to try PFMT first because of the side-effects associated with drug therapy • PFMT and surgery are both effective, but many clinicians and women may prefer PFMT as a first-line therapy because it is less invasive • PFMT and VC are both effective. PFMT is the preferred first choice because there is less leakage and some women cannot or do not like to use VCs • PFMT is better than clenbuterol or phenylpropanolamine hydrochloride as first-line therapy because of the side-effects experienced with the medications • A combination of PFMT + BT may be better than PFMT alone in short-term Women with UUI or MUI • PFMT and BT are both effective as first-line conservative therapies • PFMT is better than oxybutynin as first-line therapy

GR

A B

C

A B B B C C B B C B B

GR = grade of recommendation; PFMT = pelvic floor muscle training; UI = urinary incontinence; SUI = stress urinary incontinence; EStim = electrical stimulation; BT = bladder training; VC = vaginal cone; UUI = urgency urinary incontinence; MUI = mixed urinary incontinence.

30

Update march 2009

Figure 3: Algorithm for initial management of UI in women

   



 

   

   

 



       s  

                   



           



    

      

     

           

               

     



5.3

Specialised management of UI in women

5.3.1 Assessment Women with ‘complicated’ incontinence requiring specialist management will probably need additional testing to rule out any underlying pathology, i.e. cytology, cysto-urethroscopy or urinary tract imaging. If these tests reveal no further pathology, the patient should be treated for UI by initial or specialised management options, as appropriate (Figure 4). Women who have failed initial management and with an impaired QoL are likely to request further treatment. If initial management has been given an adequate trial, then interventional therapy may be helpful. Urodynamic testing to diagnose the type of UI is highly recommended prior to intervention if the results are likely to influence the choice of management. It may also be helpful to test urethral function by urethral pressure profile or leak point pressure during urodynamic testing. A systematic assessment for POP is highly recommended. The Pelvic Organ Prolapes Quantification (POPQ) method should be used in research studies. Co-existing POP should be treated. 5.3.2 Treatment If urodynamic SUI is confirmed, the following treatment options may be recommended for patients with some bladder-neck and urethral mobility: • full range of non-surgical treatments • retropubic suspension procedures • bladder neck/sub-urethral sling operations. It may be helpful to correct symptomatic POP at the same time. For patients with limited bladder-neck mobility, consider using bladder neck sling procedures, injectable bulking agents and the artificial urinary sphincter. Urgency incontinence (overactive bladder) secondary to idiopathic DO may be treated by neuromodulation or bladder augmentation. Botulinum toxin injection can be used to treat symptomatic DO unresponsive to other therapies (grade of recommendation: C). Botulinum toxin is currently being used for detrusor injection ‘off-label’ for this indication. Patients with voiding dysfunction leading to significant post-void residual urine may have bladder outlet obstruction or detrusor underactivity. Pelvic organ prolapse is a common cause of voiding dysfunction.

Update march 2009

31

Figure 4: Algorithm for specialised management of UI in women

   

 

  

       

   

   

 



5.4

                        

   

      

 



 

            

          

 

 

       

    

    

    

Surgery for UI in women

Surgical approaches to UI in women are listed in Table 8. There are various confounding variables for successful surgery (Table 9). The true incidence of complications associated with surgery for UI is not known, due to a lack of standard methods of reporting and definitions. In addition, there is a discrepancy between academic and community practice. However, there appears to be a low incidence of most complications, which makes it difficult to perform power calculations for RCTs. National registries provide some information about the level of complications. Complications are less likely with proper surgical training (level of evidence: 2-3) and skills can be maintained by performing at least 20 cases annually for each primary procedure (National Institute of Clinical Excellence, NICE). Table 8: Surgery for UI in women Surgical approach Anterior colporrhaphy • Outcome of anterior colporrhaphy is comparable to needle suspension, but less effective than open colposuspension. The effectiveness deteriorates substantially with time • Anterior colporrhaphy is not recommended as treatment of SUI alone Open colposuspension • Similar success compared to mid-urethral retropubic slings • Similar success compared to bladder neck slings • Similar success compared to transobturator slings • Risk of voiding dysfunction is higher than with TVT • Risk of voiding dysfunction is less than with slings • Prolapse after colposuspension is more likely than after TVT • The risk of de-novo DO is the same as after TVT • Mitrofanoff urethroplasty, BNS suspension, and paravaginal repair are not recommended for treatment of SUI alone • Open colposuspension is an effective, long-lasting treatment for primary SUI Laparoscopic colposuspension • Laparoscopic colposuspension is comparable to open colposuspension when performed by experienced laparoscopic surgeons • Equal or higher cure rates compared to TVT • Shorter operating time and faster recovery compared to TVT

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GR

2 A 1 1-2 2 1 1 1 1 B A 1-2 1-2 1-2

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• Laparoscopic colposuspension is an option for treating SUI B •L  aparoscopic colposuspension should only be performed by experienced laparoscopic NR surgeons Traditional sling procedures • Autologous fascial sling is effective 1 • Autologous fascial sling may be more effective than biological and synthetic slings 2 • Adverse events may be more common than with non-autologous materials 3 •A  utologous fascial sling is recommended as an effective, long-lasting treatment for SUI A Urethral bulking agents • Urethral bulking agents show similar symptomatic improvement with both placebo and 1 autologous fat • Less effective than conventional surgery 2 • No evidence to show that any bulking agent is more effective than another 2 • No data to compare urethral bulking agents with non-surgical treatments or with other 2 minimal-access surgical techniques B • Women should be aware that efficacy of ureteral bulking agents decreases with time, repeat injections may be necessary, and efficacy is less than that of other surgical techniques Mid-urethral tapes • TVT® is more effective than SPARC® tape 2 2 • IVS® has similar efficacy as TVT®, but a higher complication rate Mid-urethral tapes vs other procedures 1-2 • TVT® is equally effective as colposuspension and traditional sling operations ® 1-2 •O  peration time, hospital stay and return to normal activity is shorter with TVT than with colposuspension • Post-operative voiding problems and need for prolapse surgery are more common with 1-2 colposuspension Retropubic tapes vs transobturator tapes • Similar efficacy up to 12 months • Similar complication rates in Finnish study 1 • Relative risk of bladder injury increased by 6-fold for retropubic sling • Relative risk of urethral injury increased by 4-fold for transobturator sling Contraindications for mid-urethral slings • Absolute contraindications are urethrovaginal fistula, urethral diverticulum, intra-operative 4 urethral injury and untreated urinary malignancy • Increased risk of complications including failure with radiotherapy, UTI, steroids, COPD, anticoagulant therapy, vaginal atrophy, congenital anomalies (exstrophy, ureteral ectopy, etc) and planned pregnancy ‘Mini-slings’ • Data immature, no recommendation possible NR Surgery for detrusor overactivity • Sacral neuromodulation appears to have benefit for patients with urgency incontinence, as 1-3 A well as urgency and frequency • Posterior tibial nerve stimulation is effective, but durability is a concern 3-4 Urethral diverticulae • No grade A recommendations regarding optimal diagnostic algorithm or adjuvant therapy of concomitant SUI • One long-term study showing recurrence of diverticulum in 17%, de-novo SUI in 38%, and 3 dyspareunia in 22% Non-obstetric urinary fistulae 2-4 • No grade A recommendation for fistula evaluation, timing of corrective intervention, methods and adjuncts of correction, and associated management strategies. All evidence is based on clinical series and/or case studies and lacks randomised and/or controlled studies LE = level of evidence; GR = grade of recommendation; SUI = stress urinary incontinence; TVT = tension-free vaginal tape; NR = no recommendation possible; MMK = Marshall-Marchetti-Krantz; BNS = bladder-neck suspension; DO = detrusor overactivity; IVS = intravaginal slingplasty; UTI = urinary tract infection; COPD = chronic obstructive pulmonary disease.

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Table 9: Confounding variables for use of surgery for UI in women Confounding variables for use of surgery • Age • Physical activity • Medical illness • Psychiatric illness • Obesity • Parity • Previous incontinence surgery • Hysterectomy during anti-incontinence procedure • Race • Severity and duration of symptoms • Overactive bladder • Urethral occlusive forces • Surgical factors 5.4.1 Outcome measures Until a universal outcome tool has been established, multiple outcome measures must be used. They include: • symptoms and separate bother questionnaire • clinically important outcomes (pad use, re-operation rates, anticholinergics, clean intermittent selfcatherisation (CIC) and recurrent UTIs) • complications • QoL tool with ‘minimal clinically important difference’ (MCID) Global Impression Index • health-economic outcome. Recommendations for surgical treatment of SUI Surgical procedure GR • Anterior colporrhaphy NR • Transvaginal BNS (needle) NR • Burch procedure: open A • Burch procedure: laparoscopic (by experienced laparoscopic surgeon only) B • Paravaginal NR • MMK urethroplasy NR • BN sling: autologous fascia A • Sub-urethral slings (TVT) A • Urethral bulking agents B NR = no recommendation possible; BNS = bladder-neck suspension; GR = grade of recommendation; MMK = Marshall-Marchetti-Krantz; BN = bladder neck; TVT = tension-free vaginal tape.

5.6 REFERENCES* •

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Richter HE, Diokno A, Kenton K, Norton P, Albo M, Kraus S, Moalli P, Chai TC, Zimmern P, Litman H, Tennstedt S; Urinary Incontinence Treatment Network. Predictors of treatment failure 24 months after surgery for stress urinary incontinence. J Urol 2008;179(3):1024-30. http://www.ncbi.nlm.nih.gov/pubmed/18206917 El-Barky E, El-Shazly A, El-Wahab OA, Kehinde EO, Al-Hunayan A, Al-Awadi, KA. Tension free vaginal tape versus Burch colposuspension for treatment of female stress urinary incontinence. Int Urol Nephrol 2005;37(2):277-81. http://www.ncbi.nlm.nih.gov/pubmed/16142556 Ankardal M, Milsom I, Stjerndahl JH, Engh ME. A three-armed randomized trial comparing open Burch colposuspension using sutures with laparoscopic colposuspension using sutures and laparoscopic colposuspension using mesh and staples in women with stress urinary incontinence. Acta Obstet Gynecol Scand 2005;84(8):773-9. http://www.ncbi.nlm.nih.gov/pubmed/16026404 Ustün Y, Engin-Ustün Y, Güngör M, Tezcan S. Randomized comparison of Burch urethropexy procedures concomitant with gynecologic operations. Gynecol Obstet Invest 2005;59(1):19-23. http://www.ncbi.nlm.nih.gov/pubmed/15627777 Kitchener HC, Dunn G, Lawton V, Reid F, Nelson L, Smith AR. & Group, O. B. O. T. C. S. Laparoscopic versus open colposuspension—results of a prospective randomised controlled trial. BJOG 2006;113(9):1007-13. http://www.ncbi.nlm.nih.gov/pubmed/16956332 Dietz HP, Wilson PD. Laparoscopic colposuspension versus urethropexy: a case-control series. Int Urogynecol J Pelvic Floor Dysfunct 2005;16(1):15-8. http://www.ncbi.nlm.nih.gov/pubmed/15647961 McCracken GR, Henderson NA, Ashe RG. Five year follow-up comparing tension-free vaginal tape and colposuspension. Ulster Med J 2007;76(3):146-9. http://www.ncbi.nlm.nih.gov/pubmed/17853641 Sun MJ, Ng SC, Tsui KP, Chang NE, Lin KC, Chen GD. Are there any predictors for failed Burch colposuspension? Taiwan J Obstet Gynecol 2006;45(1):33-8. http://www.ncbi.nlm.nih.gov/pubmed/17272205 Ng S, Tee YT, Tsui KP, Chen GD. Is the role of Burch colposuspension fading away in this epoch for treating female urinary incontinence? Int Urogynecol J Pelvic Floor Dysfunct 2007;18(8):937-42. http://www.ncbi.nlm.nih.gov/pubmed/17139462 Rardin CR, Sung VW, Hampton BS, Clemons JL, Aguilar V, Sokol ER. Long-term follow-up of a transvaginal Burch urethropexy for stress urinary incontinence. Am J Obstet Gynecol 2007;197(6):656. e1-e5. http://www.ncbi.nlm.nih.gov/pubmed/18060969 Reid SV, Parys BT. Long-term 5-year followup of the results of the vesica procedure. J Urol 2005;173(4):1234-6. http://www.ncbi.nlm.nih.gov/pubmed/15758759 Gregorakis A, Bouropoulos C, Dimitriou D, Rallis G, Vernadakis S, Papadopoulos IN, Kastriotis I. Delayed reaction to the Dacron buttress used in Stamey bladder neck suspension. Int Urol Nephrol 2006;38(2):269-72. http://www.ncbi.nlm.nih.gov/pubmed/16868695 Smith A, Rovner E. Long-term chronic complications from Stamey endoscopic bladder neck suspension: a case series. Int Urogynecol J Pelvic Floor Dysfunct 2006;17(3):290-4. http://www.ncbi.nlm.nih.gov/pubmed/15965575 Mirosh M, Epp A. TVT vs laparoscopic Burch colposuspension for the treatment of stress urinary incontinence. International Continence Society. 35th annual meeting. Montreal, Canada, 2005. Dean NM, Herbison P, Ellis G, Wison D. Laparoscopic colposuspension and tension-free vaginal tape: a systematic review. BJOG 2006;113(12):1345-53. http://www.ingentaconnect.com/content/bsc/bjo/2006/00000113/00000012/art00002;jsessionid=194 6gsz6wq8wg.alexandra Tan E, Tekkis PP, Cornish J, Teoh TG, Darzi AW, Khullar V. Laparoscopic versus open colposuspension for urodynamic stress incontinence. Neurourol Urodyn 2007;26(2):158-69. http://www.ncbi.nlm.nih.gov/pubmed/17252603 Jelovsek JE, Barber MD, Karram MM, Walters MD, Paraiso MF. Randomised trial of laparoscopic Burch colposuspension versus tension-free vaginal tape: long-term follow up. BJOG 2008;115(2):21925; discussion 225. http://www.ncbi.nlm.nih.gov/pubmed/18081602

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Valpas A, Rissanen P, Kujansuu E, Nilsson CG. A cost-effectiveness analysis of tension-free vaginal tape versus laparoscopic mesh colposuspension for primary female stress incontinence. Acta Obstet Gynecol Scand 2006;85(12):1485-90. http://www.ncbi.nlm.nih.gov/pubmed/17260226 Corcos J, Collet JP, Shapiro S, Herschorn S, Radomski SB, Schick E, Gajewski JB, Benedetti A, MacRamallah E, Hyams B. Multicenter randomized clinical trial comparing surgery and collagen injections for treatment of female stress urinary incontinence. Urology 2005;65(5):898-904. http://www.ncbi.nlm.nih.gov/pubmed/15882720 Maher CF, O’Reilly BA, Dwyer PL, Carey MP, Cornish A, Schulter P. Pubovaginal sling versus transurethral Macroplastique for stress urinary incontinence and intrinsic sphincter deficiency: a prospective randomised controlled trial. BJOG 2005;112(6):797-801. http://www.ncbi.nlm.nih.gov/pubmed/15924540 Appell R, Roger D, Robert M, Ira K, Hubbard W. Clinical experience with coaptite® urological bulking agent. International Continence Society, 33rd annual meeting, 2005. Florence, Italy. Bano F, Barrington JW, Dyer R. Comparison between porcine dermal implant (Permacol) and silicone injection (Macroplastique) for urodynamic stress incontinence. International Urogynecology Journal & Pelvic Floor Dysfunction 2005;16(2):147-50. http://www.ncbi.nlm.nih.gov/pubmed/15378234 Mayer RD, Dmochowski RR, Appell RA, Sand PK, Klimberg IW, Jacoby K, Graham CW, Snyder JA, Nitti VW, Winters JC. Multicenter prospective randomized 52-week trial of calcium hydroxylapatite versus bovine dermal collagen for treatment of stress urinary incontinence. Urology 2007;69(5): 876-80. http://www.ncbi.nlm.nih.gov/pubmed/17482925 Ghoniem G, Bernhard P, Corcos J, Comiter C, Tomera K, Westney O, Herschorn S, Lucente V, Smith J, Wahle G, Mulcahy J. Multicenter randomised controlled trial to evaluate Macroplastique® urethral bulking agent for the Treatment of female stress urinary incontinence. International Continence Society, 35th annual meeting, 2005. Montreal, Canada. Abdelwahab HA, Ghoniem GM. Obstructive suburethral mass after transurethral injection of dextranomer/hyaluronic acid copolymer. Int Urogynecol J 2007;18(11);1379-80. http://www.ncbi.nlm.nih.gov/pubmed/17437054 Petrou SP, Pak RW, Lightner DJ. Simple aspiration technique to address voiding dysfunction associated with transurethral injection of dextranomer/hyaluronic acid copolymer. Urology 2006;68(1):186-8. http://www.ncbi.nlm.nih.gov/pubmed/16777199 Hagemeier T, Blau U, Gauruder-Burmester A, Tunn R. [Paraurethral abscess developing after midurethral Zuidex-injection in women with stress urinary incontinence -- management of complications and retrospective comparison with bladder neck located injection technique]. Zentralbl Gynakol 2006;128(2):68-70. [article in German] http://www.ncbi.nlm.nih.gov/pubmed/16673247 Madjar S, Sharma AK, Waltzer WC, Frischer Z, Secrest CL. Periurethral mass formations following bulking agent injection for the treatment of urinary incontinence. J Urol 2006;175(4):1408-10. http://www.ncbi.nlm.nih.gov/pubmed/16516009 Wadie BS, Edwan A, Nabeeh AM. Autologous fascial sling vs polypropylene tape at short-term followup: a prospective randomized study. J Urol 2005;174(3):990-3. http://www.ncbi.nlm.nih.gov/pubmed/16094020 Guerrero K, Watkins A, Emery S, Wareham K, Stephenson T, Logan V, Lucas M. A randomised controlled trial comparing two autologous fascial sling techniques for the treatment of stress urinary incontinence in women: short, medium and long-term follow-up. International Urogynecology Journal & Pelvic Floor Dysfunction 2007;18(11):1263-70. http://www.biomedexperts.com/Abstract.bme/17347792 McBride AW, Ellerkmann RM, Bent AE, Melick CF. Comparison of long-term outcomes of autologous fascia lata slings with Suspend Tutoplast fascia lata allograft slings for stress incontinence. Am J Obstet Gynecol 2005;192(5):1677-81. http://www.ncbi.nlm.nih.gov/pubmed/15902176 Simsiman AJ, Powell CR, Stratford RR, Menefee SA. Suburethral sling materials: best outcome with autologous tissue. Am J Obstet Gynecol 2005;193(6):2112-6. http://www.ncbi.nlm.nih.gov/pubmed/16325625

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Campeau L, Tu LM, Lemieux MC, Naud A, Karsenty G, Schick E, Corcos J. A multicenter, prospective, randomized clinical trial comparing tension-free vaginal tape surgery and no treatment for the management of stress urinary incontinence in elderly women. Neurourol Urodyn 2007;26(7):990-4. http://www.ncbi.nlm.nih.gov/pubmed/17638307 Foote AJ, Maughan V, Carne C. Laparoscopic colposuspension versus vaginal suburethral slingplasty: a randomised prospective trial. Aust N Z J Obstet Gynaecol 2006;46(6):517-20. http://www.ncbi.nlm.nih.gov/pubmed/17116057 Andonian S, Chen T, St-Denis B, Corcos J. Randomized clinical trial comparing suprapubic arch sling (SPARC) and tension-free vaginal tape (TVT): one-year results. Eur Urol 2005;47(4):537-41. http://www.ncbi.nlm.nih.gov/pubmed/15774255 Lord HE, Taylor JD, Finn JC, Tsokos N, Jeffery JT, Atherton MJ, Evans SF, Bremner AP, Elder GO, Holman CD. A randomized controlled equivalence trial of short-term complications and efficacy of tension-free vaginal tape and suprapubic urethral support sling for treating stress incontinence. BJU Int 2006;98(2):367-76. http://www.ncbi.nlm.nih.gov/pubmed/16879679 Lim YN, Muller R, Corstiaans A, Dietz HP, Barry C, Rane A. Suburethral slingplasty evaluation study in North Queensland, Australia: the SUSPEND trial. Aust N Z J Obstet Gynaecol 2005;45(1):52-9. http://www.ncbi.nlm.nih.gov/pubmed/15730366 Meschia M, Pifarotti P, Bernasconi F, Magatti F, Viganò R, Bertozzi R, Barbacini P. Tension-free vaginal tape (TVT) and intravaginal slingplasty (IVS) for stress urinary incontinence: a multicenter randomized trial. Am J Obstet Gynecol 2006;195(5):1338-42. http://www.ncbi.nlm.nih.gov/pubmed/16769016 Zullo MA, Plotti F, Calcagno M, Marullo E, Palaia I, Bellati F, Basile S, Muzii L, Angioli R, Panici PB. One-year follow-up of tension-free vaginal tape (TVT) and trans-obturator suburethral tape from inside to outside (TVT-O) for surgical treatment of female stress urinary incontinence: a prospective randomised trial. Eur Urol 2007;51(5):1376-82; discussion 1383-4. http://www.ncbi.nlm.nih.gov/pubmed/17110021 Liapis A, Bakas P, Giner M, Creatsas G.Tension-free vaginal tape versus tension-free vaginal tape obturator in women with stress urinary incontinence. Int J Gynaecol Obstet 2006;92(1):48-51. http://www.ncbi.nlm.nih.gov/pubmed/16253254 Laurikainen E, Valpas A, Kivelä A, Kalliola T, Rinne K, Takala T, Nilsson CG. Retropubic compared with transobturator tape placement in treatment of urinary incontinence: a randomized controlled trial. Obstet Gynecol 2007;109(1):4-11. http://www.ncbi.nlm.nih.gov/pubmed/17197581 Araco F, Gravante G, Sorge R, Overton J, De Vita D, Sesti F, Piccione E. TVT-O vs TVT: a randomized trial in patients with different degrees of urinary stress incontinence. Int Urogynecol J Pelvic Floor Dysfunct 2008;19(7):917-26. http://www.ncbi.nlm.nih.gov/pubmed/18217177 Rinne K, Laurikainen E, Kivelä A, Aukee P, Takala T, Valpas A, Nilsson CG. A randomized trial comparing TVT with TVT-O: 12 months results. Int Urogynecol J Pelvic Floor Dysfunct 2008;19(8):1049-54. http://www.ncbi.nlm.nih.gov/pubmed/18373046 Andonian S, St-Denis B, Lemieux MC, Corcos J. Prospective clinical trial comparing Obtape and DUPS to TVT: one-year safety and efficacy results.[see comment]. Eur Urol 2007;52(1):245-51. http://www.ncbi.nlm.nih.gov/pubmed/17234331 Porena M, Costantini E, Frea B, Giannantoni A, Ranzoni S, Mearini L, Bini V, Kocjancic E. Tensionfree vaginal tape versus transobturator tape as surgery for stress urinary incontinence: results of a multicentre randomised trial. Eur Urol 2007;52(5):1481-90. http://www.ncbi.nlm.nih.gov/pubmed/17482343 Gillon G, Stanton SL. Long-term follow-up of surgery for urinary incontinence in elderly women. Br J Urol 1984;56(5):478-81. http://www.ncbi.nlm.nih.gov/pubmed/6534447 Gordon D, Gold R, Pauzner D, Lessing JB, Groutz A. Tension-free vaginal tape in the elderly: is it a safe procedure? Urology 2005;65(3):479-82. http://www.ncbi.nlm.nih.gov/pubmed/15780359 Lowenstein L, Kenton K, Dooley Y, R Mueller E, Brubaker L. Women who experience detrusor overactive at lower bladder volumes report greater bother. Neurourol Urodyn 2008;27(1):45-7. http://www.ncbi.nlm.nih.gov/pubmed/17600369

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Anger JT, Saigal CS, Madison R, Joyce G, Litwin MS; Urologic Diseases of America Project. Increasing Costs of Urinary Incontinence Among Female Medicare Beneficiaries. J Urol 2006;176(1):247-51; discussion 251. http://www.ncbi.nlm.nih.gov/pubmed/16753411 Anger JT, Rodríguez LV, Wang Q, Chen E, Pashos CL, Litwin MS. Racial disparities in the surgical management of stress incontinence among female Medicare beneficiaries. J Urol 2007;177(5): 1846-50. http://www.ncbi.nlm.nih.gov/pubmed/17437833 Kraus SR, Markland A, Chai TC, Stoddard A, FitzGerald MP, Leng W, Mallett V, Tennstedt SL; Urinary Incontinence Treatment Network. Race and ethnicity do not contribute to differences in preoperative urinary incontinence severity or symptom bother in women who undergo stress incontinence surgery. Am J Obstet Gynecol 2007;197(1):92.e1-e6. http://www.ncbi.nlm.nih.gov/pubmed/17618773 Daneshgari F, Moore C. Advancing the understanding of pathophysiological rationale for the treatment of stress urinary incontinence in women: the ‘trampoline theory’. BJU Int 2006;98 Suppl 1:8-14; discussion 15-6. http://www.ncbi.nlm.nih.gov/pubmed/16911594 Kjølhede P, Wahlström J, Wingren G. Pelvic floor dysfunction after Burch colposuspension--a comprehensive study. Part I. Acta Obstet Gynecol Scand 2005;84(9):894-901. http://www.ncbi.nlm.nih.gov/pubmed/16097983 Anger JT, Rodríguez LV, Wang Q, Chen E, Pashos CL, Litwin MS. Racial disparities in the surgical management of stress incontinence among female Medicare beneficiaries. J Urol 2007;177(5): 1846-50. http://www.ncbi.nlm.nih.gov/pubmed/17437833 Skriapas K, Poulakis V, Dillenburg W, de Vries R, Witzsch U, Melekos M, Becht E. Tension-free vaginal tape (TVT) in morbidly obese patients with severe urodynamic stress incontinence as last option treatment. Eur Urol 2006;49(3):544-50. http://www.ncbi.nlm.nih.gov/pubmed/16387416 Rogers RG, Lebküchner U, Kammerer-Doak DN, Thompson PK, Walters MD, Nygaard IE. Obesity and retropubic surgery for stress incontinence: is there really an increased risk of intraoperative complications? Am J Obstet Gynecol 2006;195(6):1794-8. http://www.ncbi.nlm.nih.gov/pubmed/17014816 Nam SB, Bae JH, Lee JG. Surgical considerations for recurrent stress urinary incontinence after the midurethral sling procedure: Redo midurethral sling and shortening of the tape. [Korean]. Korean J Urol 2007;48:527-35. http://www.urology.or.kr/journal/viewJournal.html?year=2007&vol=48&page=527 Moore RD, Gamble K, Miklos JR. Tension-free vaginal tape sling for recurrent stress incontinence after transobturator tape sling failure. International Urogynecology Journal & Pelvic Floor Dysfunction 2007;18:309-13. http://www.ncbi.nlm.nih.gov/pubmed/16868658 Argirovic R, Likic I, Kadija S, Milenkovic V, Ilic-Mostic T, Arsenijevic Lj. [Outcome of Burch retropubic urethropexy and the effect of concomitant abdominal hysterectomy]. Acta Chir Iugosl 2006;53(1): 77-81. http://www.ncbi.nlm.nih.gov/pubmed/16989152 Botros SM, Abramov Y, Goldberg RP, Beaumont JL, Gandhi S, Miller JJ, Sand PK. Detrusor overactivity and urge urinary incontinence [corrected] following midurethral versus bladder sling procedures. Am J Obstet Gynecol 2005;193(6):2144-8. Erratum in: Am J Obstet Gynecol 2006;194(2):595. http://www.ncbi.nlm.nih.gov/pubmed/16325631 Duckett JR & Tamilselvi A. Effect of tension-free vaginal tape in women with a urodynamic diagnosis of idiopathic detrusor overactivity and stress incontinence. BJOG: Int J Obstet Gynaecol 2006;113(1):30-3. http://www.ncbi.nlm.nih.gov/pubmed/16398768 Choe JH, Choo MS, Lee KS. The impact of tension-free vaginal tape on overactive bladder symptoms in women with stress urinary incontinence: significance of detrusor overactivity. J Urol 2008;179(1): 214-9. http://www.ncbi.nlm.nih.gov/pubmed/18001792 McLennan MT, Melick CF. Bladder perforation during tension-free vaginal tape procedures: analysis of learning curve and risk factors. Obstet Gynecol 2005;106(5 Pt 1):1000-4. http://www.ncbi.nlm.nih.gov/pubmed/16260518

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Digesu GA, Salvatore S, Chaliha C, Athanasiou S, Milani R, Khullar V. Do overactive bladder symptoms improve after repair of anterior vaginal wall prolapse? Int Urogynecol J Pelvic Floor Dysfunct 2007;18(12):1439-43. http://www.ncbi.nlm.nih.gov/pubmed/17429557 Foster RT Sr, Barber MD, Parasio MF, Walters MD, Weidner AC, Amundsen CL. A prospective assessment of overactive bladder symptoms in a cohort of elderly women who underwent transvaginal surgery for advanced pelvic organ prolapse. Am J Obstet Gynecol 2007;197(1):82.e1-e4. http://www.ncbi.nlm.nih.gov/pubmed/17618768 Boyles SH, Edwards R, Gregory W, Clark A. Complications associated with transobturator sling procedures. Int Urogynecol J Pelvic Floor Dysfunct 2007;18(1):19-22. http://www.ncbi.nlm.nih.gov/pubmed/16568214 Deng DY, Rutman M, Raz S, Rodriguez LV. Presentation and management of major complications of midurethral slings: Are complications under-reported? Neurourol Urodyn 2007;26(1):46-52. http://www.ncbi.nlm.nih.gov/pubmed/17149713 TAUB Taub DA, Hollenbeck BK, Wei JT, Dunn RL, McGuire EJ, Latini JM. Complications following surgical intervention for stress urinary incontinence: a national perspective. Neurourol Urodyn 2005;24(7):659-65. http://www.ncbi.nlm.nih.gov/pubmed/16173038 Adams E, Bardsley A, Crumlin L, Currie I, Evans L, Haslam J, Hilton P, Jones M, Lucas M, Spinks J, Townsend J, Wagg A, Dougherty M, Wyn Evans B, Jacklin P, Kwan I, Pledge D, Vahidi S. Urinary Incontinence: The management of urinary incontinence in women. In: National Collaborating Centre for Women’s and Children’s Health, Hace NIF (Ed.). London, UK. RCOG Press. ISBN 1-904752-32-2, 2006. http://www.nice.org.uk/nicemedia/pdf/CG40fullguideline.pdf Schraffordt Koops SE, Bisseling TM, Heintz AP, Vervest HA. Prospective analysis of complications of tension-free vaginal tape from The Netherlands Tension-free Vaginal Tape study. Am J Obstet Gynecol 2005;193(1):45-52. http://www.ncbi.nlm.nih.gov/pubmed/16021057 Zhu L, Lang J, Hai N, Wong F. Comparing vaginal tape and transobturator tape for the treatment of mild and moderate stress incontinence. Int J Gynaecol Obstet. 2007;99(1):14-7. http://www.ncbi.nlm.nih.gov/pubmed/17707822 Lee KS, Han DH, Choi YS, Yum SH, Song SH, Doo CK, Choo MS. A prospective trial comparing tension-free vaginal tape and transobturator vaginal tape inside-out for the surgical treatment of female stress urinary incontinence: 1-year followup. J Urol 2007;177(1):214-8. http://www.ncbi.nlm.nih.gov/pubmed/17162048 David-Montefiore E, Frobert JL, Grisard-Anaf M, Lienhart J, Bonnet K, Poncelet C, Daraï E. Perioperative complications and pain after the suburethral sling procedure for urinary stress incontinence: a French prospective randomised multicentre study comparing the retropubic and transobturator routes. Eur Urol 2006;49(1):133-8. http://www.ncbi.nlm.nih.gov/pubmed/16310932 Debodinance P. [Trans-obturator urethral sling for surgical correction of female stress urinary incontinence: Outside-in (Monarc) versus inside-out (TVT-O). Are both ways safe?]. J Gynecol Obstet Biol Reprod (Paris). 2006;35(6):571-7. [article in French] http://www.ncbi.nlm.nih.gov/pubmed/17003744 Lee KS, Choo MS, Lee YS, Han JY, Kim JY, Jung BJ, Han DH. Prospective comparison of the ‘inside-out’ and ‘outside-in’ transobturator-tape procedures for the treatment of female stress urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct. 2008;19(4):577-82. http://www.ncbi.nlm.nih.gov/pubmed/17940717 Anger JT, Litwin MS, Wang Q, Pashos CL.The effect of age on outcomes of sling surgery for urinary incontinence. J Am Geriatr Soc 2007;55(12):1927-31. http://www.ncbi.nlm.nih.gov/pubmed/18081671 Rogers RG, Lebküchner U, Kammerer-Doak DN, Thompson PK, Walters MD, Nygaard I.E. Obesity and retropubic surgery for stress incontinence: is there really an increased risk of intraoperative complications? Am J Obstet Gynecol 2006;195(6):1794-8. http://www.ncbi.nlm.nih.gov/pubmed/17014816 LaSala CA, Schimpf MO, Udoh E, O’Sullivan DM, Tulikangas P. Outcome of tension-free vaginal tape procedure when complicated by intraoperative cystotomy. Am J Obstet Gynecol 2006;195(6):1857-61. http://www.ncbi.nlm.nih.gov/pubmed/17132487

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Hodroff MA, Sutherland SE, Kesha JB, Siegel SW. Treatment of stress incontinence with the SPARC sling: intraoperative and early complications of 445 patients. Urology 2005;66(4):760-2. http://www.ncbi.nlm.nih.gov/pubmed/16230134 Davila GW, Johnson JD, Serels S. Multicenter experience with the Monarc transobturator sling system to treat stress urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct 2006;17(5):460-5. http://www.ncbi.nlm.nih.gov/pubmed/16314996 Barber MD, Gustilo-Ashby AM, Chen CC, Kaplan P, Paraiso MF, Walters MD. Perioperative complications and adverse events of the MONARC transobturator tape, compared with the tensionfree vaginal tape. Am J Obstet Gynecol 2006;195(6):1820-5. http://www.ncbi.nlm.nih.gov/pubmed/17027591 MAUDE database. 2007. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/TextSearch.cfm Gandhi S, Abramov Y, Kwon C, Beaumont JL, Botros S, Sand PK, Goldberg RP. TVT versus SPARC: comparison of outcomes for two midurethral tape procedures. Int Urogynecol J Pelvic Floor Dysfunct 2006;17(2):125-30. http://www.ncbi.nlm.nih.gov/pubmed/16079957 Rajan S, Kohli N. Retropubic hematoma after transobturator sling procedure. Obstet Gynecol 2005;106(5 Pt 2):1199-202. http://www.ncbi.nlm.nih.gov/pubmed/16260571 Kölle D, Tamussino K, Hanzal E, Tammaa A, Preyer O, Bader A, Enzelsberger H, Ralph G, Riss P; Austrian Urogynecology Working Group. Bleeding complications with the tension-free vaginal tape operation. Am J Obstet Gynecol 2005;193(6):2045-9. http://www.ncbi.nlm.nih.gov/pubmed/16325613 Roumeguère T, Quackels T, Bollens R, de Groote A, Zlotta A, Bossche MV, Schulman C. Transobturator vaginal tape (TOT) for female stress incontinence: one year follow-up in 120 patients. Eur Urol 2005;48(5):805-9. http://www.ncbi.nlm.nih.gov/pubmed/16182440 Dietz HP, Barry C, Lim Y, Rane A. TVT vs Monarc: a comparative study. Int Urogynecol J Pelvic Floor Dysfunct 2006;17(6):566-9. http://www.ncbi.nlm.nih.gov/pubmed/16525760 Morey AF, Medendorp AR, Noller MW, Mora RV, Shandera KC, Foley JP, Rivera LR, Reyna JA, Terry PJ. Transobturator versus transabdominal mid urethral slings: a multi-institutional comparison of obstructive voiding complications. J Urol 2006;175(3 Pt 1):1014-7. http://www.ncbi.nlm.nih.gov/pubmed/16469607 Mishra VC, Mishra N, Karim OM, Motiwala HG. Voiding dysfunction after tension-free vaginal tape: a conservative approach is often successful. Int Urogynecol J Pelvic Floor Dysfunct 2005;16(3):210-4; discussion 214. http://www.ncbi.nlm.nih.gov/pubmed/15372143 Starkman JS, Duffy JW 3rd, Wolter CE, Kaufman MR, Scarpero HM, Dmochowski RR. The evolution of obstruction-induced overactive bladder (OAB) symptoms following urethrolysis for female bladder outlet obstruction. J Urol 2008;179(3):1018-23. http://www.ncbi.nlm.nih.gov/pubmed/18206925 Starkman JS, Wolter C, Gomelsky A, Scarpero HM, Dmochowski RR. Voiding dysfunction following removal of eroded synthetic midurethral slings. J Urol 2006;176(3):1040-4.. http://www.ncbi.nlm.nih.gov/pubmed/16890687 Abdel-Fattah M, Sivanesan K, Ramsay I, Pringle S, Bjornsson S. How common are tape erosions? A comparison of two versions of the transobturator tension-free vaginal tape procedure. BJU Int 2006;98(3):594-8. http://www.ncbi.nlm.nih.gov/pubmed/16925759 Feifer A, Corcos J. The use of synthetic sub-urethral slings in the treatment of female stress urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct 2007;18(9):1087-95 http://www.ncbi.nlm.nih.gov/pubmed/17464439 de Boer F. Multifilament polypropylene mesh for urinary incontinence: 10 cases of infections requiring removal of the sling. BJOG 2005;112(10):1456. http://www.ncbi.nlm.nih.gov/pubmed/16167961 Siegel AL, Kim M, Goldstein M, Levey S, Ilbeigi P. High incidence of vaginal mesh extrusion using the intravaginal slingplasty sling. Urol 2005;174(4 Pt 1):1308-11. http://www.ncbi.nlm.nih.gov/pubmed/16145409

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Siegel AL. Vaginal mesh extrusion associated with use of Mentor transobturator sling. Urology 2005;66(5):995-9. http://www.ncbi.nlm.nih.gov/pubmed/16286110 Yamada BS, Govier FE, Stefanovic KB, Kobashi KC. High rate of vaginal erosions associated with the mentor ObTape. J Urol 2006;176(2):651-4; discussion 654. http://www.ncbi.nlm.nih.gov/pubmed/16813914 Robert M, Murphy M, Birch C, Swaby C, Ross S. Five cases of tape erosion after transobturator surgery for urinary incontinence. Obstet Gynecol 2006;107(2 Pt 2):472-4. http://www.ncbi.nlm.nih.gov/pubmed/16449154 Hammad FT, Kennedy-Smith A, Robinson RG. Erosions and urinary retention following polypropylene synthetic sling: Australasian survey. Eur Urol 2005;47(5):641-6; discussion 646-7. http://www.ncbi.nlm.nih.gov/pubmed/15826756 Giri SK, Drumm J, Flood HD. Endoscopic holmium laser excision of intravesical tension-free vaginal tape and polypropylene suture after anti-incontinence procedures. J Urol 2005;174(4 Pt 1):1306-7. http://www.ncbi.nlm.nih.gov/pubmed/16145408 Vervest HA, Bongers MY, van der Wurff AA. Nerve injury: an exceptional cause of pain after TVT. Int Urogynecol J Pelvic Floor Dysfunct 2006;17(6):665-7. http://www.ncbi.nlm.nih.gov/pubmed/16633884 Shah SM, Bukkapatnam R, Rodríguez LV. Impact of vaginal surgery for stress urinary incontinence on female sexual function: is the use of polypropylene mesh detrimental? Urology 2005;65(2):270-4. http://www.ncbi.nlm.nih.gov/pubmed/15708036 Babalola EO, Famuyide AO, McGuire LJ, Gebhart JB, Klingele CJ. Vaginal erosion, sinus formation, and ischiorectal abscess following transobturator tape: ObTape implantation. Int Urogynecol J Pelvic Floor Dysfunct 2006;17(4):418-21. http://www.ncbi.nlm.nih.gov/pubmed/16186998 Benassi G, Marconi L, Accorsi F, Angeloni M, Benassi L. Abscess formation at the ischiorectal fossa 7 months after the application of a synthetic transobturator sling for stress urinary incontinence in a type II diabetic woman. Int Urogynecol J Pelvic Floor Dysfunct 2007;18(6):697-9. http://www.ncbi.nlm.nih.gov/pubmed/17333445 Busby G, Broome J. Necrotising fasciitis following unrecognised bladder injury during transobturator sling procedure. BJOG 2007;114(1):111-2. http://www.ncbi.nlm.nih.gov/pubmed/17233867 Deffieux X, Donnadieu AC, Mordefroid M, Levante S, Frydman R, Fernandez H. Prepubic and thigh abscess after successive placement of two suburethral slings. Int Urogynecol J Pelvic Floor Dysfunct 2007;18(5):571-4. http://www.ncbi.nlm.nih.gov/pubmed/16832590 Goldman HB. Large thigh abscess after placement of synthetic transobturator sling. Int Urogynecol J Pelvic Floor Dysfunct 2006;17(3):295-6. http://www.ncbi.nlm.nih.gov/pubmed/15986099 Hurtado EA, McCrery RJ, Appell RA. Complications of ethylene vinyl alcohol copolymer as an off-label intra-urethral bulking agent in men with atress urinary incontinence. SUFU 2007. http://www.urotoday.com/48/browse_categories/stress_urinary_incontinence_sui/sufu_2007__ complications_of_ethylene_vinyl_alcohol_copolymer_as_an_offlabel_intraurethral_bulking_agent_in_ men_with_stress_urinary_incontinence.html Hurtado EA, McCrery RJ, Appell RA. Complications of ethylene vinyl alcohol copolymer s an intraurethral bulking agent in men with stress urinary incontinence. Urology 2008;71(4):662-5. http://www.ncbi.nlm.nih.gov/pubmed/18279931 Juang CM, Yu KJ, Chou P, Yen MS, Twu NF, Horng HC, Hsu WL. Efficacy analysis of trans-obturator tension-free vaginal tape (TVT-O) plus modified Ingelman-Sundberg procedure versus TVT-O alone in the treatment of mixed urinary incontinence: a randomized study. Eur Urol 2007;51(6):1671-8; discussion 1679. http://www.ncbi.nlm.nih.gov/pubmed/17254697 Atala A, Bauer SB, Soker S, Yoo JJ, Retik AB. Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet 2006;367(9518):1241-6. http://www.ncbi.nlm.nih.gov/pubmed/16631879 Hijaz A, Vasavada SP, Daneshgari F, Frinjari H, Goldman H, Rackley R. Complications and troubleshooting of two-stage sacral neuromodulation therapy: a single-institution experience. Urology 2006;68(3):533-7. http://www.ncbi.nlm.nih.gov/pubmed/16979724

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Van Kerrebroeck PE, van Voskuilen AC, Heesakkers JP, Lycklama á Nijholt AA, Siegel S, Jonas U, Fowler CJ, Fall M, Gajewski JB, Hassouna MM, Cappellano F, Elhilali MM, Milam DF, Das AK, Dijkema HE, van den Hombergh U. Results of sacral neuromodulation therapy for urinary voiding dysfunction: outcomes of a prospective, worldwide clinical study. J Urol 2007;178(5):2029-34. http://www.ncbi.nlm.nih.gov/pubmed/17869298 Van Voskuilen AC, Oerlemans DJ, Weil EH, de Bie RA, van Kerrebroeck PE. Long term results of neuromodulation by sacral nerve stimulation for lower urinary tract symptoms: a retrospective single center study. Eur Urol 2006;49(2):366-72. http://www.ncbi.nlm.nih.gov/pubmed/16413105 Brazzelli M, Murray A, Fraser C. Efficacy and safety of sacral nerve stimulation for urinary urge incontinence: a systematic review. J Urol 2006;175(3 Pt 1):835-41. http://www.ncbi.nlm.nih.gov/pubmed/16469561 Han DH, Jeong YS, Choo MS, Lee KS. Outcomes of surgery of female urethral diverticula classified using magnetic resonance imaging. Eur Urol 2007;51(6):1664-70. http://www.ncbi.nlm.nih.gov/pubmed/17335961 Ljungqvist L, Peeker R, Fall M. Female urethral diverticulum: 26-year followup of a large series. J Urol 2007;177(1):219-24; discussion 224. http://www.ncbi.nlm.nih.gov/pubmed/17162049 Karantanis E, Allen W, Stevermuer TL, Simons AM, O’Sullivan R, Moore KH. The repeatability of the 24-hour pad test. Int Urogynecol J Pelvic Floor Dysfunct 2005;16(1):63-8; discussion 68. http://www.ncbi.nlm.nih.gov/pubmed/15647965 Dylewski DA, Jamison MG, Borawski KM, Sherman ND, Amundsen CL, Webster GD. A statistical comparison of pad numbers versus pad weights in the quantification of urinary incontinence. Neurourol Urodyn 2007;26(1):3-7. http://www.ncbi.nlm.nih.gov/pubmed/17080415 Wyrwich KW, Bullinger M, Aaronson N, Hays RD, Patrick DL, Symonds T; The Clinical Significance Consensus Meeting Group. Estimating clinically significant differences in quality of life outcomes. Qual Life Res 2005;14(2):285-95. http://www.ncbi.nlm.nih.gov/pubmed/15892420 Yalcin I, Patrick DL, Summers K, Kinchen K, Bump RC. Minimal clinically important differences in Incontinence Quality-of-Life scores in stress urinary incontinence. Urology 2006;67(6):1304-8. http://www.ncbi.nlm.nih.gov/pubmed/16750246 Hendriks MR, Evers SM, Bleijlevens MH, van Haastregt JC, Crebolder HF, van Eijk JT. Costeffectiveness of a multidisciplinary fall prevention program in community-dwelling elderly people: a randomized controlled trial (ISRCTN 64716113). Int J Technol Assess Health Care 2008;24(2):193-202. http://www.ncbi.nlm.nih.gov/pubmed/18400123 Brazier, J. Measuring and valuing mental health for use in economic evaluation. J Health Serv Res Policy 2008;13 Suppl 3:70-5. http://www.ncbi.nlm.nih.gov/pubmed/18806195 Ghoniem G, Stanford E, Kenton K, Achtari C, Goldberg R, Mascarenhas T, Parekh M, Tamussino K, Tosson S, Lose G, Petri E. Evaluation and outcome measures in the treatment of female urinary stress incontinence: International Urogynecological Association (IUGA) guidelines for research and clinical practice. Int Urogynecol J Pelvic Floor Dysfunct 2008;19(1):5-33. http://www.ncbi.nlm.nih.gov/pubmed/18026681 Ngninkeu BN, van Heugen G, di Gregorio M, Debie B, Evans A. Laparoscopic artificial urinary sphincter in women for type III incontinence: preliminary results. Eur Urol 2005;47(6):793-7; discussion 797. http://www.ncbi.nlm.nih.gov/pubmed/15925075 Shaikh S, Ong EK, Glavind K, Cook J, N’Dow JM. Mechanical devices for urinary incontinence in women. Cochrane Database Syst Rev 200619;(2):CD001756. http://www.ncbi.nlm.nih.gov/pubmed/16625547

An exhaustive reference list is available for consultation on line at the society website (http://www.uroweb.org/ professional-resources/guidelines/) and on the guidelines CD-rom version.

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6. URINARY INCONTINENCE IN FRAIL / OLDER MEN AND WOMEN* Healthy older persons should be offered a similar range of treatment options as younger persons. Frail / older persons, however, require a different approach. Their evaluation must address the potential role of co-morbidity, current medications (prescribed, over-the-counter, and/or naturopathic), and functional and/or cognitive impairment for the management of UI. Studies and intervention in frail / older people should consider the degree of bother to the patient and/or carer, their goals for care, level of co-operation, and the overall prognosis and life expectancy. Effective management to meet the goals of care should be possible for most frail elderly persons.

6.1

History and symptom assessment

6.1.1 General principles Because frail / older men and women have a very high prevalence of UI, active case finding and screening for UI should be done in all frail / older persons (grade of recommendation: A). The history should identify co-morbid conditions and medications likely to cause or worsen UI. Recommendations for evaluation Recommendations GR Rectal examination for faecal loading or impaction C Functional assessment (mobility, transfers, manual dexterity, ability to successfully toilet A Screening test for depression B Cognitive assessment to assist in planning management C GR = grade of recommendation The mnemonic DIAPPERS (Delirium, Infection, Atrophic vaginitis, Pharmaceuticals, Psychological condition, Excess urine output, Reduced mobility, Stool impaction) includes some co-morbid conditions and factors to be considered. Two alterations from the original mnemonic should be noted; they are: • atrophic vaginitis does not by itself cause UI and should not be treated solely for the purpose of decreasing UI alone (grade of recommendation: B). • current consensus criteria for diagnosis of UTIs are both poorly sensitive and non-specific in nursinghome residents (level of evidence: 2). The patient and/or their carer should be asked directly about: • the degree of bother of UI (grade of recommendation: B). • goals for UI care (dryness, specific decrease in symptom severity, quality of life, reduction of co-morbidity, decreased care burden) (grade of recommendation: B). • the likely level of co-operation with management (grade of recommendation: C). It is also important to consider the patient’s overall prognosis and remaining life expectancy (grade of recommendation: C). All patients must be screened for haematuria (grade of recommendation: C), as it is not known if treatment of otherwise asymptomatic bacteriuria and pyuria is beneficial (no recommendation possible). Such treatment may cause harm by increasing the risk of antibody resistance and causing severe adverse effects, such as Clostridium difficile colitis (grade of recommendation: C). There is insufficient evidence to recommend a clinical stress test in frail / older persons. 6.1.2 Nocturia For frail / older people with bothersome nocturia, assessment should focus on identifying the potential underlying cause(s), including (grade of recommendation: C): • nocturnal polyuria • primary sleep problem (including sleep apnoea) • conditions resulting in a low voided volumes (e.g. elevated post-voiding residual) co-morbidity. A bladder diary (frequency-volume chart) or wet checks may be useful in the evaluation of patients with nocturia (grade of recommendation: C). Wet checks can be used to assess UI frequency in long-term care residents (grade of recommendation: C). * This section of the guidelines focuses on frail / older men and women. It has been based on the recommendations of the ICI committee chaired by Catherine Dubeau.

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Update march 2009

6.1.3 Post-void residual (PVR) volume A post-void residual volume (PVR) is impractical to obtain in many care settings. However, there is compelling clinical experience for measuring PVR in selected frail / older persons with: • diabetes mellitus (especially if longstanding) • prior episodes of urinary retention or history of high PVR • recurrent UTIs • medications that impair bladder emptying (e.g. anticholinergics) • chronic constipation • persistent or worsening UI despite treatment with antimuscarinics • prior urodynamic study demonstrating detrusor underactivity and/or bladder outlet obstruction (grade of recommendation: C). Treatment of co-existing conditions (e.g. constipation) and stopping anticholinergic drugs may reduce PVR. There is no consensus regarding what constitutes ‘high’ PVR in any population. A trial of catheter decompression may be considered in patients with PVR > 200–500 mL, in whom high PVR may be a major contributor to UI or bothersome frequency (grade of recommendation: C).

6.2

Clinical diagnosis

The most common types of UI in frail / older persons are urgency UI, stress UI, and mixed UI (in frail / older women). Frail / older persons with urgency UI often have concomitant detrusor underactivity with an elevated PVR in the absence of outlet obstruction, a condition called detrusor hyperactivity with impaired contractility during voiding (DHIC). There is no published evidence that antimuscarinics are less effective or cause retention in persons with DHIC (no recommendation possible).

6.3

Initial management

Initial treatment should be individualised and influenced by goals of care, treatment preferences, and estimated remaining life expectancy, as well as the most likely clinical diagnosis (grade of recommendation: C). In some patients, it is important to recognise that contained UI (e.g. managed with pads) may be the only possible outcome for UI that persists after treatment of contributing co-morbidity and other factors. This is especially true for frail persons with no or minimal mobility (i.e. require the help of at least two persons to transfer), advanced dementia (i.e. unable to state their own name), and/or nocturnal UI. Conservative and behavioural therapies for UI include: • lifestyle changes (grade of recommendation: C) • bladder training in fit or alert patients (grade of recommendation: B) • prompted voiding for frail and cognitively impaired patients (grade of recommendation: A). For selected, cognitively intact, frail persons, pelvic muscle exercises may be considered, but they have not been well studied in this population (grade of recommendation: C). 6.3.1 Drug therapy Any drug treatment should be started with a low dose and titrated with regular review, until the desired improvement has been achieved or there are adverse effects. Recommendations for drug therapy in frail / older men and women with UI Recommendations GR • A trial of antimuscarinic drugs may be considered as an adjunct to conservative therapy of UUI A-C, depending on agent •S  imilarly, alpha-blockers may be cautiously considered in frail men with suspected outlet C obstruction from prostate disease •B  ecause DDAVP (vasopressin) carries a high risk of clinically significant hyponatraemia, it A should not be used in frail / older persons to treat nocturia or nocturnal polyuria GR = grade of recommendation

6.4

Ongoing management and reassessment

Urinary incontinence can usually be managed successfully using a combination of the above approaches. However, if initial management does not provide sufficient improvement in UI, then the next step should be to reassess the patient for contributing co-morbidity and/or functional impairment and to treat it.

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6.5

Specialised management

Specialist referral should be considered if the initial assessment finds that a frail / older person with UI has: • Other significant factors (e.g. pain, haematuria) • UI symptoms that cannot be classified as urgency, stress, or mixed incontinence, or other complicated co-morbidity, which the primary clinician is unable to address (e.g. dementia, functional impairment) • An insufficient response to initial management. The type of specialist will depend on local resources and the reason for referral. Surgical specialists could include urologists or gynaecologists. Patients with functional impairment could be referred to a geriatrician or physical therapist. Continence nurse specialists may be helpful for homebound patients. The decision to refer a patient should take into account the goals of care, patient/carer’s desire for invasive therapy, and estimated life expectancy. 6.5.1 Surgical approaches to UI in frail / older men and women Age itself is not a contraindication to incontinence surgery (grade of recommendation: C). Before surgery is considered, all patients should undergo the following. Recommendations for patient care prior to surgery Recommendations GR • Evaluation and treatment for any co-morbidity, medications and cognitive and/or functional C impairment that may be contributing to UI and/or could compromise the outcome of the planned surgery. For example, artificial sphincter should not be placed in men with dementia, who cannot manage the device on their own • An adequate trial of conservative therapy followed by reassessment of the need for surgery C • A discussion with the patient and/or carer to make sure that the anticipated surgical outcome is C consistent with the preferred goals of care in the context of the patient’s remaining life expectancy • Urodynamic testing because the clinical diagnosis may be inaccurate B • Pre-operative assessment and peri-operative care to establish risks for, and to minimise, common post-operative complications in the elderly, such as: - delirium and infection A - dehydration and falls C GR = grade of recommendation Figure 5: Management of UI in the frail / older men and women

   

               

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





 

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  

  

   



              

 







       

     



   



  

 s 

 

46

 

Update march 2009

6.6 REFERENCES* •

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Baztan JJ, Arias E, Gonzalez N, de Prada MIR. New-onset urinary incontinence and rehabilitation outcomes in frail older patients. Age Ageing 2005;34(2):172-5. http://www.ncbi.nlm.nih.gov/pubmed/15713862 Morrison A, Levy R. Fraction of Nursing Home Admissions Attributable to Urinary Incontinence: Value in Health. Blackwell Publishing Ltd, 2006, vol. 9, pp. 272-274. Boyington J, Howard D, Carter-Edwards L, Gooden K, Erdem N, Jallah Y, Busby-Whitehead J. Differences in resident characteristics and prevalence of urinary incontinence in nursing homes in the southeastern United States. Nurs Res 2007;56(2):97-107. http://www.ncbi.nlm.nih.gov/pubmed/17356440 Anger JT, Saigal CS, Pace J, Rodríguez LV, Litwin MS. True prevalence of urinary incontinence among female nursing home residents. Urology 2006;67(2):281-7. http://www.ncbi.nlm.nih.gov/pubmed/16461078 Inouye SK, Studenski S, Tinetti ME, Kuchel GA. Geriatric syndromes: clinical, research, and policy implications of a core geriatric concept. J Am Geriatr Soc 2007;55(5):780-91. http://www.ncbi.nlm.nih.gov/pubmed/17493201 Dubeau CE. Beyond the bladder: management of urinary incontinence in older women. Clin Obstet Gynecol 2007;50(3):720-34. http://www.ncbi.nlm.nih.gov/pubmed/17762420 Griffiths D, Derbyshire S, Stenger A, Resnick N. Brain control of normal and overactive bladder. J Urol 2005;174:1862-7. Tadic SD, Griffiths D, Schaefer W, Resnick NM. Abnormal connections in the supraspinal bladder control network in women with urge urinary incontinence. Neuroimage 2008;39(4):1647-53. http://www.ncbi.nlm.nih.gov/pubmed/18089297 Griffiths D, Tadic SD. Bladder control, urgency, and urge incontinence: Evidence from functional brain imaging. Neurourol Urodyn 2007. Andrews-Hanna JR, Snyder AZ, Vincent JL, Lustig C, Head D, Raichle ME, Buckner RL. Disruption of large-scale brain systems in advanced aging. Neuron 2007;56(5):924-35. http://www.ncbi.nlm.nih.gov/pubmed/18054866 Pfisterer MH, Griffiths DJ, Schaefer W, Resnick NM. The effect of age on lower urinary tract function: a study in women. J Am Geriatr Soc 2006;54(3):405-12. http://www.ncbi.nlm.nih.gov/pubmed/16551306 Taylor JA, III, Kuchel GA. Detrusor underactivity: Clinical features and pathogenesis of an underdiagnosed geriatric condition. J Am Geriatr Soc 2006;54(12):1920-32. http://www.ncbi.nlm.nih.gov/pubmed/17198500 Taylor J, III. Null mutation for macrophage migration inhibitory factor (MIF) is associated with less aggressive bladder cancer in mice. BMC Cancer 2007;7:135. http://www.ncbi.nlm.nih.gov/pubmed/17650334 Pfisterer MH, Griffiths DJ, Rosenberg L, Schaefer W, Resnick NM. The impact of detrusor overactivity on bladder function in younger and older women. J Urol 2006;175(5):1777-83. http://www.ncbi.nlm.nih.gov/pubmed/16600758 Yang J, Yang SH. Huang WC. Functional correlates of Doppler flow study of the female urethral vasculature. Ultrasound in Obstet Gynecol 2006;28(1):96-102. http://www.ncbi.nlm.nih.gov/pubmed/16758440 Siracusano S: Bertolotto M. Cucchi A. Lampropoulou N. Tiberio A. Gasparini C. Ciciliato S. Belgrano E. Application of ultrasound contrast agents for the characterization of female urethral vascularization in healthy pre- and postmenopausal volunteers: preliminary report. Eur Urol 2006;50(6):1316-22. http://www.ncbi.nlm.nih.gov/pubmed/16831513 Liang C: Chang SD. Chang YL. Wei TY. Wu HM. Chao AS. Three-dimensional power Doppler measurement of perfusion of the periurethral tissue in incontinent women -- a preliminary report. Acta Obstet Gynecol Scand 2006;85(5):608-13. http://www.ncbi.nlm.nih.gov/pubmed/16752242 Clobes A: DeLancey JO. Morgan DM. Urethral circular smooth muscle in young and old women. Am J Obstet Gynecol 2008;198(5):587.e1-e5. Trowbridge ER: Wei JT. Fenner DE. Ashton-Miller JA. Delancey JO. Effects of aging on lower urinary tract and pelvic floor function in nulliparous women. Obstet Gynecol 2007;109(3):715-20. http://www.ncbi.nlm.nih.gov/pubmed/17329525 Kenton K: Lowenstein L. Simmons J. Brubaker L. Aging and overactive bladder may be associated with loss of urethral sensation in women. Neurourol Urodyn 2007;26(7):981-4.

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Kenton K: Simmons J. FitzGerald MP. Lowenstein L. Brubaker L. Urethral and bladder current perception thresholds: normative data in women. J Urol 2007;178(1):189-92;discussion192. http://www.ncbi.nlm.nih.gov/pubmed/17499783 Lawrence J: Lukacz ES. Nager CW. Hsu JW. Luber KM. Prevalence and co-occurrence of pelvic floor disorders in community-dwelling women. Obstet Gynecol 2008;111(3):678-85. Talasz H, Himmer-Perschak G. Marth E. Fischer-Colbrie J. Hoefner E. Lechleitner M. Evaluation of pelvic floor muscle function in a random group of adult women in Austria. Int Urogynecol J 2008;19(1):131-5. http://www.ncbi.nlm.nih.gov/pubmed/17876492 Jundt K, Kiening M, Fischer P, Bergauer F, Rauch E, Janni W, Peschers U, Dimpfl T. Is the histomorphological concept of female pelvic floor and its changes due to age and vaginal delivery correct? Neurourol Urodyn 2005;24(1):44-50. http://www.ncbi.nlm.nih.gov/pubmed/15573382 Fox J: Fletcher JG. Zinsmeister AR. Seide B. Riederer SJ. Bharucha AE. Effect of aging on anorectal and pelvic floor functions in females. Dis Colon Rectum 2006;49(11):1726-35. Pal L, Hailpern SM. Santoro NF. Freeman R. Barad D. Kipersztok S. Barnabei VM. WassertheilSmoller S. Association of pelvic organ prolapse and fractures in postmenopausal women: analysis of baseline data from the Women’s Health Initiative Estrogen Plus Progestin trial. Menopause 2008;15(1):59-66. http://www.ncbi.nlm.nih.gov/pubmed/18257143 Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, Hulley S, Herd A, Khan S, Newby LK, Waters D, Vittinghoff E, Wenger N; HERS Research Group. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2008;288;49-57. http://www.ncbi.nlm.nih.gov/pubmed/12090862 Tan J: Lukacz ES. Menefee SA. Luber KM. Albo ME. Nager CW. Determinants of vaginal length. Am J Obstet Gynecol 2006;195(6):1846-50. Mishra V, Allen DJ. Nicolaou C. Sharif H. Hudd C. Karim OM. Motiwala HG. Laniado ME. Does intraprostatic inflammation have a role in the pathogenesis and progression of benign prostatic hyperplasia? BJU Int 2007;100(2):327-31. http://www.ncbi.nlm.nih.gov/pubmed/17617139 Juthani-Mehta M, Tinetti M, Perrelli E, Towle V, Van Ness P, Quagliarello V. Diagnostic accuracy of criteria for urinary tract infection in a cohort of nursing home residents. J Am Geriatr Soc 2007;55(7):1072-7. http://www.ncbi.nlm.nih.gov/pubmed/17608881 Cigolle CT, Langa KM, Kabeto MU, Zhiyi T and Blaum CS: Geriatric Conditions and Disability: The Health and Retirement Study. Ann Intern Med 2007;147(3):156-64. http://www.ncbi.nlm.nih.gov/pubmed/17679703 Rait G, Fletcher A, Smeeth L, Brayne C, Stirling S, Nunes M, Breeze E, Ng ES, Bulpitt CJ, Jones D, Tulloch AJ. Prevalence of cognitive impairment: results from the MRC trial of assessment and management of older people in the community. Age Ageing 2005;34(3):242-8. http://www.ncbi.nlm.nih.gov/pubmed/15863409 Mecocci P, von Strauss E, Cherubini A, Ercolani S, Mariani E, Senin U, Winblad B, Fratiglioni L. Cognitive impairment is the major risk factor for development of geriatric syndromes during hospitalization: results from the GIFA study. Dement Geriatr Cogn Disord 2005;20(4):262-9. http://www.ncbi.nlm.nih.gov/pubmed/16103670 Huang A, Brown J, Thom D, Fink H, Yaffe K. Study of Osteoporotic Fractures Research Group. Urinary incontinence in older community-dwelling women: the role of cognitive and physical function decline. Obstet Gynecol 2007;109(4):909-16. http://www.ncbi.nlm.nih.gov/pubmed/17400853 Pantoni L: Leukoaraiosis: from an ancient term to an actual marker of poor prognosis. Stroke 2008;39:1401-3. http://www.ncbi.nlm.nih.gov/pubmed/18340098 Pantoni L, Garcia JH. The significance of cerebral white matter abnormalities 100 years after Binswanger’s report. A review. Stroke 2005;26(7):1293-301. http://www.ncbi.nlm.nih.gov/pubmed/7604429 Wullner U, T. Schmitz-Hubsch GA, R. Fimmers, A. Spottke, W. H.Oertel, G. Deuschl TK, K. Eggert on behalf of the KNP e.V. Autonomic dysfunction in 3414 Parkinson’s disease patients enrolled in the German Network on Parkinson’s disease (KNP e.V.): the effect of ageing. Eur J Neurol 2007;14: 1405–8.

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Balash Y, Peretz C, Leibovich G, Herman T, Hausdorff J, Giladi N. Falls in outpatients with Parkinson’s disease. J Neurol 2005;252:1310-5. http://www.ncbi.nlm.nih.gov/pubmed/15895303 Fultz NH, Rahrig Jenkins K, Østbye T, Taylor JDH, Kabeto MU and Langa KM: The impact of own and spouse’s urinary incontinence on depressive symptoms. Soc Sci Med 2005;60:2537-48. http://www.ncbi.nlm.nih.gov/pubmed/15814179 Yoshida Y, Kim H, Iwasa H, Kwon J, Sugiura M, Furuna T, Yoshida H and Suzuki T: Prevalence and characteristics of urinary incontinence in community-dwelling-elderly as determined by comprehensive health examination and interview for the prevention of geriatric syndrome and bedridden state. Nippon Ronen Igakkai Zasshi 2007;44:83-9. http://www.ncbi.nlm.nih.gov/pubmed/17337859 Song H and Bae J: Prevalence of urinary incontinence and lower urinary tract symptoms for community-dwelling elderly 85 years of age and older. J Wound Ostomy Continence Nurs 2007;34: 535-41. http://www.ncbi.nlm.nih.gov/pubmed/17876216 Ko Y, Lin S, Salmon J and Bron M: The impact of urinary incontinence on quality of life of the elderly. Am J Managed Care 2005;11(4 Suppl):S103-S111. http://www.ncbi.nlm.nih.gov/pubmed/16161383 Nelson RL and Furner SE: Risk factors for the development of fecal and urinary incontinence in Wisconsin nursing home residents. Maturitas 2005;52:26-31. http://www.ncbi.nlm.nih.gov/pubmed/16143223 Landi F, Onder G, Cesari M, Zamboni V, Russo A, Barillaro C and Bernabei R: The Silvernet-HC study group. Functional decline in frail community-dwelling stroke patients. J Neurol 2006;13:17-23. http://www.ncbi.nlm.nih.gov/pubmed/16420389 Takazawa K and Arisawa K: Relationship between the type of urinary incontinence and falls among frail elderly women in Japan. J Med Invest 2005;52:165-71. http://www.ncbi.nlm.nih.gov/pubmed/16167534 Chen JS, March LM, Schwarz J, Zochling J, Makaroff J, Sitoh YY, Lau TC, Lord SR, Cameron ID, Cumming RG, Sambrook PN. A multivariate regression model predicted falls in residents living in intermediate hostel care. J Clinical Epidemiol 2005;58: 503-8. http://www.ncbi.nlm.nih.gov/pubmed/15845337 Becker C, Loy S, Sander S, Nikolaus T, Rissmann U and Kron M: An algorithm to screen long-term care residents at risk for accidental falls. Aging Clin Exp Res 2005;17:186-92. http://www.ncbi.nlm.nih.gov/pubmed/16110730 Woodford H and George J: NICE guidelines on urinary incontinence in women. Age Ageing 2007;36:349-50. DuBeau CE, Ouslander JG and Palmer MH: Knowledge and attitudes of nursing home staff and surveyors about the revised federal guidance for incontinence care. Gerontologist 2007;47:468-79. http://www.ncbi.nlm.nih.gov/pubmed/17766668 Fung C, Spencer B, Eslami M and Crandall C: Quality indicators for the screening and care of urinary incontinence in vulnerable elders. J Am Geriatr Soc 2007;55 Suppl 2:S443-S449. http://www.ncbi.nlm.nih.gov/pubmed/17910569 Wagg A, Potter J, Irwin P, Lowe D, Pearson M. National audit of continence care for older people: management of urinary incontinence. Age Ageing 2008;37:39–44. Wagg A, Mian S, Lowe D, Potter J, Pearson M. National audit of continence care for older people: results of a pilot study. J Eval Clin Pract 2005;11:525-32. http://www.ncbi.nlm.nih.gov/pubmed/16364105 van Gerwen M and Lagro-Janssen A. Diagnostic value of patient history and physical examination in elderly patients with urinary incontinence; a literature review [De diagnostische waarde van anamnese en lichamelijk onderzoek bij ouderen met urine-incontinentie; een overzicht van de literatuur]. Ned Tijdschr Geneeskd 2006;150:1771-5. [article in Dutch] Jansen L and Forbes D: The psychometric testing of a urinary incontinence nursing assessment instrument. J Wound Ostomy Continence Nurs 2006;33(1):69-76. http://www.ncbi.nlm.nih.gov/pubmed/16444108 Ouslander JG, Griffiths PC, McConnell E, Riolo L, Kutner M and Schnelle J: Functional incidental training: a randomized, controlled, crossover trial in Veterans Affairs nursing homes. J Am Geriatr Soc 2005 Jul;53(7):1091-100. http://www.ncbi.nlm.nih.gov/pubmed/16108924 DuBeau C, Simon S, Morris JN. The Impact of urinary incontinence on quality of life in nursing home residents, 2006.

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Fonda D, Abrams P. Cure sometimes, help always--a “continence paradigm” for all ages and conditions. Neurourol Urodyn 2006;25(3):290-2. http://www.ncbi.nlm.nih.gov/pubmed/16496393 Cai L, Lubitz J. Was there compression of disability for older Americans from 1992 to 2003? Demography 2007;44(3):479-95. http://www.ncbi.nlm.nih.gov/pubmed/17913007 Kincade JE, Dougherty MC, Carlson JR, Hunter GS and Busby-Whitehead J: Randomized clinical trial of efficacy of self-monitoring techniques to treat urinary incontinence in women. Neurourol Urodyn 2007;26(4):507-11. http://www.ncbi.nlm.nih.gov/pubmed/17366526 Townsend MK, Curhan GC, Resnick NM, Grodstein F. BMI, Waist Circumference, and Incident Urinary Incontinence in Older Women. Obesity (Silver Spring) 2008;16(4):881-6. http://www.ncbi.nlm.nih.gov/pubmed/18379564 Perrin L, Dauphinee SW, Corcos J, Hanley JA and Kuchel GA: Pelvic floor muscle training with biofeedback and bladder training in elderly women: a feasibility study. J Wound Ostomy Continence Nurs 2005;32(3):186-99. http://www.ncbi.nlm.nih.gov/pubmed/15931150 Palmer MH: Effectiveness of prompted voiding for incontinent nursing home residents. In: Melnyk BM, Fineout-Overholt E, eds. Evidence-based practice in nursing & healthcare: a guide to the best practice. Lippincott Williams & Williams, 2005, pp CD20-CD30. Ostaszkiewicz J. A clinical nursing leadership model for enhancing continence care for older adults in a subacute inpatient care setting. J Wound Ostomy Continence Nurs 2006;33(6):624-9. http://www.ncbi.nlm.nih.gov/pubmed/17108772 Ostaszkiewicz J, Roe B and Johnston L. Effects of timed voiding for the management of urinary incontinence in adults: systematic review. J Adv Nurs 2005;52(4):420-31. http://www.ncbi.nlm.nih.gov/pubmed/16268846 van Houten P, Achterberg W, Ribbe M. Urinary incontinence in disabled elderly women: a randomized clinical trial on the effect of training mobility and toileting skills to achieve independent toileting. Gerontology 2007;53(4):205-10. http://www.ncbi.nlm.nih.gov/pubmed/17347567 Campeau L, Tu L, Lemieux M, Naud A, Karsenty G, Schick E, Corcos J. A multicenter, prospective, randomized clinical trial comparing tension-free vaginal tape surgery and no treatment for the management of stress urinary incontinence in elderly women. Neurourol Urodyn 2007;26(7):990-4. http://www.ncbi.nlm.nih.gov/pubmed/17638307 Dalpiaz O, Primus G, Schips L. SPARC sling system for treatment of female stress urinary incontinence in the elderly. Eur Urol 2006;50(4):826-30; discussion 830-1. http://www.ncbi.nlm.nih.gov/pubmed/16687203 Britton A, Russell R. Multidisciplinary team interventions for delirium in patients with chronic cognitive impairment. Cochrane Database Syst Rev 2007;(2):CD000395. http://www.ncbi.nlm.nih.gov/pubmed/17636635 Cathcart P, van der Meulen J, Armitage J, Emberton M. Incidence of primary and recurrent acute urinary retention between 1998 and 2003 in England. J Urol 2006;176(1):200-4; discussion 204. http://www.ncbi.nlm.nih.gov/pubmed/16753401 Gehrich A: Stany MP. Fischer JR. Buller J. Zahn CM. Establishing a mean postvoid residual volume in asymptomatic perimenopausal and postmenopausal women. Obstet Gynecol 2007;110(4):827-32. http://www.ncbi.nlm.nih.gov/pubmed/17906016 Tang MWS, Kwok TCY, Hui E, Woo J. Intermittent versus indwelling urinary catheterization in older female patients. Maturitas 2006;53:274-281. Wu J, Baguley IJ. Urinary Retention in a General Rehabilitation Unit: Prevalence, Clinical Outcome, and the Role of Screening. Arch Phys Med Rehabil 2005 Sep;86(9):1772-7. http://www.ncbi.nlm.nih.gov/pubmed/16181941 Haylen B, Krishnan S, Schulz S, Verity L, Law M, Zhou J, Sutherst J. Has the true prevalence of voiding difficulty in urogynecology patients been underestimated? Int Urogynecol J Pelvic Floor Dysfunct 2007;18(1):53-6. Epub 2006. http://www.ncbi.nlm.nih.gov/pubmed/16596458 Lukacz E: DuHamel E. Menefee SA. Luber KM. Elevated postvoid residual in women with pelvic floor disorders: prevalence and associated risk factors. Int Urogynecol J Pelvic Floor Dysfunct 2007;18(4):397-400. Epub 2006. http://www.ncbi.nlm.nih.gov/pubmed/16804634 Pilloni S, Krhut J, Mair D, Madersbacher H, Kessler TM. Intermittent catheterisation in older people: a

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valuable alternative to an indwelling catheter? Age Ageing 2005;34(1):57-60. http://www.ncbi.nlm.nih.gov/pubmed/15537679 Omli R: Skotnes LH. Mykletun A. Bakke AM. Kuhry E. Residual urine as a risk factor for lower urinary tract infection: a 1-year follow-up study in nursing homes. J Am Geriatr Soc 2008;56(5):871-4. http://www.ncbi.nlm.nih.gov/pubmed/18331294 Cohen R, Wilkins KM, Ostroff R, Tampi RR. Olanzapine and acute urinary retention in two geriatric patients. Am J Geriatr Pharmacother 2007;5(3):241-6. http://www.ncbi.nlm.nih.gov/pubmed/17996664 Semaan W, Doyon J, Jolicoeur F, Duchesneau J. Dose-dependent urinary retention following olanzapine administration. Ann Pharmacother 2006;40(9):1693. http://www.ncbi.nlm.nih.gov/pubmed/16896022 Matsumoto M, Inoue K. Predictors of institutionalization in elderly people living at home: the impact of incontinence and commode use in rural Japan. J Cross Cult Gerontol 2007;22(4):421-32. http://www.ncbi.nlm.nih.gov/pubmed/17763930

An exhaustive reference list is available for consultation on line at the society website (http://www.uroweb.org/ professional-resources/guidelines/) and on the guidelines CD-rom version.

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7. ABBREVIATIONS USED IN THE TEXT This list is not comprehensive for the most common abbreviations.

AUS artificial urinary sphincter CaP cancer of the prostate CS Caesarean section BF biofeedback BOO bladder outlet obstruction BPO benign prostatic obstruction BT bladder training COX inhibitor cyclo-oxygenase inhibitor DHIC detrusor hyperactivity with impaired contractility during voiding DIAPPERS Delirium, Infection, Atrophic vaginitis, Pharmaceuticals, Psychological condition, Excess urine output, Reduced mobility, Stool impaction DO detrusor overactivity EStim electrical stimulation GR grade of recommendation (modified Oxford system) HIFU high-intensity focused ultrasound LE level of evidence (modified Oxford system) MStim magnetic stimulation MUI mixed urinary incontinence OAB overactive bladder PFMT pelvic floor muscle training PDE-5 inhibitor phosphodiesterase-type 5 inhibitor POP pelvic organ prolapse PVR post-void residual (urine) QoL Quality of Life RCT randomised controlled trial RP radical prostatectomy SUI stress urinary incontinence TURP transurethral resection of prostate TUIP transurethral incision of the prostate (TUIP) UPP urethral pressure profile UUI urgency urinary incontinence UTI urinary tract infection VC vaginal cones

Conflict of interest All members of the Incontinence Guidelines writing panel have provided disclosure statements on all relationships that they have and that might be perceived to be a potential source of conflict of interest. This information is kept on file in the European Association of Urology Central Office database. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

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Guidelines on

Urological Infections M. Grabe (Chairman), M.C. Bishop, T.E. Bjerklund-Johansen, H. Botto, M. Çek, B. Lobel, K.G. Naber, J. Palou, P. Tenke, F. Wagenlehner

© European Association of Urology 2009

TABLE OF CONTENTS

page

1. INTRODUCTION 1.1 Pathogenesis of urinary tract infections 1.2 Microbiological and other laboratory findings 1.3 Classification of urological infections 1.4 Aim of guidelines 1.5 Methods 1.6 Level of evidence and grade of guideline recommendation 1.7 References 2. UNCOMPLICATED URINARY TRACT INFECTIONS IN ADULTS 2.1 Summary and Recommendations 2.1.1 Definition 2.1.2 Aetiological spectrum 2.1.3 Acute uncomplicated cystitis in pre-menopausal, non-pregnant women 2.1.4 Acute uncomplicated pyelonephritis in pre-menopausal, non-pregnant women 2.1.5 Recurrent (uncomplicated) UTIs in women 2.1.6 UTIs in pregnancy 2.1.7 UTIs in post-menopausal women 2.1.8 Acute uncomplicated UTIs in young men 2.1.9 Asymptomatic bacteriuria 2.2 Background 2.3 Definition 2.4 Aetiological spectrum 2.5 Acute uncomplicated cystitis in pre-menopausal, non-pregnant women 2.5.1 Incidence, risk factors, morbidity 2.5.2 Diagnosis 2.5.3 Treatment 2.5.4 Post-treatment follow-up 2.6 Acute uncomplicated pyelonephritis in pre-menopausal, non-pregnant women 2.6.1 Diagnosis 2.6.2 Treatment 2.6.3 Post-treatment follow-up 2.7 Recurrent (uncomplicated) UTIs in women 2.7.1 Background 2.7.2 Prophylactic antimicrobial regimens 2.7.3 Alternative prophylactic methods 2.8 UTIs in pregnancy 2.8.1 Epidemiology 2.8.2 Asymptomatic bacteriuria 2.8.3 Acute cystitis during pregnancy 2.8.4 Acute pyelonephritis in pregnancy 2.9 UTIs in postmenopausal women 2.10 Acute uncomplicated UTIs in young men 2.10.1 Pathogenesis and risk factors 2.10.2 Diagnosis 2.10.3 Treatment 2.11 Asymptomatic bacteriuria 2.12 References

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3. URINARY TRACT INFECTIONS IN CHILDREN 3.1 Summary and recommendations 3.2 Background 3.3 Aetiology 3.4 Pathogenesis and risk factors 3.5 Signs and symptoms 3.6 Classification 3.6.1 Severe UTI 3.6.2 Simple UTI

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3.7 Diagnosis 3.7.1 Physical examination 3.7.2 Laboratory tests 3.7.2.1 Collection of urine 3.7.2.1.1 Suprapubic bladder aspiration 3.7.2.1.2 Bladder catheterization 3.7.2.1.3 Plastic bag attached to the genitalia 3.7.2.2 Quantification of bacteriuria 3.7.2.3 Other biochemical markers 3.7.2.3.1 Nitrite 3.7.2.3.2 Leucocyte esterase 3.7.2.3.3 C-reactive protein 3.7.2.3.4 Urinary N-acetyl-ß-glucosaminidase 3.7.2.3.5 Interleukin-6 3.7.3 Imaging of the urinary tract 3.7.3.1 Ultrasonography 3.7.3.2 Radionuclide studies 3.7.3.3 Cystourethrography 3.7.3.3.1 Conventional voiding cystourethrography 3.7.3.3.2 Radionuclide cystography (indirect) 3.7.3.3.3 Cystosonography 3.7.3.4 Additional imaging 3.7.3.5 Urodynamic evaluation 3.8 Schedule of investigation 3.9 Treatment 3.9.1 Severe UTIs 3.9.2 Simple UTIs 3.9.3 Prophylaxis 3.10 Acknowledgement 3.11 References

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4. UTIs IN RENAL INSUFFICIENCY, TRANSPLANT RECIPIENTS, DIABETES MELLITUS AND IMMUNOSUPRESSION 4.1 Summary 4.1.1 Acute effects of UTI on the kidney 4.1.2 Chronic renal disease and UTI 4.1.2.1 Adult polycystic kidney disease (APCKD) 4.1.2.2 Calculi and UTI 4.1.2.3 Obstruction and UTI 4.1.3 UTI in renal transplantation and immunosuppression 4.1.4 Antibiotic treatment for UTI in renal insufficiency and after renal transplantation 4.2 Background 4.3 Acute effects of a UTI on the kidney 4.3.1 Vesicoureteric and intrarenal reflux 4.3.2 Obstructive neuropathy 4.3.3 Renal effects of severe UTI 4.3.4 Acute effects of UTI on the normal kidney 4.3.5 Renal scarring 4.3.6 Specific conditions in which an acute UTI causes renal damage 4.3.6.1 Diabetes mellitus 4.3.6.2 Tuberculosis 4.4 Chronic renal disease and UTI 4.4.1 Adult dominant polycystic kidney disease (ADPK) 4.4.2 Renal calculi 4.5 UTI in renal transplantation 4.5.1 Donor organ infection 4.5.2 Graft failure 4.5.3 Kidney and whole-organ pancreas transplantation 4.6 Antibiotic therapy in renal failure/transplantation 4.6.1 Treatment of UTI in renal transplant recipients

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4.6.2 Fungal infections 4.6.3 Schistosomiasis Immunosuppression 4.7.1 HIV infection 4.7.2 Viral and fungal infections References 4.8.1 Further reading

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5. COMPLICATED UTIs DUE TO UROLOGICAL DISORDERS 5.1 Summary and recommendations 5.2 Definitions and classification 5.2.1 Clinical presentation 5.2.2 Urine cultures 5.3 Microbiology 5.3.1 Spectrum and antibiotic resistance 5.3.2 Complicated UTIs associated with urinary stones 5.3.3 Complicated UTIs associated with urinary catheters 5.4 Treatment 5.4.1 General principles 5.4.2 Choice of antibiotics 5.4.3 Duration of antibiotic therapy 5.4.4 Complicated UTIs associated with urinary stones 5.4.5 Complicated UTIs associated with indwelling catheters 5.4.6 Complicated UTIs in spinal-cord injured patients 5.4.7 Follow-up after treatment 5.5 Conclusions 5.6 References 6. CATHETER-ASSOCIATED UTIs 6.1 Abstract 6.2 Summary of recommendations 6.3 References 7. SEPSIS IN UROLOGY (UROSEPSIS) 7.1 Summary and recommendations 7.2 Background 7.3 Definition and clinical manifestation of sepsis in urology 7.4 Physiology and biochemical markers 7.4.1 Cytokines as markers of the septic response 7.4.2 Procalcitonin is a potential marker of sepsis 7.5 Prevention 7.5.1 Preventive measures of proven or probable efficacy 7.5.2 Appropriate peri-operative antimicrobial prophylaxis 7.5.3 Preventive measures of debatable efficacy 7.5.4 Ineffective or counterproductive measures 7.6 Treatment 7.6.1 Relief of obstruction 7.6.2 Antimicrobial therapy 7.6.3 Adjunctive measures 7.7 Conclusion 7.8 Acknowledgement 7.9 References

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URETHRITIS 8.1 Definition 8.2 Epidemiology 8.3 Pathogens 8.4 Route of infection and pathogenesis 8.5 Clinical course 8.6 Diagnosis

60 60 60 61 61 61 61 61 62 62 62 62 63 63 63 63 64 64 64 65 66 66 67

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8.7 8.8 8.9

Therapy Prevention References

73 73 73

9. PROSTATITIS AND CHRONIC PELVIC PAIN SYNDROME 9.1 Summary and recommendations 9.2 Introduction and definition 9.3 Diagnosis 9.3.1 History and symptoms 9.3.1.1 Symptom questionnaires 9.3.2 Clinical findings 9.3.3 Urine cultures and expressed prostatic secretion 9.3.4 Perineal biopsy 9.3.5 Other tests 9.3.6 Classification systems 9.3.7 Diagnostic evaluation 9.3.8 Additional investigations 9.4 Treatment 9.4.1 Antibiotics 9.4.2 Antibiotics and α-blockers in combination therapy 9.4.3 Other oral medication 9.4.4 Intraprostatic injection of antibiotics 9.4.5 Surgery 9.4.6 Other treatment forms 9.5 References

74 74 74 75 75 75 75 75 76 76 76 77 77 78 78 78 79 79 79 79 79

10. EPIDIDYMITIS AND ORCHITIS 10.1 Definition and classification 10.2 Incidence and prevalence 10.3 Morbidity 10.4 Pathogenesis and pathology 10.5 Diagnosis 10.5.1 Differential diagnosis 10.6 Treatment 10.7 References 11. PERI-OPERATIVE ANTIBACTERIAL PROPHYLAXIS IN UROLOGY 11.1 Summary 11.2 Introduction 11.3 Goals of peri-operative antibacterial prophylaxis 11.4 Risk factors 11.5 Principles of antibiotic prophylaxis 11.5.1 Timing 11.5.2 Route of administration 11.5.3 Duration of the regimen 11.5.4 Choice of antibiotics 11.6 Prophylactic regimens in defined procedures 11.6.1 Diagnostic procedures 11.6.2 Endo-urological treatment procedures 11.6.3 Laparoscopic surgery 11.6.4 Open urological operations without bowel segment with or without opening of the urinary tract 11.6.5 Open urological operations with bowel segment 11.6.6 Post-operative drainage of the urinary tract 11.6.7 Implant of prosthetic devices 11.7 References

82 82 82 83 83 83 83 83 84

89 89 89 90

12. SPECIFIC INFECTIONS 12.1 Urogenital Tuberculosis 12.1.1 Reference

92 92 92

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12.2

Urogenital Schistosomiasis 12.2.1 Reference

92 93

13.

SEXUALLY TRANSMITTED INFECTIONS 13.1 Reference

93 93

14. APPENDICES 14.1 Criteria for the diagnosis of a UTI 14.1.1 References 14.2 Recommendations for antimicrobial therapy in urology 14.3 Recommendations for antibiotic prescribing in renal failure 14.4 Recommendations for peri-operative antibacterial prophylaxis in urology 14.5 Chronic Prostatitis Symptom Index (CPSI) 14.6 Meares & Stamey localization technique 14.7 Antibacterial agents 14.7.1 Penicillins 14.7.1.1 Aminopenicillins 14.7.1.2 Acylaminopenicillins 14.7.1.3 Isoxazolylpenicillins 14.7.2 Parental cephalosporins 14.7.2.1 Group 1 cephalosporins 14.7.2.2 Group 2 cephalosporins 14.7.2.3 Group 3a cephalosporins 14.7.2.4 Group 3b cephalosporins 14.7.2.5 Group 4 cephalosporins 14.7.2.6 Group 5 cephalosporins 14.7.3 Oral cephalosporins 14.7.3.1 Group 1 oral cephalosporins 14.7.3.2 Group 2 oral cephalosporins 14.7.3.3 Group 3 oral cephalosporins 14.7.4 Monobactrams 14.7.5 Carpabenens 14.7.6 Fluoroquinolones 14.7.6.1 Group 1 fluoroquinolones 14.7.6.2 Group 2 fluoroquinolones 14.7.6.3 Group 3 fluoroquinolones 14.7.7 Co-trimoxazole 14.7.8 Fosfomycin 14.7.9 Nitrofurantoin 14.7.10 Macrolides 14.7.11 Tetracyclines 14.7.12 Aminoglycosides 14.7.13 Glycopeptides 14.7.14 Oxazolidinones 14.7.15 References 14.8 Relevant bacteria for urological infections 15. ABBREVIATIONS USED IN THE TEXT

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93 93 94 94 95 97 99 100 101 102 102 102 102 102 102 102 102 102 103 103 103 104 104 104 104 104 104 105 105 105 106 106 106 106 106 106 106 107 107 108 109

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1. INTRODUCTION Urinary tract infections (UTIs) are among the most prevalent infectious diseases with a substantial financial burden on society. Unfortunately, in Europe, there are no good data concerning the prevalence of various types of UTIs and their impact on the quality of life of the affected population. Nor is there good data regarding the impact of UTIs on economics in general and that of the health care system especially. For a well-functioning public health system, such data are urgently needed. Data obtained from other countries and societies, e.g. the USA, can only be applied with caution to the European situation. In the USA, UTIs are responsible for over 7 million physician visits annually, including more than 2 million visits for cystitis (1). Approximately 15% of all community-prescribed antibiotics in the USA are dispensed for UTI, at an estimated annual cost of over US $1 billion (2). Furthermore, the direct and indirect costs associated with community-acquired UTIs in the USA alone exceed an estimated US $1.6 billion (1). Urinary tract infections account for more than 100,000 hospital admissions annually, most often for pyelonephritis (1). They also account for at least 40% of all hospital-acquired infections and are in the majority of cases catheter-associated (2-4). Nosocomial bacteriuria develops in up to 25% of patients requiring a urinary catheter for > 7 days, with a daily risk of 5% (5). It has been estimated that an episode of nosocomial bacteriuria adds US $500-1,000 to the direct cost of acute-care hospitalization (6). In addition, the pathogens are fully exposed to the nosocomial environment, including selective pressure by antibiotic or antiseptic substances. Nosocomial UTIs therefore comprise perhaps the largest institutional reservoir of nosocomial antibiotic-resistant pathogens (5).

1.1 Pathogenesis of urinary tract infections Micro-organisms can reach the urinary tract by haematogenous or lymphatic spread, but there is abundant clinical and experimental evidence to show that the ascent of micro-organisms from the urethra is the most common pathway leading to a UTI, especially organisms of enteric origin (i.e. Escherichia coli and other Enterobacteriaceae). This provides a logical explanation for the greater frequency of UTIs in women than in men and for the increased risk of infection following bladder catheterization or instrumentation. A single insertion of a catheter into the urinary bladder in ambulatory patients results in urinary infection in 1-2% of cases. Indwelling catheters with open-drainage systems result in bacteriuria in almost 100% of cases within 3-4 days. The use of a closed-drainage system, including a valve preventing retrograde flow, delays the onset of infection, but ultimately does not prevent it. It is thought that bacteria migrate within the mucopurulent space between the urethra and catheter, and that this leads to the development of bacteriuria in almost all patients within about 4 weeks. Haematogenous infection of the urinary tract is restricted to a few relatively uncommon microbes, such as Staphylococcus aureus, Candida spp., Salmonella spp. and Mycobacterium tuberculosis, which cause primary infections elsewhere in the body. Candida albicans readily causes a clinical UTI via the haematogenous route, but is also an infrequent cause of an ascending infection if an indwelling catheter is present or following antibiotic therapy. The concept of bacterial virulence or pathogenicity in the urinary tract infers that not all bacterial species are equally capable of inducing infection. The more compromised the natural defence mechanisms (e.g. obstruction, bladder catheterization), the fewer the virulence requirements of any bacterial strain to induce infection. This is supported by the well-documented in-vitro observation that bacteria isolated from patients with a complicated UTI frequently fail to express virulence factors. The virulence concept also suggests that certain bacterial strains within a species are uniquely equipped with specialized virulence factors, e.g. different types of pili, which facilitate the ascent of bacteria from the faecal flora, introitus vaginae or periurethral area up the urethra into the bladder, or, less frequently, allow the organisms to reach the kidneys to induce systemic inflammation.

1.2

Microbiological and other laboratory findings

The number of bacteria is considered relevant for the diagnosis of a UTI. In 1960, Kass developed the concept of ’significant‘ bacteriuria (> 105 cfu) in the context of pyelonephritis in pregnancy (7). Although this concept introduced quantitative microbiology into the diagnostics of infectious diseases and is therefore still of general importance, it has recently become clear that there is no fixed number of significant bacteriuria, which can be applied to all kinds of UTIs and in all circumstances. As described in Appendix 12.1, the following bacterial counts are clinically relevant: • > 103 colony-forming units (cfu) of uropathogen/mL of a mid-stream sample of urine (MSU) in acute uncomplicated cystitis in a woman • > 104 cfu uropathogen/mL of MSU in acute uncomplicated pyelonephritis in a woman

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• > 105 cfu uropathogen/mL of MSU in a woman, or > 104 cfu uropathogen/mL of MSU in a man or in straight catheter urine in women in a complicated UTI. In a suprapubic bladder puncture specimen, any count of bacteria is relevant. The problem of counting low numbers, however, has to be considered. If an inoculum of 0.1 mL of urine is used and 10 identical colonies are necessary for statistical reasons of confidence, then in this setting, the lowest number that can be counted is 102 cfu uropathogen/mL. Asymptomatic bacteriuria is diagnosed if two cultures of the same bacterial strain (in most cases the species only is available) taken > 24 hours apart show bacteriuria of > 105 cfu uropathogen/mL. It is obvious that methods of urine collection and culture, as well as the quality of laboratory investigations, may vary. Two levels of standard must therefore be used for the management of patients. A basic standard level is necessary for routine assessment, while a higher standard level is required for scientific assessment and in special clinical circumstances, e.g. fever of unknown origin in immunocompromised patients. In research, the need for a precise definition of sampling methods, the time that urine is kept in the bladder, etc., must be recognized and these parameters carefully recorded. In clinical routine assessment, a number of basic criteria must be looked at before a diagnosis can be established, including: • clinical symptoms • results of selected laboratory tests (blood, urine or expressed prostatic secretion [EPS]) • evidence of the presence of microbes by culturing or other specific tests. Most of these investigations can today be performed in any laboratory. It has to be considered, however, that microbiological methods and definitions applied must follow accepted standards concerning specimen transport, pathogen identification and antimicrobial susceptibility testing. Since these methods, and also microbiological definitions, may vary from country to country and institution to institution, e.g. the breakpoints for classification of a pathogen as susceptible or resistant, it is important to report not only the results but also which methods and standards were applied, e.g. the European Committee for Antimicrobial Susceptibility Testing (EUCAST) (8-10), the National Committee for Clinical Laboratory Standards (NCCLS) (11). Mixing results obtained by different methods, e.g. rates of bacterial resistance, can be problematic and requires careful interpretation. Histological investigation sometimes shows the presence of non-specific inflammation. Only in some cases, such findings (e.g. prostatitis in patients who have elevated levels of prostate-specific antigen [PSA]) may help determine the appropriate treatment, whereas in more specific inflammations, such as tuberculosis, actinomycosis, etc., histology may be diagnostic. In general, however, histological findings usually contribute very little to the treatment decision.

1.3

Classification of urological infections

For practical reasons, this section of the guidelines is called Guidelines on Urological Infections. It includes the management of urinary tract infections in both male and females and the infections of the male genital tract, leaving out the female genital tract infections, clinically bound to the field of gynaecology. The guidelines focus on urology and therefore also look into the prevention of urogenital infections associated, or not, with urological interventions. For clinical reasons, however, UTIs and infections of the male genital tract are classified according to the predominant clinical symptoms: • uncomplicated lower UTI (cystitis) • uncomplicated pyelonephritis • complicated UTI with or without pyelonephritis • urosepsis • urethritis • special forms: prostatitis, epididymitis and orchitis. The clinical presentation and management of different UTI categories may vary during life and may depend on the patient’s condition. Therefore, special patient groups (the elderly, those with underlying diseases and the immunocompromised) have also to be considered. Criteria for the diagnosis of a UTI, modified according to the guidelines of the Infectious Diseases Society of America (IDSA) (12) and European Society of Clinical Microbiology and Infectious Diseases (ESCMID) (13), are summarized in Appendix 14.1. There is still an ongoing discussion about how guidelines on UTI could be improved (14).

1.4

Aim of guidelines

These EAU guidelines cover the UTI categories as listed above in section 1.3 on classification and provide some general advice on the diagnosis and management of male and female urinary UTIs. It is hoped that the guidelines may assist not only the urologist, but also physicians from other medical specialities in their daily practice.

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1.5

Methods

The members of the UTI Working Group (K.G. Naber (chairman), B. Bergman, M.C. Bishop, T.E. Bjerklund-Johansen, H. Botto, B. Lobel, F. Jiminez Cruz, F.P. Selvaggi) of the EAU Guidelines Office established the first version of these guidelines in several consensus conferences. The first edition was published in 2001 in Geneva by the EAU (15) and in a more condensed version was published for the first time in 2001 (16). The members of the current UTI Working Group (M. Grabe [chairman], M.C. Bishop, T.E. Bjerklund-Johansen, H. Botto, M. Çek, B. Lobel, K.G. Naber, J. Palou, P. Tenke) updated the guidelines in several consensus conferences thereafter and subsequently added several chapters, one of which comprises a chapter on catheter-associated UTI. EAU guidelines on special forms of urogenital infections, such as sexual transmitted infections (17), urogenital tuberculosis (18) and urogenital schistosomiasis (19), have been published elsewhere. Chapters 12 and 13 of the present guidelines present separate short summaries including a reference link. For literature review, PubMed was searched for published meta-analyses, which were used as far as available. Otherwise there was a non-structured literature review process by the group members. Each member was responsible for one chapter (reporter). The first draft of each chapter was sent to the committee members asking for comments, which were then considered, discussed and incorporated accordingly. The formal agreement to each updated chapter was achieved by the EAU working group in a series of meetings.

1.6

Level of evidence and grade of guideline recommendations

In the updated guidelines, the studies cited from the literature were rated according to the level of evidence and the recommendations were graded accordingly (Tables 1.1 and 1.2). Table 1.1: Levels of evidence, modified from Sackett et al (20). Level Ia Ib IIa IIb III IV

Type of evidence Evidence obtained from meta-analysis of randomized trials Evidence obtained from at least one randomized trial Evidence obtained from at least one well-designed controlled study without randomization Evidence obtained from at least one other type of well-designed quasi-experimental study Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case reports Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities

Table 1.2: Grades of recommendations, modified from Sackett et al (20). Grade A B C

Nature of recommendations Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomized trial Based on well-conducted clinical studies, but without randomized clinical studies Made despite the absence of directly applicable clinical studies of good quality

1.7

References

1.

Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Am J Med 2002;113 Suppl 1A:5S-13S. http://www.ncbi.nlm.nih.gov/pubmed/12113866 Mazzulli T. Resistance trends in urinary tract pathogens and impact on management. J Urol 2002;168(4 Pt 2):1720-22. http://www.ncbi.nlm.nih.gov/pubmed/12352343 Gales AC, Jones RN, Gordon KA, Sader HS, Wilke WW, Beach ML, Pfaller MA, Doern GV. Activity and spectrum of 22 antimicrobial agents tested against urinary tract infection pathogens in hospitalized patients in Latin America: report from the second year of the SENTRY antimicrobial surveillance program (1998). J Antimicrob Chemother 2000;45(3):295-303. http://www.ncbi.nlm.nih.gov/pubmed/10702547 Rüden H, Gastmeier P, Daschner FD, Schumacher M. Nosocomial and community-acquired infections in Germany. Summary of the results of the First National Prevalence Study (NIDEP). Infection 1997;25(4):199-202. http://www.ncbi.nlm.nih.gov/pubmed/9266256

2.

3.

4.

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5.

6.

7. 8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

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Maki DG, Tambyah PA. Engineering out the risk for infection with urinary catheters. Emerg Infect Dis 2001;7(2):342-7. http://www.ncbi.nlm.nih.gov/pubmed/11294737 Patton JP, Nash DB, Abrutyn E. Urinary tract infection: economic considerations. Med Clin North Am 1991;75(2):495-513. http://www.ncbi.nlm.nih.gov/pubmed/1996046 Kass EH. Bacteriuria and pyelonephritis of pregnancy. Arch Intern Med 1960;105:194-8. http://www.ncbi.nlm.nih.gov/pubmed/14404662 European Committee for Antimicrobial Susceptibility Testing (EUCAST) of the European Society of Clinical Microbiology and Infectious Dieases (ESCMID). EUCAST Definitive Document E.DEF 3.1, June 2000: Determination of minimum inhibitory concentrations (MICs) of antibacterial agents by agar dilution. Clin Microbiol Infect 2000;6(9):503-8. http://www.ncbi.nlm.nih.gov/pubmed/11168186 European Committee for Antimicrobial Susceptibility Testing (EUCAST) of the European Society of Clinical Microbiology and Infectious Dieases (ESCMID). EUCAST Definitive Document E. Def 1.2, May 2000: Terminology relating to methods for the determination of susceptibility of bacteria to antimicrobial agents. Clin Microbiol Infect 2000;6(9):503-8. http://www.ncbi.nlm.nih.gov/pubmed/11168186 European Committee for Antimicrobial Susceptibility Testing (EUCAST) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID). EUCAST Definitive Document E.DEF 2.1, August 2000: Determination of antimicrobial susceptibility test breakpoints. Clin Microbiol Infect 2000;6(10):570-2. http://www.ncbi.nlm.nih.gov/pubmed/11168058 National Committee for Clinical Laboratory Standards (NCCLS). Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved Standard 4th Edition M7-A5 (2002) and M100-S12, 2004. Wayne, PA. Rubin RH, Shapiro ED, Andriole VT, Davis RJ, Stamm WE. Evaluation of new anti-infective drugs for the treatment of urinary tract infection. Infectious Diseases Society of America and the Food and Drug Administration. Clin Infect Dis 1992;15 Suppl 1:S216-S227. http://www.ncbi.nlm.nih.gov/pubmed/1477233 Rubin RH, Shapiro ED, Andriole VT, Davies RJ, Stamm WE, with modifications by a European Working Party (Norrby SR). General guidelines for the evaluation of new anti-infective drugs for the treatment of UTI. Taufkirchen, Germany: The European Society of Clinical Microbiology and Infectious Diseases, 1993;294-310. Naber KG. Experience with the new guidelines on evaluation of new anti-infective drugs for the treatment of urinary tract infections. Int J Antimicrob Agents 1999;11(3-4):189-96; discussion 213-6. http://www.ncbi.nlm.nih.gov/pubmed/10394969 Naber KG, Bergman B, Bjerklund-Johansen TE, Botto H, Lobel B, Jiminez Cruz F, Selvaggi FP. Guidelines on urinary and male genital tract infections. In: EAU Guidelines. Edition presented at the 16th EAU Congress, Geneva, Switzerland, 2001. ISBN 90-806179-3-9. Naber KG, Bergman B, Bishop MC, Bjerklund-Johansen TE, Botto H, Lobel B, Jininez Cruz F, Selvaggi FP; Urinary Tract Infection (UTI) Working Group of the Health Care Office (HCO) of the European Association of Urology (EAU). EAU guidelines for the management of urinary and male genital tract infections. Eur Urol 2001;40(5):576-88. http://www.ncbi.nlm.nih.gov/pubmed/11752870 Schneede P, Tenke P, Hofstetter AG; Urinary Tract Infection Working Group of the Health Care Office of the European Association of Urology. Sexually transmitted diseases (STDs) – a synoptic overview for urologists. Eur Urol 2003;44(1):1-7. http://www.ncbi.nlm.nih.gov/pubmed/12814668 Cek M, Lenk S, Naber KG, Bishop MC, Johansen TE, Botto H, Grabe M, Lobel B, Redorta JP, Tenke P; Members of the Urinary Tract Infection (UTI) Working Group of the European Association of Urology (EAU) Guidelines Office. EAU guidelines for the management of genitourinary tuberculosis. Eur Urol 2005;48(3):353-62. http://www.ncbi.nlm.nih.gov/pubmed/15982799 Bichler KH, Savatovsky I; the Members of the Urinary Tract Infection (UTI) Working Group of the Guidelines Office of the European Association of Urology (EAU):, Naber KG, Bischop MC, BjerklundJohansen TE, Botto H, Cek M, Grabe M, Lobel B, Redorta JP, Tenke P. EAU guidelines for the management of urogenital schistosomiasis. Eur Urol 2006;49(6):998-1003. http://www.ncbi.nlm.nih.gov/pubmed/16519990

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Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998. http://www.cebm.net/index.aspx?o=1025 [access date December 2008].

2. Uncomplicated urinary tract infections in adult 2.1

Summary and recommendations

2.1.1 Definition Acute, uncomplicated UTIs in adults include episodes of acute cystitis and acute pyelonephritis in otherwise healthy individuals. These UTIs are seen mostly in women who have none of the factors known to increase the risk of complications or of treatment failure. 2.1.2 Aetiological spectrum The spectrum of aetiological agents is similar in uncomplicated upper and lower UTIs, with E. coli the causative pathogen in approximately 70-95% of cases and Staphylococcus saprophyticus in about 5-10% of cases. Occasionally, other Enterobacteriaceae, such as Proteus mirabilis and Klebsiella spp., are isolated (IIb). 2.1.3 Acute uncomplicated cystitis in pre-menopausal, non-pregnant women Besides physical examination, urinalysis (e.g. using a dipstick method), including the assessment of white and red blood cells and nitrites, is recommended for routine diagnosis (B). Colony counts > 103 cfu uropathogen/ mL are considered to be a clinically relevant bacteriuria (IIb). Short courses of antimicrobials are highly effective and are desirable because of the improved compliance that they promote, their lower cost and lower frequency of adverse reactions. Single-dose therapy (with some exceptions) is generally less effective than the same antibiotic used for a longer duration. However, with most suitable antimicrobials, there is little to be gained from treatment given beyond 3 days and the risk of adverse events is higher (IaA). Trimethoprim (TMP) or TMP-sulphamethoxazole (SMX) can only be recommended as first-line drugs for empirical therapy in communities with rates of uropathogen resistance to TMP of less than 20% (IbA). Otherwise, fluoroquinolones, fosfomycin trometamol, pivmecillinam and nitrofurantoin are recommended as alternative oral drugs for empirical therapy. However, in some areas, the rate of fluoroquinolone-resistant E. coli is also increasing. Urinalysis, including a dipstick method, is sufficient for routine follow-up. Post-treatment cultures in asymptomatic patients may not be indicated. In women whose symptoms do not resolve, or which resolve and then recur within 2 weeks, urine culture and antimicrobial susceptibility testing should be performed (IVC). 2.1.4 Acute uncomplicated pyelonephritis in pre-menopausal, non-pregnant women Acute pyelonephritis is suggested by flank pain, nausea and vomiting, fever (> 38°C), or costovertebral angle tenderness. It may occur in the absence of cystitis symptoms, e.g. dysuria, frequency. Besides physical examination, urinalysis (e.g. using a dipstick method), including the assessment of white and red blood cells and nitrites, is recommended for routine diagnosis (C). Colony counts > 104 cfu uropathogen/mL can be considered to be a clinically relevant bacteriuria (IIb). An evaluation of the upper urinary tract with ultrasound should be performed to rule out urinary obstruction or renal stone disease (C). Additional investigations, such as an unenhanced helical computed tomography (CT), an excretory urogram, or dimercaptosuccinic acid (DMSA) scan, should be considered if the patients remain febrile after 72 hours of treatment to rule out further complicating factors, e.g. urolithiasis, renal or perinephric abscesses (C). As first-line therapy in mild cases, an oral fluoroquinolone for 7 days is recommended in areas where the rate of fluoroquinolone-resistant E. coli is still low ( 7 days at presentation • Diabetes mellitus • Immunosuppression. These factors only provide guidance to the clinician who must decide, based on limited clinical information, whether to embark on a more extensive evaluation and treatment course. It is generally safe to assume that a pre-menopausal, non-pregnant woman with acute onset of dysuria, frequency or urgency, who has not recently been instrumented or treated with antimicrobials and who has no history of a genitourinary tract abnormality, has an uncomplicated lower (cystitis) or upper (pyelonephritis) UTI (1). Recurrent UTIs are common among pre-menopausal, sexually active, healthy women, even though they generally have anatomically and physiologically normal urinary tracts. Whether a UTI in pregnancy by itself is to be classified as an uncomplicated or a complicated UTI remains debatable. Although data on UTIs in healthy post-menopausal women without genitourinary abnormalities are limited, it is likely that most UTIs in such women are also uncomplicated. Data on UTIs in healthy adult men are sparse and much less is known about the optimal diagnostic and therapeutic approaches to UTIs in men.

2.4

Aetiological spectrum

The spectrum of aetiological agents is similar in uncomplicated upper and lower UTIs, with E. coli being the causative pathogen in approximately 70-95% of cases and S. saprophyticus in about 5-19% of cases, whereas S. saprophyticus is less frequently found in pyelonephritis than in cystitis. Occasionally, other Enterobacteriaceae, such as P. mirabilis and Klebsiella spp., or enterococci (mostly in mixed cultures indicating contamination), are isolated from such patients. In as many as 10-15% of symptomatic patients, bacteriuria cannot be detected using routine methods (1, 3).

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2.5

Acute uncomplicated cystitis in pre-menopausal, non-pregnant women

At this stage in life, the incidence of acute uncomplicated cystitis is high and this infection is associated with considerable morbidity. Therefore, even small improvements in diagnostics, therapy or prophylaxis have a high impact on public health. 2.5.1 Incidence, risk factors, morbidity A prospective study at a university health centre or a health maintenance organization (HMO) revealed an incidence of 0.7 per person-year in the university cohort and 0.5 per person-year in the HMO cohort (4). Cohort and case control studies in young women showed that the risk is strongly and independently associated with recent sexual intercourse, recent use of diaphragm with spermicide, preceding asymptomatic bacteriuria, a history of recurrent UTI, the age of first UTI and history of UTI in the mother (4-6). On average, each episode of this type of UTI in pre-menopausal women was shown to be associated with 6.1 days of symptoms, 2.4 days of restricted activity, 1.2 days in which they were not able to attend classes or work and 0.4 days in bed (7). 2.5.2 Diagnosis A non-pregnant pre-menopausal woman presenting with acute dysuria usually has one of three types of infection (1): • acute cystitis • acute urethritis, caused by Chlamydia trachomatis, Neisseria gonorrhoeae, or herpes simplex virus • vaginitis caused by Candida spp. or Trichomonas vaginalis. A distinction between these three entities can usually be made with a high degree of certainty from the history and physical examination (1). Acute cystitis is more likely if the woman complains of urgency and suprapubic pain; has suprapubic tenderness; is a diaphragm-spermicide user; has symptoms that mimic those of previously confirmed cystitis; or has recently undergone urethral instrumentation. Although approximately 40% of women with cystitis have haematuria, this is not a predictor of a complicated infection. Urethritis caused by N. gonorrhoeae or C. trachomatis is relatively more likely if a women has had a new sexual partner in the past few weeks or if her sexual partner has urethral symptoms; there is a past history of a sexually transmitted disease (STD); symptoms were of gradual onset over several weeks and there are accompanying vaginal symptoms such as vaginal discharge or odour. Vaginitis is suggested by the presence of vaginal discharge or odour, pruritus, dyspareunia, external dysuria and no increased frequency or urgency. Urinalysis (e.g. using a dipstick method) to look for pyuria, haematuria and nitrites is indicated if a UTI is suspected. Pyuria is present in almost all women with an acutely symptomatic UTI and in most women with urethritis caused by N. gonorrhoeae or C. trachomatis; its absence strongly suggests an alternative diagnosis. The definitive diagnosis of a UTI is made in the presence of significant bacteriuria, the definition of which remains somewhat controversial. The traditional standard for significant bacteriuria is > 105 cfu uropathogen/ mL in voided MSU, based on studies of women with acute pyelonephritis and asymptomatic bacteriuria that were carried out four decades ago (8). Several more recent studies have shown that this is an insensitive standard when applied to acutely symptomatic women and that approximately one-third to one-half of cases of acute cystitis have bacteriuria < 105 cfu/mL (9) (II). For practical purposes, colony counts > 103 cfu/mL should be used for the diagnosis of acute uncomplicated cystitis (10, 11). The determination of a urine culture is generally not necessary in women with uncomplicated cystitis because the causative organisms and their antimicrobial susceptibility profiles are predictable. Also, culture results become available only after the patient’s symptoms have resolved or are considerably improved. Voided MSU or straight catheter (by trained urological personnel) urine cultures should probably be performed if the patient’s symptoms are not characteristic of a UTI. The laboratory must be instructed to look for ‘low count’ bacteriuria if such UTIs are to be detected. A pelvic examination is indicated if any of the factors suggesting urethritis or vaginitis listed above are present or if there is doubt as to the diagnosis. A pelvic examination should include a careful evaluation for evidence of vaginitis, urethral discharge, or herpetic ulcerations; a cervical examination for evidence of cervicitis and cervical and urethral cultures for N. gonorrhoeae and C. trachomatis (or other sensitive and specific tests in first-voided urine in the morning, such as polymerase chain reaction tests). 2.5.3 Treatment There seems to be no long-term adverse effects with respect to renal function or increased mortality associated with acute uncomplicated cystitis, even in women who experience frequent recurrences, and in the non-pregnant population. Untreated cystitis rarely progresses to symptomatic upper tract infection. Thus, the significance of lower tract infection in non-pregnant women seems to be limited to the morbidity of symptoms caused by the infection, which can lead to substantial disruption of the lives of affected individuals.

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In fact, most lower UTIs (50-70%) clear spontaneously if untreated, although symptoms may persist for several months. In a prospective, placebo-controlled study (12) (Ib), 288 patients were treated with placebo for 7 days, of whom 39% dropped out after the first follow-up visit (8-10 days). The spontaneous cure rate of symptoms was 28% after the first week, while 37% had neither symptoms nor bacteriuria after 5-7 weeks. In another study (13) (Ib), symptomatic improvement and cure occurred in 52% of 33 placebo-treated patients with bacteriologically proven urinary tract infection after 1 week, but only 20% of these patients showed bacteriological eradication as well. Both parameters were significantly lower than in the group of patients treated with nitrofurantoin (100 mg four times daily for 3 days). Knowledge of the antimicrobial susceptibility profile of uropathogens causing uncomplicated UTIs in the community should guide therapeutic decisions, although the trend away from routinely culturing patients with uncomplicated cystitis may unfortunately lead to the lack of such data. The resistance pattern of E. coli strains causing an uncomplicated UTI, however, may vary considerably between European regions and countries, so that no general recommendations are suitable throughout Europe. In an international survey of the antimicrobial susceptibility of uropathogens from uncomplicated UTI, the overall resistance rate was lowest in the Nordic countries and Austria and highest in Portugal and Spain (3, 14) (IIb). Short courses of antimicrobials are highly effective in the treatment of acute uncomplicated cystitis in pre-menopausal women (15, 16) (Ia). Short-course regimens are desirable because of the improved compliance that they promote, their lower cost, and lower frequency of adverse reactions. However, in assessing the potential cost advantages of short-course regimens, it is necessary to consider the potential added expense associated with treatment failures or recurrences arising from short-course therapy. It is also important to consider the potential psychological aspects of single-dose therapy; as symptoms may not subside for 2 or 3 days, the patient may have misgivings during this time about the ‘insufficient’ treatment provided to her. Such a scenario may result in unnecessary visits or calls to the physician. A wide variety of antimicrobial regimens comprising different drugs, doses, schedules and durations have been used to treat these common bacterial infections. Only a few of these regimens have been compared directly in adequately designed studies. To develop evidence-based guidelines for the antimicrobial therapy of uncomplicated acute bacterial cystitis and pyelonephritis in women, a committee of the IDSA systematically reviewed the English medical literature up to 1997 and developed guidelines for the antimicrobial treatment of acute uncomplicated bacterial cystitis and pyelonephritis in women (16). The UTI Working Group of the EAU Guidelines Office has used this database and more recent publications to develop the following, updated, guidelines on antimicrobial therapy. The following antimicrobials were considered by the UTI Working Group: trimethoprim (TMP), trimethoprim-sulfamethoxazole (TMP-SMX), fluoroquinolones (ciprofloxacin, enoxacin, fleroxacin, gatifloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin), ß-lactams (amoxycillin, ampicillin-like compounds, cefadroxil, cefuroxime axetil, cefpodoxime proxetil, ceftibuten, pivmecillinam, ritipenem axetil), fosfomycin trometamol, and nitrofurantoin. The following conclusions about antimicrobial therapy can be made: i) Treatment duration In otherwise healthy, adult, non-pregnant women with acute uncomplicated cystitis, single-dose therapy (with some exceptions) is significantly less effective in eradicating initial bacteriuria than are longer durations of treatment with antimicrobials tested in this manner, such as TMP-SMX, TMP, norfloxacin, ciprofloxacin, fleroxacin, and as a group ß-lactams. However, TMP-SMX, TMP, norfloxacin, ciprofloxacin, and fleroxacin given for 3 days are as effective as the same antimicrobials used over longer durations. Longer treatment usually shows a higher rate of adverse events (Ib). Although not examined in controlled trials, cystitis caused by S. saprophyticus may respond better to longer treatment durations, e.g. 7 days (16) (IIIB). ii) Trimethoprim, co-trimoxazole TMP-SMX was the most studied drug (30 studies). A 3-day regimen with TMP-SMX can therefore be considered to be the standard therapy (IaA). TMP alone was equivalent to TMP-SMX with regard to eradication and adverse effects. However, a recent study on more than 10,000 Dutch women revealed that better results were obtained for trimethoprim prescribed for 5-7 days than for 3 days (17) (IIaB). Considering possible rare, but serious, adverse effects caused by sulphonamides, TMP alone may be considered the preferred drug over TMP-SMX (IIIC). TMP or TMP-SMX can be recommended as first-line drugs for empirical therapy, but only in communities with rates of uropathogen resistance to TMP < 10-20% because there is a close correlation between susceptibility and the eradication of E. coli on the one hand and resistance and persistence of the uropathogen on the other (18, 19) (Ib). The risk of emerging resistant uropathogens in the case of recurrence was also much higher when using TMP as a first-line drug than when using pivmecillinam or ciprofloxacin (20) (III), which had the lowest risk of the drugs investigated.

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iii) Fluoroquinolones The fluoroquinolones (ciprofloxacin, fleroxacin, norfloxacin and ofloxacin) are equivalent to TMP-SMX when given as a 3-day regimen (IbA). Pefloxacin and rufloxacin, each as single-day therapies, are interesting options and may be equivalent to TMP-SMX in the eradication of bacteriuria and its recurrence. Questions remain as to the possibility of a higher incidence of adverse effects with these agents than with other recommended therapies (21-24) (IbB). Two more recent studies investigated short-term therapy with levofloxacin and with the extended-release formulation of ciprofloxacin (CiproXR). A 3-day regimen with levofloxacin, 250 mg once daily, was similarly effective to a 3-day regimen of ofloxacin 200 mg twice daily, but with levofloxacin there was a trend to lesser adverse events (25) (IbA). A 3-day course with CiproXR (500 mg) once daily was equivalent in regard to efficacy and safety as a course of conventional ciprofloxacin (250 mg twice daily) (26) (IbA). Fluoroquinolones are more expensive than TMP and TMP-SMX, and are thus not recommended as first-line drugs for empirical therapy except in communities with rates of uropathogen resistance to TMP > 10-20%. Concern about fluoroquinolone resistance led practitioners to be appropriately hesitant about the widespread use of fluoroquinolones for the routine treatment of uncomplicated UTIs, although there are no published studies demonstrating that short-course fluoroquinolone therapy for acute cystitis in women results in the selection of fluoroquinolone-resistant flora (27-29) (III). In some countries, however, the resistance of E. coli to fluoroquinolones has already increased to more than 10%. In this situation, alternative oral drugs should be considered for empirical therapy (see Table 2.3). Treatment with any of these agents should result in more than 90% eradication of the bacteriuria. iv) ß-lactam antibiotics In general, ß-lactams as a group are less effective than the aforementioned drugs (III). No sufficiently large comparative studies between one of the above recommended regimens (3-day TMP, TMP-SMX, or one of the above-mentioned fluoroquinolones) and second- and third-generation oral cephalosporins or an aminopenicillin plus a BLI were available for the IDSA analysis (16). Only one study of adequate size compared a 3-day course of ß-lactam antimicrobial (pivmecillinam) with treatment for a longer duration (30) (Ib). The study found that 3 days of therapy were equivalent to 7 days of therapy with regard to the eradication of the initial bacteriuria, although the shorter treatment was associated with an increased incidence of recurrence. Pooled bacteriological outcomes from more recent studies showed that 7 days of pivmecillinam, 200 mg twice daily, and 3 days of norfloxacin, 400 mg twice daily, have similar results (31, 32) (IbA). With pivmecillinam, however, the rate of vaginal candidiasis was significantly lower than with norfloxacin (33) (Ib). Pivmecillinam also shows low resistance rates for E. coli and other Enterobacteriaceae, without cross-resistance to other antimicrobials used for the treatment of UTI (14, 34) (IIb). In general, first- and second-generation oral cephalosporines are not recommended as first-line antimicrobials for a 3-day treatment of uncomplicated UTI (16, 35, 36) (IbA). However, among third-generation oral cephalosporins, a 3-day course with cefpodoxime-proxetil (200 mg twice daily) was as safe and effective as that of TMP-SMX in 133 evaluable patients (37) (IbA). In contrast, a more recent study of 370 women (38) showed that a 3-day regimen of amoxycillin-clavulanate (500 mg/125 mg twice daily) was not as effective as a 3-day regimen of ciprofloxacin (250 mg twice daily) even in women infected with susceptible strains (Ib). This difference may be due to the inferior ability of amoxycillin-clavulanate to eradicate vaginal E. coli, facilitating early re-infection. v) Fosfomycin Fosfomycin trometamol was evaluated as single-dose (3 g) therapy by a meta-analysis comprising 15 comparative trials on 2048 patients (39) (IaA), in whom short-term bacteriological eradication was identified in 1540 patients with confirmed UTI, and obtained with fosfomycin trometamol in 85.6% of cases and with other treatments (single dose and 3-7 day regimens) in 86.7% of cases. In patients who completed long-term follow-up, the overall eradication rate with fosfomycin trometamol (84.6%) was significantly (p 38°C), or costovertebral angle tenderness, and may occur with or without cystitis symptoms. The presentation of an acute uncomplicated pyelonephritis usually varies from a mild to a moderate illness. A life-threatening condition with multi-organ system dysfunction, including sepsis syndrome with or without shock and renal failure, must be considered a complicated case. Urinalysis is indicated to look for pyuria and haematuria. In contrast to cystitis, 80-95% of episodes of pyelonephritis are associated with > 105 cfu uropathogen/mL (62). For routine diagnosis, a breakpoint 4 of 10 cfu/mL can be recommended (10, 11). An evaluation of the upper urinary tract with ultrasound (63) should be performed to rule out urinary obstruction. Additional investigations, such as an unenhanced helical computed tomography (64) (to rule out urolithiasis), an excretory urogram or DMSA scan, according to the clinical situation should be considered if the patient remains febrile after 72 hours of treatment to rule out further complicating factors, e.g. urolithiasis, renal or perinephric abscesses. Routine performance of an

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excretory urogram in patients with acute uncomplicated pyelonephritis has little value because most adults with uncomplicated acute pyelonephritis have a normal upper urinary tract. 2.6.2 Treatment Of several hundred articles screened by the IDSA group (16), only five were prospective, randomized, controlled trials (8, 64-68) and the following conclusions can be drawn for initial therapy from their analysis and the five studies (69-72) published thereafter. 1. TMP-SMX is preferred over ampicillin (IbA) (no controlled study used TMP alone). 2. Two weeks of therapy with TMP-SMX for acute uncomplicated pyelonephritis appears to be adequate for the majority of women (IbA). In some studies with various antibiotics, e.g. aminoglycosides (but none that were sufficiently powered), an even shorter duration of therapy of 5-7 days was recommended (IIIB). 3. In communities in which the resistance rate of E. coli to TMP is > 10%, a fluoroquinolone should be recommended as the drug of choice for empirical therapy. It was demonstrated that a 7-day regimen of ciprofloxacin, 500 mg twice daily, showed a significantly higher rate of bacterial eradication and a lower rate of adverse effects when compared with a 14-day therapy using TMP-SMX, 960 mg twice daily (69) (IbA). The higher efficacy seen with ciprofloxacin was mainly due to TMP-resistant E. coli strains. In clinical trials, the following fluoroquinolones were comparable to conventional ciprofloxacin 500 mg twice daily, ciprofloxacin extended release formulation (1000 mg once daily), gatifloxacin (400 mg once daily), levofloxacin (250 mg twice daily), and lomefloxacin (400 mg once daily) (70-72) (IbA). 4. For an aminopenicillin plus a BLI, as well as for most group two and group three oral cephalosporins, there are no sufficiently powered comparative studies versus a fluoroquinolone or TMP-SMX. In a prospectively randomized study, a 10-day therapy with cefpodoxime proxetil 200 mg twice daily showed equivalent clinical efficacy as that with ciprofloxacin 500 mg twice daily (73) (IbA). 5. In areas with a rate of E. coli resistance to fluoroquinolones > 10% and in situations in which fluoroquinolones are contraindicated (e.g. pregnancy, lactating women, adolescence), an aminopenicillin plus a BLI, or a group three oral cephalosporin is recommended, either for initial use, or if a patient has to be switched to an oral regimen (IIIB). Based on this analysis, the UTI Working Group of the EAU Guidelines Office recommends in mild and moderate cases an oral fluoroquinolone for 7 days as first-line therapy. In situations where a fluoroquinolone is not indicated (see above), a group three oral cephalosporin, e.g. cefpodoxime proxetil, may be an alternative for empirical therapy (B). If a Gram-positive organism is seen on the initial Gram stain, an aminopenicillin plus a BLI is recommended (B). More severe cases of acute uncomplicated pyelonephritis should be admitted to hospital and, if the patient cannot take oral medication, treated parenterally with a fluoroquinolone, an aminopenicillin plus a BLI, a group three cephalosporin, or an aminoglycoside (B). With improvement, the patient can be switched to an oral regimen using one of the above-mentioned antibacterials (if active against the infecting organism) to complete the 1-2 weeks’ course of therapy (B). In Table 2.4, the oral antimicrobial treatment options of acute uncomplicated pyelonephritis in adult pre-menopausal non-pregnant women according to level of evidence and grade of recommendations as defined in the Introduction (Section 1) are summarized (see also the recommendations in Appendix 12.2). Although approximately 12% of patients hospitalized with acute uncomplicated pyelonephritis have bacteraemia (74), it is common practice to obtain blood cultures only if the patient appears ill enough to warrant hospitalization. There is no evidence that bacteraemia has prognostic significance or warrants longer therapy in an otherwise healthy individual with pyelonephritis.

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Substance Dosage Duration LE GR Author, year Ref Remarks Ciprofloxacin 500 mg bid 7 days Ib A Talan 2000 69 a) Ciprofloxacin significantly more effective than cetriaxone/TMP-SMX and with trend b) towards less AE CiproXR 1000 mg od 7-10 days Ib A Talan 2004 70 b) Efficacy and tolerance of extended release ciprofloxacin (ciproXR) 1000 mg od b) equivalent with 10-day conventional ciprofloxacin Cefpodoxime* 200 mg bid 10 days Ib B Naber 2001 73 c) Clinically equivalent with ciprofloxacin 500 mg bid Gatifloxacin 400 mg od 10 days Ib A Naber 2004 71 d) Equivalent with ciprofloxacin 500 mg bid, not available in Europe Levofloxacin 250 mg od 10 days Ib A Richard 1998 72 e) Equivalent with ciprofloxacin 500 mg bid Lomefloxacin 400 mg od 10 days Ib B Richard 1998 72 f ) Study statistically underpowered TMP-SMX 160/800 mg bid 14 days Ib B Stamm 1987 68 g) Only if uropathogen is known to be susceptible to TMP Talan 2004 70 *Cefpodoxime proxetil. LE = level of evidence; GR = grade of recommendation; TMP = trimethoprim; SMX = sulphamethoxazole; tid = three times daily; bid = twice daily; od = once daily; AE = adverse events.

Table 2.4: Oral treatment options of acute uncomplicated pyelonephritis in adult pre-menopausal non-pregnant women according to level of evidence and grade of recommendation. (For parenteral therapy, see text.)

2.6.3 Post-treatment follow-up Routine post-treatment cultures in an asymptomatic patient may not be indicated; routine urinalysis using a dipstick method is sufficient. In women whose pyelonephritis symptoms do not improve within 3 days, or that resolve and then recur within 2 weeks, a repeat urine culture, antimicrobial susceptibility testing and an appropriate investigation, such as renal ultrasound or scan, should be performed. In the patient with no urological abnormality, it should be assumed that the infecting organism is not susceptible to the agent originally used and retreatment with a 2-week regimen using another agent should be considered. For those patients who relapse with the same pathogen as the initially infecting strain, a 6-week regimen is usually curative. An overview of the clinical management of acute pyelonephritis is shown in Figure 2.1. Figure 2.1. Clinical management of acute pyelonephritis Symptoms and signs of pyelonephritis (fever, flank pain, pyuria, leucocytosis)

No

Nausea, vomiting or sepsis syndrome

Urinalysis and urine culture Ultrasonography Outpatient treatment Oral therapy: 7-14 days • Fluoroquinolone • Aminopenicillin plus a BLI • Cephalosporin (3rd gen) • TMP-SMX, only if susceptibility of pathogen is confirmed



Improvement within 72 hours



• Oral therapy • Urine culture 4 days on and 10 days off therapy • Urological evaluation if indicated

Yes

Urinalysis, urine and blood cultures Ultrasonography Inpatient treatment Start parenteral therapy: 1-3 days • Fluoroquinolone • Aminopenicillin plus a BLI • Cephalosporin (3rd gen) • Aminoglycoside Total therapy duration: 14-21 days

No improvement or deterioration • Hospitalize outpatient • Review cultures and sensitivities • Urological evaluation for complicating factors • Drain obstruction or abscess

BLI = ß-lactamase inhibitor; TMP = trimethoprim; SMX = sulphamethoxazole.

2.7

Recurrent (uncomplicated) UTIs in women

2.7.1 Background Recurrent urinary tract infection (RUTI) is defined in the literature by three episodes of UTI in the last 12 months or two episodes in the last 6 months. Risk factors for RUTI are genetic and behavioural (75) (IIa). Some studies estimate that 20-30% of women who have a UTI will have a RUTI (76). Women who are non-secretors of blood group substances have an increased occurrence of RUTI (77) (IIa). A secretor is defined as a person who secretes their blood type antigens into body fluids and secretions, such as saliva, etc. A non-secretor on the other hand puts little to none of their blood type antigens into these fluids. In the USA about 20% of the population are non-secretors. Women with RUTI have an increased frequency of urinary infection in firstdegree female relatives (78) (IIa). In addition, E. coli, the most common uropathogen, adheres more readily to epithelial cells in women who experience RUTI (79, 80) (IIb). Behavioural factors associated with RUTI include sexual activity, with a particularly high risk in those who use spermicides as a birth control method (81,82) (IIa). According to cohort and case control studies (4-6) (IIa), risk factors associated with RUTI in sexually active premenopausal women are frequency of sexual intercourse, spermicide use, age of first UTI (less than 15 years of age indicates a greater risk of RUTI) and history of UTI in the mother, suggesting that genetic factors and/or long-term environmental exposures might predispose to this condition. Following the menopause, risk factors strongly associated with RUTI are vesical prolapse, incontinence and post-voiding residual urine. Other risk factors such as blood group substance non-secretor status and a history of UTI before the menopause need to be confirmed by further research (83). Recurrent UTIs result in significant discomfort for women and have a high impact on ambulatory health care costs as a result of outpatient visits, diagnostic tests and prescriptions. Different approaches have been proposed for the prevention of RUTI, including non-pharmacological therapies, such as voiding after

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sexual intercourse or the ingestion of cranberry juice (84), and the use of antibiotics as preventive therapy given regularly or postcoital prophylaxis in sexually active women. With respect to antibiotic prophylaxis, it is not known which antibiotic schedule is best or the optimal duration of prophylaxis, the incidence of adverse events, or the recurrence of infections after stopped prophylaxis or treatment compliance. 2.7.2 Prophylactic antimicrobial regimens One effective approach for the management of recurrent uncomplicated UTI is the prevention of infection through the use of long-term, prophylactic antimicrobials taken on a regular basis at bedtime (85-87) (Ib) or postcoital (88) (Ib). In a Cochrane review (89) (Ia) every published randomized controlled trial from 1966 to April 2004 was analyzed in which antibiotics were used as a preventive strategy for recurrent UTIs and administered for at least 6 months. Nineteen out of 108 studies involving 1120 women were eligible for inclusion. In nine of these studies one antibiotic regimen was compared with placebo. In another seven studies different antibiotic regimens were compared concerning microbiological outcome, while in another three studies antibiotic regimens with non-antibiotic regimes were compared concerning microbiological outcome (Table 2.5) (90-107). During active prophylaxis the rate of microbiological recurrence per patient-year was 0 to 0.9 per patient-year in the antibiotic group, which was significantly lower than 0.8 to 3.6 per patient-year in the placebo group. The relative risk of having one microbiological recurrence was 0.21 (95% CI 0.13-0.34), significantly favouring antibiotic prophylaxis. For clinical recurrences the relative risk was 0.15 (95% CI 0.08-0.28), significantly favouring antibiotic prophylaxis. The relative risk of having one microbiological recurrence after prophylaxis was 0.82 (95% CI 0.44-1.53). The relative risk for severe side effects was 1.58 (95% CI 0.47-5.28) and for other side effects the relative risk was 1.78 (95% CI 1.06-3.00), significantly favouring placebo. Side effects included vaginal and oral candidiasis and gastrointestinal symptoms. Generally, the number of patients with microbiological recurrent UTIs decreased by eightfold as compared to the period of time before prophylaxis and compared to placebo by fivefold. The UTI episodes per patient-year was reduced in general by 95% during antimicrobial prophylaxis as compared to the period of time before prophylaxis. The initial duration of prophylactic therapy was usually 6 months or 1 year. However, for co-trimoxazole (TMP-SMX), continuous prophylaxis for as long as 2 (86) or 5 years (85) has remained efficacious. Prophylaxis does not appear to modify the natural history of a recurrent UTI. When discontinued, even after extended periods, approximately 60% of women will become re-infected within 3-4 months. Thus, prophylaxis did not appear to exert a long-term effect on the baseline infection rate (108) (III).

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8/49 Nitrofurantoin 50 mg24h 2/26 Nitrofurantoin 100 mg/24h 16/38 Nitrofurantoin 100 mg/24h 1/13 Nitrofurantoin 100 mg/24h 1/12 Cinoxacin 500 mg/24h 17/185 Pefloxacin 400 mg/mon 2/70 Ciprofloxacin 125 mg/24h 47/393 (12.0%)

8/48 20.0 0/26 7.2 4/34 19.2 1/13 8.5 2/14 10.3 52/176 22.6 2/65 12.2 69/376 (18.4%)

(0.40-2.40) (0.25-99.4) (1.33-9.66) (0.07-14,3) (0.06-5.66) (0.19-0.52) (0.13-6.40)

Brumfitt 1995 Nunez 1990 Brumfitt 1985 Stamm 1980 Seppanen 1988 Guibert 1995 Melekos 1997

Martens 1995 Martorana 1984 Schaeffer 1982 Scheckler 1982 Nicolle 1989 Rugendorff 1987 Stamm 1980 Bailey 1971 Gower 1975 Stamm 1980 Stapleton 1990

0.06 (0.01-0.39) 0.43 (0.24-0.75) 0.43 (0.09-1.99) 0.13 (0.02-0.96) 0.06 (0.00-0.85) 0.29 (0.12-0.72) 0.09 (0.01-0.63) 0.20 (0.07-0.61) 0.09 (0.01-0.62) 0.11 (0.02-0.75) 0.15 (0.04-0.58) 0.21 (0.13-0.34)

0.98 5.00 3.58 1.00 0.58 0.31 0.93

Author, Year

Relative Risk (95% CI)

100 101 102 97 103 104 105

91 92 93 94 95 96 97 98 99 97 90

Ref

Antibiotics vs Non-antibiotics Nitrofurantoin 50 mg/12h 4/43 Meth. hippurate 1 g/12h 19/56 0.27 (0.10-0.75) Brumfitt 1981 106 Trimethoprim 100 mg/24h 8/20 Povidone iodine Topical 10/19 0.76 (0.38-1.51) Brumfitt 1983 107 Trimethoprim 100 mg/24h 8/20 Meth. hippurate 1 g/12h 10/25 1.00 (0.49-2.05) Brumfitt 1983 107 TMP-SMX = trimethoprim-sulphamethoxazole; Meth. hippurate = methanamine hippurate.

Antibiotic vs Antibiotic Cefaclor 250 mg/24 Norfloxacin 400 mg/24 Trimethoprim 100 mg/24h TMP-SMX 40/200 mg/24h Trimethoprim 100 mg/24h Pefloxacin 400 mg/weekly Ciprofloxacin 125 mg postcoital Total

Substance Dosage n/N Comparator Dosage n/N Weight (%) Antibiotic vs Placebo Cinoxacin 250 mg/24h 1/23 Placebo 17/22 5.4 Cinoxacin 500 mg/24h 8/21 Placebo 17/19 24.2 Cinoxacin 500 mg/24h 2/15 Placebo 4/13 7.9 Cinoxacin 500 mg/24h 1/20 Placebo 8/21 5.1 Norfloxacin 200 mg/24h 0/11 Placebo 10/13 2.9 Norfloxacin 200 mg/24h 4/18 Placebo 13/17 16.0 Nitrofurantoin 100 mg/24h 1/13 Placebo 5/6 5.5 Nitrofurantoin 50 mg/24h 3/25 Placebo 15/25 12.5 Cephalexin 125 mg/24h 1/20 Placebo 13/23 5.3 TMP-SMX 40/200 mg/24h 1/13 Placebo 5/7 5.3 TMP-SMX 40/200 mg postcoital 2/16 Placebo 9/11 9.8 Total 24/195 (12.3%) 116/177 (65.5%)

Table 2.5: Efficacy (reduction of microbiological recurrences) of antibiotics for preventing recurrent urinary tract infection in non-pregnant women (modified according 85) with a study period of at least 6 months

The recommendations for antimicrobial regimens for the prevention (prophylaxis) of recurrent uncomplicated UTI in pre-menopausal women are listed in Table 2.6. Trimethoprim, co-trimoxazole or nitrofurantoin can still be considered as the standard regimen. Fosfomycin trometamol (FT), 3g every 10 days for 6 months can be considered as an alternative as shown by a recent placebo (PL) controlled study in 302 evaluable non-pregnant females suffering from recurrent lower UTI (109) (Ib). The UTI episodes per patientyear (0.14 vs 2.97), the time to first infection recurrence (38 days vs 6 days), the percentage of patients with at least one episode of recurrent UTI (7.0% vs 75.0%), and the number of UTI episodes per patient during 6 months treatment (0.07 vs 1.44) and during the 6 months, follow-up, period (0.55 vs 1.54) were all statistically in favour of the FT-treated group. In cases of ‘breakthrough’ infection due to resistant pathogens, low doses of fluoroquinolones may also be used. No increased emergence of resistance was observed (101, 105). During pregnancy, an oral first-generation cephalosporin is recommended. An alternative prophylactic approach is post-intercourse prophylaxis for women in whom episodes of infection are associated with sexual intercourse (88, 89, 105) (IbA). Generally, for this approach, the same antimicrobials can be used in the same doses as though recommended for continuous prophylaxis. A patientinitiated treatment may also be suitable for management in well-informed, young women, in whom the rate of recurrent episodes is not too common (112). This is, however, strictly speaking, not prophylaxis but early treatment. Table 2.6: Recommendations for antimicrobial prophylaxis of recurrent uncomplicated UTI in women (IA) Agent1 Standard regimen: • Nitrofurantoin • Nitrofurantoin macrocrystals • Trimethoprim-sulphamethoxazole • Trimethoprim • Fosfomycin trometamil

Dose 50 mg/day (98) 100 mg/day (101, 106) 40/200 mg/day (97) or three times weekly (110) 100 mg/day (103) 3 g/10 day (109)

‘Breakthrough’ infections: • Ciprofloxacin • Norfloxacin • Pefloxacin

125 mg/day (105) 200-400 mg/day (101, 111) 800 mg/week (104)

During pregnancy: • Cephalexin Cefaclor

125 mg/day (99) 250 mg/day (100)

1

Taken at bedtime.

2.7.3 Alternative prophylactic methods Alternative methods, such as the acidification of urine (113), cranberry juice (84), extract from uvae ursi and the vaginal application of lactobacilli (114, 115), show variable effects. A meta-analysis of five, placebocontrolled, double-blind studies using oral immuno-active E. coli fractions (UroVaxom) resulted in a significant reduction of recurrent infections as compared with placebo (116) (Ia). In a recently published study (117) (Ib), a total of 453 patients were included in a placebo-controlled, double-blind study. Patients received either the immunotherapeutic OM-89 (UroVaxom) or a matching placebo. After receiving one capsule per day for 90 days, patients had 3 months without treatment, before being given one capsule on the first 10 days in the following 3 months. Patients were followed up for 12 months from the beginning of treatment. The mean rate of post-baseline UTI episodes was significantly lower in the active group than in the placebo group (0.84 vs 1.28; p 2%. In socially stable populations with a low prevalence of asymptomatic bacteriuria, screening programmes may be not necessary (125) (IIIB). On the other hand, a sharp reduction in the annual incidence of pyelonephritis could be achieved following the introduction of a programme to screen and treat asymptomatic bacteriuria among pregnant women (123) (IIaB). To avoid unnecessary treatment, asymptomatic bacteriuria is defined as two consecutive positive cultures of the same species. The false-positive rate of a single MSU may be as high as 40% (IIb). Therefore, women with a positive urine culture should be asked to return within 1-2 weeks, at which time, after stressing the importance of a careful cleansing of the vulva before micturition, a second MSU or straight catheter urine specimen is obtained for culture (IIaB). Treatment should be based on antibiotic sensitivity testing and usually involves a 5- to 7-day course of antibiotics (124) (IIIB); however, some authors recommend short-term therapy, as for acute cystitis (126) (IIaB). Follow-up cultures should be obtained 1-4 weeks after treatment and at least once more before delivery (IIIB). A Cochrane analysis of eight studies involving 400 patients was performed concerning the duration of treatment for asymptomatic bacteriuria during pregnancy (127). All the studies were comparisons of singledose treatment with 4-7 days of treatment, though it should be noted that the trials were generally of poor quality. The analysis found no difference in ‘no-cure’ rates between single dose and short course (4-7 day)

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treatment for asymptomatic bacteriuria in pregnant women (relative risk 1.13, 95% CI 0.82-1.54), as well as in recurrent asymptomatic bacteriuria (relative risk 1.08, 95% CI 0.70-1.66). However, these results showed significant heterogeneity. No differences were detected for preterm births and pyelonephritis, but the trials involved had a small sample size. Treatment of longer duration was associated with increased adverse events (relative risk 0.53, 95% CI 0.31-0.91). Overall, there was therefore not enough evidence to evaluate whether single dose or longer-duration doses were more effective in treating asymptomatic bacteriuria in pregnant women (C). Since a single dose costs less and is likely to increase patient compliance, this comparison should be explored in an adequately powered randomized controlled trial. 2.8.3 Acute cystitis during pregnancy Most symptomatic UTIs in pregnant women present as acute cystitis, as occurs in non-pregnant women. Usually a 7-day treatment course is recommended, e.g. with pivmecillinam (128) (IbA). Short-term therapy is not as established in pregnant women as it is in non-pregnant women, but it is recommended by smaller studies and expert opinion (126) (IIaB). Fosfomycin trometamol (3 g single dose) or second- and thirdgeneration oral cephalosporins (e.g. ceftibuten 400 mg once daily) could be considered candidates for effective short-term therapy (129) (IIaB). Otherwise conventional therapy with amoxycillin, cephalexin or nitrofurantoin is recommended (IVC). Follow-up urine cultures should be obtained after therapy to demonstrate eradication of the bacteriuria. As in non-pregnant women, there is no advantage to be gained by using long-term prophylaxis except for recurrent infections. Low-dose cephalexin (125-250 mg) or nitrofurantoin (50 mg) at night are recommended for prophylaxis against re-infection if indicated, lasting up to and including the puerperium. Postcoital prophylaxis may be an alternative approach (130, 131) (IIaB). 2.8.4 Acute pyelonephritis in pregnancy Acute pyelonephritis tends to occur during the later stages of pregnancy, usually in the last trimester. A review by Gilstrap et al. (132) found acute pyelonephritis in 2% of 24,000 obstetric patients. The incidence is increased in the puerperium. Characteristically, the patient is acutely ill with high fever, leucocytosis and costovertebral angle pain. Bacteraemia is common, but mortality and complications are low when the patient is treated with effective therapy. The major causes of concern are the presence of underlying urological abnormalities and associated risks to the mother and fetus, such as toxaemia, hypertension, prematurity and perinatal mortality. Currently, antimicrobial therapy is so effective that, even with bacteraemia, almost all patients with uncomplicated pyelonephritis do well and become afebrile within a few days. Recommended antibiotics include second- or third-generation cephalosporins, an aminopenicillin plus a BLI, or an aminoglycoside. During pregnancy, quinolones, tetracyclines and TMP should not be used during the first trimester, while sulphonamides should not be used in the last trimester (133, 134). In cases of delayed defeverescence and upper tract dilatation, a ureteral stent may be indicated and antimicrobial prophylaxis until delivery and including the puerperium should be considered (C). In a Cochrane analysis on treatments for symptomatic UTIs during pregnancy, eight studies were included recruiting a total of 905 pregnant women. In most of the comparisons, there were no significant differences between treatments with regard to cure rates, recurrent infection, incidence of preterm delivery and premature rupture of membranes, admission to the neonatal intensive care unit, need for change of antibiotic and incidence of prolonged pyrexia. Although antibiotic treatment is effective for the cure of UTIs (A), there are insufficient data to recommend any specific treatment regimen for symptomatic UTIs during pregnancy. Complications were very rare. Future studies should evaluate the most promising antibiotics, in terms of class, timing, dose, acceptibility, maternal and neonatal outcomes and costs (135).

2.9

UTIs in post-menopausal women

The normal vagina contains only low numbers of Gram-negative enteric bacteria because of competition from the resident microbial flora. Lactobacilli account for the low vaginal pH. They tend to be less abundant in post-menopausal women and after antimicrobial therapy. Oestrogens are presumed to exert a protective force against recurrent UTIs in post-menopausal women because they enhance the growth of lactobacilli and decrease vaginal pH (136) (IIb). Gram-negative enteric bacteria do not ordinarily colonize the vagina in post-menopausal women unless these women are prone to recurrent UTIs (137) (IIb). In post-menopausal women with recurrent UTIs, therapy with oral (138, 139) or intravaginal oestriol (136) reduced significantly the rate of recurrence (IbA). For other patients, an antimicrobial prophylactic regimen (see previously) should be recommended in addition to hormonal treatment. In the case of an acute UTI, the antimicrobial treatment policy is similar to that in pre-menopausal women. Short-term therapy in post-menopausal women is not, however, as well documented as in younger women. Raz et al. (140) (Ib) published a study in post-menopausal women (mean age 65 years) with an uncomplicated UTI in which ofloxacin, 200 mg once daily for 3 days, was significantly more effective in both

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27

short- and long-term follow-up than a 7-day course of cephalexin, 500 mg four times daily, even though all the uropathogens were susceptible to the two agents. In another double-blind study (46) (Ib), including a total of 183 post-menopausal women of at least 65 years of age with acute uncomplicated UTI, similar results were obtained with either a 3-day or a 7-day oral course of ciprofloxacin 250 mg two times daily (bacterial eradication 2 days after treatment 98% vs 93%, p=0.16), but the shorter course was better tolerated. The rate of bacterial eradication in this study was generally high and the rate of bacterial resistance to ciprofloxacin low. However, these results should not be extended to the frail elderly population with significant comorbidities, who frequently present with UTI caused by Gram-negative or resistant organisms. In the case of RUTI, a urological or gynaecological evaluation should be performed in order to eliminate a tumour, obstructive problems, detrusor failure or a genital infection (IVC).

2.10

Acute uncomplicated UTIs in young men

2.10.1 Pathogenesis and risk factors It has been conventional to consider all UTIs in men as complicated because most UTIs occurring in the newborn, infant or elderly male are associated with urological abnormalities, bladder outlet obstruction or instrumentation. A UTI in an otherwise healthy adult man between the ages of 15 and 50 years is very uncommon. In Norway, a rate of 6-8 UTIs per year per 10,000 men aged 21-50 years has been reported (141). The large difference in the prevalence of UTIs between men and women is thought to be caused by a variety of factors, including the greater distance between the usual source of uropathogens (the anus and the urethral meatus); the drier environment surrounding the male urethra; the greater length of the male urethra; and the antibacterial activity of the prostatic fluid. It has become clear, however, that a small number of men aged 15-50 years suffer acute uncomplicated UTIs. The exact reasons for such infections are not clear, but risk factors associated with such infections include intercourse with an infected partner, anal intercourse and lack of circumcision (142); however, these factors are not always present. More than 90% of men with febrile UTI (fever > 38.0°C), with or without clinical symptoms of pyelonephritis, have a concomitant infection of the prostate, as measured by transient increases in serum PSA and prostate volume (143), irrespective of prostatic tenderness. 2.10.2 Diagnosis The symptoms of uncomplicated UTIs in men are similar to those in women. Urethritis must be ruled out in sexually active men using a urethral Gram stain or a first-voided urine specimen wet mount to look for urethral leucocytosis. A urethral Gram stain demonstrating leucocytes and predominant Gram-negative rods suggests E. coli urethritis, which may precede or accompany a UTI. Dysuria is common to both UTI and urethritis. The aetiological agents that cause uncomplicated UTIs in men are also similar to those in women. Krieger et al. (144) noted that 93% of 40 uncomplicated UTIs in men were caused by E. coli. 2.10.3 Treatment Due to the infrequency with which UTIs occur in this group of men, data from controlled treatment studies are non-existent. Empirical use of the agents discussed previously for uncomplicated cystitis or pyelonephritis in women are recommended (IIIB). Nitrofurantoin should not be used in men with a UTI, since it does not achieve reliable tissue concentrations (IVC). For acute uncomplicated pyelonephritis, the use of a fluoroquinolone as initial empirical treatment is recommended in areas where the rate of E. coli resistance to fluoroquinolones is low (< 10%) (IIaB). Otherwise, alternative drugs have to be considered (see Table 2.4). Since in most men with febrile UTI or pyelonephritis, prostatic involvement also has to be considered, the goal of treatment is not only to sterilize the urine, but also to eradicate the prostatic infection. Thus, antimicrobials with good prostatic tissue and fluid penetration are preferable, e.g. fluoroquinolones (143) (IIbB). Although it is possible that short-course treatment is effective in men with uncomplicated cystitis, there are no studies to support this practice. It is therefore recommended that such men receive a minimum of 7 days of therapy because of the relatively greater likelihood of an occult complicating factor in men compared with women (IIIB). Also, longer treatment may reduce the likelihood of persistent prostatic infection. There was, however, no statistically significant difference in outcome when men with febrile UTI were treated orally for 2 or 4 weeks with ciprofloxacin 500 mg twice daily, but the study did not have sufficient statistical power to show equivalence (145) (IIaB). Serum PSA should not be analyzed in conjunction with, or earlier than 6 months after, an episode of febrile UTI, unless prostate cancer is otherwise suspected (143) (IIbB). The value of a urological evaluation in a man who has had a single uncomplicated UTI has not been determined. Urological evaluation should be carried out routinely in adolescents and in men with febrile UTI, pyelonephritis and recurrent infections, or whenever a complicating factor is present (IIIB).

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2.11

Asymptomatic bacteriuria

Asymptomatic bacteriuria is common (146-150). Populations with structural or functional abnormalities of the genitourinary tract may have an exceedingly high prevalence of bacteriuria, but even healthy individuals frequently have positive urine cultures. Asymptomatic bacteriuria is seldom associated with adverse outcomes. Pregnant women (see section 2.8.2) and individuals undergoing traumatic genitourinary interventions are at risk for complications of bacteriuria and show benefit from screening and treatment programmes (124) (IbA). Although some experts (151) recommend screening for renal transplant recipients, the benefits for these patients are less clear; no recommendation can therefore be made (124). For other populations, including most bacteriuric individuals, negative outcomes attributable to asymptomatic bacteriuria have not been described. Screening for or treatment of asymptomatic bacteriuria is not recommended for the following persons (124): • pre-menopausal, non-pregnant women (IbA) • diabetic women (IbA) • older persons living in community (IIaB) • elderly institutionalized subjects (IbA) • persons with spinal cord injury (IIaB) • catheterized patients while the catheter remains in situ (IaA). In fact, treatment of bacteriuria may be associated with harmful outcomes, such as increased shortterm frequency of symptomatic infection, adverse drug effects, and re-infection with organisms of increased antimicrobial resistance. Screening for asymptomatic bacteriuria and treatment is recommended only for selected groups where benefit has been shown (124): • pregnant women (IbA) • before transurethral resection of the prostate (IbA) and other traumatic urological interventions (IIaB). Antimicrobial therapy should be initiated before the procedure (124) (IIaB). Short-term antimicrobial treatment of asymptomatic women with catheter-acquired bacteriuria that persists 48 hours after removal of the indwelling catheter may be considered (124, 152) (IIaB).

2.12

References

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Gupta K, Hooton TM, Roberts PL, Stamm WE. Patient-initiated treatment of uncomplicated recurrent urinary tract infections in young women. Ann Intern Med 2001;135(1):9-16. http://www.ncbi.nlm.nih.gov/pubmed/6981163 Fünfstück R, Straube E, Schildbach O, Tietz U. [Prevention of reinfection by L-methionine in patients with recurrent urinary tract infection] Med Klinik (Munich) 1997;92(10):574-81. http://www.ncbi.nlm.nih.gov/pubmed/9446004 Reid G. Probiotic therapy and functional food for prevention of urinary tract infections: State of the Art and Science. Curr Infect Dis Rep 2000;2(6):518-22. http://www.ncbi.nlm.nih.gov/pubmed/11095902 Baerheim A, Larsen E, Digranes A. Vaginal application of lactobacilli in the prophylaxis of recurrent lower urinary tract infection in women. Scand J Prim Health Care 1994;12(4):239-43. http://www.ncbi.nlm.nih.gov/pubmed/7863140 Bauer HW, Rahlfs VW, Lauener PA, Blessmann GS. Prevention of recurrent urinary tract infections with immuno-active E. coli fractions: a meta-analysis of five placebo-controlled double-blind studies. Int J Antimicrob Agents 2002;19(6):451-6. http://www.ncbi.nlm.nih.gov/pubmed/12135831 Bauer HW, Alloussi S, Egger G, Blümlein HM, Cozma G, Schulman CC; Multicenter UTI Study Group. A long-term, multicenter, double-blind study of an Escherichia coli extract (OM-89) in female patients with recurrent urinary tract infections. Eur Urol 2005;47(4):542-8. http://www.ncbi.nlm.nih.gov/pubmed/15774256 Riedasch G, Möhring K. [Immunotherapy in women with recurrent urinary tract infections.] Therapiewoche 1986;6:896-900. [German] Uehling DT, Hopkins WJ, Elkahwaji JE, Schmidt DM, Leverson GE. Phase 2 clinical trial of a vaginal mucosal vaccine for urinary tract infections. J Urol 2003;170(3):867-69. http://www.ncbi.nlm.nih.gov/pubmed/12913718 MacLean AB. Urinary tract infection in pregnancy. Br J Urol 1997;80 Suppl 1:10-3. http://www.ncbi.nlm.nih.gov/pubmed/9240218 Kass EH. Bacteriuria and pyelonephritis of pregnancy. Arch Intern Med 1960;105:194-8. http://www.ncbi.nlm.nih.gov/pubmed/14404662 Stenqvist K, Dahlén-Nilsson I, Lidin-Janson G, Lincoln K, Odén A, Rignell S, Svanborg-Edén C. Bacteriuria in pregnancy. Frequency and risk of acquisition. Am J Epidemiol 1989;129(2):372-9. http://www.ncbi.nlm.nih.gov/pubmed/2912046 Gratacós E, Torres PJ, Vila J, Alonso PL, Cararach V. Screening and treatment of asymptomatic bacteriuria in pregnancy prevent pyelonephritis. J Infect Dis 1994;169(6):1390-2. http://www.ncbi.nlm.nih.gov/pubmed/8195624 Nicolle LE, Bradley S, Colgan R, Rice JC, Schaeffer A, Hooton TM; Infectious Diseases Society of America; American Society of Nephrology; American Geriatric Society. Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis 2005;40(5):643-54. http://www.ncbi.nlm.nih.gov/pubmed/15714408 Wadland WC, Plante DA. Screening for asymptomatic bacteriuria in pregnancy. A decision and cost analysis. J Fam Pract 1989;29(4):372-6. http://www.ncbi.nlm.nih.gov/pubmed/2794885 Bailey RR. Single-dose/short-term therapy in children and in pregnant women. Infection 1994; 22 Suppl 1:S47-S48. http://www.ncbi.nlm.nih.gov/pubmed/8050794 Villar J, Lydon-Rochelle MT, Gülmezoglu AM, Roganti A. Duration of treatment for asymptomatic bacteriuria during pregnancy. Cochrane Database Syst Rev 2000;(2):CD000491. http://www.ncbi.nlm.nih.gov/pubmed/10796207 Nicolle LE. Pivmecillinam for the treatment of acute uncomplicated urinary infection. Int J Clin Pract 1999;53(8):612-7. http://www.ncbi.nlm.nih.gov/pubmed/10692756 Krcmery S, Hromec J, Demesova D. Treatment of lower urinary tract infection in pregnancy. Int J Antimicrob Agents 2001;17(4):279-82. http://www.ncbi.nlm.nih.gov/pubmed/11295408 Pfau A, Sacks TG. Effective prophylaxis for recurrent urinary tract infections during pregnancy. Clin Infect Dis 1992;14(4):810-4. http://www.ncbi.nlm.nih.gov/pubmed/1576275

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3. URINARY TRACT INFECTIONS IN CHILDREN 3.1

Summary and recommendations

Urinary tract infection (UTI) in children is a frequent health problem, with the incidence of UTIs only a little lower than the incidences for upper respiratory and digestive infections. The incidence of UTI varies depending on age and sex. In the first year of life, mostly the first 3 months, UTI is more common in boys (3.7%) than in girls (2%), after which the incidence changes, being 3% in girls and 1.1% in boys. Paediatric UTI is the most common cause of fever of unknown origin in boys less than 3 years. The clinical presentation of a UTI in infants and young children can vary from fever to gastrointestinal, lower or upper urinary tract symptoms. Investigation should be undertaken after two episodes of a UTI in girls and one in boys (B). The objective is to rule out the unusual occurrence of obstruction, vesicoureteric reflux (VUR) and dysfunctional voiding, e.g. as caused by a neuropathic disorder. Chronic pyelonephritic renal scarring develops very early in life due to the combination of a UTI, intrarenal reflux and VUR. It sometimes arises in utero due to dysplasia. Although rare, renal scarring may lead to severe long-term complications such as hypertension and chronic renal failure. Vesicoureteric reflux is treated with long-term prophylactic antibiotics (B). Surgical re-implantation or endoscopic treatment is reserved for the small number of children with breakthrough infection (B). In the treatment of a UTI in children, short courses are not advised and therefore treatment is continued for 5-7 days and longer (A). If the child is severely ill with vomiting and dehydration, hospital admission is required and parenteral antibiotics are given initially (A).

3.2

Background

The urinary tract is a common source of infection in children and infants. It represents the most common bacterial infection in children less than 2 years of age (1) (IIa). The outcome of a UTI is usually benign, but in early infancy it can progress to renal scarring, especially when associated with congenital anomalies of the urinary tract. Delayed sequelae related to renal scarring include hypertension, proteinuria, renal damage and even chronic renal failure, requiring dialysis treatment in a significant number of adults (2) (IIa). The risk of a UTI during the first decade of life is 1% in males and 3% in females (3). It has been suggested that 5% of schoolgirls and up to 0.5% of schoolboys undergo at least one episode of UTI during their school life. The incidence is different for children under 3 months of age, when it is more common in males. The incidence of asymptomatic bacteriuria is 0.7-3.4% in neonates, 0.7-1.3% in infants under 3 months of age and between 0.2% and 0.8% in preschool boys and girls, respectively (3). The incidence of symptomatic bacteriuria is 0.14% in neonates, with a further increase to 0.7% in boys and 2.8% in girls aged less than 6 months. The overall recurrence rate for the neonatal period has been reported to be 25% (3, 4).

3.3

Aetiology

The common pathogenic sources are Gram-negative, mainly enteric, organisms. Of these, Escherichia coli is responsible for 90% of episodes of UTIs (5). Gram-positive organisms (particularly enterococci and staphylocci) represent 5-7% of cases. Hospital-acquired infections show a wider pattern of aggressive organisms, such as Klebsiella, Serratia and Pseudomonas spp. Groups A and B streptococci are relatively common in the newborn (6). There is an increasing trend towards the isolation of Staphylococcus saprophyticus in UTIs in children, although the role of this organism is still debatable (7).

3.4 Pathogenesis and risk factors The urinary tract is a sterile space with an impermeable lining. Retrograde ascent is the most common mechanism of infection. Nosocomial infection and involvement as part of a systemic infection are less common (8).

38

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Obstruction and dysfunction are among the most common causes of urinary infection. Phimosis predisposes to UTI (9,10) (IIa). Enterobacteria derived from intestinal flora colonize the preputial sac, glandular surface and the distal urethra. Among these organisms are strains of E. coli expressing P fimbriae which adhere to the inner layer of the preputial skin and to uroepithelial cells (11). A wide variety of congenital urinary tract abnormalities can cause UTIs through obstruction, e.g. urethral valves, pelvi-ureteric junction obstruction or non-obstructive urinary stasis (e.g. prune belly syndrome, VUR). More mundane but significant causes of UTIs include labial adhesion and chronic constipation (7). Dysfunctional voiding in an otherwise normal child may result in infrequent bladder emptying aided by delaying manoeuvres, e.g. crossing legs, sitting on heels (12). Neuropathic bladder dysfunction (spina bifida, sphincter dyssynergia, etc) may lead to postvoid residual urine and secondary VUR (4). The link between renal damage and UTIs is controversial. The mechanism in obstructive nephropathy is self-evident, but more subtle changes occur where there is VUR. Almost certainly the necessary components include VUR, intrarenal reflux and a UTI. These must all work together in early childhood when the growing kidney is likely to be susceptible to parenchymal infection. Later on in childhood, the presence of bacteriuria seems irrelevant to the progression of existing scars or the very unusual formation of new scars. Another confounding factor is that many so-called scars are dysplastic renal tissue which developed in utero (13).

3.5

Signs and symptoms

Symptoms are non-specific, and vary with the age of the child and the severity of the disease. Epididymoorchitis is extremely unusual. With scrotal pain and inflammation in a boy, testicular torsion has to be considered. A UTI in neonates may be non-specific and with no localization. In small children, a UTI may present with gastrointestinal signs, such as vomiting and diarrhoea. In the first weeks of life, 13.6% of patients with fever have a UTI (14). Rarely, septic shock will be the presentation. Signs of a UTI may be vague in small children, but later on, when they are older than 2 years, frequent voiding, dysuria and suprapubic, abdominal or lumbar pain may appear with or without fever.

3.6

Classification

Urinary tract infections may be classified either as a first episode or recurrent, or according to severity (simple or severe). Recurrent UTI may be subclassified into three groups (8): • Unresolved infection: subtherapeutic level of antimicrobial, non-compliance with treatment, malabsorption, resistant pathogens. • Bacterial persistence: may be due to a nidus for persistent infection in the urinary tract. surgical correction or medical treatment for urinary dysfunction may be needed. • Reinfection: each episode is a new infection acquired from periurethral, perineal or rectal flora. From the clinical point of view, severe and simple forms of UTIs should be differentiated because to some extent the severity of symptoms dictates the degree of urgency with which investigation and treatment are to be undertaken (Table 3.1). Table 3.1: Clinical classification of urinary tract infections (UTIs) in children Severe UT • Fever > 39°C • Persistent vomiting • Serious dehydration • Poor treatment compliance

Simple UTI • Mild pyrexia • Good fluid intake • Slight dehydration • Good treatment compliance

3.6.1 Severe UTI Severe UTI is related to the presence of fever of > 39ºC, the feeling of being ill, persistent vomiting, and moderate or severe dehydration. 3.6.2 Simple UTI A child with a simple UTI may have only mild pyrexia, but is able to take fluids and oral medication. The child is only slightly or not dehydrated and has a good expected level of compliance. When a low level of compliance is expected, such a child should be managed as one with a severe UTI.

3.7

Diagnosis

3.7.1 Physical examination It is mandatory to look for phimosis, labial adhesion, signs of pyelonephritis, epididymo-orchitis, and stigmata

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of spina bifida, e.g. hairy patch on the sacral skin. The absence of fever does not exclude the presence of an infective process. 3.7.2 Laboratory tests The definitive diagnosis of infection in children requires a positive urine culture (8, 15). Urine must be obtained under bacteriologically reliable conditions when undertaking a urine specimen culture (16). A positive urine culture is defined as the presence of more than 100,000 cfu/mL of one pathogen. The urine specimen may be difficult to obtain in a child less than 4 years old and different methods are advised since there is a high risk of contamination (17, 18). 3.7.2.1 Collection of the urine 3.7.2.1.1 Suprapubic bladder aspiration Suprapubic bladder aspiration is the most sensitive method, even though urine may be obtained in 23-99% of cases (8, 18). 3.7.2.1.2 Bladder catheterization Bladder catheterization is also a most sensitive method, even though there is the risk of introduction of nosocomial pathogens (8, 19). 3.7.2.1.3 Plastic bag attached to the genitalia Prospective studies showed a high incidence of false-positive results, ranging from 85-99% (8, 18). It is helpful when the culture is negative (8, 18) and has a positive predictive value of 15% (16). In order to obtain a urine sample in the best condition in children under 2 years of age (girls and uncircumcised boys without sphincteric control), it is better to use suprapubic bladder aspiration or bladder catheterization. In older children with sphincteric control, midstream urine (MSU) collection is possible and reliable (18). 3.7.2.2 Quantification of bacteriuria The final concentration of bacteria in urine is directly related to the method of collection, diuresis, method of storage and transport of the specimen (15). The classical definition of significant bacteriuria of more than 105 cfu/mL is still used and depends on the clinical environment (15, 17). The presence of pyuria (more than 5 leucocytes per field) and bacteriuria in a fresh urine sample will reinforce the clinical diagnosis of UTI (17). In boys, when the urine is obtained by bladder catheterization, the urine culture is considered positive with more than 104 cfu/mL. Even though Hoberman (20) identified a micro-organism in 65% of cases with colony counts between 10,000 and 50,000 cfu/mL, there was a mixed growth pattern suggesting contamination. In these cases, it is better to repeat the culture or to evaluate the presence of other signs, such as pyuria, nitrites or other biochemical markers (15). The collection of MSU or in a collecting bag of more than 105 cfu/mL is considered positive (16) (Table 3.2). Table 3.2: Criteria of UTI in children Urine specimen from suprapubic Urine specimen from bladder bladder puncture catheterization > 1,000-50,000 cfu/mL Any number of cfu/mL (at least 10 identical colonies)

Urine specimen from midstream void > 104 cfu/mL with symptoms > 105 cfu/mL without symptoms

3.7.2.3 Other biochemical markers The presence of other biochemical markers in a urine sample are useful to establish the diagnosis of UTI (8). The most frequent markers are nitrite and leucocyte esterase usually combined in a dipstick test. 3.7.2.3.1 Nitrite This is the degradation product of the nitrates of bacterial metabolism, particularly of Gram-negative bacteria. When an infection is caused by Gram-positive bacteria, the test may be negative (8, 16). Limitations of the nitrite test include: • not all uropathogens reduce nitrate to nitrite, e.g. Pseudomonas aeruginosa, enterococci • even nitrite-producing pathogens may show a negative test result, due to the short transit time in the bladder in cases of high diuresis and urine dilution, e.g. neonates. The nitrite test has a sensitivity of only 45-60%, but a very good specificity of 85-98% (8, 17, 21).

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3.7.2.3.2 Leucocyte esterase Leucocyte esterase is produced by the activity of leucocytes. The test for leucocyte esterase has a sensitivity of 48-86% and a specificity of 17-93% (8, 17, 20, 21). A combination of nitrite and leucocyte esterase testing improves sensitivity and specificity, but carries the risk of false-positive results (21). The dipstick test has become useful to exclude rapidly and reliably the presence of a UTI, provided both nitrite and leucocyte esterase tests are negative. If the tests are positive, it is better to confirm the results in combination with the clinical symptoms and other tests (17, 21). Bacteriuria without pyuria may be found: • in bacterial contamination • in colonization (asymptomatic bacteriuria) • when collecting a specimen before the onset of an inflammatory reaction. In such cases, it is advisable to repeat the urinalysis after 24 hours to clarify the situation. Even in febrile children with a positive urine culture, the absence of pyuria may cast doubt on the diagnosis of UTI. Instead, asymptomatic bacteriuria with a concomitant septic focus responsible for the febrile syndrome has to be considered. Bacteriuria without pyuria is found in 0.5% of specimens. This figure corresponds well with the estimated rate of asymptomatic bacteriuria in childhood (20, 22) (IIa). Pyuria without bacteriuria may be due to: • incomplete antimicrobial treatment of UTI • urolithiasis and foreign bodies • infections caused by Mycobacterium tuberculosis and other fastidious bacteria, e.g. Chlamydia trachomatis. Thus, either bacteriuria or pyuria may not be considered reliable parameters to diagnose or exclude UTI. Their assessment can be influenced by other factors, such as the degree of hydration, method of specimen collection, mode of centrifugation, volume in which sediment is resuspended and subjective interpretation of results (23). However, according to Landau et al. (24), pyuria in febrile children is indicative of acute pyelonephritis. For all of these reasons, in neonates and children under 6 months of age, either pyuria, bacteriuria or the nitrite test, separately, have minimal predictive value for UTI (25, 26) (III). In contrast, the positive predictive value of significant Gram staining with pyuria is 85% (20) (IIb). In older children, pyuria with a positive nitrite test is more reliable for the diagnosis of UTI, with a positive predictive value of 98%. Combining bacteriuria and pyuria in febrile children, the findings of > 10 WBC/mm3 and > 50,000 cfu/ mL in a specimen collected by catheterization are significant for a UTI and discriminate between infection and contamination (20, 25). 3.7.2.3.3 C-reactive protein Although non-specific in febrile children with bacteriuria, C-reactive protein seems to be useful in distinguishing between acute pyelonephritis and other causes of bacteriuria. It is considered significant at a concentration above 20 µg/mL. 3.7.2.3.4 Urinary N-acetyl-ß-glucosaminidase This is a marker of tubular damage. It is increased in a febrile UTI and may become a reliable diagnostic test for UTIs, although it is also elevated in VUR (27). 3.7.2.3.5 Interleukin-6 The clinical use of urinary concentrations of interleukin-6 in UTIs (28) is still at the research stage. 3.7.3 Imaging of the urinary tract A ‘gold standard’ imaging technique has to be cost-effective, painless, safe, with minimal or nil radiation, and an ability to detect any significant structural anomaly. Current techniques do not fulfil all such requirements. 3.7.3.1 Ultrasonography Ultrasonography (US) has become very useful in children because of its safety, speed and high accuracy in identifying the anatomy and size of the renal parenchyma and collecting system (29). It is subjective and therefore operator-dependent, and gives no information on renal function. However, scars can be identified, although not as well as with technetium-99m dimercaptosuccinic acid (Tc-99m DMSA) scanning (29, 30) (IIa). This technique has been shown to be very sensitive and excretory urography must be reserved only for when images need to be morphologically clarified (31) (IIa).

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3.7.3.2 Radionuclide studies Tc-99m DMSA is a radiopharmaceutical that is bound to the basement membrane of proximal renal tubular cells; half of the dose remains in the renal cortex after 6 hours. This technique is helpful in determining functional renal mass and ensures an accurate diagnosis of cortical scarring by showing areas of hypoactivity indicating lack of function. A UTI interferes with the uptake of this radiotracer by the proximal renal tubular cells, and may show areas of focal defect in the renal parenchyma. A star-shaped defect in the renal parenchyma may indicate an acute episode of pyelonephritis. A focal defect in the renal cortex usually indicates a chronic lesion or a ‘renal scar’ (32-34) (IIa). A focal scarring or a smooth uniform loss of renal substance as demonstrated by Tc-99m DMSA has generally been regarded as being associated with VUR (reflux nephropathy) (35, 36). However, Rushton et al. (37) stated that significant renal scarring may develop, regardless of the existence or absence of VUR. Ransley and Risdon (38) reported that Tc-99m DMSA showed a specificity of 100% and sensitivity of 80% for renal scarring. The use of Tc-99m DMSA scans can be helpful in the early diagnosis of acute pyelonephritis. About 50-85% of children will show positive findings in the first week. Minimal parenchymal defects, when characterized by a slight area of hypoactivity, can resolve with antimicrobial therapy (39, 40). However, defects lasting longer than 5 months are considered to be renal scarring (41) (IIa). Tc-99m DMSA scans are considered more sensitive than excretory urography and ultrasonography in the detection of renal scars (42-45). It remains questionable whether radionuclide scans could substitute for echography as a first-line diagnostic approach in children with a UTI (46, 47). 3.7.3.3 Cystourethrography 3.7.3.3.1 Conventional voiding cystourethrography Voiding cystourethrography (VCU) is the most widely used radiological exploration for the study of the lower urinary tract and especially of VUR. It is considered mandatory in the evaluation of UTIs in children less than 1 year of age. Its main drawbacks are the risk of infection, the need for retrogrades filling of the bladder and the possible deleterious effect of radiation on children (48). In recent years, tailored low-dose fluoroscopic VCU has been used for the evaluation of VUR in girls in order to minimize radiological exposure (49). Voiding cystourethrography is mandatory in the assessment of febrile childhood UTI, even in the presence of normal ultrasonography. Up to 23% of these patients may reveal VUR (50). 3.7.3.3.2 Radionuclide cystography (indirect) This investigation is performed by prolonging the period of scanning after the injection of Tc-99m diethylene triamine pentaacetate (DTPA) or mercaptoacetyltriglycine (MAG-3) as part of a dynamic renography. It represents an attractive alternative to conventional cystography, especially when following patients with reflux, because of its lower dose of radiation. Disadvantages are a poor image resolution and difficulty in detecting lower urinary tract abnormalities (51, 52). 3.7.3.3.3 Cystosonography Contrast material-enhanced voiding ultrasonography has been introduced for the diagnoses of VUR without irradiation (47,52). Further studies are necessary to determine the role of this new imaging modality in UTI. 3.7.3.4 Additional imaging Excretory urography remains a valuable tool in the evaluation of the urinary tract in children, but its use in UTIs is debatable unless preliminary imaging has demonstrated abnormalities requiring further investigation. The major disadvantages in infants are the risks of side effects from exposure to contrast media and radiation (53). However, the role of excretory urography is declining with the increasing technical superiority of CT (54) and MRI. However, the indications for their use is still limited in UTI. 3.7.3.5 Urodynamic evaluation When voiding dysfunction is suspected, e.g. incontinence, residual urine, increased bladder wall thickness, urodynamic evaluation with uroflowmetry, (video) cystometry, including pressure flow studies, and electromyography should be considered.

3.8

Schedule of investigation

Screening of infants for asymptomatic bacteriuria is unlikely to prevent pyelonephritic scar formation, as these usually develop very early in infancy. Only a minority of children with a UTI have an underlying urological disorder, but when present such a disorder can cause considerable morbidity. Thus, after a maximum of two UTI episodes in a girl and one episode in a boy, investigations should be undertaken (Figure 3.1), but not in the

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case of asymptomatic bacteriuria (51-58). The need for DTPA/MAG-3 scanning is determined by the ultrasound findings, particularly if there is suspicion of an obstructive lesion. Figure 3.1. Schedule of investigation of a UTI in a child



Physical examination + Urinalysis/urine culture

> 2 UTI episodes in girls



Echography + VCU



Optional : Intravenous urography DMSA scan

> 1 UTI episode in boys

DMSA = dimercaptosuccinic acid; UTI = urinary tract infection; VCU = voiding cystourethrography.

3.9

Treatment

Treatment has four main goals: 1. elimination of symptoms and eradication of bacteriuria in the acute episode 2. prevention of renal scarring 3. prevention of a recurrent UTI 4. correction of associated urological lesions. 3.9.1 Severe UTIs A severe UTI requires adequate parenteral fluid replacement and appropriate antimicrobial treatment, preferably with cephalosporins (third generation). If a Gram-positive UTI is suspected by Gram stain, it is useful to administer aminoglycosides in combination with ampicillin or amoxycillin/clavulanate (59) (IIa). Antimicrobial treatment has to be initiated on an empirical basis, but should be adjusted according to culture results as soon as possible. In patients with an allergy to cephalosporins, aztreonam or gentamicin may be used. When aminoglycosides are necessary, serum levels should be monitored for dose adjustment. Chloramphenicol, sulphonamides, tetracyclines, rifampicin, amphotericin B and quinolones should be avoided. The use of ceftriaxone must also be avoided due to its undesired side effect of jaundice. A wide variety of antimicrobials can be used in older children, with the exception of tetracyclines (because of teeth staining). Fluorinated quinolones may produce cartilage toxicity (58), but if necessary may be used as second-line therapy in the treatment of serious infections, since musculoskeletal adverse events are of moderate intensity and transient (60, 61). For a safety period of 24-36 hours, parenteral therapy should be administered. When the child becomes afebrile and is able to take fluids, he/she may be given an oral agent to complete the 10-14 days of treatment, which may be continued on an outpatient basis. This provides some advantages, such as less psychological impact on the child and more comfort for the whole family. It is also less expensive, well tolerated and eventually prevents opportunistic infections (20). The preferred oral antimicrobials are: trimethoprim (TMP), co-trimoxazole (TMP plus sulphamethoxazole), an oral cephalosporin, or amoxycillin/clavulanate. However, the indication for TMP is declining in areas with increasing resistance. In children less than 3 years of age, who have difficulty taking oral medications, parenteral treatment for 7-10 days seems advisable, with similar results to those with oral treatment (62). If there are significant abnormalities in the urinary tract (e.g. VUR, obstruction), appropriate urological intervention should be considered. If renal scarring is detected, the patient will need careful follow-up by a paediatrician in anticipation of sequelae such as hypertension, renal function impairment and recurrent UTI. An overview of the treatment of febrile UTIs in children is given in Figure 3.2 and the dosing of antimicrobial agents is outlined in Table 3.3 (63).

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Figure 3.2. Treatment of febrile UTIs in children

Severe UTI

Simple UTI

parental therapy until afebrile • adequate hydration • cephalosporins (third generation) • amoxycillin/clavulanate if cocci are present

oral therapy parenteral single-dose therapy (only in case) of doubtful compliance) • cephalosporins (third generation) • gentamicin

oral therapy to complete 10-14 days of treatment

oral therapy to complete 5-7 days of treatment



• amoxycillin • cephalosporins • trimethoprim



• • • •

daily oral prophylaxis nirofurantoin cefalexin trimethoprim

3.9.2 Simple UTIs A simple UTI is considered to be a low-risk infection in children. Oral empirical treatment with TMP, an oral cephalosporin or amoxycillin/clavulanate is recommended, according to the local resistance pattern. The duration of treatment in uncomplicated UTIs treated orally should be 5-7 days (64, 65) (Ib). A single parenteral dose may be used in cases of doubtful compliance and with a normal urinary tract (66) (IIa). If the response is poor or complications develop, the child must be admitted to hospital for parenteral treatment (67). 3.9.3 Prophylaxis If there is an increased risk of pyelonephritis, e.g. VUR, and recurrent UTI, low-dose antibiotic prophylaxis is recommended (68,69) (IIa). It may also be used after an acute episode of UTI until the diagnostic work-up is completed. The most effective antimicrobial agents are: nitrofurantoin, TMP, cephalexin and cefaclor (68).

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3.10

Acknowledgement

With our grateful thanks, the chapter on UTIs in children was updated also by Jorge Caffaratti Sfulcini, Paediatric Urology, Fundació Puigvert, Barcelona, Spain, as co-author. Table 3.3: Dosing of antimicrobial agents in children aged 3 months to 12 years* Antimicrobial agent Ampicillin Ampicillin

Application Intravenous Intravenous

Age 3-12 months 1-12 years

Total dosage per day 100-300 mg/kg BW 60-150 (-300) mg/kg BW

Doses per day 3 3

Amoxycillin Oral

3 months to 12 years

50-100 mg/kg BW

2-3

Amoxycillin/clavulanate Intravenous Amoxycillin/clavulanate Oral Cephalexin Treatment Oral Prophylaxis Oral

3 months to 12 years 3 months to 12 years

60-100 mg/kg BW

3

37.5-75 mg/kg BW

2-3

50-100 mg/kg BW

3

10 mg/kg BW

1-2

3 months to 12 years 1-12 years

Cefaclor • Treatment Oral 3 months to 50-100 mg/kg BW 3 12 years • Prophylaxis Oral 1-12 years 10 mg/kg BW 1-2 Cefixime Oral 3 months to 8-12 mg/kg BW 1-2 12 years Cetriaxone Intravenous 3 months to 50-100 mg/kg BW 1 12 years Aztreonam Intravenous 3 months to (50)-100 mg/kg BW 3 12 years Gentamicin Intravenous 3-12 months 5-7.5 mg/kg BW 1-3 Gentamicin Intravenous 1-2 years 5 mg/kg BW 1-3 Trimethoprim • Treatment Oral 1-12 years 6 mg/kg BW 2 • Prophylaxis Oral 1-12 years 1-2 mg/kg BW 1 Nitrofurantoin • Treatment Oral 1-12 years 3-5 mg/kg BW 2 • Prophylaxis Oral 1-12 years 1mg/kg BW 1-2 BW = body weight. * Adapted from ref. 63.

3.11

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Elison BS, Taylor D, Van der Wall H, Pereira JK, Cahill S, Rosenberg AR, Farnworth RH, Murray IP. Comparison of DMSA scintigraphy with intravenous urography for the detection of renal scarring and its correlation with vesicoureteric reflux. Br J Urol 1992;69(3):294-302. http://www.ncbi.nlm.nih.gov/pubmed/1314684 MacKenzie JR, Fowler K, Hollman AS, Tappin D, Murphy AV, Beattie TJ, Azmy AF. The value of ultrasound in the child with an acute urinary tract infection. Br J Urol 1994;74(2):240-4. http://www.ncbi.nlm.nih.gov/pubmed/7921944 Mucci B, Maguire B. Does routine ultrasound have a role in the investigation of children with urinary tract infection? Clin Radiol 1994;49(5):324-5. http://www.ncbi.nlm.nih.gov/pubmed/8013196 Westwood ME, Whiting PF, Cooper J, Watt IS, Kleijnen J. Further investigation of confirmed urinary tract infection (UTI) in children under five years: a systematic review. BMC Pediatr 2005;5(1):2. http://www.ncbi.nlm.nih.gov/pubmed/15769296 Haycock GB. A practical approach to evaluating urinary tract infection in children. Pediatr Nephrol 1991;5(4):401-2. http://www.ncbi.nlm.nih.gov/pubmed/1654977 Kleinman PK, Diamond BA, Karellas A, Spevak MR, Nimkin K, Belanger P. Tailored low-dose fluoroscopic voiding cystourethrography for the reevaluation of vesicoureteral reflux in girls. AJR Am J Roentgenol 1994;162(5):1151-6. http://www.ncbi.nlm.nih.gov/pubmed/8166001 Kass EJ, Kernen KM, Carey JM. Paediatric urinary tract infection and the necessity of complete urological imaging. BJU Int 2000;86(1):94-6. http://www.ncbi.nlm.nih.gov/pubmed/10886091 De Sadeleer C, De Boe V, Keuppens F, Desprechins B, Verboven M, Piepsz A. How good is technetium-99m mercaptoacetyltriglycine indirect cystography? Eur J Nucl Med 1994;21(3):223-7. http://www.ncbi.nlm.nih.gov/pubmed/8200390 Piaggio G, Degl’ Innocenti ML, Tomà P, Calevo MG, Perfumo F. Cystosonography and voiding cystourethrography in the diagnosis of vesicoureteral reflux. Pediatr Nephrol 2003;18(1):18-22. http://www.ncbi.nlm.nih.gov/pubmed/12488985 Vela Navarrete R. [Urinary tract infections in children.] In: Tratado de urología tomo I. Jiménez Cruz JF, Rioja LA, eds. Barcelona: Ed Prous, 1993; pp. 499-507. [article in Spanish] Huang JJ, Sung JM, Chen KW, Ruaan MK, Shu GH, Chuang YC. Acute bacterial nephritis: a clinicoradiologic correlation based on computer tomography. Am J Med 1992;93(3):289-98. http://www.ncbi.nlm.nih.gov/pubmed/1524081 Majd M, Rushton HG, Jantausch B, Wiedermann BL. Relationship among vesicoureteral reflux, Pfimbriated Escherichia coli, and acute pyelonephritis in children with febrile urinary tract infection. J Pediatr 1991;119(4):578-85. http://www.ncbi.nlm.nih.gov/pubmed/1681043 Melis K, Vandevivere J, Hoskens C, Vervaet A, Sand A, Van Acker KJ. Involvement of the renal parenchyma in acute urinary tract infection: the contribution of 99mTc dimercaptosuccinic acid scan. Eur J Pediatr 1992;151(7):536-9. http://www.ncbi.nlm.nih.gov/pubmed/1327798 Smellie JM, Rigden SP. Pitfalls in the investigation of children with urinary tract infection. Arch Dis Child 1995;72(3):251-8. http://www.ncbi.nlm.nih.gov/pubmed/7741579 Smellie JM, Rigden SP, Prescod NP. Urinary tract infection: a comparison of four methods of investigation. Arch Dis Child 1995;72(3):247-50. http://www.ncbi.nlm.nih.gov/pubmed/7741578 Broseta E, Jimenez-Cruz JF. [Urinary tract infection in children.] In: Broseta E, Jimenez-Cruz JF, eds. Infeccion urinaria. Madrid: Ed Aula Medica, 1999; pp. 185-194. [article in Spanish] Grady R. Safety profile of quinolone antibiotics in the pediatric population. Pediatr Infect Dis J 2003;22(12):1128-32. http://www.ncbi.nlm.nih.gov/pubmed/7741578 [No authors listed.] Fluoroquinoles in children: poorly defined risk of joint damage. Prescrire Int 2004;13(73):184-6. http://www.ncbi.nlm.nih.gov/pubmed/15499700 Bloomfield P, Hodson EM, Craig JC. Antibiotics for acute pyelonephritis in children. Cohrane Database Syst Rev 2005;(1):CD003772. http://www.ncbi.nlm.nih.gov/pubmed/15674914

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63. 64.

65.

66.

67.

68.

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Deutsche Gesellschaft für pädiatrische Infektiologie e.V. (DGPI) (ed). [Textbook for infections in children and adolescents.] 4th edn. Futuramed: Munich, 2003, pp. 148-157. [article in German] Michael M, Hodson EM, Craig JC, Martin S, Moyer VA. Short versus standard duration oral antibiotic therapy for acute urinary tract infection in children. Cochrane Database Syst Rev 2003;(1):CD003966. http://www.ncbi.nlm.nih.gov/pubmed/12535494 Tran D, Muchant DG, Aronoff SC. Short-course versus conventional length antimicrobial therapy for uncomplicated lower urinary tract infections in children: a meta-analysis of 1279 patients. J Pediatr 2001;139(1):93-9. http://www.ncbi.nlm.nih.gov/pubmed/11445800 Khan AJ. Efficacy of single-dose therapy of urinary tract infection in infants and children: a review. J Nalt Med Assoc 1994;86(9):690-6. http://www.ncbi.nlm.nih.gov/pubmed/7966433 Hellerstein S. Urinary tract infections. Old and new concepts. Pediatr Clin North Am 1995;42(6): 1433-57. http://www.ncbi.nlm.nih.gov/pubmed/8614594 Smellie JM, Gruneberg RN, Bantock HM, Prescod N. Prophylactic co-trimoxazole and trimethoprim in the management of urinary tract infection in children. Pediatr Nephrol 1988;2(1):12-7. http://www.ncbi.nlm.nih.gov/pubmed/3152984 Arant BS Jr. Vesicoureteral reflux and evidence-based management. J Pediatr 2001;139(5):620-1. http://www.ncbi.nlm.nih.gov/pubmed/11713435

4. UTIs IN RENAL INSUFFICIENCY, TRANSPLANT RECIPIENTS, DIABETES MELLITUS AND IMMUNOSUPPRESSION 4.1

Summary

4.1.1 Acute effects of UTI on the kidney In acute pyelonephritis very dramatic changes can occur with focal reduction in perfusion on imaging and corresponding renal tubular dysfunction. However, if in the adult, the kidney is normal beforehand, chronic renal damage is most unlikely. There is no evidence that more prolonged or intensive antibiotic treatment of acute pyelonephritis will shorten the episode or prevent complications. In diabetes mellitus, overwhelming infection can predispose to pyogenic infection with intrarenal perinephric abscess formation, emphysematous pyelonephritis, and, very rarely, a specific form of infective interstitial nephropathy. Papillary necrosis is a common consequence of pyelonephritis in diabetics. Females are more prone to asymptomatic bacteriuria than diabetic men but in both sexes progression to clinical pyelonephritis is more likely than in normal individuals. The risk factors for developing asymptomatic bacteriuria differ between type I and type II diabetes. It is arguable that diabetic patients are susceptible to rapid progression of parenchymal infection. However, the clearance of asymptomatic bacteriuria should not be attempted if the intention is to prevent complications, notably acute pyelonephritis (A). 4.1.2 Chronic renal disease and UTI There are several factors of general potential importance predisposing to infection in uraemia, including the loss of several urinary defence mechanisms and a degree of immunosuppression. Typically, adult polycystic kidney disease (APCKD), gross vesicoureteric reflux (VUR) and endstage obstructive uropathy will harbour infective foci or promote ascending infection, but not invariably so. Clearly, severe urinary tract infection (UTI) with accompanying bacteraemia can hasten progression of renal failure, but there is little evidence that vigorous treatment of lesser degrees of infection or prophylaxis will slow renal functional impairment once it is established (C). In patients with VUR and UTI in endstage chronic renal failure bilateral nephroureterectomy should only be undertaken as a last resort (B). 4.1.2.1 Adult polycystic kidney disease (APCKD) In patients with acute pyelonephritis and infected cysts (presenting as recurrent bacteraemia or ‘local sepsis’) treatment requires a long course of high-dose systemic fluoroquinolones, followed by prophylaxis. Bilateral

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nephrectomy should be utilized as a last resort (B). 4.1.2.2 Calculi and UTI Management is similar to that for patients without renal impairment, i.e. to clear the stones if possible and to minimize antibiotic treatment if the calculus cannot be removed. Nephrectomy should be performed as a last resort, but even residual renal function may be of vital importance (B). 4.1.2.3 Obstruction and UTI As in all other situations, the combination of obstruction and infection is dangerous and should be treated vigorously. Obstruction may be covert and require specific diagnostic tests, e.g. video-urodynamics, upper tract pressure flow studies. 4.1.3 UTI in renal transplantation and immunosuppression The need to correct uropathy or to remove a potential focus of infection in a diseased endstage kidney is more pressing in a patient enlisted for renal transplantation. Even so, the results of nephrectomy for a scarred or hydronephrotic kidney may be disappointing. Immunosuppression is of secondary importance, although if this is extreme, immunosuppression will promote, at least, persistent bacteriuria, which may become symptomatic. In the context of renal transplantation, UTI is very common, but immunosuppression is only one of many factors which are mainly classified as ‘surgical’. HIV infection is associated with acute and chronic renal disease, possibly through the mechanisms of thrombotic microangiopathy and immune mediated glomerulonephritis. Steroids, angiotensin-converting enzyme (ACE) inhibitors and highly active retroviral therapy appear to have reduced progression to endstage renal disease. 4.1.4 Antibiotic treatment for UTI in renal insufficiency and after renal transplantation The principles of antibiotic treatment for UTI in the presence of renal impairment, during dialysis treatment and after renal transplantation, is discussed in the text and summarized in Tables 3.1-3.4.

4.2

Background

Whenever UTI is present in patients with renal insufficiency, problems arise in both the treatment of infection and the management of the renal disease. There are also important scientific issues to be considered concerning the cause, special susceptibilities, effects and complications of renal parenchymal infection, particularly in the immunosuppressed patient. This part of the guidelines can be subdivided into four sections. 1. What are the acute effects of UTI on the kidney and do the lesions become chronic? 2. Does chronic renal disease progress more quickly as a result of infection and do particular renal diseases predispose to UTI? 3. Are immunosuppressed patients prone to UTI particularly in the context of renal transplantation? Is UTI a significant cause of graft failure? 4. Which problems arise in antibiotic therapy in patients with renal insufficiency and after renal transplantation?

4.3

Acute effects of UTI on the kidney

Some authors regard acute pyelonephritis as ‘complicated’ because in their view it may cause renal scarring in a previously normal kidney (1,2) (IIa). Pathologically, a similar process may occur in such fundamentally different situations as obstructive and reflux nephropathies, although the distribution and extent of the lesions may be different (3-5) (IIa). 4.3.1 Vesicoureteric and intrarenal reflux The effects of VUR and intrarenal reflux on the renal parenchyma and the contribution of ascending infection are still unresolved. Renal scarring can certainly be acquired as a result of these three factors, although, in almost all cases, this usually occurs very early in life. In this narrow age range, developmental renal dysplasia must be a major consideration in the pathogenesis of chronic pyelonephritis. Although acute infection is important in the early stages of this disease, the status of either recurrent acute urinary infection or asymptomatic bacteriuria specifically in the progression of scar formation is tenuous. Prophylactic antibiotics will therefore offer little benefit in preserving renal tissue in reflux nephropathy in the older child and adult, even if the reflux has not already been successfully treated (6) (A). However, further discussion of reflux nephropathy is beyond the scope of these guidelines.

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4.3.2 Obstructive neuropathy Obstruction occurring through a voiding disorder or supravesically causes renal tubular dysfunction and ultimately renal damage, mainly through the process of apoptosis. Infection enhances the process of parenchymal loss. In extreme cases, pyonephrosis, perinephric abscess and widespread systemic sepsis will develop. Obstruction has to be cleared if infection is to be eradicated (7) (A). A detailed discussion of obstructive nephropathy is not appropriate here, but the kidney which is permanently damaged from any cause will have less reserve to withstand the effects of reflux, obstruction and infection. In any circumstances, the combination of obstruction and infection is a surgical emergency and both must be relieved without delay. It is sometimes difficult to exclude an element of obstruction when discussing the pathogenesis of putative infective renal damage in the alleged normal kidney. Urinary calculi and pregnancy can cause urinary stasis and an intermittent increase in pressure in the upper tracts, which can cause subtle and persistent damage. 4.3.3 Renal effects of severe UTI Severe infection can lead to renal functional impairment through sepsis, endotoxaemia, hypotension and poor renal perfusion, as part of the process of multiorgan failure. The presence of renal calculi and diabetes mellitus will further reduce host defences (8). 4.3.4 Acute effects of UTI on the normal kidney The acute effects of UTI on the normal kidney are complex. They are worth reviewing as they may provide a lead in deciding how chronic changes can occur and therefore a basis for the development of guidelines on the prevention of renal damage. Escherichia coli is the commonest of the Gram-negative organisms isolated in the majority of patients with acute pyelonephritis. The proportion of infections caused by E. coli is lower in adults than children (69% vs 80%) (9) (IIb). Virulent organisms cause direct cellular injury, usually after colonizing the renal pelvis. Damage can also occur indirectly from the effects of inflammatory mediators. Metastatic infection will rarely cause renal infection, presenting as cortical abscesses and usually only in susceptible individuals (see the sections below on Diabetes mellitus and Immunosuppression) (10). Bacterial infection in the urinary tract can induce fever and elevate acute phase reactants, such as C-reactive protein and erythrocyte sedimentation rate (ESR). Bacterial infection also elicits immunoglobulin A and cytokine responses (11) (IIb). In particular, serum levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) are elevated (12, 13) (IIb). Tissue damage is reflected by urinary secretion of tubular proteins and enzymes, such as α2-macroglobulin, ß2-microglobulin and N-acetyl-ß-D-glucosaminadase enzyme (NDMA). In functional terms, there may be a loss of concentrating power which can persist long term (14, 15) (IIb). The fact that there is a serological immune response and bacteria become coated with antibodies to various antigenic components of the micro-organism is regarded as evidence of an immune response and therefore of exposure to microorganisms which are potentially damaging to the renal parenchyma (16) (IIb). There are many identifiable factors relating to virulence of the bacterial cell and to its ability to adhere to the mucosa as a preliminary to invasion (17). For example, type 1 pili or fimbriae will combine with mannose receptors on the uromucoid, which is part of the protective mucopolysaccharide layer found on uroepithelial cells lining the urinary tract. Type 2 or P fimbriae bind to glycolipids of the blood group substances which are secreted by the host urothelium. In practical terms, E. coli micro-organisms which are pathological to the kidney appear to express P (or pyelonephritis-associated) or type 2 fimbriae, at least in children where 90% of individuals with acute pyelonephritis express these micro-organisms compared with a much smaller proportion of those who have had cystitis or asymptomatic bacteriuria (18) (IIb). Bacterial adhesion may be of variable benefit to the micro-organism, as its attachment may mean that it is easier for host defence mechanisms to localize and abolish it (19). The cellular and humeral inflammatory host response is also a critical part of host defence. Various cytokines (e.g. IL-6, IL-8) are responsible for inducing leucocyte migration and may be intrinsically deficient in converting asymptomatic bacterial colonization to clinical infection. Paradoxically, reduced adhesiveness can facilitate silent penetration into the renal parenchyma. In a Swedish study, a group of 160 patients who had recently suffered an acute UTI all developed reduced concentrating power, even though a significant proportion (40%) did not develop a febrile illness. In the majority of these patients, the infiltrating bacteria had reduced adhesive characteristics, perhaps facilitating their penetration into the renal parenchyma and promoting more permanent structural and functional damage (15) (IIb). 4.3.5 Renal scarring The possible development of scarring, as a result of UTI in the absence of reflux, obstruction or calculi, is

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controversial (20) (IIa). It is agreed that dramatic reduction in renal perfusion and excretion can occur acutely and so-called ‘lobar nephronia’ has been demonstrated with the newer methods of imaging, such as CT or dimercaptosuccinic acid (DMSA) scanning, but not with standard intravenous urography (IVU). A study has shown that 55% of patients with no pre-existing lesions developed acute parenchymal lesions during an episode of acute pyelonephritis (2) (IIa). These lesions were found to have persisted 3-6 months later at follow-up in 77% of patients (9) (III). An earlier study by Alwall (21) described 29 women followed for 20-30 years with evidence of increasing renal damage and chronic pyelonephritis upon biopsy (III). As this study would have used cruder diagnostic techniques, which might not have identified pre-existing disease, patients may have had renal damage initially. Over such a long period, it was impossible to exclude other causes of renal impairment and interstitial nephropathy, e.g. analgesic abuse. This important issue is clarified by a recent more critical study of DMSA scanning during the acute phase of acute pyelonephritis. In the study, 37 of 81 patients had one or more perfusion defects, of which the majority resolved within 3 months. In lesions that persisted, further imaging invariably showed evidence of reflux or obstructive nephropathy that must have predated the acute infective episode (22) (IIa). In summary, small parenchymal scars demonstrated by modern imaging may develop as a result of acute non-obstructive pyelonephritis. However, such patients do not develop chronic renal failure and the scar is a very different lesion from the typical scar of reflux nephropathy. This is reflected in clinical experience. Thus, in acute pyelonephritis, IVU or DMSA scanning during an acute urinary infection can have very alarming and dramatic results, but in practical terms the observed changes will mostly resolve. The poor correlation between the severity of the symptoms in an episode of acute pyelonephritis and the risk of permanent damage, which is very small, should discourage the clinician from prescribing excessive antibiotic treatment beyond that needed to suppress the acute inflammatory reaction (A). In the future, the rare occurrence of renal damage apparently arising from acute or recurrent uncomplicated UTI may be prevented by targeting long-term treatment at selected patients. These patients will have been identified as having an intrinsic genetic defect in the host response of cytokine release to infection. Such a genetic defect would be even more important if a patient also had structural abnormalities causing complicated UTI. 4.3.6 Specific conditions in which an acute UTI causes renal damage There are several specific conditions in which acute UTI can cause renal damage: 4.3.6.1 Diabetes mellitus Asymptomatic bacteriuria is common in diabetic women. In a prospective study of non-pregnant women with diabetes mellitus, 26% had significant bacteriuria (> 105 cfu/mL) compared with 6% of controls. Women with type I diabetes were particularly at risk if they had had diabetes for a long time or complications had developed, particularly peripheral neuropathy and proteinuria. Risk factors in patients with type II diabetes were old age, proteinuria, a low body mass index and a past history of recurrent UTIs (23) (IIa). Diabetes mellitus increases the risk of acute pyelonephritis from infection by Enterobacteriaceae originating in the lower urogenital tract. Klebsiella infection is particularly common (25% compared with 12% in non-diabetics). Asymptomatic bacteriuria is common in female diabetics (though not in males). If left untreated, it may lead to renal functional impairment (24). The mechanism is ill-understood and, as in uncomplicated acute pyelonephritis, a direct causal link is dubious. Other subtle factors may be present, such as an underlying diabetic nephropathy (25) and autonomic neuropathy causing voiding dysfunction. Impaired host resistance is thought to predispose to the persistence of nephropathogenic organisms, but specific evidence is lacking for the development of renal complications. Glycosuria inhibits phagocytosis and perhaps cellular immunity and encourages bacterial adherence. However, diabetic women with asymptomatic bacteriuria can have good glycaemic control, but still show reduced urinary cytokine and leucocyte concentration (although polymorph function is normal). Interestingly, poor glycaemic control has not been shown to increase the risk of bacteriuria (26). It has always been recognized that diabetic patients are particularly susceptible to rapid progression of renal parenchymal infection and ensuing complications. Until recently, there was no consensus on the questions of pre-emptive screening, treatment and prophylaxis of asymptomatic bacteriuria. However, these issues have been addressed in a placebo-controlled double-blind randomized trial (27) (Ib), which concluded that treatment did not reduce complications and diabetes should not therefore be regarded as an indication for screening or treatment of asymptomatic bacteriuria. The findings from this trial were subsequently recognized in the guidelines published by the Infectious Diseases Society of America (IDSA) on the diagnosis and treatment of asymptomatic bacteriuria in general (28).

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Diabetic patients are also prone to an under-reported and probably unusual form of infective interstitial nephritis, which is sometimes infected by gas-forming organisms, with a high mortality (emphysematous pyelonephritis) (29). This is characterized histologically by acute pyogenic infiltrate with microabscesses and the development of acute renal failure. The origin of the organisms may be haematogenous. Even in the absence of obstruction, acute parenchymal infection may progress insidiously to form an intrarenal abscess which ruptures leading to a perinephric collection and a psoas abscess. The presentation can occasionally be quite indolent. Papillary necrosis is common in diabetics, particularly in association with acute pyelonephritis. It is certainly associated with permanent renal parenchymal scarring, although it is difficult to exclude obstruction by the sloughed papillae as the cause of the nephropathy. Antibiotic prophylaxis in the treatment of asymptomatic bacteriuria is probably required (C). 4.3.6.2 Tuberculosis Tuberculosis can cause both acute and chronic renal damage through bilateral renal infiltration. Rarely, this can lead to endstage renal failure. However, a more subtle form of interstitial granulomatous disease can occur, which is sufficient to cause renal failure in the absence of fibrosis, calcification or obstruction (30,31) (III) Tuberculosis and leprosy can cause renal damage through the development of amyloid and also of a form of proliferative glomerulonephritis (32, 33). (IIb). For more details see EAU guidelines on genitourinary tuberculosis (34).

4.4

Chronic renal disease and UTI

There are good reasons why all uraemic patients should be prone to UTI and why UTI should increase the rate of deterioration of function. The antibacterial properties of normal urine, due to urea or low pH and high osmolality, may be lost (35). Uraemic patients are also mildly immunosuppressed and the formation of protective uroepithelial mucus may be inhibited (36-38) (IIb). However, apart from a few exceptions, there is little evidence for a causal relationship between preexisting chronic renal disease and persisting UTI (7). The results of removing a scarred or hydronephrotic kidney in the hope of curing infection are often disappointing. The few exceptions include the following. 4.4.1 Adult dominant polycystic kidney disease (ADPK) Urinary tract infection is a prominent complication of ADPK, with symptomatic UTI being the presenting feature in 23-42% of patients, who are usually female (39). It may be difficult to obtain a positive culture on standard laboratory media, but pyuria is common, particularly in the later stages of disease progression. Acute pyelonephritis is common and may originate from pyogenic infection in the cysts (40) (III). The efficacy of antibiotic treatment may depend on whether cysts are derived from proximal (active secretion) or distal tubules (passive diffusion) and on the liposolubility of the agent used. Cephalosporins, gentamicin and ampicillin, which are standard treatments of acute pyelonephritis and require active transport, are often ineffective (41) (IIb). Fluoroquinolones are generally the most effective (A). After transplantation, overall graft and patient survival rates do not differ between ADPK and control groups (42) (IIa). However, despite close monitoring of patients, UTI and septicaemic episodes are still a significant cause of morbidity, so that bilateral nephrectomy may be the only option. Polycystic disease is not to be confused with acquired renal cystic disease of the endstage kidney which has no predisposition to UTI. The issue of whether urological complications including UTI affect the progression of renal failure in polycystic disease or in any other renal pathology is controversial. Severe symptomatic UTI may indicate an adverse prognosis, particularly in males with ADPK. 4.4.2 Renal calculi Nephrolithiasis, particularly from infective struvite stones, obstructive uropathy and gross reflux, clearly do promote infection, although not always so. However, it is doubtful whether vigorous treatment of asymptomatic bacteriuria or even mild clinical UTI will make any difference to the progression of renal disease (43) (III). It is disappointing that, as yet, there are few studies providing long-term serial data identifying renal damage and its causal relationship with infection. In this respect, it is of some interest that a study of 100 patients undergoing reflux prevention surgery at least 20 years before has recently been published (44). It was concluded that even patients whose reflux prevention surgery had been successful were prone to recurrent UTI, hypertension and complications, which even occasionally included progressive renal scarring. Such consequences should at least inform the patient’s decision in deciding between surgical and medical treatment of VUR.

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4.5

UTI in renal transplantation

Urinary tract infection is common after renal transplantation. Bacteriuria is present in 35-80% of patients, although the risk has been reduced by improvements in donation surgery, which have lowered the dose of immunosuppressive therapy and of prophylactic antibiotics (45). 4.5.1 Donor organ infection Early factors predisposing to UTI include infection in the transplanted kidney. Clearly, the organ donor should be screened for a variety of viral and bacterial infections. Detailed discussion of this process is beyond the limits of these guidelines. However, it must be acknowledged that the urinary tract of the cadaver donor is rarely investigated, even if the mid-stream urine (MSU) culture is positive. Antibiotics are given empirically, but usually the first suspicion of occurrence of a renal tract abnormality is raised during the organ donation operation. Under these circumstances, only the most obvious renal or ureteric abnormality will be detected. Very occasionally, organ donation will be abandoned at this late stage. After the kidney is removed from its storage box, the effluent from the renal vein and surrounding fluid in the sterile plastic bags containing the excised kidney should ideally be cultured as micro-organisms are likely to have been introduced during the donation process. Bladder catheters and ureteric stents promote the loss of the glycosoaminoglycan layer from the uroepithelium, as well as providing a source of micro-organism within the mucous biofilm covering the foreign body. Infection in the native kidneys may worsen considerably as a result of maximum immunosuppression. In patients with a renal transplant the following problems are most troublesome: papillary necrosis, particularly in diabetes mellitus (46), massive infective VUR, polycystic disease and infective calculi. There is also concern about the increasing number of children with congenital uropathies, often associated with neuropathic bladder dysfunction and the sinister combination of intravesical obstruction, poor bladder compliance, residual urine and VUR. A full urodynamic assessment, establishing a routine of intermittent self-catheterization and any necessary bladder surgery must be completed well in advance of renal transplantation. Urinary diversions and bladder augmentation and substitution have also been successfully completed in patients on dialysis treatment and after transplantation, though bacteriuria is common and may require antibiotic treatment (47). In the first 3 months, UTI is more likely to be symptomatic with a high rate of relapse. Later on, there is a lower rate of pyelonephritis and bacteraemia and a better response to antibiotics unless there are urological complications (e.g. fistula, obstruction). Infarction, either of the whole kidney or of a segment due to arterial damage, can promote UTI through bacterial colonization of dead tissue. This often occurs by commensal or fastidious pathogens. The infection may be impossible to eradicate until the kidney or at least the dead segment is removed. 4.5.2 Graft failure There are several potential mechanisms by which severe UTI can cause graft failure. There was an early suggestion that reflux into the graft could lead to pyelonephritis and parenchymal scarring. However, these findings have not been confirmed and most surgeons do not make a special effort to perform an antireflux anastomosis. Infection can theoretically induce graft failure by three other mechanisms, such as by the direct effect of cytokines, growth factors (e.g. tumour necrosis factor) and free radicals as part of the inflammation cascade (45). Urinary tract infections can also reactivate cytomegalovirus infection, which can lead to acute transplant rejection. Sometimes it can be very difficult to distinguish rejection from infection (48) (IIb). For many years, the polyomavirus type BK has been listed as a possible candidate for causing transplant ureteric stenosis. Improved detection of so-called ‘decoy cells’ in urine and of virus DNA by polymerase chain reaction has confirmed the causal relationship between infection and obstruction, but also with interstitial nephropathy progressing to graft loss in possibly 5% of recipients. The virus is susceptible to treatment with an antiviral agent (cidofovir) (49) (IIa). 4.5.3 Kidney and whole-organ pancreas transplantation Simultaneous kidney and whole-organ pancreas transplantation can present specific urological complications when the bladder is chosen for drainage of exocrine secretions. These may include recurrent UTI, chemical urethritis and bladder calculi of sufficient severity to warrant cystoenteric conversion. The risk of such complications is minimized if urodynamic abnormalities, e.g. obstruction, are identified and corrected well in advance of the transplant procedure (50) (III).

4.6

Antibiotic therapy in renal failure/transplantation

Much of the detailed information on antibiotic prescribing in renal failure is summarized in Tables 4.1-4.5 and appendix 14.3. It is important to note that peritoneal dialysis and haemodialysis will clear certain antibiotics,

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which should either be avoided or given in much higher dosage. Secondly, there are important interactions to consider between immunosuppressive agents and antibiotics. Table 4.1: Use of antibiotics for UTI with renal impairment • Most antibiotics have a wide therapeutic index. No adjustment of dose is necessary until GFR < 20 mL/min, except antibiotics with nephrotoxic potential, e.g. aminoglycoside • Drugs removed by dialysis should be administered after a dialysis treatment • Combination of loop diuretics, e.g. furosemide and a cephalosporin, is nephrotoxic • Nitrofurantoin and tetracyclines are contraindicated, but not doxycyclin GFR = glomerular filtration rate. Table 4.2: Clearance of antibiotics at haemodialysis Dialyzed Slightly dialyzed Not dialyzed Amoxycillin/ampicillin Fluoroquinolones* Amphotericin Carbenicillin Co-trimoxazole Methicillin Cephalosporins* Erythromycin Teicoplanin Aminoglycosides* Vancomycin Trimethoprim Metronidazole Aztreonam* Fluconazole* * Drugs cleared by peritoneal dialysis. Table 4.3: Treatment of tuberculosis in renal failure Rifampicin and INAH not cleared by dialysis. Give pyridoxine. Ethambutol not dialyzed. Reduce dose if GFR < 30 mL/min Avoid rifampicin with cyclosporine

Table 4.4: Recommendations for prevention and treatment of UTI in renal transplanation • Treat infection in recipient before transplantation • Culture donor tissue sample and perfusate • Perioperative antibiotic prophylaxis. • 6-month low-dose TMP-SMX (co-trimoxazole) (IbA) • Empirical treatment of overt infection (quinolone, TMP-SMX for 10-14 days) TMX = trimethoprim-sulphamethoxazole. Table 4.5: Drug interactions with cyclosporin and tacrolimus Rifampicin Erythromycin Aminoglycosides TMP-SMX Amphotericin B TMP-SMX = trimethoprim-sulphamethoxazole. 4.6.1 Treatment of UTI in renal transplant recipients The treatment of a symptomatic UTI is similar to treatment given to non-transplant patients. However, a short course of treatment has yet to be established and in most cases a 10-14 day course of treatment will be given. The choice of antibiotic is dictated by the special need for penetration into the renal parenchyma rather than for merely a ‘mucosal’ antibiotic. Fluoroquinolones seem to be particularly effective. There is good evidence for the beneficial effects of treating asymptomatic bacteriuria in the first 6 months after renal transplantation (51) (IIa). Patients must be investigated for a surgical complication. In most units, the combination of trimethoprim and sulphamethoxazole (TMP-SMX, co-trimoxazole) is effective in preventing UTI (52) (Ib). It will also prevent Pneumocystis carinii pneumonia (PCP) and infection with

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other rare fastidious organisms. Low-dose antibiotic prophylaxis with co-trimoxazole has been recommended for 6 months after transplantation. This will cover the high-risk period when infection is more likely to be symptomatic and associated with acute graft impairment. At a low dose, adverse interactions with cyclosporin do not occur, although the higher dose advocated by some units will result in synergistic nephrotoxicity with trimethoprim. A number of other drug interactions need to be considered, e.g. gentamicin, TMP-SMX and amphotericin B promote cyclosporin and tacrolimus toxicity. Rifampicin and eythromycin also interact with calcineurin inhibitors by increasing cytochrome p450 synthetase and inhibiting hepatic cyclosporin A metabolism. In any patients with relapsing or recurrent infection, an anatomical cause, such as a urological complication in the transplant kidney or recipient bladder dysfunction, must be considered and treated vigorously. 4.6.2 Fungal infections Candidal infections can occur in any immunosuppressed patient, but are more common in diabetic patients and those with chronic residual urine and where there is an indwelling catheter or stent. It is wise to treat all patients even when they are asymptomatic with antifungal agents (fluconazole, amphotericin B plus flucytosine). Removal of the catheter or stents is usually necessary (B). 4.6.3 Schistosomiasis Schistosomiasis is a familiar problem for patients treated for endstage renal failure from locations where the disease is endemic. Renal transplantation is possible, even when live donors and recipients have active lesions provided they are treated. Combined medication (praziquantil and oxaminoquine) are recommended for 1 month. In a trial comparing infected patients with those free of schistosomiasis, there is no difference between the incidences of acute and chronic rejection. However, UTI and urological complications occurred in the infected group and a higher cyclosporin dosage was required. Despite this, however, it was concluded that active schistosomiasis did not preclude transplantation (53) (III). For further details on schistosomiasis in genitourinary tract infections see Bichler et al. (54).

4.7

Immunosuppression

It is well known that viral and fungal infections are common in immunosuppressed patients. 4.7.1 HIV infection HIV infection can lead to acute renal failure through non-specific severe systemic illness, and to chronic renal failure through a variety of nephropathies. These include HIV-induced thrombotic microangiopathy, immunemediated glomerulonephritis and nephropathy due to virus-induced cellular damage, primarily to the glomerular epithelial cell. Combination therapy using corticosteroids, ACE inhibitors and highly active antiretroviral therapy seems to delay and prevent progression of nephropathy, although evidence from randomized trials is not available (55). HIV infection is therefore no longer a contraindication to renal replacement therapy. The place of immunosuppression per se in the development of UTI remains unresolved (56). Patients with endstage renal failure are generally not particularly susceptible to the usual Gram-negative urinary pathogens, although they may acquire unusual and granulomatous infections. Patients have evidence of reduced cellular and humoral immunity. However, the situation is a little clearer in male patients with HIV and AIDS where there is a close relationship between CD4 counts and the risk of bacteriuria, particularly in patients whose counts are less than 200 cells/mL (57). About 40% of patients with bacteriuria will be asymptomatic. In these patients, PCP prophylaxis of the type used in transplant patients may not reduce the rate of bacteriuria, perhaps due to the previous development of resistant organisms. 4.7.2 Viral and fungal infections Viral and fungal infections are relatively common in immunosuppressed patients.

4.8

References

1.

2.

Kincaid-Smith P, Fairley KF. Complicated urinary tract infection in adults. In: Cattell WR, ed. Infections of the kidney and urinary tract. Oxford: Oxford Medical Publications (Oxford University Press), 1996, pp. 186-205. Meyrier A, Condamin MC, Fernet M, Labigne-Roussel A, Simon P, Callard P, Rianfray M, Soilleux M, Groc A. Frequency of development of early cortical scarring in acute primary pyelonephritis. Kidney Int 1989;35(2):696-703. http://www.ncbi.nlm.nih.gov/pubmed/2651759

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Matz LR, Hodson CJ, Craven JD. Experimental obstructive nephropathy in the pig. 3. Renal artery changes in experimental hydronephrosis, with special reference to renal artery stenosis due to fibromuscular hyperplasia. Br J Urol 1969;41 Suppl:36-41. http://www.ncbi.nlm.nih.gov/pubmed/5359479 Hodson CJ, Maling TM, McManamon PJ, Lewis MG. The pathogenesis of reflux nephropathy (chronic atrophic pyelonephritis). Br J Radiol 1975;Suppl 13:1-26. http://www.ncbi.nlm.nih.gov/pubmed/766885 Bishop MC. Obstructive uropathy. In: Mundy AR, ed. Scientific basis of urology. Edinburgh: Churchill Livingstone 1987, pp. 115-151. Bailey RR. Vesico-ureteric reflux and reflux nephropathy. In: Cameron S et al., eds. Oxford textbook of clinical nephrology. Oxford: Oxford University Press,1992, pp. 1983–2002. Bishop MC. Urosurgical management of urinary tract infection. J Antimicrob Chemother 1994;33 Suppl A:74-91. http://www.ncbi.nlm.nih.gov/pubmed/7928839 Roberts JA. Management of pyelonephritis and upper urinary tract infections. Urol Clin North Am 1999;26(4):753-63. http://www.ncbi.nlm.nih.gov/pubmed/10584616 Fraser IR, Birch D, Fairley KF, John S, Lichtenstein M, Tress B, Kincaid-Smith PS. A prospective study of cortical scarring in acute febrile pyelonephritis in adults: clinical and bacteriological characteristics. Clin Nephrol 1995;43(3):159-64. http://www.ncbi.nlm.nih.gov/pubmed/7774071 George NJ. Urinary tract infection. In: Mundy AR, George NJ, Fitzpatrick JM, Neill DE, eds. Scientific basis of urology. 2nd edition. ISIS Medical Media, 1998, pp. 143-173. Svanborg C, de Man P, Sandberg T. Renal involvement in urinary tract infection. Kidney Int 1991;39(3):541-9. http://www.ncbi.nlm.nih.gov/pubmed/2062037 Hedges S, Stenqvist K, Lidin-Janson G, Martinell J, Sandberg T, Svanborg C. Comparison of urine and serum concentrations of interleukin-6 in women with acute pyelonephritis or asymptomatic bacteriuria. J Infect Dis 1992;166(3):653-6. http://www.ncbi.nlm.nih.gov/pubmed/1500753 Jacobson SH, Hylander B, Wretlind B, Brauner A. Interleukin-6 and interleukin-8 in serum and urine in patients with acute pyelonephritis in relation to bacterial- virulence-associated traits and renal function. Nephron 1994;67(2):172-9. http://www.ncbi.nlm.nih.gov/pubmed/7915403 Ronald AR, Cutler RE, Turck M. Effect of bacteriuria on renal concentrating mechanisms. Ann Intern Med 1996;70(4):723-33. http://www.ncbi.nlm.nih.gov/pubmed/5771530 de Man P, Cläeson I, Johnson IM, Jodal U, Svanborg Edén C. Bacterial attachment as a predictor of renal abnormalities in boys with urinary tract infection. J Pediatr 1989;115(6):915–22. http://www.ncbi.nlm.nih.gov/pubmed/2685219 Percival A, Birumfitt W, Delouvois J. Serum antibody levels as an indication of clinically inapparent pyelonephritis. Lancet 1964;2:1027-33. http://www.ncbi.nlm.nih.gov/pubmed/14206013 Wullt B, Bergsten G, Fischer H. Application of laboratory research in UTI. European Urology EAU Update Series 2, 2004, pp. 116-124. Kallenius G, Mollby R, Svenson SB, Helin I, Hultberg H, Cedergren B, Winberg J. Occurrence of Pfimbriated Escherichia coli in urinary tract infections. Lancet 1981;2(8260-8261):1369-72. http://www.ncbi.nlm.nih.gov/pubmed/6171697 Mulvey MA, Schilling JD, Martinez JJ, Hultgren SJ. Bad bugs and beleaguered bladders: interplay between uropathogenic Escherichia coli and innate host defenses. Proc Natl Acad Sci USA 2000:97(16):8829-35. http://www.ncbi.nlm.nih.gov/pubmed/10922042 Gordon I, Barkovics M, Pindoria S, Cole TJ, Woolf AS. Primary vesicoureteric reflux as a predictor of renal damage in children hospitalized with urinary tract infection: a systematic review and metaanalysis. J Am Soc Nephrol 2003;14(3):739-44. http://www.ncbi.nlm.nih.gov/pubmed/12595511

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Alwall N. On controversial and open questions about the course and complications of non-obstructive urinary tract infection in adult women. Follow-up for up to 80 months of 707 participants in a population study and evaluation of a clinical series of 36 selected women with a history of urinary tract infection for up to 40 years. Acta Med Scand 1978;203(5):369-77. http://www.ncbi.nlm.nih.gov/pubmed/665302 Bailey RR, Lynn KL, Robson RA, Smith AH, Maling TM, Turner JG. DMSA renal scans in adults with acute pyelonephritis. Clin Nephrol 1996;46(2):99-104. http://www.ncbi.nlm.nih.gov/pubmed/8869786 Geerlings SE, Stolk RP, Camps MJ, Netten PM, Hoekstra JB, Bouter KP, Bravenboer B, Collet JT, Jansz AR, Hoepelman AI. Asymptomatic bacteriuria may be considered a complication in women with diabetes. Diabetes Mellitus Women Asymptomatic Bacteriuria Utrecht Study Group. Diabetes Care 2000;23(6):744-9. http://www.ncbi.nlm.nih.gov/pubmed/10840989 Ooi BS, Chen BT, Yu M. Prevalence and site of bacteriuria in diabetes mellitus. Postgrad Med J 1974;50(586):497-9. http://www.ncbi.nlm.nih.gov/pubmed/4464512 Korzeniowski OM. Urinary tract infection in the impaired host. Med Clin North Am 1991;75(2):391-404. http://www.ncbi.nlm.nih.gov/pubmed/1996041 Mackie AD, Drury PL. Urinary tract infection in diabetes mellitus. In: Cattell WR, ed. Infections of the kidney and urinary tract. Oxford: Oxford, Medical Publications (Oxford University Press), 1996, pp. 218-233. Harding GK, Zhanel GG, Nicolle LE, Cheang M; Manitoba Diabetes Urinary Tract Infection Study Group. Antimicrobial treatment of diabetic women with asymptomatic bacteriuria. N Eng J Med 2002;347(20):1576-83. http://www.ncbi.nlm.nih.gov/pubmed/12432044 Nicolle LE, Bradley S, Colgan R, Rice JC, Schaeffer A, Hooton TM; Infectious Diseases Society of America; American Society of Nephrology; American Geriatric Society. Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis 2005;40(5):643-54. http://www.ncbi.nlm.nih.gov/pubmed/15714408 Cattell WR. Urinary tract infection and acute renal failure. In: Raine AE, ed. Advanced renal medicine. Oxford: Oxford University Press, 1992, pp. 302-313. Mallinson WJ, Fuller RW, Levison DA, Baker LR, Cattell WR. Diffuse interstitial renal tuberculosis – an unusual cause of renal failure. Q J Med 1981;50(198):137-48. http://www.ncbi.nlm.nih.gov/pubmed/7302115 Morgan SH, Eastwood JB, Baker LR. Tuberculous interstitial nephritis - the tip of an iceberg? Tubercle 1990;71(1):5-6. http://www.ncbi.nlm.nih.gov/pubmed/2371760 McAdam KP, Anders RF, Smith SR, Russell DA, Price MA. Association of amyloidosis with erythema nodosum leprosum reactions and recurrent neutrophil leucocytosis in leprosy. Lancet 1975;2(7935): 572-3. http://www.ncbi.nlm.nih.gov/pubmed/51405 Ng WL, Scollard DM, Hua A. Glomerulonephritis in leprosy. Am J Clin Pathol 1981;76(3):321-9. http://www.ncbi.nlm.nih.gov/pubmed/6456662 Cek M, Lenk S, Naber KG, Bishop MC, Johansen TE, Botto H, Grabe M, Lobel B, Redorta JP, Tenke P; Members of the Urinary Tract Infection (UTI) Working Group of the European Association of Urology (EAU) Guidelines Office. EAU guidelines for the management of genitourinary tuberculosis. Eur Urol 2005;48(3):353-62. http://www.ncbi.nlm.nih.gov/pubmed/15982799 Neal DE Jr. Host defense mechanisms in urinary tract infections. Urol Clin North Am 1999;26(4): 677-86, vii. http://www.ncbi.nlm.nih.gov/pubmed/10584610 Khan I H, Catto GR. Long-term complications of dialysis: infection. Kidney Int Suppl 1993;41:S143–S148. http://www.ncbi.nlm.nih.gov/pubmed/8320909 Kessler M, Hoen B, Mayeux D, Hestin D, Fontenaille C. Bacteremia in patients on chronic hemodialysis. A multicenter prospective survey. Nephron 1993;64(1):95-100. http://www.ncbi.nlm.nih.gov/pubmed/8502343

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Saitoh H, Nakamura K, Hida M, Satoh T. Urinary tract infection in oliguric patients with chronic renal failure. J Urol 1985;133(6):990-3. http://www.ncbi.nlm.nih.gov/pubmed/3999225 Elzinga LW, Bennett WM. Miscellaneous renal and systemic complications of autosomal dominant polycystic kidney disease including infection. In: Watson ML and Torres VE, eds. Polycystic kidney disease. Oxford: Oxford Clinical Nephrology series (Oxford University Press), 1996, pp. 483-499. Sklar AH, Caruana RJ, Lammers JE, Strauser GD. Renal infections in autosomal dominant polycystic kidney disease. Am J Kidney Dis 1987;10(2):81-8. http://www.ncbi.nlm.nih.gov/pubmed/3300296 Schwab SJ, Bander SJ, Klahr S. Renal infection in autosomal dominant polycystic kidney disease. Am J Med 1987;82(4):714-8. http://www.ncbi.nlm.nih.gov/pubmed/3565428 Stiasny B, Ziebell D, Graf S, Hauser LA, Schulze BD. Clinical aspects of renal transplantation in polycystic kidney disease. Clin Nephrol 2002;58(1):16-24. http://www.ncbi.nlm.nih.gov/pubmed/12141402 Gower PE. A prospective study of patients with radiological pyelonephritis, papillary necrosis and obstructive atrophy. Q J Med 1976;45(187):315-49. http://www.ncbi.nlm.nih.gov/pubmed/940921 Mor Y, Leibovitch I, Zalts R, Lotan D, Jonas P, Ramon J. Analysis of the long term outcome of surgically corrected vesico-ureteric reflux. BJU Int 2003;92(1):97-100. http://www.ncbi.nlm.nih.gov/pubmed/12823390 Tolkoff-Rubin NE, Rubin RH. Urinary tract infection in the renal transplant recipient. In: Bergan T, ed. Urinary tract infections. Basel: Karger 1997, pp. 27-33. Tolkoff-Rubin NE, Rubin RH. The infectious disease problems of the diabetic renal transplant recipient. Infect Dis Clin North Am 1995;9(1):117-30. http://www.ncbi.nlm.nih.gov/pubmed/7769213 Müller T, Arbeiter K, Aufricht C. Renal function in meningomyelocele: risk factors, chronic renal failure, renal replacement therapy and transplantation. Curr Opin Urol 2002;12(6):479-84. http://www.ncbi.nlm.nih.gov/pubmed/12409876 Steinhoff J, Einecke G, Niederstadt C, de Groot K, Fricke L, Machnik H, Sack K. Renal graft rejection or urinary tract infection? The value of myeloperoxidase, C-reactive protein, and alpha2-macroglobulin in the urine. Transplantation 1997;64(3):443-7. http://www.ncbi.nlm.nih.gov/pubmed/9275111 Keller LS, Peh CA, Nolan J, Bannister KM, Clarkson AR, Faull RJ. BK transplant nephropathy successfully treated with cidofovir. Nephrol Dial Transplant 2003;18(5):1013-4. http://www.ncbi.nlm.nih.gov/pubmed/12686681 Blanchet P, Droupy S, Eschwege P, Hammoudi Y, Durrbach A, Charpentier B, Benoit G. Urodynamic testing predicts long term urological complications following simultaneous pancreas-kidney transplantation. Clin Transplant 2003;17(1):26-31. http://www.ncbi.nlm.nih.gov/pubmed/12588318 Snydman DR. Posttransplant microbiological surveillance. Clin Infect Dis 2001;33 Suppl 1:S22-S25. http://www.ncbi.nlm.nih.gov/pubmed/11389518 Fox BC, Sollinger HW, Belzer FO, Maki DG. A prospective, randomised double-blind study of trimethoprim-sulfamethoxazole for prophylaxis of infection in renal transplantation: clinical efficacy, absorption of trimethoprim-sulphamethoxazole, effects on the microflora, and the cost-benefit of prophylaxis. Am J Med 1990;89(3):255-74. http://www.ncbi.nlm.nih.gov/pubmed/2118307 Mahmoud KM, Sobh MA, El-Agroudy AE, Mostafa FE, Baz ME, Shokeir AA, Ghoneim MA. Impact of schistosomiasis on patient and graft outcome after renal transplantation: 10 years’ follow-up. Nephrol Dial Transplant 2001;16(11):2214-21. http://www.ncbi.nlm.nih.gov/pubmed/11682670 Bichler KH, Savatovsky I; the Members of the Urinary Tract Infection (UTI) Working Group of the Guidelines Office of the European Association of Urology (EAU):, Naber KG, Bischop MC, BjerklundJohansen TE, Botto H, Cek M, Grabe M, Lobel B, Redorta JP, Tenke P. Eur Urol 2006;49(6):998-1003. http://www.ncbi.nlm.nih.gov/pubmed/16519990 Kimmel PL, Barisoni L, Kopp JB. Pathogenesis and treatment of HIV-associated renal diseases: lessons from clinical and animal studies, molecular pathologic correlations, and genetic investigations. Ann Intern Med 2003;139(3):214-26. http://www.ncbi.nlm.nih.gov/pubmed/12899589

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56.

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Tolkoff-Rubin NE, Rubin RH. Urinary tract infection in the immunocompromised host. Lessons from kidney transplantation and the AIDS epidemic. Infect Dis Clin North Am 1997;11(3):707-17. http://www.ncbi.nlm.nih.gov/pubmed/9378931 Van Dooyeweert DA, Schneider MM, Borleffs JC, Hoepelman AI. Bacteriuria in male patients infected with human immunodeficiency virus type 1. In: Bergan T, ed. Urinary tract infections. Basel: Karger, 1997, pp 37-45.

4.8.1 Further reading Antibiotic prescribing in renal failure: evidence base of guidelines. Information has been derived from the following standard reference sources: 1. BMA and RPSGB. British national formulary. Summary of product characteristics from electronic medicines compendium for individual drugs. Datapharm Communications Ltd. Available from http://emc.medicines.org.uk 2. Ashley C, Currie A. The renal drug handbook. 2nd edn. Oxford: Radcliffe Medical Press, 2004.

5. COMPLICATED UTIs DUE TO UROLOGICAL DISORDERS 5.1

Summary and recommendations

A complicated urinary tract infection (UTI) is an infection associated with a condition, such as a structural or functional abnormality of the genitourinary tract, or the presence of an underlying disease that interferes with host defence mechanisms, which increase the risks of acquiring infection or of failing therapy. A broad range of bacteria can cause a complicated UTI. The spectrum is much larger than in uncomplicated UTIs and bacteria are more likely to be resistant to antimicrobials, especially in a treatmentrelated complicated UTI. Enterobacteriaceae are the predominant pathogens, with Escherichia coli being the most common pathogen. However, non-fermenters (e.g. Pseudomonas aeruginosa) and Gram-positive cocci (e.g. staphylococci and enterococci) may also play an important role, depending on the underlying conditions. Treatment strategy depends on the severity of the illness. Treatment encompasses three goals: management of the urological abnormality, antimicrobial therapy, and supportive care when needed. Hospitalization is often required. To avoid the emergence of resistant strains, therapy should be guided by urine culture whenever possible. If empirical therapy is necessary, the antibacterial spectrum of the antibiotic agent should include the most relevant pathogens (A). A fluoroquinolone with mainly renal excretion, an aminopenicillin plus a ß-lactam inhibitor (BLI), a Group 2 or 3a cephalosporin or, in the case of parenteral therapy, an aminoglycoside, are recommended alternatives (1bB). In case of failure of initial therapy, or in case of clinically severe infection, a broader-spectrum antibiotic should be chosen that is also active against Pseudomonas (1bB), e.g. a fluoroquinolone (if not used for initial therapy), an acylaminopenicillin (piperacillin) plus a BLI, a Group 3b cephalosporin, or a carbapenem, with or without combination with an aminoglycoside (1bB). The duration of therapy is usually 7-14 days (1bA), but has sometimes to be prolonged for up to 21 days (1bA). Until predisposing factors are completely removed, true cure without recurrent infection is usually not possible. Therefore, a urine culture should be carried out 5-9 days after the completion of therapy and also 4-6 weeks later (B).

5.2

Definitions and classification

A complicated UTI is an infection associated with a condition, such as structural or functional abnormalities of the genitourinary tract or the presence of an underlying disease, which increases the risks of acquiring an infection or of failing therapy (1-3). Two criteria are mandatory to define a complicated UTI: a positive urine culture and one or more of the factors listed in Table 5.1.

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Table 5.1 Factors that suggest a potential complicated UTI • • • • • • • •

The presence of an indwelling catheter, stent or splint (urethral, ureteral, renal) or the use of intermittent bladder catheterization A post-void residual urine of > 100 mL An obstructive uropathy of any aetiology, e.g. bladder outlet obstruction (including neurogenic urinary bladder), stones and tumour Vesicoureteric reflux or other functional abnormalities Urinary tract modifications, such as an ileal loop or pouch Chemical or radiation injuries of the uroepithelium Peri- and post-operative UTI Renal insufficiency and transplantation, diabetes mellitus and immunodeficiency

Complicated UTI can arise in a heterogeneous group of patients. But neither patient age nor gender per se are part of the definition of a complicated UTI. With regard to prognosis and clinical studies, it is advisable to stratify complicated UTIs due to urological disorders into at least two groups (4): 1. Patients in whom the complicating factors could be eliminated by therapy, e.g. stone extraction, removal of an indwelling catheter. 2. Patients in whom the complicating factor could not be or is not removed satisfactorily during therapy, e.g. permanent indwelling catheter, stone residuals after treatment or neurogenic bladder. 5.2.1 Clinical presentation A complicated UTI may or may not be associated with clinical symptoms (e.g. dysuria, urgency, frequency, flank pain, costovertebral angle tenderness, suprapubic pain and fever). Clinical presentation may vary from severe obstructive acute pyelonephritis with imminent urosepsis to a catheter-associated post-operative UTI, which might disappear spontaneously as soon as the catheter is removed. It also has to be recognized that symptoms, especially lower urinary tract sympoms (LUTS), are not only caused by UTIs but also by other urological disorders, such as benign prostatic hyperplasia (BPH), TURP, etc. Apart from urological abnormalities, concomitant medical conditions, such as diabetes mellitus (10%) and renal failure, which can be related to urological abnormalities (5), are often present in a complicated UTI. These are discussed in more details in Sections 4.1.3 and 4.1.4 on UTIs in renal insufficiency, transplant recipients, diabetes mellitus and immunosuppression. 5.2.2 Urine cultures Significant bacteriuria in a complicated UTI is defined by counts of > 105 cfu/mL and > 104 cfu/mL, in the MSU of women and men, respectively (1, 2). If a straight catheter urine sample is taken, > 104 cfu/mL can be considered relevant. For an asymptomatic patient, two consecutive urine cultures (at least 24 hours apart) yielding > 105 cfu/mL of the same micro-organism are required. The requirement for pyuria is > 10 WBC per high-power field (x 400) in the resuspended sediment of a centrifuged aliquot of urine or per mm3 in unspun urine. A dipstick method can also be used for routine assessment, including a leucocyte esterase test, haemoglobin and probably a nitrite reaction.

5.3

Microbiology

5.3.1 Spectrum and antibiotic resistance Patients with a complicated UTI, both community and hospital-acquired, tend to show a diversity of microorganisms with a higher prevalence of resistance against antimicrobials, and higher rates of treatment failure if the underlying abnormality cannot be corrected. However, the presence of a resistant strain on its own is not enough to define a complicated UTI. Urinary abnormality (anatomical or functional) or the presence of an underlying disease predisposing to a UTI is also necessary. A broad range of bacteria can cause a complicated UTI. The spectrum is much larger than with an uncomplicated UTI and the bacteria are more likely to be antibiotic-resistant (especially in a treatmentrelated complicated UTI) than those isolated in an uncomplicated UTI. Escherichia coli, Proteus, Klebsiella, Pseudomonas, Serratia spp. and enterococci are the usual strains found in cultures. Enterobacteriaceae predominate (60-75%) (6-8), with E. coli as the most common pathogen, particularly if the UTI is a first infection. Otherwise, the bacterial spectrum may vary from time to time and from one hospital to another. 5.3.2 Complicated UTIs associated with urinary stones In the subset of complicated UTIs related to urinary stones, the frequency of E. coli and enterococci infection seems less important pathogens. In contrast, a greater portion of Proteus spp. and Pseudomonas (9) is found.

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Of the urease-producing organisms, Proteus, Providencia, Morganella spp., and Corynebacterium urealyticum are predominant, but Klebsiella, Pseudomonas, Serratia and staphylococci are also urease producers to a certain extent. Among patients with staghorn calculus disease, 88% were found to have a UTI at the time of diagnosis, with 82% of patients infected with urease-producing organisms (10). The enzyme, urease, splits urea into carbon dioxide and ammonia. The resulting increase in ammonia in the urine injures the glycosaminoglycan (GAG) layer, which in turn increases bacterial adherence (11) and enhances the formation of struvite crystals. These aggregate to form renal stones and incrustations on urinary catheters (12). The pathogenic potential of coagulase-negative staphylococci and non-group D streptococci is controversial (13, 14). Under certain circumstances, such as the presence of a stone or foreign bodies, staphylococci can be relevant pathogens. Otherwise, staphylococci are not so common in complicated UTIs (0-11%), according to published reports (6, 15). 5.3.3 Complicated UTIs associated with urinary catheters In catheter-associated UTIs, the distribution of micro-organisms is similar (16), and biofilm has to be considered. Antimicrobial therapy may only be effective in the early stages of the infection (15). For more details see chapter 6 on catheter associated UTI.

5.4

Treatment

5.4.1 General principles Treatment strategy depends on the severity of the illness. Appropriate antimicrobial therapy and the management of the urological abnormality are mandatory. If needed, supportive care is given. Hospitalization is often necessary depending on the severity of the illness. 5.4.2 Choice of antibiotics Empirical treatment of a symptomatic complicated UTI requires a knowledge of the spectrum of possible pathogens and local antibiotic resistance patterns, as well as assessment of the severity of the underlying urological abnormality (including the evaluation of renal function). Bacteraemia is usually reported too late to influence the choice of antibiotics. However, suspicion of bacteraemia must influence the empirical treatment. Most important for the prognosis is still the severity of the associated illness and of the underlying urological condition. Many therapeutic trials have been published on the use of specific antimicrobial therapies in complicated UTIs. Unfortunately, most reports are of limited use for the practical management of the patient in a day-to-day situation because of limitations such as: • poor characterization of the patient populations • unclear evaluation of the severity of the illness • nosocomial and community-acquired infections are not accurately distinguished • urological outcome is seldom taken into consideration. Intense use of any antimicrobial, especially when used on an empirical basis in this group of patients with a high likelihood of recurrent infection, will lead to the emergence of resistant micro-organisms in subsequent infections. Whenever possible, empirical therapy should be replaced by a therapy adjusted for the specific infective organism(s) identified in the urine culture. Therefore, a urine specimen for culture must be obtained prior to initiating therapy and the selection of an antimicrobial agent should be re-evaluated once culture results are available (7). So far, it has not been shown that any agent or class of agents is superior in a case where the infective organism is susceptible to the drug administered. In patients with renal failure, whether related to a urological abnormality or not, appropriate dose adjustments have to be made. If empirical treatment is necessary, fluoroquinolones with mainly renal excretion are recommended because they have a large spectrum of antimicrobial activity covering most of the expected pathogens and they reach high concentration levels both in urine and the urogenital tissues. Fluoroquinolones can be used orally as well as parenterally. An aminopenicillin plus a BLI, a Group 2 or 3a cephalosporin, or, in the case of parenteral therapy, an aminoglycoside, are alternatives. A new Group 1 oral carbapenem, ertapenem, in a prospective randomized trial, has been shown to be as effective as ceftriaxone (17). In most countries, E. coli shows a high rate of resistance against TMP-SMX (18% in the last US evaluation) (16) and should therefore be avoided as a first-line treatment. Fosfomycin trometamol is licensed only for a single-dose therapy of uncomplicated cystitis (18). The aminopenicillins, ampicillin or amoxicillin, are no longer sufficiently active against E. coli. In the case of failure of initial therapy, or if microbiological results are not yet available, or as initial therapy in the case of clinically severe infection, treatment should be switched to an antibiotic with a broader spectrum that is also active against Pseudomonas, such as a fluoroquinolone (if not used for initial therapy),

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an acylaminopenicillin (piperacillin) plus a BLI, a Group 3b cephalosporin, or a carbapenem, eventually in combination with an aminoglycoside. Similarly, many experts concur that empirical therapy for the institutionalized or hospitalized patients with a serious UTI should include an intravenous antipseudomonal agent because of an increased risk of urosepsis (19). Patients can generally be treated as outpatients. In more severe cases (e.g. hospitalized patients), antibiotics have to be given parenterally. A combination of an aminoglycoside with a BLI or a fluoroquinolone is widely used for empirical therapy. After a few days of parenteral therapy and clinical improvement, patients can be switched to oral treatment. Therapy has to be reconsidered when the infective strains have been identified and their susceptibilities are known. The successful treatment of a complicated UTI always combines effective antimicrobial therapy, optimal management of the underlying urological abnormalities or other diseases, and sufficient lifesupporting measures. The antibacterial treatment options are summarized in Table 5.2 and Appendix 12.2 (Recommendations for antimicrobial therapy in urology). 5.4.3 Duration of antibiotic therapy Treatment for 7-14 days is generally recommended, but the duration should be closely related to the treatment of the underlying abnormality (1). Sometimes, a prolongation for up to 21 days, according to the clinical situation, is necessary (2). 5.4.4 Complicated UTIs associated with urinary stones If a nidus of either a stone or an infection remains, stone growth will occur. Complete removal of the stones and adequate antimicrobial therapy are both needed. Eradication of the infection will probably eliminate the growth of struvite calculi (20). Long-term antimicrobial therapy should be considered if complete removal of the stone can not be achieved (21). 5.4.5 Complicated UTIs associated with indwelling catheters Current data do not support the treatment of asymptomatic bacteriuria, either during short-term catheterization (< 30 days) or during long-term catheterization, because it will promote the emergence of resistant strains (22,23). In short-term catheterization, antibiotics may delay the onset of bacteriuria, but do not reduce complications (24). A symptomatic complicated UTI associated with an indwelling catheter is treated with an agent with as narrow a spectrum as possible, based on culture and sensitivity results. The optimal duration is not well established. Treatment durations that are both too short as well as too long may cause the emergence of resistant strains. A 7-day course may be a reasonable compromise. 5.4.6 Complicated UTIs in spinal-cord injured patients It is generally accepted that asymptomatic bacteriuria in these patients should not be treated (25), even in cases of intermittent catheterization. For symptomatic episodes of infection in the spinal-cord injured patient, only a few studies have investigated the most appropriate agent and the most appropriate duration of therapy. Currently, 7-10 days of therapy is most commonly used. There is no superiority of one agent or class of antimicrobials in this group of patients. Antimicrobial treatment options are summarized in Table 5.2. Table 5.2

Antimicrobial treatment options for empiric therapy

Antibiotics recommended for initial empirical treatment • Fluoroquinolones • Aminopenicillin plus a BLI • Cephalosporin (Groups 2 or 3a) • Aminoglycoside Antibiotics recommended for empirical treatment in case of initial failure or for severe cases • Fluoroquinolone (if not used for initial therapy) • Ureidopenicillin (piperacillin) plus BLI • Cephalosporin (Group 3b) • Carbapenem • Combination therapy: - Aminoglycoside + BLI - Aminoglycoside + fluoroquinolone Antibiotics not recommended for empirical treatment • Aminopenicillins, e.g. amoxicillin, ampicillin

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• Trimethoprim-sulphamethoxazole (only if susceptibility of pathogen is known) • Fosfomycin trometamol BLI = ß-lactam inhibitor 5.4.7 Follow-up after treatment The greater likelihood of the involvement of resistant micro-organisms in complicated UTIs is another feature of these infectious diseases. This is not a priori related to the urinary abnormality, but is related more to the fact that patients with a complicated UTI tend to have recurrent infection (7). For these reasons, prior to and after the completion of the antimicrobial treatment, urine cultures must be obtained for the identification of the micro-organisms and the evaluation of susceptibility testing.

5.5

Conclusions

Until predisposing factors are completely removed, true cure (i.e. without recurrent infection) is usually not possible. Correction of these abnormalities must be performed, whenever possible, as an essential part of treatment. Recurrent infection is the rule when the underlying urological abnormality cannot be removed: either relapse (e.g. with the same micro-organism) or a re-infection (e.g. with a new micro-organism). For this reason, a urine culture has to be carried out between 5 and 9 days after the completion of therapy and repeated between 4 and 6 weeks later.

5.6

References

1.

Rubin RH, Shapiro ED, Andriole VT, Davis RJ, Stamm WE. Evaluation of new anti-infective drugs for the treatment of urinary tract infection. Infectious Diseases Society of America and the Food and Drug Administration. Clin Infect Dis 1992;15 Suppl 1:S216-S227. http://www.ncbi.nlm.nih.gov/pubmed/1477233 Rubin RH, Shapiro ED, Andriole VT, Davis RJ, Stamm WE, with modifications by a European Working Party. General guidelines for the evaluation of new anti-infective drugs for the treatment of UTI. Taufkirchen, Germany: The European Society of Clinical Microbiology and Infectious Diseases, 1993, pp. 240-310. Kumazawa J, Matsumoto T. Complicated UTIs. In: Bergan T, ed. UTIs. Infectiology. Vol 1. Basel: Karger, 1997, pp. 19-26. Naber KG. Experience with the new guidelines on evaluation of new anti-infective drugs for the treatment of urinary tract infections. Int J Antimicrob Agents 1999;11(3-4):189-96. http://www.ncbi.nlm.nih.gov/pubmed/10394969 Sharifi R, Geckler R, Childs S. Treatment of urinary tract infections: selecting an appropriate broadspectrum antibiotic for nosocomial infections. Am J Med 1996;100(6A):76S-82S. http://www.ncbi.nlm.nih.gov/pubmed/8678101 Frankenschmidt A, Naber KG, Bischoff W, Kullmann K. Once-daily fleroxacin versus twice-daily ciprofloxacin in the treatment of complicated urinary tract infections. J Urol 1997;158(4):1494-9. http://www.ncbi.nlm.nih.gov/pubmed/9302150 Nicolle LE. A practical guide to the management of complicated urinary tract infection. Drugs 1997;53(4):583-92. http://www.ncbi.nlm.nih.gov/pubmed/9098661 Cox CE, Holloway WJ, Geckler RW. A multicenter comparative study of meropenem and imipenem/ cilastatin in the treatment of complicated urinary tract infections in hospitalized patients. Clin Infect Dis 1995;21(1):86-92. http://www.ncbi.nlm.nih.gov/pubmed/7578765 Dobardzic AM, Dobardzic R. Epidemiological features of complicated UTI in a district hospital of Kuwait. Eur J Epidemiol 1997;13(4):465-70. http://www.ncbi.nlm.nih.gov/pubmed/9258554 Emori TG, Gaynes RP. An overview of nosocomial infections, including the role of the microbiology laboratory. Clin Microbiol Rev 1993;6(4):428-42. http://www.ncbi.nlm.nih.gov/pubmed/8269394 Parsons CL, Stauffer C, Mulholland SG, Griffith DP. Effect of ammonium on bacterial adherence to bladder transitional epithelium. J Urol 1984;132(2):365-6. http://www.ncbi.nlm.nih.gov/pubmed/6376829 Dumanski AJ, Hedelin H, Edin-Liljergen A, Beauchemin D, McLean RJ. Unique ability of the Proteus mirabilis capsule to enhance mineral growth in infectious urinary calculi. Infect Immun 1994;62(7):2998-3003. http://www.ncbi.nlm.nih.gov/pubmed/8005688

2.

3. 4.

5.

6.

7.

8.

9.

10.

11.

12.

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13.

14.

15.

16.

17.

18.

19.

20. 21.

22.

23.

24.

25.

Stamm WE, Hooton TM. Management of urinary tract infections in adults. N Engl J Med 1993;329(18):1328-34. http://www.ncbi.nlm.nih.gov/pubmed/8413414 US Department of Health and Human Services, Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Guidance for Industry. Complicated urinary tract infections and pyelonephritis-developing antimicrobial drugs for treatment. Clin-Anti. Rockville, MD: Drug Information Branch. Division of Communications Management, 1998. http://www.fda.gov/cder/guidance/2559dft.htm Reid G. Biofilms in infectious disease and on medical devices. Int J Antimicrob Agents 1999;11(34):223-6. http://www.ncbi.nlm.nih.gov/pubmed/10394974 Sahm DF, Vaughan D, Thornsberry C. Antimicrobial resistance profiles among Escherichia (EC) urinary tract isolates in the United States: a current view. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Francisco, CA, USA, 1999: Abstract 611. http://www.thebody.com/confs/icaac99/icaac99.html Wells WG, Woods GL, Jiang Q, Gesser RM. Treatment of complicated urinary tract infection in adults: combined analysis of two randomized, double-blind, multicentre trials comparing ertapenem and ceftriaxone followed by an appropriate oral therapy. J Antimicrob Chemother 2004;53 Suppl 2:ii67-74. http://www.ncbi.nlm.nih.gov/pubmed/15150185 Lerner SA, Price S, Kulkarni S. Microbiological studies of fosfomycin trometamol against urinary isolates in vitro. In: New trends in urinary tract infections. Williams N, ed. Basel: Karger, 1988, pp. 121129. Carson C, Naber KG. Role of fluoroquinolones in the treatment of serious bacterial urinary tract infections. Drugs 2004;64(12):1359-73. http://www.ncbi.nlm.nih.gov/pubmed/15200349 Griffith DP, Osborne CA. Infection (urease) stones. Miner Electrolyte Metab 1987;13(4):278-85. http://www.ncbi.nlm.nih.gov/pubmed/3306321 Beck EM, Riehle RA Jr. The fate of residual fragments after extracorporeal shock wave lithotripsy monotherapy of infection stones. J Urol 1991;145(1):6-9. http://www.ncbi.nlm.nih.gov/pubmed/1984100 Alling B, Brandberg A, Seeberg S, Svanborg A. Effect of consecutive antibacterial therapy on bacteriuria in hospitalized geriatric patients. Scand J Infect Dis 1975;7(3):201-7. http://www.ncbi.nlm.nih.gov/pubmed/809837 Warren JW, Anthony WC, Hoopes JM, Muncie HL Jr. Cephalexin for susceptible bacteriuria in afebrile, long term catheterized patients. JAMA 1982;248(4):454-8. http://www.ncbi.nlm.nih.gov/pubmed/7045440 Yoshikawa TT, Nicolle LE, Norman DC. Management of complicated urinary tract infection in older patients. J Am Geriatr Soc 1996;44(10):1235-41. http://www.ncbi.nlm.nih.gov/pubmed/8856005 National Institute on Disability and Rehabilitation Research. The prevention and management of urinary tract infections among people with spinal cord injuries. National Institute on Disability and Rehabilitation Research Consensus Statement. January 27-29, 1992. J Am Paraplegia Soc 1992;15(3):194-204. http://www.ncbi.nlm.nih.gov/pubmed/1500945

6. CATHETER-ASSOCIATED UTIs Based on the EAU guidelines published in 2007 (ISBN-13:978-90-70244-59-0) the following text presents the findings of a comprehensive update produced as a collaborative effort by the European Society for Infection in Urology (the ESIU is a full EAU section office), the Urological Association of Asia, the Asian Association of UTI/ STD, the Western Pacific Society for Chemotherapy, the Federation of European Societies for Chemotherapy and Infection, and the International Society of Chemotherapy for Infection and Cancer. This text was recently published as “The European and Asian guidelines on management and prevention of catheter-associated urinary tract infections” (1). Since the complete document is available online, only the abstract and a summary of the recommendations are presented here.

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6.1

Abstract

We surveyed the extensive literature regarding the development, therapy and prevention of catheterassociated urinary tract infections (UTIs). We systematically searched for meta-analyses of randomised controlled trials available in Medline giving preference to the Cochrane Central Register of Controlled Trials and also considered other relevant publications, rating them on the basis of their quality. The studies’ recommendations, rated according to a modification of the US Department of Health and Human Services (1992), give a close-to-evidence based guideline for all medical disciplines, with special emphasis on urology where catheter-care is an important issue. The survey found that the urinary tract is the commonest source of nosocomial infection, particularly when the bladder is catheterised (Level of evidence: 2a). Most catheter-associated UTIs are derived from the patient’s own colonic flora (Level of evidence: 2b) and the catheter predisposes to UTI in several ways. The most important risk factor for the development of catheter-associated bacteriuria is the duration of catheterisation (Level of evidence: 2a). Most episodes of short-term catheter-associated bacteriuria are asymptomatic and are caused by a single organism (Level of evidence: 2a). Further organisms tend to be acquired by patients catheterised for more than 30 days. The clinician should be aware of two priorities: the catheter system should remain closed and the duration of catheterisation should be minimal (Grade of recommendation: A). While the catheter is in place, systemic antimicrobial treatment of asymptomatic catheter-associated bacteriuria is not recommended (Grade of recommendation: A), except for some special cases. Routine urine culture in an asymptomatic catheterised patient is also not recommended (Grade of recommendation: C) because treatment is in general not necessary. Antibiotic treatment is recommended only for symptomatic infection (Grade of recommendation: B). Long-term antibiotic suppressive therapy is not effective (Grade of recommendation: A). Antibiotic irrigation of the catheter and bladder is of no advantage (Grade of recommendation: A). Routine urine cultures are not recommended if the catheter is draining properly (Grade of recommendation: C). A minority of patients can be managed with the use of the non-return (flip) valve catheter, avoiding the closed drainage bag. Such patients may exchange the convenience of on-demand drainage with an increased risk of infection. Patients with urethral catheters in place for 10 years or more should be screened annually for bladder cancer (Grade of recommendation: C). Clinicians should always consider alternatives to indwelling urethral catheters that are less prone to causing symptomatic infection. In appropriate patients, suprapubic catheters, condom drainage systems and intermittent catheterisation are each preferable to indwelling urethral catheterisation (Grade of recommendation: B).

6.2

Summary of Recommendations

Recommendation GR* General aspects 1. Written catheter care protocols are necessary. B 2. Health care workers should observe protocols on hand hygiene and the need to use A disposable gloves between catheterised patients. Catheter insertion and choice of catheter 3. An indwelling catheter should be introduced under antiseptic conditions. B 4. Urethral trauma should be minimised by the use of adequate lubricant and the smallest B possible catheter calibre. 5. Antibiotic-impregnated catheters may decrease the frequency of asymptomatic bacteriuria B within 1 week. There is, however, no evidence they decrease symptomatic infection. Therefore, they cannot be recommended routinely. 6. Silver alloy catheters significantly reduce the incidence of asymptomatic bacteriuria, but B only for less than 1 week. There was some evidence of reduced risk for symptomatic UTI. Therefore they may be useful in some settings. Prevention 7. The catheter system should remain closed. A 8. The duration of catheterisation should be minimal. A 9. Topical antiseptics or antibiotics applied to the catheter, urethra or meatus are not A recommended. 10. Benefits from prophylactic antibiotics and antiseptic substances have never been A established, therefore they are not recommended. 11. Removal of the indwelling catheter after non-urological operation before midnight may B be beneficial.

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12. Long-term indwelling catheters should be changed in intervals adapted to the individual patient, but must be changed before blockage is likely to occur, however there is no evidence for the exact intervals of changing catheters. 13. Chronic antibiotic suppressive therapy is generally not recommended. Diagnostics 14. Routine urine culture in asymptomatic catheterised patients is not recommended. 15. Urine, and in septic patients also blood for culture must be taken before any antimicrobial therapy is started. 16. Febrile episodes are only found in less than 10% of catheterised patients living in a long-term facility. It is therefore extremely important to rule out other sources of fever. Treatment 17. Whilst the catheter is in place, systemic antimicrobial treatment of asymptomatic catheter-associated bacteriuria is not recommended, except in certain circumstances: especially prior to traumatic urinary tract interventions. 18. In case of asymptomatic candiduria, neither systemic nor local antifungal therapy is indicated, but removal of the catheter or stent should be considered. 19. Antimicrobial treatment is recommended only for symptomatic infection. 20. In case of symptomatic catheter associated UTI it may be reasonable to replace or remove the catheter before starting antimicrobial therapy if the indwelling catheter has been in place for more than 7 days. 21. For empiric therapy broad-spectrum antibiotics should be given based on local susceptibility patterns. 22. After culture results are available antibiotic therapy has to be adjusted according to sensitivities of the pathogens. 23. In case of candiduria associated with urinary symptoms or if candiduria is the sign of a systemic infection, systemic therapy with antifungals are indicated. 24. Elderly female patients may need treatment if bacteriuria does not resolve spontaneously after catheter removal. Alternative drainage systems 25. There is limited evidence that post-operative intermittent catheterisation reduces the risk of bacteriuria compared with indwelling catheter. No recommendation can be made. 26. In appropriate patients suprapubic, condom drainage system or intermittent catheter are preferable to indwelling urethral catheter. 27. There is little evidence suggesting that antibiotic prophylaxis decreases bacteriuria in patients using intermittent catheterisation, therefore it is not recommended. Long-term follow up 28. Patients with urethral catheters in place for 10 years or more should be screened for bladder cancer *GR = grade of recommendation

B

A B C A

A

A/C B B

C B B C

C B B

C

6.3

Reference

1.

Tenke P, Kovacs B, Bjerklund Johansen TE, Matsumoto T, Tambyah PA, Naber KG. European and Asian guidelines on management and prevention of catheter-associated urinary tract infections. Int J Antimicrob Agents 2008;31S: S68-S78. http://www.ischemo.org/abstracts/TenkeIJAA2008.pdf

7. SEPSIS syndrome IN UROLOGY (UROSEPSIS) 7.1

Summary and recommendations

Patients with urosepsis should be diagnosed at an early stage, especially in the case of a complicated UTI. The systemic inflammatory response syndrome, known as SIRS (fever or hypothermia, hyperleucocytosis or leucopenia, tachycardia, tachypnoea), is recognized as the first event in a cascade to multi-organ failure. Mortality is considerably increased when severe sepsis or septic shock are present, though the prognosis of urosepsis is globally better than sepsis due to other infectious sites. The treatment of urosepsis calls for the combination of adequate life-supporting care, appropriate and prompt antibiotic therapy, adjunctive measures (e.g. sympathomimetic amines, hydrocortisone, blood glucose control, recombinant activated protein C) and the optimal management of urinary tract disorders

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(IaA). The drainage of any obstruction in the urinary tract is essential as first-line treatment (IbA). Urologists are recommended to treat patients in collaboration with intensive care and infectious diseases specialists (IIaB). Urosepsis can due to both community- or nosocomial-acquired infections. Most nosocomial urosepsis can be avoided by measures used to prevent nosocomial infection, e.g. reduction of hospital stay, early removal of indwelling urethral catheters, avoidance of unnecessary urethral catheterizations, correct use of closed catheter systems and attention to simple daily asepsis techniques in order to avoid crossinfection (IIaB).

7.2

Background

Urinary tract infections can manifest as bacteriuria with limited clinical symptoms, sepsis or severe sepsis, depending on localized or systemic extension. Sepsis is diagnosed when clinical evidence of infection is accompanied by signs of systemic inflammation (fever or hypothermia, tachycardia, tachypnoea, leucocyturia or leucopenia). Severe sepsis is defined by the presence of symptoms of organ dysfunction, and septic shock by the presence of a persistent hypotension associated with tissue anoxia. Severe sepsis is a severe situation with a reported mortality rate ranging from 20% to 42% (1). Most severe sepsis reported in the literature is related to pulmonary (50%) or abdominal infections (24%), with UTIs accounting for only 5% (2). Sepsis is commoner in men than in women (3). In recent years, the incidence of sepsis has increased by 8.7% per year (1), but the associated mortality has decreased suggesting improved management of patients (the total in-hospital mortality rate fell from 27.8% to 17.9% during the period 19952000) (4). Globally (this is not true for urosepsis), the rate of sepsis due to fungal organisms increased while Gram-positive bacteria became the predominant pathogen in sepsis even if in urosepsis Gram-negative bacteria remain predominant. In urosepsis, as in other types of sepsis, the severity of sepsis depends mostly upon the host response. Patients who are more likely to develop urosepsis include: elderly patients; diabetics; immunosuppressed patients, such as transplant recipients; patients receiving cancer chemotherapy or corticosteroids; and patients with acquired immunodeficiency syndrome. Urosepsis also depends on local factors, such as urinary tract calculi, obstruction at any level in the urinary tract, congenital uropathies, neurogenic bladder disorders or endoscopic manoeuvres. However, all patients can be affected by bacterial species capable of inducing inflammation within the urinary tract. Moreover, it is now recognized that SIRS may be present without infection (pancreatitis, burns, non-septic shock, etc) (5). For therapeutic purposes, the diagnostic criteria of sepsis should identify patients at an early stage of the syndrome, prompting urologists and intensive care specialists to search for and treat infection, apply appropriate therapy, and monitor for organ failure and other complications.

7.3

Definition and clinical manifestation of sepsis in urology

The clinical evidence of UTI is based on symptoms, physical examination, sonographic and radiological features, and laboratory data, such as bacteriuria and leucocyturia. The following definitions apply (Table 7.1): • Sepsis is a systemic response to infection. The symptoms of SIRS which were initially considered to be ‘mandatory’ for the diagnosis of sepsis (5), are now considered to be alerting symptoms (6). Many other clinical or biological symptoms must be considered. • Severe sepsis is sepsis associated with organ dysfunction. • Septic shock is persistence of hypoperfusion or hypotension despite fluid resuscitation. • Refractory septic shock is defined by an absence of response to therapy. Table 7.1: Clinical diagnostic criteria of sepsis and septic shock (5, 6) Disorder Infection Bacteraemia Systemic inflammatory response syndrome (SIRS)

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Definition Presence of organisms in a normally sterile site that is usually, but not necessarily, accompanied by an inflammatory host response Bacteria present in blood as confirmed by culture. May be transient Response to a wide variety of clinical insults, which can be infectious, as in sepsis but may be non-infectious in aetiology (e.g. burns, pancreatitis). This systemic response is manifested by two or more of the following conditions: Temperature > 38°C or < 36°C Heart rate > 90 beats min Respiratory rate > 20 breaths/min or PaCO2 < 32mmHg (< 4.3kPa) 3 WBC > 12,000 cells/mm3 or < 4,000 cells/mm or > 10% immature (band) forms

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Sepsis Hypotension Severe sepsis Septic shock Refractory septic shock

Activation of the inflammatory process due to infection A systolic blood pressure of < 90mmHg or a reduction of > 40mmHg from baseline in the absence of other causes of hypotension Sepsis associated with organ dysfunction, hypoperfusion or hypotension. Hypoperfusion and perfusion abnormalities may include but are not limited to lactic acidosis, oliguria or an acute alteration of mental status Sepsis with hypotension despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include, but are not limited to lactic acidosis, oliguria, or an acute alteration in mental status. Patients who are on inotropic or vasopressor agents may not be hypotensive at the time that perfusion abnormalities are measured Septic shock that last for more than 1 hour and does not respond to fluid administration or pharmacological intervention

7.4 Physiology and biochemical markers Micro-organisms reach the urinary tract by way of the ascending, haematogenous, or lymphatic routes. For urosepsis to be established, the pathogens have to reach the bloodstream. The risk of bacteriaemia is increased in severe UTIs, such as pyelonephritis and acute bacterial prostatitis (ABP), and is facilitated by obstruction. Escherichia coli remains the most prevalent micro-organism. Particularly in several countries, some bacterial strains can be resistant to quinolones or third-generation cephalosporins. Some micro-organisms are multi-resistant, such as methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa and Serratia spp. and therefore difficult to treat. Most commonly, the condition develops in compromised patients (e.g. those with diabetes or the immunosuppressed) with typical signs of generalized sepsis associated with local signs of infection. A fatal outcome is described in 20-40% of all patients. 7.4.1 Cytokines as markers of the septic response Cytokines are involved in the pathogenesis of sepsis syndrome. They are peptides that regulate the amplitude and duration of the host inflammatory response. They are released from various cells including monocytes, macrophages and endothelial cells, in response to various infectious stimuli. When they become bound to specific receptors on other cells, cytokines change their behaviour in the inflammatory response. The complex balance between pro- and anti-inflammatory responses is modified in severe sepsis. An immunodepressive phasis follows the initial pro-inflammatory mechanism. Other cytokines are involved such as interleukins. Tumour necrosis factor-α (TNF-9  pt), interleukin-1 (IL-1), IL-6, and IL-8 are cytokines that are associated with sepsis. Sepsis may indicate an immune system that is severely compromised and unable to eradicate pathogens or a non-regulated and excessive activation of inflammation or both. A genetic predisposition is more than likely to explain sepsis in several patients. Mechanisms of organ failure and death in patients with sepsis remain only partially understood (2). 7.4.2 Procalcitonin is a potential marker of sepsis Procalcitonin is the propeptide of calcitonin, but is devoid of hormonal activity. Normally in healthy humans, levels are undetectable. During severe generalized infections (bacterial, parasitic and fungal) with systemic manifestations, procalcitonin levels may rise to > 100 ng/mL. In contrast, during severe viral infections or inflammatory reactions of non-infectious origin, procalcitonin levels show only a moderate or no increase. The exact site of procalcitonin production during sepsis is not known. Procalcitonin monitoring may be useful in patients likely to develop a SIRS of infectious origin. High procalcitonin levels, or an abrupt increase in levels in these patients, should prompt a search for the source of infection. Procalcitonin may be useful in differentiating between infectious and non-infectious causes of severe inflammatory status (7, 8).

7.5 Prevention Septic shock is the most frequent cause of death for patients hospitalized for both community and nosocomial acquired infection (20-40%). Sepsis initiates the cascade that progresses to severe sepsis and then septic shock in a clinical continuum. Urosepsis treatment calls for the combination of treatment of the cause (obstruction), adequate life-supporting care and appropriate antibiotic therapy (2). In such a situation it is recommended that urologists collaborate with intensive care and infectious disease specialists for the best management of the patient. 7.5.1 Preventive measures of proven or probable efficacy (9, 10) The most effective methods to prevent nosocomial urosepsis are the same as those used to prevent other nosocomial infections:

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• •

• •

• • •

Isolation of all patients infected with multi-resistant organisms to avoid cross-infection. Prudent use of antimicrobial agents, both in prophylaxis and in treatment of established infections, to avoid selection of resistant strains. Antibiotic agents should be chosen according to the predominant pathogens at a given site of infection in the hospital environment. Reduction in hospital stay. It is well known that long in-patient periods prior to surgery lead to a greater incidence of nosocomial infections. Early removal of indwelling urethral catheters, as soon as allowed by the patient’s condition. Nosocomial UTIs are promoted by bladder catheterization as well as by ureteral stenting (11). Antibiotic prophylaxis does not prevent stent colonization, which appears in 100% of patients with a permanent ureteral stent and in 70% of those temporarily stented. Use of closed catheter drainage and minimization of breaks in the integrity of the system, e.g. for urine sampling or bladder wash-out. Use of least invasive method to release urinary tract obstruction until the patient is stabilized. Attention to simple everyday techniques to assure asepsis, including the routine use of protective, disposable gloves, frequent hand disinfection, and using infectious disease control measures to prevent cross-infections.

7.5.2 Appropriate peri-operative antimicrobial prophylaxis For appropriate peri-operative antimicrobial prophylaxis, see Section 11. The potential side effects of antibiotics must be considered prior to their administration in a prophylactic regimen. 7.5.3 • •

Preventive measures of debatable efficacy Instillation of antibiotic or antiseptic drugs into catheters and drainage bags. Use of urinary catheters coated with antibiotics or silver.

7.5.4 •

Ineffective or counterproductive measures Continuous or intermittent bladder irrigations with antibiotics or urinary antiseptics that increase the risk of infection with resistant bacteria (9, 12). Routine administration of antimicrobial drugs to catheterized patients, which reduces the incidence of bacteriuria only for a few days and increases the risk of infection with multi-resistant bacteria (9,12). Its use may be reserved for immunosuppressed patients.

•

7.6

Treatment

7.6.1 Relief of obstruction Drainage of any obstruction in the urinary tract and removal of foreign bodies, such as urinary catheters or stones, may themselves cause resolution of symptoms and lead to recovery. These are key components of the strategy. This condition is an absolute emergency. 7.6.2 Antimicrobial therapy Empirical initial treatment should provide broad antimicrobial coverage and should later be adapted on the basis of culture results. The antibacterial treatment options are summarized in Appendix 12. 7.6.3 Adjunctive measures (12, 13) The management of fluid and electrolyte balance is a crucial aspect of patient care in sepsis syndrome, particularly when the clinical course is complicated by shock. The use of human albumin is debatable. An early goal-directed therapy has been shown to reduce mortality (14). Volaemic expansion and vasopressor therapy have considerable impact on the outcome. Early intervention with appropriate measures to maintain adequate tissue perfusion and oxygen delivery by prompt institution of fluid therapy, stabilization of arterial pressure and providing sufficient oxygen transport capacity are highly effective. Hydrocortisone (with a debate on dosage) is useful in patients with relative insufficiency in the pituitary gland-adrenal cortex axis (ACTH test) (15). Tight blood glucose control by administration of insulin doses up to 50 units/hour is associated with a reduction in mortality (16). Recombinant activated protein C (dotrecogin alpha) is a new drug that has been approved for therapy of severe sepsis since November 2002. This expensive treatment has been proven to be more effective in patients with more severe disease, as assessed by Acute Physiology and Chronic Health Evaluation (APACHE) II scores > 25 or the presence of > two organ dysfunctions (17). The best strategy has been summarized and graded according to a careful evidence-based methodology in the recently published ‘Surviving Sepsis Guidelines’ (18).

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7.7

Conclusion

Sepsis syndrome in urology remains a severe situation with a mortality rate as high as 20-40%. A recent campaign, ‘Surviving Sepsis Guidelines’, aimed at reducing mortality by 25% in the next few years has been published recently (18). Early recognition of the symptoms may decrease the mortality by timely treatment of urinary tract disorders, e.g. obstruction, urolithiasis. Adequate life-support measures and appropriate antibiotic treatment provide the best conditions for improving patients’ survival. The prevention of sepsis syndrome is dependent on good practice to avoid nosocomial infections and using antibiotic prophylaxis and therapy in a prudent and well-accepted manner.

7.8

Acknowledgement

The authors are thankful to Jean M. Carlet, Head of Intensive Care, Hôpital Saint Joseph, Paris, France, for reviewing this manuscript on urosepsis.

7.9

References

1.

Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003;348(16):1546-54. http://www.ncbi.nlm.nih.gov/pubmed/12700374 Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003;348(2):13850. http://www.ncbi.nlm.nih.gov/pubmed/12519925 Rosser CJ, Bare RL, Meredith JW. Urinary tract infections in the critically ill patient with a urinary catheter. Am J Surg 1999;177(4):287-90. http://www.ncbi.nlm.nih.gov/pubmed/10326844 Brun-Buisson C, Meshaka P, Pinton P, Vallet B; EPISEPSIS Study Group. EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units. Intensive Care Med 2004;30(4):580-8. http://www.ncbi.nlm.nih.gov/pubmed/14997295 Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/ SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992;101(6):1644-55. http://www.ncbi.nlm.nih.gov/pubmed/1303622 Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G; SCCM/ESICM/ACCP/ATS/SIS. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003;31(4):1250-6. http://www.ncbi.nlm.nih.gov/pubmed/12682500 Brunkhorst FM, Wegscheider K, Forycki ZF, Brunkhorst R. Procalcitonin for early diagnosis and differentiation of SIRS, sepsis, severe sepsis and septic shock. Intensive Care Med. 2000;26(Suppl.2):S148-S152 . http://www.ncbi.nlm.nih.gov/pubmed/18470710 Harbarth S, Holeckova K, Froidevaux C, Pittet D, Ricou B, Grau GE, Vadas L, Pugin J; Geneva Sepsis Network. Diagnostic value of procalcitonin, interleukin-6, and interleukin-8 in critically ill patients admitted with suspected sepsis. Am J Respir Crit Care Med 2001;164(3):396-402. http://www.ncbi.nlm.nih.gov/pubmed/11500339 Carlet J, Dumay MF, Gottot S, Gouin F, Pappo M. (Guideliness for prevention of nosocomial infections in intensive care unit.) Arnette Ed Paris 1994:41-53. [article in French] Riedl CR, Plas E, Hübner WA, Zimmer H, Ulrich W, Pflüger H. Bacterial colonization of ureteral stents. Eur Urol 1999;36(1):53-9. http://www.ncbi.nlm.nih.gov/pubmed/10364656 DeGroot-Kosolcharoen J, Guse R, Jones JM. Evaluation of a urinary catheter with a preconnected closed drainage bag. Infect Control Hosp Epidemiol 1988;9(2):72-6. http://www.ncbi.nlm.nih.gov/pubmed/3343502 Persky L, Liesen D, Yangco B. Reduced urosepsis in a veterans’ hospital. Urology 1992;39(5):443-5. http://www.ncbi.nlm.nih.gov/pubmed/1580035 Glück T, Opal SM. Advances in sepsis therapy. Drugs 2004;64(8):837-59. http://www.ncbi.nlm.nih.gov/pubmed/15059039 Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345(19):1368-77. http://www.ncbi.nlm.nih.gov/pubmed/11794169

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3.

4.

5.

6.

7.

8.

9. 10.

11.

12. 13. 14.

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15.

16.

17.

18.

Annane D, Sebille V, Charpentier C, Bollaert PE, François B, Korach JM, Capellier G, Cohen Y, Azouley E, Troch´ G, Chaumet-Riffaut P, Bellissant E. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288(7):86271. http://www.ncbi.nlm.nih.gov/pubmed/12186604 van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001;345(19):1359-67. http://www.ncbi.nlm.nih.gov/pubmed/11794168 Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriquez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr. Recombinant Human Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344(10):699-709. http://www.ncbi.nlm.nih.gov/pubmed/11236773 Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM; Surviving Sepsis Campaign Management Guidelines Committee. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004;32:858-73. http://www.ncbi.nlm.nih.gov/pubmed/15090974

8. URETHRITIS 8.1

Definition

Primary urethritis has to be differentiated from secondary urethritis, which may be found in patients with indwelling catheters or urethral strictures and can be caused by uropathogens or by staphylococci. Besides infective causes of urethritis, chemical, mechanical and non-infective inflammatory causes also have to be considered, such as Reiter’s, Behçet’s and Wegener’s diseases (1). Only selected aspects of primary urethritis will be discussed in this chapter (2). For further details see also the EAU guidelines on sexually transmitted diseases (3).

8.2

Epidemiology

From a therapeutic and clinical point of view, gonorrhoeal urethritis has to be differentiated from non-specific urethritis. Non-specific urethritis is much more frequent in Central Europe than gonorrhoeal urethritis. There is a correlation between promiscuity and low socio-economic status and the frequency of infections due to N. gonorrhoeae and C. trachomatis. Infection is spread by sexual contact.

8.3 Pathogens Pathogens include N. gonorrhoeae, C. trachomatis, Mycoplasma genitalium and T. vaginalis. The frequency of the different species varies between patient populations (4-8). Mycoplasma hominis probably does not cause urethritis, while Ureaplasma urealyticum is an infrequent cause. In most cases, clinical evidence of Mycoplasma or Ureaplasma is due to an asymptomatic colonization of the urogenital tract.

8.4

Route of infection and pathogenesis

Causative agents either remain extracellularly on the epithelial layer or penetrate into the epithelium (N. gonorrhoeae, C. trachomatis) causing a pyogenic infection. Although arising from urethritis, chlamydiae and gonococci can spread further through the genito-urinary tract to cause epididymitis in the male or cervicitis, endometritis and salpingitis in the female.

8.5

Clinical course

Purulent discharge and alguria are symptoms of urethritis. However, many infections of the urethra are asymptomatic.

8.6

Diagnosis

A Gram stain of a urethral discharge or a urethral smear showing more than five leucocytes per high power field (x 1,000) and, eventually, gonococci located intracellularly as Gram-negative diplococci, indicate pyogenic urethritis. A positive leucocyte esterase test or > 10 leucocytes per high power field (x 400) in the first voiding

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urine specimen are diagnostic. In all patients with urethritis, and when sexual transmission is suspected, the aim should be to identify the pathogenic organisms. If an amplification system is used for identifying the pathogens, the first voiding urine specimen can be taken instead of a urethral smear. Trichomonas can usually be identified microscopically.

8.7

Therapy

The following guidelines for therapy comply with the recommendations of the Center for Disease Control and Prevention (9-11). The following antimicrobials can be recommended for the treatment of gonorrhoea: • Cefixime, 400 mg orally as a single dose • Ceftriaxone, 125 mg intramuscularly (with local anaesthetic) as a single dose • Ciprofloxacin, 500 mg orally as single dose • Ofloxacin, 400 mg orally as single dose • Levofloxacin, 250 mg orally as as single dose. Please note that fluoroquinolones, such as ciprofloxacin, levofloxacin, and ofloxacin, are contraindicated in adolescents ( 103 cfu/mL*

> 10 WBC/mm3 > 104 cfu/mL*

> 10 WBC/mm3 > 105 cfu/mL* in women > 104 cfu/mL* in men, or in straight catheter urine in women > 10 WBC/mm3 > 105 cfu/mL* in two consecutive MSU cultures > 24 hours apart

93

5 Recurrent UTI At least three episodes of < 103 cfu/mL* (antimicrobial prophylaxis) uncomplicated infection documented by culture in last 12 months: women only; no structural/functional abnormalities MSU = mid-stream sample of urine; UTI = urinary tract infection; WBC = white blood cells. All pyuria counts refer to unspun urine. *Uropathogen in MSU culture.

14.1.1 References 1.

2.

3.

Rubin RH, Shapiro ED, Andriole VT, Davis RJ, Stamm WE. Evaluation of new anti-infective drugs for the treatment of urinary tract infection. Infectious Diseases Society of America and the Food and Drug Administration. Clin Infect Dis 1992;15 Suppl 1:S216-S227. http://www.ncbi.nlm.nih.gov/pubmed/1477233 Rubin RH, Shapiro ED, Andriole VT, Davies RJ, Stamm WE, with modifications by a European Working Party (Norrby SR). General guidelines for the evaluation of new anti-infective drugs for the treatment of UTI. Taufkirchen, Germany: The European Society of Clinical Microbiology and Infectious Diseases, 1993; pp. 294-310. Naber KG. Experience with the new guidelines on evaluation of new anti-infective drugs for the treatment of urinary tract infections. Int J Antimicrob Agents 1999;11(3-4):189-96. http://www.ncbi.nlm.nih.gov/pubmed/10394969

14.2 Recommendations for antimicrobial therapy in urology Diagnosis Most frequent Initial, empirical Therapy duration pathogen/species antimicrobial therapy Cystitis • E. coli • Trimethoprim-sulphamethoxazole° 3 days acute, • Klebsiella • Fluoroquinolone* (1-)3 days uncomplicated • Proteus • Fosfomycin trometamol 1 day • Staphylococci • Pivmecillinam (3-)7 days • Nitrofurantoin (5-)7 days Pyelonephritis • E. coli • Fluoroquinolone* 7-10 days acute, • Proteus • Cephalosporin (group 3a) uncomplicated • Klebsiella Alternatives: • Other enterobacteria • Aminopenicillin/BLI • Staphylococci • Aminoglycoside UTI with • E. coli • Fluoroquinolone* 3-5 days after complicating • Enterococci • Aminopenicillin/BLI defeverescence or factors • Pseudomonas • Cephalosporin (group 2) control/elimination • Staphylococci • Cephalosporin (group 3a) of complicating Nosocomial UTI • Klebsiella • Aminoglycoside factor • Proteus In case of failure of initial therapy Pyelonephritis • Enterobacter within 1-3 days or in clinically severe acute, • Other enterobacteria cases: complicated • (Candida) Anti-Pseudomonas active: • Fluoroquinolone, if not used initially • Acylaminopenicillin/BLI • Cephalosporin (group 3b) • Carbapenem • ± Aminoglycoside In case of Candida: • Fluconazole • Amphotericin B Prostatitis acute, chronic

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• E. coli • Other enterobacteria • Pseudomonas

• Fluoroquinolone* Acute: Alternative in acute bacterial prostatitis: 2-4 weeks • Cephalosporin (group 3a/b)

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Epididymitis acute

• Enterococci • Staphylococci • Chlamydia • Ureaplasma

In case of Chlamydia or Ureaplasma: • Doxycycline • Macrolide

Chronic: 4-6 weeks or longer

Urosepsis • E. coli • Cephalosporin (group 3a/b) 3-5 days after • Other enterobacteria • Fluoroquinolone* defeverescence or After urological • Anti-Pseudomonas active control/elimination interventions – multi- acylaminopenicillin/BLI of complicating resistant pathogens: • Carbapenem factor • Pseudomonas • ± Aminoglycoside • Proteus • Serratia • Enterobacter BLI = ß-lactamase inhibitor; UTI = urinary tract infection. *Fluoroquinolone with mainly renal excretion (see text). °Only in areas with resistance rate < 20% (for E. coli).

14.3 Recommendations for antibiotic prescribing in renal failure Antibiotic GFR (ml/min Mild Moderate Severe 50-20 20-10 90% (90). Persistent bleeding is the main indication for a reconstruction attempt (91). The majority of patients with grade 4 and 5 renal injuries present with major associated injuries, and consequently experience high exploration and nephrectomy rates (92), although emerging data indicate that many of these patients can be managed safely with an expectant approach. Although almost all grade 4 patients with penetrating injury require renal exploration, only 20% of those with blunt trauma do (93). Isolated grade 4 renal injuries represent a unique situation to treat the patient based solely on the extent of the renal injury, thus non-operative management is used more frequently. Persistent bleeding represents the main indication for renal exploration and reconstruction. In all cases of severe renal injury, non-operative management should occur only after complete renal staging in haemodynamically stable patients (91). Penetrating wounds have traditionally been approached surgically. However, stable patients should undergo complete staging to define the full extent of the injury. Renal gunshot injuries should be explored only if they involve the hilum or are accompanied by signs of continued bleeding, ureteral injuries, or renal pelvis lacerations (94).

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Low-velocity gunshot and stab wounds of minor degree may be managed conservatively with an acceptably good outcome (95). Tissue damage from high-velocity gunshot injuries, on the other hand, might be more extensive and nephrectomy could be required. Non-operative management of renal gunshot wounds in selected stable patients is associated with a high rate of success (96-98). If the site of penetration by stab wound is posterior to the anterior axillary line, 88% of such renal injuries can be managed non-operatively (99). Injuries to the flank are more likely to be grade 3, while injuries to the abdomen are more likely to be grade 1. A systematic approach based on clinical, laboratory and radiological evaluation might minimise negative exploration without increasing morbidity from missed injury (61). Renal stab wounds producing major renal injuries (grade 3 or higher) are more unpredictable and are associated with a higher rate of delayed complications if treated expectantly (100).

2.4.4 Recommendations Recommendations GR • Following grade 1-4 blunt renal trauma, stable patients should be managed conservatively B with bed-rest, prophylactic antibiotics and continuous monitoring of vital signs until haematuria resolves • Following grade 1-3 stab and low-velocity gunshot wounds, stable patients, after B complete staging, should be selected for expectant management • Indications for surgical management include: • haemodynamic instability • exploration for associated injuries • expanding or pulsatile peri-renal haematoma identified during laparotomy • grade 5 injury • incidental finding of pre-existing renal pathology requiring surgical therapy B • Renal reconstruction should be attempted in cases where the primary goal of controlling B haemorrhage is achieved and a sufficient amount of renal parenchyma is viable GR = grade of recommendation 2.4.5 Post-operative care and follow-up Patients who are successfully treated conservatively carry some risk of complications. This risk correlates with increasing grade. Repeat imaging 2-4 days after trauma minimises the risk of missed complications, especially in grade 3-5 blunt renal injuries (101). However, the utility of frequent CT scanning after injury has never been satisfactorily proven. CT scans should always be performed on patients with fever, unexplained decreasing haematocrit, or significant flank pain. Nuclear renal scans are useful for documenting and tracking functional recovery in patients following renal reconstruction before discharge from hospital (97). To detect many of the delayed complications, an excretory urogram is recommended within 3 months of major renal injury, although benefit to the patient has not yet been proven in the literature. Follow-up should involve physical examination, urinalysis, individualised radiological investigation, serial blood pressure measurement and serum determination of renal function (60, 64). Follow-up examinations should continue until healing is documented and laboratory findings have stabilised, although checking for latent renovascular hypertension may need to continue for years (102). The literature is generally inadequate on the subject of the long-term consequences of trauma on renal tissue. It appears that on histopathological evaluation, renal tissue may appear dystrophic following some cases of conservative management of minor renal injuries (103).

2.4.6 Recommendations Recommendations GR • Repeat imaging is recommended for all hospitalised patients within 2-4 days of significant B renal trauma (although no specific data exists). Repeat imaging is always recommended in cases of fever, flank pain, or falling haematocrit • Nuclear scintigraphy before discharge from the hospital is useful for documenting functional C recovery • Within 3 months of major renal injury, patients’ follow-up should involve: C 1. physical examination

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•

2. urinalysis 3. individualised radiological investigation 4. serial blood pressure measurement 5. serum determination of renal function Long-term follow-up should be decided on a case-by-case basis but should at the very least involve monitoring for renovascular hypertension GR = grade of recommendation

C

2.4.7 Complications Early complications occur within the first month after injury and can be bleeding, infection, peri-nephric abscess, sepsis, urinary fistula, hypertension, urinary extravasation and urinoma. Delayed complications include bleeding, hydronephrosis, calculus formation, chronic pyelonephritis, hypertension, arteriovenous fistula, hydronephrosis and pseudoaneurysms. Delayed retroperitoneal bleeding usually occurs within several weeks of an injury or procedure and may be life-threatening. Selective angiographic embolisation is the preferred treatment (104). Peri-nephric abscess formation is usually best managed by percutaneous drainage, although open drainage may sometimes be required (60). Percutaneous management of complications may pose less risk of renal loss than re-operation, which may lead to nephrectomy when infected tissues make reconstruction difficult. Renal trauma is a rare cause of hypertension, mostly in young men. The frequency of post-traumatic hypertension is estimated to be less than 5% in all published series (105, 106). Hypertension may occur acutely as a result of external compression from peri-renal haematoma (Page kidney), or chronically because of compressive scar formation (Goldblatt kidney). Hypertension is usually renin-dependent and associated with parenchymal injury. Renin-mediated hypertension may occur as a long-term complication; aetiologies include renal artery thrombosis, segmental arterial thrombosis, renal artery stenosis (Goldblatt kidney), devitalised fragments and arteriovenous fistulae. Arteriography is informative in cases of post-traumatic hypertension (107). Treatment is required if the hypertension persists, and could include medical management, excision of the ischaemic parenchymal segment, vascular reconstruction, or total nephrectomy (108). Urinary extravasation after renal reconstruction often subsides without intervention as long as ureteral obstruction and infection are not present. Ureteral retrograde stenting may improve drainage and allow healing (109). Persistent urinary extravasation from an otherwise viable kidney after blunt trauma often responds to stent placement and/or percutaneous drainage as necessary (63). Arteriovenous fistulae usually present with delayed onset of significant haematuria, most often after penetrating trauma. Percutaneous embolisation is often effective for symptomatic arteriovenous fistulae, but larger ones may require surgery (110). The development of pseudoaneurysm is a rare complication following blunt renal trauma. In numerous case reports, transcatheter embolisation appears to be a reliable minimally invasive solution (111, 112). Acute renal colic from a retained missile has been reported, and can be managed endoscopically if possible (113). Other unusual late complications, such as duodenal obstruction, may result from retroperitoneal haematoma following blunt renal trauma (114).

2.4.8 Recommendations Recommendations GR • Complications following renal trauma require a thorough radiographic evaluation B • Medical management and minimally invasive techniques should be the first choice for the C management of complications • Renal salvage should be the surgeon’s aim for patients in whom surgical intervention is C necessary GR = grade of recommendation 2.4.9 Paediatric renal trauma Blunt renal trauma is the most common injury seen in children and accounts for more than 90% of renal injuries in the paediatric population (115, 116). Children are more susceptible to renal trauma than adults. Differences in anatomy and physiology, as well as the higher incidence of pre-existing renal disease, make children

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more likely to sustain injury. The kidneys are lower in the abdomen, less well-protected by the lower ribs and muscles of the flank and abdomen, more mobile, have less protective peri-renal fat and are proportionately larger in the abdomen than in adults (117-119). History and physical examination are very important factors in the evaluation of the paediatric patient with suspected renal trauma. Unlike adults, hypotension is an unreliable sign in children, as an outpouring of catecholamines can maintain blood pressure despite a significant volume of blood loss. Hypotension is less common in children, and significant injury can be present despite stable blood pressures (120). Another important difference from adults is that children with microscopic haematuria or normal urinalyses and stable vital signs may have sustained significant renal injury (121). Haematuria is an important clinical sign of paediatric renal injury and is directly related to the severity of that renal injury and the presence of associated injuries (122). The radiographic evaluation of children with suspected renal trauma is still controversial. Stein et al. proposed that all paediatric patients with any degree of haematuria should be evaluated for renal trauma (123). In contrast, Morey et al. concluded that significant injuries are unlikely in the absence of gross or significant microscopic haematuria (> 50 rbc/hpf) (124). Nguyen and Das proposed a low threshold for renal imaging following renal trauma. The instances of its use should include patients with blunt abdominal trauma with any level of haematuria, patients with associated abdominal injury regardless of the findings of urinalysis, and patients with normal urinalyses but in whom the mechanism of injury has a high index of suspicion for renal trauma (i.e. rapid deceleration event, direct flank trauma, falls from a height) (125). After studying 720 paediatric trauma cases, Santucci et al. concluded that the decision for imaging based on the adult criteria of gross haematuria, shock and significant deceleration injury is appropriate (126). Ultrasound is considered a reliable method of screening and following the course of renal injury in paediatric patients with blunt renal trauma in Europe, although it is used much less frequently in the USA (127, 128). Ultrasound is used in some centres, mostly in stable cases with abnormal urinalyses and/or findings suggestive of a major injury (129). The diagnostic accuracy of IVP is superior to that of ultrasound, and should be performed as an emergency procedure if CT scan is not available (130). CT is the best imaging modality, however, and those with multiple injuries or suspected renal trauma should be evaluated by contrast-enhanced CT if possible (131, 132). The use of MRI in paediatric patients with vesicoureteral reflux found that MRI at 1.5 T was better than dimercaptosuccinic acid (DMSA) scans in detecting small renal parenchymal lesions (133), although MRI has little proven use in the acute management of the trauma patient. Conservative treatment for grade 1-2 renal injuries is clearly defined, and these injuries should be managed expectantly (134). Non-operative management results in an excellent long-term outcome in the majority of cases (135). Non-operative management of high grade renal injuries is effective and is recommended for stable children, but requires close clinical observation, serial CT, and frequent reassessment of the patient’s overall condition (136). The length of hospital stay does not increase with worsening severity of renal injury, but is determined by the severity of non-renal injuries (137). Haemodynamic instability and a diagnosed grade 5 injury are the strongest indications for operative management (59, 120, 136). Stable patients with urinary extravasation can also be managed expectantly since most urinomas resolve spontaneously. In cases where there is persistent leakage, the placement of a ureteral stent or percutaneous drainage is feasible and curative in most cases. Early placement of a ureteral stent can be considered for paediatric patients with blunt renal trauma who demonstrate an absence of contrast material in the ipsilateral ureter, as clinical indications for stent placement will likely develop (138). Major kidney trauma has significant consequences on the opposite side. Post-traumatic functional evaluation by DMSA scintigraphy 8 days after major injury is a valid prognostic indicator of later function, but its clinical utility has never been established. Children with renal injuries that fail with non-surgical therapy appear to do so in a median time of 4 hours, but the majority of patients fail within the first 24 hours (139). The failure rate of non-surgical management for renal injuries is 3% (140). Buckley and McAninch presented an algorithm for the management of paediatric renal injuries based on the 25 year experience of the San Francisco General Hospital, which is highly recommended (135) (Figure 1).

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Mild renal injuries do not require follow-up imaging. Follow-up is only recommended for patients with major injuries as there is an increased risk of delayed complications and loss of renal function (139). The majority of patients with severe renal injuries develop parenchymal scars. Radionuclide scans such as DMSA can be useful in the early diagnosis of scars and consequent hypertension (141).

2.4.10 Recommendations Recommendations GR • Indications for radiographic evaluation of children suspected of renal trauma include: 1. blunt and penetrating trauma patients with any level of haematuria 2. patients with associated abdominal injury regardless of the findings of urinalysis 3. patients with normal urinalyses who sustained a rapid deceleration event, direct flank trauma, B or a fall from a height • Ultrasonography is considered a reliable method of screening and monitoring blunt B renal injuries by some researchers, but is not universally accepted • CT scanning is the imaging study of choice for staging renal injuries B • Haemodynamic instability and a diagnosed grade 5 injury are absolute indications for B surgical exploration GR = grade of recommendation 2.4.11 Renal injury in the polytrauma patient Approximately 8-10% of blunt and penetrating abdominal injuries involve the kidneys. The incidence of associated injury in penetrating renal trauma ranges from 77-100%. Gunshot wounds are associated with organ injury more often than are stab wounds. The majority of patients with penetrating renal trauma have associated adjacent organ injuries that may complicate treatment. In the absence of an expanding haematoma with haemodynamic instability, associated multiorgan injuries do not increase the risk of nephrectomy (142). Blunt and penetrating trauma equally contributed to combined renal and pancreatic injury, as reported by Rosen and McAninch (143). Renal preservation was achieved in most patients, and the complication rate of the series was 15% (143). A similar rate of complications (16%) was reported in patients with simultaneous colon and renal injury. In a report reviewing this combination of injuries over a period of 17 years, 58% of patients underwent an exploration, with nephrectomies performed in 16% of explorations (144). Renal injuries seem to be rather rare in patients with blunt chest trauma. In a recent study of polytrauma patients, conservative management was safely attempted without increasing morbidity (145). In polytrauma patients undergoing partial or total nephrectomy, there is no increased mortality or renal failure rate (146).

2.4.12 Recommendations Recommendations GR • Polytrauma patients with associated renal injuries should be evaluated on the basis of the C most threatening injury • In cases where surgical intervention is chosen, all associated injuries should be evaluated C simultaneously • The decision for conservative management should consider all injuries independently C GR = grade of recommendation

2.5 Iatrogenic renal injuries 2.5.1 Iatrogenic vascular injuries Iatrogenic main renal artery injuries with perforation or rupture are rare. They are usually reported after renal artery angioplasty or stenting, and have an incidence of 1.6% (147). One case of an iatrogenic renal artery perforation as a complication of cardiac catheterisation has also been reported (148). Since most iatrogenic renal artery lesions occur during endovascular procedures, there are no reports on the clinical symptoms, but only on the angiographic findings. Arteriovenous fistulae, pseudoaneurysms, arterial dissection or contrast extravasation are the possible radiological findings in these traumatic vascular lesions. Traditional therapy for renal perforation has been renal artery ligation followed by bypass grafting or nephrectomy, but nowadays the treatment for acute iatrogenic rupture of the main renal artery is balloon tamponade. However, in case of failure, the immediate availability of a stent graft is vital.

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Patients with iatrogenic operative injuries are strikingly different from those with penetrating, blunt or catheterrelated vascular trauma. Renal vessels are vulnerable during oncological procedures. Factors that increase technical difficulty are previous operation, tumour recurrence, radiation exposure and chronic inflammatory changes. Renal vein injuries during elective abdominal operations represent a serious complication with significant morbidity. Most patients with operative venous injuries have partial lacerations that can be managed with relatively simple techniques, such as venorrhaphy. Patch angioplasty with autologous vein or polytetrafluoroethylene (ePTFE) graft may be required if venorrhaphy is not possible (149). Some renal vascular injuries, such as pseudoaneurysms following nephron-sparing surgery, can be managed by transcatheter embolisation (150).

2.5.2 Renal transplantation The orthotopic kidney is protected from external force by muscles, Gerota’s fascia and peri-nephric fat. A renal graft is located in the lower pelvis in the iliac fossa and is therefore more susceptible to injury, especially from direct blows to the abdomen. The transplanted kidney, unlike the native kidney, is fixed in position by a thick fibrotic capsule that develops post-transplant. Also, the transplant kidney is not suspended by the renal vessels, so deceleration events that cause pedicle injury to a native kidney are less likely to affect a transplanted kidney (151). As transplant recipients return to more active lifestyles, including a significant risk of becoming a trauma victim, a renal graft is liable to be severely affected by trauma that might not cause any injury to a native kidney. In transplant recipients it is very important to know patients’ baseline renal function (152). The knowledge of an abnormal renal baseline may prevent unnecessary extensive diagnostic evaluation. Radiographic evaluation should proceed as for the native kidney. The increased risk for contrast nephrotoxicity can be minimised with adequate hydration. A CT scan is the test of choice for a stable injured transplant recipient, as it will identify renal and associated intra-abdominal injuries and will also indirectly assess renal blood flow and function. A renal duplex examination can be also very helpful for identifying isolated trauma to the transplanted kidney and for identifying renal blood flow. Radionuclide scans might reveal urine leaks and are good for assessing overall blood flow and renal function, while angiography can assess blood flow and identify specific arterial injuries. The surgical management of an injured transplanted kidney is complex. A very short vascular pedicle and ureter, dense scarring, and a fibrous capsule may prevent any attempt at the direct repair of the parenchymal, collecting system and vascular pedicle injuries. Grade 1-3 injuries can be managed non-operatively. Grade 4-5 injuries might require exploration with debridement and drainage. Major injuries could require a subcapsular nephrectomy. Renovascular injuries have a poor prognosis. Renal arteriography may be helpful with embolisation of the main artery to stop bleeding, or with more selective embolisation to salvage part of the kidney. When renal graft injury occurs, saving the patient’s life is the first priority, but saving the graft is also very important to maintain renal function. Iatrogenic vascular injuries of renal transplants can be managed by embolisation. Angiographic embolisation often fails, and is associated with a high complication rate and high eventual nephrectomy rate (153). On the other hand, transcatheter embolisation is highly effective for biopsy-related vascular injury in the transplanted kidney.

2.5.3 Percutaneous renal procedures Percutaneous nephrostomy is achieved in nearly all patients without major complications. Haematuria is common for a few days, but massive retroperitoneal haemorrhage is rare. Small subcapsular renal haematomas resolve spontaneously, while arteriovenous-calyceal fistulae are best managed by angiographic embolisation. If a nephrostomy catheter is seen to transfix the renal pelvis, the possibility of injury to a large renal artery must be considered. The misplaced nephrostomy catheter should be withdrawn over a guidewire, and renal artery embolisation might enable rapid arrest of a life-threatening haemorrhage (154). In more complex cases, CT could be used to detect possible catheter malposition and successfully guide catheter repositioning into the renal collecting system (155). Renal pelvis injuries can occur during percutaneous nephrostomy placement. Haemorrhage can be prevented 18

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by avoiding puncture in anticoagulated or coagulopathic patients, careful puncture on to target calyceals, and avoidance of medial punctures. A pelvic injury is less likely to happen if the dilator is not advanced further than the calyx, the peelaway sheaths are handled with care, especially when advanced around the pelviureteric junction, and kinking of the guidewires is avoided (156). Percutaneous renal biopsy is a relatively safe procedure. Haemorrhage, arteriovenous fistula and renal capsular artery pseudoaneurysm might occur. Arteriovenous fistula might present with severe hypertension and is managed by embolisation (157). A pseudoaneurysm should be suspected if the patient presents with flank pain and decreasing haematocrit without haematuria. Arteriography and transarterial embolisation is the appropriate therapy (158). Percutaneous nephrolithotomy (PCNL) is a popular procedure in which stones in the renal pelvis are removed via a nephroscope, often after ultrasonic or electrohydraulic disruption. The complications include haemorrhage, extravasation and absorption of large volumes of irrigation fluid, fever, infection, colonic perforation, arteriovenous fistulae, and pneumothorax. Extravasation of fluid is often due to a tear in the pelvicalyceal system. A close watch on irrigation fluid input and output is required for early recognition of the complication. Termination of the procedure if the renal pelvis is torn or ruptured is a safe choice. Apart from intraoperative evaluation of serum electrolytes, acid-base status and oxygenation, the monitoring of airway pressure is a good indicator of this complication. Metabolic acidosis, hyponatraemia, hypokalaemia, peritonism and ileus are due to absorption of large volumes of irrigation fluids. Management of this complication requires close monitoring, placement of an abdominal or retroperitoneal drain, correction of acidosis and supportive measures (159). The diagnosis of a colon injury during or after percutaneous renal surgery can be elusive because symptoms are often variable. An unrecognised or untreated colon injury can result in abscess formation, septicaemia, and/or nephrocolic or colocutaneous fistula. Surgical exploration is inevitable when the patient experiences haemorrhage, pneumoperitoneum and peritonitis. The majority of these cases can be successfully managed conservatively. The consistent application of proper techniques, avoidance of puncturing the kidney lateral to the posterior axillary line, and puncture of the upper pole calyx when feasible, will help prevent the injuries. Vascular injuries with renal bleeding are quite frequent and can occur at any stage of the percutaneous procedure, requiring transfusion in 1-11% of cases. A high number of punctures and incorrect choice of puncture site (access that is too medial or direct puncture of the renal pelvis) have been suggested as the cause of vascular lesions after percutaneous procedures. Renal bleeding can arise from both venous and arterial lesions. Bleeding from venous vessels could be profuse at the end of a procedure, but is generally controlled by simple measures, such as placing the patient supine to reduce abdominal compression, positioning a nephrostomy catheter, and forcing diuresis through hydration and parenteral administration of mannitol after clamping of the nephrostomy catheter. In the case of major venous trauma with massive haemorrhage, patients with concomitant renal insufficiency can be treated without open exploration or angiographic embolisation using a Council balloon catheter (160). Arterial lesions may induce acute or late post-operative bleeding. Severe acute bleeding usually arises from injury to the anterior or posterior segmental arteries. Delayed bleeding is usually caused by interlobar and lower pole artery lesions, often arteriovenous fistulae and post-traumatic aneurysms. Duplex ultrasound and CT angiography can diagnose vascular injuries. Hyperselective renal embolisation is considered the most appropriate technique for the treatment of iatrogenic vascular lesions. It is essential to identify the precise site of the lesion so as to be as selective as possible and reduce the risk of renal dysfunction. Hyperselective catheterisation of the renal artery branches is achieved by means of either hydrophilic 5 French catheters or coaxial systems with low profile microcatheters (2.6 French). The use of an embolic agent helps in performing a distal and irreversible occlusion with complete haemostasis. A variety of embolic materials have been used; microcoils, homologous clots, detachable balloons, polyvinyl alcohol particles, gelfoam, silicone rubber, cotton pellets and silk filaments. The choice of the embolic agent is dependent mainly on the blood flow entity at the level of the lesion, the vessel size and the operator’s experience. Finally, complications of endopyelotomy can be classified as major (vascular injury), and minor (infection,

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urinoma) (161). Preventive steps, along with proper patient selection, minimise the risk for these complications.

2.5.4 RECOMMENDATIONS Recommendations GR • Iatrogenic rupture of the main renal artery should be treated with balloon tamponade, and, C in case of failure, with a stent graft • Surgical venous injuries should be managed with venorrhaphy or patch angioplasty C • The transplanted kidney should be evaluated on the basis of renal function, type of injury and C the patients’ condition • Hyperselective embolisation may control arterial bleeding during percutaneous procedures C GR = grade of recommendation

2.6 Suggestions for future research studies Among the topics that would be useful subjects for future research studies are: • blunt trauma grade 5 patients, as it appears that some of them may benefit from non-surgical management • the necessity and nature of follow-up imaging • the value of the administration of antibiotics in low-grade renal injuries selected for conservative management.

2.7 Algorithms Figure 1 is an algorithm for the management of renal trauma in children. Figures 2 and 3 show the suggested treatment of blunt and penetrating renal injuries in adults. Figure 1: Algorithm for the management of paediatric renal trauma (119)

Paediatric renal trauma Blunt

Penetrating

ua

ua

>50 rbc/hpf or deceleration injury

ua

5 rbc/hpf Stable

Unstable

CT scan

Abdominal exploration

Observe Observe

Observe

Renal exploration

Observe

20

nl

IVP nl

Renal exploration

abnl Renal exploration

Observe

IVP abnl Renal exploration

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Abnormal IVP

Pulsatile or expanding

Retroperitoneal haematoma

Grade 5

Observation, bed rest, serial Ht, antibiotics

Associated injuries requiring laparotomy

Renal exploration‡

Stable

Grade 1-2 Grade 3-4

Renal imaging†

Gross haematueria

Stable

Rapid deceleraton Injury or Major associated injuries

Observation

Microscopic haematueria

Determine haemodynamic stability

Suspected adult blunt Renal trauma*

Unstable

Normal IVP

Emergency laparotomy One-shot IVP

Figure 2: Evaluation of blunt renal trauma in adults

*Suspected renal trauma results from reported mechanism of injury and physical examination. † Renal imaging: CT scans are the gold standard for evaluating blunt and penetrating renal injuries in stable patients. In settings where the method is not available, the urologist should rely on other imaging modalities (IVP, angiography, radiographic scintigraphy, MRI). ‡ Renal exploration: Although renal salvage is a primary goal for the urologist, decisions concerning the viability of the organ and the type of reconstruction are made during the operation.

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Renal exploration‡ Associated injuries requiring laparotomy

Stable

Observation Grade 1-2 Grade 4-5

Observation, bed rest, serial Ht, antibiotics

Grade 3

Renal imaging†

Stable

Pulsatile or expanding

Retroperitoneal haematoma

Normal IVP

Determine haemodynamic stability

Suspected adult penetrating Renal trauma*

Unstable

Emergency laparotomy One-shot IVP

Abnormal IVP

Figure 3: Evaluation of penetrating renal trauma in adults

*Suspected renal trauma results from reported mechanism of injury and physical examination. † Renal imaging: CT scans are the gold standard for evaluating blunt and penetrating renal injuries in stable patients. In settings where the method is not available, the urologist should rely on other imaging modalities (IVP, angiography, radiographic scintigraphy, MRI). ‡ Renal exploration: Although renal salvage is a primary goal for the urologist, decisions concerning the viability of the organ and the type of reconstruction are made during the operation.

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Santucci RA, McAninch JM. Grade IV renal injuries: evaluation, treatment, and outcome. World J Surg 2001;25(12):1565-72. http://www.ncbi.nlm.nih.gov/pubmed/11775193 Shariat SF, Jenkins A, Roehrborn CG, Karam JA, Stage KH, Karakiewicz PI. Features and outcomes of patients with grade IV renal injury. BJU Int 2008;102(6):728-33; discussion 733. http://www.ncbi.nlm.nih.gov/pubmed/18435808 Velmahos GC, Demetriades D, Cornwell EE 3rd, Belzberg H, Murray J, Asensio J, Berne TV. Selective management of renal gunshot wounds. Br J Surg 1998;85(8):1121-4. http://www.ncbi.nlm.nih.gov/pubmed/9718011 Baniel J, Schein M. The management of penetrating trauma to the urinary tract. J Am Coll Surg 1994;178(4):417-25. http://www.ncbi.nlm.nih.gov/pubmed/8149045 DuBose J, Inaba K, Teixeira PG, Pepe A, Dunham MB, McKenney M. Selective non-operative management of solid organ injury following abdominal gunshot wounds. Injury 2007;38(9):1084-90. http://www.ncbi.nlm.nih.gov/pubmed/17544428 Wessells H, Deirmenjian J, McAninch JW. Preservation of renal function after reconstruction for trauma: quantitative assessment with radionuclide scintigraphy. J Urol 1997;157(5):1583-6. http://www.ncbi.nlm.nih.gov/pubmed/9112481 Shefler A, Gremitzky A, Vainrib M, Tykochinsky G, Shalev M, Richter S, Erlich N, Schiwartz I, Leibovitch I. [The role of nonoperative management of penetrating renal trauma]. Harefuah 2007;146(5):345-8, 406-7. [article in Hebrew.] http://www.ncbi.nlm.nih.gov/pubmed/17674549 Bernath AS, Schutte H, Fernandez RR, Addonizio JC. Stab wounds of the kidney: conservative management in flank penetration. J Urol 1983;129(3):468-70. http://www.ncbi.nlm.nih.gov/pubmed/6834529 Wessells H, McAninch JW, Meyer A, Bruce J. Criteria for nonoperative treatment of significant penetrating renal lacerations. J Urol 1997;157(1):24-7. http://www.ncbi.nlm.nih.gov/pubmed/8976207 Blankenship JC, Gavant ML, Cox CE, Chauhan RD, Gingrich JR. Importance of delayed imaging for blunt renal trauma. World J Surg 2001;25(12):1561-4. http://www.ncbi.nlm.nih.gov/pubmed/11775192 Dunfee BL, Lucey BC, Soto JA. Development of renal scars on CT after abdominal trauma: does grade of injury matter? AJR Am J Roentgenol 2008;190(5):1174-9. http://www.ncbi.nlm.nih.gov/pubmed/18430828 Pruthi RS, Issa MM, Kabalin JN, Terris MK. Renal masses presenting 25 and 50 years following blunt renal trauma. Urol Int 1998;61(1):43-6. http://www.ncbi.nlm.nih.gov/pubmed/9792983 Heyns CF, van Vollenhoven P. Increasing role of angiography and segmental artery embolization in the management of renal stab wounds. J Urol 1992;147(5):1231-4. http://www.ncbi.nlm.nih.gov/pubmed/1569655 Monstrey SJ, Beerthuizen GI, vander Werken C, Debruyne FM, Goris RJ. Renal trauma and hypertension. J Trauma 1989;29(1):65-70. http://www.ncbi.nlm.nih.gov/pubmed/2911106 Lebech A, Strange-Vognsen HH. [Hypertension following blunt kidney injury]. Ugeskr Laeger 1990;152(14):994-7. [article in Danish] http://www.ncbi.nlm.nih.gov/pubmed/2183457 Montgomery RC, Richardson JD, Harty JI. Posttraumatic renovascular hypertension after occult renal injury. J Trauma 1998;45(1):106-10. http://www.ncbi.nlm.nih.gov/pubmed/9680021 Chedid A, Le Coz S, Rossignol P, Bobrie G, Herpin D, Plouin PF. Blunt renal trauma-induced hypertension: prevalence, presentation, and outcome. Am J Hypertens 2006;19(5):500-4. http://www.ncbi.nlm.nih.gov/pubmed/16647623 Haas CA, Reigle MD, Selzman AA, Elder JS, Spirnak JP. Use of ureteral stents in the management of major renal trauma with urinary extravasation: is there a role?. J Endourol 1998;12(6):545-9. http://www.ncbi.nlm.nih.gov/pubmed/9895260 Wang KT, Hou CJ, Hsieh JJ, Chou YS, Tsai CH. Late development of renal arteriovenous fistula following gunshot trauma – a case report. Angiology 1998;49(5):415-18. http://www.ncbi.nlm.nih.gov/pubmed/9591535

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Franco de Castro A, Gibanel Garanto R, Real MI, Rodríguez Casado A, Cetina Herrando A, Gutiérrez del Pozo R, Montanyà X, Vázquez F, Alcover García JB. [Selective embolization of post-traumatic renal pseudoaneurysm in monorenal patient]. Actas Urol Esp 2001;25(1):64-6. [article in Spanish] http://www.ncbi.nlm.nih.gov/pubmed/11284371 Miller DC, Forauer A, Faerber GJ. Successful angioembolization of renal artery pseudoaneurysms after blunt abdominal trauma. Urology 2002;59(3):444. http://www.ncbi.nlm.nih.gov/pubmed/11880095 Harrington TG, Kandel LB. Renal colic following a gunshot wound to the abdomen: the birdshot calculus. J Urol 1997;157(4):1351-2. http://www.ncbi.nlm.nih.gov/pubmed/9120940 Park JK, Yang SO, Park SC. Duodenal obstruction by retroperitoneal hematoma induced by severe blunt renal trauma. J Urol 2001;165(6Pt1):1993-4. http://www.ncbi.nlm.nih.gov/pubmed/11371904 McAleer IM, Kaplan GW, Scherz HC, Packer MG, Lynch FP. Genitourinary trauma in the pediatric patient. Urology 1993;42(5):563-7; discussion 567-8. http://www.ncbi.nlm.nih.gov/pubmed/8236601 Morse TS: Renal injuries. Pediatr Clin North Am 1975;22(2):379-91. http://www.ncbi.nlm.nih.gov/pubmed/1124221 Elshihabi I, Elshihabi S, Arar M. An overview of renal trauma. Curr Opin Pediatr 1998;10(2):162-6. http://www.ncbi.nlm.nih.gov/pubmed/9608894 Brown SL, Elder JS, Spirnak JP. Are pediatric patients more susceptible to major renal injury from blunt trauma? A comparative study. J Urol 1998;160(1):138-40. http://www.ncbi.nlm.nih.gov/pubmed/9628634 Chopra P, St-Vil D, Yazbeck S. Blunt renal trauma-blessing in disguise?. J Pediatr Surg 2002;37(5):779-82. http://www.ncbi.nlm.nih.gov/pubmed/11987100 Quinlan DM, Gearhart JP. Blunt renal trauma in childhood. Features indicating severe injury. Br J Urol 1990;66(5):526-31. http://www.ncbi.nlm.nih.gov/pubmed/2249124 Angus LD, Tachmes L, Kahn S, Gulmi F, Gintautas J, Shaftan GW. Surgical management of pediatric renal trauma: an urban experience. Am Surg 1993;59(6):388-94. http://www.ncbi.nlm.nih.gov/pubmed/8507066 Stalker HP, Kaufman RA, Stedje K. The significance of hematuria in children after blunt abdominal trauma. AJR Am J Roentgenol 1990;154(3):569-71. http://www.ncbi.nlm.nih.gov/pubmed/2106223 Stein JP, Kaji DM, Eastham J, Freeman JA, Esrig D, Hardy BE. Blunt renal trauma in the pediatric population: indications for radiographic evaluation. Urology 1994;44(3):406-10. http://www.ncbi.nlm.nih.gov/pubmed/8073555 Morey AF, Bruce JE, McAninch JW. Efficacy of radiographic imaging in pediatric blunt renal trauma. J Urol 1996;156(6):2014-18. http://www.ncbi.nlm.nih.gov/pubmed/8911380 Nguyen MM, Das S. Pediatric renal trauma. Urology 2002;59(5):762-6; discussion 766-7. http://www.ncbi.nlm.nih.gov/pubmed/11992916 Santucci RA, Langenburg SE, Zachareas MJ. Traumatic hematuria in children can be evaluated as in adults. J Urol 2004;171(2Pt1):822-5. http://www.ncbi.nlm.nih.gov/pubmed/14713834 Luks FI, Lemire A, St-Vil D, Di Lorenzo M, Filiatrault D, Ouimet A. Blunt abdominal trauma in children: the practical value of ultrasonography. J Trauma 1993;34(5):607-10; discussion 610-1. http://www.ncbi.nlm.nih.gov/pubmed/8496996 Wessel LM, Jester I, Scholz S, Arnold R, Lorenz C, Wirth H, Waag KL. [Diagnostic and therapeutic consequences of kidney injuries in pediatric blunt abdominal trauma]. Urologe A 2000;39(5):425-31. [article in German] http://www.ncbi.nlm.nih.gov/pubmed/11045043 Perez-Brayfield MR, Gatti JM, Smith EA, Broecker B, Massad C, Scherz H, Kirsch AJ. Blunt traumatic hematuria in children. Is a simplified algorithm justified?. J Urol 2002;167(6):2543-6; discussion 2546-7. http://www.ncbi.nlm.nih.gov/pubmed/11992085

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Mayor B, Gudinchet F, Wicky S, Reinberg O, Schnyder P. Imaging evaluation of blunt renal trauma in children: diagnostic accuracy of intravenous pyelography and ultrasonography. Pediatr Radiol 1995;25(3):214-8. http://www.ncbi.nlm.nih.gov/pubmed/7644308 Turnock RR, Sprigg A, Lloyd DA. Computed tomography in the management of blunt abdominal trauma in children. Br J Surg 1993;80(8):982-4. http://www.ncbi.nlm.nih.gov/pubmed/8402096 Carpio F, Morey AF. Radiographic staging of renal injuries. World J Urol 1999;17(2):66-70. http://www.ncbi.nlm.nih.gov/pubmed/10367363 Takeda M, Katayama Y, Tsutsui T, Takahashi H, Komeyama T, Mizusawa T, Sato S. Value of dimercaptosuccinic acid single photon emission computed tomography and magnetic resonance imaging in detecting renal injury in pediatric patients with vesicoureteral reflux. Comparison with dimercaptosuccinic acid planar scintigraphy and intravenous pyelography. Eur Urol 1994;25(4):320-5. http://www.ncbi.nlm.nih.gov/pubmed/8056025 Levy JB, Baskin LS, Ewalt DH, Zderic SA, Bellah R, Snyder HM 3rd, Templeton J, Duckett JW. Nonoperative management of blunt pediatric major renal trauma. Urology 1993;42(4):418-24. http://www.ncbi.nlm.nih.gov/pubmed/8212441 Buckley JC, McAninch JW. Pediatric renal injuries: management guidelines from a 25-year experience. J Urol 2004;172(2):687-90; discussion 690. http://www.ncbi.nlm.nih.gov/pubmed/15247762 Henderson CG, Sedberry-Ross S, Pickard R, Bulas DI, Duffy BJ, Tsung D, Eichelberger MR, Belman AB, Rushton HG. Management of high grade renal trauma: 20-year experience at a pediatric level I trauma center. J Urol 2007;178(1):246-50; discussion 250. http://www.ncbi.nlm.nih.gov/pubmed/17499798 Broghammer JA, Langenburg SE, Smith SJ, Santucci RA. Pediatric blunt renal trauma: its conservative management and patterns of associated injuries. Urology 2006;67(4):823-7. http://www.ncbi.nlm.nih.gov/pubmed/16566992 Cannon GM Jr, Polsky EG, Smaldone MC, Gaines BA, Schneck FX, Bellinger MF, Docimo SG, Wu HY. Computerized tomography findings in pediatric renal trauma – indications for early intervention? J Urol 2008;179(4):1529-32; discussion 1532-3. http://www.ncbi.nlm.nih.gov/pubmed/18295268 Nance ML, Holmes JH 4th, Wiebe DJ. Timeline to operative intervention for solid organ injuries in children. J Trauma 2006;61(6):1389-92. http://www.ncbi.nlm.nih.gov/pubmed/17159681 Holmes JH 4th, Wiebe DJ, Tataria M, Mattix KD, Mooney DP, Scaife ER, Brown RL, Groner JI, Brundage SI, Tres Scherer LR 3rd, Nance ML. The failure of nonoperative management in pediatric solid organ injury: a multi-institutional experience. J Trauma 2005;59(6):1309-13. http://www.ncbi.nlm.nih.gov/pubmed/16394902 Surana R, Khan A, Fitzgerald RJ. Scarring following renal trauma in children. Br J Urol 1995;75(5): 663-5. http://www.ncbi.nlm.nih.gov/pubmed/7613804 Kansas BT, Eddy MJ, Mydlo JH, Uzzo RG. Incidence and management of penetrating renal trauma in patients with multiorgan injury: extended experience at an inner city trauma center. J Urol 2004;172(4Pt1):1355-60. http://www.ncbi.nlm.nih.gov/pubmed/15371841 Rosen MA, McAninch JW. Management of combined renal and pancreatic trauma. J Urol 1994;152(1):22-5. http://www.ncbi.nlm.nih.gov/pubmed/8201670 Wessells H, McAninch JW. Effect of colon injury on the management of simultaneous renal trauma. J Urol 1996;155(6):1852-6. http://www.ncbi.nlm.nih.gov/pubmed/8618272 Sartorelli KH, Frumiento C, Rogers FB, Osler TM. Nonoperative management of hepatic, splenic, and renal injuries in adults with multiple injuries. J Trauma. 2000;49(1):56-61; discussion 61-2. http://www.ncbi.nlm.nih.gov/pubmed/10912858 Cass AS, Luxenberg M, Gleich P, Smith C. Deaths from urologic injury due to external trauma. J Trauma 1987;27(3):319-21. http://www.ncbi.nlm.nih.gov/pubmed/3560276 Morris CS, Bonnevie GJ, Najarian KE. Nonsurgical treatment of acute iatrogenic renal artery injuries occurring after renal artery angioplasty and stenting. AJR Am J Roentgenol 2001;177(6):1353-7. http://www.ncbi.nlm.nih.gov/pubmed/11717082

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Bates MC, Shamsham FM, Faulknier B, Crotty B. Successful treatment of iatrogenic renal artery perforation with an autologous vein-covered stent. Catheter Cardiovasc Interv 2002;57(1):39-43. http://www.ncbi.nlm.nih.gov/pubmed/12203925 Oderich GS, Panneton JM, Hofer J, Bower TC, Cherry KJ Jr, Sullivan T, Noel AA, Kalra M, Gloviczki P. Iatrogenic operative injuries of abdominal and pelvic veins: a potentially lethal complication. J Vasc Surg 2004;39(5):931-6. http://www.ncbi.nlm.nih.gov/pubmed/15111840 Taneja M, Tan KT. Renal vascular injuries following nephron-sparing surgery and their endovascular management. Singapore Med J 2008;49(1):63-6. http://www.ncbi.nlm.nih.gov/pubmed/18204772 Barone GW, Sailors DM, Hudec WA, Ketel BL. Trauma management in solid organ transplant recipients. J Emerg Med 1997;15(2):169-76. http://www.ncbi.nlm.nih.gov/pubmed/9144057 Del Pizzo JJ, Jacobs SC, Sklar GN. Ureteroscopic evaluation in renal transplant recipients. J Endourol 1998;12(2):135-8. http://www.ncbi.nlm.nih.gov/pubmed/9607439 Dorffner R, Thurnher S, Prokesch R, Bankier A, Turetschek K, Schmidt A, Lammer J. Embolization of iatrogenic vascular injuries of renal transplants: immediate and follow-up results. Cardiovasc Intervent Radiol 1998;21(2):129-34. http://www.ncbi.nlm.nih.gov/pubmed/9502679 Cowan NC, Traill ZC, Phillips AJ, Gleeson FV. Direct percutaneous transrenal embolization for renal artery injury following percutaneous nephrostomy. Br J Radiol 1998;71(851):1199-201. http://www.ncbi.nlm.nih.gov/pubmed/10434916 Jones CD, McGahan JP. Computed tomographic evaluation and guided correction of malpositioned nephrostomy catheters. Abdom Imaging 1999;24(4):422-5. http://www.ncbi.nlm.nih.gov/pubmed/10390572 Lewis S, Patel U. Major complications after percutaneous nephrostomy – lessons from a department audit. Clin Radiol 2004;59(2):171-9. http://www.ncbi.nlm.nih.gov/pubmed/14746788 Ozdemir S, Cekirge S, Kara A, Bakkaloğlu A. A rare complication of renal biopsy in a child with membranoproliferative glomerulonephritis. Int Urol Nephrol 1998;30(6):689-92. http://www.ncbi.nlm.nih.gov/pubmed/10195861 Silberzweig JE, Tey S, Winston JA, Mitty HA. Percutaneous renal biopsy complicated by renal capsular artery pseudoaneurysm. Am J Kidney Dis 1998;31(3):533-5. http://www.ncbi.nlm.nih.gov/pubmed/9506693 Ghai B, Dureja GP, Arvind P. Massive intraabdominal extravasation of fluid: a life threatening complication following percutaneous nephrolithotomy. Int Urol Nephrol 2003;35(3):315-18. http://www.ncbi.nlm.nih.gov/pubmed/15160530 Gupta M, Bellman GC, Smith AD. Massive hemorrhage from renal vein injury during percutaneous renal surgery: endourological management. J Urol 1997;157(3):795-7. http://www.ncbi.nlm.nih.gov/pubmed/9072568 Bellman GC. Complications of endopyelotomy. J Endourol 1996;10(2):177-81. http://www.ncbi.nlm.nih.gov/pubmed/8728685

3. URETERAL TRAUMA 3.1 Introduction The ureter is the sole conduit for urinary transport between the kidney and the bladder. Thus, any ureteral injury can threaten the function of the ipsilateral kidney. This small, mobile, worm-like, peristalsing, urotheliallined tube runs inferiorly from the renal pelvis in the retroperitoneal space. It lies anterior to the muscles of the posterior abdominal wall and lateral to the vertebral column, before descending into the bony ring of the pelvis to enter the bladder. Any external injury to the flank or back and any calamity within the bony pelvis therefore places the ureter at risk. Perhaps because of its protected location, its small size and its mobility, trauma to the ureter is relatively rare and accounts for only 1% of all urinary tract trauma. Thus, there is a relatively small volume of published clinical experience upon which to base recommendations of management.

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3.2 Aetiology The largest and most contemporary review of ureteral trauma in the European literature is from Dobrowolski et al. in Poland (1). These authors retrospectively analyzed the records of patients with upper urinary tract injuries presenting to 61 urology departments between 1995 and 1999. They identified 452 ureteral injuries. Of these, 340 (75%) were iatrogenic, 81 (18%) were from blunt trauma, and 31 (7%) were from penetrating trauma. Of the 340 iatrogenic injuries, 247 (73%) were gynaecological in origin, 46 (14%) were general surgical and 47 (14%) were urological. It is therefore important to note that ureteral injury is much more likely to occur from activity within a hospital rather than from injuries sustained outside. Dobrowolski et al. estimate the frequency of ureteral injury during gynaecological pelvic surgical procedures to be 1.6 per 1000 (1). Of the total ureteral injuries identified, the injury was in the upper third in 60 cases (13%), in the middle third in 61 cases (13%), and in the lower third in 331 (74%). The median time to diagnosis was 3.3 h. The most common diagnostic investigation was intravenous urography (IVU), which was used in 244 patients; retrograde ureteropyelography was used in 98 patients; and ureteral catheterization was used in 125. The diagnosis was also established at open surgery in 104 patients. This snapshot of ureteral trauma in a modern European setting is similar to that seen in the USA (2).

3.3 Diagnosis 3.3.1 Clinical diagnosis There are no classic clinical symptoms and signs associated with acute ureteral trauma caused by external injury (3). In view of this, the diagnosis must be one of suspicion. Ureteral trauma should be suspected in all cases of penetrating abdominal injury, especially gunshot wounds, and also in cases of blunt deceleration trauma, in which the kidney and renal pelvis can be torn away from the ureter. This deceleration injury is more likely to occur in children because of their hyperextensible vertebral column (4). Haematuria is also a poor indicator of injury, as it is present in only half of those with ureteral trauma (5). It is possible for isolated ureteral injuries to be missed. Such patients tend to present with subsequent evidence of upper tract obstruction, urinary fistula formation and sepsis (6). After gynaecological pelvic surgery, any woman who complains of flank pain, develops vaginal leakage of urine or becomes septic should also be suspected of having injury to the ureter or bladder and should be investigated appropriately. At surgery, when the ureter is explored to exclude injury, the use of intravenous indigo carmine or methylene blue is to be recommended. This will help reveal the site of injury by leakage of blue-stained urine. This is especially important in partial tears. 3.3.2 Radiological diagnosis Ureteral injury may cause radiological signs of upper urinary tract obstruction but the sine qua non of ureteral injury is extravasation of radiological contrast material (3). This sign can be produced by the use of intravenous pyelography (IVP), giving 2 mg of contrast material per kilogram of body weight. However, because of the increasing use of computed tomography (CT) scanning in polytraumatized patients, the diagnosis is increasingly made with this modality. If a high suspicion of ureteral injury exists and the CT scan is non-diagnostic, then a ‘poor man’s IVP’can be obtained by taking a plain kidney-ureter-bladder (KUB) film 30 minutes after intravenous injection of CT contrast medium. If this is also non-diagnostic and a suspicion of injury still exists, then retrograde pyelography should be undertaken as the gold standard investigation.

3.4

Classification

The American Association for the Surgery of Trauma has classified ureteral injuries as shown in Table 4 (7). Table 4: Classification of ureteral injury Grade I II III IV V

3.5

Description of injury Haematoma only Laceration < 50% of circumference Laceration > 50% of circumference Complete tear < 2 cm of devascularization Complete tear > 2 cm of devascularization

Management

3.5.1 Partial injuries These can be defined as grade I to II lesions. Once recognized, they can be managed with ureteral stenting or by placement of a nephrostomy tube to divert urine (3). There is no prospective clinical trial comparing outcomes between these techniques. We believe that ureteral stenting is probably superior because a stent

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across the injury will allow secure drainage of the kidney, as well as providing canalization and stabilization of the injury. We believe that this will reduce the subsequent risk of stricture. The stent may be placed in an antegrade or retrograde fashion. In all cases, fluoroscopy and ureteropyelography with radio-opaque contrast should be used to guide stent placement. The procedure should commence with the passage of a hydrophilic atraumatic guidewire across the damaged segment of ureter. Once across the site of the injury, an access catheter can be backloaded over the wire and passed across the injury. The hydrophilic wire can then be exchanged for a 0.038-inch wire, and the stent deployed. If this technique is utilized, a bladder catheter should be left in place for 2 days to limit stent reflux during voiding until mucosal healing has begun. The stent should be left in place for at least 3 weeks. The patient should have a follow-up dynamic renogram and IVP between 3 and 6 months, or sooner if lateralizing flank pain develops. If there is evidence of stricture, then this should be managed by endo-urological or open surgical techniques, as appropriate. If a grade II or III injury is encountered during immediate surgical exploration of an iatrogenic injury, then primary closure of the ureteral ends over a stent may be recommended, with placement of an external, non suction drain adjacent to the injury. 3.5.2 Complete injuries These are grade III to V injuries. Successful repair should utilize the principles outlined in Table 5. Table 5: Principles of repair of complete injury • • • • • •

Debridement of ureteral ends to fresh tissue Spatulation of ureteral ends Placement of internal stent Watertight closure of reconstructed ureter with absorbable suture Placement of external, non-suction drain Isolation of injury with peritoneum or omentum

The type of reconstructive repair procedure chosen by the surgeon depends on the nature and site of the injury (3). The options are depicted in Figure 4. Figure 4: Diagram of the options for repair of complete injuries, based on the site of the injury

Upper third:

Uretero-ureterostomy Transuretero-ureterostomy Ureterocalycostomy

Middle third:

Uretero-ureterostomy Transuretero-ureterostomy Boari flap and reimplantation

Lower third:

Direct reimplantation Psoas hitch Blandy cystoplasty

Complete:

Ileal interposition Autotransplantation

3.5.3 Sterile surgery 3.5.3.1 Uretero-ureterostomy Using the principles outlined above, the ureteral ends are debrided and freshened. The ends are spatulated.

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An internal JJ stent is inserted and the ends are closed over the stent using an interrupted 4/0 vicryl suture. An external, non-suction drain is placed at the site of the injury, and a catheter is left in the bladder. The bladder catheter can be removed after 2 days. The wound drain can be removed 2 days later if drainage is low. The stent should be removed after 6 weeks, and a follow-up renogram and IVP should be obtained after 3 months to assess the patency of the repair. 3.5.3.2 Ureterocalycostomy In cases were the pelvi-ureteral junction has been destroyed, the lower pole of the affected kidney can be amputated to expose the lower pole infundibulum and calyces. The distal ureteral end can then be debrided and spatulated, and anastomosed to the lower pole calyx, over an internal stent, using an interrupted 4/0 vicryl suture. An external, non-suction drain is placed at the site of the injury and a catheter is left in the bladder. The bladder catheter can be removed after 2 days. The wound drain can be removed 2 days later if drainage is low. The stent should be removed after 6 weeks and a follow-up renogram and IVP should be obtained after 3 months to assess the patency of the repair. 3.5.3.3 Transuretero-ureterostomy The distal end of the injured ureter is ligated with an absorbable suture. The proximal end is debrided and spatulated. This end is then transposed across the midline through a retroperitoneal window above the level of the inferior mesenteric artery. A 1.5 cm ureterotomy is made on the medial aspect of the contralateral ureter. A stent is placed from the ipsilateral kidney, through the anastomosis, and down the distal contralateral ureter into the bladder. A watertight anastomosis is fashioned using an interrupted 4/0 vicryl suture. An external, nonsuction drain is placed at the site of the injury, and a catheter is left in the bladder. The bladder catheter can be removed after 2 days. The wound drain can be removed 2 days later if drainage is low. The stent should be removed after 6 weeks, and a follow-up renogram and IVP should be obtained after 3 months to assess the patency of the repair. 3.5.3.4 Ureteroneocystostomy with Boari flap The proximal ureteral end is debrided and spatulated. A traction suture is placed. The distal ureteral end is ligated with an absorbable suture. The bladder is filled with 200-300 ml of normal saline via a urethral catheter, and controlling stay sutures are placed on the bladder. The L-shaped flap is raised, its base being approximately four times wider than the width of the ureter to be implanted. The ureter is pulled through a submucosal tunnel in the flap and secured to the bladder mucosa using an interrupted 4/0 vicryl suture. Anchoring sutures can be placed at the serosal aspect of the ureter to secure it to the bladder. A stent is placed across the neo-ureterocystostomy, and a suprapubic catheter is placed in the bladder. The bladder is then closed in two layers with 2/0 vicryl sutures. An external, non-suction drain should be placed at the site of the reimplant; it can be removed after 2 days. The urethral catheter can be removed at the same time. The suprapubic catheter can be removed after a cystogram at 2 weeks, and the stent can be removed after 6 weeks. An IVP and renogram should be obtained 3 months thereafter to confirm the patency of the neocystostomy. 3.5.3.5 Ureterocystostomy and psoas hitch The proximal ureteral end is debrided and spatulated. A traction suture is placed. The distal ureteral end is ligated with an absorbable suture. The fundus of the bladder is mobilized, and the contralateral superior vesical pedicle may be divided to improve fundal mobility. The bladder is filled with 200-300 ml of normal saline via a urethral catheter, and controlling stay sutures are placed. A cystotomy (Blandy) is performed perpendicular to the line of the ureter. Two fingers are placed inside the bladder to stretch it gently towards the ipsilateral psoas tendon. Three non-absorbable 2/0 sutures are placed between the bladder wall and the tendon, with care being taken to avoid the genitofemoral nerve. Ureteroneocystostomy is then undertaken using either the Leadbetter-Politano or Lich-Gregoire techniques. A JJ stent is placed across the reimplant, and a suprapubic catheter is placed in the bladder. The bladder is then closed in two layers with 2/0 vicryl in the line of the ureter, thus providing extra length to the hitch. The anastomosis is thus under no tension. An external, non-suction drain should be placed at the site of the reimplant, and can be removed after 2 days. The urethral catheter can be removed at the same time. The suprapubic catheter can be removed after a cystogram at 2 weeks, and the stent can be removed after 6 weeks. An IVP and renogram should be obtained 3 months thereafter to confirm the patency of the neocystostomy. 3.5.3.6 Ileal interposition graft In cases of long segment ureteral destruction, the ureter can be totally replaced using the distal ileum. This should be avoided in patients with coincidental gastrointestinal disease, such as Crohn’s disease, and in

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patients with impaired renal function. A 25-cm length of ileum is taken out of bowel continuity about 20 cm proximal to the ileocaecal valve. Gastrointestinal continuity is restored with an ileo-ileal anastomosis using interrupted 3/0 seromuscular vicryl. The mesenteric is repaired using 2/0 vicryl. The ileal segment is placed in the isoperistaltic orientation between the renal pelvis and the bladder. Ileo-pelvic and cysto-ileal end-to-end anastomoses are fashioned using 2/0 vicryl. A nephrostomy tube should be inserted into the ipsilateral kidney to decompress the affected upper tract. A catheter should be placed in the bladder. External, non-suction drains should cover the proximal and distal anastomoses. Lastly, the reconstruction should be wrapped in omentum. The wound drains can be removed after 2 days. A nephrostogram should be performed after 3 weeks; if no leakage is demonstrated, the nephrostomy can be clamped and then removed. Finally, the urinary catheter can be removed. Follow-up should include IVP and renography at 3 months, together with testing for the levels of serum creatinine, chloride, bicarbonate and base excess, looking for evidence of hyperchloraemic metabolic acidosis. 3.5.3.7 Autotransplantation If complete ureteral disruption should occur in the presence of coincidental gastrointestinal disease or impaired renal function, then autotransplantation of the affected renal unit can be undertaken. The renal artery and vein are divided long at the aorta and cava. The kidney is moved to the pelvis, and vascular continuity is restored using 5/0 prolene for the artery and 4/0 prolene for the vein. A Lich-Gregoire extravesical neoureterocystostomy can then be fashioned to re-establish urinary drainage. This need not be stented. A covering external, non-suction drain should be placed, and a catheter inserted in the bladder. The drain can be removed after 2 days, if dry, and the catheter removed after a cystogram at 2 weeks. Again, follow-up at 3 months with IVP and renogram is recommended. 3.5.3.8 Nephrectomy There is one circumstance in which immediate nephrectomy should be undertaken. This is when ureteral injury complicates the repair of an abdominal aortic aneurysm or other vascular procedure in which a vascular prosthesis is to be implanted. We feel that immediate excision of the corrupted renal unit and its damaged ureter leads to less chance of urinary leak, urinoma, sepsis and graft infection.

3.6 REFERENCES 1.

2.

3. 4.

5.

6.

7.

Dobrowolski Z, Kusionowicz J, Drewniak T, Habrat W, Lipczynski W, Jakubik P and Weglarz W. Renal and ureteric trauma: diagnosis and management in Poland. BJU Int 2002;89(7):748-51. http://www.ncbi.nlm.nih.gov/pubmed/11966637 Palmer LS, Rosenbaum RR, Gershbaum MD, Kreutzer ER. Penetrating ureteral trauma at an urban trauma center: 10-year experience. Urology 1999;54(1):34-6. http://www.ncbi.nlm.nih.gov/pubmed/10414723 Armenakas NA. Ureteral trauma: surgical repair. Atlas Urol Clin North Am 1998;6:71-84. Morey AF, Bruce JE, McAninch JW. Efficacy of radiographic imaging in pediatric blunt renal trauma. J Urol 1996;156(6):2014-8. http://www.ncbi.nlm.nih.gov/pubmed/8911380 Medina D, Lavery R, Ross SE, Livingston DH. Ureteral trauma: preoperative studies neither predict injury nor prevent missed injuries. J Am Coll Surg 1998;186(6):641-4. http://www.ncbi.nlm.nih.gov/pubmed/9632150 McGinty DM, Mendez R. Traumatic ureteral injuries with delayed recognition. Urology 1997;10(2): 115-7. http://www.ncbi.nlm.nih.gov/pubmed/898448 Moore EE, Cogbill TH, Jurkovitch GJ, McAninch JW, Champion HR, Gennarelli TA, Malangoni MA, Shackford SR, Trafton PG. Organ injury scaling. III: Chest wall, abdominal vascular, ureter, bladder, and urethra. J Trauma 1992;33(3):337-9. http://www.ncbi.nlm.nih.gov/pubmed/1404499

4. BLADDER TRAUMA 4.1 Background Among abdominal injuries that require surgical repair, 2% involve the bladder (1). Blunt or penetrating trauma account for 67-86% and 14-33% of bladder ruptures, respectively (2-4). Motor vehicle accidents are the

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most common cause (90%) of bladder ruptureby blunt trauma is (5-7). In the setting of blunt trauma, bladder rupture may be classified as either extraperitoneal with leakage of urine limited to the perivesical space, or intraperitoneal, in which the peritoneal surface has been disrupted, with concomitant urinary extravasation. Bladder trauma: facts and figures • 70-97% of patients with bladder injuries caused by blunt trauma have associated pelvic fractures (3, 8, 9). • Pubic symphysis diastasis, sacroiliac diastasis, and sacral, iliac, and pubic rami fractures are significantly associated with bladder rupture, whereas isolated acetabular fractures are not (10, 11). • > 50% of the associated pelvic fractures are of the pubic ramus (12). • Up to 30% of patients with pelvic fractures will have some degree of bladder injury (13). • Major bladder injury occurs in only 5-10% of patients who have pelvic fracture(s) (7, 14). • > 85% of patients with pelvic fractures have associated injuries in other organ systems (8), with a mortality rate of 22-44% (12, 13, 15). • Approximately 25% of intraperitoneal bladder ruptures occur in patients who do not have pelvic fracture(s) (7). During a motor vehicle accident, traumatic forces can be transferred to the bladder by the seatbelt; injuries usually occur in patients with a full bladder. The degree of distension of the bladder with urine determines its shape and, to some degree, the injury it sustains. A fully distended bladder can be ruptured by a light blow; however, an empty bladder is seldom injured, except by crushing or penetrating wounds. Pelvic scars or preexisting pelvic pathology can influence susceptibility to injury (16). Combined intra- and extraperitoneal rupture may occur in 2-20% of cases (7, 17-19). Simultaneous bladder and prostate-membranous urethra ruptures occur in 10-29% of male patients (10). Several studies investigating pelvic fractures and associated injuries in paediatric patients reported a lower incidence of urogenital injury (7-14%) (20-23), than in comparative adult series (7, 13, 14). In seven paediatric series (20-26), the average rate of bladder injury in patients with pelvic fractures was 4%. Motor vehicle accidents were the cause of the trauma in 97% of cases (26). 4.1.1 Iatrogenic trauma During lower abdominal operations, the bladder is the most frequently injured genitourinary organ (27). Most iatrogenic injuries occur during: • open abdominal or pelvic surgery (85%) • anterior vaginal surgery (9%) • laparoscopy (6%). The majority (92%) of these injuries are graded as III-IV, using the American Association for the Surgery of Trauma (AAST) scale (27). Most injuries occur during obstetric and gynaecological procedures (52-61%), followed by urological (12-39%) and general surgical (9-26%) interventions (27, 28). Of the general surgical operations that result in iatrogenic injury to the bladder, most involve resection of bowel as a result of malignancy, diverticulitis or inflammatory diseases (27, 28). Bladder injury occurs during gynaecological operations in 0.3-8.3% of cases (29-34). Concurrent antiincontinence surgery significantly increases the risk of injury to the bladder (13% vs 3%; P= 0.049) (34). Most cases of urological iatrogenic trauma occur during vaginal operations and laparoscopy (27, 28). The incidence of bladder wall perforation is generally low (1%) during transurethral resection of bladder tumours, and most (88%) can be managed by catheter drainage (35, 36). Transurethral resection of the prostate is also associated with low injury rates (37). Routine cystoscopy is an important adjunct to the major gynaecological procedures, and its omission may result in underestimation of iatrogenic bladder injury. An extensive review of the literature indicated that in studies not involving routine cystoscopy, the frequency of bladder injury varied from 0.2/1000 to 19.5/1000, with an overall frequency of 2.6/1000. Only 52% of bladder injuries were identified and managed intraoperatively (31). In studies involving routine cystoscopy, the frequency of bladder injury varied from 0.0/1000 to 29.2/1000, with an overall frequency of 10.4/1000. Up to 85% of unsuspected bladder injuries were identified with the use of cystoscopy and were managed successfully intraoperatively (31). Routine cystoscopy is recommended after any type of incontinence surgery as it enables identification of unsuspected bladder injury in 85% of patients (31, 32, 34, 38). Surgical procedures for the correction of stress urinary incontinence can also result in bladder trauma. The

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rate of bladder injury is below 3% in Burch colposuspension (39-41). Bladder injury is the most common complication of the tension-free vaginal tape (TVT) procedure, with an incidence of 2.0-11.5% (42-47) and up to 19% in patients with prior failed incontinence surgery (48). The transobturator tape (TOT) procedure minimizes the retropubic needle passage, and the incidence of bladder injury is expected to be low. Although during early experience with this technique rates of injury were similar to those associated with the TVT procedure (39), a recent meta-analysis indicated a lower incidence of bladder injuries (odds ratio: 0.12; 95% confidence interval: 0.05-0.33) with TOT procedures (49).

4.2

Classification

Table 6: Bladder injury scale1 Grade* Description I Hematoma Contusion, intramural hematoma Laceration Partial thickness II Laceration Extraperitoneal bladder wall laceration 2 cm) or intraperitoneal (2 cm V Laceration Intraperitoneal or extraperitoneal bladder wall laceration extending into the bladder neck or ureteral orifice (trigone) *Advance one grade for multiple injuries up to grade III 1 Adapted from the AAST.

4.3 Risk factors Individuals who driving under the influence of alcohol are likely to have a distended bladder and a motor vehicle accident. Driving after drinking alcohol is therefore a risk factor for bladder injury (19) (level of evidence: 3). Concurrent anti-incontinence surgery during gynaecological procedures results in a fourfold increased risk of bladder injury, and is therefore a risk factor for iatrogenic bladder trauma (34) (level of evidence: 3).

4.4 Diagnosis The most common signs and symptoms in patients with major bladder injuries are gross haematuria (82%) and abdominal tenderness (62%) (3). Other findings may include inability to void, bruises over the suprapubic region and abdominal distension (6). Extravasation of urine may result in swelling in the perineum, scrotum and thighs, as well as along the anterior abdominal wall within the potential space between the transversalis fascia and the parietal peritoneum. 4.4.1 Macroscopic (gross) haematuria Gross haematuria indicates urological trauma (level of evidence: 3). Traumatic bladder rupture is strongly correlated with the combination of pelvic fracture and gross haematuria; Morey et al. reported gross haematuria in all their patients with bladder rupture, and 85% had pelvic fractures (50). Thus, the classic combination of pelvic fracture and gross haematuria constitutes an absolute indication for immediate cystography in patients who have blunt trauma (3, 7, 13, 50) (level of evidence: 3). The presence of gross blood at the urethral meatus is diagnostic of a urethral injury (level of evidence: 3). A Foley catheter should not be inserted before a retrograde urethrogram has been carried out to ensure urethral integrity (51). Although grossly clear urine in a trauma patient without a pelvic fracture virtually eliminates the possibility of bladder rupture, 2-10% of patients with bladder rupture may have only microhaematuria or no haematuria at all (5, 51). In a retrospective review of more than 8000 paediatric trauma patients, of those cases with pelvic fractures, only one patient (0.5%) had an extraperitoneal bladder rupture (26). Lower urogenital injury occurred in six patients (2.8%). The absence of gross haematuria ruled out serious injury in this cohort. Based on this data, no further work-up was recommended in paediatric patients with pelvic fractures without gross haematuria. It is recommended that patients with gross haematuria, multiple associated injuries or significant abnormalities found on physical examination should be further evaluated with retrograde urethrography and cystography (level of evidence: 3).

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4.4.2 Microscopic haematuria In the trauma patient with a pelvic ring fracture, microscopic haematuria might indicate bladder laceration, and further investigation is warranted (level of evidence: 3). However, the exact quantity of blood in the urine that should trigger investigation is controversial. • Morgan et al. reported that no ruptures were seen in patients with 35-50 rbc/ hpf, no perforation would have been missed in their series. • Fuhrman et al. (53) believe that cystography in blunt trauma should be restricted to patients with gross haematuria, which they defined as > 200 rbc/hpf. They also thought that a retrograde urethrogram should be carried out first. Existing data do not support lower urinary tract imaging in all patients with pelvic fracture or microscopic haematuria alone. Hochberg and Stone (54) concluded that cystography might be safely reserved for those patients with pelvic fracture considered to be high risk for bladder injury (significant pubic arch involvement, gross haematuria and/or haemodynamic instability), as 90% of patients in their series with pelvic fracture did not have a bladder rupture. These observations do not appear to be valid for paediatric trauma patients. Abou-Jaoude et al. (55) reported a threshold for radiological evaluation of ≥ 20 rbc/hpf would miss 25% of cases with bladder injury. In contrast with other reported series (26), they suggested that lower urogenital tract evaluation in paediatric trauma patients, especially in the presence of pelvic fractures, should be based as much on clinical judgment as on the presence of haematuria (55) (level of evidence: 3). 4.4.3 Cystography Retrograde cystography is the standard diagnostic procedure in the evaluation of bladder trauma (7, 13, 56-58) (level of evidence: 3). This is the most accurate radiological study to identify bladder rupture. When adequate bladder filling and post-void images are obtained, cystography has an accuracy rate of 85-100% (5, 7, 59, 60). Bladder rupture is usually diagnosed when the contrast is identified outside the bladder. Adequate distension of the urinary bladder is crucial to demonstrating perforation, especially in cases of penetrating trauma, as most instances of a false-negative retrograde cystography were found in this situation (56). Cystography requires plain film, filled film, and post-drainage films (as a minimum) (level of evidence: 3); halffilled film and obliques are optional. For the highest diagnostic accuracy, the bladder must be distended using instillation of at least 350 mL of contrast medium by gravity. Bladder injury may be identified only on the postdrainage film in approximately 10% of cases (7). False-negative findings may result from incorrectly performed studies with less than 250 mL of contrast instillation or omission of a post-drainage film (61) (level of evidence: 3). Only a correctly performed cystography should be used to exclude bladder injury (7). 4.4.4 Excretory urography (intravenous pyelogram) An intravenous pyelogram (IVP) is inadequate for evaluation of the bladder and urethra after trauma, not only because of dilution of the contrast material within the bladder, but also because resting intravesical pressure is simply too low to demonstrate a small tear (16, 62). An IVP has a low accuracy (15-25%) (15) , and clinical studies have indicated that IVP has an unacceptably high false-negative rate (64-84%), which precludes its use as a diagnostic tool in bladder injuries (52, 59, 63) (level of evidence: 3). 4.4.5 Ultrasound (US) Although, the use of US in bladder rupture has been described (64), it is not routine for evaluation of bladder injury. Free peritoneal fluid in the presence of normal viscera, or failure to visualize the bladder after transurethral saline instillation, are highly suggestive of bladder rupture (66) (level of evidence: 3). Practically, however, US is not definitive in bladder or urethral trauma and is almost never used. 4.4.6 Computed tomography (CT) CT is clearly the method of choice for the evaluation of patients with blunt or penetrating abdominal and/or pelvic trauma (level of evidence: 3). However, routine CT is not reliable in the diagnosis of bladder rupture, even if an inserted urethral catheter is clamped. CT demonstrates intraperitoneal and extraperitoneal fluid, but cannot differentiate urine from ascites. As with IVP, the bladder is usually inadequately distended to reveal extravasation through a bladder laceration or perforation during routine abdominal and pelvic studies. Thus, a negative study cannot be entirely trusted,

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and routine CT cannot exclude bladder injury (12, 16, 65). In a review of the cystograms and CT scans (CT cystography) of 25 patients who underwent both investigations during the initial evaluation of blunt abdominal trauma, five patients were found to have bladder rupture, three of which were extraperitoneal and two intraperitoneal (66); all of the injuries were detected by both studies. It was concluded that delayed imaging or contrast instillation could provide the adequate bladder distention needed to demonstrate contrast extravasation from the injury site. Similarly, in a series of 316 patients, 44 cases were diagnosed with bladder ruptures (60). In patients who underwent a formal surgical repair, 82% had operative findings that exactly matched the CT cystography interpretation. Either retrograde cystography or CT cystography are diagnostic procedures of choice for suspected bladder injury (51). CT cystography can be used in place of conventional cystography (overall sensitivity 95% and specificity 100%) (level of evidence: 3), especially in patients undergoing CT scanning for other associated injuries (60). However, this procedure should be performed using retrograde filling of the bladder with a minimum of 350 mL of dilute contrast material (7, 66, 67). In conclusion, CT cystographic features may lead to accurate classification of bladder injury and allow prompt, effective treatment without further radiation exposure and the additional cost of conventional cystography (70) (level of evidence: 3). 4.4.7 Angiography Angiography is seldom, if ever, indicated. It can be useful in identifying an occult source of bleeding and can guide its subsequent therapeutic embolization (16). 4.4.8 Magnetic resonance imaging (MRI) It is extremely difficult to monitor a seriously injured patient in a strong magnetic field; MRI therefore has little place in the evaluation of acute bladder (16). The use of MRI has been described for later evaluation of urethral injury (69-71). 4.4.9 Cystoscopy Mainly useful in iatrogenic trauma, routine cystoscopy identifies 85% of the unsuspected injuries to the bladder that would otherwise go unnoticed (31, 34, 39). Thus, it must be use as an adjunct to major gynaecological operations as well as surgical interventions for incontinence (level of evidence: 3).

4.5

Treatment

The first priority in the treatment of bladder injuries is stabilization of the patient and treatment of associated life-threatening injuries (level of evidence: 3). 4.5.1 Blunt trauma: extraperitoneal rupture Most patients with extraperitoneal rupture can be managed safely by catheter drainage alone, even in the presence of extensive retroperitoneal or scrotal extravasation (61) (level of evidence: 3). Obstruction of the catheter by clots or tissue debris must be prevented for healing to occur. A success rate of ˃90% was reported with this approach in extraperitoneal rupture (5): 87% of the ruptures were healed in 10 days, and virtually all were healed in 3 weeks (57). However, bladder neck involvement (2), the presence of bone fragments in the bladder wall, or entrapment of the bladder wall will necessitate surgical intervention (19) (level of evidence: 3). 4.5.2 Blunt trauma: intraperitoneal rupture Intraperitoneal ruptures occurring after blunt trauma should always be managed by surgical exploration (level of evidence: 3). This type of injury involves a high degree of force and, because of the severity of associated injuries, carries a high mortality (20-40%) ((72). Lacerations are usually large in these cases, with the potential risk of peritonitis due to urine leakage if left untreated (61). Abdominal organs should be inspected for possible associated injuries, and urinoma must be drained, if present. 4.5.3 Penetrating injuries All bladder perforations resulting from penetrating trauma should undergo emergency exploration and repair (61) (level of evidence: 3). 4.5.4. Iatrogenic injuries Iatrogenic bladder perforations can occur during any pelvic, abdominal, or vaginal procedure (27). Prompt intraoperative recognition is extremely important to ensure a successful repair. Generally, suture repair is

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satisfactory, limiting unnecessary extravesical dissection (level of evidence: 3). Most (> 95%) of urinary bladder injuries sustained during gynaecological operations are detected and can be managed during surgery (73). Repair can be performed either transvaginally or abdominally. Simple catheter drainage is sufficient in most cases of bladder perforation during transurethral resection of prostate or bladder tumours (36-38) (level of evidence: 3).

4.6 Recommendations 4.6.1 General Recommendation GR Stabilization of the patient is always the priority in cases with associated injuries B GR = grade of recommendation 4.6.2 Diagnosis Recommendation GR • Immediate cystography is required in the presence of haematuria and pelvic fracture B • Diagnosis should be made with retrograde cystography with a minimum of 350 mL of B gravity-filled contrast medium • For cystography, the minimum requirement includes a plain film, filled film, and post-drainage B film. Half-filled film and obliques are optional • CT cystography can be used with equal efficacy if the patient is undergoing CT scanning for B associated injuries • Routine cystoscopy is recommended after major gynaecological operations and/or incontinence B surgery GR= grade of recommendation 4.6.3 Treatment Recommendation GR • In the absence of bladder neck involvement and/or associated injuries that require surgical B intervention, extraperitoneal bladder ruptures caused by blunt trauma are managed by catheter drainage alone • Intraperitoneal bladder ruptures by blunt trauma, and any type of bladder injury by penetrating B trauma, must be managed by emergency surgical exploration and repair • The technique of surgical repair used depends on the surgeon’s preference, but a two-layer B closure with absorbable sutures achieves a safe repair of the bladder wall GR = grade of recommendation

4.7 REFERENCES 1.

2.

3.

4. 5. 6. 7. 8.

9.

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Carlin BI, Resnick MI. Indications and techniques for urologic evaluation of the trauma patient with suspected urologic injury. Semin Urol 1995;13(1):9-24. http://www.ncbi.nlm.nih.gov/pubmed/7597359 Corriere JN Jr, Sandler CM. Management of the ruptured bladder: seven years of experience with 111 cases. J Trauma 1986;26(9):830-3. http://www.ncbi.nlm.nih.gov/pubmed/3746959 Carroll PR, McAninch JW. Major bladder trauma: mechanisms of injury and a unified method of diagnosis and repair. J Urol 1984;132(2):254-7. http://www.ncbi.nlm.nih.gov/pubmed/6737572 McConnell JD, Wilkerson MD, Peters PC. Rupture of the bladder. Urol Clin North Am 1982;9(2):293-6. http://www.ncbi.nlm.nih.gov/pubmed/7101594 Cass AS and Luxenberg M. Features of 164 bladder ruptures. J Urol 1987;138(4):743-5. http://www.ncbi.nlm.nih.gov/pubmed/3656524 Sagalowsky AI, Peters PC. Genitourinary trauma. In: Walsh PC, Retik AB, Vaughan ED Jr, Wein AJ (eds). Campbell’s Urology, 7th ed. 1998, WB Saunders: Philadelphia, pp. 3085-3120. Sandler CM, Goldman SM, Kawashima A. Lower urinary tract trauma. World J Urol 1998;16(1):69-75. http://www.ncbi.nlm.nih.gov/pubmed/9542018 Flancbaum L, Morgan AS, Fleisher M, Cox EF. Blunt bladder trauma: manifestation of severe injury. Urology 1988;31(3):220-2. http://www.ncbi.nlm.nih.gov/pubmed/3347970 Castle WN, Richardson JR Jr, Walton BJ. Unsuspected intraperitoneal rupture of bladder presenting with abdominal free air. Urology 1986;28(6):521-3. http://www.ncbi.nlm.nih.gov/pubmed/3787926

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10.

11.

12.

13.

14.

15.

16.

17. 18.

19. 20. 21. 22.

23.

24.

25.

26.

27.

28.

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Morgan DE, Nallamala LK, Kenney PJ, Mayo MS and Rue LW 3rd. CT cystography: radiographic and clinical predictors of bladder rupture. Am J Roentgenol 2000;174(1):89-95. http://www.ncbi.nlm.nih.gov/pubmed/10628460 Aihara R, Blansfield JS, Millham FH, LaMorte WW, Hirsch EF. Fracture locations influence the likelihood of rectal and lower urinary tract injuries in patients sustaining pelvic fractures. J Trauma 2002;52(2):205-8;discussion 208-9. http://www.ncbi.nlm.nih.gov/pubmed/11834976 Cass AS. Diagnostic studies in bladder rupture. Indications and techniques. Urol Clin North Am 1989;16(2):267-73. http://www.ncbi.nlm.nih.gov/pubmed/2652855 Rehm CG, Mure AJ, O’Malley KF, Ross SE. Blunt traumatic bladder rupture: the role of retrograde cystogram. Ann Emerg Med 1991;20(8):845-7. http://www.ncbi.nlm.nih.gov/pubmed/1854066 Coppola PT, Coppola M. Emergency department evaluation and treatment of pelvic fractures. Emerg Med Clin North Am 2000;18(1):1-27, v. http://www.ncbi.nlm.nih.gov/pubmed/10678158 Festini G, Gregorutti S, Reina G, Bellis GB. Isolated intraperitoneal bladder rupture in patients with alcohol intoxication and minor abdominal trauma. Ann Emerg Med 1991;20(12):1371-2. http://www.ncbi.nlm.nih.gov/pubmed/1746742 Ben-Menachem Y, Coldwell DM, Young JW, Burgess AR. Hemorrhage associated with pelvic fractures: causes, diagnosis, and emergent management. Am J Roentgenol 1991;157(5):1005-14. http://www.ncbi.nlm.nih.gov/pubmed/1927786 Cass AS. The multiple injured patient with bladder trauma. J Trauma 1984;24(8):731-4. http://www.ncbi.nlm.nih.gov/pubmed/6471137 Taffet R. Management of pelvic fractures with concomitant urologic injuries. Orthop Clin North Am 1997;28(3):389-96. http://www.ncbi.nlm.nih.gov/pubmed/9208831 Dreitlein DA, Suner S, Basler J. Genitourinary trauma. Emerg Med Clin North Am 2001;19(3):569-90. http://www.ncbi.nlm.nih.gov/pubmed/11554276 Reed MH. Pelvic fractures in children. J Can Assoc Radiol 1976;27(4):255-61. http://www.ncbi.nlm.nih.gov/pubmed/993239 Torode I, Zieg D. Pelvic fractures in children. J Pediatr Orthop 1985;5(1):76-84. http://www.ncbi.nlm.nih.gov/pubmed/993239 Musemeche CA, Fischer RP, Cotler HB, Andrassy RJ. Selective management of paediatric pelvic fractures: a conservative approach. J Pediatr Surg 1987;22(6):538-40. http://www.ncbi.nlm.nih.gov/pubmed/3612446 Bond SJ, Gotschall CS, Eichelberger MR. Predictors of abdominal injury in children with pelvic fracture. J Trauma 1991;31(8):1169-73. http://www.ncbi.nlm.nih.gov/pubmed/1875444 Reichard SA, Helikson MA, Shorter N, White RI Jr, Shemeta DW, Haller JA Jr. Pelvic fractures in children – review of 120 patients with a new look at general management. J Pediatr Surg 1980;15(6):727-34. http://www.ncbi.nlm.nih.gov/pubmed/7463272 Koraitim MM, Marzouk ME, Atta MA, Orabi SS. Risk factors and mechanism of urethral injury in pelvic fractures. Br J Urol 1996;77(6):876-80. http://www.ncbi.nlm.nih.gov/pubmed/8705225 Tarman GJ, Kaplan GW, Lerman SL, McAleer IM, Losasso BE. Lower genitourinary injury and pelvic fractures in paediatric patients. Urology 2002;59(1):123-6. http://www.ncbi.nlm.nih.gov/pubmed/11796295 Armenakas NA, Pareek G, Fracchia JA. Iatrogenic bladder perforations: longterm followup of 65 patients. J Am Coll Surg 2004;198(1):78-82. http://www.ncbi.nlm.nih.gov/pubmed/14698314 Dobrowolski ZF, Lipczynski W, Drewniak T, Jakubik P, Kusionowicz J. External and iatrogenic trauma of the urinary bladder: a survey in Poland. BJU Int 2002;89(7):755-6. http://www.ncbi.nlm.nih.gov/pubmed/11966639 Ostrzenski A, Ostrzenska KM. Bladder injury during laparoscopic surgery. Obstet Gynecol Surv 1998;53(3):175-80. http://www.ncbi.nlm.nih.gov/pubmed/9513988

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Harkki-Siren P, Sjoberg J, Tiitinen A. Urinary tract injuries after hysterectomy. Obstet Gynecol 1998;92(1):113-8. http://www.ncbi.nlm.nih.gov/pubmed/9649105 Gilmour DT, Dwyer PL, Carey MP. Lower urinary tract injury during gynecologic surgery and its detection by intraoperative cystoscopy. Obstet Gynecol 1999;94(5Pt2):883-9. http://www.ncbi.nlm.nih.gov/pubmed/10546778 Mendez LE. Iatrogenic injuries in gynecologic cancer surgery. Surg Clin North Am 2001;81(4):897-923. http://www.ncbi.nlm.nih.gov/pubmed/11551133 Makinen J, Johansson J, Tomas C, Tomas E, Heinonen PK, Laatikainen T, Kauko M, Heikkinen AM, Sjoberg J. Morbidity of 10 110 hysterectomies by type of approach. Hum Reprod 2001;16(7):1473-8. http://www.ncbi.nlm.nih.gov/pubmed/11425832 Vakili B, Chesson RR, Kyle BL, Shobeiri SA, Echols KT, Gist R, Zheng YT, Nolan TE. The incidence of urinary tract injury during hysterectomy: a prospective analysis based on universal cystoscopy. Am J Obstet Gynecol 2005;192(5):1599-604. http://www.ncbi.nlm.nih.gov/pubmed/15902164 Skolarikos A, Chrisofos M, Ferakis N, Papatsoris A, Dellis A, Deliveliotis C. Does the management of bladder perforation during transurethral resection of superficial bladder tumors predispose to extravesical tumor recurrence? J Urol 2005;173(6):1908-11. http://www.ncbi.nlm.nih.gov/pubmed/15879773 Murshidi MS. Intraperitoneal rupture of the urinary bladder during transurethral resection of transitional cell carcinoma. Acta Urol Belg 1988;56(1):68-73. http://www.ncbi.nlm.nih.gov/pubmed/3364323 Donovan JL, Peters TJ, Neal DE, Brookes ST, Gujral S, Chacko KN, Wright M, Kennedy LG, Abrams P. A randomized trial comparing transurethral resection of the prostate, laser therapy and conservative treatment of men with symptoms associated with benign prostatic enlargement: The CLasP study. J Urol 2000;164(1):65-70. http://www.ncbi.nlm.nih.gov/pubmed/10840426 Minaglia S, Ozel B, Klutke C, Ballard C, Klutke J. Bladder injury during transobturator sling. Urology 2004;64(2):376-7. http://www.ncbi.nlm.nih.gov/pubmed/15302505 Dwyer PL, Carey MP, Rosamilia A. Suture injury to the urinary tract in urethral suspension procedures for stress incontinence. Int Urogynecol J Pelvic Floor Dysfunct 1999;10(1):15-21. http://www.ncbi.nlm.nih.gov/pubmed/10207762 Gill EJ, Elser DM, Bonidie MJ, Roberts KM, Hurt WG. The routine use of cystoscopy with the Burch procedure. Am J Obstet Gynecol 2001;185(2):345-8. http://www.ncbi.nlm.nih.gov/pubmed/11518889 Kenton K, Oldham L, Brubaker L. Open Burch urethropexy has a low rate of perioperative complications. Am J Obstet Gynecol 2002;187(1):107-10. http://www.ncbi.nlm.nih.gov/pubmed/12114897 Olsson I, Kroon U. A three-year postoperative evaluation of tension-free vaginal tape. Gynecol Obstet Invest 1999;48(4):267-9. http://www.ncbi.nlm.nih.gov/pubmed/10592431 Soulie M, Cuvillier X, Benaissa A, Mouly P, Larroque JM, Bernstein J, Soulie R, Tollon C, Brucher P, Vazzoler N, Seguin P, Pontonnier F, Plante P. The tension-free transvaginal tape procedure in the treatment of female urinary stress incontinence: a French prospective multicentre study. Eur Urol 2001;39(6):709-14; discussion 715. http://www.ncbi.nlm.nih.gov/pubmed/11464062 Tamussino KF, Hanzal E, Kolle D, Ralph G, Riss PA. Tension-free vaginal tape operation: results of the Austrian registry. Obstet Gynecol 2001;98(5Pt1):732-6. http://www.ncbi.nlm.nih.gov/pubmed/11704161 Meschia M, Pifarotti P, Bernasconi F, Guercio E, Maffiolini M, Magatti F, Spreafico L. Tension-Free vaginal tape: analysis of outcomes and complications in 404 stress incontinent women. Int Urogynecol J Pelvic Floor Dysfunct 2001;12 Suppl 2:S24-S27. http://www.ncbi.nlm.nih.gov/pubmed/11450976 Agostini A, Bretelle F, Franchi F, Roger V, Cravello L, Blanc B. Immediate complications of tension-free vaginal tape (TVT): Results of a French Survey. Eur J Obstet Gynecol Reprod Biol 2006;124(2):237-9. Epub 2005. http://www.ncbi.nlm.nih.gov/pubmed/16095800

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Kuuva N, Nilsson CG. A nationwide analysis of complications associated with the tension-free vaginal tape (TVT) procedure. Acta Obstet Gynecol Scand 2002;81(1):72-7. http://www.ncbi.nlm.nih.gov/pubmed/11942891 Azam U, Frazer MI, Kozman EL, Ward K, Hilton P, Rane A. The tension-free vaginal tape procedure in women with previous failed stress incontinence surgery. J Urol 2001;166(2):554-6. http://www.ncbi.nlm.nih.gov/pubmed/11458067 Latthe PM. Review of transobturator and retropubic tape procedures for stress urinary incontinence. Curr Opin Obstet Gynecol 2008;20(4):331-6. http://www.ncbi.nlm.nih.gov/pubmed/18660683 Morey AF, Iverson AJ, Swan A, Harmon WJ, Spore SS, Bhayani S, Brandes SB. Bladder rupture after blunt trauma: guidelines for diagnostic imaging. J Trauma 2001;51(4):683-6. http://www.ncbi.nlm.nih.gov/pubmed/11586159 Schneider RE. Genitourinary trauma. Emerg Med Clin North Am 1993;11(1):137-45. http://www.ncbi.nlm.nih.gov/pubmed/8432245 Werkman HA, Jansen C, Klein JP, Ten Duis HJ. Urinary tract injuries in multiply-injured patients: a rational guideline for the initial assessment. Injury 1991;22(6):471-4. http://www.ncbi.nlm.nih.gov/pubmed/1757139 Fuhrman GM, Simmons GT, Davidson BS, Buerk CA. The single indication for cystography in blunt trauma. Am Surg 1993;59(6):335-7. http://www.ncbi.nlm.nih.gov/pubmed/8507053 Hochberg E, Stone NN. Bladder rupture associated with pelvic fracture due to blunt trauma. Urology 1993;41(6):531-3. http://www.ncbi.nlm.nih.gov/pubmed/8516988 Abou-Jaoude WA, Sugarman JM, Fallat ME, Casale AJ. Indicators of genitourinary tract injury or anomaly in cases of paediatric blunt trauma. J Pediatr Surg 1996;31(1):86-9;discussion 90. http://www.ncbi.nlm.nih.gov/pubmed/8632293 Baniel J, Schein M. The management of penetrating trauma to the urinary tract. J Am Coll Surg 1994;178(4):417-25. http://www.ncbi.nlm.nih.gov/pubmed/8149045 Corriere JN, Sandler CM. Management of extraperitoneal bladder rupture. Urol Clin North Am 1989;16(2):275-7. http://www.ncbi.nlm.nih.gov/pubmed/2711545 Stine RJ, Avila JA, Lemons MF, Sickorez GJ. Diagnostic and therapeutic urologic procedures. Emerg Med Clin North Am 1988;6(3):547-78. http://www.ncbi.nlm.nih.gov/pubmed/3292227 Carroll PR, McAninch JW. Major bladder trauma: the accuracy of cystography. J Urol 983;130(5): 887-8. http://www.ncbi.nlm.nih.gov/pubmed/6632094 Deck AJ, Shaves S, Talner L, Porter JR. Computerized tomography cystography for the diagnosis of traumatic bladder rupture. J Urol 2000;164(1):43-6. http://www.ncbi.nlm.nih.gov/pubmed/10840421 Morey AF, Hernandez J, McAninch JW. Reconstructive surgery for trauma of the lower urinary tract. Urol Clin North Am 1999;26(1):49-60, viii. http://www.ncbi.nlm.nih.gov/pubmed/10086050 Bonavita JA, Pollack HM. Trauma of the adult bladder and urethra. Semin Roentgenol 1983;18(4): 299-306. http://www.ncbi.nlm.nih.gov/pubmed/6359436 MacMahon R, Hosking D, Ramsey EW. Management of blunt injury to the lower urinary tract. Can J Surg 1983;26(5):415-8. http://www.ncbi.nlm.nih.gov/pubmed/6616359 Bigongiari LR, Zarnow H. Traumatic, inflammatory, neoplastic and miscellaneous lesions of the bladder. In: Land EK (ed.). Medical Radiology of the Lower Urinary Tract, 1994, Springer Verlag: Berlin, pp. 70-147. Mee SL, McAninch JW, Federle MP. Computerized tomography in bladder rupture: diagnostic limitations. J Urol 1987;137(2):207-9. http://www.ncbi.nlm.nih.gov/pubmed/3806805 Horstman WG, McClennan BL, Heiken JP. Comparison of computed tomography and conventional cystography for detection of traumatic bladder rupture. Urol Radiol 1991;12(4):188-93. http://www.ncbi.nlm.nih.gov/pubmed/2042269

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Lis LE, Cohen AJ. CT cystography in the evaluation of bladder trauma. J Comput Assist Tomogr 1990;14(3):386-9. http://www.ncbi.nlm.nih.gov/pubmed/2335605 Vaccaro JP, Brody JM. CT cystography in the evaluation of major bladder trauma. Radiographics 2000;20(5):1373-81. http://www.ncbi.nlm.nih.gov/pubmed/10992026 Dixon CM, Hricak H, McAninch JW. Magnetic resonance imaging of traumatic posterior urethral defects and pelvic crush injuries. J Urol 1992;148(4):1162-5. http://www.ncbi.nlm.nih.gov/pubmed/1404629 Armenakas NA, McAninch JW, Lue TF, Dixon CM, Hricak H. Posttraumatic impotence: magnetic resonance imaging and duplex ultrasound in diagnosis and management. J Urol 1993;149(5Pt2): 1272-5. http://www.ncbi.nlm.nih.gov/pubmed/8479013 Narumi Y, Hricak H, Armenakas NA, Dixon CM, McAninch JW. MR imaging of traumatic posterior urethral injury. Radiology 1993;188(2):439-43. http://www.ncbi.nlm.nih.gov/pubmed/8327694 Thomae KR, Kilambi NK, Poole G V. Method of urinary diversion in nonurethral traumatic bladder injuries: retrospective analysis of 70 cases. Am Surg 1998;64(1):77-80;discussion 80-1. http://www.ncbi.nlm.nih.gov/pubmed/9457042 Soong YK, Yu HT, Wang CJ, Lee CL, Huang HY. Urinary tract injury in laparoscopic-assisted vaginal hysterectomy. J Minim Invasive Gynecol 2007;14(5):600-5. http://www.ncbi.nlm.nih.gov/pubmed/17848321

5. URETHRAL TRAUMA 5.1 Anatomical and aetiological considerations The male urethra is divided into the anterior and posterior sections by the urogenital diaphragm. The posterior urethra consists of the prostatic and the membranous urethra. The anterior urethra consists of the bulbar and penile urethra. Only the posterior urethra exists in the female; the anterior urethra corresponds to the labia minora, which results from persistent separation of the urethral folds on the ventral surfaces of the genital tubercle. 5.1.1 Posterior urethral injuries Road traffic accidents, falls, and crush injuries can cause pelvic fractures, which result in injuries to the posterior urethra. About two-thirds (70%) of pelvic fractures occur because of motor vehicle accidents. The incidence of pelvic fracture is 20% in survivors of motor accidents where fatalities have occurred. The incidence is nearly 50% in fatal pedestrian accidents. Twenty-five per cent of cases result from a fall from a height (1, 2). Altogether, blunt trauma accounts for more than 90% of urethral injuries (3). Overall, the male posterior urethra is injured in 4-19% and the female urethra in 0-6% of all pelvic fractures (2, 4-12). The female urethra is rarely injured, except by contusion or laceration by bone fragments. During crush or deceleration impact injury, the severe shearing forces necessary to fracture the pelvis are transmitted to the prostatomembranous junction, resulting in disruption of the prostate from its connection to the anterior urethra at the prostatic apex. Retrograde urethrography and magnetic resonance imaging (MRI) correlates to this location of the injury (13, 14). Cadaveric studies suggest that in most cases the membranous urethra is torn distally to the urogenital diaphragm (15). An accurate knowledge of the functional anatomy of the sphincter mechanism is essential to the success of posterior urethral surgery. Continence after anastomotic reconstruction of subprostatic pelvic fracture urethral distraction defects depends upon the function of the bladder neck and of the distal urethral sphincter mechanism, each of which is competent and independently capable of maintaining continence in the absence of the other (16). Unstable pelvic fractures (8, 11, 17-21), bilateral ischiopubic rami fractures (‘straddle fracture’), and symphysis pubis diastasis have the highest likelihood of injuring the posterior urethra. In particular, the combination of

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straddle fractures with diastasis of the sacroiliac joint has the highest risk of urethral injury; the odds ratio is about 7 times higher than for either straddle injuries or sacroiliac (‘Malgaigne’) fractures alone (Table 7) (2). Table 7: Odds ratio of suffering urethral injury with different types of pelvic fracture Type of fracture Single ramus Ipsilateral rami Malgaigne’s (vertical shear) Straddle Straddle plus sacroiliac

Odds ratio 0.6 0.8 3.4 3.9 24.0

Lower urinary tract injury has been reported in about 16% of patients with unilateral rami fractures and in 41% of patients with bilateral rami fractures (22). Anteroposterior compression injuries from frontal crushes produce more severe pelvic fractures, major retroperitoneal bleeding and more frequent injury to the lower urinary tract than do lateral crashes (23). Prostatomembranous urethral injuries can vary from simple stretching (25%) to partial rupture (25%) or complete disruptions (50%) (2). The more severe injuries result in prostatourethral displacement, with progressive scar formation encompassing the rupture defect. The incidence of double injuries involving the urethra and the bladder ranges between 10% and 20% in males, and may be intraperitoneal (17-39%), extraperitoneal (56-78%), or both (2, 7). Urethral injuries, by themselves, are never life-threatening, except as a consequence of their close association with pelvic fractures and multiple organ injuries, which occur in about 27% of cases. Initially, the assessment and management of other associated injuries is usually more important than the assessment and management of the urethral injury (24). The American Association for Surgery of Trauma (AAST) has proposed the classification given in Table 8. Table 8: Organ injury scaling III classification of urethral injuries (25) Grade Description Appearance I Contusion Blood at the urethral meatus; Normal urethrogram II Stretch injury Elongation of the urethra without extravasation on urethrography III Partial disruption Extravasation of contrast at injury site with contrast visualised in the bladder IV Complete disruption Extravasation of contrast at injury site without visualisation in the bladder; < 2 cm of urethral separation V Complete disruption Complete transection with > 2 cm urethral separation or extension into the prostate or vagina New classifications provide an anatomical classification and a means of comparing treatment strategies and outcomes (26, 27). The classification shown in Table 9 combines the best of previous classifications and has direct implications in clinical management. Table 9: Classification of blunt anterior and posterior urethra Grade Description Appearance I Stretch injury Elongation of the urethra without extravasation on urethrography II Contusion Blood at the urethral meatus No extravasation on urethrography III Partial disruption of Extravasation of contrast at injury site with contrast visualised in anterior or posterior the proximal urethra or bladder urethra IV Complete disruption Extravasation of contrast at injury site without visualisation of proximal of anterior urethra urethral or bladder V Complete disruption Extravasation of contrast at injury site without visualisation of bladder of posterior urethra

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VI

Complete or partial disruption of posterior urethra with associated tear of the bladder neck or vagina

Clinical management is according to the injury grade: • grade I no treatment required • grades II and III can be managed conservatively with suprapubic cystostomy or urethral catheterisation • grades IV and V will require open or endoscopic treatment, primary or delayed • grade VI requires primary open repair. 5.1.1.1 Urethral injuries in children Urethral injuries in children are similar to those in adults. The only significant difference is that straddle pelvic fractures, Malgaigne’s fractures or the association of straddle plus sacroiliac joint fracture is more common in children than in adults. In addition, posterior urethral injuries can involve the prostatic urethra and the bladder neck, as well as the membranous urethra. The tear is often in the prostatic urethra or at the bladder neck because of the rudimentary nature of the prostate, and is more likely to be a complete rupture (69% versus 42%). Urethral stretching is less common than in adults. The more proximal the injury, the greater the risk of incontinence, impotence and stricture (2, 24, 28, 29). 5.1.1.2 Urethral injuries in women These are rare events since the female urethra is short and mobile, without any significant attachments to the pubic bone. They usually occur in children. They are often accompanied by severe pelvic fractures, where bony fragments of the fractured pelvis can lacerate the urethra. Urethral injuries in females frequently extend into the bladder neck or vagina, and often disrupt the normal continence mechanism (4, 12). Injury to the female urethra is usually a partial tear of the anterior wall and is rarely a complete disruption of the proximal or distal urethra (29). 5.1.1.3 Penetrating injuries to the perineum These can occur after external violence such as gunshot or stab wounds, or as iatrogenic injuries caused by endoscopic instruments or during surgery for vaginal repair. In developing countries, urethral and bladder neck damage occur quite often as a result of ischaemic injury during obstructed labour. 5.1.2 Anterior urethral injuries Anterior urethral injuries result from blunt trauma more frequently than from penetrating trauma (Table 10). Table 10: Aetiology of anterior urethral injuries Cause Blunt trauma Sexual intercourse Penetrating trauma Constriction bands Iatrogenic injuries

Example • Vehicular accidents • Fall astride (straddle) • Kicks in the perineum • Blows in the perineum from bicycle handlebars, tops of fences, etc. • Penile fractures • Urethral intraluminal stimulation • Gunshot wounds • Stab wounds • Dog bites • External impalement • Penile amputations • Paraplegia • Endoscopic instruments • Urethral catheters/dilators

5.1.2.1 Blunt trauma Vehicular accidents, falls or blows cause most anterior urethral injuries. In contrast to posterior urethral trauma, they are rarely associated with pelvic fractures. They are usually straddle-type injuries caused by blows of blunt objects against the perineum, such as bicycle handlebars or the top of a fence. In this type of accident, the

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relatively immobile bulbar urethra is trapped and compressed by a direct force on it against the inferior surface of the symphysis pubis. These injuries are more common in children than in adults (28). 5.1.2.2 Intercourse-related trauma A less common cause of blunt anterior urethral trauma is penile fracture. This rupture of the corpus cavernosum usually occurs during intercourse. In these injuries, the urethra is involved in 20% of the cases (30). Intraluminal stimulation of the urethra with foreign objects has also been reported to cause anterior urethral trauma. Most are short and incomplete, and occur in the distal penile urethra. Surgery is rarely indicated and depends on the degree and extent of injury to the urethra. 5.1.2.3 Penetrating trauma Penetrating injuries to the anterior urethra usually result from gunshot wounds and involve the pendulous and bulbar urethral segments equally. These injuries are associated with penile and testicular injury. These can involve the rectum, which may result in pelvic abscesses and the formation of fistulae (31, 32). Other less frequent causes of external anterior urethral injuries include stab wounds, penile amputation and impalement. 5.1.2.4 Constriction band-related trauma Individuals with paraplegia who use a constriction device for urinary incontinence and forget to release the band because of the lack of sensation can cause severe ischaemic injuries involving the penis and urethra. 5. 1.2.5 Iatrogenic trauma Iatrogenic urethral injuries caused by instruments are by far the most common cause of urethral trauma. Urethral ischaemic injuries related to cardiac bypass procedures are not infrequent and can result in long and fibrotic strictures. A separate section in this chapter discusses iatrognic trauma in more detail (see section 4.6).

5.2 Diagnosis: initial emergency assessment 5.2.1 Clinical assessment The initial management of urethral injury is resuscitation of the patient. In the absence of blood at the meatus or genital haematoma, a urological injury is very unlikely and is excluded by catheterisation. Maintain airway and respiratory function, secure the cervical spine if necessary, and address blood loss if present. This is particularly important in posterior urethral injuries because of their close association with pelvic fractures. The next step includes taking a complete history and carrying out physical, laboratory and radiographic evaluations in order to identify all injuries accurately. A diagnosis of acute urethral trauma should be suspected from the history. A pelvic fracture, or any external penile or perineal trauma, can be suggestive of urethral trauma (33, 34). For penetrating injuries, the type of weapon used, including the calibre of the bullet, is helpful in assessing potential tissue damage. In a conscious patient, a thorough voiding history should be obtained to establish the time of last urination, the force of the urinary stream, whether urination is painful and whether haematuria is present. The following clinical indicators of acute urethral trauma warrant a complete urethral evaluation. 5.2.1.1 Blood at the meatus This is present in 37-93% of patients with posterior urethral injury, and in at least 75% of patients with anterior urethral trauma (35, 36). When blood is present at the urethral meatus, do not attempt urethral instrumentation until the entire urethra is imaged. In an unstable patient, attempt to pass a urethral catheter, but if there is any difficulty, place a suprapubic catheter and perform a retrograde urethrogram when appropriate. It is extremely unlikely that gentle passage of a urethral catheter will do any additional damage (37, 38), although it has been suggested that this may convert a partial tear into one that is complete (39). There are no convincing data indicating a higher rate of infection or urethral stricture after a single attempt at catheterisation (3). Indeed, if a urethral injury is suspected, urethrography prior to attempted catheterisation is the most prudent approach. 5.2.1.2 Blood at the vaginal introitus This is present in more than 80% of female patients with pelvic fractures and co-existing urethral injuries (4). 5.2.1.3 Haematuria Although non-specific, haematuria on a first-voided specimen may indicate urethral injury. The amount of

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urethral bleeding correlates poorly with the severity of the injury, as a mucosal contusion or small partial tear may be accompanied by copious bleeding, while total transection of the urethra may result in little bleeding (40). 5.2.1.4 Pain on urination or inability to void The inability to void suggests urethral disruption. 5.2.1.5 Haematoma or swelling With anterior urethral trauma, the pattern of the haematoma can be useful in identifying the anatomical boundaries violated by the injury. Extravasation of blood or urine in a sleeve distribution along the penile shaft indicates that the injury is confined by Buck’s fascia. Disruption of Buck’s fascia results in a pattern of extravasation limited only by Colles’ fascia, and can extend to the coracoclavicular fascia superiorly and the fascia lata inferiorly. This results in a characteristic butterfly pattern of bruising in the perineum. In female patients with severe pelvic fractures, the presence of labial swelling may be an indicator of urethral injury. It can be caused by urinary extravasation and warrants immediate attention. 5.2.1.6 High-riding prostate This is a relatively unreliable finding in the acute phase since the pelvic haematoma associated with pelvic fractures often precludes the adequate palpation of a small prostate, particularly in younger men (3). A boggy mass is usually palpated without recognition of a prostate gland (41). Rectal examination is more important as a tool to screen for rectal injuries, which can be associated with pelvic fractures. Blood on the examination finger is suggestive of a rectal injury. Assessment of concomitant genital injuries is mandatory in every case of external urethral trauma. 5.2.2 Radiographic examination Retrograde urethrography is the gold standard for evaluating urethral injury (5, 29). A scout film should be performed first to assess the radiographic technique, and to detect pelvic fractures and foreign bodies, such as bullets. This is performed using a Foley catheter in the fossa navicularis, with the balloon inflated using 1-2 mL of saline to occlude the urethra. Then, 20-30 mL of contrast material is injected while films are taken in a 30° oblique position. When severe pelvic fractures and associated patient discomfort are present, the oblique position may not always be possible. The radiographic appearance of the urethra permits classification of the injury and facilitates the subsequent management. If posterior urethral injury is suspected, a suprapubic catheter is inserted. Later on, a simultaneous cystogram and ascending urethrogram can be carried out to assess the site, severity and length of the urethral injury. This is usually done after 3 months if a delayed repair is considered. When the proximal urethra is not visualised in a simultaneous cystogram and urethrogram, either MRI of the posterior urethra (42) or endoscopy through the suprapubic tract is used to define the anatomy of the posterior urethra. Since manipulation in the bladder can cause the bladder neck to open and give the false impression of incompetence, the endoscopic appearance of the bladder neck should be noted immediately on placing the scope into the bladder (43). After assessing the endoscopic appearance of the bladder neck, the flexible endoscope can be advanced through the bladder neck into the posterior urethra to the level of obstruction. If there is a question about the length of the distraction, a simultaneous retrograde urethrogram can be performed while the endoscope is in the posterior urethra. The radiographic appearance of the bladder neck is important, but is not as reliable an indicator of continence as the endoscopic appearance is. Furthermore, there are patients who, despite evidence of an open or scarred bladder neck, will have acceptable continence after reconstruction. For this reason, the need for concomitant bladder neck surgery at the time of urethral reconstruction is debatable (43, 44). Ultrasonography is not a routine investigation in the initial assessment of urethral injuries but can be very useful in determining the position of pelvic haematomas, or the exact location of the bladder when a suprapubic catheter is indicated. Computed tomography and MRI have no place in the initial assessment of urethral injuries. However, they are useful in defining distorted pelvic anatomy after severe injury and assessing associated injuries of penile crura, bladder, kidneys and intra-abdominal organs (14, 45).

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5.2.3 Endoscopic examination Urethroscopy does not have any role in the initial diagnosis of urethral trauma in males. In females, however, where the short urethra precludes adequate retrograde urethrography, urethroscopy is an important adjunct to the physical examination for the identification and staging of urethral injuries (46).

5.3

Management

The management of urethral injuries remains controversial because of the variety of injury patterns, associated injuries and treatment options available. In addition, urethral injuries are relatively uncommon, hence the limited experience of most urologists worldwide and the absence of randomised prospective studies. 5.3.1 Anterior urethral injuries 5.3.1.1 Blunt injuries Partial tears can be managed with a suprapubic catheter or with urethral catheterisation (29, 37, 47). Suprapubic cystostomy has the advantage that it not only diverts the urine away from the site of injury, but also avoids urethral manipulation (48), as well as allowing for a simultaneous study to be carried out at a later date. If the bladder is not easily palpable suprapubically, transabdominal sonography should be used to guide the placement of the catheter. The cystostomy tube is maintained for approximately 4 weeks to allow urethral healing. Voiding cystourethrography is then performed. Remove the suprapubic tube if normal voiding can be re-established and neither contrast extravasation nor stricture is present. The potential early complications of acute urethral injuries include strictures and infections. Extravasated blood or urine from the urethral tear produces an inflammatory reaction that can progress to the formation of an abscess. The extent of the infection depends on the fascial planes violated (see section 4.2). The potential sequelae of these infections include urethrocutaneous fistulae, peri-urethral diverticulae and, rarely, necrotising fasciitis. Prompt urinary diversion coupled with the appropriate administration of antibiotics decreases the incidence of these complications. After the patient has adequately recovered from any associated injuries, and the urethral injury has stabilised, the urethra can be thoroughly re-evaluated radiographically. When necessary, the appropriate reconstructive procedure is planned. Blunt anterior urethral injuries are associated with spongiosal contusion, which makes it more difficult to evaluate the limits of urethral debridement in the acute phase. Acute or early urethroplasty is therefore not indicated, and the best management is simply suprapubic diversion. Satisfactory urethral luminal recanalisation occurs in approximately 50% of partial anterior urethral disruptions (47, 49). Short and flimsy strictures are managed with optical urethrotomy or urethral dilatation. Denser strictures require formal urethral reconstruction. Anastomotic urethroplasty is indicated in strictures of less than 1 cm in length. Longer strictures of the anterior urethra should not be repaired by an end-to-end anastomosis, in order to avoid chordee. In these cases, flap urethroplasty is indicated. Almost all complete ruptures of the anterior urethra require anastomotic or patch urethroplasty at 3-6 months. The only exception to this is urethral injury associated with penile fracture; this usually results in partial urethral disruption and can be repaired at the time of cavernosal closure. 5.3.1.2 Open injuries 5.3.1.2.1 Male urethral injuries Stab wounds, gunshot wounds and dog bites to the urethra often involve the penis and testes and often require immediate exploration. During surgery, the urethral injury can be surgically evaluated and repaired as needed. Urethral strictures form in fewer than 15% of these patients (50). Primary urethral suturing involves direct visualisation of the severed urethral ends and creation of a watertight, tension-free repair. The patient should be in a supine position. Use a circumferential subcoronal incision to deglove the penis. In complete disruptions, the corpus spongiosum is mobilised at the level of the injury and the urethral ends dissected distally and proximally. Urethral ends are spatulated, and end-to-end anastomosis is fashioned over

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a 14 French Foley catheter. Suture small lacerations with fine absorbable material. Careful overclosure of the corpus spongiosum and skin prevents the subsequent formation of fistulae (24). Keep urethral debridement to a minimum since the spongiosum is well vascularised and will usually heal well. As with any surgery, give pre-operative antimicrobial prophylaxis. Some experts recommend the post-operative continuation of prophylactic antibiotics, but we are not aware of any data that prove that they help. After 10-14 days, obtain a peri-catheter retrograde urethrogram with the urethral catheter in situ. Provided there is no leakage at the anastomotic site, remove the urethral catheter. If there is leakage, leave the catheter in and repeat the cystourethrogram 1 week later. If the urethra is so extensively disrupted that primary anastomosis is not feasible, then primary repair should be aborted. This occurs with defects of more than 1-1.5 cm in length. One should marsupialise the urethra preparatory to a two-stage urethral repair, and consider a suprapubic urinary diversion. Perform a delayed elective procedure a minimum of 3 months after injury. There is no role for acute placement of a graft or flap in the initial management of any urethral injury, since contamination or decreased blood supply can compromise such a repair (33). 5.3.1.2.2 Female urethral injuries Most female urethral disruptions can be sutured primarily. These injuries often occur together with bladder ruptures. Frequently, if the bladder injury is going to be repaired primarily, the urethral disruption can be repaired at the same time. For proximal urethral injuries, urethral exposure is best obtained transvesically. Distal urethral injuries can be approached vaginally (29). Early repair of post-traumatic urethral fistulae can also be accomplished transvaginally (4, 12). 5.3.2 Posterior urethral injuries It is important to distinguish between inflammatory or iatrogenic posterior urethral strictures and true pelvic fracture urethral distraction defects as the principles of their surgical management are entirely different. Urethral stricture indicates a narrowing of the urethral lumen. In urethral distraction defects, there is a gap between the two otherwise normal ends of the urethra. The dismembered ends of the urethra retract, and the space between them fills with fibrous tissue. There is no urethral wall in the scarred space, and any lumen represents merely a fistulous tract between the urethral stumps. A further difference between inflammatory strictures and distraction defects is that the urethral stumps are usually not fibrotic and can be re-anastomosed without tension after distraction injury. Once anastomosed, they usually heal without stricture (51). Erectile dysfunction occurs in 20-60% of patients after traumatic posterior urethral rupture (51-55). The most important determining factor associated with impotence is the severity of the initial injury. The incidence of erectile dysfunction being caused by the open surgical repair itself is 5% or less (51, 56). Erectile dysfunction seems to be a direct result of the pelvic fracture plus urethral injury. King reported an incidence of 42% in cases of pelvic fracture and urethral injury, but only 5% when the urethra was not injured (53). Barbagli et al. reported an incidence of 60% in patients with posterior urethral injury, compared with 14% in patients with bulbar injury (57). Factors that correlate with the development of impotence are age, defect length and the type of fracture. Bilateral pubic rami fractures are the most frequent cause of impotence. Impotence is most commonly neurogenic, due to bilateral damage of the cavernous nerves at the prostatomembranous urethra behind the symphysis pubis (58, 59). Associated vasculogenic erectile failure may occur in up to 80% of cases (60). Dixon et al. presented evidence that impotence may also be a consequence of avulsion of the corporus cavernosum from the ischium (14). In this series, five out of six patients with avulsion of the corporus cavernosum off the inferior pubic ramus, were impotent. Spontaneous return of potency may occur up to 2 years after injury (42). Gibson reported an incidence of improved sexual function after 18 months in 21% of patients (52). 5.3.2.1 Partial urethral rupture Manage partial tears of the posterior urethra with a suprapubic or urethral catheter. Perform urethrography at 2-weekly intervals until healing has occurred (29, 37). They may heal without significant scarring or obstruction if managed by diversion alone (48,61). Manage residual or subsequent stricture with urethral dilatation or optical urethrotomy if short and flimsy, and with anastomotic urethroplasty if dense or long (24, 37). 5.3.2.2 Complete urethral rupture Acute treatment options include: • primary endoscopic realignment or

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immediate open urethroplasty (which should be considered experimental and rarely or never used in patients without associated rectal or bladder neck injury). Delayed treatment options include: • ‘delayed primary urethroplasty’ (which implies primary repair 2 weeks after injury and for which there is a lack of supporting evidence in male patients) • delayed formal urethroplasty at 3 months after injury (the most standard approach) • delayed endoscopic incision of the scar tissue between the urethral ends (so-called ‘cut-to-the-light’ or similar procedures). •

5.3.2.3 Primary realignment The management of complete posterior rupture of the urethra has changed in recent years. There is now more active orthopaedic management of pelvic fractures with immediate external and internal fixation. This has led to the option of early repair of urethral injuries (37). In the absence of indications for immediate exploration, posterior urethral disruption can be managed in a delayed primary fashion. Primary realignment requires placement of a suprapubic tube at the time of initial injury, with repair undertaken when the patient is stable, usually within 7 days. At this time, patients are stable, and most pelvic bleeding has resolved. The aim of internal realignment is to correct severe distraction injuries rather than to prevent a stricture occurring, although it will also ensure that it is easily treated if it does occur (62). Open realignment has been described (63), but it should be performed only in patients who undergo open abdominal or pelvic surgery for associated injuries or internal bone fixation. Haematomas that prevent adequate pelvic descent can be evacuated at this point in these cases. Concomitant bladder neck or rectal injuries should usually be repaired immediately, and open or endoscopic urethral realignment over a catheter at the same time might be advisable. The reasons for immediate repair of bladder neck and rectal injury are: 1. Unrepaired bladder neck injury risks incontinence and infection of the pelvic fractures 2. Unrepaired rectal injury carries the obvious risk of sepsis and fistula, and early exploration is Indicated to evacuate contaminated haematomas and perform colostomy 3. Urethral realignment over a stenting catheter is appropriate in such cases (29, 40, 64-66). The overall condition of the patient and the extent of the associated injuries greatly affect the decision to proceed with primary realignment. Most patients with pelvic crush injuries have multiple organ injuries. Associated lower extremity fractures can prevent placement in the lithotomy position, which may be required for primary realignment (although bedside flexible cystoscopy can be used). Head injuries increase the adverse risks of anaesthesia. If these conditions are controlled, such that a haemodynamically stable patient can safely undergo a lengthier anaesthesia and can be placed in the lithotomy position, endoscopic urethral realignment could be considered during the first 2 weeks after trauma. The proposed benefits of primary alignment are: 1. A lower stricture rate than with suprapubic catheter placement alone (69% versus 10%) (6), which avoids a second operation for urethral reconstruction in about one-third of patients (3) 2. If scarring occurs, restoration of urethral continuity is simplified and may be accomplished by endoscopic procedures or dilatation 3. If urethroplasty is required later, it is technically easier when the prostate and urethra are well aligned; the disadvantage might be a higher incidence of erectile dysfunction and incontinence when compared with delayed reconstruction (6, 67). The great variation of techniques used for primary realignment procedures confuses any comparison with delayed repair procedures (68-71). Primary realignment techniques include: • simple passage of a catheter across the defect (70) • catheter realignment using flexible/rigid endoscopes and biplanar fluoroscopy (72, 73) • use of interlocking sounds (‘railroading’) or magnetic catheters to place the catheter (71, 74) • pelvic haematoma evacuation and dissection of the prostatic apex (with or without suture anastomosis) over a catheter • catheter traction or perineal traction sutures to pull the prostate back to its normal location (75). Realignment may be insufficient to join the margins of the severed urethra completely, and 1.5-4.0 cm defects

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have been observed even after catheter realignment (76). This finding agrees with experimental animal data, which show that when the urethra is transacted and an apparently good urethral junction is achieved by catheter traction, there is no evidence of epithelialisation of the mucosal gap, but rather that the intervening area is filled with fibrous tissue (77). Traction on the catheter might not improve the healing of the urethra, and could in fact harm continence. Sustained traction on the Foley balloon catheter can damage the remaining sphincter mechanism at the bladder neck as a result of pressure necrosis (3, 64). Series that use immediate urethral realignment with minimal traction without suture repair bolsters report the most favourable results (Table 11). Endoscopic primary realignment fulfils these criteria and should be used when a primary procedure is contemplated. Open primary realignment in the absence of bladder neck injury or rectal injury has no place in the treatment of posterior urethral injuries because of its higher morbidity. Table 11: Results of immediate realignment in complete urethral disruption (68, 70, 72, 74, 77-91) Series

Ref.no.

No. of patients

Gibson (1974)

77

35†

Crassweller et al. (1977)

78

38

Malek et al. (1977)‡

79

7

Gelbard et al. (1989)

72

7

Cohen et al. (1991)

80

4

Melekos et al. (1992)

81

4

Follis et al. (1992)

68

20

El-Abd (1995)

82

44

Gheiler and Frontera (1997) Londergan et al. (1997)

83

3

84

4

Elliott and Barrett (1997) Porter et al. (1997)

85

53

70

10

Rehman et al. (1998)

86

3

Sahin et al. (1998)

87

5

Tahan et al. (1999)

88

13

Jepson et al. (1999)

89

8

Asci et al. (1999)

90

20

Ying-Hao et al. (2000)

91

4

Moudouni et al. (2001)

92

23

Mouraviev et al. (2005)

74

57

Total

362

Follow-up months (range) n/a – (24-240) 168 (96-264) 10.2 (2-24) 28 (17-35) n/a 42 (1-360) n/a 6 (5-9) 20.2 (12-35) 126 (1->120) 10.9 (2-31) – (11-26) 31 (21-53) 29 50.4 (35-85) 39 (19-78) 56 (39-85) 68 (18-155) < 24 (2-15)

Erectile Incontincence dysfunction 12 (34%) 19/42 (45%) 0

1 (3%) n/a

1/6 (16.7%) 2 (50%) 0

0

4 (20%) 35 (79.5%) 0

2 (10%) 0

1 (25%) 11 (21%) 1/7 (14%) 1 (16.7%) 1 (20%) 3 (23%) 3 (37.5%) 4 (20%) 0

0

4/29 (14%) 19/57 (34%) 130/368 (35.3%)§

0

0 0

0

2 (3.8%) 0 0 1 (20%) 0 1 (12.5%) 2 (10%) 0 0 10/57 (10%) 19/362 (5.2%)

Restricture rate 26 (74.3%) 12 (31.6%) 1 (14.3%) 2 (33%) 2 (50%) 4 (100%) 12 (60%) 44 (100%) 1 (33.3%) 3 (75%) 36 (68%) 5 (50%) 2 (66.7%) 4 (80%) 5 (38.5%) 5 (62.5%) 9 (45%) 1 (25%) 16 (69.5%) 28/57 (49%) 218/362 (60.2%)

*Stricture that requires internal urethrotomy, or open urethroplasty, or more than one dilatation; patients with partial rupture; ‡children; §some partial ruptures included. †5

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This type of summary of the literature suggests that immediate realignment is associated with an impotence rate of approximately 35%, an incontinence rate of 5% and a restricture rate of 60%. 5.3.2.4 Immediate open urethroplasty Immediate open urethroplasty of posterior injuries is not indicated because of poor visualisation and the inability to assess accurately the degree of urethral disruption during the acute phase, characterised by extensive swelling and ecchymosis. The difficulty in identifying structures and planes hampers adequate mobilisation and subsequent surgical apposition (24). Incontinence and impotence rates are higher than with the other techniques described in these guidelines (impotence 56%, incontinence 21%, restricture 49%) (6, 29, 48, 62, 65, 93, 94). However, in posterior urethral injuries associated with concomitant bladder neck or rectal injuries, immediate open exploration, repair and urethral realignment over a catheter is advisable (29, 40, 64-66). In children, similar results have been reported with delayed repair and immediate open urethroplasty (63). 5.3.2.5 Delayed primary urethroplasty Delayed primary urethroplasty is mainly indicated in female urethral disruption, although no large series exists. It requires placement of a suprapubic tube at the time of initial injury, with repair undertaken when the patient is stable, usually within 7 days. Fewer than 50 cases have been reported, and most of these are individual case reports only (12). Delayed primary repair tries to preserve as much urethral length as possible, and to avoid the urethra becoming embedded in dense scar tissue with consequent incontinence. Surgical exploration should be attempted via the retropubic route for proximal injuries, and the vaginal route for distal injuries (29). 5.3.2.6 Delayed urethroplasty Delayed urethroplasty is the procedure of choice and the gold standard for the treatment of posterior urethral distraction defects. Most posterior urethral distraction defects are short, and these can generally be resolved by a perineal approach anastomotic repair, provided that they are not associated with extensive haematoma-fibrosis and the bladder neck mechanism is occlusive and competent. After division of the bulbar urethra at the distal point of obliteration, mobilisation of a normal bulbar urethra to the base of the penis generally achieves 4-5 cm of elastic lengthening. This is usually sufficient to achieve a tension-free 2 cm spatulated overlap anastomosis, after bridging a gap of 2.0-2.5 cm without rerouting (24). This technique has the advantage that associated injuries, damaged skin and tissues, and pelvic haematoma have resolved by the time it is performed. The only problem with this approach would be the length of time that the patient must have a suprapubic catheter in place before definitive treatment. When the prostatobulbar gap is longer than 2-3 cm as a result of a high dislocation of the prostate, or when the available elongation of the mobilised urethra has been foreshortened by damage caused by a previous surgical procedure, additional procedures may be required. The following manoeuvres are carried out sequentially to gain sufficient anterior urethral mobility to bridge up to 8 cm of separation, and are referred to as the ‘progressive perineal approach’ (95): • midline separation of the proximal corporal bodies • inferior pubectomy • supracorporal urethral rerouting. In addition to its use as an initial therapy for posterior urethral distraction injuries, the progressive perineal approach can also be applied successfully to salvage procedures following failed repair. There is a number of circumstances that might preclude successful perineal anastomotic repair as either initial or salvage therapy. These circumstances probably represent fewer than 5% of cases and are shown in Table 12 (96, 97).

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Table 12: C  ircumstances that might preclude successful perineal anastomotic repair as either initial or salvage therapy (96, 97) Circumstance Distraction defects longer than 7-8 cm

Fistulae Synchronous anterior urethral stricture Urinary incontinence

Alternati ve procedure A tubed interposition flap of penile or peri-neoscrotal skin can be used for reconstruction. This is seldom required and most patients that require the use of flap urethroplasties have previous failed repairs of posterior urethral rupture (see section 4.3.2.7). These might require a combined abdominoperineal approach to secure adequate closure. The presence of anterior urethral stricture may compromise the blood supply to the bulbar urethra following division of the bulbar arteries, and these patients should be treated cautiously. The distal urethral sphincter mechanism could be defunctionalised by urethral distraction, so urinary continence may be maintained primarily by the proximal bladder neck sphincter. Concomitant bladder neck injury might increase incontinence, and could require an abdominoperineal procedure to allow simultaneous bladder neck and urethral reconstruction. The most common cause of bladder neck incompetence is the circumferential tethering of the uninjured bladder neck by scarring. In such cases, it is usually possible to restore functional competence of the bladder neck by mobilising it meticulously. This can be accomplished by removal of the dense haematomafibrosis anchoring the bladder neck to the pubis, anteriorly and laterally. Secondary rescarring is prevented by placement of a local omental flap (44, 98).

The results of various techniques are reviewed by Koraitim (66) in a personal series of 100 patients combined with a review of 771 patients from published reports. Immediate and early realignment (n = 326) was associated with rates of 53% for stricture, 5% for incontinence, and 36% for impotence. Of the patients successfully managed with immediate realignment, 42% needed subsequent instrumentation to attempt stabilisation of stricture. Urethroplasty was ultimately necessary in 33%. Primary suturing (n = 37) was associated with rates of 49% for stricture, 21% for incontinence, and 56% for impotence. In comparison, inserting a suprapubic catheter before delayed repair (n = 508) was associated with rates of 97% for stricture, 4% for incontinence, and 19% for impotence. The restricture rate after delayed anastomotic urethroplasty was less than 10% (28, 38, 43, 51, 55, 99-102), and the risk of impotence caused by delayed urethroplasty was about 5% (37, 51, 55, 56, 65, 103-105). The gold standard remains delayed urethral repair at a minimum of 3 months after trauma, using a one-stage perineal approach. The results obtained in children are similar to those in adults. The higher incidence of abdominal surgery simply reflects the greater propensity to damage of the bladder neck in children (105-106). 5.3.2.7 Reconstruction of failed repair of posterior urethral rupture Restenosis after delayed urethral repair mostly occurs within 6 months. If the anastomosis has a normal calibre at 6 months, then it is extremely unlikely that the patient will develop further stricturing (38). The principles of salvage repair are similar to those of the initial procedure. Progressive perineal anastomotic repair alone can be successful in 85% of salvage urethroplasties. If an anastomotic repair cannot be performed, a one-stage substitution urethroplasty using a pedicle island of penile skin might be possible and could be more desirable than the final alternative, a two-stage scrotourethral inlay procedure or mesh splitthickness skin graft urethroplasty (63, 107, 108). The main indications for a combined abdominoperineal surgical approach are: • the presence of fistulous tracts to the bladder base, abdominal wall or rectum • peri-urethral epithelialised cavities • an ability to achieve the lithotomy position (97).

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Restenosis to a luminal calibre of 12 French Foley catheter or smaller is required before a reduction in the urinary flow is perceived as abnormal (109). A wide calibre stricture may be observed or gently dilated. Optical urethrotomy is an alternative, particularly for a short, narrow stricture. 5.3.2.8 Delayed endoscopic optical incision The principles of the procedure were described by Sachse in 1974 (109). A curved metal sound is passed through the suprapubic cystostomy into the blind-ended proximal urethra. The direct vision urethrotome is inserted into the urethra, and cuts are made towards the sound. Blandy described a modification of this procedure: suprapubic passage of a cystoscope for transillumination of the thin perineal membrane and transurethral ‘cutting-to-the-light’ with an electrode (110). Today, the cutto-the-light technique is sometimes carried out using C-arm fluoroscopy for stereotactic guidance. The urethral catheter is left in place for between 1 and 3 weeks, and the suprapubic drainage for an additional 2 weeks to confirm consistent voiding (111). The results of several small series have been reported and are summarised in Table 13. Table 13: Results of optical urethrotomy for traumatically obliterated pelvic urethra (82, 112-116, 118-123) Series

Ref. no.

n

Gupta and Gill (1986)

112

10

Chiouet et al. (1988)

113

8

Marshall (1989)

114

10

Barry (1989)

115

12

DeVries and Anderson (1990)

116

4

Kernohan et al. (1990)

118

7

Yasuda et al. (1991)

119

17

Quint and Stanisic (1993)

120

10

82

284

Goel et al. (1997)

121

13

Levine and Wessells (2001)

122

6

Dogra and Nabi (2002)*

123

61

El-Abd (1995)

Total

445

Follow-up No. (%) requiring repeat months (range) urethrotomy 15.1 10 (6-24) (100%) 43 7 (12-79) (87.5%) n/a 10 (100%) 22 6 (1.5-85) (50%) 3 days). These patients suffer from a higher rate of orchiectomy than acutely-operated patients, even in nonruptured testis (10, 22, 29, 60, 61). Early surgical intervention resulted in > 90% preservation of the testis whereas delayed surgery necessitates orchiectomy in 45-55% (22). Additionally, non-operative management is associated with prolonged hospital stays. Large hematocoles should be treated surgically, irrespective of testicle contusion or rupture. At the very least, the blood-clot should be evacuated from the tunica vaginalis sac to relieve disability and hasten recovery. Patients initially treated nonoperatively may need delayed surgery if they develop

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update march 2009

infection or undue pain. In testicular rupture, surgical exploration with excision of necrotic testicular tubules and closure of the tunica albuginea is indicated. This results in a high rate of testicular preservation and normal endocrine function. Traumatic dislocation of the testis is treated by manual replacement and secondary orchidopexy. If primary manual reposition cannot be performed, immediate orchidopexy is indicated. 6.5.2.2 Penetrating trauma Penetrating injuries to the scrotum require surgical exploration with conservative debridement of non-viable tissue. Depending on the extent of the injury, primary reconstruction of testis and scrotum can be performed in most cases. In complete disruption of the spermatic cord, realignment without vaso-vasostomy may be considered if surgically feasible (62). Staged secondary microsurgical vaso-vasostomy can be performed after rehabilitation, although there are only a few cases reported (62). If there is extensive destruction of the tunica albuginea, mobilization of a free tunica vaginalis flap can be performed for testicular closure. If the patient is unstable or reconstruction cannot be achieved, orchiectomy is indicated. Prophylactic antibiotics are recommended by experts after scrotal penetrating trauma, although data to support this approach is lacking. Tetanus prophylaxis is mandatory. Postoperative complications were reported in 8% of patients who underwent testicular repair after penetrating trauma (13). Extended laceration of scrotal skin requires surgical intervention for skin closure. Due to the elasticity of the scrotum, most defects can be primarily closed, even if the lacerated skin is only minimally attached to scrotum (29). Local wound management with extensive initial wound debridement and washout is important for scrotal convalescence. 6.5.3 Vulvar injuries Blunt trauma to the vulva is rare and commonly present as a large haematoma. However, in contrast to men, blunt vulvar or perineal trauma may be associated with voiding problems. Bladder catheterization will usually be required. Vulvar haematomas usually do not require surgical intervention, although they can cause significant blood loss, even requiring red blood cell transfusions. Data are scarce (25-27, 44), but in haemodynamically stable women, non-steroidal anti-inflammatory medication and cold packs are used. In massive vulvar haematoma or haemodynamically unstable patients, surgical intervention, lavage and drainage is indicated (63). Antibiotics are recommended by experts after major vulvar trauma, but data supporting this approach are lacking. It is important to emphasize that vulvar haematoma and/or blood at the vaginal introitus are an indication for vaginal exploration under sedation or general anaesthesia in order to identify possible associated vaginal and/or rectal injuries (44). In case of vulvar laceration, suturing after conservative debridement is indicated. If there are associated injuries to the vagina, these can be repaired immediately by primary suturing. Additional injuries to the bladder, rectum or bowel may require laparotomy for closure. The rectal injuries may also require colostomy.

6.6 REFERENCES 1.

2. 3.

4.

5.

6.

7.

Brandes SB, Buckman RF, Chelsky MJ, Hanno PM. External genitalia gunshot wounds: a ten-year experience with fifty-six cases. J Trauma 1995;39(2):266-71. http://www.ncbi.nlm.nih.gov/pubmed/7674395 Marekovic Z, Derezic D, Krhen I, Kastelan Z. Urogenital war injuries. Mil Med 1997;162(5):346-8. http://www.ncbi.nlm.nih.gov/pubmed/9155106 Salvatierra O Jr, Rigdon WO, Norris DM, Brady TW. Vietnam experience with 252 urological war injuries. J Urol 1969;101(4):615-20. http://www.ncbi.nlm.nih.gov/pubmed/5776049 Tucak A, Lukacevic T, Kuvezdic H, Petek Z, Novak R. Urogenital wounds during the war in Croatia in 1991/1992. J Urol 1995;153(1):121-2. http://www.ncbi.nlm.nih.gov/pubmed/7966742 Archbold JA, Barros d’sa AA, Morrison E. Genito-urinary tract injuries of civil hostilities. Br J Surg 1981;68(9):625-631. http://www.ncbi.nlm.nih.gov/pubmed/7272689 Tiguert R, Harb JF, Hurley PM, Gomes De Oliveira J, Castillo-Frontera RJ, Triest JA, Gheiler EL. Management of shotgun injuries to the pelvis and lower genitourinary system. Urology 2000;55(2): 193-7. http://www.ncbi.nlm.nih.gov/pubmed/10688077 Cline KJ, Mata JA, Venable DD, Eastham JA. Penetrating trauma to the male external genitalia. J Trauma 1998;44(3):492-4 . http://www.ncbi.nlm.nih.gov/pubmed/9529176

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8.

9.

10. 11.

12.

13.

14.

15. 16.

17. 18.

19.

20. 21.

22. 23. 24. 25.

26.

27.

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7. MASS CASUALTY EVENTS, TRIAGE AND DAMAGE CONTROL 7.1 Definition A mass casualty event is one in which the number of injured people is significantly higher than the number of healthcare providers available (1). A mass casualty disaster does not therefore necessarily involve a large number of victims, but is related to the disproportion between the number of victims and the size of the medical team available (2, 3). There is little published data on how best to handle these events.

7.2

Causes of mass casualty events

Potential mass casualty events include: • The collapse of buildings or bridges • earthquakes • floods • tsunamis • train collisions • aircraft catastrophes • civilian terrorism.

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Most mass injury caused by civilian terrorism is caused by explosions. The combined effects of blast, shrapnel, bomb projectiles and burns result in multiple penetrating injuries involving several body systems and unpredictable degrees of damage.

7.3

Mechanisms of explosive injury

The mechanism of injury in explosions is divided into three phases: • Primary blast injury: this is caused by the powerful shock wave that spreads from the site of the explosion. The most commonly injured organs are those containing air (lungs and ears), but any tissue can be damaged by the pressure wave passing through the body. Urogenital injuries as a direct result of primary blast have not been described in survivors of blast injuries. • Secondary blast injury: this is produced by the debris and projectiles set in motion by the explosion. Penetrating injuries to the urogenital system, as to any organ, have been described. • Tertiary injury: this occurs when the victim displaced by the blast wave hits a fixed object. An acceleration-deceleration mechanism produces severe injuries to organs, large blood vessels and bones. Blunt renal, ureteral and bladder injuries are induced by this mechanism. The patterns and severity of injury after explosions differ according to the location of the event. Explosions in confined spaces (e.g. buildings or buses) are more devastating than those that occur in open spaces because of amplification of the blast wave by reflection, and structural collapse, which can cause further injury.

7.4

Triage

Triage after mass casualty events is difficult, controversial, and full of difficult ethical and moral questions. Disaster triage requires one to differentiate the few critically injured that can be saved by immediate intervention from the many with non-life-threatening injuries for whom treatment can be delayed. Triage divides patients into four groups (4, 5): 1. Patients with life-threatening injuries that require immediate intervention, presenting with Airway compromise, Breathing failure and/or Circulatory compromise from ongoing external haemorrhage. 2. Patients with severe but non-life-threatening injuries, in whom treatment can be acceptably delayed: major fractures, vascular injuries of the limbs and large soft tissue wounds. 3. ‘Walking wounded’ with minimal injuries. 4. Patients who are so severely injured that treatment would require allocation of resources and time that would deny other, more salvageable patients, timely care. These patients are given minimal or no treatment, and re-evaluated when resources become available. There is no absolute definition for this group because triage is individualised according to the number and severity of casualties related to the available resources. Triage contradicts the everyday principles of care, in which the goal is maximal and optimal care for every individual patient. Triage is necessary in mass casualty scenarios because of the need to provide effective treatment to the maximum number of salvageable patients within the limited resources. 7.4.1 Primary triage Primary triage begins when trained medical teams arrive at the event. It is concerned with the initial stabilisation and rapid evacuation of the prioritised victims to the nearest hospital. 7.4.2 Secondary triage Secondary triage begins at the medical facility that is receiving the mass casualties. The most experienced trauma surgeon who is not taking part in surgical or resuscitation procedures performs triage. 7.4.3 Re-triage Re-triage is performed frequently. After all the victims have undergone triage, the senior surgeon repeats triage and reclassifies patients as necessary. Repeat triage is important. It avoids under-triage, which results in serious injury being missed, or over-triage, which results in some patients being assigned for immediate care when in fact they do not have critical injuries. The surgeon in charge is responsible for directing specialty surgical consultants, including urologists, and assigning them responsibility for specific patients as dictated by the specific injuries.

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7.5

Principles of ‘damage control’

Damage control is a prioritised three-phase approach to patients with major injuries (6). The first phase consists of rapid control of haemorrhage, wound contamination, and faecal spillage using simple measures and temporary abdominal closure. The second phase is resuscitation in the intensive care unit (ICU), with the goal of restoring normal temperature, coagulation, perfusion and oxygenation of tissues. Then, in the third stage, definitive surgery and abdominal wall closure is performed in stable patients. Damage control is a life-saving strategy for patients with multiple injuries that has been adopted by trauma surgeons as a result of the observation that such patients often die from hypothermia, coagulopathy, and acidosis-induced physiological insults (7, 8, 9). In unstable patients, extensive and time-consuming reconstructive procedures could further destabilise the patient beyond recovery. Identifying those critically injured patients who are candidates for damage control is difficult. The most senior trauma surgeon should make the decisions, in co-operation with other specialist surgeons. Damage control principles have also been successfully adopted in the context of civilian mass casualty events, military field surgery, and initial treatment in rural areas with long-range transfers (9, 10).

7.6 Urological aspects of ‘damage control’ In events involving mass casualties, the principles of triage and damage control are the same. Damage control can theoretically lower the mortality rates by allowing a limited number of qualified personnel to treat more patients. Urologists are frequently consulted in patients with multiple injuries, and should be familiar with the damage control approach. Damage control is well suited to urological trauma, and should result in more efficient interaction with the trauma team, improved patient survival and lower morbidity. In fact, because urological surgery is often elective, management of urological trauma has traditionally consisted of temporary measures followed by definitive surgery later on, which meshes well with modern damage control principles (8). It is important to be aware of damage control opportunities, and to maximise the quality of care with creative improvisation. 7.6.1 The urological consultation in the emergency room during mass casualty events 7.6.1.1 Responsibility and primary overall assessment After primary assessment and triage by the surgeon in charge, a urological consultation might be required for patients triaged to groups 2 (severe but not immediately life-threatening injuries) and 3 (‘walking wounded’ with mild injuries). The urologist might even become primarily responsible for these patients if they are stable and have few other injuries. It is important to remember that under-triage can happen during a mass casualty event. A complete re-assessment of the patient assigned must therefore be performed, paying attention to the whole body so as to detect previously unnoticed injuries. This assessment should be quick but comprehensive. Conduct a rapid ABCDE survey (Airway, Breathing, Circulation, Disability or neurological status, Exposure) as dictated by advanced trauma life support (ATLS) principles (3). Urological care should begin only after the patient is cleared for the presence of other injuries. 7.6.1.2 Imaging Evaluation of patients with penetrating and blunt abdominal or pelvic trauma usually includes imaging procedures such as contrast computed tomography (CT) scans or retrograde cystourethrography (11, 12). However, when mass casualty protocols are instituted, decisions on care must be made with a minimum of imaging procedures. In those situations, create a unidirectional flow of patients in order to avoid the bottleneck that usually occurs in imaging departments. The ‘normal’ pattern of sending patients for imaging and then returning them to the accident and emergency department for re-evaluation may not be feasible. 7.6.1.3 Primary management Following initial primary evaluation, there are several possible scenarios: 1. Haemodynamically unstable patients with suspected intra-abdominal bleeding are transferred urgently to the operating theatre without any pre-operative imaging. 2. Stable patients with suspected renal injuries (penetrating trauma to the upper abdomen/flanks/ lower chest, blunt abdominal trauma and gross haematuria) should have delayed imaging once the

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protocols of mass casualties are cancelled, or when resources become available. These patients should be transferred to surgical wards and re-evaluated by the urologist as soon as possible. 3. Patients with suspected bladder or urethral injuries (pelvic fractures, high riding prostate on rectal examination, blood at the urethral meatus and/or inability to void) need to undergo imaging of the lower urinary tract, but this is not urgent as these injures are not considered life-threatening (13). 4. In cases of suspected urethral injuries, the ‘minimal acceptable treatment’ will be one gentle trial of catheterising the bladder or insertion of a suprapubic cystostomy, followed by transfer of the patient to the surgical ward for later evaluation (14). 5. Bladder injuries following blunt or penetrating trauma are usually associated with other severe injuries (15) and thus require a prioritising surgical approach. The first priority in this scenario is the treatment of the associated life-threatening injuries. Bladder drainage is a sufficient first measure, but should be followed by delayed evaluation aiming to obtain accurate diagnosis and to distinguish between intraperitoneal and extraperitoneal bladder rupture. 6. Blunt injuries of the external genitalia are often isolated and can be managed conservatively. On the other hand, penetrating injuries of the genitalia are often associated with injuries of adjacent abdominal organs and haemodynamic instability (7). In mass casualty scenarios, external genital injuries should be operated on only if they have resulted in major haemorrhage. Surgery can be performed in the operating theatre or in a well-equipped shock room in the accident and emergency department. Compression dressings, or clamping/ligation of bleeding vessels are highly efficient manoeuvres that require a minimum of time. When severe haemorrhage is not present, any further diagnostic steps can be postponed. The patient can be transferred to the surgical ward for later re-evaluation followed by delayed reconstruction. Urological consultations during a mass casualty scenario should be performed according to the following principles: 1. Rule out under-triage by the surgeon in charge, and perform a rapid primary survey of every patient. 2. Avoid unnecessary imaging procedures such as CT scans and retrograde urethrography. These procedures should be performed later, after re-evaluation of the patient, and after mass casualty protocols have been suspended. 3. Treat unstable patients who are to have surgery using damage control principles. 4. Stable patients with suspected renal injuries should be transferred to the surgical ward without imaging procedures. Re-evaluate if there is any change in their haemodynamic status, or when possible as dictated by the constraints of the mass casualty event. Patients managed in this delayed fashion should be treated according to traditional trauma management protocols. 5. ‘Minimal acceptable’ procedures should be performed in order to transfer patients to the surgical wards, e.g. suprapubic drainage of the bladder when bladder or urethral injuries are suspected, clamping and ligation of bleeding vessels from wounds to the external genitalia, etc. 7.6.2 The urological consultation in the operating room during mass casualty events During emergency laparotomy, urologists are usually present in the operating theatre along with the general surgeons. During mass casualty events, the principle of ‘minimum acceptable intervention’ for the ‘maximum salvageable outcome’ applies. Procedures should be directed at the rapid control of active bleeding, and management of urinary extravasation by simple diversion measures. Complex and time-consuming reconstructive procedures should be delayed whenever possible. 7.6.2.1 Renal trauma The ultimate goal of all renal exploration in the setting of major traumatic renal injury is to control lifethreatening bleeding and to preserve the maximal amount of viable renal parenchyma (16). Renal reconstruction might be too time-consuming in the context of an unstable, multiply injured patient, or in the scenario of mass casualties in which the operating theatre should not be occupied by time-consuming reconstructive procedures (17). Whenever major active haemorrhage of renal origin can be ruled out, it is best not to explore the injured kidney, even if a secondary delayed laparotomy will eventually be needed (18). In unstable patients, packing the renal fossa with laparotomy pads and transferring the patient to the surgical ICU is best. Later, a planned second-look laparotomy is better than time-consuming reconstruction (19).

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Alternatively, especially in briskly bleeding patients, speedy nephrectomy may be required. Haemostatic techniques, many of which were developed for hepatic surgery and splenic trauma, can be used to control renal parenchymal bleeding (20): • mattress sutures through the parenchyma (renorrhaphy), similar to the sutures used in extensive hepatorrhaphy (7) • packing with dry folded laparotomy pads as described for peri-hepatic tamponade (7) • Fibrin hemostatic agents, may be used to control bleeding. • absorbable mesh kidney bags maintain renal parenchymal fragments in contact with each other and ensure lasting haemostasis (21) • urinary extravasation may be ignored during the acute phase; acutely, urine leak will be drained by intraoperatively placed drains; defer ureteral stents or percutaneous nephrostomies • the abdomen is temporarily closed with towel clips or other measures. Following urgent primary exploration, patients should be carefully monitored in an ICU. When they are sufficiently stable, begin radiological assessment of their injuries and plan their definitive operative management accordingly. Delayed imaging is obtained by CT scan. If the extent of renal injury has not been clearly defined at the initial laparotomy (by choosing not to explore the retroperitoneal haematoma), a CT scan performed before the second laparotomy can help in decision-making. CT allows the existence and function of the contralateral kidney to be documented, the kidney injury to be graded according to traditional protocols, and a clinical plan to be created, which will then determine the selection of operative or non-operative management of the renal trauma, and whether nephrectomy or reconstruction is to be attempted. In patients who are haemodynamically unstable after the initial acute damage control laparotomy, or in patients with deteriorating haemodynamic parameters (indicating ongoing or delayed bleeding), the management options are angiographic embolisation of the bleeding kidney or re-operation. This decision should be made according to several factors: • the general status of the patient • the presence of associated injuries that have been treated according to damage control principles (bowel injuries, packed liver, or splenic injuries) and that need re-operation irrespective of the renal injury • the availability of angiography. 7.6.2.2 Ureteral injuries Although excellent results can be achieved with acute ureteral reconstruction, the surgery is time-consuming and might not be appropriate in the mass casualty setting. During mass casualty events, diagnostic procedures such as the intraoperative injection of indigo carmine, intraoperative intravenous pyelography (IVP) or retrograde ueretropyelography that are intended to evaluate ureteral injuries should be discouraged. If a ureteral injury is suspected but not clearly identified, a drain may be left in place. If urine leaks, a nephrostomy tube can be placed post-operatively. If a partial ureteral tear is identified (less than half circumference) and the ureter looks viable, a double J-stent may be inserted over a guide wire through the tear, and the tear quickly closed with interrupted absorbable stitches. When complete ureteral injuries are identified, definitive repair should not be performed. Dissection of the ureteral stumps should be avoided as it interferes with the blood supply. Instead: • place a single J or 8 French feeding tube into the ureter • tie the distal end of the ureter over the tube • exteriorise it through a small stab incision • tie it to the skin. The distal ureteral stump does not need to be ligated, and any unnecessary manipulation should be avoided. Tying off the injured ureteral segment and inserting a percutaneous nephrostomy post-operatively (22, 23) is a viable alternative, but is not the procedure of choice.

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In rare, selected cases, nephrectomy is required to treat ureteral injury, but only in cases of severe associated injuries of the ipsilateral kidney (24). Ureteral injuries are rarely life-threatening and should be addressed only after other injuries have been attended to. In an unstable patient, temporary measures to control urine spillage should be performed, for example: • tying off of the injured ureteral segment and post-operative insertion of percutaneous nephrostomy (15, 19) • placement of a single J or feeding tube into the ureter, tying the distal end of the ureter over the tube and exteriorising it (15, 19, 23). Intraoperative placement of a nephrostomy tube is time-consuming and should be avoided (15, 19). 7.6.2.3 Bladder injury Bladder injuries should be classified, when time and resources allow, as extraperitoneal or intraperitoneal. Extraperitoneal injuries can usually be managed with bladder drainage alone. Intraperitoneal injuries require surgical exploration and layered closure of the bladder wall (13). The degree to which penetrating bladder injury can be treated non-surgically is not known. However, non-surgical management of iatrogenic bladder injuries has been reported, and could be effective after penetrating injury (11, 19). 7.6.2.3.1 Auxiliary damage control measures Examples of auxiliary damage control measures that could be applicable include: • the placement of externalised ureteral stents can provide external urinary drainage in extensive bladder rupture (19) • packing or arteriography and selective embolisation can be applied in cases of bladder haemorrhage in patients who are unsuitable for urgent pelvic exploration (13, 19) • the placement of a pelvic suction drain for urinary evacuation (19). 7.6.2.4 Urethral injury Urethral injury of any kind is never life-threatening per se, but the associated injuries might cause haemodynamic instability. The patient is usually seen by the urologist during an operation performed because of the other injuries. In this situation, no matter whether the urethral tear is posterior or anterior, partial or complete, drainage through a suprapubic or urethral catheter should be obtained without prior imaging. 7.6.2.5 Injury of the external genitalia Traumatic injuries of the external genitalia are much more common in men than in women, probably because of the anatomical differences (11, 25). Blunt injuries of the genitalia are usually isolated, and can be managed conservatively. Penetrating injuries of the genitalia are often associated with injuries of adjacent abdominal organs and related haemodynamic instability (12). In mass casualty events, both types of injury should be managed by watchful waiting. Urethral or testicular imaging and surgical exploration should be deferred. 7.6.2.5.1 Temporary damage control measures Temporary damage control measure that might be applicable include: • compression dressing of the penis • packing of penetrating testicular injuries • tampons for vulvar lacerations.

7.7 Summary • • •

 amage control surgery has become the standard approach in the management of unstable D patients, and is especially useful in a mass trauma event. Medical teams should be well prepared ahead of time to deal with mass casualty events. All surgical sub-specialists involved in trauma management should be very familiar with the principles of triage and damage control.

7.8 REFERENCES 1. 2. 3.

Slater MS, Trunkey DD. Terrorism in America. An evolving threat. Arch Surg 1997;132(10):1059-66 http://www.ncbi.nlm.nih.gov/pubmed/9336502 Caro D. Major disasters. Lancet 1974:30;2(7892):1309-10. http://www.ncbi.nlm.nih.gov/pubmed/4139541 Weighlt JA, Krantz BE, Ali J et al. Advanced Trauma Life Support Student Course Manual. American College of Surgeons Committee on Trauma, 6th edn. Chicago, 1997.

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Frykberg ER. Medical management of disasters and mass casualties from terrorist bombings: how can we cope?. J Trauma 2002;53(2):201-12. http://www.ncbi.nlm.nih.gov/pubmed/12169923 Jacobs LM Jr, Ramp JM, Breay JM. An emergency medical system approach to disaster planning. J Trauma 1979;19(3):157-62. http://www.ncbi.nlm.nih.gov/pubmed/458880 Rotondo MF, Schwab CW, McGonigal MD, Phillips GR 3rd, Fruchterman TM, Kauder DR, Latenser BA, Angood PA. ‘Damage control’: an approach for improved survival in exsanguinating penetrating abdominal injury. J Trauma 1993;35(3):375-82. http://www.ncbi.nlm.nih.gov/pubmed/8371295 Feliciano DV, Moore EE, Mattox KL. Trauma damage control. In: Mattox KL, Feliciano DV, Moore EE (eds). Trauma, 4th edn, New York: McGraw-Hill, 2000, Chapter 39, pp. 907-931. Hirshberg A, Mattox KL. ‘Damage control’ in trauma surgery. Br J Surg 1993;80(12):1501-2. http://www.ncbi.nlm.nih.gov/pubmed/8298911 Rignault DP. Recent progress in surgery for the victims of disaster, terrorism, and war--Introduction. World J Surg. 1992 Sep-Oct;16(5):885-7. http://www.ncbi.nlm.nih.gov/pubmed/1462624 Holcomb JB, Helling TS, Hirshberg A. Military, civilian and rural application of the damage control philosophy. Mil Med 2001;166(6):490-3. http://www.ncbi.nlm.nih.gov/pubmed/11413725 Lynch D, Martínez-Piñeiro L, Plas E, Serafetinidis E, Turkeri L, Santucci R, Hohenfellner M. Guidelines on urological trauma. European Association of Urology. Edition presented at the 23rd EAU Annual Congress, 2008, ISBN 978-90-70244-91-0 http://www.uroweb.org/files/uploadedfiles/guidelines/urotrauma.pdf Krieger JN, Algood CB, Mason JT, Copass MK, Ansell JS. Urological trauma in the Pacific Northwest: etiology, distribution, management and outcome. J Urol 1984;132(1):70-3. http://www.ncbi.nlm.nih.gov/pubmed/6726964 Pansadoro A, Franco G, Laurenti C, Pansadoro V. Conservative treatment of intraperitoneal bladder perforation during transurethral resection of bladder tumor. Urology 2002;60(4):682-4. http://www.ncbi.nlm.nih.gov/pubmed/12385934 Peterson NE. Genitourinary trauma, in Mattox KL, Feliciano DV, Moore EE (eds). Trauma, 4th edn, New York: McGraw-Hill, 2000, Chapter 37, pp. 839-79. McAninch JW, Santucci RA. Genitourinary trauma, In: Walsh PC., Retik AB, Darracott Vaughan E, Jr., Wein AJ (eds). In: Campbell’s Urology, 8th edn. Philadelphia: W.B. Saunders, 2002, Chapter 105, pp. 3707-3744. Brandes SB, McAninch JW. Renal trauma: a practical guide to evaluation and management. Digital Urology Journal. http://www.duj.com/Article/McAninch/McAninch.html Brandes SB, McAninch JW. Reconstructive surgery for trauma of the upper urinary tract. Urol Clin North Am 1999;26(1):183-99. http://www.ncbi.nlm.nih.gov/pubmed/10086060 Wessells H, McAninch JW, Meyer A, Bruce J. Criteria for nonoperative treatment of significant penetrating renal lacerations. J Urol 1997;157(1):24-7. http://4www.ncbi.nlm.nih.gov/pubmed/8976207 Coburn M. Damage control for urologic injuries. Surg Clin N Am 1997;77(4):821- 34. http://www.ncbi.nlm.nih.gov/pubmed/9291984 Shekarris B, Stoller ML. The use of fibrin sealant in urology. J Urol 2002;167(3):1218-25. http://www.ncbi.nlm.nih.gov/pubmed/11832701 Chaabouni MN, Bittard M. Application of peri-renal prosthesis (vicryl mesh) in the conservative treatment of multiple ruptured kidney fragments. Ann Urol 1996;30(2):61-3. http://www.ncbi.nlm.nih.gov/pubmed/8767808 Brandes S, Coburn M, Armenakas N, McAninch J. Diagnosis and management of ureteric injury: an evidence based analysis. BJU Int 2004;94(3):277-89. http://www.ncbi.nlm.nih.gov/pubmed/15291852 Best CD, Petrone P, Buscarini M, Demiray S, Kuncir E, Kimbrell B, Asensio JA. Traumatic ureteral injuries: a single institution experience validating the American Association for the Surgery of TraumaOrgan Injury Scale grading scale. J Urol 2005;173(4):1202-5. http://www.ncbi.nlm.nih.gov/pubmed/15758748

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25.

Hirshberg A, Wall MJ Jr, Mattox KL. Planned reoperation for trauma: a two year experience with 124 consecutive patients. J Trauma 1994;37(3):365-9. http://www.ncbi.nlm.nih.gov/pubmed/8083894 Van der Horst C, Martinez Portillio FJ, Seif C, Groth W, Jünemann KP. Male genital injury: diagnostics and treatment. BJU Int 2004;93(7):927-30. http://www.ncbi.nlm.nih.gov/pubmed/15142139

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8. ABBREVIATIONS USED IN THE TEXT This list is not comprehensive for the most common abbreviations AAST ATLS BT BUN CT DMSA EBRT ePTFE GR HIV hpf ICU IVP KUB MRI m/s PCNL rbc/hpf TOT TUR-P TVT

American Association for the Surgery of Trauma advanced trauma life support Transperineal, interstitial, permanent prostate brachytherapy blood urea nitrogen computed tomography dimercaptosuccinic acid External beam radiotherapy polytetrafluoroethylene grade of recommendation human immunodeficiency virus high-power field itensive care unit intravenous pyelography/pyelogram kidney-ureter-bladder magnetic resonance imaging metres per second percutaneous nephrolithotomy red blood cells per high-power field transobturator tape Transurethral resection of the prostate tension-free vaginal tape

Conflict of interest All members of the Urological Traume Guidelines writing panel have provided disclosure statements on all relationships that they have and that might be perceived to be a potential source of conflict of interest. This information is kept on file in the European Association of Urology Central Office database. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

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Guidelines on

Pain Management P. Bader (chair), D. Echtle, V. Fonteyne, G. De Meerleer, E.G. Papaioannou, J.H. Vranken

© European Association of Urology 2009

Table of Contents 1.

INTRODUCTION 1.2 Reference

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2 BACKGROUND 2.1 Definition of pain 2.2 What is suffering? 2.3 Nociception and innervation 2.4 Neuropathic pain 2.5 Innervation of the urogenital system 2.6 Pain evaluation and measurement 2.6.1 Pain evaluation 2.6.2 Assessing pain intensity and quality of life 2.7 References

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3 CANCER PAIN MANAGEMENT (General) 3.1 Classification of cancer pain 3.1.1 References 3.2 General principles of cancer pain management 3.3 Non-pharmacological therapies 3.3.1 Surgery 3.3.1.1 References 3.3.2 Radionuclides 3.3.2.1 Clinical background 3.3.2.2 Radiopharmaceuticals: physical characteristics 3.3.2.3 Indications and contraindications 3.3.2.4 Contraindications 3.3.2.5 References 3.3.3 Radiotherapy for metastatic bone pain 3.3.3.1 Clinical background 3.3.3.2 Mechanism of pain relief by radiotherapy 3.3.3.3 Imaging 3.3.3.4 Radiotherapy scheme 3.3.3.5 Spinal cord compression 3.3.3.6 Pathological fractures 3.3.3.7 Side-effects 3.3.3.8 References 3.3.4 Physical/psychological therapy 3.3.4.1 Physical therapies 3.3.4.2 Psychological therapies 3.4 Pharmacotherapy 3.4.1 Antibiotics 3.4.2 Chemotherapy 3.4.3 References 3.4.4 Bisphosphonates 3.4.4.1 Mechanisms of action 3.4.4.2 Effects and side-effects 3.4.4.3 References 3.4.5 Systemic analgesic pharmacotherapy- the ‘analgesic ladder’ 3.4.5.1 Non-opioid analgesics 3.4.5.2 Opioid analgesics 3.4.5.2.1 O  pioid administration Non-invasive routes Invasive routes Dosing 3.4.5.2.2 Adverse effects and their management 3.4.5.2.3 Adjuvant analgesics 3.4.5.2.4 References

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3.4.5.3 3.4.5.4

Treatment of neuropathic pain 3.4.5.3.1 Antidepressants 3.4.5.3.2 Anticonvulsant medication 3.4.5.3.3 Topical analgesics 3.4.5.3.4 NMDA receptor antagonists 3.4.5.3.5 Other drug treatments 3.4.5.3.6 Summary treatment of neuropathic pain Invasive analgesic techniques 3.4.5.4.1 Peripheral nerve catheterisation in the management of cancer pain 3.4.5.4.2 Neurolytic blocks to control visceral cancer pain 3.4.5.4.3 Epidural and intrathecal opioid application 3.4.5.4.4 Chemical rhizotomy 3.4.5.4.5 Cordotomy 3.4.5.5 References 3.5 Quality of life 3.5.1 Conclusions 3.5.2 References 4 PAIN MANAGEMENT IN UROLOGICAL CANCERS 4.1 Pain management in prostate cancer patients 4.1.1 Clinical presentation 4.1.2 Pain due to local impairment 4.1.2.1 Invasion of soft tissue or a hollow viscus 4.1.2.2 Bladder outlet obstruction 4.1.2.3 Ureteric obstruction 4.1.2.4 Lymphoedema 4.1.2.5 Ileus 4.1.3 Pain due to metastases 4.1.3.1 Bone metastases 4.1.3.1.1 Hormone therapy 4.1.3.1.2 Side-effects 4.1.3.1.3 Efficacy 4.1.3.1.4 Problems 4.1.3.1.5 Radiotherapy 4.1.3.1.6 Orthopaedic surgery 4.1.3.1.7 Radioisotopes 4.1.3.1.8 Bisphosphonates 4.1.3.1.9 Calcitonin 4.1.3.1.10 Chemotherapy 4.1.4 Systemic analgesic pharmacotherapy (the ‘analgesic ladder’) 4.1.5 Spinal cord compression 4.1.6 Hepatic invasion 4.1.7 Pain due to cancer treatment 4.1.7.1 Acute pain associated with hormonal therapy Luteinising hormone-releasing hormone (LHRH) tumour flare in prostate cancer 4.1.7.2 Chronic pain associated with hormonal therapy Gynaecomastia 4.1.8 Conclusions 4.1.9 Recommendations at a glance (stage M1) 4.1.10 References 4.2 Pain management in transitional cell carcinoma patients 4.2.1 Clinical presentation 4.2.2 Origin of tumour-related pain 4.2.3 Pain due to local impairment 4.2.4 Pain due to metastases 4.2.5 References 4.3 Pain management in renal cell carcinoma patients

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4.3.1 Clinical presentation 4.3.2 Pain due to local impairment 4.3.3 Pain due to metastases 4.3.4 References 4.4. Pain management in patients with adrenal carcinoma 4.4.1 Malignant phaeochromocytoma 4.4.2 Treatment of pain 4.4.2.1 Adrenocortical carcinomas 4.4.2.2 Treatment of the pain depending on its origin 4.4.3 References 4.5 Pain management in penile cancer patients 4.5.1 Clinical presentation 4.5.2 Pain due to local impairment 4.5.3 Lymphoedema 4.5.4 Pain due to metastases 4.5.5 Conclusions 4.5.6 References 4.6. Pain management in testicular cancer patients 4.6.1 Clinical presentation 4.6.2 Pain due to local impairment 4.6.3 Pain due to metastases 4.6.4 References 4.7. Recommendations at a glance 5 POST-OPERATIVE PAIN MANAGEMENT 5.1 Background 5.2 The importance of effective post-operative pain management 5.2.1 The aims of effective post-operative pain management 5.3 Pre- and post-operative pain management methods 5.3.1 Pre-operative patient preparation 5.3.2 Pain assessment 5.3.3 Pre-emptive analgesia 5.3.4 Systemic analgesic techniques 5.3.4.1 Non-steroidal anti-inflammatory drugs (NSAIDs) 5.3.4.2 Paracetamol Combinations of paracetamol with opiods 5.3.4.3 Metamizole (dipyrone) 5.3.4.4 Opioids 5.3.4.5 Patient-controlled analgesia 5.3.4.6 Fentanyl 5.3.4.7 Opioid equi-analgesic doses 5.3.5 Regional analgesic techniques 5.3.5.1 Local anaesthetic agents 5.3.5.2 Epidural analgesia 5.2.5.3 Patient-controlled epidural analgesia (PCEA) 5.3.5.4 Neural blocks 5.3.5.5 Wound infiltration 5.3.5.6 Continuous wound instillation 5.3.6 Multi-modal analgesia 5.3.7 Special populations 5.3.7.1 Ambulatory surgical patients 5.3.7.2 Geriatric patients 5.3.7.3 Obese patients 5.3.7.4 Other groups 5.3.8 Post-operative pain management teams 5.4 Specific pain treatment after different urological operations 5.4.1 Extracorporeal shock wave lithotripsy (ESWL) 5.4.2 Endoscopic procedures 5.4.2.1 Transurethral procedures 5.4.2.2 Percutaneous endoscopic procedures

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5.4.2.3 Laparoscopic procedures 5.4.3 Open surgery 5.4.3.1 Minor operations of the scrotum/penis and the inguinal approach 5.4.3.2 Transvaginal surgery 5.4.3.3 Perineal open surgery 5.4.3.4 Transperitoneal laparotomy 5.4.3.5 Suprapubic/retropubic extraperitoneal laparotomy 5.4.3.6 Retroperitoneal approach – flank incision – thoracoabdominal approach 5.5 Dosage and method of delivery of some important analgesics 5.5.1 NSAIDs 5.5.2 NSAIDs with antipyretic effect 5.5.3 Selective COX-2 inhibitor 5.5.4. Opioids 5.6 References

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ABBREVIATIONS USED IN THE TEXT

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1. INTRODUCTION The European Association of Urology (EAU) Guidelines Group for Pain Management have prepared this guidelines document to assist medical professionals in appraising the evidence-based management of pain in urological practice. These guidelines include general advice on pain assessment, with a focus on treatment strategies relating to common medical conditions and painful procedures. No attempts have been made to exhaustingly cover the topic of pain. The multidisciplinary panel of experts responsible for this document includes three urologists, two radiotherapists and two anaesthesiologists. The recommendations provided in the current guidelines are based on a systemic literature search using Medline, the Cochrane Central Register of Controlled Trials, and reference lists in publications and review articles. Where possible a level of evidence (LE) and/or grade of recommendation (GR) have been assigned (1). Recommendations are graded in order to provide transparency between the underlying evidence and the recommendation given (Tables 1 and 2). It has to be emphasised that the current guidelines contain information for the treatment of an individual patient according to a standardised general approach. Publication history information: The Pain Management Guidelines were first published in 2003, with a partial update in 2007, followed by the current full text update. Additionally, a quick reference guide is available. All texts can be viewed and downloaded for personal use at the society website: http://www.uroweb.org/professional-resources/ guidelines/. Table 1: Level of evidence Level Type of evidence 1a Evidence obtained from meta-analysis of randomised trials 1b Evidence obtained from at least one randomised trial 2a Evidence obtained from one well-designed controlled study without randomisation 2b Evidence obtained from at least one other type of well-designed quasi-experimental study 3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case reports 4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities Modified from Sackett et al. (1). Table 2: Grade of recommendation Grade Nature of recommendations A Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomised trial B Based on well-conducted clinical studies, but without randomised clinical trials C Made despite the absence of directly applicable clinical studies of good quality Modified from Sackett et al. (1).

1.2

REFERENCE

1.

Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998. http://www.cebm.net/index.aspx?o=1025 [accessed February 2009].

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2. Background 2.1

Definition of pain

Pain is the most common symptom of any illness. The physician’s therapeutic task is twofold: • to discover and treat the cause of the pain • to treat the pain itself, irrespective of whether the underlying cause is treatable, in order to provide relief from it and reduce the suffering caused by it. The International Association for the Study of Pain (IASP) has proposed the following working definition: pain is ‘an unpleasant sensory and emotional experience associated with either actual or potential tissue damage, or described in terms of such damage’ (1). The alerting function of pain evokes protective responses (reflex motor withdrawal and behavioural responses), and is intended to keep tissue damage to a minimum. The capacity to experience pain has a protective role. If tissue damage (cellular breakdown with liberation of biochemical substances) is unavoidable, a cascade of changes occurs in the peripheral and central nervous system responsible for the perception of pain (2). A distinction can be made between adaptive and maladaptive pain (3). Acute pain – usually occurring in response to an identifiable noxious event with stimulation of the nociceptive system (from the periphery through the spinal cord, brain stem, and thalamus to the cerebral cortex where the sensation is perceived) – has a time-limited course during which treatment, if necessary, is aimed at correcting the underlying pathological process. Acute pain is useful or adaptive because it is a vital physiological sensation that alerts a person to something harmful in the environment that should be avoided. Additionally, if tissue injury occurs (following a noxious stimulus), adaptive pain induces a (reversible) state of localised hypersensitivity (stimuli that would normally not cause pain now cause pain) in and around the injured area, resulting in an avoidance of the damaged part. This adaptive, inflammatory pain tries to aid in repair after tissue damage, promoting healing. In contrast, maladaptive (pathological) pain offers no biological advantage because it is uncoupled from a noxious stimulus or tissue healing. Maladaptive pain is an expression of an inappropriate plasticity or modifiability of the nervous system, and is usually persistent or recurrent. Maladaptive pain may occur in response to damage to the nervous system (peripheral nerve, dorsal root ganglion, dorsal root, central nervous system), and is known as neuropathic pain. Essentially, maladaptive (neuropathic) pain is pain as a disease (3-5).

2.2.

What is suffering?

Pain is a complex experience entailing physiological, sensory, affective, cognitive and behavioural components. An individual’s perception of the intensity of pain relates to the interactions of physical, psychological, cultural and spiritual factors (6). Although the control of pain is central to any effort to relieve suffering, and pain and suffering are closely identified, they are nevertheless distinct. To define suffering, a psychosocial perspective has been adapted in which suffering is best viewed as a subjective phenomenon that can be influenced by biological, psychological, and social processes. Patients can experience severe pain without suffering (e.g. during childbirth), and suffering can include physical pain, but it is by no means limited to it. Patient distress also results from factors other than pain that add to suffering, such as anxiety, depression, nightmares, change in body perception, and changes in professional and social function. The differences between pain and suffering are most pronounced in cancer pain patients. Cancer is one of the medical conditions patients fear most: patients and their families are not only convinced that it is the beginning of the end and the patients will certainly die, but they also expect that the patients will die in horrible, excruciating pain (7, 8). Addressing these psychosocial sources as well as the medical sources should be the primary goal of a pain clinic, and can be achieved through a multidisciplinary approach (6).

2.3 Nociception and innervation Structure of the peripheral neural apparatus Sensory information from the skin is transmitted to the central nervous system (dorsal horn of the spinal cord) via three different types of primary sensory neurones: Aβ-, Aδ-, and C-fibres. These primary afferent neurones are responsible for transducing mechanical, chemical and thermal information

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into electrical activity. Although all three classes can transmit non-nociceptive information, under physiological circumstances only C-fibres (dull pain) and Aδ-fibres (sharp pain) are capable of transmitting nociceptive information from the periphery to the dorsal horn of the spinal cord. Thus, under normal circumstances, Aβ-fibres are responsive only to non-noxious mechanical stimuli, including touch, vibration and pressure (9-12). Nociceptive information for the viscera reaches the central nervous system along the sympathetic chains and pelvic parasympathetic chain. However, the density of visceral afferents is low compared with the skin, which can explain the poor localisation of noxious stimuli in the viscera (responsible for the diffuse nature of visceral pain) (13). The role of the dorsal horn The nociceptors terminate in a highly ordered way in the dorsal horn of the spinal cord, with the thinly myelinated Aδ fibres ending in laminae I and V, and the unmyelinated C-fibres ending in lamina II. These high threshold sensory fibres activate a large number of second order interneurones and projection neurones in the spinal cord. The activity generated by nociceptor input is transferred, after complex active processing in the dorsal horn, directly, or via brain stem relay nuclei, to the thalamus and then on to the cortex, where the sensation of pain is generated. Following integration in the dorsal horn, the pain signal is conducted through ascending pathways to the thalamus which, in interaction with limbic circuits, plays a crucial role in the reception and processing of nociceptive information en route to the cortex (12, 14). Brain areas involved in nociception and pain Nociceptive messages become more and more difficult to follow as they travel further along the central nervous system (CNS). Numerous brain areas are involved in the various components of pain, which include: • a sensory-discriminative component that refers to the capacity to analyse location, intensity and duration of the nociceptive stimulus • an affective component that gives rise to the unpleasant character of painful perception • a cognitive and evaluative component, which is involved in the phenomena of anticipation, attention, suggestion and past experiences. Although several circuits responsible for the sensory-discriminative and affective-cognitive components of pain can be distinguished, the global experience of pain, involves complex interactive neural networks of cerebral structures and multiple thalamocorticolimbic pathways (12, 14, 15).

2.4. Neuropathic pain Definition of neuropathic pain Neuropathic pain is defined by the IASP as ‘pain initiated or caused by a primary lesion or dysfunction of the nervous system’ (2). This trauma to neural tissue produces abnormalities of neural function that are perceived by the patient as the symptoms and signs of neuropathic pain. On examination, both negative and positive sensory symptoms may be present. Positive signs include pain, paraesthesia, dysaesthesia, hyperalgesia and allodynia. Negative signs involve sensory deficits (hypoaesthesia and hypoalgesia), weakness, and reflex changes. Clinically, patients may complain of spontaneous ongoing pain (stimulus-independent pain) that is burning, with intermittent shooting or electric shock-like (lancinating) sensations, and/or have pain hypersensitivity evoked in response to stimuli (stimulus-evoked pain) such as hyperalgesia and allodynia (16, 17). Mechanisms of neuropathic pain Studies in animal models describe a number of peripheral and central pathophysiological processes after nerve injury that would be the basis of the underlying neuropathic pain mechanism. A change in function, chemistry, and the structure of neurones (neural plasticity) leads to the production of the altered sensitivity characteristics of neuropathic pain. Peripheral sensitisation acts on the nociceptors, and central sensitisation takes place at various levels ranging from the dorsal horn to the brain. In addition, abnormal interactions between the sympathetic and sensory pathways contribute to mechanisms mediating neuropathic pain (14, 18). Summary of peripheral processes involved in neuropathic pain The peripheral processes involved in neuropathic pain are: • nociceptor sensitisation • alteration in ion channel expression • neuronal hyperexcitability with ectopic and spontaneous discharge (alteration in the expression of sodium channels and overactive calcium channels)

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• • • •

sprouting of collateral fibres from intact and damaged sensory axons into denervated areas non-synaptic ‘ephatic’ interactions between neurones phenotypic switch of Aβ-fibres (substance-P and calcitonin gene-related peptide release) sprouting of sympathetic fibres into the primary afferent fibres and the dorsal root ganglia (sympathetic-induced pain).

Summary of central processes involved in neuropathic pain The central processes involved in neuropathic pain are: • N-methyl-D-aspartate receptor activation • wind up: progressive increase in excitability during the course of the stimulus • translation-dependent central sensitisation: - hyperalgesia - secondary hyperalgesia - allodynia • activated microglia release proinflammatory cytokines and growth factors that further activate these cells, creating a positive feedback circuit and inducing pathological pain • transcription-dependent central sensitisation may induce permanent phenotypic/morphological changes • sprouting of A-fibres in lamina II • loss of spinal inhibitory control (gamma-aminobutyric acid, glycine) • cholecystokinin increase dampens µ-opioid inhibitory mechanisms.

2.5

Innervation of the urogenital system

The differences between the mechanisms of nociception in the skin and viscera are emphasised by studies of the response properties of visceral afferents from the urinary tract (19-21). Ureter The only sensation that can be evoked from the ureter is pain, whereas other organs such as the bladder can give rise to several sensations ranging from mild fullness to pain. Ureteric afferents were thinly myelinated or unmyelinated, and responded to direct probing of a limited area of tissue. Two populations of afferents were distinguished by Cervero and Jänig (22). The first responded to contractions of the ureter and could also be excited by low levels of distension (average threshold 8 mmHg). They appeared to encode levels of distension throughout and beyond the physiological range. The second group did not respond to peristaltic contractions of the ureter, but they could be excited by distension with a wide range of thresholds. When ureters were perfused intraluminally, higher pressure thresholds were seen, although some at least still appeared to respond to distension to only 10 mmHg (22). Systemic administration of morphine, a μ-opiate receptor agonist, produces a dose-dependent decrease of pain caused by ureteric distension (23). Urinary bladder Two distinct groups of afferent fibres capable of signalling noxious stimuli have been identified in the urinary bladder. Most visceral afferents from the urinary bladder are unmyelinated fibres, although a population of myelinated A-fibres is also present (19). The majority of visceral primary afferents from the bladder, urethra, and reproductive and other pelvic organs encode for both noxious and non-noxious stimuli (19-21). Graded distension of the healthy urinary bladder in humans initially gives rise to a sensation of fullness and eventually pain as volume increases and intravesical pressure exceeds about 25-35 mmHg (24-27). In the inflamed bladder, the sensations during bladder emptying become unpleasant and painful. Nearly all afferents are small, myelinated or unmyelinated, and travel with sympathetic (hypogastric) or parasympathetic (pelvic) nerves. Some exhibit a low level of ongoing discharge when the bladder is empty. Distension excited mainly thin myelinated afferents, with pressure thresholds corresponding to the values where humans report the first sensation of fullness. Nearly all units were activated by the intraluminal pressures reached during normal, non-painful micturition. The activation of a numerically significant population of initially unresponsive afferents indicates that peripheral afferent mechanisms encoding pain from pelvic viscera are highly malleable, and are strongly affected by the state of the tissue. These peripheral changes are obviously likely to be important for signalling pain and discomfort in inflammatory conditions.

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Male reproductive organs The sensory innervation of the testes (dog model) shows that more than 95% of the fibres of the superior spermatic nerve are unmyelinated, with the great majority having polymodal properties (i.e. responding to mechanical, chemical and thermal stimuli) (28). Myelinated and unmyelinated afferents fibres form a homogeneous group with polymodal receptors in testis and/or epididymis. Prostaglandins did not excite but sensitised the afferents to other stimuli (29).

2.6

Pain evaluation and measurement

2.6.1 Pain Evaluation Health professionals should ask about pain, and the patient’s self-report should be the primary source of assessment. Clinicians should assess pain with easily administered rating scales, and should document the efficacy of pain relief at regular intervals after starting or changing treatment. Systematic evaluation of pain involves the following steps. • Evaluate its severity. • Take a detailed history of the pain, including an assessment of its intensity and character. • Evaluate the psychological state of the patient, including an assessment of mood and coping responses. • Perform a physical examination, emphasising the neurological examination. • Perform an appropriate diagnostic work-up to determine the cause of the pain, which may include tumour markers. • Perform radiological studies, scans, etc. • Re-evaluate therapy. The initial evaluation of pain should include a description of the pain using the PQRST characteristics: P Q R S T

Palliative or provocative factors: ‘What makes it less intense?’ Quality: ‘What is it like?’ Radiation: ‘Does it spread anywhere else?’ Severity: ‘How severe is it?’ Temporal factors: ‘Is it there all the time, or does it come and go?’

Pain in patients with cancer is a complex phenomenon consisting of many different aspects. Not all pains will be of malignant origin. For example, cancer patients might have pain from arthritis or cervical spondylosis. They will often have more than one pain problem, and each pain must be individually assessed and evaluated. Some pains may be due to muscular spasm rather than the cancer itself. A key principle is constantly to re-evaluate pain and the effect and side-effects of analgesic therapy. Pain in cancer patients could be caused by the cancer itself (e.g. tumour pressure on nerve plexus or tumour infiltration), or could be due to secondary muscular spasm. In addition, pain could be secondary to cancer treatments, e.g. radiation-induced brachial plexopathy, or might have no relation to the cancer, e.g. arthritis. In general, cancer pain consists of two broad diagnostic types: nociceptive and neuropathic pain. When evaluating pain, it is useful to try to determine whether the pain is one of these types or a mixture of the two. Nociceptive pain includes bone pain and soft tissue pain. Typically it is described as a dull, aching pain. This type of pain will be largely sensitive to non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. Neuropathic pain is pain as a result of damage to the peripheral or central nervous system. It is usually described as a burning or sharp, shooting pain. Neuropathic pain is usually not particularly responsive to NSAIDs or opioids. Adjuvant analgesics such as anti-depressants and anti-convulsants should be used in the first instance. 2.6.2 Assessing pain intensity and quality of life There are several ratings scales available to assess pain. There are single-item ratings of pain intensity and pain relief such as the visual analogue scale (unidimensional) or the verbal rating scale, and multiple-item assessments (multidimensional) that measure not only pain intensity but also additional dimensions of the pain experience, including emotional, affective, cognitive and social items (quality of life questionnaires). Rating pain using a visual analogue scale (VAS, Figure 1) or collection of VAS scales (such as the brief pain inventory) is an essential part of pain assessment. It allows some form of comparison to be made, and facilitates assessment of the efficacy of treatment. The ease of use (and ease of analysis) of the VAS has resulted in its widespread adoption for the measurement of pain intensity in clinical studies. In addition, the 10

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VAS score for pain intensity has consistently demonstrated sensitivity to changes in pain levels associated with treatment, especially in acute pain states. Although the VAS appears to be an attractive method to evaluate pain intensity and changes in pain, there are, however, several limitations for this measurement tool for assessing chronic pain. In chronic pain syndromes, the VAS has shown significant weakness in sensitivity owing to large variability between subjects, probably because of emotional, affective, and cognitive responses to pain together with behavioural and cultural biases, items that are not measured by a unidimensional tool. In addition, increased age and a greater amount of opioid consumption have been shown to be associated with a higher failure rate with the VAS score for measurement of pain intensity. Figure 1: Visual analogue scale

0 —————————————————————————————————————————- 10

Visual analogue scale Describe your pain on a scale of 0 to 10

No Mild Moderate Severe pain

3 |

4 |

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6 |

7 |

➝

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Worst possible pain

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To study the effects of both physical and non-physical influences on patient well-being, an instrument must assess more dimensions than the intensity of pain or other physical symptoms. Several validated questionnaires to assess various quality of life dimensions are available, including the Medical Outcomes Short-Form Health Survey Questionnaire 36 (SF-36), and the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) (30-34).

2.7

REFERENCES

1.

Merskey H, Bogduk N (eds). Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms. Seattle: IASP Press,1994. Jacobson L, Mariano AJ. General considerations of chronic pain. In: Loeser JD, ed. Bonica’s Management of Pain. Philadelphia: Lippincott Willimas & Wilkins, 2001, pp. 241-254. Woolf CJ. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med 2004;140(6):441-51. http://www.ncbi.nlm.nih.gov/pubmed/15023710 Scholtz J, Woolf CJ. Can we conquer pain? Nat Neurosci 2002;5 Suppl:1062-7. http://www.ncbi.nlm.nih.gov/pubmed/12403987 Wiertelak EP, Smith KP, Furness L, Mooney-Heiberger K, Mayr T, Maier SF, Watkins LR. Acute and conditioned hyperalgesic responses to illness. Pain 1994;56(2):227-34. http://www.ncbi.nlm.nih.gov/pubmed/8008412

2. 3.

4. 5.

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Turk DC, Sist TC, Okifuji A, Miner MF, Florio G, Harrison P, Massey J, Lema ML, Zevon MA. Adaptation to metastatic cancer cancer pain, regional/local cancer pain and non-cancer pain: role of psychological and behavioral factors. Pain 1998;74(2-3):247-56. http://www.ncbi.nlm.nih.gov/pubmed/9520239 7. Portenoy RK, Lesage P. Management of cancer pain. Lancet 1999;353(9165):1695-700. http://www.ncbi.nlm.nih.gov/pubmed/10335806 8. Cassel EJ. The nature of suffering. N Eng J Med 1982;306(11):639-45. http://www.ncbi.nlm.nih.gov/pubmed/7057823 9. Belemonte C, Cervero F. Neurobiology of Nociceptors. Oxford: Oxford University Press, 1996. 10. Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature 2001;413(6852):203-10. http://www.ncbi.nlm.nih.gov/pubmed/11557989 11. Willis WD, Westlund KN. Neuroanatomy of the pain system and of the pathways that modulate pain. J Clin Neurophysiol 1997;14(1):2-31. http://www.ncbi.nlm.nih.gov/pubmed/9013357 12. Romanelli P, Esposito V. The functional anatomy of neuropathic pain. Neurosurg Clin NAm 2004;15(3):257-68. http://www.ncbi.nlm.nih.gov/pubmed/15246335 13. Westlund KN. Visceral nociception. Curr Rev Pain 2000;4(6):478-87. http://www.ncbi.nlm.nih.gov/pubmed/11060594 14. Millan MJ. The induction of pain: an integrative review. Prog Neurobiol 1999;57(1):1-164. http://www.ncbi.nlm.nih.gov/pubmed/9987804 15. Apkarian AV, Bushnell MC, Treede RD, Zubieta JK. Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain 2005;9(4):463-84. http://www.ncbi.nlm.nih.gov/pubmed/15979027 16. Chong MS, Bajwa ZH. Diagnosis and treatment of neuropathic pain. J Pain Symptom Manage 2003;25(5 Suppl):S4-S11. http://www.ncbi.nlm.nih.gov/pubmed/12694987 17. Rasmussen PV, Sindrup SH, Jensen TS, Bach FW. Symptoms and signs in patients with suspected neuropathic pain. Pain 2004;110(1-2):461-9. http://www.ncbi.nlm.nih.gov/pubmed/15275799 18. Besson JM. The neurobiology of pain. Lancet 1999;353(9164):1610-15. http://www.ncbi.nlm.nih.gov/pubmed/10334274 19. Häbler HJ, Jänig W, Koltzenburg M. Activation of unmyelinated afferent fibres by mechanical stimuli and inflammation of the urinary bladder in the cat. J Physiol 1990;425:545-62. http://www.ncbi.nlm.nih.gov/pubmed/2213588 20. Bahns E, Ernsberger U, Jänig W, Nelke A. Functional characteristics of lumbar visceral afferent fibres from the urinary bladder and the urethra in the cat. Pflügers Arch 1986;407(5):510-18. http://www.ncbi.nlm.nih.gov/pubmed/3786110 21. Bahns E, Halsband U, Jänig W. Responses of sacral visceral afferent fibres from the lower urinary tract, colon, and anus to mechanical stimulation. Pflügers Arch 1987;410(3):296-303. http://www.ncbi.nlm.nih.gov/pubmed/3684516 22. Cervero F, Jänig W. Visceral nociceptors: A new world order?. Trends Neurosci. 1992;15(10):374-8. http://www.ncbi.nlm.nih.gov/pubmed/1279857 23. Roza C, Laird JM. Pressor responses to distension of the ureter in anaesthetised rats: characterisation of a model of acute visceral pain. Neurosci Lett 1995 Sep 22;198(1):9-12. 24. Roberts WJ, Elardo SM. Sympathetic activation of A-delta nociceptors. Somatosens Res 1985;3(1): 33-44. http://www.ncbi.nlm.nih.gov/pubmed/2999942 25. Seltzer Z, Devor M. Ephaptic transmission in chronically damaged peripheral nerves. Neurology 1979;29(7):1061-4. http://www.ncbi.nlm.nih.gov/pubmed/224343 26. Kruger L, Perl ER, Sedivec MJ. Fine structure of myelinated mechanical nociceptor endings in cat hairy skin. J Comp Neurol 1981;198(1):137-54. http://www.ncbi.nlm.nih.gov/pubmed/7229137 27. Treede R-D, Meyer RA, Raja SN, Campbell JN. Peripheral and central mechanisms of cutaneous hyperalgesia. Prog Neurobiol 1992;38(4):397-421. http://www.ncbi.nlm.nih.gov/pubmed/1574584 28. Kumazawa T. Sensory innervation of reproductive organs. Prog Brain Res 1986;67:115-31. http://www.ncbi.nlm.nih.gov/pubmed/3823468

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29. 30. 31.

32.

33.

34.

Meyer RA, Campbell JN, Raja SN. Peripheral neural mechanisms of nociception In: Wall PD, Melzack R (eds). Textbook of Pain. 3rd ed. Edinburgh: Churchill Livingston, 1994, pp. 13-44. Jensen MP. The validity and reliability of pain measures in adults with cancer. J Pain 2003;4(1):2-21. http://www.ncbi.nlm.nih.gov/pubmed/14622723 Rosier EM, Iadarola MJ, Coghill RC. Reproducibility of pain measurement and pain perception. Pain 2002;98(1-2):205-16. http://www.ncbi.nlm.nih.gov/pubmed/12098633 Fosnocht DE, Chapman CR, Swanson ER, Donaldson GW. Correlation of change in visual analog scale with pain relief in the ED. Am J Emerg Med 2005;23(1):55-9. http://www.ncbi.nlm.nih.gov/pubmed/15672339 Graham B. Generic health instruments, visual analog scales, and the measurement of clinical phenomena. J Rheumatol 1999;26(5):1022-3. http://www.ncbi.nlm.nih.gov/pubmed/10332963 Scott DL, Garrood T. Quality of life measures: use and abuse. Ballieres Best Pract Research Clinical Rheumatol 2000;14(4):663-87. http://www.ncbi.nlm.nih.gov/pubmed/11092795

3. CANCER PAIN MANAGEMENT (GENERAL) 3.1

Classification of cancer pain

Figure 2 shows the classification of cancer pain. Figure 2: Classification of cancer pain Bone Nociceptive Soft tissue Viscus (e.g. bowel, bladder) Pain Neuropathic Nerve compression Nerve infiltration Urogenital neoplasms frequently metastasise to bone (e.g. spine, pelvis, skull), and such bone metastases are associated with pathological fractures, hypercalcaemia and neurological deficits, leading to substantial impairment of quality of life. The release of algogenic substances in the tissue, microfractures and periosteal tension are the main mechanism for pain sensation (1). Pain caused by bone metastases is nociceptive pain, but can become associated with neuropathic pain if the tumour invades or compresses a nerve, neural plexus or spinal cord. One-third of patients with tumour-related pain are affected by neuropathic pain components (2). Nociceptive pain is well localised. Initially it occurs on physical movement, but later might also occur at rest. Neuropathic pain frequently has a constant ‘burning’ character. The efficacy of opioids may be diminished in neuropathic pain, and hence additional co-analgesics are necessary (3). Patients with severe neuropathic pain are a special challenge. Psychological changes frequently occur and specific therapeutic intervention may be necessary (4). The WHO recommends a stepwise scheme for the treatment of cancer pain syndromes and for neoplastic bone pain. Bisphosphonates and calcitonin are helpful for stabilising bone metabolism. Epidural and intrathecal opioids are sometimes useful in managing bone pain from metastases. Nerve destruction by intrathecal or epidural phenol is sometimes useful in selected patients with neuropathic pain (5). 3.1.1 1.

References Mercadante S. Malignant bone pain: pathophysiology and treatment. Pain 1997;69(1-2):1-18. http://www.ncbi.nlm.nih.gov/pubmed/9060007

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2.

3.

4.

5.

Grond S, Zech D, Diefenbach C, Radbruch L, Lehmann KA. Assessment of cancer pain: a prospective evaluation of 2266 cancer patients referred to a pain service. Pain 1996;64(1):107-14. http://www.ncbi.nlm.nih.gov/pubmed/8867252 Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 1999;83(3):389-400. http://www.ncbi.nlm.nih.gov/pubmed/10568846 Mercadante S, Portenoy RK. Opioid poorly-responsive cancer pain. Part 3. Clinical strategies to improve opioid responsiveness. J Pain Symptom Manage 2001;21(4):338-54. http://www.ncbi.nlm.nih.gov/pubmed/11312049 Stevens RA, Stotz A. Neurolytic blocks for management of oncologic pain. Cancer Res Ther Control 1999;9:345-53.

3.2 General Principles of cancer pain management The therapeutic strategy depends on the four goals of care: 1. Prolonging survival 2. Optimising comfort 3. Optimising function 4. Relieving pain (Figure 3). Figure 3: Tumour pain helix Pain Escalation Sleeplessness



Depression

Worries



Hopelessness



Despair

Isolation

The hierarchy of general treatment principles in Table 3 is intended to offer guidance through the decisionmaking process. Table 3: Hierarchy of general treatment principles 1 2 3 4 5 6

Individualised treatment for each patient Causal therapy to be preferred over symptomatic therapy Local therapy to be preferred over systemic therapy Systemic therapy with increasing invasiveness (World Health Organization [WHO] ladder) Conformance with palliative guidelines Both psychological counselling and physical therapy from the very beginning

The guiding principle of care is the individualisation of therapy. Through a process of repeated evaluations, the selection and administration of therapy is individualised so that a favourable balance between pain relief and adverse effects is achieved and maintained. The next steps in the hierarchy, especially points 2 to 4, necessitate a continuing risk-to-benefit assessment between therapeutic outcome versus tolerability and willingness to accept adverse effects. The more invasive the therapy, the more difficult the decisions become. This is particularly true of palliative medicine, since here there are limited prospects of healing and there is also the problem of working against time.

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If local therapy is not feasible or cannot be well tolerated, then symptomatic measures are appropriate, although local therapy is to be given preference over systemic treatment. In simple cases, measures such as drainage and stenting can make analgesic medication redundant. Examples include inserting a gastric probe, a ureteral stent, a percutaneous nephrostomy, or a bladder catheter. To cite another example, patients who receive an artificial anus due to recurrent subileus caused by peritoneal carcinomatosis are relieved of their pain immediately. The indication stands in direct relation to the severity of the disease and the operation, especially if there are no prospects of healing. Cases such as these, however, are sometimes in particular need of the invasive measures described above. This is not only to relieve pain for the rest of the patient’s days, but also to improve the general quality of life, even though invasive operations may also have a negative impact on the patient’s wellbeing. Examples can include evisceration to prevent cloaca in cervical carcinoma, or implanting a prosthetic hip due to a pathological fracture originating in metastasised bladder or kidney cancer. A gradual strategy (level of evidence: 4) can be considered when dose escalation of a systemically administered opioid fails to yield a satisfactory result. The steps to follow are as follows. • Switch to another opioid • Intervene with an appropriate primary therapy or other non-invasive analgesic approach • Pursue psychological, rehabilitative and neurostimulatory techniques (e.g. transcutaneous electrical nerve stimulation) • Use invasive analgesic techniques. This approach should be based on a careful evaluation of the likelihood and duration of the analgesic benefit, the immediate risks, and the morbidity of the procedure (epidural infusion) • Use neurodestructive procedures (chemical or surgical neurolysis, coeliac plexus blockade) • Finally, some patients with advanced cancer who have comfort as the overriding goal of care, can elect to be deeply sedated. As is widely discussed in pain-management literature, the importance of physiotherapy and psychological counselling cannot be emphasised too strongly. For further discussion of these points see the sections above. In conclusion, pain management can be highly effective, especially when interdisciplinary co-operation occurs: pain can be overcome.

3.3. Non-pharmacological therapies 3.3.1 Surgery Surgery may have a role in the relief of symptoms caused by specific problems, such as obstruction of a hollow viscus, unstable bony structures and compression of neural tissues or draining of symptomatic ascites (1-3). The potential benefits must be weighed against the risks of surgery, the anticipated length of hospitalisation and convalescence, and the predicted duration of benefit. Radical surgery to excise locally advanced disease in patients with no evidence of metastatic spread may be palliative, and potentially increase the survival of some patients (4) (level of evidence: 2b). 3.3.1.1 References 1. Williams MR. The place of surgery in terminal care. In: Saunders C (ed) The management of terminal disease. London: Edward Arnold, 1984; pp. 148-153. 2. Boraas M. Palliative surgery. Semin Oncol 1985;12(4):368-74. http://www.ncbi.nlm.nih.gov/pubmed/2417321 3. Sundaresan N, DiGiacinto GV. Antitumor and antinociceptive approaches to control cancer pain. Med Clin North Am 1987;71(2):329-48. http://www.ncbi.nlm.nih.gov/pubmed/2881035 4. Temple WJ, Ketcham AS. Sacral resection for control of pelvic tumours. Am J Surg 1992;163(4):370-4. http://www.ncbi.nlm.nih.gov/pubmed/1373043 3.3.2 Radionuclides 3.3.2.1 Clinical background Metastatic bone pain means bone pain arising from secondary skeletal malignancy. Refractory to treatment means resistant to treatments such as conventional analgesics or antitumour therapy (chemotherapy or hormone manipulation), or having multisite symptoms that are not easily controlled by external beam radiotherapy.

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Bone metastases are the most frequent source of pain during the evolution of cancers (1). Approximately 30% of patients with osseous metastases have such a degree of pain that analgesics are required and day-to-day activities are disturbed (1): the pain interferes with patients’ quality of life, causing anxiety, isolation, immobility, depression and sleeplessness. In single lesions, bone stability and pain reduction can be achieved by external beam radiotherapy (level of evidence: Ib; grade of recommendation: A). About 80-90% of these patients will experience durable pain relief, but many will further develop multiple painful metastases (1) 3.3.2.2 Radiopharmaceuticals: physical characteristics The main physical characteristics of radiopharmaceuticals are as follows. • 89Sr (strontium-89 chloride) emits a beta particle with a maximum energy of 1.46 MeV, a mean energy of 0.58 MeV, an average soft-tissue range of 2.4 mm and 0.01% abundant gamma emission with a 0.91 MeV photopeak. The physical half-life is 50.5 days (2, 3). 153 •  Sm (samarium-153 lexidronam) emits a beta particle with a maximum energy of 0.81 MeV, a mean energy of 0.23 MeV, an average soft-tissue range of 0.6 mm and 28% abundant 0.103 MeV gamma emission with a 0.103-MeV photo peak. The physical half-life is 1.9 days (4). • 186Re (renium-186 etidronate) emits a beta particle with a maximum energy of 1.07 MeV, a mean energy of 0.349 MeV, an average soft-tissue range of 1.1 mm and a 9% abundant gamma emission with a 0.137–Mev photopeak. The physical half-life is 3.7 days (5). • Therapy in this context means the intravenous administration of 89Sr chloride or 153Sm lexidronam (153Sm ethylenediaminetetramethylenephosphonate [EDTMP]). There is no clear difference in treatment response between 89Sr, 153Sm and 186Re (2). However, in view of the half-life of the different isotopes, there is a difference in onset of response, duration of response and toxixity. For 153Sm and 186Re, the onset of response is rapid but duraion is shorter (6, 7). Note that 186Re is no longer used in many European countries. 3.3.2.3 Indications and contraindications and 153Sm lexidronam are indicated for the treatment of bone pain resulting from skeletal metastases involving more than one site and associated with an osteoblastic response on bone scan (1, 8-15) (level of evidence: 2, grade of recommendation: B), which is a focal increased skeletal metabolic activity that is caused by osseous reaction to bone metastasis. Within the urological tumours, bone metastases from prostate cancer are most frequently osteoblastic (80%), compared with ± 0% when bone metastases arise from renal cell carcinoma. 89Sr

89Sr

and 153Sm lexidronam have no place in the management of acute or chronic spinal cord compression or in treating pathological fracture (1, 8, 11) (level of evidence: 2, grade of recommendation: B). Of patients presenting with osteoblastic metastases, 60-80% benefit from 89Sr and/or 153Sm lexidronam (1) (level of evidence: 2). The choice between the two radiopharmaceuticals depends solely on practical considerations. 89Sr and/or 153Sm lexidronam should be administered by a slow (89Sr) or bolus (153Sm lexidronam) injection using an intravenous catheter. The recommended doses to be administered are 148 MBq (89Sr) (16) and 37 MBq/kg (153Sm) (1, 16) (level of evidence: 2). There is a risk of temporary increase in bone pain (pain flare) in about 10% of the patients (3, 6, 7, 17). This “flare phenomenon” generally occurs 2-4 days after 153Sm lexidronam and 1-2 weeks after 89Sr (acute sideeffect) (1, 4, 8, 11, 12, 15, 18) and is associated with good clinical response (level of evidence: 2) (3, 6, 7, 17). A transient increase in analgesia is sometimes necessary. Pain reduction is unlikely to occur within the first week, and can occur as late as one month after injection. Analgesics should therefore continue to be prescribed to patients until bone pain improves (grade of recommendation: B). Late side-effects include temporary myelosuppression (platelets, white blood cells) approximately 4 weeks after administration of 153Sm lexidronam and 6 weeks after 89Sr (1, 4, 8, 11, 12, 15, 18) (level of evidence: 2). Recovery occurs 4-6 weeks later depending on bone marrow reserve. In general, there is no significant effect on haemoglobin. Radiation exposure to family members and the public can be present for 2-4 days after 153Sm lexidronam, and 7-10 days after 89Sr (4, 8, 11, 13-15, 18, 19, 20-23) (level of evidence: 2). Information concerning

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radioprotection should be provided (grade of recommendation: B). If the pain responds to the initial treatment, administration of 153Sm lexidronam can be repeated at intervals of 8-12 weeks in the presence of recurrent pain (1, 2, 23) (level of evidence: 2, grade of recommendation: B). The response rate for second and subsequent treatments may be lower than on the first occasion (1, 8, 12, 23) (level of evidence: 2). 3.3.2.4 Contraindications Absolute contraindications • During or shortly after (less than 4 weeks) myelotoxic chemotherapy (all compounds except cisplatin) or hemibody external radiation therapy (less than 12 weeks). The delay between the end of these treatments and the start of metabolic radiotherapy is necessary in order to avoid severe haematopoietic toxicity. However, treatment can be safely combined with limited local field external beam radiotherapy (level of evidence: 3, grade of recommendation: C). • Known hypersensitivity to EDTMP or similar phosphonate compounds for 153Sm lexidronam (1). • Glomerular filtration rate (GFR) < 30 mL/min (1, 2). • Pregnancy; continued breast-feeding (2). Relative contraindications • Radiopharmaceuticals are not recommended for women of child-bearing age (negative pregnancy test and contraception absolutely required). • Acute or chronic severe renal failure (GFR of 30-60 mL/min): the dose administered should be adapted (if the GFR is > 60 mL/min, reduce the normal dosage by 25%; if the GFR is between 30 mL/min and 60 mL/min, reduce the normal dosage by 50%) (expert opinion: level 4). Measurement of GFR is performed in the presence of elevated creatinine > 20 mg/L. • Solitary painful lesion: external limited field radiotherapy should be performed (16, 24) (level of evidence Ib). Caution Caution must be used in the following circumstances: • risk of fracture • nervous or spinal cord compression that requires other treatments in an emergency: external radiotherapy or surgery, or a combination of the two • urinary incontinence: special recommendations including catheterization before administration of the radionuclide. The catheter should remain in place for 4 days (89Sr ), 3 days (186Re) and 24 hours (153Sm) respectively (2) (grade of recommendation: A). • compromised bone marrow reserve • white blood cell count of < 2500/µL (expert opinion, level 5) (preferably > 3500/μL according to European Association of Nuclear Medicine guidelines) (2). • platelets < 80,000/µL (expert opinion, level 5) (preferably > 100,000/μL according to European Association of Nuclear Medicine guidelines) (2). • Haemoglobin 3 months

Radiotherapy Medically inoperable ≥ 48 h < 3 months Highly sensitive

Unknown Present 1 focus

Known Absent > 1 foci

A randomised, prospective trial has demonstrated that patients treated with a combination of surgery followed by radiotherapy can remain ambulatory longer, and those who are not ambulatory at presentation have a better chance of regaining ambulatory function, than those treated with radiotherapy alone (52) (level of evidence: 1B). 3.3.3.6 Pathological fractures In patients with impending pathological fracture, a prophylactic orthopaedic procedure should be considered. Several publications advise post-operative radiotherapy after (prophylactic) orthopaedic procedures for bone metastases (53) (level of evidence: 3). Some authors argue that if bone cement is used for fixation, postoperative radiotherapy is not needed (53-55) (level of evidence: 3). 3.3.3.7 Side-effects Side-effects are related to the total dose, fractionation size and the localisation of the metastases (56) (level of evidence: 3) and include: • pain flare-up (within 24 h and due to oedema) • symptoms depend on the treatment field and location and can include: - nausea (especially with larger fields) - diarrhoea - irritation of the throat and oesophagus. These side-effects are mostly transient within a few days (56). 3.3.3.8 References 1. Bates T. A review of local radiotherapy in the treatment of bone metastases and cord compression. Int J Radiat Oncol Biol Phys 1992:23(1):217-21. http://www.ncbi.nlm.nih.gov/pubmed/1374063 2. Maher E. The use of palliative radiotherapy in the management of breast cancer. Eur J Cancer 1992;28(2-3):706-10. http://www.ncbi.nlm.nih.gov/pubmed/1375488 3. McQuay HJ, Collins SL, Carroll D. Radiotherapy for the palliation of painful bone metastases. Cochrane Database Sys Rev 2000;(2):CD001793. http://www.ncbi.nlm.nih.gov/pubmed/10796822

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Wu JS, Wong R, Johnston M, Bezjak A, Whelan T; Cancer Care Ontario Practice Guidelines Initiative Supportive Care Group. Meta-analysis of dose-fractionation radiotherapy trials for the palliation of painful bone metastases. Int J Radiat Oncol Biol Phys 2003;55(3):594-605. http://www.ncbi.nlm.nih.gov/pubmed/12573746 5. Sze WM, Shelley M, Held I et al. Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy--a systematic review of randomised trials. Clin Oncol 2003;15(6): 345-52. http://www.ncbi.nlm.nih.gov/pubmed/14524489 6. Agarawal JP, Swangsilpa T, van der Linden Y, et al. The role of external beam radiotherapy in the management of bone metastases. Clin Oncol 2006;18(10):747-60. http://www.ncbi.nlm.nih.gov/pubmed/17168210 7. The Bone Trial Working Party. 8 Gy single fraction radiotherapy for the treatment of metastatic skeletal pain: randomised comparison with a multifraction schedule over 12 months of patient follow-up. The Bone Trial Working Party. Radiother Oncol 1999;52(2):111-21. http://www.ncbi.nlm.nih.gov/pubmed/10577696 8. Mercadante S. Malignant bone pain: pathophysiology and treatment. Pain 1997;69(1-2):1-18. http://www.ncbi.nlm.nih.gov/pubmed/9060007 9. Vakaet LA, Boterberg T. Pain control by ionizing radiation of bone metastasis. Int J Dev Biol 2004;48(5-6):599-606. http://www.ncbi.nlm.nih.gov/pubmed/15349834 10. Price P, Hoskin PJ, Easton D, et al. Prospective randomised trial of single and multifraction radiotherapy schedules in the treatment of painful bony metastases. Radiother Oncol 1986;6(4): 247–55. http://www.ncbi.nlm.nih.gov/pubmed/3775071 11. Even-Sapir E, Metser U, Mishani E et al. The detection of bone metastases in patients with highrisk prostate cancer: 99mTc-MDP Planar bone scintigraphy, single- and multi-field-of-view SPECT, 18F-fluoride PET, and 18F-fluoride PET/CT. J Nucl Med 2006;47(2):287-97. http://www.ncbi.nlm.nih.gov/pubmed/16455635 12. Cook GJ, Fogelman I. The role of positron emission tomography in skeletal disease. Semin Nucl Med 2001;31(1):50-61. http://www.ncbi.nlm.nih.gov/pubmed/11200205 13. Gates GF. Bone SPECT imaging of the painful back. Clin Nucl Med. 1996;21(7):560-71. http://www.ncbi.nlm.nih.gov/pubmed/8818471 14. Ryan PJ, Evans PA, Gibson T, et al. Chronic low back pain: Comparison of bone SPECT with radiography and CT. Radiology 1992;182(3):849-54. http://www.ncbi.nlm.nih.gov/pubmed/1531544 15. Bach F, Larsen BH, Rohde K, et al. Metastatic spinal cord compression, occurrence, symptoms, clinical presentation and prognosis in 398 patients with spinal cord compression. Acta Neurochir 1990;107(1-2):37-43. http://www.ncbi.nlm.nih.gov/pubmed/2096606 16. Lecouvet FE, Geukens D, Stainier A, Jamar F, Jamart J, d’Othée BJ, Therasse P, Vande Berg B, Tombal B. Magnetic resonance imaging of the axial skeleton for detecting bone metastases in patients with high risk prostate cancer: diagnostic and cost-effectiviness and comparison with current detection strategies. J Clin Oncol 2007;25(22):3281-7. http://www.ncbi.nlm.nih.gov/pubmed/17664475 17. Rodallec MH, Feydy A, Larousserie F, Anract P, Campagna R, Babinet A, Zins M, Drapé JL. Diagnostic imaging of solitary tumors of the spine: what to do and say. Radiographics 2008;28(4):1019-41. http://www.ncbi.nlm.nih.gov/pubmed/18635627 18. Helweg-Larsen S, Wagner A, Kjaer L, et al. Comparison of myelography combined with postmyelographic spinal CT and MRI in suspected metastatic disease of the spinal canal. J Neurooncol 1992;13(3):231-7. http://www.ncbi.nlm.nih.gov/pubmed/1517800 19. Hagenau C, Grosh W, Currie M, Wiley RG. Comparison of spinal magnetic resonance imaging and myelography in cancer patients. J Clin Oncol 1987;5(10):1663-9. http://www.ncbi.nlm.nih.gov/pubmed/3655863 20. Ghanem N, Uhl M, Brink I, Schäfler O, Kelly T, Moser E, Langer M. Diagnostic value of MRI in comparison to scintigraphy, PET, MS-CT and PET-CT for the detection of metastases of bone. Eur J Radiol 2005;55(1):41-55. http://www.ncbi.nlm.nih.gov/pubmed/15950100

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Gabriel K, Schiff D. Metastatic spinal cord compression by solid tumors. Semin Neurol 2004;24: 375-83. http://www.ncbi.nlm.nih.gov/pubmed/15637649 22. Baur A, Stäbler A, Arbogast S Duerr HR, Bartl R, Reiser M. Acute osteoporotic and neoplastic vertebral compression fractures: fluid sign at MR imaging. Radiology 2002;225(3):730-5. http://www.ncbi.nlm.nih.gov/pubmed/12461253 23. Jung HS, Jee WH, McCauley TR, Ha KY, Choi KH. Discrimination of metastatic from acute osteoporotic compression fractures with MR imaging. Radiographics 2003;23(1):179-87. http://www.ncbi.nlm.nih.gov/pubmed/12533652 24. Loblaw DA, Perry J, Chambers A, Laperriere NJ. Systematic review of the diagnosis and management of malignant extradural spinal cord compression: the Cancer Care Ontario Practice Guidelines Initiative’s Neuro-Oncology Disease Site Group. J Clin Oncol 2005:23(9);2028-37. http://www.ncbi.nlm.nih.gov/pubmed/15774794 25. Li KC, Poon PY. Sensitivity and specificity of MRI in detecting malignant spinal cord benign compression fractures of vertebrae. Magn Reson Imaging 1988;6(5):547-56. http://www.ncbi.nlm.nih.gov/pubmed/3067022 26. Steenland E, Leer JW, van Houwelingen H, et al. The effect of a single fraction compared to multiple fractions on painful bone metastases: a global analysis of the Dutch Bone metastasis study. Radiother Oncol 1999;52(2):101-9. http://www.ncbi.nlm.nih.gov/pubmed/10577695 27. Roos DE, Turner SL, O’Brien PC, Smith JG, Spry NA, Burmeister BH, Hoskin PJ, Ball DL; TranTasman Radiation Oncology Group, TROG 96.05. Randomized trial of 8 Gy in 1 versus 20 Gy in 5 fractions of radiotherapy for neuropathic pain due to bone metastases (Trans-Tasman Raciation Oncology gRoup, TROG 96.05). Radiother Oncol, 2005;75(1):54-63. http://www.ncbi.nlm.nih.gov/pubmed/15878101 28. Hartsell WF, Scott CB, Bruner DW Scarantino CW, Ivker RA, Roach M 3rd, Suh JH, Demas WF, Movsas B, Petersen IA, Konski AA, Cleeland CS, Janjan NA, DeSilvo M. Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst 2005;97(11):798-804. http://www.ncbi.nlm.nih.gov/pubmed/15928300 29. Agarawal JP, Swangsilpa T, van der Linden Y, Rades D, Jeremic B, Hoskin PJ. The role of external beam radiotherapy in the management of bone metastases. Clin Oncol 2006;18(10):747-60. http://www.ncbi.nlm.nih.gov/pubmed/17168210 30. Jeremic B. Single fraction external beam radiation therapy in the treatment of localized metastatic bone pain. A review. J Pain Symptom Manag 2001;22(6):1048-58. http://www.ncbi.nlm.nih.gov/pubmed/11738168 31. Hoskin PJ, Price P, Easton D, Regans J, Austin D, Palmer S, Yarnold JR. A prospective randomised trial of 4 Gy or 8 Gy single doses in the treatment of metastatic bone pain. Radiot Oncol 1992;23(2):74-8. http://www.ncbi.nlm.nih.gov/pubmed/1372126 32. Jeremic B, Shibamoto Y, Acimovic L, Milicic B, Milisvljevic S, Nikolic N, Aleksandrovic J, Igrutinovic I. A randomized trial of three single-dose radiation therapy regimens in the treatment of metastatic bone pain. Int J Radiat Oncol Biol Phys 1998;42(1):161-7. http://www.ncbi.nlm.nih.gov/pubmed/9747834 33. Singh D, Yi WS, Brasacchio RA, Muhs AG, Smudzin T, Williams JP, Messing E, Okunieff P. Is there a favourable subset of patients with prostate cancer who develop oligometastases?.Int J Radiat Oncol Biol Phys 2004;58(2):3-10. http://www.ncbi.nlm.nih.gov/pubmed/14697414 34. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol 1995;13(1):8-10. http://www.ncbi.nlm.nih.gov/pubmed/7799047 35. Downey RJ, Ng KK. The management of non-small-cell lung cancer with oligometastases. Chest Surg Clin North Am 2001;11(1):121–32. http://www.ncbi.nlm.nih.gov/pubmed/11253594 36. Klimo PJ, Schmidt MH. Surgical management of spinal metastases. Oncologist 2004;9(2)88-92. http://theoncologist.alphamedpress.org/cgi/content/full/9/2/188 37. Helweg-Larsen S, Sorenson PS. Symptoms and signs in metastatic spinal cord compression: a study of progression from first symptom until diagnosis in 153 patients. Eur J Cancer, 1994;30A(3):396-8. http://www.ncbi.nlm.nih.gov/pubmed/8204366

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Rades D, Stalpers LJ, Veninga T, et al. Evaluation of functional outcome and local control after radiotherapy for metastatic spinal cord compression in patients with prostate cancer. J Urol 2006;175:552-6. http://www.ncbi.nlm.nih.gov/pubmed/16406994 Sorensen PS, Helweg-Larsen S, Mouridsen H, Hansen HH. Effect of high-dose dexamethasone in carcinomatous metastatic spinal cord compression treated with radiotherapy: a randomized trial. Eur J Cancer 1994;30A(1):22-7. http://www.ncbi.nlm.nih.gov/pubmed/8142159 Rades D, Stalpers LJ, Veninga T Schulte R, Hoskin PJ, Obralic N, Bajrovic A, Rudat V, Schwarz R, Hulshof MC, Poortmans P, Schild SE. Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression. J Clin Oncol 2005;23(15):3366-75. http://www.ncbi.nlm.nih.gov/pubmed/15908648 Maranzano E, Bellavita R, Rossi R, De Angelis V, Frattegiani A, Bagnoli R, Mignogna M, Beneventi S, Lupattelli M, Ponticelli P, Biti GP, Latini P. Short-course versus split-course radiotherapy in metastatic spinal cord compression: results of a phase III, randomized multicenter trial. J Clin Oncol 2005;23(15):3358-65. http://www.ncbi.nlm.nih.gov/pubmed/15738534 George R, Jeba J, Ramkumar G, Chacko AG, Leng M, Tharyan P. Interventions for the treatment of metastatic extradural spinal cord compression in adults. Cochrane Database Syst Rev 2008;8(4):CD006716. http://www.ncbi.nlm.nih.gov/pubmed/18843728 Rades D, Lange M, Veninga T, et al. Preliminary results of spinal cord compression recurrence evaluation (score-1) study comparing short-course versus long-course radiotherapy for local control of malignant epidural spinal cord compression. Int J Radiat Oncol Biol Phys 2009;73(1):228-34. http://www.ncbi.nlm.nih.gov/pubmed/18539406 Young RF, Post EM, King GA. Treatment of spinal epidural metastases. Randomized prospective comparison of laminectomy and radiotherapy. J Neurosurg 1980;53(6):741-8. http://www.ncbi.nlm.nih.gov/pubmed/7441333 Findlay GF. Adverse effects of the management of spinal cord compression. J Neurol Neurosurg Psychiatry 1984;47(8):761-8. http://www.ncbi.nlm.nih.gov/pubmed/6470717 Fourney DR, Abi-Said D, Lang FF McCutcheon IE, Gokaslan ZL. Use of pedicle screw fixation management of malignant spinal disease: experience in 100 consecutive procedures. J Neurosurg 2001;94(1Suppl):25-37. http://www.ncbi.nlm.nih.gov/pubmed/11147865 North RB, LaRocca VR, Schwartz J North CA, Zahurak M, Davis RF, McAfee PC. Surgical management of spinal metastases: analysis of prognostic factors during a 10-year experience. J Neurosurg 2005;2(5):564-73. http://www.ncbi.nlm.nih.gov/pubmed/15945430 Wang JC, Boland P, Mitra N, Yamada Y, Lis E, Stubblefield M, Bilsky MH. Single-stage posterolateral transpedicular approach for resection of epidural metastatic spine tumors involving the vertebral body with circumferential reconstruction: results in 140 patients. J Neurosurg 2004;1(3):287-98. http://www.ncbi.nlm.nih.gov/pubmed/15478367 Klimo P, Thompson CJ, Kestle JRW, Schmidt MH. A meta-analysis of surgery versus conventional radiotherapy for the treatment of metastatic spinal epidural disease. Neuro Oncol 2005;7(1):64-76. http://www.ncbi.nlm.nih.gov/pubmed/15701283 Witham TF, Khavkin YA, Gallia GL, Wolinsky JP, Gokaslan ZL. Surgery insight: current management of epidural spinal cord compression from metastatic spine disease. Nat Clin Pract Neurol 2006;2(2): 87-94. http://www.ncbi.nlm.nih.gov/pubmed/16932530 Cole JS, Patchell RA. Metastatic epidural spinal cord compression. Lancet Neurol 2008;7(5):459-66. http://www.ncbi.nlm.nih.gov/pubmed/18420159 Patchell RA, Tibbs PA, Regine WF, Payne R, Saris S, Kryscio RJ, Mohiuddin M, Young B. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet 2005;366(9486):643-8. http://www.ncbi.nlm.nih.gov/pubmed/16112300 Townsed PW, Smalley SR, Cozad SC et al. Role of postoperative radiation therapy afterstabilization of fractures caused by metastatic disease. Int J Radiat Oncol Biol Phys 1995;31(1): 43-9. http://www.ncbi.nlm.nih.gov/pubmed/7995767

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54. Haentjens P, De Neve W, Opdecam P. Prosthesis for the treatment of metastatic bone disease of the hip: effects of radiotherapy. Bull Cancer 1995;82(11):961-70. http://www.ncbi.nlm.nih.gov/pubmed/8535023 55. Dijkstra S, Stapert J, Boxma H, Wiggers T. Treatment of pathological fractures of the humeral shaft due to bone metastases: a comparison of intramedullary locking nail and plate osteosyntesis with adjunctive bone cement. Eur J Surg Oncol 1996;22(6):621-6. http://www.ncbi.nlm.nih.gov/pubmed/9005151 56. Saarto T, Janes R, Tnehunen M et al. Palliative radiotherapy in the treatment for skeletal metastases. Eur J Pain 2002;6(5):323-30. http://www.ncbi.nlm.nih.gov/pubmed/12160506 3.3.4 Physical/psychological therapy 3.3.4.1 Physical therapies Physical techniques can be used to optimise function in patients with chronic cancer pain or enhance analgesia through the application of modalities such as electrical stimulation, heat or cryotherapy. The treatment of lymphoedema with wraps, pressure stockings or pneumatic pump devices can both improve function and relieve pain and a feeling of heaviness. The use of orthotic devices can immobilise and support painful or weakened structures, and assistive devices can be of great value to patients with pain precipitated by weightbearing or ambulation (level of evidence: 4). 3.3.4.2 Psychological therapies Psychological approaches are an integral part of the care of cancer patients with pain. All patients can benefit from psychological assessment and support (1, 2). Therapies include the following. • Cognitive-behavioural interventions can help some patients decrease the perception of distress engendered by the pain through the development of new coping skills, and the modification of thoughts, feeling and behaviours. • Relaxation methods may be able to reduce muscular tension and emotional arousal, or enhance pain tolerance (3). • Other approaches reduce anticipatory anxiety, which can lead to avoidant behaviours, or lessen the distress associated with the pain. Figure 4: Pain factors



Physical

Social Suffering Emotional

Spiritual

3.4

Pharmacotherapy

The success of therapy for cancer pain depends on the ability of the clinician to assess the presenting problems, identify and evaluate pain syndromes, and formulate a plan for comprehensive continuing care. This requires familiarity with a range of therapeutic options and an approach to long-term care that is responsive to the changing needs of the patient. This approach emphasises the need to incorporate pain treatment within a broader therapeutic agenda, in which tumour control, symptom palliation (physical and psychological), and functional rehabilitation are addressed concurrently.

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3.4.1 Antibiotics Antibiotics may be analgesic when the source of the pain involves infection (e.g. pyonephrosis, abscess, osteitis pubis). In some cases, infection may be occult and confirmed only by the symptomatic relief provided by empirical treatment with these drugs (4) (level of evidence: 2b). 3.4.2 Chemotherapy The likelihood of a successful effect on pain is generally related to the likelihood of tumour response. There is a strong clinical impression that tumour shrinkage is generally associated with relief of pain, although there are some reports of analgesic value even in the absence of significant tumour shrinkage (5) (level of evidence: 1a). 3.4.3 1.

2. 3. 4.

5.

References Fishman B. The treatment of suffering in patients with cancer pain: cognitive behavioral approaches. In: Foley K M, Bonica J J, Ventafridda V, eds. Second International Congress on Cancer Pain. Advances in pain research and therapy, vol 16. NY: Raven Press, 1990, USA, pp. 301-316. Turk D, Meichenbaum D, Genest M. Pain and behavioral medicine: A Cognitive-Behavioral Perspective. NY: Guilford Press, 1983, USA. Linton SL, Melin L. Applied relaxation in the management of cancer pain. Behav Psychother 1983;11:337-50. Coyle N, Portenoy RK. Infection as a cause of rapidly increasing pain in cancer patients. J Pain Symptom Manage 1991;6(4):266-9. http://www.ncbi.nlm.nih.gov/pubmed/2030303 Patt YZ, Peters RE, Chuang VP, Wallace S, Claghorn L, Mavligit G. Palliation of pelvic recurrence of colorectal cancer with intraarterial 5-fluorouracil and mitomycin. Cancer 1985;56(9):2175-80. http://www.ncbi.nlm.nih.gov/pubmed/2996749

3.4.4 BISPHOSPHONATES Bisphosphonates are pyrophosphate analogues. 3.4.4.1 Mechanisms of action There are four mechanisms of action. • Inhibition of bone resorption. This commences 24-48 hours after administration. The target cells are the osteoclasts. The inhibition of bone resorption is performed by three different mechanisms corresponding to the three generations of bisphosphonates. There are four distinct effects on osteoclasts: 1. reduction of osteoclastic activity 2. inhibition of osteoclast adhesion 3. decrease in number of osteoclasts 4. induction of osteoclast apoptosis. • Inhibition of crystallisation and mineralisation: clinically not relevant. • Promotion of osteoblastic bone formation and production of osteoclast resorption inhibitor. • Anti-angiogenic effect and effect on tumour cells. 3.4.4.2 Effects and side-effects The main effects are: • decrease of the risk of skeleton-related events (for example hormone refractory prostate cancer with bone metastasis [1]) (level of evidence Ib) (grade of recommendation: A). • pain response in 60-85% of the patients (1-3) (level of evidence Ib) (grade of recommendation: A). Side-effects The main side-effects are: • ‘flu-like’ symptoms (20-40%), bone pain, fever, fatigue, arthralgia and myalgia (all < 10%) • hypocalcaemia (caution: rapid infusion – older patients with vitamin D deficiency) • acute renal failure (rapid infusion); always check renal function (glomerular filtration rate) • osteonecrosis of the jaw bones (only after iv therapy) • gastrointestinal symptoms can occur after oral administration (2-10%). Points for attention The main points to note are (all grade B recommendations): • recognise and treat dehydration before administration of bisphosphonates • a reduction in the dose is necessary in the event of impaired renal function while using zoledronate (4)

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(level of evidence 2). avoid simultaneous administration of aminoglycosides (5) perform clinical examination of the patient’s mouth and jaws; avoid oral/dental surgery during administration of iv bisphosphonates (6-10) (level of evidence 2).

3.4.4.3 References 1. Saad H, Higano C, Sartor O, Colombel M, Murray R, Mason MD, Tubaro A, Schulman C. The role of bisphosphonates in the treatment of prostate cancer: recommendations from an expert panel. Clin Genitourin Cancer 2006;4(4):257-62. http://www.ncbi.nlm.nih.gov/pubmed/16729908 2. Heidenreich A, Hofmann R, Engelmann U. The use of bisphosphonates for the palliative treatment of painful bone metastasis due to hormone refractory prostate cancer. J Urol 2001;165(1):136-40. http://www.ncbi.nlm.nih.gov/pubmed/11125382 3. Weinfurt K, Anstrom K, Castel L, Schulman KA, Saad F. Effect of zoledronic acid on pain associated with bone metastasis in patients with prostate cancer. Ann Oncol 2006;17(6):986-9. http://www.ncbi.nlm.nih.gov/pubmed/16533874 4. Chang J, Green L, Beitz J. Renal failure with the use of zoledronic acid. N Engl J Med 2003;349(17):1676-9. http://www.ncbi.nlm.nih.gov/pubmed/14573746 5. Rogers M, Gordon S, Benford H. Cellular and molecular mechanisms of action of bisphosphonates. Cancer 2000;88(12):2961-78. http://www.ncbi.nlm.nih.gov/pubmed/10898340 6. Picket F. Bisphosphonate-associated osteonecrosis of the jaw: a literature review and clinical practice guidelines. J Dent Hyg 2006;80(3):10. http://www.ncbi.nlm.nih.gov/pubmed/16953991 7. Ruggiero S, Mehrota B, Rosenberg T, Engroff S. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62(5):527-34. http://www.ncbi.nlm.nih.gov/pubmed/15122554 8. Schwartz H. Osteonecrosis and bisphosphonates: correlation versus causation. J Oral Maxillofac Surg 2004;62(6):763. http://www.ncbi.nlm.nih.gov/pubmed/15181903 9. Tarassoff P, Csermak K. Avascular necrosis of the jaws: risk factors in metastatic cancer patients. J Oral Maxillofac Surg 2003;61(10):1238-9. http://www.ncbi.nlm.nih.gov/pubmed/14586868 10. Van den Wyngaert T, Huizing M, Vermorken JB. Bisphosphonates and osteonecrosis of the jaw: cause and effect or a post hoc fallacy? Ann Oncol 2006;17(8):1197-204. http://www.ncbi.nlm.nih.gov/pubmed/16873439 FURTHER READING • Barret J, Worth E, Bauss F, Epstein S. Ibandronate: a clinical, pharmalogical and pharmacokinetic update. J Clin Pharmacol 2004;44(9):951-65. http://www.ncbi.nlm.nih.gov/pubmed/15317823 • Bauss F, Body J. Ibandronate in metastatic bone disease: a review of preclinical data. Anticancer Drugs 2005;16(2):107-18. http://www.ncbi.nlm.nih.gov/pubmed/15655407 • Body JJ, Bartl R, Burckhardt P, Delmas PD, Diel IJ, Fleisch H, Kanis JA, Kyle RA, Mundy GR, Paterson AH, Rubens RD. Current use of bisphosphonates in oncology: International Bone and Cancer Study Group. J Clin Oncol 1998;16(12):3890-9. http://www.ncbi.nlm.nih.gov/pubmed/9850035 • Boissier S, Ferreras M, Peyruchaud O, Magnetto S, Ebetino FH, Colombel M, Delmas P, Delaissé JM, Clézardin P. Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res 2000;60(11):2949-54. http://www.ncbi.nlm.nih.gov/pubmed/10850442 • Boissier S, Magnetto S, Frappart L, Cuzin B, Ebetino FH, Delmas PD, Clézardin P. Bisphosphonates inhibit breast and prostate carcinoma cell adhesion to mineralized and unmineralized bone extracellular matrices. Cancer Res 1997;57(18):3890-4. http://www.ncbi.nlm.nih.gov/pubmed/9307266 • Carter G, Goss A. Bisphosphonates and avascular necrosis of the jaw. J Aust Dent 2003;48(4):268. http://www.ncbi.nlm.nih.gov/pubmed/14738134

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Corey E, Brown L, Quinn J. Zoledronic acid exhibits inhibitory effects on osteoblastic and osteolytic metastases of prostate cancer. Clin Cancer Res 2003;9(1):295-306. http://www.ncbi.nlm.nih.gov/pubmed/12538482 Eastham JA, McKiernan JM, Oefelein MG, Saad F, Schulman C, Smith M. Consensus guidelines: the use of IV bisphosphonates in the management of bone complications for patients with advanced prostate cancer. Am J Urol Rev 2004;2(2)(Supp.2):1-40. http://www.zometa.at/download/Consensus%20Guidelines%20Supplement_Am%20J%20Uro%20 2004.pdf Green J, Rogers M. Pharmacologic profile of zoledronic acid: a highly potent inhibitor of bone resorption. Drug Dev Res 2002;55:210-24. http://www3.interscience.wiley.com/journal/94519262/abstract Hoskin P. Bisphosphonates and radiation therapy for palliation of metastatic bone disease. Cancer Treat Rev 2003;29(4):321-7. http://www.ncbi.nlm.nih.gov/pubmed/12927572 Hirschberg R. Nephrotoxicity of third-generation, intravenous bisphosphonates. Toxicology 2004;196(1-2):165-7. http://www.ncbi.nlm.nih.gov/pubmed/15036766 Lin J. Bisphosphonates: a review of their pharmacokinetic properties. Bone 1996;18(2):75-85. http://www.ncbi.nlm.nih.gov/pubmed/8833200 Lipton A, Zheng M, Seaman J. Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinoma. Cancer 2003;98(5):962-9. http://www.ncbi.nlm.nih.gov/pubmed/12942563 Markowitz GS, Fine PL, Stack JI, Kunis CL, Radhakrishnan J, Palecki W, Park J, Nasr SH, Hoh S, Siegel DS, D’Agati VD. Toxic acute tubular necrosis following treatment with zoledronate (Zometa). Kidney Int 2003;64(1):281-9. http://www.ncbi.nlm.nih.gov/pubmed/12787420 Marx R. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61:1115-7. http://www.ncbi.nlm.nih.gov/pubmed/12966493 Migliorati C. Bisphosphonates and oral cavity avascular bone necrosis. J Clin Oncol 2003;21(22): 4253-4. http://www.ncbi.nlm.nih.gov/pubmed/14615459 Nancollas G, Tang R, Phipps R, Henneman Z, Gulde S, Wu W, Mangood A, Russell RG, Ebetino FH. Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone 2006;38(5):617-27. http://www.ncbi.nlm.nih.gov/pubmed/16046206 Perry C, Figgitt D. Zoledronic acid: a review of its use in patients with advanced cancer. Drugs 2004;64(11):1197-211. http://www.ncbi.nlm.nih.gov/pubmed/15161327 Roodman D. Biology of osteoclast activation in cancer. J Clin Oncol 2001;19:3562-71. http://jco.ascopubs.org/cgi/content/full/19/15/3562 Santini D, Vespasiani G, Vincenti B. The antineoplastic role of bisphosphonates: from basic research to clinical evidence. Ann Oncol 2003;14(10):1468-76. http://www.ncbi.nlm.nih.gov/pubmed/14504045 Tanvetyanon T, Stiff P. Management of the adverse effects associated with intravenous bisphosphonates. Ann Oncol 2006;17(6):897-907. http://www.ncbi.nlm.nih.gov/pubmed/16547070 Saad F, Higano CS, Sartor O, Colombel M, Murray R, Mason MD, Tubaro A, Schulman C. The role of bisphosphonates in the treatment of prostate cancer: recommendations from an expert panel. Clin Genitourin Cancer 2006; 4(4): 257-62. http://www.ncbi.nlm.nih.gov/pubmed/16729908

3.4.5 Systemic analgesic pharmacotherapy - the ‘analgesic ladder’ Analgesic pharmacotherapy is the mainstay of cancer pain management (1-3). Although concurrent use of other interventions is valuable in many patients, and essential in some, analgesic drugs are needed in almost every case. Based on clinical convention, analgesic drugs can be separated into three groups: • non-opioid analgesics • opioid analgesics • adjuvant analgesics, which are drugs with other primary indications that can be effective analgesics in

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specific circumstances. An expert committee convened by the Cancer Unit of the WHO has proposed a useful approach to drug selection for cancer pain, which has become known as the ‘analgesic ladder’ (1, 3). When combined with appropriate dosing guidelines, this approach is capable of providing adequate relief to 70-90% of patients (4, 5). Emphasising that pain intensity should be the prime consideration in analgesic selection, the approach advocates three basic steps (Figure 4) (level of evidence: 1a). Figure 4: The World Health Organization’s ‘analgesic ladder’



Step3 Non-opioid analgesics + strong opioids + adjuvant analgesics

Step 2 Non-opioid analgesics + weak opioids + adjuvant analgesics Step 1 Non-opioid analgesics + adjuvant analgesics

Step 1 Patients with mild to moderate cancer-related pain should be treated with a non-opioid analgesic, which should be combined with an adjuvant analgesic if a specific indication for one exists. Step 2 Patients who present with moderate to severe pain, or who fail to achieve adequate relief after a trial of a non-opioid analgesics, should be treated with a weak opioid. This treatment is typically accomplished using a combination product containing a non-opioid (e.g. aspirin or paracetamol) and an opioid (such as codeine, oxycodone or propoxyphene). This drug can also be co-administered with an adjuvant analgesic. Step 3 Patients who present with severe pain, or who fail to achieve adequate relief following appropriate administration of drugs on the second rung of the ‘analgesic ladder’, should receive a strong opioid, such as morphine or hydromorphone. This drug may also be combined with a non-opioid analgesic or an adjuvant drug. 3.4.5.1 Non-opioid analgesics The main points to note are: • non-opioid analgesics = aspirin, paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) • can be useful alone for mild to moderate pain (step 1 of the analgesic ladder) • provide analgesia when combined with opioids • have a ceiling effect of analgesic efficacy • no tolerance or physical dependence • inhibit the enzyme cyclo-oxygenase and block the synthesis of prostaglandins • involvement of central mechanisms are also likely in paracetamol analgesia (6) • potential adverse effects (7): bleeding diathesis due to inhibition of platelet aggregation, gastroduodenopathy (including peptic ulcer disease) and renal impairment, are the most common; less common adverse effects include confusion, precipitation of cardiac failure and exacerbation of hypertension; particular caution must be used in elderly patients and those with blood-clotting disorders, predisposition to peptic ulceration, impaired renal function and concurrent corticosteroid therapy • non-acetylated salicylates (choline magnesium trisalicylate and salsalate) are preferred in patients who have a predilection to bleeding; these drugs have less effect on platelet aggregation and no effect on bleeding time at the usual clinical doses

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•

 aracetamol also rarely produces gastrointestinal toxicity and there are no adverse effects on platelet p function; hepatic toxicity is possible, however, and patients with chronic alcoholism and liver disease can develop severe hepatotoxicity at the usual therapeutic doses (8).

3.4.5.2 Opioid analgesics Cancer pain of moderate or severe intensity should generally be treated with a systemically administered opioid analgesic (9). Classification Classification is based on their interactions with the various receptor subtypes: • agonist: most commonly used in clinical pain management, no ceiling effect • agonist-antagonist (pentazocine, nalbuphine and butorphanol): ceiling effect for analgesia. Relative potency and equi-analgesic doses By convention, the relative potency of each of the commonly used opioids is based on a comparison with 10 mg of parenteral morphine. Equi-analgesic dose information provides guidelines for dose selection when the drug or route of administration is changed (10). Selecting patients for opioid therapy A trial of systemic opioid therapy should be administered to all cancer patients with moderate or severe pain. This is true regardless of the pain mechanism (10-13). Patients who present with severe pain should be treated with a ‘strong’ opioid from the start. Patients with moderate pain are commonly treated with a combination drug containing paracetamol or aspirin plus codeine, oxycodone or propoxyphene. The dose of these combination products can be increased until the maximum dose of the non-opioid co-analgesic is attained (e.g. 4000 mg paracetamol). 3.4.5.2.1 Opioid administration Opioid selection Factors to consider include the following: • pain intensity • patient age • prior opioid therapy (response to previous trials of opioid therapy) • co-existing disease • influence of underlying illness and characteristics of the opioid and concurrent medications. Routes of administration Classification is on the basis of the degree of invasiveness. Opioids should be administered by the least invasive and safest route capable of providing adequate analgesia. In a survey of patients with advanced cancer, more than half required two or more routes of administration prior to death, and almost a quarter required three or more. Non-invasive routes • Oral routes are the preferred approach in routine practice. Alternative routes are necessary for patients who have impaired swallowing or gastrointestinal dysfunction, those who require a very rapid onset of analgesia, and those who are unable to utilise or tolerate the oral route. • Rectal suppositories containing oxycodone, hydromorphone, oxycodone and morphine in combination have been formulated, and controlled-release morphine tablets can also be administered per rectum. The potency of opioids administered rectally is believed to approximate to oral dosing (14). • Transdermal routes: fentanyl and buprenorphine are the opioids for transdermal administration. The system has been demonstrated to be effective in post-operative pain and cancer pain (15). In addition, the fentanyl transdermal therapeutic system dosing interval is usually 72 hours, but some patients require a 48-hour schedule. There is some interindividual variability in fentanyl bioavailability by this route, and this phenomenon, combined with large differences in elimination pharmacokinetics, necessitates dose titration in most cases (16). The efficacy of fentanyl administered transdermally is equal to morphine. The incidence of side-effects such as sedation and constipation are lower compared with morphine (17, 18) (level of evidence: 1b). Transdermal patches capable of delivering 12, 25, 50, 75 and 100 mg/h are available. Multiple patches can be used simultaneously for patients who require higher doses. Currently, the limitations of the transdermal delivery system include its cost and the requirement for an alternative short-acting opioid

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for breakthrough pain. Recently, buprenorphine has become available for transdermal administration. Buprenorphine, a highaffinity partial μ-opioid agonist, is in clinical use for the treatment of acute and chronic pain (19). Its analgesic effect is comparable with that of other opioids, and it shows no relevant analgesic ceiling effect throughout the therapeutic dose range (20). Unlike full μ-opioid agonists, at higher doses, buprenorphine’s physiological and subjective effects, including respiratory depression and euphoria, reach a plateau. This ceiling may limit the abuse potential, and might result in a wider safety margin (21). Additionally, dose adaptations are not necessary in patients with renal and/or hepatic impairment. Pre-clinical and clinical trials demonstrate the effectiveness of buprenorphine in the treatment of neuropathic pain. In a human model, administration of buprenorphine led to the alleviation of hyperalgesia (comparable with S(+)-ketamine). These studies provide promising evidence for the use of buprenorphine in neuropathic pain conditions. • Sublingual absorption of any opioid could potentially yield clinical benefits, but bioavailability is very poor with drugs that are not highly lipophilic and the likelihood of an adequate response is consequently low (22). Sublingual buprenorphine, a relatively lipophilic partial agonist, can provide adequate relief of mild to moderate cancer pain. Overall, however, the sublingual route has limited value due to the lack of formulations, poor absorption of most drugs, and the inability to deliver high doses or prevent swallowing of the dose. An oral transmucosal formulation of fentanyl, which incorporates the drug into a sugar base, is useful for providing rapid relief of breakthrough pain (23, 24). Additionally, this opioid delivery system using fentanyl is more effective in terms of pain relief than oral morphine (level of evidence: 2). Recommendation GR • Oral transmucosal administration of fentanyl should be used to provide rapid pain relief of B breakthrough pain. The starting dose is 400 μg; or 200 μg in the elderly, those with a history of opioid sensitivity or underlying pulmonary disease GR = grade of recommendation Invasive routes For patients undergoing a trial of systemic drug administration, a parenteral route must be considered when the oral route is not available. Repeated parenteral bolus injections, which can be administered by intravenously (iv), intramuscularly (im) or subcutaneously (sc), may be useful in some patients, but are often compromised by the occurrence of prominent ‘bolus’ effects (toxicity at peak concentration and/or pain breakthrough at the trough). Repetitive im injections are a common practice, but they are painful and offer no pharmacokinetic advantage; their use is not recommended (25). • Intravenous bolus administration provides the most rapid onset and shortest duration of action. Time to peak effect correlates with the lipid solubility of the opioid, and ranges from 2-5 minutes for methadone, to 10-15 minutes for morphine (26). This approach is appropriate in two settings: - to provide parenteral opioids, usually transiently, to patients who already have venous access and are unable to tolerate oral opioids - to treat very severe pain, for which iv doses can be repeated at an interval as brief as that determined by the time to peak effect, if necessary, until adequate relief is achieved. • Continuous parenteral infusions are useful for many patients who cannot be maintained on oral opioids. Long-term infusions may be administered iv or sc. In practice, the major indication for continuous infusion occurs in patients who are unable to swallow or absorb opioids. Continuous infusion is also used in some patients whose high opioid requirement renders oral treatment impractical (27). Ambulatory patients can easily use a continuous sc infusion using a 27-gauge ‘butterfly’ needle. The butterfly can be left under the skin for up to a week. A recent study demonstrated that the bioavailability of hydromorphone is 78% by this route (28), and clinical experience suggests that dosing may proceed in a manner identical to that for continuous iv infusion. A range of pumps is available that vary in complexity, cost and ability to provide patient-controlled ‘rescue doses’ as an adjunct to a continuous basal infusion. Opioids suitable for continuous sc infusion must be soluble, well absorbed and non-irritant. Extensive experience has been reported with diamorphine, hydromorphone, oxycodone and morphine (29). Methadone appears to be relatively irritating and is not preferred (30). To maintain the comfort of an infusion site, the sc infusion rate should not exceed 5 cc/h. The infraclavicular and anterior chest sites provide the greatest freedom of movement for patients, but other sites can be used. A single infusion site can usually be maintained for 5-7 days.

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Changing routes of administration The switch between oral and parenteral routes should be guided by a knowledge of relative potency to avoid subsequent overdosing or underdosing. In calculating the equi-analgesic dose, the potencies of the iv, sc and im routes are considered equivalent. Perform changes in steps slowly, e.g. gradually reducing the parenteral dose and increasing the oral dose over a 2-3 day period (level of evidence: 3). Dosing Around-the-clock’ (ATC) dosing Patients with continuous or frequent pain generally benefit from scheduled ‘around-the-clock’ dosing, which can provide the patient with continuous relief by preventing the pain from recurring. Clinical vigilance is required, however, when this approach is used in patients with no previous opioid exposure. Patients should also be provided with a so-called ‘rescue dose’, which is a supplemental dose offered on an ‘as needed’ basis to treat pain that breaks through the regular schedule. The integration of ‘around-the-clock’ dosing with ‘rescue doses’ provides a gradual method for safe and rational dose escalation, which is applicable to all routes of opioid administration. Controlled-release drug formulations Controlled release preparations of oral opioids can lessen the inconvenience associated with the use of ‘around-the-clock’ administration of drugs with a short duration of action. Numerous studies have demonstrated the safety and efficacy of these preparations in cancer patients with pain (31, 32). ‘As needed’ (prn) dosing This strategy is beneficial when rapid dose escalation is needed or therapy is begun with a long half-life opioid such as methadone or levorphanol. ‘As needed’ dosing may also be appropriate for patients who have rapidly decreasing analgesic requirements or intermittent pains separated by pain-free intervals. Patient-controlled analgesia (PCA) This is a technique of parenteral drug administration in which the patient controls an infusion device that delivers a bolus of analgesic drug ‘on demand’ according to parameters set by the physician. Long-term PCA in cancer patients is most commonly accomplished via the subcutaneous route using an ambulatory infusion device. In most cases, PCA is added to a basal infusion rate and acts essentially as a rescue dose. 3.4.5.2.2 Adverse effects and their management Tolerance Patients vary greatly in the opioid dose required to manage pain (400-2000 mg of im morphine per 24 hours) (33). The induction of true analgesic tolerance that could compromise the utility of treatment can only be said to occur if a patient manifests the need for increasing opioid doses in the absence of other factors (e.g. progressive disease) that would be capable of explaining the increase in pain. Extensive clinical experience suggests that most patients who require an escalation in dose to manage increasing pain have demonstrable progression of disease (34). These observations suggest that true pharmacological tolerance to the analgesic effects of opioids is not a common clinical problem. This conclusion has two important implications: • concern about tolerance should not impede the use of opioids early in the course of the disease • worsening pain in a patient receiving a stable dose of opioids should not be attributed to tolerance, but should be assessed as presumptive evidence of disease progression or, less commonly, increasing psychological distress. Adverse drug interactions The potential for additive side-effects and serious toxicity from drug combinations must be recognised. The sedative effect of an opioid may add to that produced by numerous other centrally acting drugs, such as anxiolytics, neuroleptics and antidepressants. Likewise, constipation produced by opioids is probably worsened by anticholinergic drugs. Respiratory depression Respiratory depression is potentially the most serious adverse effect of opioid therapy. All phases of respiratory activity (rate, minute volume and tidal exchange) may be impaired by these drugs. Clinically significant respiratory depression is always accompanied by other signs of central nervous system depression, including sedation and mental clouding. With repeated opioid administration, tolerance appears to develop rapidly to the respiratory depressant effects of the opioid drugs. As a result, opioid analgesics can be used in the management of chronic cancer pain without significant risk of respiratory depression. When respiratory depression occurs in patients on chronic opioid therapy, administration of the specific opioid antagonist

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naloxone usually improves ventilation. Sedation Sedation usually persists until tolerance to this effect develops, usually within a period of days to weeks. It is useful to forewarn patients of this potential, and thereby reduce anxiety and encourage avoidance of activities such as driving that may be dangerous if sedation occurs. Some patients have a persistent problem with sedation, particularly in combination with other sedating drugs or co-existent diseases such as dementia, metabolic encephalopathy or brain metastases. Confusion and delirium Confusion is a greatly feared effect of opioid drugs, and mild cognitive impairment is common (35). However, similar to sedation, pure opioid-induced encephalopathy appears to be transient in most patients, persisting from days to 1-2 weeks. Although persistent confusion attributable to opioids alone does occur, the aetiology of persistent delirium is usually related to the combined effect of the opioid and other contributing factors, including electrolyte disorders, neoplastic involvement of the central nervous system, sepsis, vital organ failure and hypoxaemia (36). A stepwise approach to management often culminates in a trial of a neuroleptic drug. Haloperidol in low doses (0.5-1.0 mg orally or 0.25-0.5 mg iv or im) is most commonly recommended because of its efficacy and low incidence of cardiovascular and anticholinergic effects. Constipation Constipation is the most common adverse effect of chronic opioid therapy (37-39). Laxative medications should be prescribed prophylactically. There are no controlled comparisons of the various laxatives for opioid-induced constipation, and published recommendations are based entirely on anecdotal experience. Combination therapy is frequently used, particularly co-administration of a softening agent (docusate) and a cathartic (e.g. senna, bisocodyl or phenolphthalein). The doses of these drugs should be increased as necessary, and an osmotic laxative (e.g. milk of magnesia) should be added if needed. Chronic lactulose therapy is an alternative that some patients prefer, and occasional patients are managed with intermittent colonic lavage using an oral bowel preparation. Nausea and vomiting Opioids may produce nausea and vomiting through both central and peripheral mechanisms. These drugs stimulate the medullary chemoreceptor trigger zone, increase vestibular sensitivity, and have effects on the gastrointestinal tract (including increased gastric antral tone, diminished motility and delayed gastric emptying). In ambulatory patients, the incidence of nausea and vomiting has been estimated to be 10-40% and 15-40%, respectively (40). The likelihood of these effects is greatest at the start of opioid therapy. Metoclopramide is the most reasonable initial treatment. Tolerance typically develops within weeks. Routine prophylactic administration of an antiemetic is not necessary. The serotonin antagonists (e.g. ondansetron) are not likely to be effective with opioid-induced symptoms since they do not eliminate apomorphine-induced vomiting and motion sickness, which appear to be appropriate models for opioid effects. Clinical trials of the latter agents are needed to confirm this conclusion. Addiction and dependence Confusion about physical dependence and addiction augment the fear of opioid drugs and contribute substantially to the undertreatment of pain (41). Patients with chronic cancer pain have a ‘therapeutic dependence’ on their analgesic pharmacotherapy. This relationship may or may not be associated with the development of physical dependence, but is virtually never associated with addiction. The medical use of opioids is very rarely associated with the development of addiction (42). Although there are no prospective studies in patients with chronic cancer pain, there is extensive clinical experience that affirms the extremely low risk of addiction in this population (level of evidence: 3). Healthcare providers, patients and families often require vigorous and repeated reassurance that the risk of addiction is extremely small. 3.4.5.2.3 Adjuvant analgesics An ‘adjuvant analgesic’ is defined as a drug that has a primary indication other than pain but is analgesic in some conditions. These drugs may be combined with primary analgesics in any of the three steps of the ‘analgesic ladder’ to improve the outcome for patients who cannot otherwise attain an acceptable balance

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between relief and side-effects. In the management of cancer pain, adjuvant analgesics can be broadly classified on the basis of conventional use. The following three groups are distinguished. •

•

•

Corticosteroids  These are among the most widely used adjuvant analgesics (43, 44). They have been demonstrated to have analgesic effects, to improve quality of life significantly (45), and to have beneficial effects on appetite, nausea, mood and malaise in the cancer population (46). The mechanism of analgesia produced by these drugs may involve anti-oedemic effects, anti-inflammatory effects, and a direct influence on the electrical activity in damaged nerves. Patients with advanced cancer who experience pain and other symptoms may respond favourably to a relatively small dose of corticosteroids (e.g. dexamethasone 1-2 mg twice daily) (level of evidence: 2a). Neuroleptics  The role of neuroleptic drugs in the management of cancer pain is limited. Methotrimeprazine is a proven analgesic that has been very useful in bedridden patients with advanced cancer who experience pain associated with anxiety, restlessness or nausea. In this setting, the sedative, anxiolytic and antiemetic effects of this drug can be highly favourable, and side-effects, such as orthostatic hypotension, are less of an issue. A prudent dosing schedule begins with 5-10 mg every 6 hours, which is gradually increased as needed (level of evidence: 1a). Benzodiazepines  Benzodiazepines have an analgesic effect (47), but this must be balanced by the potential for side-effects, including sedation and confusion. These drugs are generally used only if another indication exists, such as anxiety or insomnia (level of evidence: 2b).

3.4.5.2.4 References 1. World Health Organization. Cancer pain relief and palliative Care. Report of a WHO expert committee. World Health Organization Technical Report Series, 804. Geneva, Switzerland: World Health Organization, 1990. http://www.who.int/bookorders/anglais/detart1.jsp 2. Foley KM. The treatment of cancer pain. N Eng J Med 1985;313(2):84-95. http://www.ncbi.nlm.nih.gov/pubmed/2582259 3. World Health Organization. Cancer pain relief. World Health Organization. Geneva, Switzerland: World Health Organization, 1986. 4. Schug SA, Zech D, Dorr U. Cancer pain management according to WHO analgesic guidelines. J Pain Symptom Manage 1990;5(1):27-32. http://www.ncbi.nlm.nih.gov/pubmed/2324558 5. Grond S, Zech D, Schug SA, Lynch J, Lehman KA. Validation of the World Health Organization guidelines for cancer pain relief during the last days and hours of life. J Pain Symptom Manage 1991;6(7):411-22. http://www.ncbi.nlm.nih.gov/pubmed/1940485 6. Malmberg AB, Yaksh TL. Hyperalgesia mediated by spinal glutamate and substance P receptor blocked by spinal cyclooxygenase inhibition. Science 1992;92(5074):1276-9. http://www.ncbi.nlm.nih.gov/pubmed/1381521 7. Brooks PM, Day RO. Nonsteroidal antiinflammatory drugs - differences and similarities. N Eng J Med 1991;324(24):1716-25. http://www.ncbi.nlm.nih.gov/pubmed/2034249 8. Seeff LB, Cuccherini BA, Zimmerman HJ, Adler E, Benjamin SB. Acetaminophen hepatotoxicity in alcoholics. A therapeutic misadventure. Ann Intern Med 1986;104(3):399-404. http://www.ncbi.nlm.nih.gov/pubmed/3511825 9. Hanks GW, Conno F, Cherny N, Hanna M, Kalso E, McQuay HJ, Mercadante S, Meynadier J, Poulain P, Ripamonti C, Radbruch L, Casas JR, Sawe J, Twycross RG, Ventafridda V; Expert Working Group of the Research Network of the European Association for Palliative Care. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer 2001;84(5):587-93. http://www.ncbi.nlm.nih.gov/pubmed/11237376 10. Cherny NI, Thaler HT, Friedlander-Klar H, Lapin J, Foley KM, Houde R, Portenoy RK. Opioid responsiveness of cancer pain syndromes caused by neuropathic or nociceptive mechanisms: a combined analysis of controlled, single-dose studies. Neurology 1994;44(5):857-61. http://www.ncbi.nlm.nih.gov/pubmed/7514771 11. Jadad AR, Carroll D, Glynn CJ, Moore RA, McQuay HJ. Morphine responsiveness of chronic pain: double blind randomised crossover study with patient controlled analgesia. Lancet 1992;339(8806):1367-71. http://www.ncbi.nlm.nih.gov/pubmed/1350803

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12.

McQuay HJ, Jadad AR, Carroll D, Faura C, Glynn CJ, Moore RA, Liu Y. Opioid sensitivity of chronic pain: a patient-controlled analgesia method. Anaesthesia 1992;47(9):757-67. http://www.ncbi.nlm.nih.gov/pubmed/1415972 13. Eisenberg E, McNicol ED, Carr DB. Efficacy and safety of opioid agonists in the treatment of neuropathic pain of nonmalignant origin: systematic review and meta-analysis of randomized controlled trials. JAMA 2005;293(24):3043-52. http://www.ncbi.nlm.nih.gov/pubmed/15972567 14. Hanning CD. The rectal absorption of opioids. In: Benedetti C, Chapman C R, Giron G, eds. Opioid analgesia. Advances in pain research and therapy, vol 14. NY: Raven Press, 1990, pp. 259-269. 15. Calis KA, Kohler DR, Corso DM. Transdermally administered fentanyl for pain management. Clin Pharm 1992;11(1):22-36. http://www.ncbi.nlm.nih.gov/pubmed/1730176 16. Portenoy RK, Southam MA, Gupta SK, Lapin J, Layman M, Inturrisi CE, Foley KM. Transdermal fentanyl for cancer pain. Repeated dose pharmacokinetics. Anesthesiology 1993;78(1):36-43. http://www.ncbi.nlm.nih.gov/pubmed/8424569 17. Clark AJ, Ahmedzai SH, Allan LG, Camacho F, Horbay GL, Richarz U, Simpson K. Efficacy and safety of transdermal fentanyl and sustained-release oral morphine in patients with cancer and chronic noncancer pain. Curr Med Res Opin 2004;20(9):1419-28. http://www.ncbi.nlm.nih.gov/pubmed/15383190 18. Ahmedzai S, Brooks D. Transdermal fentanyl versus sustained-release oral morphine in cancer pain: preference, efficacy, and quality of life. J Pain Symptom Manage 1997;13(5):254-61. http://www.ncbi.nlm.nih.gov/pubmed/9185430 19. Koppert W, Ihmsen H, Körber N, Wehrfritz A, Sittl R, Schmelz M, Schüuttler J. Different profiles of buprenorphine-induced analgesia and antihyperalgesia in a human pain model. Pain 2005;118 (1-2):15–22. http://www.ncbi.nlm.nih.gov/pubmed/16154698 20. Sittl R. Transdermal buprenorphine in the treatment of chronic pain. Expert Rev Neurother 2005;5(3):315-23. http://www.ncbi.nlm.nih.gov/pubmed/15938664 21. Johnson RE, Fudala PJ, Payne R. Buprenorphine: considerations for pain management. J Pain Symptom Manage 2005;29(3):297-326. http://www.ncbi.nlm.nih.gov/pubmed/15781180 22. Weinberg DS, Inturrisi CE, Reidenberg B, Moulin DE, Nip TJ, Wallenstein S, Houde RW, Foley KM. Sublingual absorption of selected opioid analgesics. Clin Pharmacol Ther 1988;44(3):335-42. http://www.ncbi.nlm.nih.gov/pubmed/2458208 23. Coluzzi PH, Schwartzberg L, Conroy JD, Charapata S, Gay M, Busch MA, Chavez J, Ashley J, Lebo D, McCracken M, Portenoy RK. Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain 2001;91 (1-2):123-30. http://www.ncbi.nlm.nih.gov/pubmed/11240084 24. Fine PG, Marcus M, DeBoer AJ, Van der Oord B. An open label study of oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough cancer pain. Pain 1991;45(2):149-53. http://www.ncbi.nlm.nih.gov/pubmed/1876422 25. American Pain Society. Principles of analgesic use in the treatment of acute pain and chronic cancer pain. A concise guide to medical practice, 3rd edn. Skokie, IL: American Pain Society, 1992. 26. Chapman CR, Hill HF, Saeger L, Gavrin J. Profiles of opioid analgesia in humans after intravenous bolus administration: alfentanil, fentanyl and morphine compared on experimental pain. Pain 1990;43(1):47-55. http://www.ncbi.nlm.nih.gov/pubmed/1980537 27. Storey P, Hill HH Jr , St Louis RH, Tarver EE. Subcutaneous infusions for control of cancer symptoms. J Pain Symptom Manage 1990;5(1):33-41. http://www.ncbi.nlm.nih.gov/pubmed/1969887 28. Moulin DE, Kreeft JH, Murray-Parsons N, Bouquillon AI. Comparison of continuous subcutaneous and intravenous hydromorphone infusions for management of cancer pain. Lancet 1991;337(8739):465-8. http://www.ncbi.nlm.nih.gov/pubmed/1704089 29. Moulin DE, Johnson NG, Murray-Parsons N, Geoghegan MF, Goodwin VA, Chester MA. Subcutaneous narcotic infusions for cancer pain: treatment outcome and guidelines for use. CMAJ 1992;146(6):891-7. http://www.ncbi.nlm.nih.gov/pubmed/1371946

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30.

31.

32.

33.

34. 35.

36. 37.

38. 39. 40.

41.

42.

43.

44.

45.

46.

47.

Bruera E, Fainsinger R, Moore M, Thibault R, Spoldi E, Ventafridda V. Local toxicity with subcutaneous methadone. Experience of two centers. Pain 1991;45(2):141-3. http://www.ncbi.nlm.nih.gov/pubmed/1876420 Kaiko RF. Clinical protocol and role of controlled release morphine the surgical patient. In: Stanley TH, Ashburn MA, Fine PG, eds. Anesthesiology in pain management. Dordrecht, The Netherlands: Kluwer Academic, 1991, pp. 193-212. Walsh TD, MacDonald N, Bruera E, Shepard KV, Michaud M, Zanes R. A controlled study of sustained-release morphine sulfate tablets in chronic pain from advanced cancer. Am J Clin Oncol 1992;15(3):268-72. http://www.ncbi.nlm.nih.gov/pubmed/1590284 Coyle N, Adelhardt J, Foley KM, Portenoy RK. Character of terminal illness in the advanced cancer patient: pain and other symptoms during last four weeks of life. J Pain Symptom Manage 1990;5(2):83-93. http://www.ncbi.nlm.nih.gov/pubmed/2348092 Foley KM. Clinical tolerance to opioids. In: Basbaum AI, Bessom JM, eds. Towards a newpharmacotherapy of pain. Chichester, UK: Dahlem Konferenzen, John Wiley, 1991, pp. 181-204. Bruera E, Macmillan K, Hanson J, MacDonald RN. The cognitive effects of the administration of narcotic analgesics in patients with cancer pain. Pain 1989;39(1):13-6. http://www.ncbi.nlm.nih.gov/pubmed/2812850 Breitbart W, Holland JC. Psychiatric complications of cancer. Curr Ther in Hematol Oncol 1988;3: 268-75. Inturrisi CE. Management of cancer pain. Pharmacology and principles of management. Cancer 1989;63(11 Suppl):2308-20. http://www.ncbi.nlm.nih.gov/pubmed/2566371 Walsh TD. Prevention of opioid side effects. J Pain Symptom Manage 1990;5(6):362-7. http://www.ncbi.nlm.nih.gov/pubmed/1980127 Sykes NP. Oral naloxone in opioid- associated constipation. Lancet 1991;337(8755):1475. http://www.ncbi.nlm.nih.gov/pubmed/1675336 Campora E, Merlini L, Pace M, Bruzzone M, Luzzani M, Gottlieb A, Rosso R. The incidence of narcotic induced emesis. J Pain Symptom Manage 1991;6(7):428-30. http://www.ncbi.nlm.nih.gov/pubmed/1940487 Schuster CR. Does treatment of cancer pain with narcotics produce junkies?. In: Hill CS, Fields WS, eds. Drug treatment of cancer pain in a drug oriented society. Advances in pain research and therapy, vol 11. NY: Raven Press, 1989; pp. 1-3. Chapman CR, Hill HF. Prolonged morphine self-administration and addiction liability. Evaluation of two theories in a bone marrow transplant unit. Cancer 1989;63(8):1636-44. http://www.ncbi.nlm.nih.gov/pubmed/2466551 Walsh TD. Adjuvant analgesic therapy in cancer pain. In: Foley KM, Bonica JJ, Ventafridda V (eds). The Second International Conference on Cancer Pain. Advances in pain research and therapy, vol 16. New York, NY: Raven Press, 1990, pp. 155-168. Della Cuna GR, Pellegrini A, Piazzi M. Effect of methylprednisolone sodium succinate on quality of life in preterminal cancer patients. A placebo controlled multicenter study. The Methylprednisolone Preterminal Cancer Study Group. Eur J Cancer Clin Oncol 1989;25(12):1817-21. http://www.ncbi.nlm.nih.gov/pubmed/2698804 Tannock I, Gospodarowicz M, Meakin W, Panzarella T, Stewart L, Rider W. Treatment of metastatic prostatic cancer with low-dose prednisone: evaluation of pain and quality of life as pragmatic indices of response. J Clin Oncol 1989;7(5):590-7. http://www.ncbi.nlm.nih.gov/pubmed/2709088 Wilcox JC, Corr J, Shaw J, Richardson M, Calman KC, Drennan M. Prednisolone as appetite stimulant in patients with cancer. Br Med J (Clin Res Ed) 1984;288(6410):27. http://www.ncbi.nlm.nih.gov/pubmed/6418303 Fernandez F, Adams F, Holmes VF. Analgesic effect of alprazolam in patients with chronic, organic pain of malignant origin. J Clin Psychopharmacol 1987;7(3):167-9. http://www.ncbi.nlm.nih.gov/pubmed/3597802

3.4.5.3 Treatment of neuropathic pain Numerous treatment options are available for relieving neuropathic pain, including opioids, with which patients experience significant pain reduction with greater satisfaction than with antidepressants (1, 2). Although opioids are clearly efficacious in the treatment of neuropathic pain, the prospect of commencing an analgesic whose use may be complicated by analgesic tolerance, withdrawal reactions after discontinuation, and always a

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(slight) possibility of addiction is not satisfactory (3). Beside opioids, the available therapies shown to be effective in managing neuropathic pain include antidepressants, anticonvulsants, topical treatments (lidocaine patch, capsaicin), N-methyl-D-aspartate (NMDA) receptor antagonists, baclofen, local anaesthetics, and clonidine (4, 5). 3.4.5.3.1 Antidepressants There is clear evidence for the effectiveness of antidepressants in the treatment of neuropathic pain (5). The primary mode of action is an interaction with pathways running through the spinal cord from serotoninergic and noradrenergic structures in the brain stem and mid-brain. Tricyclic antidepressants (TCA) including amitriptyline, nortriptyline (metabolite of amitriptyline), imipramine, and desipramine (metabolite of imipramine), are often the first drugs selected to alleviate neuropathic pain (level of evidence: 1a) (6, 7). The mechanism of action is predominantly by blocking the reuptake of norepinephrine and serotonin (dualacting), together with a blockade of neuronal membrane ion channels (reducing neuronal influx of Ca2+ or Na+), and interaction with adenosine and NMDA receptors. However, treatment with these analgesics may be compromised (and outweighed) by their side-effects. TCA must be used cautiously in patients with a history of cardiovascular disorders, glaucoma, and urine retention. In addition, combination therapy with monoaminooxidase inhibitors could result in the development of serotonin syndrome. Duloxetine enhances both serotonin and norepinephrine function in descending modulatory pathways. It has weak affinity for the dopamine transporter and insignificant affinity at several neurotransmitters, including muscarinic, histamine, glutamate, and gamma-aminobutyric acid (GABA) receptors. Duloxetine has demonstrated a significant pain-relieving effect with a generally favourable side-effect profile in painful diabetic neuropathy (7) (level of evidence: 1b). Selective serotonin reuptake inhibitors (SSRI: sertraline, paroxetine, fluoxetine and citalopram) selectively inhibit the reuptake of serotonin. These antidepressants have a more favourable side-effect profile than TCA, but their effectiveness in managing neuropathic pain is disputed due to conflicting reports in the available literature (second-line pharmacological treatment). Recommendation GR • Amitriptyline and nortriptyline are the first line treatment for neuropathic pain; nortriptyline has A fewer side-effects • TCA must be used cautiously in patients with a history of cardiovascular disorders, glaucoma, and urine retention • Duloxetine is the first-line treatment for neuropathic pain due to diabetic polyneuropathy A • Duloxetine may be tried as an analgesic in other neuropathic pain syndromes GPP GGP = good clinical practice; GR = grade of recommendation 3.4.5.3.2 Anticonvulsant medication The rationale for the use of antiepileptic drugs in treating neuropathic pain is the reduction of neuronal hyperexcitability, one of the key processes in the development and maintenance of neuropathic pain (8). Different anticonvulsants have demonstrated pain relief by a blockade of neuronal membrane ion channels (reducing neuronal influx of Ca2+ or Na+), effects on neurotransmitters (enhancement of GABA, inhibition of glutamate release), and/or neuromodulation systems (blocking the NMDA receptor) (9, 10). Initially, carbamazepine and phenytoin were used for the treatment of trigeminus neuralgia. Although both drugs reduce neuropathic pain, their attendant side-effects and complicated pharmacokinetic profile limit their use in treating neuropathic pain. Despite the introduction of these newer anticonvulsants with a more favourable side-effect profile, carbamazepine remains the drug of choice in treatment of trigeminus neuralgia (level of evidence: 1a) (11). However, oxcarbazepine (10-keto analogue of carbamazepine), a new anticonvulsant with similar mechanism of action to that of carbamazepine but with a better side-effect profile, may replace carbamazepine for treating trigeminus neuralgia (12). Gabapentin and pregabalin (level of evidence: 1a) are emerging as first-line treatments for neuropathic pain (reducing elements of central sensitisation), especially in post-zoster neuralgia and diabetic polyneuropathy (13-15). More recently, the combination of gabapentin with opioids seems to display synergistic effects in relieving neuropathic pain (16, 17). Gabapentin has a favourable safety profile with minimal concern for drug interactions and no interference with hepatic enzymes. However, renal failure results in higher gabapentin concentrations and a longer elimination half-life, making dose adjustments necessary. Pregabalin (3-isobutyl

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GABA) is a structural analogue of gabapentin, but showed greater analgesic activity in rodent models of neuropathic pain than gabapentin (18). Recent studies confirm the effectiveness of pregabalin in peripheral (including post-herpetic neuralgia and diabetic polyneuropathy) and central neuropathic pain (19). Recommendation GR • Gabapentin and pregabalin are first line treatments for neuropathic pain, especially if TCA are A contraindicated GR = grade of recommendation 3.4.5.3.3 Topical analgesics Neuropathic pain syndromes are typically associated with touch-evoked allodynia and hyperalgesia that impair patients’ quality of life. Besides treatment with anticonvulsants and antidepressants, the application of a topical drug on to the painful area of skin can be effective in treating ongoing pain and allodynia, supporting the idea that peripheral actions are of key importance in the initiation and maintenance of neuropathic pain. Topical treatments for neuropathic pain include the 5% lidocaine patch, and capsaicin. The 5% lidocaine patch, a targeted peripheral analgesic, is effective in the treatment of post-herpetic neuralgia and a variety of other focal peripheral neuropathies (20, 21) (first-line pharmacological treatment; level of evidence: 1b). The 5% lidocaine patch (up to three patches, once daily for 12 hours) is applied to the painful skin, covering as much of the affected area as possible. Capsaicin causes pain due to a release of substance P (initiating nociceptive firing) from the nociceptive terminals. Subsequently, an analgesic response follows because prolonged exposure to capsaicin desensitises the nociceptive terminals and elevates the pain threshold. Capsaicin (third-line pharmacological treatment) reduces pain in a variety of neuropathic pain conditions (including post-herpetic neuralgia, diabetic neuropathy and painful polyneuropathy), and it is applied in a 0.075% concentration (22) (level of evidence: 3). Recommendations GR • Lidocaine 5% should be used as an adjuvant in patients suffering from post-herpetic neuralgia A • Capsaicin may be used as an adjuvant in patients with neuropathic pain C GR = grade of recommendation 3.4.5.3.4 NMDA receptor antagonists Within the dorsal horn, ionotropic glutamate receptors (NMDA, α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate [AMPA], kainate) and metabotropic glutamate receptors are all involved in neuropathic pain (23). However, the actions of excitatory amino acids (glutamate) on the NMDA receptor is considered a pivotal event in the phenomenon of ‘wind up’ and neuronal hyperexcitability (enhancement and prolongation of sensory transmission) that eventually leads to allodynia, and primary and secondary hyperalgesia. Subanaesthetic doses of ketamine, and its active enantiomer S(+)-ketamine, given parenterally, neuraxially, nasally, transdermally or orally, alleviate pain post-operatively and in a variety of neuropathic pain syndromes, including central pain (24) (level of evidence: 2b). Unfortunately, administration of ketamine may result in unwanted changes in mood, conscious perception, and intellectual performance. Additionally, psychomimetic side-effects (including visual and auditory hallucinations, dissociation, and nightmares) are prominent with ketamine, limiting its usefulness and widespread use in treating neuropathic pain (25). Thus, although ketamine has analgesic properties in patients with chronic neuropathic pain, because of its side-effects, ketamine has to be reserved as a third-line option for when other standard analgesic treatments are exhausted (26, 27). Recommendation GR Ketamine is effective as an analgesic in neuropathic pain. However, it may be responsible for B severe life-threatening side-effects and should be reserved for specialised pain clinics as a last resort (third-line treatment) GR = grade of recommendation 3.4.5.3.5 Other drug treatments Baclofen, a muscle relaxant, exerts its analgesic effect via an agonistic effect on the inhibitory GABABreceptors. Baclofen has demonstrated efficacy in patients with trigeminal neuralgia, but not in patients with other neuropathic pain conditions (28). However, this analgesic also has antispasticity properties and may

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induce analgesia by relieving muscle spasms, a frequent accompaniment of acute neuropathic pain. Baclofen can be considered a second-line agent for trigeminus neuralgia, or a third-line agent in neuropathic pain syndromes (level of evidence: 3). Mexilitine, an oral analogue of lidocaine, is effective in a number of chronic neuropathic pain conditions (29). After a successful trial with iv lidocaine, treatment with mexilitine seems to be justified (second-line pharmacological treatment). However, their role in the management of neuropathic pain is limited due to adverse gastrointestinal (33% of patients), central nervous system, and cardiac effects (level of evidence: 3). Clonidine, an α2-adrenoreceptor agonist, is available as a patch for transdermal administration and has been used in neuropathic pain states. When used topically, it seems to enhance the release of endogenous encephalin-like substances. Its use in neuropathic pain treatment, however, is focused on intrathecal or epidural administration, in combination with an opioid and/or local anaesthetics. Clonidine has been shown to improve pain control in combination with intrathecal opioids and/or local anaesthetics because of a possible supra-additive effect during neuropathic pain treatment (30) (level of evidence: 2b). 3.4.5.3.6 Summary: treatment of neuropathic pain Figure 5 gives a summary of the treatment of neuropathic pain. Figure 5: The treatment of neuropathic pain

First Line Agent

• Aminotriptyline • Pregabalin, gabapentin • Duloxetine* • Lidocaine 5% patch†

• Opioids/tramadol‡ Second Line Agent

Third Line Agent

• Baclofen • Mexilitine • Capsaicin 0.075% • Ketamine§

* = first-line treatment in diabetic polyneuropathy only † = first-line treatment in post-herpetic neuralgia only ‡ = first-line treatment in patients with neuropathic cancer pain only § = ketamine is an anaesthetic.

3.4.5.4 Invasive analgesic techniques The results of the WHO ‘analgesic ladder’ validation studies suggest that 10-30% of patients with cancer pain do not achieve a satisfactory balance between relief and side-effects using systemic pharmacotherapy alone without unacceptable drug toxicity (31, 32). Anaesthetic and neurosurgical techniques may reduce the need for systemically administered opioids for the achievement of adequate analgesia. 3.4.5.4.1 Peripheral nerve catheterisation in the management of cancer pain Tumour infiltration or compression of a peripheral nerve or plexus can result in severe neuropathic pain resistant to pharmacological treatment. In these patients the following is recommended (33,34).

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Recommendation GR Reversible regional anaesthetic techniques must be considered for the management of GPP neuropathic pain GR = grade of recommendation; GPP = good clinical practice 3.4.5.4.2 Neurolytic blocks to control visceral cancer pain Visceral cancer pain is primarily treated with NSAIDs and opioids. However, different neurolytic blockades have been described to optimise palliative treatment for cancer in the viscera. Continuation of the pharmacological therapy can, however, be necessary because these patients experience frequently co-existing somatic and neuropathic pain not relieved by neurolytic blockades. Different approaches to achieving neurolysis, including the coeliac plexus block and the superior hypogastric plexus block, have been described (35, 36). A coeliac plexus block is indicated to treat pain secondary to malignancies of the retroperitoneum or upper abdomen (distal part of the stomach, pancreas, liver, gall bladder) (37) (level of evidence: 1b). A superior hypogastric plexus block has proven utility for pelvic pain (rectum, vaginal fundus, bladder, prostate, testes, seminal vesicles, uterus and ovaries) due to a neoplasm that is refractory to more conservative (i.e. pharmacological) treatment (level of evidence: 3) (38- 40). 3.4.5.4.3 Epidural and intrathecal opioid application The delivery of low opioid doses near the sites of action in the spinal cord may decrease supraspinallymediated adverse effects. Compared with neuroablative therapies, spinal opioids have the advantage of preserving sensation, strength and sympathetic function (41, 42). Contraindications include bleeding diathesis, profound leucopenia and sepsis. A temporary trial of spinal opioid therapy should be performed to assess the potential benefits of this approach before implantation of a permanent catheter. In some patients, the addition of a low concentration of a local anaesthetic, such as 0.125-0.25% bupivacaine, to an epidural/intrathecal opioid has been demonstrated to increase analgesic effect without increasing toxicity (43, 44). The potential morbidity for these procedures indicates the need for a well-trained clinician and long-term monitoring (level of evidence: 2). Recommendation GR Continuous intrathecal or epidural administration of morphine may be considered in patients with B inadequate pain relief despite escalating doses with sequential strong opioids, or the development of side-effects (nausea, vomiting, constipation, drowsiness, sedation) limiting further dose increase GR = grade of recommendation 3.4.5.4.4 Chemical rhizotomy Chemical rhizotomy, produced by the instillation of a neurolytic solution into either the epidural or intrathecal space, can be an effective method of pain control for patients with otherwise refractory localised pain syndromes (45, 46). The technique is most commonly used in the management of chest-wall pain due to tumour invasion of somatic and neural structures. Other indications include refractory upper limb, lower limb, pelvic or perineal pain (lower end block). Because of the significant risk of increased disability through weakness, sphincter incompetence and loss of positional sense, chemical rhizotomy of lumbosacral nerve roots is best reserved for patients with limited function and pre-existent urinary diversion. Adverse effects can be related to the injection technique (spinal headache, mechanical neural damage, infection and arachnoiditis) or to the destruction of non-nociceptive nerve fibres (47) (level of evidence: 4). Recommendation GR Lower end block may be considered in patients with intractable perineal pain (bladder, rectum) that C has insufficient responded to more conservative therapy. This technique may only be performed in patients with loss of sphincter function (rectum and/or bladder) GR = grade of recommendation 3.4.5.4.5 Cordotomy During cordotomy, the anterolateral spinothalamic tract is sectioned to produce contralateral loss of pain and temperature sensibility. The patient with severe unilateral pain arising in the torso or lower extremity is most likely to benefit from this procedure. The percutaneous technique is generally preferred. Significant pain relief is achieved in more than 90% of patients during the period immediately following cordotomy (48). Of surviving patients, 50% have recurrent pain after 1 year. Repeat cordotomy can sometimes be effective.

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The neurological complications of cordotomy include paresis, ataxia and bladder dysfunction (49) (level of evidence: 3). 3.4.5.5 References 1. Namaka M, Gramlich CR, Ruhlen D, Melanson M, Sutton I, Major J. A treatment algorithm for neuropathic pain. Clin Ther 2004;26(7):951-79. http://www.ncbi.nlm.nih.gov/pubmed/15336464 2. Ballantine JC, Mao J. Opioid therapy for chronic pain. N Engl J Med 2003;349(20):1943-53. http://www.ncbi.nlm.nih.gov/pubmed/14614170 3. Rowbotham MC, Twilling L, Davies PS, Reisner L, Taylor K, Mohr D. Oral opioid therapy for chronic peripheral and central neuropathic pain. N Engl J Med 2003;348(13):1223-32. http://www.ncbi.nlm.nih.gov/pubmed/12660386 4. Dworkin RH, O’Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, Kalso EA, Loeser JD, Miaskowski C, Nurmikko TJ, Portenoy RK, Rice AS, Stacey BR, Treede RD, Turk DC, Wallace MS. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 2007;132(3):237-51. http://www.ncbi.nlm.nih.gov/pubmed/17920770 5. Dworkin RH, Backonja M, Rowbotham MC, Allen RR, Argoff CR, Bennett GJ, Bushnell MC, Farrar JT, Galer BS, Haythornthwaite JA, Hewitt DJ, Loeser JD, Max MB, Saltarelli M, Schmader KE, Stein C, Thompson D, Turk DC, Wallace MS, Watkins LR, Weinstein SM. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 2003;60(11):1524-34. http://www.ncbi.nlm.nih.gov/pubmed/14623723 6. Kakuyama M, Fukuda K. The role of antidepressants in the treatment of chronic pain. Pain Rev 2000:7;119-128. 7. Sindrup SH, Otto M, Finnerup NB, Jensen TS. Antidepressants in the treatment of neuropathic pain. Basic Clin Pharmacol Toxicol 2005:96(6);399-409. http://www.ncbi.nlm.nih.gov/pubmed/15910402 8. Jensen TS. Anticonvulsants in neuropathic pain: rationale and clinical evidence. Eur J Pain 2002:6(Suppl.A);61-8. http://www.ncbi.nlm.nih.gov/pubmed/11888243 9. Rogawski MA, Loscher W. The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions. Nat Med 2004:10(7);685-92. http://www.ncbi.nlm.nih.gov/pubmed/15229516 10. Vinik A. Clinical review: use of antiepileptic drugs in the treatment of chronic painful diabetic neuropathy. J Clin Endocrinol Metab 2005:90(8);4936-45. http://www.ncbi.nlm.nih.gov/pubmed/15899953 11. Collins SL, Moore RA, McQuay HJ, Wiffen P. Antidepressants and Anticonvulsants for Diabetic Neuropathy and Postherpetic Neuralgia: A Quantitative Systematic Review. J. Pain Symptom Manage 2000:20(6);449-58. http://www.ncbi.nlm.nih.gov/pubmed/11131263 12. Guay DR. Oxcarbazepine, topiramate, levetiracetam, and zonisamide: potential use in neuropathic pain. Am J Geriatr Pharmacother 2003:1(1);18-37. http://www.ncbi.nlm.nih.gov/pubmed/15555463 13. Spina E, Perugi G. Antiepileptic drugs: indications other than epilepsy. Epileptic Disord 2004:6(2); 57-75. http://www.ncbi.nlm.nih.gov/pubmed/15246950 14. Nicholson B. Gabapentin use in neuropathic pain syndromes. Acta Neurol Scand 2000:101(6);359-71. http://www.ncbi.nlm.nih.gov/pubmed/10877151 15. Vranken JH, Dijkgraaf MG, Kruis MR, van der Vegt MH, Hollmann MW, Heesen M. Pregabalin in patients with central neuropathic pain: A randomized, double-blind, placebo-controlled trial of a flexible-dose regimen. Pain 2008:136(1-2);150-7. http://www.ncbi.nlm.nih.gov/pubmed/17703885 16. Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine, gabapentin, or their combination for neuropathic pain. N Eng J Med 2005:352(13);1324-34. http://www.ncbi.nlm.nih.gov/pubmed/15800228 17. Bennett MI, Simpson KH. Gabapentin in the treatment of neuropathic pain. Palliat Med 2004:18(1); 5-11. http://www.ncbi.nlm.nih.gov/pubmed/14982201

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Frampton JE, Foster RH. Pregabalin in the treatment of postherpetic neuralgia. Drugs 2005:65(1); 111-8; discussion 119-20. http://www.ncbi.nlm.nih.gov/pubmed/15610058 19. Ryvlin P. Defining success in clinical trials – profiling pregabalin, the newest AED. Eur J Neurol 2005:12 Suppl 4;12-21. http://www.ncbi.nlm.nih.gov/pubmed/16144536 20. Meier T, Wasner G, Faust M, Kuntzer T, Ochsner F, Hueppe M, Bogousslavsky J, Baron R. Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study. Pain 2003:106(1-2);151-8. http://www.ncbi.nlm.nih.gov/pubmed/14581122 21. Galer BS, Jensen MP, Ma T, Davies PS, Rowbotham MC. The lidocaine patch 5% effectively treats all neuropathic pain qualities: results of a randomized, double-blind, vehicle-controlled, 3-week efficacy study with use of the neuropathic pain scale. Clin J Pain 2002;18(5):297-301. http://www.ncbi.nlm.nih.gov/pubmed/12218500 22. Sindrup SH, Jensen TS. Pharmacologic treatment of pain in polyneuropathy. Neurology 2000;55(7):915-20. http://www.ncbi.nlm.nih.gov/pubmed/11061244 23. Fisher K, Coderre TJ, Hagen NA. Targeting the NMDA receptor for chronic pain management: preclinical animal studies, recent clinical experience and future research directions. J Pain Symptom Manage 2000:20(5);358-73. http://www.ncbi.nlm.nih.gov/pubmed/11068158 24. Vranken JH, Dijkgraaf MG, Kruis MR, van Dasselaar NT, van der Vegt, MH. Iontophoretic administration of S(+)-ketamine in patients with intractable central pain: a placebo-controlled trial. Pain 2005:118(1-2);224-31. http://www.ncbi.nlm.nih.gov/pubmed/16202531 25. Fisher K, Hagen NA. Analgesic effect of oral ketamine in chronic neuropathic pain of spinal origin: a case report. J Pain Symptom Manage 1999:18(1);61-6. http://www.ncbi.nlm.nih.gov/pubmed/10439575 26. Enarson MC, Hayes H, Woodroffe MA. Clinical experiences with oral ketamine. J Pain Symptom Manage 1999:17(5);384-6. http://www.ncbi.nlm.nih.gov/pubmed/10355218 27. Hocking G, Cousins MJ. Ketamine in chronic pain: an evidence-based review. Anesth Analg 2003;97(6):1730-9. http://www.ncbi.nlm.nih.gov/pubmed/14633551 28. Fromm GH, Terrence CF, Chatta AS. Baclofen in the treatment of trigeminus neuralgia: double blind study and long term follow up. Ann Neurol 1984:15(3);240-4. http://www.ncbi.nlm.nih.gov/pubmed/6372646 29. Chabal C, Jacobson L, Mariano A, Chaney E, Britell CW. The use of oral mexiletine for the treatment of peripheral nerve injury. Anesthesiology 1992:76(4);513-17. http://www.ncbi.nlm.nih.gov/pubmed/1312797 30. Eisenach JC, De Kock M, Klimscha W. Alpha 2 adrenergic agonists for regional anesthesia: a clinical review of clonidine (1984-1995). Anesthesiology 1996:85(3);655-74. http://www.ncbi.nlm.nih.gov/pubmed/8853097 31. Schug SA, Zech D, Dorr U. Cancer pain management according to WHO analgesic guidelines. J Pain Symptom Manage 1990;5(1):27-32. http://www.ncbi.nlm.nih.gov/pubmed/2324558 32. Grond S, Zech D, Schug SA, Lynch J, Lehman KA. Validation of the World Health Organization guidelines for cancer pain relief during the last days and hours of life. J Pain Symptom Manage 1991;6(7):411-22. http://www.ncbi.nlm.nih.gov/pubmed/1940485 33. Vranken JH, Zuurmond WW, de Lange JJ. Continuous brachial plexus lock as treatment for the Pancoast’s syndrome. Clin J Pain 2000:16(4);327-33. http://www.ncbi.nlm.nih.gov/pubmed/11153789 34. Bridenbaugh PO, Wedel DJ. The lower extremity: somatic blockade. In: CousinsMJ, Bridenbaugh PO (eds). Neural Blockade in Clinical Anesthesia and Management of Pain, 3rd ed. 1998, Philadelphia: Lippincott-Raven, pp. 373-394. 35. Eisenberg E, Carr DB, Chalmers TC. Neurolytic celiac plexus block for treatment of cancer pain: a meta-analysis. Anesth Analg 1995;80(2):290-5. http://www.ncbi.nlm.nih.gov/pubmed/7818115

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36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

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Plancarte R, de Leon-Casasola O, El-Helaly M, Allende S, Lema MJ. Neurolytic superior hypogastric plexus block for chronic pelvic pain associated with cancer. Reg Anesth 1997;22(6):562-8. http://www.ncbi.nlm.nih.gov/pubmed/9425974 Kawamata M, Ishitani K, Ishikawa K, Sasaki H, Ota K, Omote K, Namiki A. Comparison between celiac plexus block and morphine treatment on quality of life in patients with pancreatic cancer pain. Pain 1996;64(3):597-602. http://www.ncbi.nlm.nih.gov/pubmed/8783327 de Leon Casasola OA, Kent E, Lema MJ. Neurolytic superior hypogastric plexus block for chronic pelvic pain associated with cancer. Pain 1993;54(2):145-51. http://www.ncbi.nlm.nih.gov/pubmed/8233527 Lillemoe KD, Cameron JL, Kaufman HS, Yeo CJ, Pitt HA, Sauter PK. Chemical splanchnicectomy in patients with unresectable pancreatic cancer. A prospective randomized trial. Ann Surg 1993;217(5):447-55; discussion 456-7. http://www.ncbi.nlm.nih.gov/pubmed/7683868 Suleyman Ozyalcin N, Talu GK, Camlica H, Erdine S. Efficacy of coeliac plexus and splanchnic nerve blockades in body and tail located pancreatic cancer pain. Eur J Pain 2004;8(6):539-45. http://www.ncbi.nlm.nih.gov/pubmed/15531222 Smith TJ, Staats PS, Deer T, Stearns LJ, Rauck RL, Boortz-Marx RL, Buchser E, Català E, Bryce DA, Coyne PJ, Pool GE; Implantable Drug Delivery Systems Study Group. Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol 2002;20(19):4040-9. http://www.ncbi.nlm.nih.gov/pubmed/12351602 Ballantyne JC, Carwood CM. Comparative efficacy of epidural, subarachnoid, and intracerebroventricular opioids in patients with pain due to cancer. Cochrane Database Syst Rev 2005;(1):CD005178. http://www.ncbi.nlm.nih.gov/pubmed/15654707 Deer TR, Caraway DL, Kim CK, Dempsey CD, Stewart CD, McNeil KF. Clinical experience with intrathecal bupivacaine in combination with opioid for the treatment of chronic pain related to failed back surgery syndrome and metastatic cancer pain of the spine. Spine J 2002;2(4):274–8. http://www.ncbi.nlm.nih.gov/pubmed/14589479 van Dongen RTM, Crul BJP, von Egmond J. Intrathecal coadministration of bupivacaine diminishes morphine dose progression during longterm intrathecal infusion in cancer patients. Clin J Pain 1999;15(3):166–72. http://www.ncbi.nlm.nih.gov/pubmed/10524468 Candido K, Stevens RA. Intrathecal neurolytic blocks for the relief of cancer pain. Best Pract Res Clin Anaesthesiol 2003;17(3):407-28. http://www.ncbi.nlm.nih.gov/pubmed/14529011 Slatkin NE, Rhiner M. Phenol saddle blocks for intractable pain at end of life: report of 19 four cases and literature review. Am J Hosp Palliat Care 2003;20(1):62-6. http://www.ncbi.nlm.nih.gov/pubmed/12568439 Rodriguez-Bigas M, Petrelli NJ, Herrera L, West C. Intrathecal phenol rhizotomy for management of pain in recurrent unresectable carcinoma of the rectum. Surg Gynecol Obstet 1991;173(1):41-4. http://www.ncbi.nlm.nih.gov/pubmed/1866669 Crul BJ, Blok LM, van Egmond J, van Dongen RTM. The present role of percutaneous cervical cordotomy for the treatment of cancer pain. J Headache Pain 2005;6(1):24-9. http://www.ncbi.nlm.nih.gov/pubmed/16362188 Sanders M, Zuurmond W. Safety of unilateral and bilateral percutaneous cervical cordotomy in 80 terminally ill cancer patients. J Clin Oncol 1995;13(6):1509-12. http://www.ncbi.nlm.nih.gov/pubmed/7751899

Quality of life

Issues that affect quality of life include the following: • Anxiety  Anxiety is a common symptom associated with patients near the end of life. Currently there is insufficient evidence about the role of drugs in the treatment of anxiety associated with terminal illness, and it is therefore not possible to draw any conclusions about the effectiveness of pharmacotherapy in anxiety in terminally ill patients (1). • Cancer-related fatigue  Fatigue associated with cancer is a significant problem. It can occur because of the side-effects of treatment or because of the disease itself. It can have a significant impact on a person’s ability to function. The causes of fatigue are not fully understood and so it is very difficult to treat it appropriately. Trials of erythropoietin and darbopoeitin (for anaemic patients on chemotherapy)

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•

•

and psychostimulants provide evidence for improvement in cancer-related fatigue at a clinically meaningful level. There are no data to support the use of paroxetine or progestational steroids for the treatment of cancer-related fatigue. The obvious candidate drug for use in a large-scale cancerrelated fatigue study is methylphenidate (2). Sexual dysfunction  The proportion of people living with and surviving cancer is growing. This has led to an increased awareness of the importance of quality of life, including sexual function, in people with cancer. Sexual dysfunction is a potential long-term complication of cancer treatments. There is some evidence that, following treatment for prostate cancer, transurethral alprostadil and vacuum constriction devices reduce sexual dysfunction, although negative effects were fairly common, and that vaginal lubricating creams reduce sexual dysfunction. PDE5 inhibitors are an effective treatment for sexual dysfunction secondary to treatments for prostate cancer (3). Selenium  Selenium is a mineral necessary for human health. Selenium acts against cell damage in the body and might help to alleviate treatment side-effects such as nausea, diarrhoea or lymph retention in the limbs in cancer patients. Selenium supplements are frequently used by cancer patients. To date there is insufficient evidence that selenium supplementation alleviates the sideeffects of tumour-specific chemotherapy or radiotherapy treatments, or that it improves the aftereffects of surgery or quality of life in cancer patients, or that it reduces secondary lymphoedema (4).

3.5.1 Conclusions The goal of analgesic therapy in cancer patients is to optimise analgesia with the minimum of side-effects. Currently available techniques can provide adequate relief for the large majority of patients. Most will need ongoing analgesic therapy, and requirements often change as the disease progresses. Patients with refractory pain should have access to specialists in pain management or palliative medicine who can provide an integrated multidisciplinary approach. 3.5.2 1.

2.

3.

4.

References Jackson KC, Lipman AG. Drug therapy for anxiety in palliative care. Cochrane Database Syst Rev 2004;(1):CD004596. http://www.ncbi.nlm.nih.gov/pubmed/14974072 Minton O, Stone P, Richardson A, Sharpe M, Hotopf MM. Drug therapy for the management of cancer related fatigue. Cochrane Database Syst Rev 2008 Jan 23;(1):CD006704 http://www.ncbi.nlm.nih.gov/pubmed/18254112 Miles CL, Candy B, Jones L, Williams R, Tookman A, King M. Interventions for sexual dysfunction following treatments for cancer. Cochrane Database Syst Rev 2007 Oct 17;(4):CD005540 http://www.ncbi.nlm.nih.gov/pubmed/17943864 Dennert G, Horneber M. Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients. Cochrane Database Syst Rev 2006 Jul 19;3:CD005037 http://www.ncbi.nlm.nih.gov/pubmed/16856073

4. PAIN MANAGEMENT IN UROLOGICAL CANCERS 4.1

Pain management in prostate cancer patients

4.1.1 Clinical presentation Pain can occur in both the early and advanced stages of prostate cancer (PCa). In early cases it may be a presenting symptom, have clinical usefulness and therefore be tolerated by (and at least partly acceptable to) the patient. In advanced disease, it no longer has a specific diagnostic meaning but only serves to underline the patient’s illness (1). Pain could be caused directly by the cancer (77%), be related to the cancer treatment (19%), or be unrelated to either (3%) (2). Pain is more common, and a real challenge, in advanced disease, and pain management must therefore focus on the symptomatic patient with metastases. The overall incidence of chronic pain in PCa patients is about 30-50%, but as patients enter the terminal phase of their illness this figure rises to 90% (3). Pain may be directly attributable to tumour growth in three main areas, which include tumour infiltration of bone, nerve or a hollow viscus.

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4.1.2 Pain due to local impairment 4.1.2.1 Invasion of soft tissue or a hollow viscus The relief of pain caused by invasion of a hollow viscus is the domain of surgery and minimally invasive procedures (e.g. catheter, stent, nephrostomy tube). 4.1.2.2 Bladder outlet obstruction Continuous growth of the prostate can lead to an outlet obstruction. Lower urinary tract symptoms (LUTS) can occur, especially stranguria and an inability to void. In these cases of acute pain, prompt relief is necessary. The best method is inserting a suprapubic catheter and starting hormonal treatment in case of advanced disease. If after 3 months the outlet obstruction persists, a transurethral palliative resection (TURP) could be performed for palliative reasons. 4.1.2.3. Ureteric obstruction Ureteric obstruction is most frequently caused by tumour compression or infiltration within the true pelvis (4-7). Less commonly, obstruction can be more proximal, associated with retroperitoneal metastases. In most cases, obstruction is typically asymmetric. Untreated progressive ureteric obstruction results in bilateral hydronephrosis and subsequent renal failure. In terminal cancer patients, the decision to drain the kidneys can be difficult. It is good practice to drain symptomatic hydronephrosis at once, and to drain only one kidney (the one with the better function) in asymptomatic patients. A nephrostomy tube is superior to a double-J stent for drainage because the routine endoscopic changes of the stent in the following months could be increasingly difficult in a continuously growing prostate gland. Another reason is that the nephrostomy tube can be changed without anaesthesia. 4.1.2.4 Lymphoedema Patients with a huge prostate mass and/or lymph node metastases in the pelvis very often show lymphoedema of the legs. The treatment of lymphoedema includes physiatric techniques such as wraps, pressure stockings or pneumatic pump devices. These can both improve function and relieve pain and heaviness. 4.1.2.5 Ileus Local obstruction of the rectum is a common occurrence in advanced cancer of the prostate and can lead to abdominal pain caused by ileus. Peritoneal involvement, which is rare, can also result in ileus. Surgery must be performed in case of mechanical obstruction. Paralytic ileus due to tumour infiltration of a nerve plexus or secondary to analgesics may require laxatives for opioid-induced constipation to improve motility and reduce pain. 4.1.3 Pain due to metastases 4.1.3.1 Bone metastases The following points should be noted. • Bone metastases are the most common cause of chronic pain in the prostate cancer population (8, 9). • Widespread bony metastases causing multifocal pain are frequent. • More than 25% of patients with bony metastases are pain-free (10). • Patients with multiple bony metastases typically report pain in only a few sites. • The factors that convert a painless lesion to a painful one are unknown. • Bone metastases could potentially cause pain by: - endosteal or periosteal nociceptor activation (by mechanical distortion or release of chemical mediators) - tumour growth into adjacent soft tissues or nerves - other complex mechanisms (9). The choice of treatment will depend on the tumour site, histology, stage and the patient’s physical and emotional condition. Although therapies are being developed that will target tumour cells specifically, the most commonly used techniques will continue to result in a degree of damage to normal tissues with consequent side-effects. In each case, the benefits and side-effects should be considered. The therapeutic options with fewer side-effects should be administered first. The options are: • hormone therapy • radiotherapy • orthopaedic surgery • radioisotopes • bisphosphonates

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• • •

calcitonin chemotherapy systemic analgesic pharmacotherapy (the ‘analgesic ladder’).

Other pain management tools such as nerve blocks are rarely used. 4.1.3.1.1 Hormone therapy Huggins and Hodges (11) first noted the effect of exogenous oestrogen administration on prostatic carcinoma. Hormone changes may cause complex endocrine effects, such as pituitary inhibition of luteinising hormone (LH), follicle-stimulating hormone (FSH) and prolactin, as well as changes in endogenous corticosteroid hormone production (12). A variety of additive or ablative hormone manipulations have been employed, including oestrogen, anti-androgen (cyproterone, flutamide), oestrogen-mustine complex (estramustine), progestogens, aminoglutethimide, gonadotrophin-releasing hormone (GnRH) analogues, orchidectomy, adrenalectomy and hypophysectomy. Corticosteroids are also used for the palliation of pain, particularly the kind due to bone deposits. 4.1.3.1.2 Side-effects Hormone therapy is generally much better tolerated than chemotherapy. There can also be a ‘flare’ or temporary exacerbation of pain with it, which is generally a predictor of subsequent response (13). The side-effects that must be considered are: • GnRH analogues and orchidectomy: - loss of body hair - testicular atrophy - gynaecomastia - loss of libido - impotence - relatively low cardiovascular mortality rate - psychological morbidity. • Anti-androgens: - gynaecomastia (more often if used alone than when used in combination with GnRH analogues) - hepatic impairment - less sexual dysfunction. • Cyproterone acetate: - fewer side-effects than oestrogens - lower incidence of cardiovascular complications. • Oestrogens: - loss of body hair - testicular atrophy - gynaecomastia - loss of libido - impotence - higher mortality from cardiac and cerebrovascular disease in long-term administration. • Adrenalectomy: - major operative procedure. • Hypophysectomy: - small but significant mortality rate - hormone replacement is subsequently required for life. 4.1.3.1.3 Efficacy In a collected series of protocols, pain relief has been estimated at between 35% (14) and 70% (15). The differences may be due to the selection of patients and problems in pain measurement. Well-differentiated prostatic carcinoma is more likely to respond to hormones than are poorly differentiated tumours. Manipulations that include replacement corticosteroid therapy or have additional corticoid effects seem to give higher response rates. Corticosteroids are also used for the palliation of pain, particularly in bone metastases.

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4.1.3.1.4 Problems To date, most patients with adenocarcinoma of the prostate present in early tumour stages and undergo radical surgery or radiotherapy. In cases of prostate-specific antigen (PSA) recurrence and/or symptoms, hormone therapy is indicated and patients can be asymptomatic for years. Pain is associated with a hormoneresistant tumour in progression, which necessitates alternative management options for the treatment of pain. 4.1.3.1.5 Radiotherapy In the management of metastatic adenocarcinoma of the prostate, radiotherapy is associated with palliation of pain from osseous metastases and improving quality of life. Radiation therapy is well known to be effective in treating painful sites, and might also be effective in reducing the propensity for adjuvantly treated disease to become symptomatic in the majority of patients (16). This effect does not appear to be significantly influenced by dose-time relationships or histology. The proportion of patients achieving complete pain relief approaches 80% (17) (see also section 3.3.3). The main points to note are: • the role of radiotherapy in the management of pain due to bone metastases is unquestionable • radiotherapy techniques vary widely, from a large dose given as a single treatment to as many as 20 smaller treatments given over 4 weeks • dose-time factors: the biological effect of the radiation depends not only on the total dose delivered, but also on the number of separate treatments and the total time over which the irradiation therapy is administered • palliative doses are smaller than maximum tolerance doses • field size is a compromise • avoid treating larger volumes than necessary in order to minimise morbidity • bear in mind that radiological evidence of a deposit may considerably underestimate the extent of disease. 4.1.3.1.6 Orthopaedic surgery If more than 50% of the thickness of the cortex of a long bone is eroded by metastasis, prophylactic fixation rather than radiotherapy alone should be considered to avoid pathological fractures. Internal fixation should be followed by postoperative radiotherapy because there is a real danger of continued tumour growth and further structural weakness (18, 19). Radiotherapy should not be withheld for fear of inhibiting bone healing and regrowth. There is good evidence that palliative doses of radiotherapy are associated with recalcification (20). 4.1.3.1.7 Radioisotopes Widespread axial skeletal involvement in PCa has been successfully treated with systemically administered bone-seeking radioisotopes (see also section 3.3.2). Commonly used radionuclides are strontium-89 chloride (89Sr) and samarium-153-ethylenediaminetetramethylene phosphonic acid (153Sm-EDTMP). The addition of 89Sr (single injection of 10.8 mCi [399.6 MBq]) is an effective adjuvant therapy to local field radiotherapy, reducing disease progression, as evidenced by new sites of pain, the requirement for further radiotherapy, and analgesic support (16), and improving quality of life. There is some evidence to indicate that radioisotopes could give complete reduction in pain over one to six months, with no increase in analgesic use, although adverse effects, specifically leucocytopenia and thrombocytopenia, have also been experienced (21). 4.1.3.1.8 Bisphosphonates Complications of bone metastases include pain, fractures, and spinal cord compression. Bisphosphonates are a standard part of supportive care for patients with bone metastases, and there is evidence to support their effectiveness in providing some pain relief. Bisphosphonates act by inhibiting osteoclast activities and are a potential therapeutic option for metastatic prostate cancer. In recent studies, there was no statistically significant difference between the bisphosphonate groups and the control groups in terms of prostate cancer death, disease progression, radiological response and PSA response. However, bisphosphonates should be considered for patients with metastatic prostate cancer for the treatment of refractory bone pain and prevention of skeletal events (22). Zoledronic acid, a nitrogen-containing third-generation bisphosphonate, is effective in the treatment of complications of metastatic bone disease. Its efficacy and safety has been established in three pivotal prospective, randomised controlled trials involving more than 3000 patients (23). Although they appear

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osteoblastic on radiographic imaging, most bone metastases are characterised by excess osteoclast volume and activity. In addition, pathological osteoclast activation is associated with increased risk of skeletal complications. Zoledronic acid, a potent inhibitor of osteoclast activity, differentiation, and survival, decreases the risk of skeletal complications in men with androgen-independent PCa and bone metastases. Other bisphosphonates, including pamidronate and clodronate, seem to be less effective in this setting (24). Zoledronic acid administration for 1 year to patients with hormone-sensitive PCa and bone metastases who were receiving androgen-deprivation therapy was safe and prevented bone loss, as demonstrated by significant increases in bone mineral density and sustained suppression of biochemical markers of bone turnover (25). Zoledronic acid (4 mg intravenously over 15 minutes every 3-4 weeks) decreased the frequency of skeleton-related events, delayed the time to a first skeleton-related event, and reduced pain (23). Visual analogue scale improvement is positively correlated with a decrease of C-telopeptide and bone phosphatase alkaline (p < 0.05) serum levels (26). Additional studies are needed to determine the optimal timing, schedule, and duration of treatment in men with bone metastases, as well as the potential role of bisphosphonates in other settings, including the prevention of bone metastases (see also section 3.4.4). 4.1.3.1.9 Calcitonin The limited evidence currently available does not support the use of calcitonin to control pain arising from bone metastases (27). 4.1.3.1.10 Chemotherapy In about 80% of men with metastatic PCa, primary androgen ablation leads to symptomatic improvement and to a reduction in the serum levels of PSA, but the disease eventually becomes refractory to hormone treatment. Systemic chemotherapy should be reserved for this patient group. Recent data from randomised studies, particularly those using docetaxel, have provided encouraging improvements in overall survival, palliation of symptoms, and improvements in quality of life (28). In advanced disease, previous clinical trials using single-agent chemotherapy have shown poor results. Newer studies suggest multiagent chemotherapies may be more effective. A randomised trial showed that mitoxantrone plus low-dose prednisone relieved pain and improved the quality of life more frequently than did prednisolone alone. Many other studies have confirmed the symptomatic effect of this chemotherapy regimen, but none has found that this approach improved survival as well. A PSA-response rate and a reduction of pain were also reported with other combined chemotherapies. Individual concepts had to be developed for the patient, as these chemotherapy regimens were associated with side-effects and none showed a survival benefit. PSA response rates to selected combined chemotherapy regimens are shown in Table 5. Table 5: PSA response rates to selected combined chemotherapy regimens Chemotherapy agent Ketoconazole Vinblastine Estramustine Mitoxantrone Paclitaxel

Plus + doxorubicin + estramustine + etoposide + prednisone + estramustine

Response rate (%) 55 54-61 39-58 33 53

In 2004, two randomised trials/phase III studies (TAX-327 and SWOG 9916) comparing docetaxel-based chemotherapies with mitoxantrone-based regimes were published (25, 26). It was demonstrated that docetaxel-based regimens have a very good symptomatic effect, one that is significantly better than the mitoxantrone-based approach (Table 6). Additionally, for the first time, a significant survival benefit was shown for the docetaxel group (18.9 versus 16.5 months).

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Table 6: Docetaxel-based chemotherapy versus mitoxantrone-based regimens Chemotherapy Plus Frequency agent Docetaxel + prednisone Every 3 weeks Docetaxel + prednisone Weekly Mitoxantrone + prednisone Every 3 weeks

Response rate (29) Pain (%) Quality of life (%) 35 22 31 23 22 13

Although most of these regimens have associated side-effects, such as fatigue, mild myelosuppression, and gastrointestinal irritation, they are generally well tolerated by the majority of patients (30). The docetaxel-based regimens are now the standard of care for patients with advanced hormone-refractory PCa. Soft-tissue lesions could be influenced to a greater extent than bony metastases. Pain management by chemotherapy could be effective, although it is much more cost-intensive than the administration of opioids, and the survival advantage is limited. 4.1.4 Systemic analgesic pharmacotherapy (the ‘analgesic ladder’) In cases of insufficient pain management with the treatments described above, systemic analgesic pharmacotherapy should be administered (see section 3.4). In most cases, the World Health organization (WHO) ladder scheme is the treatment of choice. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used, often in combination with an opioid, for the treatment of cancer pain. Short-term studies have shown that NSAIDs alone are effective in managing cancer pain, with side-effects similar to placebo, and that in about 50% of studies, increasing the dose of NSAID can increase efficacy without increasing the incidence of side-effects. Studies have not demonstrated a large clinical difference when combining an opioid with an NSAID versus either medication alone (31). Tramadol extended-release tablets and dihydrocodeine extended-release tablets were effective for the management of chronic tumour pain associated with prostate cancer with bone metastasis at the WHO Step II. Tramadol extended-release tablets provided slightly better pain management and a lower incidence of side-effects, particularly with regard to constipation (32). The treatment of constipation in palliative care is based on inadequate experimental evidence. There persists an uncertainty about the ‘best’ management of constipation in this group of patients (33). Oral morphine is an effective analgesic for cancer pain. There is qualitative evidence for the effectiveness of oral morphine that compares well with other available opioids. There is limited evidence to suggest that transmucosal fentanyl provides more rapid pain relief for breakthrough pain than morphine (34). Morphine is the gold standard for the management of moderate to severe cancer-related pain. Alternatives to morphine are now available, including hydromorphone. The limited evidence available does not demonstrate any clinically significant difference between hydromorphone and other strong opioids such as morphine (35). For patients with inadequate pain relief and intolerable opioid-related toxicity/adverse effects, a switch to an alternative opioid may be the only option for symptomatic relief. However, the evidence to support the practice of opioid switching is largely anecdotal or based on observational and uncontrolled studies (36). Breakthrough pain is a common and debilitating component of pain in patients with cancer. There is evidence that oral transmucosal fentanyl citrate is an effective treatment in the management of breakthrough pain (37). 4.1.5 Spinal cord compression Spinal cord compression can be due to the collapse of a vertebral body or to pressure from an extradural tumour within the spinal canal. Prodromal pain is a feature in 96% of these patients. The overall incidence in PCa patients is less than 10% (38). Thoracic cord compression is the most common area (70%), and the incidence of multiple extradural sites can be as high as 18% (39). Definitive treatment with surgery (anterior decompression with spinal stabilisation) or radiotherapy should be considered. Sometimes the symptom of local back pain disappears despite increasing motor deficits. This is due to the evolving sensory component of the paraplegia. The use of corticosteroids (typically dexamethasone 16 mg daily) to treat oedema of the cord is temporary. There is some evidence of benefit from decompressive surgery in ambulant patients with poor prognostic factors for radiotherapy, and in non-ambulant patients with a single area of compression, paraplegia < 48

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hours’ duration, non-radiosensitive tumours and a predicted survival of more than three months. High-dose corticosteroids carry a significant risk of serious adverse effects (40). 4.1.6 Hepatic invasion Hepatic invasion by secondary tumour is a common cause of severe hypochondrial pain, often radiating to the back and shoulder blade. The mechanism may be the stretching of nerve endings in the liver capsule, diaphragmatic irritation, or haemorrhage into a necrotic area of tumour. Liver pain can often be controlled by conventional titration of appropriate analgesics against the pain or with corticosteroids. Whole liver palliative radiotherapy can also be useful in carefully selected patients with refractory pain, with far fewer side-effects than the alternatives of intra-arterial chemotherapy or hepatic artery embolisation. Hepatic irradiation can improve abdominal pain with little toxicity in more than half of patients (41). Doses should not exceed 30 Gy in 15 daily fractions or its equivalent if radiation hepatitis is to be avoided. 4.1.7 Pain due to cancer treatment 4.1.7.1 Acute pain associated with hormonal therapy Luteinising hormone-releasing hormone (LHRH) tumour flare in prostate cancer Initiation of LHRH therapy for PCa produces a transient symptom flare in 5-25% of patients (42, 43). The flare is presumably caused by an initial stimulation of LH release before suppression is achieved (43, 44). The syndrome typically presents as an exacerbation of bone pain or urinary retention. Spinal cord compression and sudden death have also been reported (42). Symptom flare is usually observed within the first week of therapy, and lasts 1-3 weeks in the absence of androgen antagonist therapy. Co-administration of an androgen antagonist at the start of LHRH agonist therapy can prevent this phenomenon (45). 4.1.7.2 Chronic pain associated with hormonal therapy Gynaecomastia Chronic gynaecomastia and breast tenderness are common complications of anti-androgen therapies for PCa. The incidence of this syndrome varies between drugs. It is frequently associated with diethylstilboestrol (46), is less common with flutamide and cyproterone (47-49), and is uncommon among patients receiving LHRH agonist therapy (49). In the elderly, gynaecomastia must be distinguished from primary breast cancer or a secondary cancer in the breast (50). 4.1.8 Conclusions Radiotherapy, chemotherapy and hormone therapy are all valuable techniques for the relief of cancer pain, and those concerned with the care of cancer patients must have some knowledge of the potential of all these therapies. The side-effects caused by the inappropriate use of anticancer treatments can be very distressing, and in all cases the disadvantages of a treatment must be balanced against the palliative benefit. In many patients, the best approach to pain relief will be through interdisciplinary co-operation. Well-planned clinical trials are required because there is still much to be learned about the indications, dose, frequency and optimal administration of anticancer therapies for the relief of pain. Surgery, radiotherapy, chemotherapy and hormone therapy are mainly used as antitumour treatment in the relief of pain. The rational use of any of these types of treatment demands knowledge both of tumour biology and also of the mechanisms of action of these specific oncological techniques. The therapeutic aim should be clearly understood prior to starting treatment. Radical treatment should be given if the disease is potentially curable, but the intent should be symptomatic or palliative if the tumour is advanced or widely disseminated (29). The various regimens employed to treat pain in PCa patients have been described above, and the scientific bases for their use have been explained. However, the importance of early intervention needs to be emphasised. Education of patients is crucial. They must be aware of the early signs and symptoms of metastatic disease, which does not necessarily involve pain.

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4.1.9 Recommendations at a glance (stage M1) (51-56) The levels of evidence (LE) (1a, 1b, 2a, 2b, 3, 4), grades of recommendation (GR) (A, B, C) are shown below. Recommendation ANTICANCER TREATMENT Hormonal therapy (orchiectomy, LHRH analogues, diethylstilboestrol equivalent) Total androgen blockade: flare prevention, second line Intermittent androgen suppression experimental To date monotherapy with anti-androgen not recommended First line treatment controls disease for 12 to 18 months, second line individualized Supportive care Low-dose glucocorticoids Chemotherapy Mitoxantrone plus prednisolone Estramustine + vinblastine or etoposide or paclitaxel Docetaxel PAIN MANAGEMENT Pain assessment (localization, type, severity, overall distress) Pain due to painful or unstable bony metastases (single lesions) External beam irradiation Pain due to painful bony metastases (widespread) Primary hormonal therapy Radioisotopes (strontium-89 or samarium-153) Pain due to painful metastases (many spots) Bisphosphonates Systemic pain management World Health Organization analgesic ladder step 1: NSAID or paracetamol Opioid administration Dose titration Access to breakthrough analgesia Tricyclic antidepressant and/or anticonvulsant in case of neuropathic pain

LE

GR

1a 2b 3 1b 1b

A B B A A

1b

A

1b 2b 1b

B B A

B 1b

A

1a 2

A B

1b

A

1a

A

2 1b 1a

B A A

4.1.10 References 1. Saunders CM. Appropriate treatment, appropriate death. In: Saunders CM (ed.). The Management of Terminal Malignant Disease, 2nd ed. 1984, Edward Arnold, London, p. 1. 2. Foley KM. Pain syndromes in patients with cancer. In: Bonica JJ, Ventafridda V (eds). Advances in Pain Research and Therapy 2. New York, Raven Press, 1979, pp. 59-75. 3. Twycross RG, Lack SA. Symptom control in far advanced cancer: Pain relief. London: Pitman, 1983, p. 6. 4. Fair WR. Urologic emergencies. In: DeVita VT, Hellman S, Rosengerg SA (eds). Cancer Principles and Practice of Oncology, 3rd ed. PA: Lippincott, 1989, pp. 2016-2028. 5. Greenfield A, Resnick MI. Genitourinary emergencies. Semin Oncol 1989;16(6):516-20. http://www.ncbi.nlm.nih.gov/pubmed/2688111 6. Talner LB. Specific causes of obstruction. In: Pollack HM (ed.). Clinical Urography, vol. 2. PA: Saunders, 1990, pp. 1629-1751. 7. Cherny NI, Portenoy RK. Cancer Pain: Principles of Assessment and Syndromes. In: Wall PD, Melzack R (eds). Textbook of Pain, 3rd ed. Edinburgh: Churchill Livingston, 1994. 8. Banning A, Sjøgren P, Henriksen H. Pain causes in 200 patients referred to a multidisciplinary cancer pain clinic. Pain 1991;45(1):45-8. http://www.ncbi.nlm.nih.gov/pubmed/1861877 9. Nielsen OS, Munro AJ, Tannock IF. Bone metastases: pathophysiology and management policy. J Clin Oncol 1991;9(3):509-24. http://www.ncbi.nlm.nih.gov/pubmed/1705581 10. Wagner G. Frequency of pain in patients with cancer. Recent Results Cancer Res 1984;89:64-71. http://www.ncbi.nlm.nih.gov/pubmed/6364273 11. Huggins C, Hodges VC. Studies on prostatic cancer. Cancer Research 1941;1:293-7.

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McNicol ED, Strassels S, Goudas L, Lau J, Carr DB. NSAIDS or paracetamol, alone or combined with opioids, for cancer pain. Cochrane Database of Systematic Reviews 2005, issue 2, art. no.: CD005180. http://www.ncbi.nlm.nih.gov/pubmed/15654708 32. Oliva P, Carbonell R, Giron JA, Bueno A, Sanz JM, Urieta A. Extended-release oral opiates: tramadol versus dihydrocodeine in chronic tumor pain associated to prostate cancer. Cochrane Database of Systematic Reviews: EBM Reviews – Cochrane Central Register of Controlled Trials (2008). 33. Miles CL, Fellowes D, Goodman ML, Wilkinson S. Laxatives for the management of constipation in palliative care patients. Cochrane Database of Systematic Reviews 2006, issue 4, art. no.: CD003448. http://www.ncbi.nlm.nih.gov/pubmed/17054172 34. Wiffen PJ, McQuay HJ. Oral morphine for cancer pain. Cochrane Database of Systematic Reviews 2007, issue 4, art. no.: CD003868. http://www.ncbi.nlm.nih.gov/pubmed/17943804 35. Quigley C. Hydromorphone for acute and chronic pain. Cochrane Database of Systematic Reviews 2002, issue 1, art. no.: CD003447. http://www.ncbi.nlm.nih.gov/pubmed/11869661 36. Quigley C. Opioid switching to improve pain relief and drug tolerability. Cochrane Database of Systematic Reviews 2004, issue 3, art. no.: CD004847. http://www.ncbi.nlm.nih.gov/pubmed/15266542 37. Zeppetella G, Ribeiro MDC. Opioids for the management of breakthrough (episodic) pain in cancer patients. Cochrane Database of Systematic Reviews 2006, issue 1, art. no.: CD004311. http://www.ncbi.nlm.nih.gov/pubmed/16437482 38. Hoy AM, Lucas CF. Radiotherapy, chemotherapy and hormone therapy: treatment for pain. In: Wall PD, Melzack R (eds). Textbook of Pain, 3rd ed. Edinburgh: Churchill Livingston, 1994. 39. Kramer JA. Spinal cord compression in malignancy. Palliat Med 1992;6:202-11. 40. George R, Jeba J, Ramkumar G, Chacko AG, Leng M, Tharyan P. Interventions for the treatment of metastatic extradural spinal cord compression in adults. Cochrane Database of Systematic Reviews 2008, issue 4, art. no.: CD006716. http://www.ncbi.nlm.nih.gov/pubmed/18843728 41. Borgelt BB, Gelber R, Brady LW, Griffin T, Hendrickson FR. The palliation of hepatic metastases: results of the Radiation Therapy Oncology Group pilot study. Int J Radiat Oncol Biol Phys 1981;7(5):587-91. http://www.ncbi.nlm.nih.gov/pubmed/6168623 42. Thompson IM, Zeidman EJ, Rodriguez FR. Sudden death due to disease flare with luteinizing hormone-releasing hormone agonist therapy for carcinoma of the prostate. J Urol 1990;144(6): 1479-80. http://www.ncbi.nlm.nih.gov/pubmed/2122011 43. Chrisp P, Sorkin EM. Leuprorelin. A review of its pharmacology and therapeutic use in prostatic disorders. Drugs and Aging 1991;1(6):487-509. http://www.ncbi.nlm.nih.gov/pubmed/1794035 44. Goldspiel BR, Kohler DR. Goserelin acetate implant: a depot luteinizing hormone-releasing hormone analog for advanced prostate cancer. DICP 1991;25(7-8):796-804. http://www.ncbi.nlm.nih.gov/pubmed/1835221 45. Crawford ED, Nabors W. Hormone therapy of advanced prostate cancer: where we stand today. Oncology (Williston Park)1991;5(1):21-30. http://www.ncbi.nlm.nih.gov/pubmed/1828686 46. Eberlein TJ. Gynecomastia. In: Harris J R, Hellman S, Henderson I C, Kinne D, eds. Breast diseases, 2nd ed. PA: Lippincott, 1991, pp. 46-50. 47. Delaere KP, Van Thillo EL. Flutamide monotherapy as primary treatment in advanced prostatic carcinoma. Semin Oncol 1991;18(5Suppl.6):13-8. http://www.ncbi.nlm.nih.gov/pubmed/1948117 48. Goldenberg SL, Bruchovsky N. Use of cyproterone acetate in prostate cancer. Urol Clin North Am 1991;18(1):111-22. http://www.ncbi.nlm.nih.gov/pubmed/1825143 Neumann F, Kalmus J. Cyproterone acetate in the treatment of sexual disorders: pharmacological base and clinical experience. Exp Clin Endocrinol 1991;98(2):71-80. http://www.ncbi.nlm.nih.gov/pubmed/1838080 50. Ramamurthy L, Cooper RA. Metastatic carcinoma to the male breast. Br J Radiol 1991;64(759):277-8. http://www.ncbi.nlm.nih.gov/pubmed/2021802

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National Committee on Cancer Care Workgroup on Prostate Cancer. Treatment of metastatic prostate cancer (M1). In: Ministry of Health (Singapore): Prostate Cancer 2000, National Guideline Clearinghouse (withdrawn). Scottish Intercollegiate Guidelines Network (SIGN). Control of pain in patients with cancer. A national clinical guideline 2000. http://www.sign.ac.uk/guidelines/fulltext/44/index.html American College of Radiology. ACR Appropriateness Criteria (tm) for bone metastases. In: American College of Radiology: ACR Appropriateness Criteria (tm) for metastatic bone disease, 1996 (revised 2003), National Guideline Clearinghouse. http://www.guideline.gov/summary/summary.aspx?doc_id=5911&nbr=003897&string=ACR+AND+ap propriateness+AND+criteria Cancer Care Ontario (CCO). Use of strontium-89 in patients with endocrine-refractory carcinoma of the prostate metastatic to bone, 1997 (updated online 2001), National Guideline Clearinghouse. http://www.cancercare.on.ca/pdf/pebc3-6f.pdf Schröder FH. Hormonal therapy of prostate cancer. In: Walsh P, Retik AB, Darracott Vaughan E, Wein AJ, eds. Campell’s Urology, 8th ed. 2002, Elsevier Science, vol. 4, pp. 3182-3208. Eisenberger MA. Chemotherapy for hormone-resistant prostate cancer In: Walsh P, Retik AB, Darracott Vaughan E, Wein AJ (eds). Campell’s Urology, 8th ed. 2002, Elsevier Science, vol. 4, pp. 3209-26.

Pain management in transitional cell carcinoma patients

4.2.1 Clinical presentation Urothelial cancer is the fourth most common cancer in men and the ninth in women (1). Transitional cell carcinoma (TCC) is the most frequent cancer of the bladder and upper urinary tract. It arises much more frequently in the bladder than in the collecting system (calices, renal pelvis and ureter). From the perspective of pain, there are no differences between TCC and other histotypes of urothelial malignant tumours. In bladder carcinoma, pain can be present during the natural history of the disease (early as a burning pain together with irritative symptoms, or late in the advanced disease due to local invasion of neighbouring tissues or metastatic organ invasion). TCC of the renal collecting system represents 5-10% of all kidney tumours and 5% of all TCC of the urinary tract (2). TCC of the ureter accounts for only 3% of all TCC (3). In TCC of the upper urinary tract, pain is an initial symptom in around 30% of cases. 4.2.2 Origin of tumour-related pain Bladder TCC The main causes of tumour-related pain in bladder TCC are: • obstruction of the upper urinary tract due to growth of bladder tumour close to the ureteral orifice • invasion of the surrounding areas by a locally advanced tumour (pelvic wall, nerve roots, other organs such as bowel, rectum) • bone metastases • soft tissues metastases (seldom painful). Upper urinary tract TCC The main causes of tumour-related pain in upper urinary tract TCC are: • obstruction of the upper urinary tract (presenting symptom in around 30% of cases) • acute obstruction due to blood clots • invasion of the surrounding areas by a locally advanced tumour (posterior abdominal wall, nerve roots, paraspinous muscles, other organs such as bowel, spleen, liver) • bone metastases • soft tissue metastases (seldom painful). 4.2.3 Pain due to local impairment Bladder TCC Obstruction of the ureteral orifice by tumour infiltration may lead to hydronephrosis and consecutive flank pain due to ureteral distension (visceral pain). Transurethral resection of the tumour is often effective in eliminating ureteral obstruction. Otherwise hydronephrosis is treated by temporary or permanent percutaneous nephrostomy.

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In locally advanced disease, infiltration of the contiguous soft tissue and neighbouring organs can cause acute burning pain by infiltration of the pelvic nerves (neuropathic pain). This pain is sometimes associated with paraesthesia irradiating to the lower limb or with motor deficit. If the tumour invades adjacent organs – small bowel, rectum – obstruction of these organs could occur, along with visceral pain due to distension of hollow organs. Additionally, growing bladder tumour can cause complete bladder outlet obstruction with hypogastric abdominal pain due to bladder distension. Obstruction of the lymphatic vessels by lymphadenopathy can cause lymphoedema of the lower limbs with pain due to distension of muscle fascia (somatic pain). In infiltrating and advanced bladder cancer, cystectomy (whether radical or debulking cystectomy) and urinary diversion have a positive impact on pain, removing the neoplastic mass invading the surrounding tissues. Sometimes extended operations including excision of involved bowel are indicated. Palliative surgery may be necessary in occlusive intestinal syndromes (4). Chemotherapy has some effect in 40-75% of patients with advanced disease (see guidelines on bladder cancer). Chemotherapy is able to relieve pain by decreasing the neoplastic mass in responder patients (5-9) (level of evidence: 1a). Radiotherapy can be effective in controlling pelvic pain due to local disease progression. Using 40-45 Gy on target volume, radiotherapy can reduce the local painful symptoms, but it can also worsen the irritative bladder symptoms and can induce proctitis (10) (level of evidence: 2b). Upper urinary tract TCC Locally advanced primary tumours (e.g. invasion of the posterior abdominal wall, nerve roots, paraspinous muscles, other organs such as bowel, spleen, liver) are usually managed by surgery. Sometimes extended operations including excision of involved bowel, spleen or abdominal wall muscle are indicated. In terms of the value of chemotherapy, the same considerations are valid for TCC of the upper urinary tract as for TCC of the bladder. 4.2.4 Pain due to metastases In advanced bladder or upper urinary tract TCC, haematogenous metastases to the bone are often found. No data are available in the literature concerning the specific effect of chemotherapy on bone metastases alone. Radiotherapy has a palliative analgesic role in bone metastases. Using 10 fractionated doses of 30-35 Gy, it rapidly reduces, if not eliminates, pain in 80-90% of cases (10) (level of evidence: 2b). Hemibody irradiation can also be used in diffuse bone metastases (10). No specific studies exist on the radioisotope therapy of bone metastasis in TCC. Orthopaedic surgery can stabilise pathological fractures (4). Neurosurgery may have a place in the palliation of pain derived from compression of the spinal cord. 4.2.5 1.

References Wingo PA, Tong T, Bolden S. Cancer Statistics, 1995. CA Cancer J Clin 1995;45(1):8-30. http://www.ncbi.nlm.nih.gov/pubmed/7528632 2. Fraley EE. Cancer of the renal pelvis. In: Skinner DG, De Kernion JB, eds. Genitourinary Cancer. PA: W.B. Saunders, 1978, p. 134. 3. Huben RP, Mounzer AM, Murphy GP. Tumor grade and stage as prognostic variables in upper tract urothelial tumors. Cancer 1988;62(9):2016-20. http://www.ncbi.nlm.nih.gov/pubmed/3167813 4. Mount BM, Scott JF. Palliative care of the patients with terminal cancer. In: Skinner DG, Lieskovsky G (eds). Diagnosis and Management of Genitourinary Cancer, 1988, W.B. Saunders, Philadelphia, pp. 842-863. 5. Ricci S, Galli L, Chioni A, Iannopollo M, Antonuzzo A, Francesca F, Vocaturo V, Selli C, Orlandini C, Conte P. Gemcitabine plus epirubicine in patients with advanced urothelial carcinoma who are not eligible for platinum-based regimens. Cancer 2002;95(7):1444-50. http://www.ncbi.nlm.nih.gov/pubmed/12237912 6. Sternberg CN, Yagoda A, Scher HI, Watson RC, Geller N, Herr HW, Morse MJ, Sogani PC, Vaughan ED, Bander N, et al. Methotrexate, vinblastine, doxorubicin and cisplatin for advanced transitional cell carcinoma of the urothelium. Efficacy and patterns of response and relapse. Cancer 1989;64(12): 2448-58. http://www.ncbi.nlm.nih.gov/pubmed/2819654

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7.

8.

9.

10.

4.3.

Loehrer PJ, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, Raghavan D, Stuart- Harris R, Sarosdy MF, Lowe BA, et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 1992;10(7):1066-73. http://www.ncbi.nlm.nih.gov/pubmed/1607913 Logothetis C, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, Kilbourn RG. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol 1990;8(6):1050-5. http://www.ncbi.nlm.nih.gov/pubmed/2189954 Von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomised, multinational, multicenter, Phase III study. J Clin Oncol 2000;18(17):3068-77. http://www.ncbi.nlm.nih.gov/pubmed/11001674 Friedland J. Local and systemic radiation for palliation of metastatic disease. Urol Clin North Am 1999;26(2):391-402. http://www.ncbi.nlm.nih.gov/pubmed/10361561

Pain management in renal cell carcinoma patients

4.3.1 Clinical presentation Renal cell carcinoma is mainly diagnosed incidentally. Pain cannot be expected unless a tumour invades surrounding areas or obstructs the outflow of urine owing to haemorrhage and subsequent formation of blood clots. Between 20% and 30% of patients present with metastatic disease, and 30% of patients who primarily presented with a localised kidney tumour develop metastases during follow-up. Thus 50-60% of all patients with renal cell carcinoma develop metastases during their life and may have to be treated because of symptoms, mainly pain. Renal cell carcinoma spreads mainly to lung, bone, brain, liver and ipsilateral or contralateral adrenergic glands. Patients with metastases have a maximal 2-year survival rate of 20%, which has to be considered in cases of palliative treatment. The main origins of tumour-related pain are: • invasion of the surrounding areas by a locally advanced tumour (posterior abdominal wall, nerve roots, paraspinous muscles, other organs such as bowel, spleen, liver) • obstruction of the upper urinary tract due to haemorrhage and subsequent formation of blood clots • bone metastases • soft tissue metastases (seldom painful). 4.3.2 Pain due to local impairment Patients with invasion of the surrounding areas by a locally advanced primary tumour (e.g. invasion of the posterior abdominal wall, nerve roots, paraspinous muscles, other organs such as bowel, spleen, liver) without metastases usually present with pain. Surgical management is the only effective option for this type of tumour. Sometimes extended operations that include excision of involved bowel, spleen or abdominal wall muscle are indicated. Adjuvant immunotherapy or radiotherapy is without proven benefit with regard to recurrence. Even in cases of metastatic disease, palliative nephrectomy is indicated for the control of severe symptoms such as haemorrhage, pain or paraneoplastic syndromes (GPP). The frequency with which each of these symptoms is controlled, however, is unclear and there are no data in the literature comparing efficacy of nephrectomy in palliative situations with other therapies such as angioinfarction of the tumour. Radiotherapy of soft tissue is without proven benefit with regard to pain and tumour control. There is no benefit in survival from standard pre-operative (30 Gy) or post-operative radiation therapy, and a questionable delay in local progress (1). In metastatic disease, the European Organisation for Research and Treatment of Cancer (EORTC) Genitourinary Group study 30947 demonstrated a significant increase in survival with palliative nephrectomy plus immunotherapy compared with immunotherapy (interferon-alpha) alone (median survival of 17 compared with 7 months) (2) (level of evidence: 2b). There is no special effect on pain relief from immunotherapy.

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Obstruction of the upper urinary tract due to haemorrhage and subsequent formation of blood clots is effectively treated by radical nephrectomy in non-metastatic tumour (GPP). If the patient is physically fit for surgery, this should be done to increase the quality of life, for example palliative nephrectomy in cases of metastatic tumour (GPP). There are no data in the literature about the efficacy of alternative therapies such as angioinfarction of the tumour with regard to haemorrhage and pain relief in palliative situations. According to the WHO guidelines, analgesic therapy and/or palliative drainage of the urinary tract should be used if the patient is not fit for major surgery. 4.3.3 Pain due to metastases Patients with bone metastases have a significantly better life expectancy (30 months) than those with visceral metastases (11.6 months) (3). Indications for surgery for bone metastases are solitary metastases that can be resected completely, intractable bone pain, and impending or demonstrable pathological fracture. In cases of bone metastases with extensive soft tissue involvement and corresponding severe pain, amputation of a leg or arm is sometimes required to maintain a certain quality of life. With surgery for bone metastases, a significant pain decrease is achieved in 89-91% of patients (4-6) (level of evidence: 2b/3). Additionally, surgery prevents pathological fractures and spinal compression, and there is a significant impact on survival. Pre-operative embolisation of bone metastases or embolisation alone achieves good pain relief in hypervascular bone metastases (7, 8) (level of evidence: 3). High dose radiation therapy for palliation of painful bony metastases has been shown to be effective in 50-75% of all renal cancer patients (9-11) (level of evidence: 3), and in 67% for bone metastases in general (12) (level of evidence: 2b). There is no impact on survival. In small studies, radionuclide therapy, e.g. strontium-89 (89Sr) therapy, seems to achieve good pain relief in bone metastases from renal cell carcinoma (13) (level of evidence: 3). There have been no large prospective studies with regard to long-term pain relief. Bone metastases show poor response to immunotherapy, and there is no proven benefit in pain relief. Hormonal therapy and chemotherapy are even less effective, and are therefore without any importance in pain control. Therapy for soft tissue metastases is performed in a similar manner to that for locally advanced disease. Radiotherapy for soft tissue metastases is without proven benefit in terms of pain and tumour control. There is no benefit in survival by standard pre-operative (30 Gy) or post-operative radiation therapy, and a questionable delay of local progress (1). Immunotherapy alone achieves an overall response in 15-27% of patients (14). Immunotherapy in combination with chemotherapy (interleukin-2 + interferon-alpha + 5-fluorouracil) is the most effective therapy, achieving partial tumour response in up to 46% of patients and complete response in a maximal 15%. However, these response rates are observed nearly exclusively for lung and lymph node metastases (15). Pain due to soft tissue metastases probably behaves in a manner analogous to the tumour response, but there are no data concerning pain control utilising immunotherapy. Hormonal therapy has no proven benefit concerning survival or pain relief. 4.3.4 1. 2.

References Van de Werf-Messing B. Proceedings: carcinoma of the kidney. Cancer 1973;32(5):1056-61. http://www.ncbi.nlm.nih.gov/pubmed/4757899 Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R; European Organisation for Research and Treatment of Cancer (EORTC) Genitourinary Group. Radical nephrectomy plus interferon-alfabased immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet 2001;358(9286):966-70. http://www.ncbi.nlm.nih.gov/pubmed/11583750

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3.

Bohnenkamp B, Romberg W, Sonnentag W, Feldmann U. (Prognosis of metastatic renal cell carcinoma related to the pattern of metastasis [author’s transl.]). J Cancer Res Clin Oncol 1980;96(1):105-14. [Article in German.] http://www.ncbi.nlm.nih.gov/pubmed/7358767 4. Smith EM, Kursh ED, Makley J, Resnick MI. Treatment of osseous metastases secondary to renal cell carcinoma. J Urol 1992;148(3):784-7. http://www.ncbi.nlm.nih.gov/pubmed/1512825 5. Kollender Y, Bickels J, Price WM, Kellar KL, Chen J, Merimsky O, Meller I, Malawer MM. Metastatic renal cell carcinoma of bone: indications and technique of surgical intervention. J Urol 2000;164(5):1505-8. http://www.ncbi.nlm.nih.gov/pubmed/11025692 6. Jackson RJ, Loh SC, Gokaslan ZL. Metastatic renal cell carcinoma of the spine: surgical treatment and results. J Neurosurg 2001;94(suppl.1):18-24. http://www.ncbi.nlm.nih.gov/pubmed/11147860 7. Gorich J, Solymosi L, Hasan I, Sittek H, Majdali R, Reiser M. [Embolization of bone metastases]. Radiologe 1995;35(1):55-9. [article in German.] http://www.ncbi.nlm.nih.gov/pubmed/7534427 8. Layalle I, Flandroy P, Trotteur G, Dondelinger RF. Arterial embolization of bone metastases: is it worthwhile?. J Belge Radiol 1998;81(5):223-5. http://www.ncbi.nlm.nih.gov/pubmed/9880954 9. Halperin EC, Harisiadis L. The role of radiation therapy in the management of metastatic renal cell carcinoma. Cancer 1983;51(4):614-7. http://www.ncbi.nlm.nih.gov/pubmed/6185207 10. Onufrey V, Mohiuddin M. Radiation therapy in the treatment of metastatic renal cell carcinoma. Int J Radiat Oncol Biol Phys 1985;11(11):2007-9. http://www.ncbi.nlm.nih.gov/pubmed/2414257 11. Forman JD. The role of radiation therapy in the management of carcinoma of the kidney. Sem Urol 1989;7(3):195-8. http://www.ncbi.nlm.nih.gov/pubmed/2481333 12. Chow E, Wong R, Hruby G, Connolly R, Franssen E, Fung KW, Andersson L, Schueller T, Stefaniuk K, Szumacher E, Hayter C, Pope J, Holden L, Loblaw A, Finkelstein J, Danjoux C. Prospective patientbased assessment of effectiveness of palliative radiotherapy for bone metastases. Radiother Oncol 2001; 61(1):77-82. http://www.ncbi.nlm.nih.gov/pubmed/11578732 13. Kloiber R, Molnar CP, Barnes M. Sr-89 therapy for metastatic bone disease: scintigraphic and radiographic follow-up. Radiology 1987;163(3):719-23. http://www.ncbi.nlm.nih.gov/pubmed/3575721 14. Figlin RA. Renal cell carcinoma: management of advanced disease. J Urol 1999;161(2):381-6. http://www.ncbi.nlm.nih.gov/pubmed/9915408 15. Kankuri M, Pelliniemi TT, Pyrhonen S, Nikkanen V, Helenius H, Salminen E. Feasibility of prolonged use of interferon-alpha in metastatic kidney carcinoma: a phase II study. Cancer 2001;92(4):761-7. http://www.ncbi.nlm.nih.gov/pubmed/11550145

4.4

Pain management in patients with adrenal carcinoma

Adrenal carcinoma is a rare disease and has a poor prognosis. Non-functional adrenal lesions of more than 5 cm in diameter should be removed because there is a high probability of malignancy (1). 4.4.1 Malignant phaeochromocytoma Phaeochromocytomas result from phaeochromocytes, which are the predominant cells of the adrenal medulla and are also found in the paraganglia near the aorta and in lesser quantities in the ganglia of the sympathetic nervous system (2). When correctly diagnosed and treated, the disease is curable unless there are metastases. Computed tomography (CT) and magnetic resonance imaging (MRI) have the highest sensitivity in detecting the tumour, achieving 94-100%. A 131J-MIBG (131J-metaiodobenzylguanidine) scan is positive in approximately 87% of cases (3). In cases of metastases, chemotherapy with cyclophosphamide, vincristine and dacarbazine has little effect (4) (level of evidence: 2b), but therapeutic doses of 131J-MIBG (33 GBq = 900 mCi) may produce some results (5, 6) (level of evidence: 2b). The hormone response rate is described as 50%. There is no special literature concerning pain relief with 131J-MIBG in metastatic phaeochromocytoma, but a response rate that is at least

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the same as for hormone levels should be expected. Malignant phaeochromocytomas are considered radio-resistant, although there are some cases in which radiation therapy induced partial remission (7) (level of evidence: 3). There is no information about the efficacy of radiation concerning pain relief in cases of bone or soft tissue metastases. 4.4.2 Treatment of pain The main points to note are as follows. • Soft tissue and/or bone pain due to metastases are best treated by therapeutic doses of 131J-MIBG, if the phaeochromocytoma takes up this radionuclide (8) (level of evidence: 2b). There is no literature concerning chemotherapy or radiotherapy and pain relief in metastatic phaeochromocytoma. • Treat the pain symptomatically with drugs etc. following the recommendations made in Section 3.4. 4.4.2.1 Adrenocortical carcinomas Carcinomas of the adrenal cortex are highly malignant, with both local and haematogenous metastasis. Fiveyear survival rates are 25-43% in patients treated by all modalities. Patients with distant metastases have a mean survival of only 4 months (9). An autopsy study showed metastases to lung (60%), liver (50%), lymph nodes (48%), bone (24%) and pleura/heart (10%) (10). In addition, these tumours often extend directly into adjacent structures, especially the kidney. Chemotherapy is of low efficacy. The most effective drug is mitotane, an adrenolytic drug. The tumour response rate is 25-35% (9, 11) (level of evidence: 2a). It remains to be proven whether chemotherapy prolongs survival. Radiation therapy has not been useful except for palliation and pain management (12) (level of evidence: 2b). 4.4.2.2 Treatment of the pain depending on its origin The main points to note are as follows. • Abdominal symptoms are typical symptoms when first presenting with the tumour. The treatment is surgical removal of the primary tumour, with attempts to remove the entire lesion even if resection of adjacent structures is necessary, as well as resection of the local lymph nodes. • Soft tissue and/or bone metastases causing local symptoms can be treated by radiation therapy (8, 12). There is no literature concerning chemotherapy or radiotherapy as tools for pain relief in metastatic adrenocortical carcinomas. • Treat the pain symptomatically with drugs etc. following the recommendations given in Section 3.4. 4.4.3 1.

2. 3.

4.

5.

6.

7.

References Cerfolio RJ, Vaughan ED Jr, Brennan TG Jr, Hirvela ER. Accuracy of computed tomography in predicting adrenal tumor size. Surg Gynecol Obstet 1993;176(4):307-9. http://www.ncbi.nlm.nih.gov/pubmed/8460403 Goldfien A. Phaeochromocytoma – diagnosis and management. Clin Endocr Metab 1991;10:606. Lucon AM, Pereira MA, Mendonça BB, Halpern A, Wajchenbeg BL, Arap S. Pheochromocytoma: Study of 50 cases. J Urol 1997;157(4):1208-12. http://www.ncbi.nlm.nih.gov/pubmed/9120903 Schlumberger M, Gicquel C, Lumbroso J, Tenenbaum F, Comoy E, Bosq J, Fonseca E, Ghillani PP, Aubert B, Travagli JP, et al. Malignant pheochromocytoma: clinical, biological, histologic and therapeutic data in a series of 20 patients with distant metastases. J Endocrinol Invest 1992;15(9): 631-42. http://www.ncbi.nlm.nih.gov/pubmed/1479146 Mornex R, Badet C, Peyrin L. Malignant pheochromocytoma: a series of 14 cases observed between 1966 and 1990. J Endocrinol Invest 1992;15(9):643-9. http://www.ncbi.nlm.nih.gov/pubmed/1479147 Proye C, Vix M, Goropoulos A, Kerlo P, Lecomte-Houcke M. High incidence of malignant pheochromocytoma in a surgical unit: 26 cases out of 100 patients operated from 1971 to 1991. J Endocrinol Invest 1992;15(9):651-63. http://www.ncbi.nlm.nih.gov/pubmed/1479148 Yu L, Fleckman AM, Chadha M, Sacks E, Levetan C, Vikram B. Radiation therapy of metastatic pheochromocytoma: case report and review of the literature. Am J Clin Oncol 1996;19(4):389-93. http://www.ncbi.nlm.nih.gov/pubmed/8677912

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8.

9.

10.

11.

12.

4.5.

Kopf D, Goretzki PE, Lehnert H. Clinical management of malignant adrenal tumors. J Cancer Res Clin Oncol 2001;127(3):143-55. http://www.ncbi.nlm.nih.gov/pubmed/11260859 Wooten MD, King DK. Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature. Cancer 1993;72(11):3145-55. http://www.ncbi.nlm.nih.gov/pubmed/8242539 Didolkar MS, Berscher RA, Elias EG, Moore RH. Natural history of adrenal cortical carcinoma: a clinicopathologic study of 42 patients. Cancer 1981;47(9):2153-61. http://www.ncbi.nlm.nih.gov/pubmed/7226109 Bukowski RM, Wolfe M, Levine HS, Crawford DE, Stephens RL, Gaynor E, Harker WG. Phase II trial of mitotane and cisplatin in patients with adrenal carcinoma: a Southwest Oncology Group study. J Clin Oncol 1993;11(1):161-5. http://www.ncbi.nlm.nih.gov/pubmed/8418229 Percarpio B, Knowlton AH. Radiation therapy of adrenal cortical carcinoma. Acta Radiol Ther Phys Biol 1976;15(4):288-92. http://www.ncbi.nlm.nih.gov/pubmed/62490

Pain management in penile cancer patients

4.5.1 Clinical presentation In Europe, penile cancer is a relatively rare disease; the incidence is less than 2/100,000 men per year, accounting for less than 1% of all cancers in men. It is a disease of older men, with an increase in incidence around age 60 years, peaking around the age of 80 years. The penile lesion itself usually alerts the patient to the presence of a penile cancer, which in most cases occurs on the glans (48%) and prepuce (21%). Patients with cancer of the penis seem to delay seeking medical attention (embarrassment, guilt, fear, ignorance and neglect). This level of denial is substantial, given that the penis is observed and handled every day. Pain does not develop in proportion to the extent of the local tumour, and is not usually a presenting complaint (1). To date there has been no consensus on the therapeutic management of metastatic disease, and there are few controlled studies of statistical significance that look at both penile carcinoma and cancer-related pain. Most of the principles for dealing with pain management in prostatic carcinoma are also valid here, but the following aspects should also be taken into consideration. Pain can occur in both the early and advanced stages of penile cancer. In the early stages, acute pain could be the result of a voiding dysfunction (subvesical obstruction). Chapter 4 gives details about the management of bladder outlet obstruction in prostate cancer. In advanced stages of the disease, pain is usually caused by metastases or lymph node involvement. Inguinal lymph node involvement plays an important role. Positive lymph nodes are relatively common in penile cancer, with inguinal or pelvic lymph nodes being the most frequently affected. Positive nodes may be present in over 50% of cases, and systematic lymphadenectomy is curative in about 50% of these patients. Among all the possible complications after inguinal and ilioinguinal lymphadenectomy, permanent and disabling lymphoedema of the scrotum and lower limbs is frequent. Pain can result from: • local pressure from the tumour mass or infiltration of hollow viscus organs • lymphoedema of the scrotum and lower limbs. 4.5.2 Pain due to local impairment Soft-tissue and hollow-viscus invasion Bladder outlet and ureteric obstruction is managed in the same manner as that described in Section 4.1.2.2. 4.5.3 Lymphoedema Patients with a huge inguinal tumour mass, or left with scarred inguinal tissue after lymph node dissection, very often show lymphoedema of the lower limbs. This is more frequent in cases of involvement of both inguinal and iliac nodes. The treatment of lymphoedema comprises physiatric techniques (use of wraps, pressure stockings or pneumatic pump devices), which can both improve function, and relieve pain and heaviness. The use of orthotic devices can immobilise and support painful or weakened structures, and assistive devices can be of great value to patients with pain precipitated by weight-bearing or ambulation.

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4.5.4 Pain due to metastases Anti-cancer management for pain relief The first phase of pain management entails anti-tumour treatment: usually surgery (partial or total penectomy or emasculation and lymphadenectomy), radiotherapy (not as effective, but for palliation), and chemotherapy. If this is unsuccessful or not feasible, the second phase requires systemic analgesic pharmacotherapy (WHO ladder). Experience with combined therapeutic management using chemotherapy plus surgery or radiotherapy is very limited due to the relative rarity of penile carcinomas (1) (see also guidelines for penile cancer). 4.5.5 Conclusions Currently no conclusive or universally applicable recommendations can be given on managing pain related to the treatment of metastatic penile carcinoma. To date, treatment has been experimental in nature; findings from other cancer treatment regimes must be adapted for want of a better-documented strategy. As is the case elsewhere, attention is paid to the guidelines that are appropriate for treating metastases and the involved organs (See also EAU guidelines on Penile Cancer). 4.5.6 1.

References Lynch DF Jr, Pettaway CA. Tumours of the penis. In: Walsh P, Retik AB, Darracott Vaughan E, Wein AJ (eds). Campell’s Urology, 8th ed. 2002, Elsevier Science, vol. 4, pp. 2945-2982.

4.6

Pain management in testicular cancer patients

4.6.1 Clinical presentation Testicular cancer generally affects younger men in the third or fourth decade of life. It is mainly diagnosed causally as an intrascrotal mass. Approximately 20% of patients present with scrotal or inguinal pain, which disappears after orchiectomy. Only 11% of patients complain of back of flank pain when first presenting (1). Points to note are: • primary advanced tumour with pain due to bone metastases is very rare, maximally no more than 3% at first presentation • should be treated causally by primary chemotherapy and adjuvant analgesics. 4.6.2 Pain due to local impairment Orchiectomy is an effective treatment for local pain due to the scrotal mass. 4.6.3 Pain due to metastases The main points to note are as follows. • Back or flank pain due to retroperitoneal lymphadenopathy will slowly disappear under chemotherapy as the mass decreases (level of evidence: 2b) (see guidelines for testicular cancer). Temporary analgesics are advisable (see Section 3.4.5 of these guidelines). • Retroperitoneal lymph node metastases can also cause obstruction of the ureter, leading to a symptomatic hydronephrosis with back or flank pain and perhaps additional fever. The therapy of choice is the immediate treatment of the hydronephrosis by ureteral stenting or the insertion of a percutaneous nephrostomy. • Bone pain due to bony metastases is very rare and mainly occurs in patients with primary advanced disease and relapse after chemotherapy (2, 3). Treatment may be possible by chemotherapy or second line chemotherapy (see guidelines for testicular cancer). There is no literature considering radiotherapy in cases of relapse and limitation for further chemotherapy. • Back pain and neurological symptoms due to spinal cord compression by vertebral metastases may require urgent surgery (4) (level of evidence: 3). 4.6.4 References 1. Hernes EH, Harstad K, Fosså SD. Changing incidence and delay of testicular cancer in southern Norway (1981-1992). Eur Urol 1996;30(3):349-57. http://www.ncbi.nlm.nih.gov/pubmed/8931969 2. Hitchins RN, Philip PA, Wignall B, Newlands ES, Begent RH, Rustin GJ, Bagshawe KD. Bone disease in testicular and extragonadal germ cell tumours. Br J Cancer 1988;58(6):793-6. http://www.ncbi.nlm.nih.gov/pubmed/3224081 3. Merrick MV. Bone scintigraphy in testicular tumours. Br J Urol 1987;60(2):167-9. http://www.ncbi.nlm.nih.gov/pubmed/3664206 4. Arnold PM, Morgan CJ, Morantz RA, Echard DA, Kepes JJ. Metastatic testicular cancer presenting as spinal cord compression: report of two cases. Surg Neurol 2000;54(1):27-33. http://www.ncbi.nlm.nih.gov/pubmed/11024504

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4.7.

Recommendations at a glance

Table 7 shows the efficacy of the therapeutic options in pain relief (expert opinion). Table 7: Efficacy of the therapeutic options in pain relief (expert opinion) Origin of pain RCC Therapeutic options Bone metastases Surgery +++ Radiation ++ Radionuclide + Chemotherapy – Immunotherapy – Hormone therapy – Analgesics +++ Soft tissue infiltration Surgery +++ Radiation – Chemotherapy + Immunotherapy + Hormone therapy – Analgesics +++ Nerve compression/nerve infiltration Surgery +++ Radiation + Chemotherapy + Immunotherapy + Hormone therapy – Analgesics +++

TCC

PCa

Penile cancer

Adrenergic cancer

Testicular cancer

? ++ ? ? – – +++

+ +++ +++ + – ++ +++

? ? ? ? ? – +++

? + ++ – ? – +++

+ ? – +++ ? – +++

+++ + ++ – – +++

– ++ + – ++ +++

? ? ? ? – +++

? + ++ ? – +++

+ ? +++ ? – +++

+++ + ++ – – +++

++ ++ + – ++ +++

? ? ? ? – +++

? + ? ? – +++

++ ? +++ ? – +++

RCC = renal cell carcinoma; TCC = transitional cell carcinoma; PCa = prostate cancer; ? = no conclusive data on pain control; – = no pain control; + = low pain control; ++ = moderate pain control; +++ = good pain control.

5. POST-OPERATIVE PAIN MANAGEMENT 5.1 Background Post-operative pain is defined as an expected, inevitable symptom in a surgical patient associated with surgical tissue damage, the presence of drains and tubes, post-operative complications or a combination of the above (1, 2). Post-operative pain is usually underestimated and undertreated (1, 3). Approximately 70% of surgical patients experience a certain degree (moderate, severe or extreme) of post-operative pain (3, 4) (level of evidence: 1a). The results of post-operative pain undertreatment include increased morbidity and mortality, mostly due to respiratory and thromboembolic complications, increased hospital stay, impaired quality of life, and development of chronic pain (1, 3, 5-7) (level of evidence: 1a). The aim of the post-operative pain guidelines is to establish safer and more effective pain management, to introduce proper assessment of pain and planning of pain control techniques, and to promote training of medical and nursing staff in this area (1, 3).

5.2

The importance of effective post-operative pain management

The physiological consequences of post-operative pain are shown in Table 8, all of which could delay or impair post-operative recovery and increase the economic cost of surgery as a result of the longer period of hospitalisation (13, 14) (level of evidence: 3). Inadequate post-operative pain control may also lead to the

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development of chronic pain after surgery (15, 16) (level of evidence: 2b). Table 8: Physiological consequences of post-operative pain Condition Stress response to surgery

Respiratory complications

Cardiovascular complications

Thromboembolic complications Gastrointestinal complications Musculoskeletal complications

Psychological complications

Consequences • Tissue trauma results in release of mediators of inflammation and stress hormones • Activation of this ‘stress response’ leads to: - retention of water and sodium - increase in metabolic rate • Shallow breathing • Cough suppression • Lobular collapse • Retention of pulmonary secretions • Infections • Hypertension • Tachycardia • Increased myocardial work, which may lead to: - myocardial ischaemia - angina - infarction • These are the most common cardiovascular complications after urological surgery • Reduced mobility due to inadequate pain management can lead to thromboembolic episodes • Gastric stasis • Paralytic ileus • These occur often, mostly after open urological operations • Prolonged confinement to bed due to inadequate pain management leads to: - reduced mobility - muscle atrophy • Peri-operative pain may provoke fear and anxiety, which can lead to: - anger - resentment - hostility to medical and nursing personnel • These symptoms are often accompanied by insomnia

Ref. 8

LE 2a

9

2b

10

2b

11

2a

12

2b

13

3

13, 14

3

LE = level of evidence 5.2.1 The aims of effective post-operative pain management The aims of effective post-operative pain management are: • to improve the comfort and satisfaction of the patient • to facilitate recovery and functional ability • to reduce morbidity • to promote rapid discharge from hospital (1-3) (level of evidence: 1a). Recommendation GR • Post-operative pain should be treated adequately, to avoid post-operative complications and B the development of chronic pain GR = grade of recommendation 5.3 5.3.1 • • • •

Pre- and post-operative pain management methods Pre-operative patient preparation: patient evaluation adjustment or continuation of medication in order to avoid abstinence syndrome pre-medication as part of multi-modal analgesia behavioural-cognitive interventions for the patient and family with the aim of alleviating anxiety and fear of post-operative pain. This in turn leads to a reduction in the amount of analgesia required post-

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operatively and better and more efficient pain management (1) (level of evidence: 1a). During this phase, patients should be informed about the different options and methods of post-operative analgesia and their benefits and adverse effects. This will enable them to make an informed decision together with their clinicians (1). Recommendation GR • Pre-operative assessment and preparation of the patient allow more effective pain management A GR = grade of recommendation 5.3.2 Pain assessment Careful pain assessment by the surgeon or the acute pain team can lead to more efficient pain control, adequate doses of the correct drugs, and diminished morbidity and mortality (1, 4) (level of evidence: 2a). Pain should be assessed before and after treatment. In the post-anaesthesia care unit (PACU), pain should be evaluated, treated and re-evaluated initially every 15 minutes and then every 1-2 hours. After discharge from the PACU to the surgical ward, pain should be assessed every 4-8 hours before and after treatment (17, 18). Various rating scales have been described to measure post-operative pain, but their major disadvantage is that they are all subjective, making their results difficult to evaluate, especially in patients with communication difficulties (18). Table 9 gives examples of such scales. Table 9: Post-operative pain rating scales* Type of scale

Description

• Verbal rating scale (VRS) • Visual analogue scale (VAS)

This is a five-point scale that describes pain as absent, mild, moderate, severe, very severe This is a straight line, 100 mm in length, with one end representing absence of pain and the other the most severe pain. The patient marks the line at the point that reflects the level of pain being experienced • Numerical rating scale Pain is rated numerically from 0 (absence of pain) to 10 (severe pain) (NRS) • Facial expression This is a scale of six faces showing expressions ranging from smiling to tearful. It is usually used with children or patients who have difficulty with communication • Complex pain An example is the McGill Pain Questionnaire. This consists of 20 groups of words assessment indices to describe the pain, from which the patient selects following a specific protocol

* From Jensen et al. (1992) (17) and Herr et al. (2002) (18). Recommendation GR • Adequate post-operative pain assessment can lead to more effective pain control and fewer B post-operative complications GR = grade of recommendation 5.3.3 Pre-emptive analgesia Pre-emptive or preventive analgesia is defined as the administration of analgesia before surgical incision to prevent establishment of central sensitisation from incision or inflammatory injury in order to achieve optimal post-operative pain control (19). A variety of pharmacological agents and techniques have been used for this purpose. The results of clinical trials on the efficacy of pre-emptive analgesia are controversial (19, 20) (level of evidence: 2b). 5.3.4 Systemic analgesic techniques 5.3.4.1 Non-steroidal anti-inflammatory drugs (NSAIDs) These drugs act by inhibiting cyclo-oxygenase (COX) and the subsequent production of prostaglandins. The main advantages of NSAIDs are that they produce analgesia without respiratory depression or sedation, and they seem to decrease the need for opioids (21). However, their analgesic effect is not sufficiently strong for the management of severe post-operative pain (22). Table 10 gives dosage and administration details for NSAIDs.

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Table 10: NSAIDS: drugs, dosage and administration Drug Dosage per day Route of administration Conventional NSAIDs (non-selective COX inhibitors) • Ketorolac 10-30 mg four times daily Orally or iv • Ibuprofen 400 mg three times daily Orally • Ketoprofen 50 mg four times daily Orally or iv • Diclofenac 75 mg twice daily Orally or iv 50 mg three times daily Orally or iv 100 mg twice daily Rectally COX-2 selective inhibitors • Meloxicam 15 mg once per day Orally • Lornoxicam 4-8 mg twice daily Orally or iv • Celecoxib 200 mg once per day Orally • Parecoxib 40 mg once or twice daily iv form only NSAID = non-steroidal anti-inflammatory drug; iv = intravenous. Intravenous administration of NSAIDs should start 30-60 min before the estimated end of surgery, and oral administration should start as soon as possible. Intramuscular administration of analgesic drugs for postoperative pain control is generally avoided because of the variability of serum drug concentrations and the pain caused by the injection (23). Adverse effects The main adverse effects are (22): • gastric irritation, ulcer formation, bleeding • renal impairment • bronchospasm, deterioration of asthma • platelet dysfunction, inhibition of thromboxane A2 • peri-operative bleeding • inhibition of bone healing and osteogenesis. COX-2 selective inhibitors are associated with fewer gastrointestinal complications and better bone healing and cause minimal platelet inhibition compared with non-selective COX inhibitors (24). However, COX-2 inhibitors are contraindicated for long-term use in patients with cardiovascular problems, such as myocardial infarction, angina pectoris, hypertension and atherosclerosis. This is because rofecoxib (which has already been withdrawn) caused a significant increase in thromboembolic events compared with placebo (25). The use of COX-2 inhibitors is approved for short-term post-operative pain therapy. Recommendations GR • NSAIDs are not sufficient as the sole analgesic agent after major surgery B • NSAIDS are often effective after minor or moderate surgery B • NSAIDs often decrease the need for opioids B • Avoid long-term use of COX inhibitors in patients with atherosclerotic cardiovascular disease B GR = grade of recommendation 5.3.4.2 Paracetamol Paracetamol (acetaminophen) is a relatively safe and effective antipyretic and analgesic for mild to moderate post-operative pain. In cases of severe post-operative pain, the co-administration of paracetamol with strong opioids seems to reduce the consumption of opioids (26) (level of evidence: 2). Its exact mode of action is unclear, although it may act by centrally inhibiting COX production (27). Dosage and routes of administration • 1 g four times daily (orally, iv or rectally). Dose should be reduced to 1 g three times daily in patients with hepatic impairment • Intravenous administration of paracetamol should start 30 min before the end of surgery, and oral administration as soon as possible. Adverse effects No significant adverse effects have been observed in patients receiving paracetamol for acute post-operative

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pain. Caution should be used when administering it to patients with chronic alcoholism or hepatic failure. A dose > 6 g/24 h can cause acute renal failure. Combinations of paracetamol with opioids Paracetamol in combination with an opioid (Table 11) provides adequate post-operative analgesia for mild to moderate pain without the adverse effects of strong opioids. The paracetamol/opioid combinations are given four times daily. Table 11: Dosage and administration of paracetamol/opioid combinations Paracetamol • Paracetamol 1 g • Paracetamol 600-650 mg • Paracetamol 500 mg • Paracetamol 300 mg • Paracetamol 650 mg • Paracetamol 600-650 mg • Paracetamol 325 mg

Opioid Codeine 60 mg Codeine 60 mg Codeine 30 mg Codeine 30 mg Dextropropoxyphene 65 mg Tramadol 75-100 mg Oxycodone 5 mg

Times per day x4 x4 x4 x4 x4 x4 x4

Route of administration Orally or rectally Orally or rectally Orally or rectally Orally or rectally Orally Orally Orally

Recommendations GR • Paracetamol can be very useful for post-operative pain management as it reduces the B consumption of opioids • Paracetamol can alleviate mild post-operative pain as a single therapy without major B adverse effects GR = grade of recommendation 5.3.4.3 Metamizole (dipyrone) Metamizole is an effective antipyretic and analgesic drug used for mild to moderate post-operative pain and renal colic. Its use is prohibited in the USA and some European countries because of single reported cases of neutropenia and agranulocytosis. In other countries, it is considered to be a useful analgesic and antipyretic drug for use in moderate pain. Even though data are controversial, long-term use of metamizole is best avoided (28, 29) (level of evidence: 2b). Dosage and route of administration The dose is 500-1000 mg qds (orally, iv or rectally). Adverse effects Apart from single sporadic cases of neutropenia and agranulocytosis, metamizole can cause minor sideeffects such as nausea, light hypotension and allergic reactions. Allergic reactions and the rare complication of agranulocytosis have been described only after direct iv administration, and so iv metamizole should therefore be administered as a drip (1 g in 100 mL normal saline). 5.3.4.4 Opioids Opioids are the first-line treatment for severe acute post-operative pain (Table 12). The key principle for their safe and effective use is to titrate the dose against pain relief and to minimise unwanted effects (30). Table 12: Opioids: drugs, dosage and administration Drug Strong opioids • Morphine* • Morphine* • Pethidine (meperidine) • Oxycodone Weak opioids • Tramadol • Codeine

Dosage per day

Route of administration

5-10 mg six to eight times 10-15 mg six to 12 times 50-100 mg six to eight times 5-10 mg four to six times

Orally sc or im iv, sc or im orally, iv or sc

50-100 mg four to six times 30-60 mg (combined with paracetamol) four times

orally, iv or im orally or rectally

*A simple way of calculating the daily dosage of morphine for adults (20-75 years) is: 100 – patient’s age =

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morphine per day in mg. sc = subcutaneous; im = intramuscularly; iv = intravenously. Routes of administration Opioids can be administered orally, intravenously, subcutaneously, transdermally, epidurally, intrathecally and intramuscularly. However, intramuscular administration is less common because of erratic absorption and the unnecessary pain of injection (2). 5.3.4.5 Patient-controlled analgesia (PCA) Systemic administration of opioids may follow the ‘as needed’ schedule or ‘around-the-clock’ dosing. The most effective mode is patient-controlled analgesia (PCA) (31, 32) (level of evidence: 1a). Typical PCA dosing schedules are shown in Table 13. Table 13: Typical PCA dosing schedule Drug (concentration) • Morphine (1 mg/mL) • Fentanyl (0.01 mg/mL) • Pethidine (10 mg/mL)

Bolus size 0.5-2.5 mg 10-20 μg 5-25 mg

Lockout interval (min) 5-10 5-10 5-10

Continuous infusion 0.01-0.03 mg/kg/h 0.5-0.1 μg/kg/h –

Recommendation GR • Intravenous PCA provides superior post-operative analgesia, improving patient satisfaction and A decreasing the risk of respiratory complications GR = grade of recommendation 5.3.4.6 Fentanyl Fentanyl has been administered transdermally for post-operative pain management, but its use by this route has been limited by the difficulty of titrating the drug levels (33). The fentanyl HCl iontophoretic transdermal system (fentanyl ITS) is a needle-free patient-controlled system that releases a pre-programmed dose of fentanyl on demand. It is very effective in the management of severe post-operative pain (34) (level of evidence: 1a). Adverse effects The main adverse effects are: • respiratory depression, apnoea • sedation • nausea, vomiting • pruritus • constipation • hypotension. 5.3.4.7 Opioid equi-analgesic doses The commonest parenteral and oral equi-analgesic doses of opioids are shown in Table 14. Table 14: Common equi-analgesic dosages for parenteral and oral administration of opioids* Drug • Morphine • Fentanyl • Pethidine • Oxycodone • Dextropropoxyphene • Tramadol • Codeine

Parenteral (mg) 10 0.1 75 15 – 37.5 130

Oral (mg) 30 – 300 20-30 50 150 200

*All listed opioid doses are equivalent to parenteral morphine 10 mg. The intrathecal opioid dose is 1/100th, and the epidural dose 1/10th, of the dose required systemically.

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5.3.5 Regional analgesic techniques 5.3.5.1 Local anaesthetic agents The most commonly used local anaesthetics are: • bupivacaine • L-bupivacaine • ropivacaine. Bupivacaine is considered to be cardiotoxic in high doses. L-bupivacaine and ropivacaine appear to be safer, but the degree of motor blockage they provide is not as good as that of bupivacaine. Ropivacaine has the longest duration of action. 5.3.5.2 Epidural analgesia Epidural analgesia provides excellent post-operative pain relief for extended periods after major surgical operations, reducing post-operative complications and the consumption of opioids (1, 2) (level of evidence: 1a). Typical epidural dosing schemes are shown in Table 15. Table 15: Typical epidural dosing schemes* Drug • Morphine • Fentanyl • Sufentanil • Pethidine • Bupivacaine 0.125% or ropivacaine 0.2% + fentanyl 2 μg/mL

Single dose 1-5 mg 50-100 μg 10-50 μg 10-30 mg 10-15 mL

Continuous infusion 0.1-1 mg/h 25-100 μg/h 10-20 μg/h 10-60 mg/h 2-6 mL/h

* L-bupivacaine doses are equivalent to those of bupivacaine. 5.3.5.3 Patient-controlled epidural analgesia (PCEA) Patient-controlled epidural analgesia has become very common because it allows individualisation of analgesic requirements, a decrease in the use of drugs, greater patient satisfaction and superior analgesia. In addition, PCEA seems to provide better analgesia compared with intravenous PCA (35, 36) (level of evidence: 1a). Typical PCEA dosing schemes are shown in Table 16. Table 16: Typical PCEA dosing schemes Drug

Demand dose

• Morphine • Fentanyl • Pethidine • Bupivacaine 0.125% + fentanyl 4 μg/mL • Ropivacaine 0.2% + fentanyl 5 μg/mL

100-200 μg 10-15 μg 30 mg 2 mL 2 mL

Lockout interval (min) 10-15 6 30 10 20

Continuous rate 300-600 μg/h 80-120 μg/h – 4 mL/h 5 mL/h

Recommendation GR • Epidural analgesia, especially PCEA, provides superior post-operative analgesia, reducing A complications and improving patient satisfaction. It is therefore preferable to systemic techniques (2) GR = grade of recommendation 5.3.5.4 Neural blocks Local anaesthetic blocks (intermittent and continuous) can be used after urological surgical operations to supplement post-operative analgesia (37) (level of evidence: 2a). Examples of such blocks are shown in Table 17. Note that lidocaine is not usually used because of its short duration of action.

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Table 17: Examples of neural blocks Procedure • Iliohypogastric or ilioinguinal nerve infiltration after hernia repair • Intercostal nerve infiltration • Continuous intrapleural infusion

Drug/dosage 10-20 mL bupivacaine or ropivacaine 0.25-0.5% 5-10 mL bupivacaine or ropivacaine 0.25-0.5% 10 mL/h bupivacaine or ropivacaine 0.1-0.2%

5.3.5.5 Wound infiltration Intra-operative wound infiltration with local anaesthetic (usually 10-20 mL of ropivacaine or bupivacaine 0.250.5%) can provide some post-operative analgesia and may reduce the requirement for systematic analgesia (38) (level of evidence: 2b). 5.3.5.6 Continuous wound instillation Continuous post-operative wound instillation of a local anaesthetic via a multi-hole catheter placed intraoperatively by the surgeon has been proven to provide satisfactory analgesia for moderate to severe postoperative pain, reducing the consumption of systemic analgesics (39-41) (level of evidence: 2b). 5.3.6 Multi-modal analgesia The concept of multi-modal (‘balanced’) analgesia is that effective post-operative pain control depends on the use of several different analgesics and routes of administration, which then act in synergy. The combined use of different classes of analgesics and analgesic techniques improves the effectiveness of pain relief after surgery and reduces the maximal dosage and adverse effects (42) (level of evidence: 2b). Multi-modal analgesia seems to be more effective when different drugs are administered via different routes than when different drugs are administered via a single route (1) (level of evidence: 2b). Recommendation GR • Multi-modal pain management should be employed whenever possible since it helps to B increase efficacy while minimising adverse effects GR = grade of recommendation 5.3.7 Special populations 5.3.7.1 Ambulatory surgical patients The main aim of analgesia in these patients is to achieve adequate pain relief so that patients can be discharged from hospital. It also avoids the use of opioids, the side-effects of which can prolong hospital stay (43, 44) (level of evidence: 2a). A multi-modal analgesic plan uses a combination of NSAIDs or paracetamol plus local anaesthetics used as peripheral nerve blocks, tissue infiltration, or wound instillation. In this way, ambulatory patients can be given pain relief that does not use opioids (45) (level of evidence: 2b). Recommendations GR • For post-operative pain control in out-patients, multi-modal analgesia with a combination of B NSAIDs or paracetamol plus local anaesthetics should be used • If possible, avoid opioids B GR = grade of recommendation 5.3.7.2 Geriatric patients The perception of pain appears to be reduced in geriatric patients, and the requirement for analgesia generally decreases with increasing age (46, 47). Geriatric patients can also suffer from emotional and cognitive impairments, such as depression and dementia, which could affect adequate pain management (48). Post-operative delirium in the elderly is a fairly common complication and is often multi-factorial. It may be associated with the administration of pethidine (49). Multi-modal post-operative analgesia may be the pain management technique of choice in elderly patients, as the dosages of medication required are lower. However, it is important to be vigilant for adverse reactions, as they tend to increase in number in the geriatric population (50) (level of evidence: 2b).

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Epidural analgesia might diminish the risk of post-operative delirium and respiratory complications in elderly patients (51) (level of evidence: 2b). Recommendation GR • Multi-modal and epidural analgesia are preferable for post-operative pain management in B elderly patients because these techniques are associated with fewer complications GR = grade of recommendation 5.3.7.3 Obese patients Obese patients appear to be at higher risk for certain post-operative complications, including respiratory (hypoxia, atelectasis, arrest), cardiovascular (ischaemia, arrhythmias, infarction), thromboembolic episodes, and wound infections (52, 53). Because the administration of opioids to obese patients is associated with sudden respiratory arrest, a combination of NSAIDs or paracetamol with a local anaesthetic epidural might be the safest analgesic solution (54, 55) (level of evidence: 2b). If absolutely necessary, opioids should be used with caution and under careful titration to avoid depression of the respiratory drive (55). Oxygen therapy should also be applied post-operatively to increase oxygen saturation (56). Recommendations GR • The post-operative use of opioids should be avoided in obese patients unless absolutely B necessary • An epidural of local anaesthetic in combination with NSAIDs or paracetamol is preferable B GR = grade of recommendation 5.3.7.4 Other groups Critically ill or cognitively impaired patients present special difficulties in pain management. Regional or multimodal analgesia might be more effective in such patients because drug dosages are reduced and behavioural interventions and patient-controlled methods are unsuitable (1) (level of evidence: 3). Recommendation GR • There are no sufficient data to support a specific post-operative pain management plan for C critically ill or cognitively impaired patients GR = grade of recommendation 5.3.8 Post-operative pain management teams The importance of efficient post-operative pain management has led to the development of acute postoperative pain management teams. These are multi-disciplinary teams, which generally consist of nursing and pharmacy personnel led by an anaesthesiologist. Their aims are post-operative pain assessment and treatment using various methods, including PCAs or PCEAs, and education of medical and nursing staff. Such services have been shown to improve pain relief, decrease analgesic medication-related side-effects (e.g. nausea, vomiting, pruritus, sedation and respiratory depression), improve patient satisfaction, and decrease overall costs and morbidity rates (57-9) (level of evidence: 2b). In addition, improved pain control can lead to a shorter period of hospitalisation and fewer unscheduled re-admissions after day-case surgery (60) (level of evidence: 3). However, these teams do not exist in every country. In some countries, surgeons manage mild to moderate post-operative pain, and anaesthesiologists are involved in epidurals or PCAs.

5.4 Specific pain treatment after different urological operations 5.4.1 Extracorporeal shock wave lithotripsy (ESWL) This is a minimally invasive treatment, during and after which between 33% and 59% of patients do not need any analgesia (61, 62, 63) (evidence level 2b). In those patients who do need pain relief, post-treatment pain is unlikely to be severe and oral analgesics are usually sufficient. Analgesic plan • Pre-operative assessment: see section 5.3.2. • Intra-operatively: the most experience exists for alfentanil (0.5-1.0 mg/70 kg iv), given on demand during ESWL, either by the urologist or the anaesthesiologist. Non-steroidal anti-inflammatory drugs (NSAIDs) or midazolam as pre-medication 30-45 min before treatment reduces the need for opioids

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•

during the procedure (evidence level 2b). With a pre-medication of diclofenac (100 mg rectally), only 18% of patients needed pethidine during the lithotripsy (64). After a pre-medication with midazolam (5 mg orally), 70% of patients were completely free of pain during the treatment, and if buprenorphine was added this proportion rose to 87% (65). After pre-medication with midazolam (2 mg iv, 5 min before the treatment), diclofenac or tramadol proved to be safe and effective analgesics with fewer side-effects than fentanyl (66) (evidence level 1b). Other effective regimes for intra-operative pain treatment are fentanyl (1 μg/kg iv [67]) or sufentanil or remifentanil. These drugs are usually given by the anaesthesiologist because of the risk of respiratory depression. The incidence of respiratory depression after the procedure was significantly lower (20% vs 53%) if remifentanil was used instead of sufentanil (68, 69) (evidence level 1b). There is not enough evidence to prove an advantage for any of the combinations used. Post-operative: most patients will be able to tolerate oral analgesics following this procedure. NSAIDs, metamizole, paracetamol, codeine and paracetamol combination preparations or tramadol could all be used. These drugs could be prescribed on an ‘as needed’ or a time-contingent basis. If pain is more severe or persistent, patients usually need to be examined to exclude hydronephrosis or haematoma of the kidney.

Table 18 gives drug options for after ESWL. Table 18: Analgesic drug options after ESWL Drug Diclofenac Metamizole Paracetamol Tramadol

Dosage (mg) 50 100 500-1000 500-1000 50-100

Method of administration Orally Rectally Orally Orally Orally

Frequency (max.) Three times daily Every 16 h Four times daily Four times daily Four times daily

The majority of patients for this procedure will be outpatients who have come in just for the day. Upon discharge, they should be provided with a prescription for analgesics and a contingency plan in case the pain worsens. This will reduce the incidence of unplanned hospital readmissions. Recommendations GR • Analgesics should be given on demand during and after ESWL because not all patients need B pain-relief • Premedication with NSAIDs or midazolam often decreases the need for opioids during the B procedure • iv opioids and sedation can be used in combination during ESWL; dosage is limited by C respiratory depression • Post-ESWL, analgesics with a spasmolytic effect are preferable C GR = grade of recommendation 5.4.2 Endoscopic procedures 5.4.2.1 Transurethral procedures The main procedures include: • transurethral resection of bladder tumour (TURB) • transurethral resection of bladder neck • transurethral incision of prostate • transurethral resection of prostate (TURP) • retrograde ureteroscopy (diagnostic and/or for stone treatment). These operations are usually performed under spinal anaesthesia (epidural or subarachnoid block) with the patient awake or mildly sedated. These regional anaesthetic techniques will usually provide post-operative analgesia for 4-6 h following surgery. Much of the post-operative pain is generally caused by the indwelling catheter or the double-J (ureteral stent following ureterorenoscopy), which mimics overactive bladder syndrome. For this reason, drugs with an antimuscarinic effect have been proven to be useful in addition to the opioids (70) (evidence level 1b). For post-operative pain control, oral or iv analgesia is preferable.

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Analgesic plan • Pre-operative assessment: see section 5.3.2. • Intra-operative: spinal (intrathecal or epidural) anaesthesia will provide intra-operative analgesia and last for 4-6 h post-operatively. • Post-operative: after 4-6 h, mild oral analgesics such as NSAIDs or paracetamol +/- codeine, or stronger opioids, also orally, could be used. In the case of bladder discomfort (overactive bladder syndrome) resulting from the indwelling catheter, metamizole (orally or iv), pethidine (iv) or piritramid (iv) would also be effective. In addition, antimuscarinic drugs such as oxybutynin (5 mg orally three times daily) are useful and reduce the need for opioids (70) (evidence level 1b). Table 19 lists the analgesic drug options after transurethral procedures. Table 19: Analgesic drug options after transurethral procedures Drug Diclofenac Metamizole Paracetamol Tramadol Piritramid Pethidine Morphine

Dosage (mg) 50 100 500-1000 500-1000 50-100 15 25-100 10

Method of administration Orally Rectally Orally or iv Orally or iv Orally, im, sc or iv iv or sc Orally, im, sc or iv im

Frequency (max.) Three times daily Every 16 h Four times daily Four times daily Four times daily Four times daily Four to six times daily Eight times daily

Recommendations GR • Postoperative analgesics with a spasmolytic effect or mild opioids are preferable C • Antimuscarinic drugs could be helpful in reducing discomfort resulting from the indwelling catheter B • Antimuscarinic drugs may reduce the need for opioids B GR = grade of recommendation 5.4.2.2 Percutaneous endoscopic procedures These include: • percutaneous nephrolithotomy • percutaneous endopyelotomy • percutaneous resection of pyelocaliceal tumours • antegrade ureteroscopy. The analgesic plan is the same as that for transurethral procedures, but with the additional complexity caused by the skin having been breached, which could mean that additional analgesia is required. Local anaesthetic could be infiltrated locally into the skin, e.g. 10 mL of 0.5% bupivacaine. General anaesthesia is usually required for the procedure because of the uncomfortable decubitus (prone position) and the prolonged duration of the operation. 5.4.2.3 Laparoscopic procedures These include: • laparoscopic lymph node dissection • diagnostic laparoscopy • laparoscopic removal of organ or tumour. These procedures are usually performed under general anaesthesia, and so patients cannot take oral medication for at least 4-6 h post-operatively. It is therefore necessary to use iv analgesia (or im or sc as second choice options) during this period. After this time, analgesia can be given orally or systemically, depending on bowel motility. Most data concerning post-operative pain exist for laparoscopic cholecystectomy. A particular consideration after this procedure is the development of pain in the shoulder as a result of diaphragmatic irritation following the pneumoperitoneum. This problem seems to be dependent on the intra-abdominal pressure used during the

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procedure, as reduced carbon dioxide insufflation reduces post-operative shoulder pain (71, 72, 73) (level of evidence 1b). Analgesic plan • Pre-operative assessment: see section 5.3.2. • Intra-operative: iv opioids +/- NSAIDs or metamizole administered by the anaesthesiologist. The infiltration of local anaesthetic into the port incisions reduces pain after laparoscopy (74). • Post-operative: the administration of a systemic opioid iv (im or sc), either ‘as needed’ or on a timecontingent basis, is very effective in the immediate post-operative period, but the prophylactic use of opioids after laparoscopic procedures is not recommended in order to hasten recover. NSAIDs (e.g. paracetamol and/or metamizole) and incisional local anaesthetics (multimodal concept) can be given to reduce the need for opioids (74, 75). Table 20 lists the drug options after laparoscopic surgery. Table 20: Analgesic drug options after laparoscopic surgery Drug Metamizole Paracetamol Tramadol Piritramid Morphine Diclofenac

Dosage (mg) 500-1000 500-1000 50-100 15 10 1 mg bolus 50 100

Method of administration Orally or iv Orally or iv Orally, im, sc or iv iv or sc Intermittent im iv Orally Rectally

Frequency (max.) Four times daily Four times daily Four times daily Four times daily Eight times daily PCA, 5 min lockout Three times daily Every 16 h

PCA = patient-controlled analgesia Recommendations GR • Low intra-abdominal pressure and good desufflation at the end of the procedure reduces A post-operative pain • NSAIDS are often sufficient for post-operative pain control B • NSAIDs decrease the need for opioids B GR = grade of recommendation 5.4.3 Open surgery 5.4.3.1 Minor operations of the scrotum/penis and the inguinal approach These two types of surgical operations are relatively minor and nearly all patients will be able to take oral analgesia following the operation. The operation is often performed as an ambulatory procedure under local anaesthesia or with the aid of an ilioinguinal or iliohypogastric nerve block. The analgesic options after surgery are outlined in Table 21. Table 21: Analgesic drug options after minor surgery of the scrotum, penis, and inguinal region Drug Diclofenac Paracetamol Metamizole Tramadol

Dosage (mg) 50 100 1000 500-1000 50-100

Method of administration Orally Rectally Orally Orally Orally

Frequency (max.) Three times daily Every 16 h Four times daily Four times daily Four times daily

Recommendations GR • For post-operative pain control, multimodal analgesia with a combination of NSAIDs or B paracetamol plus local anaesthetics should be used • If possible, avoid opioids for outpatients C GR = grade of recommendation

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5.4.3.2 Transvaginal surgery These procedures would include: • pelvic floor surgery • stress incontinence surgery. Local or regional anaesthesia can be used for these operations. After surgery, the analgesic options listed in Table 22 are possible. Table 22: Analgesic drug options after transvaginal urological surgery Drug Diclofenac Paracetamol Metamizole Tramadol Piritramid Pethidine Morphine

Dosage (mg) 50 100 1000 500-1000 50-100 15 25-100 10

Method of administration Orally Rectally Orally Orally or iv Orally iv or sc Orally, im, sc or iv im

Frequency (max.) Three times daily Every 16 h Four times daily Four times daily Four times daily Four times daily Four to six times daily Eight times daily

Recommendations GR • NSAIDS are often sufficiently effective after minor or moderate surgery B • NSAIDs decrease the need for opioids B GR = grade of recommendation 5.4.3.3 Perineal open surgery These procedures include: • perineal radical prostatectomy (PRPE) • posterior urethroplasty. Analgesic plan • Pre-operative assessment: see section 5.3.2. • Intra-operative: general anaesthesia is usually used, particularly for PRPE, because of the uncomfortable exaggerated lithotomy position on the operating table. Sometimes an intrathecal catheter (epidural) can be sited for intra-operative and post-operative pain control. • Post-operative: continuous epidural infusion of a combination of opioids and local anaesthetic or PCA is usually used. When systemic opioids are used, it is advisable to use them in combination with NSAIDs so as to reduce their dose and consequently their side-effects. When the patient is able to take oral analgesics, usually after 1-3 days, oral metamizole or paracetamol +/- codeine could be used. There are no data in the literature to recommend specific post-operative pain management or to show which is superior. The analgesic options that are possible after surgery are shown in Table 23. Table 23: Analgesic options after major perineal open surgery Drug Bupivacaine 0.25% + fentanyl 2 µg/mL Morphine Metamizole Paracetamol Tramadol Piritramid Diclofenac

Dosage Method of administration 5-15 mL/h Continuous epidural infusion 1 mg bolus 500-1000 mg 500-1000 mg 50-100 mg 15 mg 50 mg 100 mg

iv Orally or iv Orally or iv Orally, im, sc or iv iv or sc Orally Rectally

Frequency (max,) n.a. PCA, 5 min lockout Four times daily Four times daily Four times daily Four times daily Three times daily Every 16 h

PCA = patient-controlled analgesia.

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5.4.3.4 Transperitoneal laparotomy These include: • retroperitoneal lymph node dissection (RLND) • radical nephrectomy -/+ caval thrombectomy • cystectomy + urinary diversion. Post-operatively, patients are usually managed in an intermediate or intensive care unit. A combined general anaesthetic and regional technique is usually used. Analgesic plan • Pre-operative assessment: see section 5.3.2. • Intra-operative: general anaesthetic and regional technique; sometimes an intrapleural catheter can be sited. • Post-operative: continuous epidural infusion of a combination of opioids and local anaesthetic. Once the patient is able to take oral analgesics (dependent on bowel motility), which is usually 3-4 days after surgery, metamizole, paracetamol +/- codeine or tramadol could be used. Multimodal concepts (combining NSAIDs with opioids, fast-track strategies, keeping abdominal and urinary drainage as short as possible) are useful in reducing the need for analgesia (76). Table 24 lists the analgesic options after the transperitoneal approach. Table 24: Analgesic options after transperitoneal laparotomy Drug Bupivacaine 0.25% + fentanyl 2 µg/mL Morphine Metamizole Paracetamol Tramadol Piritramid Diclofenac

Dosage 5-15 mL/h

Method of administration Continuous epidural infusion

Frequency (max.) n.a.

1 mg bolus 500-1000 mg 500-1000 mg 50-100 mg 15 mg 50 mg 100 mg

iv Orally or iv Orally or iv Orally, im, sc or iv iv or sc Orally Rectally

PCA, 5 min lockout Four times daily Four times daily Four times daily Four times daily Three times daily Every 16 h

PCA = patient-controlled analgesia. Recommendations GR • The most effective method for systemic administration of opioids is PCA (see section 5.3.4.5), A which improves patient satisfaction and decreases the risk of respiratory complications • Epidural analgesia, especially patient-controlled epidural analgesia (PCEA), provides superior A post-operative analgesia, reducing complications and improving patient satisfaction. It is therefore preferable to systemic techniques (see sections 5.3.5.2 and 5.3.5.3). GR = grade of recommendation 5.4.3.5 Suprapubic/retropubic extraperitoneal laparotomy These procedures include: • open prostatectomy • radical retropubic prostatectomy. Post-operatively, patients are usually managed in an intermediate or intensive care unit. A combined general anaesthetic and regional technique is usually used. It will be possible to use the oral route for analgesia sooner than after a transperitoneal procedure. Oral opioids, metamizole and/or paracetamol +/- NSAIDs could be used. Analgesic plan • Pre-operative assessment: see section 5.3.2. • Intra-operative: general anaesthetic and regional technique. • Post-operative: continuous epidural infusion of a combination of opioids and local anaesthetic. Once the patient is able to take oral analgesics, usually 1-3 days after surgery, metamizole, paracetamol +/codeine, +/- NSAIDs could be used.

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Table 25 lists the post-operative analgesic options. Table 25: Analgesic options after suprapubic/retropubic extraperitoneal laparotomy Drug Bupivacaine 0.25% + fentanyl 2 µg/mL Morphine Metamizole Paracetamol Tramadol Piritramid Diclofenac

Dosage Method of administration 5-15 mL/h Continuous epidural infusion 1 mg bolus 500-1000 mg 500-1000 mg 50-100 mg 15 mg 50 mg 100 mg

iv Orally or iv Orally or iv Orally, im, sc or iv iv or sc Orally Rectally

Frequency (max.) n.a. PCA, 5 min lockout Four times daily Four times daily Four times daily Four times daily Three times daily Every 16 h

PCA = patient-controlled analgesia. 5.4.3.6 Retroperitoneal approach – flank incision – thoracoabdominal approach These procedures include: • nephrectomy • pyeloplasty • pyelonephrolithotomy. Post-operatively, patients are usually managed in an intermediate or intensive care unit. A combined general anaesthetic and regional technique is usually used. Analgesic plan • Pre-operative assessment: see section 5.3.2. • Intra-operative: general anaesthetic and regional technique; sometimes an intrapleural catheter can be sited. • Post-operative: continuous epidural infusion of a combination of opioids and local anaesthetic. Several meta-analyses have shown significantly better pain control with this technique compared with iv analgesics (77, 78). If epidural analgesia is not possible or is refused by the patient, PCA should be provided. Once the patient is able to take oral analgesics, usually 1-3 days after surgery (depending on bowel motility), paracetamol +/- codeine or metamizole could be used in addition (to reduce the need for opioids) or alone. Table 26 lists the analgesic options. Table 26: Analgesic options after retroperitoneal approach – flank incision Drug Bupivacaine 0.25% + fentanyl 2 µg/mL Morphine Metamizole Paracetamol Tramadol Piritramid Diclofenac

Dosage Method of administration 5-15 mL/h Continuous epidural infusion 1 mg bolus 500-1000 mg 500-1000 mg 50-100 mg 15 mg 50 mg 100 mg

iv Orally or iv Orally or iv Orally, im, sc or iv iv or sc Orally Rectally

Frequency (max.) n.a. PCA, 5 min lockout Four times daily Four times daily Four times daily Four times daily Three times daily Every 16 h

PCA, patient-controlled analgesia. Recommendation GR • Epidural analgesia, especially PCEA, provides superior post-operative analgesia, reducing A complications and improving patient satisfaction. It is therefore preferable to systemic techniques (see sections 5.3.5.2 and 5.3.5.3). GR = grade of recommendation

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5.5

Dosage and method of delivery of some important analgesics

5.5.1 NSAIDs Table 27 gives details of the most important drugs in this category. Table 27: Dosage and delivery of NSAIDs Drug Diclofenac Ibuprofen

Method of administration Orally Rectally Orally

Single dosage (mg) 50-75 100 200-800

Maximal dosage (mg) per 24 h 150 150 2400

5.5.2 NSAIDs with antipyretic effect Table 28 gives details of the most important drugs in this category. Table 28: Dosage and delivery of antipyretics Drug Paracetamol Metamizole

Method of administration Orally iv Orally iv

Single dosage (mg) 500-1000 1000 500-1000 1000-2500

Maximal dosage (mg/24 h) 4000 (50 mg/kg) 4000 (50 mg/kg) 4000 5000

5.5.3 Selective COX-2 inhibitor Table 29 gives details of the most important drugs in this category. Table 29: Dosage and delivery of selective COX-2 inhibitors Drug Celecoxib

Method of administration Orally

Single dosage (mg) 100-200

Maximal dosage (mg/24 h) 400

5.5.4. Opioids Table 30 gives details of the most important drugs in this category. Table 30: Dosage and delivery of opioids Drug Tramadol Dihydrocodeine Piritramid

Pethidine

Morphine*

Fentanyl†

Method of administration Orally iv Orally iv iv (PCA) sc/im Orally Rectally sc/im iv Orally Rectally sc/im iv iv (PCA) iv

Common single dosage (mg) 50 50-100 60-120 7.5-22.5 1-2 15-30 25-150 100 25-150 25-100 Starting with 10 Starting with 10 Starting with 5 Starting with 2 0.5-2.5 mg bolus 10-15 min lockout 0.05-0.1 mg (1 μg/kg)

Maximal dosage (mg) 400-600 400-600 240 ≈90 ≈300 ≈120 500 500 500 500 No maximal dose No maximal dose No maximal dose No maximal dose No maximal dose Limited by respiratory depression

PCA = patient-controlled analgesia. *A simple way of calculating the daily dosage of morphine for adults (aged 20-75 years) is: 100 – patient’s age = morphine per day in mg.

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†Strong

opioids have no real upper limit in dosage (except buprenorphine). The dose must be titrated in correlation with pain relief and depending on the individual strength of unwanted effects such as respiratory depression (see section 5.3.4.4).

5.6

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Neudecker J, Sauerland S, Neugebauer E, Bergamaschi R, Bonjer HJ, Cuschieri A, Fuchs KH, JacobiCh, Jansen FW, Koivusalo AM, Lacy A, McMahon MJ, Millat B, Schwenk W. The European Association for Endoscopic Surgery clinical practice guideline on the pneumoperitoneum for laparoscopic surgery. Surg Endosc 2002;16(7):1121-43. http://www.ncbi.nlm.nih.gov/pubmed/12015619 Kehlet H, Wilmore DW. Multimodal strategies to improve surgical outcome. Am J Surg 2002;183(6):630-41. http://www.ncbi.nlm.nih.gov/pubmed/12095591 Block BM, Liu SS, Rowlingson AJ, Cowan AR, Cowan JA Jr, Wu CL. Efficacy of postoperative epidural analgesia: a meta-analysis. JAMA 2003;290(18):2455-63. http://www.ncbi.nlm.nih.gov/pubmed/14612482 Wu CL, Cohen SR, Richman JM, Rowlingson AJ, Courpas GE, Cheung K, Lin EE, Liu SS. Efficacy of postoperative patient-controlled and continuous infusion epidural analgesia versus intravenous patient-controlled analgesia with opioids: a meta-analysis. Anesthesiology 2005;103(5):1079-88; quiz 1109-10. http://www.ncbi.nlm.nih.gov/pubmed/16249683 Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998. http://www.cebm.net/index.aspx?o=1025 [accessed February 2009].

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6. ABBREVIATIONS USED IN THE TEXT This list is not comprehensive for the most common abbreviations. AMPA ATC CNS COX CT EDTMP EORTC ESWL GABA GFR GPP IASP im iv 131J-MIBG MRI NMDA NRS NSAIDs PACU PCa PCA PCEA prn PRPE RCC RLND sc 153Sm 89Sr SRI SPECT TCA TCC TURB TURP VAS VRS WHO

α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate around-the-clock central nervous system cyclo-oxygenase computed tomography ethylenediaminetetramethylenephosphonate European Organisation for Research and Treatment of Cancer extracorporeal shock wave lithotripsy gamma-aminobutyric acid glomerular filtration rate good practice points International Association for the Study of Pain intramuscular intravenous 131J-metaiodobenzylguanidine magnetic resonance imaging N-methyl-D-aspartate numerical rating scale non-steroidal anti-inflammatory drugs post-anaesthesia care unit prostate cancer patient-controlled analgesia patient-controlled epidural analgesia as needed perineal radical prostatectomy renal cell carcinoma retroperitoneal lymph node dissection subcutaneous samarium-153 strontium-89 selective serotonin reuptake inhibitors single photon emission computed tomography tricyclic antidepressants transitional cell carcinoma transurethral resection of bladder tumour transurethral resection of prostate visual analogue scale verbal rating scale World Health Organization

Conflict of interest All members of the General Pain Management Guidelines writing panel have provided disclosure statements on all relationships that they have and that might be perceived to be a potential source of conflict of interest. This information is kept on file in the European Association of Urology Central Office database. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

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Guidelines on

Chronic Pelvic Pain M. Fall (chairman), A.P. Baranowski, S. Elneil, D. Engeler, J. Hughes, E.J. Messelink, F. Oberpenning, A.C. de C. Williams

© European Association of Urology 2009

Table of Contents

page

1. INTRODUCTION 1.1 Background 1.1.1 Definition of pain (WHO) 1.1.2 Innervation of the urogenital system 1.1.3 References 1.2 Pain evaluation and measurement 1.2.1 Pain evaluation 1.2.2 Pain measurement 1.2.3 References

5 5 5 6 6 7 7 7 8

2. CHRONIC PELVIC PAIN 2.1 Background 2.1.1 Introduction to urogenital pain syndromes 2.2 Definitions of chronic pelvic pain and terminology (Table 2) 2.3 Classification of chronic pelvic pain syndromes Table 1: EAU classification of chronic urogenital pain syndromes (page 9) Table 2: Definitions of chronic pain terminology (page 10) Table 3: ESSIC classification of types of bladder pain syndrome according to the results of cystoscopy with hydrodistension and of biopsies (page 12) 2.4 References 2.5 An algorithm for chronic pelvic pain diagnosis and treatment 2.5.1 How to use the algorithm 2.6 Chronic prostate pain/chronic prostatitis associated with chronic pelvic pain syndrome (CP/CPPS) 2.6.1 Introduction 2.6.2 Definition 2.6.3 Pathogenesis 2.6.4 Diagnosis 2.6.5 Treatment 2.6.5.1 Alpha-blockers 2.6.5.2 Antibiotic therapy 2.6.5.3 Non-steroidal anti-inflammatory drugs (NSAIDs) 2.6.5.4 Corticosteroids 2.6.5.5 Opioids 2.6.5.6 5-alpha-reductase inhibitors 2.6.5.7 Allopurinol 2.6.5.8 Phytotherapy 2.6.5.9 Muscle relaxants 2.6.5.10 Supportive therapies 2.6.5.11 Surgical management 2.6.6 References 2.7 Bladder pain syndrome/interstitial cystitis (BPS/IC) 2.7.1 Introduction 2.7.2 Definition 2.7.3 Pathogenesis 2.7.4 Epidemiology 2.7.5 Association with other diseases 2.7.6 Diagnosis 2.7.7 Biological markers 2.7.8 IC in children and males 2.7.9 Medical treatment 2.7.10 Intravesical treatment 2.7.11 Interventional treatments 2.7.12 Treatments of limited efficacy and absence of recent publications 2.7.13 Alternative and complementary treatments 2.7.14 Surgical treatment 2.7.15 References

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12 12 12 14 15 15 15 16 16 16 16 16 16 17 17 17 17 17 17 17 18 23 23 23 24 25 26 26 27 27 27 29 31 33 33 34 38

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Scrotal pain 2.8.1 Management of different conditions 2.8.2 References Urethral pain syndrome 2.9.1 Treatment 2.9.2 References

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3. PELVIC PAIN IN GYNAECOLOGICAL PRACTICE 3.1 Introduction 3.2 Clinical history 3.3 Clinical examination 3.3.1 Investigations 3.4 Dysmenorrhoea 3.5 Infection 3.5.1 Treatment 3.6 Endometriosis 3.6.1 Treatment 3.7 Gynaecological malignancy 3.8 Injuries related to childbirth 3.9 Conclusion 3.10 References

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4. NEUROLOGICAL ASPECTS 4.1 Physiology of the urogenital system 4.2 Physiology of the bladder 4.2.1 Bladder filling 4.2.2 Afferent innervation of the bladder 4.2.3 Efferent innervation of the bladder 4.2.4 Central control of micturition 4.2.5 Physiology of the genital organs 4.3 Sexual dysfunction in men and women 4.4 References

59 59 59 59 60 60 60 61 63 64

5.

NEUROGENIC CONDITIONS 5.1 Introduction 5.2 Pudendal nerve entrapment 5.3 Other neurogenic conditions 5.4 References

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6.

PELVIC FLOOR FUNCTION AND DYSFUNCTION 6.1 Introduction 6.2 Function 6.3 Dysfunction 6.4 Myofascial trigger points 6.5 Therapy 6.6 References

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7. PSYCHOLOGICAL FACTORS IN CHRONIC PELVIC PAIN 7.1 Introduction 7.2 Psychological models of pain 7.3 Methodology 7.4 Psychological factors in assessment of pelvic pain 7.4.1 Psychological risk factors in the development of pelvic pain and adaptation to it 7.4.2 Anxiety 7.4.3 Depression and catastrophizing 7.4.4 Impact of pain 7.5 Summary: assessment recommendations 7.5.1 Anxiety 7.5.2 Depression 7.5.3 Sexual and physical abuse in childhood

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7.6 7.7

Psychological factors in treatment of pelvic pain References

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8. GENERAL TREATMENT OF CHRONIC PELVIC PAIN 8.1 Simple analgesics 8.1.1 Paracetamol 8.1.2 Acidic antipyretic analgesics 8.1.3 Guidelines for use of NSAIDs and COX-2 selective agents 8.2 Neuropathic analgesics 8.2.1 Tricyclic antidepressants 8.2.2 Anticonvulsants 8.2.3 N-methyl-D-aspartate (NMDA) antagonists 8.2.4 Sodium channel blockers 8.3 Opioids 8.3.1 Guidelines for the use of opioid-like agents in chronic/non-acute urogenital pain 8.3.2 Morphine 8.3.3 Transdermal fentanyl 8.3.4 Methadone 8.3.5 Oxycodone 8.3.6 Other opioids and opioid-like agents 8.4 References 8.5 Nerve blocks 8.5.1 References 8.6 Transcutaneous electrical nerve stimulation (TENS) 8.6.1 Results of suprapubic TENS in BPS/IC 8.7 Sacral neuromodulation in pelvic pain syndromes 8.7.1 References

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ABBREVIATIONS USED IN THE TEXT

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1. INTRODUCTION 1.1 Background 1.1.1

Definition of pain (WHO) ‘Pain management is a necessity in the work of each physician.’ F. Sauerbruch, 1936

Pain can be defined as an unpleasant sensory and emotional experience associated with either real or potential tissue damage, or it can be described in terms of such damage (1). Pain is the most common symptom of any illness. In its management, firstly, the physician needs to discover and treat the cause of the pain; secondly, to treat the pain itself, whether or not the underlying cause is treatable; and thirdly to relieve the suffering caused by the pain. One function of the nervous system is to provide information about the occurrence of or the threat of injury. The sensation of pain, by its inherent aversive nature, contributes to this function. The response of the peripheral neural apparatus via primary sensory neurones (known as nociceptors), to noxious (injurious or potentially injurious) stimuli alerts the organism to injury (potential injury). Acute pain is an important and adaptive element of the normal nervous system. In chronic or persistent pain, the purpose of the pain is lost. Such pain often represents an aberration of neural processing. Nociceptive or neuropathic pain. ‘Pain’ is used to describe all sensations that are perceived as hurting; it requires the higher centres. The causes of pain may be many. For example, pain can be nociceptive or neuropathic, with many pains having both a neuropathic and nociceptive component: • Nociceptive pain is caused by direct stimulation of nociceptors in the periphery; peripheral inflammation may or may not be pressent. An example of physiological nociceptive pain is when an individual perceives pain due to hot water running over their skin resulting in the individual withdrawing from the stimulus and there is no injury. Pathological nociceptive pain, however, is often associated with tissue damage and inflammation, with inflammation having the effect of increasing the perception of pain associated with peripheral stimulation. • Neuropathic pain is caused by a lesion to the peripheral or central nervous system. Acute or chronic pain. Pain may also be described as either acute or chronic pain: • Acute pathological pain has an acute onset and is short-lived, usually less than a week or so, and is associated with tissue trauma, e.g. following surgery. Transient acute pain may also be caused by acute nerve injury, e.g. local injury to the ulnar nerve from hitting the elbow. Although the mechanisms of acute and chronic pain may overlap, the mechanisms of acute pain resolve quickly in contrast to chronic pain. • Chronic (also known as persistent) pain occurs for at least 3 months. However, the mechanisms involved are more important than the duration of the pain. Chronic pain is associated with changes in the central nervous system (CNS), which may maintain the perception of pain in the absence of acute injury. These changes may also magnify perception so that non-painful stimuli are perceived as painful (allodynia), while painful stimuli are perceived as more painful than expected (hyperalgesia). The bladder provides a good example of how changes in the CNS affect sensory perception. An acute pain insult to the bladder can produce functional changes within the CNS, so that pain persists even after removal of the stimulus. These central functional changes may also be associated with a dysaesthetic (unpleasant sensation) response; for instance, mild distension or stimulation of the bladder by urine not normally perceived, may produce the urge to urinate. Furthermore, core muscles, including pelvic muscles, may become hyperalgesic with multiple trigger points, while other organs may also become sensitive, e.g. the uterus with dyspareunia and dysmenorrhoea, the bowel with irritable bowel symptoms. The spread of abnormal sensory responses between the organs and musculoskeletal system is a well-described consequence of the CNS changes and a crucial cause of complex chronic pelvic pains. Functional abnormalities such as urinary retention may also occur. Chronic pain is associated with various psychological responses, partly due to the long duration of the pain and partly due to neuroplasticity of the CNS. Chronic pain inhibits feelings, emotions, thinking and reactions, while reduced mobility and inhibited physiological functions restrict social interactions and work. Although there are established management strategies, pain is often undertreated because many clinicians have a poor understanding of the principles of pain therapy. Efforts are needed to improve this situation. When appropriate, management should be both holistic and multidisciplinary. Deep visceral pain. There are important differences between cutaneous and deep visceral pain. Unlike cutaneous pain, deep visceral pain is diffuse and poorly localized. It may be accompanied by strong autonomic

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responses, such as sweating and changes in heart rate, blood pressure and respiration. Deep visceral pain may also be produced by stimuli that are not tissue-damaging, e.g. bowel and bladder distension (2,3), and may be associated with referred pain and cutaneous and deep tissue hyperalgesia. Modulation of pain. Pain transmission from the periphery to the higher brain centres via the spinal cord is not a simple, passive process involving exclusive pathways. The relationship between a stimulus causing pain and the way it is perceived by an individual is dramatically affected by circuitry within the spinal cord and the brain. The sensation of pain is modulated as it is transmitted upwards from the periphery to the cortex. It is modulated at a segmental level and by descending control from higher centres, with the main neurotransmitters involved being serotonin, noradrenaline and the endogenous opioids. 1.1.2 Innervation of the urogenital system Studies on the response properties of visceral afferents from the urinary tract have highlighted the differences between nociception in the skin and viscera. Most visceral primary afferents from the bladder, urethra, reproductive and other pelvic organs are encoded for both noxious and non-noxious stimuli (4-6). Increasing afferent traffic results in a change from non-noxious sensation to noxious. Ureter. Ureteric afferents are thinly myelinated or unmyelinated and respond to direct probing of a limited area of tissue. They can be differentiated into two groups (7): • The first group responds to ureteral contractions and is excited by low levels of distension (average threshold 8 mmHg). They appear to encode levels of distension throughout and beyond the physiological range. • The second group does not respond to peristaltic contractions of the ureter, but can be excited by distension with a wide range of thresholds. Urinary bladder. Two groups of afferent fibres signal noxious stimuli in the urinary bladder, mostly nonmyelinated fibres, with some myelinated fibres (4). Graded distension of the healthy urinary bladder in humans initially gives rise to a sensation of fullness and eventually pain, as the volume of urine increases and the intravesical pressure exceeds about 25-35 mmHg (8-11). In the inflamed bladder, the sensations during bladder emptying become unpleasant and painful. Nearly all visceral primary afferents from the bladder are small myelinated or unmyelinated fibres. Some afferents exhibit a low level of ongoing discharge when the bladder is empty. Distension excites mainly thin myelinated afferents, with pressure thresholds corresponding to levels at which humans report the first sensation of fullness. Nearly all afferents are activated by the intraluminal pressures reached during normal, non-painful micturition. The activation of a large number of initially unresponsive afferents indicates that peripheral afferent mechanisms encoding pain from pelvic viscera are highly malleable and are strongly affected by tissue state. These changes are important for signalling pain and discomfort in inflammatory conditions where there is a group of afferents that become activated by the inflammation. Male reproductive organs. More than 95% of fibres of the superior spermatic nerve are unmyelinated, with most showing polymodal properties (i.e. responses to mechanical, chemical and thermal stimuli) (12). Myelinated and unmyelinated afferent fibres form a homogeneous group with polymodal receptors in the testis and/or epididymis. Prostaglandins sensitize the afferents to other stimuli (13). 1.1.3 1. 2.

3. 4.

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References Foley KM, Posner J.B. Pain and its management. In: Cecil Textbook of Medicine. 18th edn. Philadelphia: WB Saunders 1988, pp. 104-112. Dubner R. Basic mechanisms of pain associated with deep tissues. Can J Physiol Pharmacol 1991;69(5):607-9. http://www.ncbi.nlm.nih.gov/pubmed/1863910 Ness TJ, Gebhart GF. Visceral pain: A review of experimental studies. Pain 1990;41(2):167-234. http://www.ncbi.nlm.nih.gov/pubmed/2195438 Häbler H-J, Jänig W, Koltzenburg M. Activation of unmyelinated afferent fibres by mechanical stimuli and inflammation of the urinary bladder in the cat. J Physiol 1990;425:545-62. http://www.ncbi.nlm.nih.gov/pubmed/2213588 Bahns E, Ernsberger U, Jänig W, Nelke A. Functional characteristics of lumbar visceral afferent fibres from the urinary bladder and the urethra in the cat. Pflügers Arch 1986;407(5):510-8. http://www.ncbi.nlm.nih.gov/pubmed/3786110

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7. 8. 9.

10.

11.

12. 13.

Bahns E, Halsband U, Jänig W. Responses of sacral visceral afferent fibres from the lower urinary tract, colon, and anus to mechanical stimulation. Pflügers Arch 1987;410(3):296-303. http://www.ncbi.nlm.nih.gov/pubmed/3684516 Cervero F, Jänig W. Visceral nociceptors: A new world order?. Trend Neurosci 1992;15(10):374-8. http://www.ncbi.nlm.nih.gov/pubmed/1279857 Roberts WJ, Elardo SM. Sympathetic activation of A-delta nociceptors. Somato Res 1985;3(1):33-44. http://www.ncbi.nlm.nih.gov/pubmed/2999942 Seltzer Z, Devor M. Ephaptic transmission in chronically damaged peripheral nerves. Neurology 1979;29(7):1061-4. http://www.ncbi.nlm.nih.gov/pubmed/224343 Kruger L, Perl ER, Sedivec MJ. Fine structure of myelinated mechanical nociceptor endings in cat hairy skin. J Comp Neurol 1981;198(1):137-54. http://www.ncbi.nlm.nih.gov/pubmed/7229137 Treede R-D, Meyer RA, Raja S N, Campbell JN. Peripheral and central mechanisms of cutaneous hyperalgesia. Prog Neurobiol 1992;38(4):397-421. http://www.ncbi.nlm.nih.gov/pubmed/1574584 Kumazawa T. Sensory innervation of reproductive organs. Prog Brain Res 1986;67:115-31. http://www.ncbi.nlm.nih.gov/pubmed/3823468 Meyer RA, Campbell JN, Raja SN. Peripheral neural mechanisms of nociception In: Wall PD, Melzack R, eds. Textbook of Pain. 3rd edn. Edinburgh: Churchill Livingstone, 1994.

1.2 Pain evaluation and measurement 1.2.1 Pain evaluation The symptom of pain must be fully evaluated. As pain is subjective, the history provides the main evaluation. Examination and investigations provide further understanding of the pain syndrome and exclude other conditions. Pain rating(s) are essential in patient and treatment evaluation. Pain evaluation includes: • Baseline and ongoing regular evaluation of severity • An initial detailed history to include: chronology of onset and progression, character, site pain perceived and radiation, aggravating and relieving factors, associated symptoms • Questions about thoughts, emotions and behaviour associated with the pain • Detailed examination, not only of the painful area but of the whole patient, particularly the musculoskeletal and nervous systems • Investigations to identify well-defined/confusable/non-pain syndromes • Regular review of the condition as appropriate and its response to interventions. 1.2.2 Pain measurement Pain can only be measured subjectively. The most reliable and well-understood method is a numerical rating scale, from 0 (no pain) to 10 (extreme pain), with half-points marked. This is superior to the widely used visual analogue scale (VAS), which is a 10-cm line with the same labels at the ends. Alternatively, a simple verbal rating scale can be used, e.g. ‘none’, ‘mild’, ‘moderate’, ‘severe’. Both numerical and verbal scales can be used by patients without the need for paper and pen, unlike the visual analogue scale. 0 No pain

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10 Extreme pain

Since pain is multidimensional, a single rating scale combines these dimensions in unknown quantities. Depending on the clinical question, treatment, patient and setting, it can be helpful to assess separately pain intensity, pain distress, and interference of pain with activities of daily life. It can also be helpful to ask about average pain, worst pain (as even if this only occurs rarely, it can still reveal what patients should avoid) and pain on, for example, bladder voiding. Pain reduction or relief is measured directly using a percentage, from 0% = no relief up to 100% = total relief. See www.britishpainsociety.org/members_pain_scales.htm for pain scales in English and other languages. The Brief Pain Inventory (1) consists of four 0 to 10 numerical scales for pain (current, average, worst, and least) and seven scales for interference with aspects of daily life: general activity, mood, walking ability, normal work, relationships with other people, sleep and enjoyment of life. The EuroQoL is a quality-of-life scale (2) available in several European languages and free for non-commercial use. It asks about mobility, self-care, pain, usual activities, and psychological status (www.euroqol.org).

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1.2.3 1.

2.

References Tan G, Jensen MP, Thornby JI, Shanti BF. Validation of the Brief Pain Inventory for chronic nonmalignant pain. J Pain 2004;5(2):133-7. http://www.ncbi.nlm.nih.gov/pubmed/15042521 Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol group. Ann Med 2001;33(5):337-43. http://www.ncbi.nlm.nih.gov/pubmed/11491192

2. CHRONIC PELVIC PAIN 2.1 Background 2.1.1 Introduction to chronic urogenital pain syndromes Pain perceived within the pelvis may arise from a range of different mechanisms, many of which remain poorly understood. Some conditions have become ‘well-defined’ over the years and it is very important that these are identified and treated by an evidence-based approach, e.g. pudendal neuralgia. Basic investigations must therefore be undertaken to rule out ‘well-defined’ pathologies. If the results are negative, a ‘well-defined’ pathology is unlikely. Any further investigations should be done only for specific indications, e.g. for subdivision of a pain syndrome. As well as ‘well-defined’ conditions, which are associated with chronic urogenital pain and are understood better. In many cases, the mechanisms involved are the neural-axial central sensitization described above and that are so familiar in other fields of chronic pain. There is now no doubt that these central changes can produce states of visceral and/or muscle hypersensitivity with long-term pain, sensory dysaesthesia and functional abnormalities. These need to be addressed, as well as the cognitive, behavioural, emotional and sexual consequences of the underlying disease process and long-term pain. This is why the assessment and management of these areas are also expanded in these guidelines and for the emphasis on a multidisciplinary approach. Earlier EAU guidelines on chronic pelvic pain (CPP) introduced a classification system aimed at replacing old-fashioned terminology based on spurious assumptions of cause. The main emphasis was to make clear that it should not be presumed that pathology would be found where the pain is perceived. The EAU guidelines moved away from using ‘prostatitis’ and ‘interstitial cystitis’ in the absence of proven inflammation or infection, while the suffixes ‘algia’ and ‘dynia’ have often been used to provide a tangible diagnosis, which in itself may have a therapeutic benefit. In this edition of the guidelines, however, we have decided to avoid such terms completely. Instead, our definitions are based on the recommendation for terminology laid down by the International Continence Society (ICS) (1) and follow the axial structure of the International Association for the Study of Pain (IASP) classification (Table 1) (2). Pain syndrome terms were introduced to indicate the multiple mechanisms involved, both physical and psychological. This approach has been reviewed on many occasions over the past few years and has been found to be robust. The EAU guidelines expand this approach, so avoiding spurious diagnostic terms, which are associated with inappropriate investigations, inappropriate treatments, inappropriate patient expectations and ultimately, a worse prognostic outlook.

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Non pelvic e.g. Neurological pain syndrome e.g. Urological

e.g. Pudendal neuralgia

Hx = History; Ex = Examination; Ix = Investigation. *The table presented is not comprehensive; for the purpose of this document the main emphasis has been on the urological pain syndromes.



Chronic Pelvic Urological Bladder pain syndrome (See Table 3 on Suprapubic ONSET Aching URINARY ANXIETY pelvic pain ESSIC classification) Inguinal Acute Burning Frequency About pain pain syndrome Urethral pain syndrome Urethral Chronic Stabbing Nocturia or putative Penile/clitoral Electric Hesitance cause of pain Prostate pain syndrome Type A inflammatory Perineal ONGOING Poor flow Other Type B non-inflammatory Rectal Sporadic Other Piss en deux Scrotal pain syndrome Testicular pain syndrome Back Cyclical Urge DEPRESSION Buttocks Continuous Urgency Attributed to Incontinance pain/impact Epididymal pain TIME Other of pain syndrome Filling Post-vasectomy Emptying GYNAECOLOGICAL Attributed to pain syndrome Immediate post e.g Menstrual other causes Late post or unattributed Penile pain syndrome SEXUAL PROVOKED e.g. Female dyspareunia SHAME, impotance GUILT related Gynaecological Endometriosis associated to disclosed pain syndrome GI or undisclosed sexual experience’s Vaginal pain syndrome MUSCULAR Hyperalgesia PTSD SYMPTOMS Vulvar pain syndrome Generalised vulvar CUTANEOUS Reexperiencing pain syndrome Allodynia Avoidance Localised Vestibular Hyperarousal vulvar pain pain syndrome syndrome MONO Clitoral SYMPTOMATIC pain DELUSIONS syndrome Anorectal Neurological e.g. Pudendal pain syndrome Muscular

Axis I Axis II Axis III Axis IV Axis V Axis VI Axis VII Axis VIII Region System End organ as identified from Referral Temporal Character Associated Psychological Hx, Ex and Ix characteristics characteristics symptoms symptoms

Table 1: EAU classification of chronic urogenital pain syndromes. This classification represents the efforts of many groups, as indicated in the main text. The work is in progress and further changes in this classification system are likely.*

2.2

Definitions of chronic pelvic pain terminology

Although this latest EAU CPP guideline retains the basic terminology used in previous EAU CPP guidelines, older terminology has been removed (Table 2). Table 2: Definitions of chronic pelvic pain terminology Terminology Chronic pelvic pain Pelvic pain syndrome Bladder pain syndrome Urethral pain syndrome Penile pain syndrome Prostate pain syndrome Scrotal pain syndrome Testicular pain syndrome Post-vasectomy pain syndrome Epididymal pain syndrome Endometriosis-associated pain syndrome Vaginal pain syndrome Vulvar pain syndrome

10

Description Non-malignant pain perceived in structures related to the pelvis of either men or women. In the case of documented nociceptive pain that becomes chronic, pain must have been continuous or recurrent for at least 6 months. If non-acute and central sensitization pain mechanisms are well documented, then the pain may be regarded as chronic, irrespective of the time period. In all cases, there often are associated negative cognitive, behavioural, sexual and emotional consequences (5,6) Persistent or recurrent episodic pelvic pain associated with symptoms suggesting lower urinary tract, sexual, bowel or gynaecological dysfunction. No proven infection or other obvious pathology (adopted from ICS 2002 report) (1) Suprapubic pain is related to bladder filling, accompanied by other symptoms such as increased daytime and night-time frequency. There is an absence of proven urinary infection or other obvious pathology. This term has been adopted from the ICS 2002 report (1), where the term painful bladder syndrome was used; the name has been changed to bladder pain syndrome to be consistent with other pain syndrome terminology (5,6). The European Society for the Study of IC/PBS (ESSIC) publication places greater emphasis on the pain being perceived in the bladder (4) Recurrent episodic urethral pain, usually on voiding, with daytime frequency and nocturia. Absence of proven infection or other obvious pathology (1) Pain within the penis that is not primarily in the urethra. Absence of proven infection or other obvious pathology (5,6) Persistent or recurrent episodic prostate pain, associated with symptoms suggestive of urinary tract and/or sexual dysfunction. No proven infection or other obvious pathology (5,6) Definition adapted from the National Institutes of Health (NIH) consensus definition and classification of prostatitis (7) and includes conditions described as ‘chronic pelvic pain syndrome’. Using the NIH classification system, prostate pain syndrome may be subdivided into type A (inflammatory) and type B (noninflammatory) Persistent or recurrent episodic scrotal pain associated with symptoms suggestive of urinary tract or sexual dysfunction. No proven epididymo-orchitis or other obvious pathology (1) Persistent or recurrent episodic pain localized to the testis on examination, which is associated with symptoms suggestive of urinary tract or sexual dysfunction. No proven epididymo-orchitis or other obvious pathology. This is a more specific definition than scrotal pain syndrome (1) Scrotal pain syndrome that follows vasectomy (1) Persistent or recurrent episodic pain localized to the epididymis on examination. Associated with symptoms suggestive of urinary tract or sexual dysfunction. No proven epididymo-orchitis or other obvious pathology (a more specific definition than scrotal pain syndrome (5,6) Chronic or recurrent pelvic pain where endometriosis is present but does not fully explain all the symptoms (5,6) Persistent or recurrent episodic vaginal pain associated with symptoms suggestive of urinary tract or sexual dysfunction. No proven vaginal infection or other obvious pathology (1) Persistent or recurrent episodic vulvar pain either related to the micturition cycle or associated with symptoms suggestive of urinary tract or sexual dysfunction. There is no proven infection or other obvious pathology (1)

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Generalized vulvar pain syndrome (formally dysaesthetic vulvodynia) Localized vulvar pain syndrome Vestibular pain syndrome (formerly vulval vestibulitis) Clitoral pain syndrome Anorectal pain syndrome Pudendal pain syndrome Perineal pain syndrome Pelvic floor muscle pain syndrome

2.3

Vulval burning or pain that cannot be consistently and tightly localized by pointpressure ‘mapping’ by probing with a cotton-tipped applicator or similar instrument. The vulvar vestibule may be involved but the discomfort is not limited to the vestibule. Clinically, the pain may occur with or without provocation (touch, pressure or friction) (8) Pain consistently and tightly localized by point-pressure mapping to one or more portions of the vulva. Clinically, pain usually occurs as a result of provocation (touch, pressure or friction) (8) Pain localized by point-pressure mapping to one or more portions of the vulval vestibule (8) Pain localized by point-pressure mapping to the clitoris (8) Persistent or recurrent, episodic rectal pain with associated rectal trigger points/tenderness related to symptoms of bowel dysfunction. No proven infection or other obvious pathology (5,6) Neuropathic-type pain arising in the distribution of the pudendal nerve with symptoms and signs of rectal, urinary tract or sexual dysfunction. No proven obvious pathology (5,6). (This is not the same as the well-defined pudendal neuralgia) Persistent or recurrent, episodic, perineal pain either related to the micturition cycle or associated with symptoms suggestive of urinary tract or sexual dysfunction. No proven infection or other obvious pathology (1) Persistent or recurrent, episodic, pelvic floor pain with associated trigger points, which is either related to the micturition cycle or associated with symptoms suggestive of urinary tract, bowel or sexual dysfunction. No proven infection or other obvious pathology (5,6)

Classification of chronic pelvic pain syndromes

The EAU classification of 2004 has been updated to provide a classification related to investigation and further management of the pain syndromes. This allows for a possible overlap of mechanisms between different conditions. It also encourages recognition of overlapping symptoms and their treatment by a multidisciplinary approach (Table 1) (3). Axes VII and VIII are very important, because they emphasize the importance of interdisciplinary, multidisciplinary assessment and management. This includes assessment and management of psychological symptoms and early involvement of the pain management centre. Currently, there is no ideal classification for conditions considered to be chronic pain syndromes. The axes used in Table 1 are based on the IASP classification (2). Much of the terminology comes from the ICS classification of chronic pain (1) with input from the International Society for the Study of Vulvovaginal Disease (ISSVD), the IASP special interest group, Pain of Urogenital Origin (PUGO) group and Specialists in Pain International Network (SPIN). The major controversy in classifying chronic pain is that a pain may involve multiple sites, aetiologies and mechanisms. At a consensus meeting led by A.P. Baranowski and a PUGO working group in November 2006, it was suggested that a patient should be described as having one or two pain syndromes in the case of pain perceived at one or two sites, respectively. If the patient’s pain was poorly localized or perceived in three or more sites, the patient would be diagnosed with chronic pelvic pain syndrome (CPPS), with no need for further system or end-organ subdivision. This decision recognized that poor localization in pain suggests overlapping mechanisms. This approach continues to be discussed and publications from a further consensus meeting are planned. A physician using the classification in Table 1 should start on the left of Table 1 and proceed to the right only if they can truly and confidently confirm the pain to be perceived in the appropriate system and organ. In many cases, it may not be possible to go further than labelling a condition as a pelvic pain syndrome. For example, in many cases previously described as ‘prostadynia’, it may not be possible to state categorically that the pain stems from the prostate and not other sites, e.g. pelvic floor muscles. Such cases are therefore labelled pelvic pain syndrome. Although bladder pain syndrome (BPS)/interstitial cystitis (IC) is well defined (see ESSIC reference [4]), many patients, who have been previously labelled as suffering from IC, would not meet the research criteria. These patients would therefore be labelled using Table 1 at some point to the left of IC, possibly as bladder pain syndrome (previously known as the painful bladder syndrome [1]). The term ‘pain syndrome’ is used when the primary pathology, which may be well defined and at one site to start with, progresses to produce a more complicated picture of pain, involving multiple sites and mechanisms. The condition has therefore become a complex of symptoms and signs, i.e. a syndrome. The axial classification includes referral, temporal and character axes. These descriptors should also be collected for audit and research purposes. It should also be noted whether or not the pain is provoked, e.g. by pressure. UPDATE MARCH 2008

11

This EAU classification system aims to draw together the expertize of specialist groups and continues to undergo revision. The European Society for the Study of IC/PBS (ESSIC) have recently shown a way forward by defining the bladder pain syndrome/IC syndrome, supported by an international consensus editorial (3,4). As with the EAU system, ESSIC excluded well-defined (confusable) conditions. ESSIC has further divided the bladder pain syndrome/IC syndrome according to the results of cystoscopy and biopsy (Table 3) (4). Table 3: ESSIC classification of types of bladder pain syndrome according to the results of cystoscopy with hydrodistension and of biopsies (4). Cystoscopy with hydrodistension Not done Normal Glomerulationsa Hunner’s lesionb Biopsy Not done XX 1X 2X 3X Normal XA 1A 2A 3A Inconclusive XB 1B 2B 3B Positivec XC 1C 2C 3C a Cystoscopy: glomerulations grade 2-3. b With or without glomerulations. c Histology showing inflammatory infiltrates and/or detrusor mastocytosis and/or granulation tissue and/or intrafascicular fibrosis.

2.4

REFERENCES

1.

Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, van Kerrebroeck P, Victor A, Wein A. The standardisation of terminology of lower urinary tract function: report from the Standardisation Subcommitte of the International Continence Society. Urology 2003 Jan;61(1):37-49. http://www.ncbi.nlm.nih.gov/pubmed/12559262 Merskey H, Bogduk N. Classification of Chronic Pain. Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. IASP Press, 2002. Baranowski AP, Abrams P, Berger RE, Buffington CA, de C Williams AC, Hanno P, Loeser JD, Nickel JC, Wesselmann U. Urogenital pain–time to accept a new approach to phenotyping and, as a consequence, management. Eur Urol 2008;53(1):33-6. http://www.ncbi.nlm.nih.gov/pubmed/17961909 van de Merwe JP, Nordling J, Bouchelouche P, Bouchelouche K, Cervigni M, Daha LK, Elneil S, Fall M, Hohlbrugger G, Irwin P, Mortensen S, van Ophoven A, Osborne JL, Peeker R, Richter B, Riedl C, Sairanen J, Tinzl M, Wyndaele JJ. Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an ESSIC poposal. Eur Urol 2008;53(1):60-7. http://www.ncbi.nlm.nih.gov/pubmed/17900797 Fall M, Baranowski AP, Fowler CJ, Lepinard V, Malone-Lee JG, Messelink EJ, Oberpenning F, Osborne JL, Schumacher S. EAU Guidelines on Chronic Pelvic Pain. In: EAU Guidelines, edition published at the 18th Annual EAU Congress, Madrid, 2003. ISBN 90-70244-06-3. http://www.ncbi.nlm.nih.gov/pubmed/15548433 Fall M, Baranowski AP, Elneil S, Engeler D, Hughes J, Messelink EJ, Oberpenning F, Williams A C de C. EAU Guidelines on Chronic Pelvic Pain. In: EAU Guidelines. 23rd Annual EAU Congress, Milan, ISBN 978-90-70244-91-0. http://www.uroweb.org/nc/professional-resources/guidelines/online/ Krieger JN, Nyberg L Jr, Nickel JC. NIH consensus definition and classification of prostatitis. JAMA 1999;282(3):236-7. http://www.ncbi.nlm.nih.gov/pubmed/10422990 Proceedings of the XVth World Congress. International Society for the Study of Vulvovaginal Disease, Santa Fe, NM, September 26-30, 1999. International Society for the Study of Vulvovaginal Disease Newsletter, Summer 2000.

2. 3.

4.

5.

6.

7.

8.

2.5 An algorithm for chronic pelvic pain diagnosis and treatment 2.5.1 How to use the algorithm The algorithm for diagnosing and treating chronic pelvic pain (CPP) (Figure 1) has been written to guide a physician through the process from diagnosis to management. A physician should follow steps 1 to 6 (Table 4), while referring to the correct column in the algorithm. Further guidance on which diagnostic tools should be used in specific pain locations is provided in different chapters of this guideline.

12

UPDATE MARCH 2008

Figure 1: An algorithm for diagnosing and managing chronic pelvic pain (CPP)

Chronic Pelvic Pain Urological

Gynaecological

Cystitis Prostatitis Urethritis Epididymoorchitis

Treat according to guidelines.

Other. Pain located in:

Bladder Prostate Urethra Scrotum All cases

Endometriosis

Additional actions to be taken when this treatment fails are based on the location of the pain: cystoscopy/biopsy TRUS / PSA uroscopy US palpation PFM

Treat according to guidelines.

If treatment of pathology found has no effect

or

Additional actions to be taken when this treatment fails are based on the location of the pain: Other. Pain located in:

Anorectal Proctitis Anal fissure Haemorrhoids

Neuromuscular

Abdomen Vulva Vagina All cases

hysteroscopy/ laparoscopy vaginal US internal exam inspection / touch test palpation PFM

If no pathology is found

Refer to a pain team

Treat according to guidelines. Additional actions to be taken when this treatment fails are based on the location of the pain:

Other. Pain located in:

Rectum Anus All cases

Pudendal neuropathy Sacral spinal cord pathology

Treat according to guidelines.

Other. Pain located in:

Pelvic floor Abdominal Perineum Other sites All cases

endoscopy / DRE endo-anal US / DRE palpation PFM

If treatment of pathology found has no effect

or

Additional actions to be taken when this treatment fails are based on the location of the pain: palpation palpation US neurophysiologic tests search for trigger points

If no pathology is found

Other Pain team Basic: anaesthetist specialized in pain management, nurse specialist. Additional: psychologist, sexologist

Refer to a pain team

Refer to a pain team

DRE = digital rectal examination; US = ultrasound; PFM = pelvic floor muscles.

UPDATE MARCH 2008

13

Table 4: Step-by-step guidance on using the algorithm for diagnosis and treatment of CPP Step Action Algorithm 1 Start by considering the organ system where the symptoms appear to First column be primarily perceived 2 ‘Well-defined’ conditions, such as cystitis, should be diagnosed and Second column and treated according to national or international guidelines upper part third column 3 When treatment has no effect on the pain, additional tests Lower part third column (e.g. cystoscopy or ultrasound) should be performed 4 When these tests reveal any pathology, this should be treated Fourth column appropriately 5 If treatment has no effect, the patient should be referred to a pain team Fifth column 6 If no well-defined condition is present or when no pathology is found by Fifth column additional tests, the patient should also be referred to a pain team The only aspect of diagnosis that is specific for CPP is where the pain is localized. However, because pain is perceived in structures related to the pelvis, this has led to many organ-specific, but often not welldefined, local disease syndromes. Because CPP is pain perceived in structures related to the pelvis, it is necessary to approach diagnosis of a patient with CPP as a chronic pain patient. Confining the diagnosis to a specific organ may overlook multisystem functional abnormalities requiring individual treatment and general aspects of pain in planning investigation and treatment. For the above reasons, we advocate early involvement of a multidisciplinary pain team. In practice, this should mean that well-known diseases, e.g. ‘true’ cystitis and endometriosis, will be diagnosed and treated early. If treating such conditions does not reduce symptoms, or such well-defined conditions are not found, then further investigation may be necessary, depending on where the pain is localized. It should be noted, however, that over-investigation may be as harmful as not performing appropriate investigations. The EAU algorithms introduce the concept of the ‘minimum investigations’ required to exclude a well-defined condition.

2.6

Chronic prostate pain/chronic prostatitis associated with chronic pelvic pain syndrome (CP/CPPS)

Figure 2: General diagnostic and treatment algorithm for chronic prostate pain

Chronic prostate pain Patient’s history Symptom scores (NIHCPSI, I-PSS) Physical examination including DRE PSA, if age >50 Uroflow Ultrasound with PVR PPMT

14

Uroflow/PVR abnormal

Urodynamics Cystoscopy

Urinary tract infection

Antibiotics

CP/CPPS NIH cat. III according to history, symptom score and PPMT

Antibiotics (only once for 4-6 weeks) Alpha-blocker and/ or Phytotherapy and/ or NSAID Supportive therapy

If treatment of pathology found has no effect or

Pelvic muscle spam

Amitriptyline or gabapentin or muscle relaxant physiotherapy, thermotherapy

DRE and/or PSA suggestive of PCA

Prostate biopsy

If no pathology is found

Refer to a pain team

UPDATE MARCH 2008

NIH-CPSI = National Institute of Health chronic prostatitis symptom index; I-PSS = international prostate symptom score; DRE = digital rectal examination; PSA = prostate-specific antigen; PVR = post-void residual urine; PPMT = pre-post-massage test; CP/CPPS = chronic prostatitis/chronic pelvic pain syndrome; PCA = prostate cancer; NSAID = non-steroidal anti-inflammatory drug. 2.6.1 Introduction Chronic prostatitis is an obscure and poorly understood disease. Restricted physical access has made it difficult to study the prostate gland, resulting in a lack of certainty about the aetiology, a lack of distinguishing clinical features, non-uniform diagnostic criteria and a protracted treatment course. In about 5-10% of cases, clinical prostatitis has a proven bacterial aetiology. The remaining 90% of cases, in which laboratory methods have not found a bacterial cause, are classified as ‘chronic non-bacterial prostatitis’ or ‘prostatodynia’ (1-3). An appreciation of the fact that symptoms do not necessarily indicate isolated prostatic disease has led to a renaming of the condition: ‘Chronic prostatitis associated with chronic pelvic pain syndrome’ (CP/CPPS). This is now the term used by the NIH for patients with symptomatic prostatitis of non-bacterial origin (4).

2.6.2

Definition

Chronic prostatitis associated with chronic pelvic pain syndrome (CP/CPPS) is discomfort or pain in the pelvic region over a minimum of 3 months, with sterile specimen cultures and either significant, or insignificant, white blood cell counts in prostate-specific specimens (i.e. semen, expressed prostatic secretions and urine collected after prostate massage) (4). According to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) classification, CP/CPPS is prostatitis category III (5) (Table 5). At present, there are no clinically relevant diagnostic or therapeutic results arising from differentiating inflammatory (NIH Cat. IIIA) from non-inflammatory (NIH Cat. IIIB) CP/CPPS. CP/CPPS Cat. III is therefore considered as one entity. According to the more general definition described in Section 2.2 (see Table 2), the disease is referred to as ‘prostate pain syndrome (CP/CPPS)’ throughout the rest of this chapter. Table 5: Classification of prostatitis according to NIDDK/NIH I. Acute bacterial prostatitis (ABP) II. Chronic bacterial prostatitis (CBP) III. Chronic pelvic pain syndrome (CPPS) A. Inflammatory CPPS: WBC in semen/EPS/VB3 B. Non-inflammatory CPPS: no WBC semen/EPS/VB3 IV. Asymptomatic inflammatory prostatitis (histological prostatitis) WBC = white blood cells; EPS = expressed prostatic secretions; VB3 = voided bladder urine-3. 2.6.3 Pathogenesis The aetiology and pathophysiology of prostate pain syndrome (CP/CPPS) remains a mystery. Acute bacterial prostatitis is a different disease to chronic prostatitis syndromes. Patients with CPPS show no evidence of inflammation; they do not have urethritis, urogenital cancer, urethral stricture, or neurological disease involving the bladder nor exhibit any overt renal tract disease (4). As often occurs with pelvic pain syndromes, there are several, poorly evidenced, hypotheses to explain the aetiology of prostate pain syndrome (CP/CPPS): • Pain and subsequent irritative and obstructive voiding symptoms may be caused by lower urinary tract obstruction (LUTS), due to bladder neck problems, detrusor sphincter dysfunction, urethral stricture or dysfunctional voiding, resulting in high-pressure voiding (6-11) • Intraprostatic ductal reflux caused by high-pressure turbulent voiding due to an anatomical abnormality (12-15) • Microbiological cause, due to apparently harmless lower urinary tract commensals which require more sensitive isolation methods to be identified (4) • Immunological processes precipitated by an unrecognized antigen or an autoimmune process (16-18). Urinary reflux into the prostatic ducts and acini might stimulate a sterile inflammatory response (13) • A neuromuscular aetiology (19-21), in which symptoms represent a type of reflex sympathetic dystrophy of the perineum and pelvic floor • An interstitial cystitis-like pathogenic mechanism based on a significant overlap of symptomatology (pain, voiding symptoms) and cystoscopic or urodynamic findings. In patients diagnosed with prostate pain syndrome (CP/CPPS), a bladder-oriented interstitial cystitis mechanism accounts for the symptoms and the prostate is involved only indirectly (22).

UPDATE MARCH 2008

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2.6.4 Diagnosis Despite its name, prostate pain syndrome (CP/CPPS) is a symptomatic diagnosis, which is diagnosed from a 3-month history of genitourinary pain and an absence of other lower urinary tract pathologies (see above). Determination of the severity of disease, its progression and treatment response can be assessed only by means of a validated symptom-scoring instrument (23,24). Quality of life should also be measured because it can be as poor as in acute myocardial infarction, unstable angina pectoris or Crohn’s disease (25,26). Reliable, valid indexes of symptoms and quality of life are the NIH Prostatitis Symptom Index (NIH-CPSI) (27) and the International Prostate Symptom Score (I-PSS) (28). These subjective outcome measures are recommended for the basic evaluation and therapeutic monitoring of patients in urological practice and have been translated and validated for many European languages. In prostate pain syndrome (CP/CPPS), urodynamic studies demonstrate decreased urinary flow rates, incomplete relaxation of the bladder neck and prostatic urethra, as well as abnormally high urethral closure pressure at rest. The external urethral sphincter is normal during urination (6,29). Laboratory diagnosis has been classically based on the four-glass test for bacterial localization (‘gold standard’) (30). Besides a sterile pre-massage urine (voided bladder urine-2 [VB2]), CP/CPPS shows less than 10,000 colony-forming units of uropathogenic bacteria in expressed prostatic secretions (EPS) and insignificant numbers of leucocytes or bacterial growth in ejaculate. However, this test is too complex for use by practising urologists (4). Diagnostic efficiency may be enhanced cost-effectively by a simple screening procedure, i.e. the two-glass test or pre-post-massage test (PPMT) (31). In an extensive analysis of both tests, PPMT was able to indicate the correct diagnosis in more than 96% of patients (32). A general algorithm for diagnosis and treatment of chronic prostatic pain is shown in Figure 2. 2.6.5 Treatment Because of the unknown cause of prostate pain syndrome (CP/CPPS), many therapies used are based on anecdote. Most patients require multimodal treatment aimed at the main symptoms and taking comorbidities into account. In the past few years, results from randomized controlled trials (RCTs) have led to advances in standard and novel treatment options. Graded recommendations are given in Table 6. 2.6.5.1 Alpha-blockers. Increasing evidence from recent RCTs has shown that alpha-blockers, e.g. terazosin (33), alfuzosin (34), doxazosin (35), tamsulosin, reduce urinary symptoms and pain in prostate pain syndrome (CP/CPPS). The effects of alpha-antagonists may include improved outflow performance by blocking the alpha-receptors of the bladder neck and prostate and by direct action on alpha1A/1D-receptors in the CNS (36). Some symptoms may be relieved in roughly 50-60% of patients. Meta-analysis of nine trials (n = 734) showed that NIH-CPSI or I-PSS was reduced significantly with treatment duration of at least 3 months. However, in contrast to some individual studies (33-36), the meta-analysis showed no beneficial effect on pain (37). In addition, treatment-naïve and/or newly diagnosed patients appeared more likely to respond to alphablockers (38), although there is not sufficient evidence to conclude that they are effective (39). Because patients with heavily re-treated disease may not significantly improve in the short term compared to placebo (40), an alpha-blocker should be given for at least 3-6 months before assessing treatment (36). 2.6.5.2 Antibiotic therapy. Empirical antibiotic therapy is widely used because some patients have improved with antimicrobial therapy. Patients responding to antibiotics should be maintained on medication for 4-6 weeks or even longer. Unfortunately, culture, leucocyte and antibody status of prostate-specific specimens do not predict antibiotic response in patients with prostate pain syndrome (CP/CPPS) (41), and prostate biopsy culture findings do not differ from those of healthy controls (42). Long-term results with trimethoprimsulphamethoxazole have remained poor (43-45). More encouraging results have been obtained with quinolones, including ciprofloxacin (46) and ofloxacin (41,47), but overall, antibiotic treatment of the prostate pain syndrome (CP/CPPS) is based only on weak evidence. After one unsuccessful course of a quinolone antibiotic over 4–6 weeks, other therapeutic options should be offered. 2.6.5.3 Non-steroidal anti-inflammatory drugs. Non-steroidal anti-inflammatory drugs may have favourable results in some patients. Immunomodulation using cytokine inhibitors or other approaches may be helpful, but proper trials are needed before this type of therapy can be recommended (48,49). Only one RCT has been published. This was for rofecoxib, which is no longer on the market; statistical significance was achieved in some of the outcome measures (50). 2.6.5.4 Corticosteroids are not recommended. A few anecdotal case reports have shown some improvement. However, no significant benefits were shown in a low-power, placebo-controlled, randomized pilot study of a short course of oral prednisolone (51).

16

UPDATE MARCH 2008

2.6.5.5 Opioids produce modest pain relief in some patients with refractory prostate pain syndrome (CP/ CPPS), though there is limited data on the long-term efficacy of opioids in non-cancer pain. Opioid treatment carries the risks of side effects, reduced quality of life, addiction, opioid tolerance and opioid-induced hyperalgesia (52). Urologists should use opioids for prostate pain syndrome (CP/CPPS) in collaboration with pain clinics and with other treatments. 2.6.5.6 5-alpha-reductase inhibitors. A few small pilot studies with 5-alpha-reductase inhibitors supported the view that finasteride may improve voiding and pain (53-56). In a randomized trial, finasteride provided better amelioration of symptoms compared to saw palmetto over a 1-year period, but lacked a placebo-control arm (57). A 6-month placebo-controlled study showed a tendency towards better outcome in favour of finasteride without statistical significance, possibly because of a lack of power (58). 2.6.5.7 Allopurinol. An RCT of allopurinol was conducted based on the hypothesis that urine reflux into prostatic ducts causes prostatic inflammation via high concentrations of purine and pyrimidine base-containing metabolites in prostatic secretions (59). However, positive results were not considered to be sufficient for recommendation by reviewers of the Cochrane Database (60). In addition, a recent randomized placebocontrolled trial of allopurinol as an adjunct to ofloxacin has not shown any benefit (61). 2.6.5.8 Phytotherapy. Positive effects of phytotherapy have been documented. Although a validated symptom score was not used, an RCT of a pollen extract (Prostat/Poltit) showed significant symptom improvement in the pollen-treated group (62). Another pollen extract, Cernilton N, provided only weak improvement. For ‘uncomplicated’ cases, a 36% cure rate could be shown over a 6-month period in a prospective study (63). Quercetin, a polyphenolic bioflavonoid with documented antioxidant and anti-inflammatory properties, improved NIH-CPSI scores significantly in a small RCT (64). In addition, high-dose oral PPS, as for interstitial cystitis, is able to ameliorate symptoms and improve quality of life significantly in men with prostate pain syndrome (CP/CPPS), suggesting a possible common aetiology (65). In contrast, treatment with saw palmetto, most commonly used for benign prostatic hyperplasia, did not improve symptoms over a 1-year period (57). 2.6.5.9 Muscle relaxants (diazepam, baclofen) are claimed to be helpful in sphincter dysfunction or pelvic floor/perineal muscle spasm, but there have been only few prospective clinical trials to support these claims (21). In a recent RCT, a triple combination of a muscle relaxant (tiocolchicoside), an anti-inflammatory drug (ibuprofen) and an alpha-blocker (doxazosin) was effective in treatment-naïve patients, but not superior to an alpha-blocker alone (66). 2.6.5.10 Supportive therapies, such as biofeedback, relaxation exercises, lifestyle changes (i.e. diet, discontinuing bike riding), acupuncture, massage therapy, chiropractic therapy or meditation, have all been claimed to improve symptoms (4,67). In a small, sham-controlled, double-blind study, 4-week electromagnetic therapy showed a significant, sustained effect over a 1-year period (68). Some patients have reported favourable effects from heat therapy, e.g. transrectal hyperthermia (69-72) and transurethral thermotherapy (7377). 2.6.5.11 Surgical management, including transurethral incision of the bladder neck (9), radical transurethral resection of the prostate (78,79) or in particular radical prostatectomy, has a very limited role and requires an additional, specific indication (67). In addition, the treatment effect of transurethral needle ablation of the prostate (TUNA) was only comparable to sham treatment (80). Table 6: Treatment of prostate pain syndrome (CP/CPPS) LE GR • Alpha-blockers 1a A • Muscle relaxants 3 C • Antimicrobial therapy 3 B

UPDATE MARCH 2008

Comment Effect on total NIH-CPSI Only very limited data Quinolones If previously untreated (naïve) only, reassess after 2-3 weeks. Duration 4-6 weeks

17

• Opioids 3 C • Non-steroidal anti- 1b B inflammatory drugs • Steroids 3 Not recommended • Immunosuppressive agents • 5-alpha-reductase inhibitors 1b B • Phytotherapy 1b-3 B • Biofeedback, 2a-3 B relaxation exercise • Lifestyle changes • Massage therapy • Chiropractor therapy • Acupuncture • Meditation • Electromagnetic therapy 1b C • Transrectal hyperthermia 3 C • Transurethral thermotherapy • Transurethral incision of 3 Not recommended the bladder neck general • Transurethral resection of the prostate • Radical prostatectomy LE = Level of evidence; GR = grade of recommendation 2.6.6 1.

2. 3.

4. 5. 6.

7.

8.

9.

10.

18

As part of multimodal therapy for treatmentrefractory pain in collaboration with pain clinics Long-term side effects have to be considered Not outside clinical trials If benign prostatic hyperplasia is present As supportive, second- line therapies

Not outside clinical trials

Specific additional indication required

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11.

12.

13.

14. 15.

16.

17.

18.

19. 20.

21.

22. 23.

24. 25.

26.

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28.

Murnaghan GF, Millard RJ. Urodynamic evaluation of bladder neck obstruction in chronic prostatitis. Br J Urol 1984;56(6):713-6. http://www.ncbi.nlm.nih.gov/pubmed/6534495 Blacklock NJ. The anatomy of the prostate: relationship with prostatic infection. Infection 1991;19(Suppl 3):S111-S114. http://www.ncbi.nlm.nih.gov/pubmed/2055644 Persson BE, Ronquist G. Evidence for a mechanistic association between nonbacterial prostatitis and levels of urate and creatinine in expressed prostatic secretion. J Urol 1996;155(3):958-60. http://www.ncbi.nlm.nih.gov/pubmed/8583617 Blacklock NJ. Anatomical factors in prostatitis. Br J Urol 1974;46(1):47-54. http://www.ncbi.nlm.nih.gov/pubmed/4406038 Kirby RS, Lowe D, Bultitude MI, Shuttleworth KE. Intra-prostatic urinary reflux: an aetiological factor in abacterial prostatitis. Br J Urol 1982;54(6):729-31. http://www.ncbi.nlm.nih.gov/pubmed/7150931 Doble A, Walker MM, Harris JR, Taylor-Robinson D, Witherow RO. Intraprostatic antibody deposition in chronic abacterial prostatitis. Br J Urol 1990;65(6):598-605. http://www.ncbi.nlm.nih.gov/pubmed/2196972 Nickel JC, Olson ME, Barabas A, Benediktsson H, Dasgupta MK, Costerton JW. Pathogenesis of chronic bacterial prostatitis in an animal model. Br J Urol 1990;66(1):47-54. http://www.ncbi.nlm.nih.gov/pubmed/2203502 Shortliffe LM, Wehner N. The characterization of bacterial and nonbacterial prostatitis by prostatic immunoglobulins. Medicine (Baltimore) 1986;65(6):399-414. http://www.ncbi.nlm.nih.gov/pubmed/3537628 Andersen JT. Treatment of prostatodynia. In: Nickel JC (ed). Textbook of Prostatitis. London: ISIS Medical Media Ltd. 1999; pp. 357-364. Egan KJ, Krieger JL. Chronic abacterial prostatitis–a urological chronic pain syndrome? Pain 1997;69(3):213-8. http://www.ncbi.nlm.nih.gov/pubmed/9085294 Osborn DE, George NJ, Rao PN, Barnard RJ, Reading C, Marklow C, Blacklock NJ. Prostatodynia– physiological characteristics and rational management with muscle relaxants. Br J Urol 1981;53(6):621-3. http://www.ncbi.nlm.nih.gov/pubmed/7032641 Sant GR, Nickel JC. Interstitial cystitis in chronic prostatitis: The same syndrome?. In: Nickle JC (ed). Textbook of Prostatitis. Oxford, UK: Medical Media, 1999, pp. 69-76. Barry MJ, Fowler FJ Jr, O’Leary MP, Bruskewitz RC, Holtgrewe HL, Mebust WK, Cockett AT. The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol 1992;148(5):1549-57; discussion 1564. http://www.ncbi.nlm.nih.gov/pubmed/1279218 Nickel JC. Effective office management of chronic prostatitis. Urol Clin North Am 1998;25(4):677-84. http://www.ncbi.nlm.nih.gov/pubmed/10026774 Wenninger K, Heiman JR, Rothman I, Berghuis JP, Berger RE. Sickness impact of chronic nonbacterial prostatitis and its correlates. J Urol 1996;155(3):965-8. http://www.ncbi.nlm.nih.gov/pubmed/8583619 McNaughton Collins M, Pontari MA, O’Leary MP, Calhoun EA, Santanna J, Landis JR, Kusek JW, Litwin MS; Chronic Prostatitis Collaborative Research Network. Quality of life is impaired in men with chronic prostatitis: the Chronic Prostatitis Collaborative Research Network. J Gen Intern Med 2001;16(10):656-62. http://www.ncbi.nlm.nih.gov/pubmed/11679032 Litwin MS, McNaughton-Collins M, Fowler FJ Jr, Nickel JC, Calhoun EA, Pontari MA, Alexander RB, Farrar JT, O’Leary MP. The National Institutes of Health chronic prostatitis symptom index: development and validation of a new outcome measure. Chronic Prostatitis Collaborative Research Network. J Urol 1999;162(2):369-75. http://www.ncbi.nlm.nih.gov/pubmed/10411041 Mebust WK, Bosch R, Donovan J, Okada K, O’Leary MA, Villers MA, et al. Symptom evaluation, quality of life and sexuality. In: Cockett ATK, Khoury S, Aso Y, et al. Proceedings of the 2nd Consultation on Benign Prostatic Hyperplasia (BPH), Paris. Channel Islands: Scientific Communication International Ltd, 1993, pp. 131-138. www.congressurology.org

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Meares EMJ, Minich W. Prostatodynia: clinical findings and rationale for treatment. In: Weidner W, Brunner H, Krause W et al. Therapy of Prostatitis. Munich: Zuckschwerdt Verlag, 1986, p. 207. Meares EM, Stamey TA. Bacteriologic localization patterns in bacterial prostatitis and urethritis. Invest Urol 1968;5(5):492-518. http://www.ncbi.nlm.nih.gov/pubmed/4870505 Nickel JC. The Pre and Post Massage Test (PPMT): a simple screen for prostatitis. Tech Urol 1997;3(1):38-43. http://www.ncbi.nlm.nih.gov/pubmed/9170224 Nickel JC, Shoskes D, Wang Y, Alexander RB, Fowler JE Jr, Zeitlin S, O’Leary MP, Pontari MA, Schaeffer AJ, Landis JR, Nyberg L, Kusek JW, Propert KJ. How does the pre-massage and postmassage 2-glass test compare to the Meares-Stamey 4-glass test in men with chronic prostatitis/ chronic pelvic pain syndrome?. J Urol 2006;176(1):119-24. http://www.ncbi.nlm.nih.gov/pubmed/16753385 Cheah PY, Liong ML, Yuen KH, Teh CL, Khor T, Yang JR, Yap HW, Krieger JN. Terazosin therapy for chronic prostatitis/chronic pelvic pain syndrome: a randomized, placebo controlled trial. J Urol 2003;169(2):592-6. http://www.ncbi.nlm.nih.gov/pubmed/12544314 Mehik A, Alas P, Nickel JC, Sarpola A, Helstrom PJ. Alfuzosin treatment for chronic prostatitis/chronic pelvic pain syndrome: a prospective, randomized, double-blind, placebo-controlled, pilot study. Urology 2003;62(3):425-9. http://www.ncbi.nlm.nih.gov/pubmed/12946740 Evliyaoglu Y, Burgut R. Lower urinary tract symptoms, pain and quality of life assessment in chronic non-bacterial prostatitis patients treated with alpha-blocking agent doxazosin; versus placebo. Int Urol Nephrol 2002;34(3):351-6. http://www.ncbi.nlm.nih.gov/pubmed/12899226 Nickel JC, Narayan P, McKay J, Doyle C. Treatment of chronic prostatitis/chronic pelvic pain syndrome with tamsulosin: a randomized double blind trial. J Urol 2004;171(4):1594-7. http://www.ncbi.nlm.nih.gov/pubmed/15017228 Yang G, Wei Q, Li H, Yang Y, Zhang S, Dong Q. The effect of alpha-adrenergic antagonists in chronic prostatitis/chronic pelvic pain syndrome: a meta-analysis of randomized controlled trials. J Androl 2006;27(6):847-52. http://www.ncbi.nlm.nih.gov/pubmed/16870951 Lee SW, Liong ML, Yuen KH, Liong YV, Krieger JN. Chronic prostatitis/chronic pelvic pain syndrome: role of alpha blocker therapy. Urol Int 2007;78(2):97-105. http://www.ncbi.nlm.nih.gov/pubmed/17293646 Mishra VC, Browne J, Emberton M. Role of alpha-blockers in type III prostatitis: a systematic review of the literature. J Urol 2007;177(1):25-30. http://www.ncbi.nlm.nih.gov/pubmed/17161995 Alexander RB, Propert KJ, Schaeffer AJ, Landis JR, Nickel JC, O’Leary MP, Pontari MA, McNaughtonCollins M, Shoskes DA, Comiter CV, Datta NS, Flower JE Jr, Nadler RB, Zeitlin SI, Knauss JS, Wang Y, Kusek JW, Nyberg LM Jr, Litwin MS; Chronic Prostatitis Collaborative Research Network. Ciprofloxacin or tamsulosin in men with chronic prostatitis/chronic pelvic pain syndrome: a randomized, double-blind trial. Ann Intern Med 2004;141(8):581-9. http://www.ncbi.nlm.nih.gov/pubmed/15492337 Nickel JC, Downey J, Johnston B, Clark J; Canadian Prostatitis Research Group. Predictors of patient response to antibiotic therapy for the chronic prostatitis/chronic pelvic pain syndrome: a prospective multicenter clinical trial. J Urol 2001;165(5):1539-44. http://www.ncbi.nlm.nih.gov/pubmed/11342913 Lee JC, Muller CH, Rothman I, Agnew KJ, Eschenbach D, Ciol MA, Turner JA, Berger RE. Prostate biopsy culture findings of men with chronic pelvic pain syndrome do not differ from those of healthy controls. J Urol 2003;169(2):587-8. http://www.ncbi.nlm.nih.gov/pubmed/12544312 Drach GW. Trimethoprim sulfamethoxazole therapy of chronic bacterial prostatitis. J Urol 1974;111(5):637-9. http://www.ncbi.nlm.nih.gov/pubmed/4274697 McGuire EJ, Lytton B. Bacterial prostatitis: treatment with trimethoprim-sulfamethoxazole. Urology 1976;7(5):499-500. http://www.ncbi.nlm.nih.gov/pubmed/1274009

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Meares EM. Long-term therapy of chronic bacterial prostatitis with trimethoprim-sulfamethoxazole. Can Med Assoc J 1975;112(13 Spec No):22-5. http://www.ncbi.nlm.nih.gov/pubmed/236820 Weidner W, Schiefer HG, Brahler E. Refractory chronic bacterial prostatitis: a re-evaluation of ciprofloxacin treatment after a median followup of 30 months. J Urol 1991;146(2):350-2. http://www.ncbi.nlm.nih.gov/pubmed/1856930 Cox CE. Ofloxacin in the management of complicated urinary tract infections, including prostatitis. Am J Med 1989;87(6C):61S-68S. http://www.ncbi.nlm.nih.gov/pubmed/2690622 Canale D, Scaricabarozzi I, Giorgi P, Turchi P, Ducci M, Menchini-Fabris GF. Use of a novel nonsteroidal anti-inflammatory drug, nimesulide, in the treatment of abacterial prostatovesiculitis. Andrologia 1993;25(3):163-6. http://www.ncbi.nlm.nih.gov/pubmed/14550427 Canale D, Turchi P, Giorgi PM, Scaricabarozzi I, Menchini-Fabris GF. Treatment of abacterial prostatovesiculitis with nimesulide. Drugs 1993;46 (Suppl 1):147-50. http://www.ncbi.nlm.nih.gov/pubmed/7506156 Nickel JC, Pontari M, Moon T, Gittelman M, Malek G, Farrington J, Pearson J, Krupa D, Bach M, Drisko J; Rofecoxib Prostatitis Investigator Team. A randomized, placebo controlled, multicenter study to evaluate the safety and efficacy of rofecoxib in the treatment of chronic nonbacterial prostatitis. J Urol 2003;169(4):1401-5. http://www.ncbi.nlm.nih.gov/pubmed/12629372 Bates SM, Hill VA, Anderson JB, Chapple CR, Spence R, Ryan C, Talbot MD. A prospective, randomized, double-blind trial to evaluate the role of a short reducing course of oral corticosteroid therapy in the treatment of chronic prostatitis/chronic pelvic pain syndrome. BJU Int 2007;99(2):355-9. http://www.ncbi.nlm.nih.gov/pubmed/17313424 Nickel JC. Opioids for chronic prostatitis and interstitial cystitis: lessons learned from the 11th World Congress on Pain. Urology 2006;68(4):697-701. http://www.ncbi.nlm.nih.gov/pubmed/17070334 Olavi L, Make L, Imo M. Effects of finasteride in patients with chronic idiopathic prostatitis: a doubleblind, placebo-controlled pilot study. Eur Urol 1998;33(Suppl. 1):33. Golio G. The use of finasteride in the treatment to chronic nonbacterial prostatitis. In: Abstracts of the 49th Annual Meeting of the Northeastern Section of the American Urological Association. Phoenix, 1997:128. Holm M, Meyhoff HH. Chronic prostatic pain. A new treatment option with finasteride?. Scand J Urol Nephrol 1997;31(2):213-5. http://www.ncbi.nlm.nih.gov/pubmed/9165592 Leskinen M, Lukkarinen O, Marttila T. Effects of finasteride in patients with inflammatory chronic pelvic pain syndrome: a double-blind, placebo-controlled, pilot study. Urology 1999;53(3):502-5. http://www.ncbi.nlm.nih.gov/pubmed/10096374 Kaplan SA, Volpe MA, Te AE. A prospective, 1-year trial using saw palmetto versus finasteride in the treatment of category III prostatitis/chronic pelvic pain syndrome. J Urol 2004;171:284-8. http://www.ncbi.nlm.nih.gov/pubmed/14665895 Nickel JC, Downey J, Pontari MA, Shoskes DA, Zeitlin SI. A randomized placebo-controlled multicentre study to evaluate the safety and efficacy of finasteride for male chronic pelvic pain syndrome (category IIIA chronic nonbacterial prostatitis). BJU Int 2004;93(7):991-5. http://www.ncbi.nlm.nih.gov/pubmed/15142149 Persson BE, Ronquist G, Ekblom M. Ameliorative effect of allopurinol on nonbacterial prostatitis: a parallel double-blind controlled study. J Urol 1996;155(3):961-4. http://www.ncbi.nlm.nih.gov/pubmed/8583618 McNaughton CO, Wilt T. Allopurinol for chronic prostatitis. Cochrane Database Syst Rev 2002;(4):CD001041. http://www.ncbi.nlm.nih.gov/pubmed/12519549 Ziaee AM, Akhavizadegan H, Karbakhsh M. Effect of allopurinol in chronic nonbacterial prostatitis: a double blind randomized clinical trial. Int Braz J Urol 2006;32(2):181-6. http://www.ncbi.nlm.nih.gov/pubmed/16650295 Elist J. Effects of pollen extract preparation Prostat/Poltit on lower urinary tract symptoms in patients with chronic nonbacterial prostatitis/chronic pelvic pain syndrome: a randomized, double-blind, placebo-controlled study. Urology 2006;67(1):60-3. http://www.ncbi.nlm.nih.gov/pubmed/16413333

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Rugendorff EW, Weidner W, Ebeling L, Buck AC. Results of treatment with pollen extract (Cernilton N) in chronic prostatitis and prostatodynia. Br J Urol 1993;71(4):433-8. http://www.ncbi.nlm.nih.gov/pubmed/8499988 Shoskes DA, Zeitlin SI, Shahed A, Rajfer J. Quercetin in men with category III chronic prostatitis: a preliminary prospective, double-blind, placebo-controlled trial. Urology 1999;54(6):960-3. http://www.ncbi.nlm.nih.gov/pubmed/10604689 Nickel JC, Forrest JB, Tomera K, Hernandez-Graulau J, Moon TD, Schaeffer AJ, Krieger JN, Zeitlin SI, Evans RJ, Lama DJ, Neal DE Jr, Sant GR. Pentosan polysulfate sodium therapy for men with chronic pelvic pain syndrome: a multicenter, randomized, placebo controlled study. J Urol 2005;173(4): 1252-5. http://www.ncbi.nlm.nih.gov/pubmed/15758763 Tugcu V, Tasci AI, Fazlioglu, Gurbuz G, Ozbek E, Sahin S, Kurtulus F, Cek M. A placebo-controlled comparison of the efficiency of triple- and monotherapy in category III B chronic pelvic pain syndrome (CPPS). Eur Urol 2007;51(4):1113-7; discussion 1118. http://www.ncbi.nlm.nih.gov/pubmed/17084960 Nickel JC. Prostatitis: evolving management strategies. Urol Clin North Am 1999;26(4):737-51. http://www.ncbi.nlm.nih.gov/pubmed/10584615 Rowe E, Smith C, Laverick L, Elkabir J, Witherow RO, Patel A. A prospective, randomized, placebo controlled, double-blind study of pelvic electromagnetic therapy for the treatment of chronic pelvic pain syndrome with 1 year of followup. J Urol 2005;173(6):2044-7. http://www.ncbi.nlm.nih.gov/pubmed/15879822 Kamihira O, Sahashi M, Yamada S et al. [Transrectal hyperthermia for chronic prostatitis.] Nippon Hinyokika Gakkai Zasshi 1993;84(6):1095-8. [article in Japanese] http://www.ncbi.nlm.nih.gov/pubmed/8345726 Kumon H, Ono N, Uno S et al. [Transrectal hyperthermia for the treatment of chronic prostatitis.] Nippon Hinyokika Gakkai Zasshi 1993;84(2):265-71. [article in Japanese] http://www.ncbi.nlm.nih.gov/pubmed/8464182 Montorsi F, Guazzoni G, Bergamaschi F, Galli L, Consonni P, Matozzo V, Barbieri L, Rigatti P. Is there a role for transrectal microwave hyperthermia of the prostate in the treatment of abacterial prostatitis and prostatodynia? Prostate 1993;22(2):139-46. http://www.ncbi.nlm.nih.gov/pubmed/8456052 Shaw TK, Watson GM, Barnes DG. Microwave hyperthermia in the treatment of chronic abacterial prostatitis and prostatodynia: results of a double-blind placebo controlled trial. J Urol 1993;149:405A. Choi NG, Soh SH, Yoon TH, Song MH. Clinical experience with transurethral microwave thermotherapy for chronic nonbacterial prostatitis and prostatodynia. J Endourol 1994;8(1):61-4. http://www.ncbi.nlm.nih.gov/pubmed/7514470 Michielsen D, Van Camp K, Wyndaele JJ, Verheyden B. Transurethral microwave thermotherapy in the treatment of chronic abacterial prostatitis: a 2 years follow-up. Acta Urol Belg 1995;63(4):1-4. http://www.ncbi.nlm.nih.gov/pubmed/8644548 Nickel JC, Sorenson R. Transurethral microwave thermotherapy of nonbacterial prostatitis and prostatodynia: initial experience. Urology 1994;44(3):458-60. http://www.ncbi.nlm.nih.gov/pubmed/8073567 Nickel JC, Sorensen R. Transurethral microwave thermotherapy for nonbacterial prostatitis: a randomized double-blind sham controlled study using new prostatitis specific assessment questionnaires. J Urol 1996;155(6):1950-4; discussion 4-5. http://www.ncbi.nlm.nih.gov/pubmed/8618295 Kastner C, Hochreiter W, Huidobro C, Cabezas J, Miller P. Cooled transurethral microwave thermotherapy for intractable chronic prostatitis–results of a pilot study after 1 year. Urology 2004;64(6):1149-54. http://www.ncbi.nlm.nih.gov/pubmed/15596188 Barnes RW, Hadley HL, O’Donoghue EP. Transurethral resection of the prostate for chronic bacterial prostatitis. Prostate 1982;3(3):215-9. http://www.ncbi.nlm.nih.gov/pubmed/7100001 Sant GR, Heaney JA, Meares EM. Radical transurethral prostatic resection in the management of chronic bacterial prostatitis. J Urol 1984;131:184A. Leskinen MJ, Kilponen A, Lukkarinen O, Tammela TL. Transurethral needle ablation for the treatment of chronic pelvic pain syndrome (category III prostatitis): a randomized, sham-controlled study. Urology 2002;60(2):300-4. http://www.ncbi.nlm.nih.gov/pubmed/12137830

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2.7 Bladder pain syndrome/interstitial cystitis (BPS/IC) 2.7.1 Introduction Interstitial cystitis describes a chronic, distressing bladder condition (1). The so-called ‘ulcer’, which is a typical cystoscopic finding in 10-50% of IC patients, was first described by Guy L Hunner at the beginning of the last century (2,3). Subsequent research (4-6) showed that IC was not a single entity, but had different endoscopic and histopathological presentations. It is very important to realise that IC is a heterogeneous spectrum of disorders, which are still poorly defined, and that inflammation is an important feature in only a subset of patients. To embrace all patients suffering from bladder pain, the terms painful bladder syndrome (PBS) or bladder pain syndrome (BPS) have been suggested as more accurate terminology (7,8). This terminology assumes that IC represents a special type of chronic inflammation of the bladder, while PBS or BPS refers to pain in the bladder region. The term bladder pain syndrome or BPS will be used in these guidelines. 2.7.2 Definition An extremely wide variety of diagnostic criteria have been used because of the difficulty in defining IC. In the late 1980s, NIDDK consensus criteria were established to ensure that scientific studies would be relatively comparable (Table 7) (9). The NIDDK criteria produce a diagnosis of IC by exclusion. Bladder pain, urgency and the finding of submucosal haemorrhages, called glomerulations, are the only positive elements. Identification of circumscribed Hunner-type lesions is an automatic inclusion criterion. Although generally accepted, the NIDDK criteria provide only a minimum framework to establish the diagnosis and some have felt them to be too restrictive for clinical use (10). Whatever the method used, heterogeneity seems currently unavoidable (6,11,12).

Table 7: NIDDK workshop research definition* of interstitial cystitis (IC) (9)** Automatic inclusions • Hunner’s ulcer Positive factors • Pain on bladder filling relieved by emptying • Pain (suprapubic, pelvic, urethral, vaginal or perineal) • Glomerulations on endoscopy • Decreased compliance on cystometrogram. Automatic exclusions • < 18 years old • Benign or malignant bladder tumours • Radiation cystitis • Tuberculous cystitis • Bacterial cystitis • Vaginitis • Cyclophosphamide cystitis • Symptomatic urethral diverticulum • Uterine, cervical, vaginal or urethral cancer • Active herpes • Bladder or lower ureteral calculi • Waking frequency < five times in 12 hours • Nocturia < two times • Symptoms relieved by antibiotics, urinary antiseptics, urinary analgesics, e.g. phenazopyridine hydrochloride • Duration < 12 months • Involuntary bladder contractions (urodynamics) • Capacity > 400 mL, absence of sensory urgency. ** B  ladder distension was defined arbitrarily as 80 cm water pressure for 1 minute (sic). Two positive factors were necessary for inclusion in the study population. Under anaesthesia, patients were sub-stratified at the end of the study into two groups according to bladder capacity < 350 mL and > 350 mL. Recently, the European Society for the Study of IC/PBS (ESSIC) has suggested a standardized scheme of diagnostic criteria (13) to make it easier to compare different studies. In a consensus statement, the

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diagnosis of bladder pain syndrome (BPS) was preferred as the general term to match the current taxonomy of chronic pain syndromes. Bladder pain syndrome should be diagnosed on the basis of symptoms of pain associated with the urinary bladder, accompanied by at least one other symptom, such as day-time and/or night-time urinary frequency, the exclusion of confusable diseases as the cause of symptoms, and if indicated, cystoscopy with hydrodistension and biopsy (Table 8) (8). Table 8: ESSIC classification of types of bladder pain syndrome according to the results of cystoscopy with hydrodistension and of biopsies (8). Cystoscopy with hydrodistension Not done Normal Glomerulationsa Hunner’s lesionb Biopsy Not done XX 1X 2X 3X Normal XA 1A 2A 3A Inconclusive XB 1B 2B 3B Positivec XC 1C 2C 3C a Cystoscopy: glomerulations grade 2-3. b With or without glomerulations. c Histology showing inflammatory infiltrates and/or detrusor mastocytosis and/or granulation tissue and/or intrafascicular fibrosis. 2.7.3 Pathogenesis There are many different hypotheses about the causes of BPS/IC. Infection. No micro-organism has been found to be the cause despite the extensive use of sophisticated microbiological detection methods. Although it has been suggested that fastidious bacteria may be responsible (14), no immunological evidence of recent or remote bacterial infection has been found (15). The results of viral culture (16,17) and polymerase chain reaction methods (18,19) have been just as disappointing. Although urine culture from a few IC patients has contained bacteria, antibiotic treatment has been ineffective. Nevertheless, the possibility of a microbiological contribution has not been looked upon as a ‘closed book’, including Helicobacter pylori, though no H. pylori DNA has been detected in bladder biopsies (20). Inflammation is an essential part of classic IC, with pancystitis and perineural inflammatory infiltrates of lymphocytes and plasma cells (17). Inflammation is scant in non-ulcer IC (6). Mast cell activation. Mast cells are multifunctional immune cells that contain highly potent inflammatory mediators, such as histamine, leukotrienes, serotonin and cytokines (21). Many of the symptoms and findings in classic IC, such as pain, frequency, oedema, fibrosis and neovascularization in the lamina propria, may be due to the release of mast cell-derived factors. There is a ten-fold increase in the mast cell count in bladder tissue from patients with classic IC compared with controls. In non-ulcer IC, however, the mast cell count is normal or only slightly increased (6,21,22). Urothelial dysfunction/glycosaminoglycan (GAG)-layer defects. All patients with IC present with fragility of the bladder mucosa, expressed as fissures or rupture of the bladder urothelium on distension (mucosal cracking). In classic IC, the presence of granulation tissue indicates a reparative process (23). In patients with classic IC, urothelial detachment and gross defects of the urothelial lining are characteristic findings. However, in some non-ulcer IC patients, multiple superficial defects are seen after bladder distension (23), including widened tight junctions and increased permeability (24,25). These changes could be consistent with defects in the GAG-layer that expose the submucosal nerve filaments to noxious chemicals in urine (26,27). Urinary uronate and sulphated GAG levels are increased in patients with severe BPS/IC, suggesting that such substances may become useful markers for monitoring (28). Autoimmune mechanisms. Numerous studies of autoantibodies have been performed since the 1970s in patients with IC (29), but the findings have been far from specific. Some of the clinical and histopathological characteristics are similar to other autoimmune phenomena. Antinuclear antibodies have been described (30,31), which has led to the hypothesis of a lupus-like reaction (32,33). In fact, only some BPS patients demonstrate autoantibodies and the proposal that autoantibody titres could reflect disease severity is untested (34). Immune deposits in bladder wall vasculature were found by Mattila (35), while other studies by the

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same group have implicated complement activation (36). Immunohistochemical and cytoflourometric analyses of the bladder mucosa have highlighted differences between classic and non-ulcer IC patients. In classic IC, intense T-cell infiltrates and B-cell nodules were seen, whereas only some T-cell infiltration was observed in non-ulcer IC (37). The inadequate description of patients in many studies, particularly when it comes to subtyping IC patients, has made it difficult to interpret data. Systemic aspects, especially the potential association with Sjögren’s syndrome, are interesting features of BPS/IC (38). Nitric oxide metabolism. Inevitably, nitric oxide synthetase activity has been scrutinized (39). Oral administration of L-arginine (40) has been shown to increase nitric oxide-related enzymes and metabolites in the urine of patients with BPS/IC (41). However, the relevance of this finding is not clear. An intriguing fact is that evaporation of nitric oxide from the urine is dramatically increased in patients with classic disease, as well as during periods of symptoms decreased by treatment; however, patients with non-ulcer IC, have similar nitric oxide levels to controls (42). To further illustrate the complexity involved, it has been suggested that inducible nitric oxide synthetase-dependent nitric oxide production may have a role in epithelial barrier dysfunction in cats with feline interstitial cystitis (43). Neurobiology. An increase in the sympathetic innervation and activation of purinergic neurotransmission has been reported in BPS patients. The S-100 family of proteins appears in Schwann cells of the peripheral nervous system (44). Decreased levels of S-100 protein were found in non-ulcer BPS patients compared with controls (45). However, this finding conflicts with that of Hohenfellner et al. (46), who used ‘polyclonal antihuman protein gene product 9.5 antibody’ and found that the overall nerve content increased in IC patients compared with controls. They did not subtype their patients into classic and non-ulcer forms. Tyrosine hydroxylase is the rate-limiting enzyme for all catecholamine synthesis. An increase in tyrosine hydroxylase immunoreactivity has been described in bladder tissue from IC patients but not in controls (47); this could be interpreted as a sign of increased sympathetic outflow. Recent reports have suggested that autonomic responses and CNS processing of afferent stimuli are altered in patients with CPP/BPS/IC (48,49). The distinctive ultrastructural appearance of specimens from patients with non-ulcer IC prompted Elbadawi and Light to hypothesize neurogenic inflammation as a trigger to a cascade of events (50). Toxic agents. Toxic constituents in the urine may cause injury to the bladder in BPS. One hypothesis is that heat labile, cationic urine components of low molecular weight may exert a cytotoxic effect (51). Defective constitutive cytokine production may decrease mucosal defences to toxic agents (52). Tamm-Horsefall protein is a factor whose protective function may be due to its sialic acid content, which is compromised in BPS/IC individuals (53). Hypoxia. A decrease in the microvascular density in the suburothelium has been observed (54). A recent study, found that bladder perfusion decreased with bladder filling in IC patients, but that the opposite occurred in controls (55). Hyperbaric oxygen therapy has been on trial in an RCT; a total of 30 treatment sessions of hyperbaric oxygenation appeared to be safe, effective and feasible (56). Complex pathogenic interactions. In recent years, more complex, multifaceted mechanisms have been proposed. Theoharides et al. have shown that activation of mast cells in close proximity to nerve terminals can be influenced by oestradiol as well as corticotrophin-releasing hormone (57). Okragly et al. found elevated levels of tryptase, nerve growth factor, neurotrophin-3 and glial cell line-derived neurotrophic factor in IC compared with controls (58). These findings prompted suggestions that IC may result from interactions between the nervous, immune and endocrine systems. Recently, it was proposed that the epithelial distribution of mast cells in classic IC could be explained by the epithelial co-expression of stem cell factor and interleukin-6 (IL-6). According to Abdel-Mageed et al., IC patients showed an increased expression of p65, a nuclear factor kappa B subunit (59). Subsequent data has shown a five-fold increase in the expression of the gene for IL-6 after activation of nuclear factor-kappa B (61), although IL-6 is a ubiquitous cytokine. 2.7.4 Epidemiology Reports of the prevalence of BPS/IC have varied tremendously. However, it should be remembered when comparing studies that most of them have used only symptomatic diagnostic criteria and/or have different study populations. The first systematic study by Oravisto et al. in 1975 found that IC affected approximately 10/100,000 (18/100,000 in women) of the population in Finland (62), with rather similar findings reported 15 years later in the USA (although figures were demonstrated to be dependent on the method of evaluation) (63), as well as in 1995 in the Netherlands with a prevalence of 8-16/100,000 (64). However, other reports claim that the prevalence of IC is underestimated and may exceed 0.5% among adults in the USA (65), with recent US reports suggesting that 50-60/100,000 may be affected (66). Thirty years after the Oravisto study, Leppilahti

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et al. (67) reported higher figures in Finland of 239/100,000 clinically confirmed probable IC and 530/100,000 possible/probable IC. These figures suggested that BPS/IC was much more common than previously thought. Recent reports generally claim higher figures than earlier ones. A recent Austrian study reported the overall prevalence of IC as 306/100,000 women, with the highest value (464/100,000) in middle-aged women (aged 40-59 years) (68). A review has claimed that 20% of women may be affected (69). In contrast, the incidence of physician-diagnosed incidence in Olmsted County (MN, USA) was extremely low at 1.1/100,000 (70). There is a female predominance of about 10:1 (4,62,71,72) and it seems that the disease is more common among Caucasians (72). The relative proportions of classic and non-ulcer disease are unclear. Messing and Stamey reported that classic IC accounted for about half of all patients with IC (5). The same rate has been reported from Sweden (12). Centres in the USA with large patient databases have found that the classic Hunner-type accounts for 5-10% of cases of BPS (74). Koziol et al. recently presented a very large study from the USA, in which classic IC accounted for approximately 20% of cases (75). Evidence that BPS may have a genetic component is increasing. According to Parsons (76), 35% of 466 patients with BPS and 33% of 166 patients with urethral syndrome reported urgency/frequency problems in female relatives. Warren et al. (77) surveyed 2,058 patients of the Interstitial Cystitis Association (ICA) for first-degree relatives with IC and found a higher prevalence than in the general population. The authors also determined the concordance of IC among ICA twins (78); among the co-twins of eight monozygotic twin respondents, five had probable or confirmed IC, while none of 26 dizygotic co-twins were affected. BPS/IC has significant economic costs. Excluding indirect costs, the incremental medical cost attributable to this symptom complex in the USA has been estimated to more than $100 million/year (63). 2.7.5 Association with other diseases An association between BPS and inflammatory bowel disease, systemic lupus erythematosus, irritable bowel syndrome, fibromyalgia and panic disorders has been reported (79-82). An excellent review has explored co-morbidities of BPS/IC with other unexplained clinical conditions presented in the literature (83). The review found a significant overlap of symptoms, suggesting a common stress response pattern, including an increased sympathetic nervous system activity in a subset of patients with many associated conditions. In this context it is interesting to note that feline interstitial cystitis leads to increased corticotrophin-releasing factor activity and decreased adrenocortical reserve. 2.7.6 Diagnosis The diagnosis of BPS is made using symptoms, examination, urine analysis, cystoscopy with hydrodistension and biopsy (see Figure 3). Patients present with characteristic pain and urinary frequency, which is sometimes extreme and always includes nocturia. The character of the pain is the key symptom of the disease: • Pain is related to the degree of bladder filling, typically increasing with increasing bladder content • It is located suprapubically, sometimes radiating to the groins, vagina, rectum or sacrum • Pain is relieved by voiding but soon returns (6,84-86). The differences between the two IC subtypes include clinical presentation and age distribution (12), and they may be discriminated non-invasively (75). The two subtypes respond differently to treatment (87-90) and express different histopathological, immunological and neurobiological features (22,23,37,45,47,91,92). Classic IC is a destructive inflammation with some patients eventually developing a small-capacity fibrotic bladder or upper urinary tract outflow obstruction. There is no such progression in non-ulcer disease (6,93). Endoscopically, classic IC displays reddened mucosal areas often associated with small vessels radiating towards a central scar, sometimes covered by a small clot or fibrin deposit (6). The scar ruptures with increasing bladder distension, producing a characteristic waterfall-type of bleeding. There is a strong association between classic IC and reduced bladder capacity under anaesthesia (6,12,94). Cystoscopy. Non-ulcer IC displays a normal bladder mucosa at initial cystoscopy. The development of glomerulations after hydrodistension is considered to be a positive diagnostic sign. A recent report showed that there was no difference in cystoscopic appearance between patients with non-ulcer IC and women without bladder symptoms about to undergo tubal ligation (95). It has also been noted that glomerulations are not always constant when observed over time (96). Some maintain that cystoscopy with hydrodistension provide little useful information above the history and physical examination findings (97,98). On the other hand, others have found a strong correlation between pain and cystoscopic findings in patients with untreated IC, with the difference in results compared to other studies possibly due to treatment effects (99). Glomerulations may be involved in the disease mechanism, as

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such findings are highly associated with overexpression of angiogenetic growth factors in the bladder and neovascularization (100). The European Society for the Study of IC/PBS (ESSIC) believes objective findings are important and that a standardized scheme of diagnostic criteria would help improve the uniformity and comparability of different studies (13). Biopsies are helpful in establishing or supporting the clinical diagnosis of both classic and non-ulcer types of disease (13,23,101). Important differential diagnoses to exclude by histological examination are carcinoma in situ and tuberculous cystitis. Potassium chloride bladder permeability test has been used in the diagnosis of IC (102), but recent reports have suggested that it lacks discriminating power (103,104). A modified test using less concentrated solution has been suggested. This test, though painless in contrast to the original procedure, decreased the maximum cystometric volume in 90% of patients with BPS/IC, but not in controls (105). Furthermore, it has been suggested that the potassium sensitivity test can help to predict the response to GAG treatment (106). Symptom scores may help to describe symptoms in an individual patient and as outcome measures. The O’Leary-Sant Symptom Index, also known as the Interstitial Cystitis Symptom Index (ICSI) has recently been validated successfully in a large study (107). 2.7.7 Biological markers. It is an attractive idea to support or even better to confirm the clinical diagnosis using a biological marker. Finding a universally helpful one is hampered by heterogeneity within the diagnostic group of BPS and by usually making a diagnosis merely on symptoms. Many candidate markers have been suggested. One of the most interesting is antiproliferative factor, which is present in BPS/IC and is associated with downregulation of heparin-binding epidermal growth factor-like growth factor (108). Nitric oxide is interesting because of its ability to discriminate classic from non-ulcer disease with minimal invasiveness (42). 2.7.8 IC in children and males According to NIDDK criteria, children aged under 18 years is an exclusion criterion. However, occasional cases of BPS of both subtypes have been identified in younger patients (109). There is increasing evidence that very young individuals and children may also be affected, though prevalence figures are low (110). Thus, BPS/IC cannot be excluded on the basis of age. There is a marked female predominance with a female to male ratio of 10:1. However, the diagnosis must also be considered in men presenting with relevant symptoms (111). It has been argued that many men diagnosed with chronic prostatitis may present with signs consistent with NIDDK criteria of BPS/IC and that these diagnoses are inter-related (112,113). However, differences in urinary markers suggest that BPS/IC and CPP/CP may be different disorders with distinct pathophysiologies (114). 2.7.9 Medical treatment Analgesics. Since pain is often a dominant symptom, many patients will try commonly used analgesics at some stage of disease. However, pain relief is disappointing because the visceral pain experienced in BPS/IC responds poorly to analgesic drugs. No systematic studies have been presented on conventional analgesics. Short-term opioids may be indicated for breakthrough or exacerbated pain and periodic flare-ups. Long-term opioids may be considered after all other available therapeutic options have been exhausted, Urologists should obtain informed consent, arrange for regular follow-up, and be prepared to recognize opioid-induced side effects (115). Because BPS/IC is a chronic disease, long-term opioids should be used only exceptionally and under close surveillance. Corticosteroids. Reports on outcome with corticosteroid therapy have been both promising (116) and discouraging (117). Soucy et al. (118) suggest a trial of prednisone (25 mg daily for 1 to 2 months, afterwards reduced to the minimum required for symptom relief) in patients with severe ulcerative IC, which is otherwise unresponsive to conventional treatment. The side effects of steroids can be very serious, making it very difficult to justify their use. Antiallergics. Mast cells may play a role in IC. Among the substances released by mast cells is histamine. Histamine receptor antagonists have been used to block the H1 receptor subtype (119) as well as the H2 receptor (120), with variable results. Hydroxyzine is a histamine H1-receptor antagonist, which blocks neuronal activation of mast cells by inhibiting serotonin secretion from thalamic mast cells and neurons (121). Hydroxyzine hydrochloride (Atarax) is usually

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given, starting with 25 mg at bedtime, increasing to 50 mg/day or if tolerated 75 mg. The most common side effects are sedation and generalized weakness that usually resolve after a period of treatment. In the first series using hydroxyzine, > 90% of patients showed an improvement across the whole range of symptoms. Interestingly, an improvement was noted in associated symptoms including migraine, irritable bowel syndrome and allergies (119). Although these initial results were supported by a further uncontrolled study (119,122), a prospective RCT of hydroxine or sodium pentosanpolysulphate (PPS) compared to placebo failed to show a statistically significant effect (123). However, the study was underpowered, which may be why it failed to demonstrate a statistically significant outcome for either drug compared to placebo. Combination therapy showed the highest response rate of 40%, with a placebo response rate of 13%. Amitriptyline. The tricyclic antidepressant, amitriptyline, has alleviated symptoms in BPS/IC, probably via mechanisms such as blockade of acetylcholine receptors, inhibition of reuptake of released serotonin and norepinephrine, and blockade of the histamine H1 receptor. It is also an anxiolytic (124). Several reports have indicated amelioration after oral amitriptyline (4,125,126). In a prospective RCT study, 48 patients (127) were treated for 4 months with amitriptyline. Drug dosages were escalated in 25 mg increments at 1-week intervals up to a maximum dosage of 100 mg. Amitriptyline significantly improved the mean symptom score, pain and urgency intensity, while frequency and functional bladder capacity improved but were not statistically significant. In a subsequent, prospective, open-label study (128), a response rate of 64% with an overall mean dose of 55 mg was seen with long-term amitriptyline for 20 months. Patient overall satisfaction was good to excellent in 46%, with significant improvement in symptoms. A therapeutic response was observed in all patients fulfilling NIDDK criteria and those with a clinical diagnosis of IC. Anticholinergic side effects (mouth dryness, weight gain) were common and considered to be a drawback of amitriptyline. Pentosanpolysulphate sodium (PPS, Elmiron) has been evaluated in double-blind, placebo-controlled studies. PPS is thought to substitute for a defect in the GAG layer. Subjective improvement of pain, urgency, frequency, but not nocturia, was reported in patients taking the drug compared to placebo (129,130). In an open multicentre study, PPS had a more favourable effect in classic IC than in non-ulcer disease (90). The normal dose is 150-200 mg twice daily between meals. However, absorption is incomplete. An RCT compares 300 mg of PPS with evaluated dosages of 600 and 900 mg in 380 IC patients. Mean ICSI scores improved significantly for all dosages (131). However, treatment response was not dose-dependent but related more to treatment duration. At 32 weeks, about half of all patients were responders. Most adverse events were mild and resolved without intervention. In contrast, a prospective RCT comparing PPS and hydroxine against placebo failed to demonstrate a statistically significant outcome for either drug, though PPS approached statistical significance (p = 0.064) (123). Combination therapy showed the highest response rate of 40% compared to 13% with placebo. For patients with an initial minor response to PPS, additional subcutaneous administration of heparin appeared helpful (132). Antibiotics have a limited role in the treatment of BPS/IC. A prospective RCT pilot study of sequential oral antibiotics in 50 patients found that overall improvement occurred in 12/25 patients in the antibiotic group and 6/25 in the placebo group, while 10 and 5 patients reported an improvement in pain and urgency, respectively. Antibiotics alone or in combination may be associated with decreased symptoms in some patients, but do not represent a major advance in therapy for BPS/IC (133). Immunosuppressants. Azathioprine, 50-100 mg daily, was given to 38 patients, resulting in disappearance of pain in 22 and urinary frequency in 20 (134). Cyclosporin A (CyA) (135) and methotrexate (136) were initially evaluated in open studies, with a good effect on pain, but a limited effect on urgency-frequency. More recent studies of CyA have reported promising results (137,138). In 23 patients, daily voidings, maximal bladder capacity and voided volume improved significantly after 1 year of treatment. The effect was maintained throughout 5 years’ follow-up, with 20/23 patients reporting no bladder pain. However, symptoms recurred within months of discontinuing CyA. In a subsequent randomized study (138), 64 patients fulfilling the NIH-criteria were randomized to 1.5 mg/kg CyA twice daily or low-dose (3 x 100 mg) PPS for 6 months. CyA was superior to PPS in all clinical outcome parameters, with the frequency of micturition significantly reduced in CyA-treated patients, and clinical global response rates of 75% (CyA) and 19% (PPS) (p < 0.001). However, there were more adverse events in the CyA arm (including induced hair growth, gingival pain and hyperplasia, paresthesias in extremities, abdominal pain, flushing, muscle pain and shaking) and only 29 patients completed the 6-month

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follow-up in both groups. During CyA therapy, careful follow-up is mandatory, including regular blood pressure measurement and serum creatinine. Gabapentin / Pregabalin Gabapentin is an antiepileptic drug, which is used as adjunctive treatment in painful disorders. Gabapentin may reduce the use of co-therapeutics, such as opioids. Two patients with IC showed improved functional capacity and received adequate pain control when gabapentin was added to their medication regimen (139). In an uncontrolled dose-escalation protocol with 21 chronic genitourinary pain patients (140), 10 had improved with gabapentin at 6 months. The study included eight IC patients, of whom five responded to gabapentin. Pregabalin is an alpha(2)-delta ligand that binds to and modulates voltage-gated calcium channels, exerting its intended effect to reduce neuropathic pain (141). Pregabalin is the second of only two medications that are US FDA-approved for the treatment of neuropathic pain associated with diabetic peripheral neuropathy; it is used for the treatment of post-herpetic neuralgia. Studies on IC are still lacking. Suplatast tosilate (IPD-1151T) is an oral immunoregulator that suppresses helper T-cell mediated allergic processes. Fourteen women with IC treated with suplatast tosilate reported significantly increased bladder capacity and decreased symptoms after 1 year of treatment. No major side effects occurred and therapeutic effects correlated with a reduction in blood eosinophils, immunoglobulin E and urinary T-cells (142). Comparative controlled data are unavailable. Quercetin is a bioflavinoid that may be effective in male pelvic pain syndrome. It was first tested in a limited, open-label study with hopeful results (143). Theoharides et al. (144) reported on the dietary supplement CystoProtek formulated from quercetin and the natural GAG components, chondroitin sulphate and sodium hyaluronate. In an uncontrolled study, symptoms were significantly improved in 37 IC patients (NIH-criteria), who had failed all forms of therapy and who took six capsules per day for 6 months. Larger controlled studies are warranted by this result. Recombinant human nerve growth factor. A small randomized study (145) was performed on 30 patients (NIH-criteria), who received either placebo or one of two dosages (0.1 or 0.3 mg/kg) of recombinant human nerve growth factor weekly for 3 months. Significant improvement was seen after 3 months as measured by subjective improvement and ICSI score, while mast cells were significantly reduced and nerve cells elevated (p < 0.05) in a dose-dependent manner. Side effects were arthralgias (5%), myalgias (4%), and myasthenia and asthenia (2%). The results suggest that recombinant human nerve growth factor is safe and shows preliminary evidence of efficacy in patients with BPS/IC, but further studies are needed to define its role. 2.7.10 Intravesical treatment Intravesical application of medications establishes high concentrations at the target with few systemic side effects. Disadvantages include the need for intermittent catheterization, which can be painful in IC patients, the cost, and the risk of infection. Local anaesthetics. There are sporadic reports of successful treatment of IC with intravesical lidocaine (146,147). Alkalization of lidocaine prior to intravesical application improved pharmacokinetics (148). In an uncontrolled study, significant immediate symptom relief was reported in 94% of patients and sustained relief after 2 weeks in 80%, using instillations of combined heparin and alkalinized lidocaine (40,000 U heparin, 2% lidocaine (160 mg), and 3 mL 8.4% sodium bicarbonate) (149). Pentosanpolysulphate sodium (PPS) is a glycoprotein aimed at replenishing the GAG layer, which is applied intravesically due to poor bioavailability following oral administration. A double-blind placebo-controlled study (150) was performed in 20 patients, of whom 10 received intravesical PPS (300 mg in 50 mL of 0.9% saline) twice a week for 3 months and 10 received placebo. At 3 months, four patients in the PPS group and two patients in the placebo group gained significant symptomatic relief. Bladder capacities showed a statistically significant increase only in patients treated with PPS. At 18 months, symptoms were relieved in eight patients, who were still receiving PPS instillations, and in four patients not receiving PPS. Intravesical heparin was proposed as a coating agent. In an open, prospective, uncontrolled trial (151), 48 IC patients received instillations of 10,000 units in 10 mL sterile water three times per week for 3 months. In over half of the patients studied, intravesical heparin controlled the symptoms, with continued improvement after 1 year of therapy. Kuo et al. (152) reported another uncontrolled trial of intravesical heparin (25,000 units twice

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a week for 3 months) in women with frequency-urgency syndrome and a positive potassium test. The study included 10 patients with IC, of whom eight reported symptomatic improvement. Baykal et al. (153) evaluated intravesical heparin plus dorsal tibial nerve stimulation in 10 refractory IC patients. Voiding frequency, pain scores and maximum cystometric capacity were significantly better after 2 and 12 months compared to pretreatment values. Hyaluronic acid (hyaluronan) is a natural proteoglycan aimed at repairing defects in the GAG layer. A response rate of 56% at week 4 and 71% at week 7 was reported in 25 patients treated with hyaluronic acid (154). After week 24, effectiveness decreased, but there was no significant toxicity. Nordling et al. (155) and Kallestrup (156) reported a 3-year follow-up of a 3-month, prospective, non-randomized study evaluating the effect of intravesical hyaluronic acid on BPS/IC symptoms. Of the 20 patients, 11 chose to continue treatment beyond the initial trial, and modest beneficial long-term effects were noted in about two-thirds of patients. Reduction in urinary frequency was less effective and mostly due to an improvement in night-time voids. Another study (157) demonstrated a similar favourable effect of hyaluronic acid on pain reduction. Forty-eight patients were treated with typical symptoms and a positive potassium (0.4 M) sensitivity test with weekly instillations of 40 mg hyaluronic acid for 10 weeks. Visual analogue scale scores showed symptom relief due to hyaluronic acid therapy, irrespective of bladder capacity. The improvement was particularly evident in patients with a reduction in C(max) < 30% compared to patients with a reduction of < 30% with 0.2 M KCl solution (p = 0.003). Chondroitin sulphate. Intravesical chondroitin sulphate (158) demonstrated beneficial effects in patients, who had given a positive potassium stimulation test, in two non-randomized, uncontrolled, open-label pilot studies. Steinhoff (159) treated 18 patients with 40 mL instilled intravesically once a week for 4 weeks and then once a month for 12 months. Thirteen of 18 patients were followed for the entire 13-month study. Twelve of these patients responded to treatment within 3-12 weeks. A total of 6/13 (46.2%) showed a good response, 2/13 (15.4%) had a fair response, 4/13 (30.8%) had a partial response, and 1/13 (7.7%) showed no response. In a second trial (160), 24 refractory patients with BPS/IC were treated with high-dose (2.0%) chondroitin sulphate instillations twice weekly for 2 weeks, then weekly with 0.2% solution for 4 weeks, and monthly thereafter for 1 year. The average symptom improvement reported in 20 patients completing the trial was 73.1% (range 50–95%). The time to optimum response was 4-6 months. More concentrated 2.0% solution was needed in eight patients to maintain results. A Canadian phase II/III non-randomized, uncontrolled, community-based, open-label efficacy and safety study is underway. Dimethyl sulphoxide (DMSO) is a chemical solvent and water-soluble liquid that penetrates cell membranes. It is claimed to have analgesic, anti-inflammatory, collagenolytic and muscle relaxant effects. It is also a scavenger of the intracellular OH radical believed to be an important trigger of the inflammatory process. It has been tested empirically and found to alleviate symptoms in IC. DMSO is now a standard treatment. In a controlled, crossover trial (161), 33 patients received instillations of 50% DMSO solution and placebo (saline). All patients received both regimens, which were administered intravesically every 2 weeks for two sessions of four treatments each. Subjective improvement was noted in 53% of patients receiving DMSO versus 18% receiving placebo, and objective improvement in 93% and 35%, respectively. Other uncontrolled trials with DMSO have reported response rates of 50-70% for a period of between 1 and 2 months (162). Rossberger et al. (163) evaluated the discomfort and long-term of DMSO instillations in a total of 28 patients. Side effects were not more common or pronounced in patients with classic compared to non-ulcer disease. After DMSO instillations, a residual treatment effect lasting 16-72 months could be seen. DMSO is contraindicated during urinary tract infections or shortly after bladder biopsy. It temporarily causes a garlic-like odour. Because there has been a case report in which DMSO treatment may have caused pigmented eye lens deposits (164), ophthalmic review should be considered during treatment. Bacillus Calmette Guérin. The tuberculosis vaccine, Bacillus Calmette-Guérin (BCG), is used for its immunomodulatory properties in the intravesical treatment of superficial bladder carcinoma. In 1997, a small prospective, double-blind pilot study on intravesical BCG demonstrated a 60% BCG versus 27% placebo response rate in 30 patients who received six weekly instillations of Tice strain BCG or placebo (165). In a subsequent 24-33 months’ follow-up report, eight of the nine responders reported favourably. BCG did not worsen symptoms in non-responders (166). However, these results are at variance with two controlled trials. In a prospective, double-blind crossover trial of BCG and DMSO (89), BCG treatment failed to demonstrate any benefit. Another randomized, placebo-controlled, double-blind trial on 260 refractory IC patients (167) reported global response rates of 12% for placebo and 21% for BCG (p = 0.062). Small improvements were observed for all secondary outcomes (voiding diary, pain, urgency, symptom indexes and adverse events), some of which were greater with BCG, but with only borderline statistical significance. In a

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subsequent study (168), 156 non-responders from both groups were offered treatment with open-label BCG. The low response rate (18%) for BCG in this series is a further argument against the routine use of BCG as treatment for BPS/IC. Vanilloids disrupt sensory neurones (169). Resiniferatoxin (RTX) is an ultrapotent analogue of the chilli pepper extract capsaicin, causing less pain on instillation and therefore no anaesthesia. Chen et al. (170) investigated RTX tolerability (0.05 µM or 0.10 µM) in 22 BPS/IC patients versus placebo. The most commonly reported adverse event was pain during instillation (RTX > 80.0%, placebo 25.0%) but no serious adverse events were reported. In a small RCT on 18 patients with hypersensitive bladder disorder and pain (171), RTX significantly reduced mean frequency, nocturia and pain scores by about 50%. In another study of seven patients with detrusor hyperreflexia, RTX improved urinary frequency, incontinence and bladder capacity (172). In a small open-label study with single-dose RTX in patients with frequency and urgency (173), RTX significantly improved lower urinary tract symptoms, urodynamic parameters, and quality of life for up to 6 months. These results are in contrast with an RCT in 163 BPS/IC patients randomly assigned to receive a single intravesical dose of 50 mL of either placebo or RTX (in the dosages 0.01, 0.05, or 0.10 µM) (174). RTX resulted in a dose-dependent increase in instillation pain, but otherwise was well tolerated. It did not improve overall symptoms, pain, urgency, frequency, nocturia, or average void volume during 12 weeks’ follow-up. More favourable results were reported from a prospective study on multiple intravesical instillations of RTX (175) (0.01 µM once weekly for 4 weeks). Among 12 patients (one drop-out for severe pain), the overall satisfactory rate was 58.3%, with several scales of symptom and quality of life significantly improved after RTX treatment. There was no significant increase in functional bladder capacity or change in urodynamic parameters. Modification of urine pH. A prospective, randomized, double-blind cross-over study was performed in 26 women, who received instillations of various pH values. There was no evidence that changes in urinary pH affected the pain associated with IC (176). 2.7.11 Interventional treatments Bladder distension. A frequently cited report by Bumpus et al. (177) claims that hydrodistension achieved symptom improvement in 100 patients over several months. However, the study did not define either patient population or symptoms and the methods used were inadequately described. Reports by Ormond (178) and Longacre (179) were just as vague during the 1930s. In 1957, an uncontrolled retrospective study was presented by Franksson (180), who treated 33 patients with repeated, up to 10-fold, distensions. Twelve patients had improved symptoms for up to 4 weeks, in 14 patients for up to 6 months, and in seven patients for up to 1 year. British studies from the 1970s reported contradictory results. Dunn et al. (181) claimed to have achieved complete absence of symptoms in 16/25 patients during a mean follow-up of 14 months using the Helmstein method (182), where an intravesical balloon is distended at the level of systolic blood pressure for 3 hours. Bladder rupture occurred in two cases. These results disagree with those of Badenoch (116), who failed to note any improvement in 44/56 patients after hydrodistension. Twenty years later, McCahy (183) rejected balloon hydrodistension because of inefficacy and a complication rate of 20%. In the recent literature, bladder necrosis following hydrodistension is extremely rare (184). In 2002, Glemain et al. (185) reported an uncontrolled study on 65 IC patients treated by 3-hour balloon hydrodistention. Treatment efficacy in the 33 retrospectively and 32 prospectively studied patients was 38% and 60% at 6 months, and 22% and 43% at 1 year, respectively. Results were superior for bladder capacities above 150 mL. Ottem and Teichmann (2006) reported a retrospective study of 84 BPS/IC patients (97), among which 56% reported short-lived improvement from hydrodistension. Rose et al. investigated bladder distension using electromotive drug administration (EMDA) (186,187), as an alternative to general anaesthesia. Among 11 patients, the distention capacity achieved by EMDA was nearly identical to that in the operating room and cystoscopic findings were similar. Yamada et al. (188) reported on repeated hydrodistension in 52 IC patients (NIH-criteria). Under epidural anaesthesia, the bladder was repeatedly distended to maximal capacity and distension was repeated on the following day for 30 minutes. Five patients were classified as good responders, 30 as moderate responders and 17 as poor responders. Overall, hydrodistension was effective for about 70% of patients for more than 3 months without serious complications. According to a study by Erickson et al. (189), the median symptom score for newly diagnosed patients decreased after distention, but only a few patients had at least 30% symptom improvement. Bladder distention altered levels of urine antiproliferative factor and heparin-binding epidermal growth factor-like growth factor towards normal. However, the mechanism of symptom relief after distention remains unknown. In a retrospective review of 185 patients who underwent hydrodistension (190), results failed to identify any statistically significant differences in objective findings (anaesthetic capacity, glomerulations) following

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distension, or any therapeutic benefits, when patients were categorized according to presenting symptoms. Although bladder hydrodistension is a common treatment for BPS/IC, scientific justification is scarce. It represents a diagnostic tool, but has a limited therapeutic role. Electromotive drug administration (EMDA) enhances tissue penetration of ionized drugs by iontophoresis. Adapted for the bladder, it uses a transurethral anode and a suprapubic skin cathode. EMDA is expensive and the subject of uncontrolled studies only. Six IC patients were treated with EMDA using lidocaine (1.5%) and 1:100,000 epinephrine in aqueous solution, while the bladder was dilated to maximum tolerance (191). Significant bladder enlargement was achieved and voiding symptoms and pain decreased. In four patients, the results were reported as ‘durable’. Rosamilia et al. (192) treated 21 women using EMDA with lidocaine and dexamethasone, followed by cystodistension. A good response was seen in 85% of patients at 2 weeks, with 63% still responding at 2 months. Complete resolution of pain was achieved in 25% of patients reviewed at 6 months. Using a similar technique, Riedl et al. (193) noted complete resolution of bladder symptoms in 8/13 patients lasting 1-17 months. Partial or short-term improvement was observed in three patients. Two patients experienced aggravated pain for several days after therapy. A 66% increase in bladder capacity was observed. Upon symptom recurrence, treatments were repeated with equal efficacy in 11 patients. Transurethral resection (TUR) coagulation and LASER. Endourological ablation of bladder tissue aims to eliminate urothelial, mostly Hunner, lesions. In a case report, Kerr (194) described a transurethral resection of a 1-cm ulcer in a woman who experienced symptom resolution for 1 year. Subsequently, Greenberg et al. (71) reported on 77 patients with Hunner ulcers treated over a 40-year period: 42 were managed conservatively, seven underwent fulguration and 28 were treated by TUR in a non-randomized fashion. Fulguration improved symptoms in 5/7 patients. All patients experienced symptom recurrence in less than 1 year and efficacy was not superior to non-surgical treatment. In another series of 30 classic IC patients (195), complete TUR of visible lesions resulted in an initial disappearance of pain in all patients and a decrease in frequency in 21 patients. A relapse was noted in onethird of patients after 2-20 months, while the remaining two-thirds were still pain-free after 2-42 months. The same group recently reported the largest series of patients with classic IC treated by complete TUR of all visible ulcers (196). A total of 259 TURs were performed on 103 patients. Ninety-two patients experienced amelioration, with symptom relief lasting longer than 3 years in 40%, while most of the remaining patients responded well to subsequent TUR. Transurethral application of the neodymium-yttrium-aluminium-garnet (Nd-YAG) laser is suggested as an alternative to TUR for endoscopic treatment in IC. Shanberg et al. (197) treated five refractory IC patients, four of whom demonstrated cessation of pain and frequency within several days. Follow-up at 3-15 months revealed no relapse except mild recurrent voiding symptoms. This series was extended to 76 patients treated at two institutions (198). Although 21 of 27 patients with Hunner ulcers noted symptom improvement, 12 experienced relapse within 18 months. In the group without ulcers, only 20 of 49 patients improved, of whom 10 required further therapy within 1 year. In a later study, 24 patients with refractory classic IC underwent ablative Nd-YAG laser ablation of Hunner’s ulcers (199). All patients showed symptom improvement within days without complications. At 23 months, mean pain and urgency scores, nocturia and voiding intervals had improved significantly. However, relapse in 11 patients required up to four additional treatments. Endourological resections are not applicable to non-ulcer IC. These techniques may provide long-term alleviation of symptoms, but none are a cure for the disease. Controlled studies are still lacking. Endourological resections are not applicable to non-ulcer BPS/ IC. These techniques may provide long-term alleviation of symptoms, but none of them cure the disease. Controlled studies are still lacking. Botulinum toxin A (BTX-A) may have an anti-nociceptive effect on bladder afferent pathways, producing both symptomatic and urodynamic improvements (200). Thirteen BPS/IC patients were injected with 100-200 IU of Dysport or BTX into 20 to 30 sites submucosally in the trigone and floor of the bladder. Overall, 9 (69%) patients noted an subjective improvement and ICSI scores improved by 70% (p < 0.05). There were significant decreases in daytime frequency, nocturia, and pain, and a significant increase in first desire to void and maximal cystometric capacity. However, these results are in contrast with another study of BTX in 10 patients with BPS/IC (201). One hundred units were injected suburothelially into 20 sites in five patients, while 100 units were injected into the trigone in the remaining five patients. None of the patients became symptom-free; two patients showed only limited improvement in bladder capacity and pain score. Hyperbaric oxygen (HBO). In a prospective pilot study, six patients underwent 30 sessions of 100% hyperbaric oxygen inhalation and were followed up over 15 months. Four patients rated the therapeutic result as excellent

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or good, while two showed only short-term amelioration (202). In a subsequent double-blind, sham-controlled study (203), 3/14 patients on HBO and no control patients were identified as responders (p < 0.05). At 12 months, three patients (21.4%) still reported a treatment response. Hyperbaric oxygenation resulted in a decrease of baseline urgency and pain (p < 0.05). ICSI scores decreased from 26 to 20 points in patients on HBO, while sham treatment did not result in any improvement. These results suggest that HBO is a safe and feasible therapeutic approach, with moderate effects on a small subgroup of BPS/IC patients. Disadvantages include high costs, limited availabiliy of treatment sites and time-consuming treatment. 2.7.12 Treatments of limited efficacy and absence of recent publications Cimetidine. The H2-blocker cimetidine has been reported to improve symptoms in bladder pain syndrome (204). Thirty-six patients were enrolled in a double-blind clinical study with oral cimetidine versus placebo for 3 months. Patients receiving cimetidine showed a significant improvement in symptom scores, pain and nocturia, although histologically the bladder mucosa showed no qualitative changes in either group (205). Prostaglandins. Misoprostol is a prostaglandin that regulates various immunological cascades. Twenty-five IC patients received 600 µg of misoprostol daily for 3 months, with responders treated for a further 6 months. At 3 months, 14 had significantly improved, with 12 showing a sustained response after a further 6 months. However, the incidence of adverse drug effects was 64% (206). L-arginine. Oral treatment with L-arginine, the substrate for nitric oxide synthase, has been reported to decrease BPS/IC-related symptoms (207-209). Nitric oxide has been shown to be elevated in patients with IC (210). However, others could not demonstrate either symptomatic relief or change in nitric oxide production after treatment (211,212). Anticholinergics. Oxybutynin is an anticholinergic drug used in overactive detrusor dysfunction. Intravesically administered oxybutynin was combined with bladder training in one study, with improvement of functional bladder capacity, volume at first sensation and cystometric bladder capacity (213). However, the effect on pain was not reported. Duloxetine inhibits both serotonin and noradrenaline reuptake. In an observational study, 48 women were prospectively treated with duloxetine for 2 months following an up-titration protocol to the target dose of 2 x 40 mg duloxetine per day over 8 weeks (214). Duloxetine did not result in significant improvement of symptoms. Administration was safe, but tolerability was poor due to nausea. Based on these preliminary data, duloxetine cannot be recommended as a therapeutic approach for BPS/IC. Clorpactin is a detergent of hypocloric acid previously used to treat IC (215-219). Due to high complication rates (217,220), clorpactin instillations can no longer be recommended. 2.7.13 Alternative and complementary treatments Behavioural bladder training techniques are attractive for BPS/IC patients with predominant symptoms of frequency/urgency but hardly any pain. Parsons et al. (221) included 21 selected BPS/IC patients on a protocol, which focused on progressively increasing micturition intervals. Fifteen patients reported a 50% decrease in urgency, frequency and nocturia, and there was a moderate increase in bladder capacity. Chaiken et al. (222) retrospectively analysed 42 patients, who had been instructed in diary keeping, timed voiding, controlled fluid intake and pelvic floor muscle training. After 12 weeks, voiding intervals increased by a mean of 93 minutes and daily micturitions were reduced by an average of nine voids. Overall, 88% of the patients reported markedly improved or improved symptoms. Diet. Dietary restrictions are among the many physical self-care strategies found among BPS/IC patients (223). In an analysis of the Interstitial Cystitis Data Base (ICDB) cohort study, special diets were among the five most commonly used therapies (224). Bade et al. (225) found that IC patients consumed significantly less calories, fat and coffee, but more fibre. Scientific data on a rationale for such diets are unavailable. The concentration of some metabolites and amino acids appears to be changed in IC (226). A study of the metabolism of the arylalkylamines (tryptophan, tyrosine, tyramine, phenylalanine) in 250 patients revealed an inability to synthesize normal amounts of serotonin and a noradrenaline metabolite. In this study, dietary restriction of acid foods and arylalkylamines lessened the symptoms, but did not alter specific abnormalities in dopamine metabolism. In another, non-randomized, prospective study of BPS/IC patients with nutrition-related exacerbations, calcium glycerophosphate was reported to ease food-related flares (227). The observed efficacy

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seems little better than would be expected with placebo. Overall, dietary management is a common self-care strategy in BPS/IC and offers a cost-effective therapeutic approach. Comprehensive instructions on how to identify individual trigger foods are given in the IC-Network Patient Handbook (228). However, scientific data are limited and dietary restriction alone does not produce complete symptomatic relief. Acupuncture. In non-curable and agonizing diseases like BPS/IC, desperate patients often try complementary medicines, such as acupuncture. However, scientific evidence for such treatments is often poor, with contradictory results from a few low-evidence reports on acupuncture, with any effects appearing to be limited and temporary. A significant increase in capacity occurred after acupuncture in 52 women with 85% reporting an improvement in frequency, urgency and dysuria and symptoms (229). However, at follow-up at 1 and 3 years, these effects were no longer detectable and the authors concluded that repeated acupuncture was necessary to maintain beneficial effects (230). In a non-randomized comparison in females with urethral syndrome, 128 patients treated by acupuncture and traditional Chinese medicine were compared to 52 patients treated by Western medicine as controls. Efficacy rates and urodynamic parameters were significantly better in the acupuncture group (231). In contrast, in a prospective study on the effect of acupuncture in IC (232), no differences in frequency, voided volumes or symptom scores were noted and only one patient improved for a short period of time. Hypnosis is a therapeutic adjunct in the management of cancer, surgical disease and chronic pain. Although used in urological patients (233,234), there is no scientific data on its effect on IC symptoms. Physiotherapy. General body exercise may be beneficial in some BPS/IC patients (235). An uncontrolled trial of transvaginal manual therapy of the pelvic floor musculature (Thiele massage) in 21 BPS/IC patients with high-tone dysfunction of the pelvic floor resulted in statistically significant improvement on several assessment scales (236). Langford (237) prospectively examined the role of specific levator ani trigger point injections in 18 females with CPP. Each trigger point was identified by intravaginal palpation and injected with 5 mL of a mixture of 10 mL of 0.25% bupivacaine, 10 mL of 2% lidocaine and 1 mL (40 mg) of triamcinolone. A total of 13 out of 18 (72%) women improved with the first trigger point injection, with 6 out of 18 (33%) women completely pain-free. Intravaginal electrical stimulation was applied to 24 women with CPP in the form of ten 30-minute applications, two or three times per week. Stimulation was effective in alleviating pain, as evaluated at the end of treatment and 2 weeks, 4 weeks and 7 months after completion of treatment (p < 0.05). There were significantly fewer complaints of dyspareunia following treatment (p = 0.0005) (238). 2.7.14 Surgical treatment When all efforts fail to relieve disabling symptoms, surgical removal of the diseased bladder is the ultimate option (239-242). Three major techniques of bladder resection are common: • supratrigonal (i.e. trigone-sparing) cystectomy • subtrigonal cystectomy • radical cystectomy including excision of the urethra. All techniques require substitution of the excised bladder tissue, mostly performed with bowel segments. Techniques without bladder removal. As early as 1967, Turner-Warwick reported that mere bladder augmentation without removal of the diseased tissue was not appropriate (243). Sporadic reports that unresected IC bladders cease to cause symptoms when excluded from the flow or urine are scarce (5,244). Supratrigonal cystectomy with subsequent bladder augmentation represents the most favoured continencepreserving surgical technique. Various intestinal segments have been used for trigonal augmentation, including ileum (116,245-252), ileocecum (251-258), right colon (116,252,259), and sigma (246,248,249,254,258). Substituting gastric segments (260,261) seems to be less helpful because the production of gastric acids may maintain dysuria and persistent pain. The therapeutic success of supratrigonal cystectomy has been reported in many studies. In 1966, von Garrelts reported excellent results in 8/13 patients with a follow-up of 12-72 months (248). In 1977, Bruce et al. achieved satisfactory relief of IC symptoms by ileocystoplasty and colocystoplasty in eight patients (246). Dounis and Gow reported seven IC patients whose pain and frequency were considerably improved after supratrigonal cystectomy with ileocecal augmentation (262). In 1991, Kontturi et al. employed segments of colon and sigmoid colon in 12 cases (258). All five

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patients augmented with sigmoid colon remained symptom-free over 4.7 years of follow-up. Two of seven cases augmented with colon required secondary cystectomy with formation of an ileal conduit. Nielsen et al. reported a series of eight patients undergoing supratrigonal cystectomy with ileocaecocystoplasty. While symptoms resolved in two patients, treatment failure in another six patients necessitated secondary cystectomy and ileal conduit formation (253). Linn et al. (263) followed six BPS/IC patients after supratrigonal cystectomy with an ileocecal augmentation for a period of 30 months and reported that all patients were symptom-free and voided spontaneously. In 2002, Van Ophoven et al. (239) reported the long-term results of trigone-preserving cystectomy and consecutive orthotopic substitution enteroplasty in 18 women with IC, using ileocaecal (n = 10) or ileal (n = 8) segments. At a mean follow-up of nearly 5 years, 14 patients were completely pain-free, 12 voided spontaneously and 15 had complete resolution of dysuria. Ileocaecal bowel segments showed superior functional results, since in the group augmented with ileum, three patients required self-catheterization and one a suprapubic catheter. Overall, surgery achieved a significant improvement in diurnal and nocturnal frequencies, functional bladder capacity and symptom scores, with only two treatment failures. In more recent reports with longer follow-ups, the debate on the outcome of BPS/IC patients undergoing cystectomy continues and results vary greatly between different surgeons and patient populations. Chakravarti (264) presented a retrospective review of 11 patients, who had undergone a trigonepreserving orthotopic substitution caecocystoplasty for intractable classical IC and were followed up for a mean period of 9 years. All had symptomatic relief and an increase in bladder capacity to normal. There was no mortality and minimal post-operative morbidity, with two patients requiring intermittent self-catheterization due to high residual volumes. No significant urinary reflux or metabolic complications were noted. However, two patients required a cystectomy after 4 and 6 years, respectively, due to recurrent trigonal disease in one patient and urethrotrigonal hypersensitivity following intermittent self-catheterization in the other. One patient developed an advanced adenocarcinoma in the caecal segment 7 years after the primary operation. Blaivas et al. (265) reported less favourable results. Long-term outcomes of augmentation enterocystoplasty or continent urinary diversion were analysed in 76 patients with benign urological disorders, including seven patients with a clinical diagnosis of IC. The BPS/IC patients all failed surgical treatment because of persistent pelvic pain and failure to achieve adequate bladder capacity rather than because of incontinence. The authors currently consider BPS/IC to be a contraindication for enterocystoplasty. In contrast, Navalon et al. (266) reported a 32-month follow-up of four women suffering refractory IC who underwent supratrigonal cystectomy with orthotopic substitution iliocystoplasty. Suprapubic pain disappeared in all cases, as well as lower urinary tract symptoms, with good control of urinary frequency day and night in the immediate post-operative period. All patients reported high satisfaction with the outcome. Subtrigonal cystectomy. Although less popular, subtrigonal cystectomy has also been reported (263,267-270). Subtrigonal resection has the potential of removing the trigone as a possible disease site, but at the cost of requiring ureteral reimplantation with associated risks of leakage, stricture and reflux. Nurse et al. reported trigonal disease in 50% within their cohort (13/25) and blamed surgical failures on the trigone left in place (271). In contrast, Linn et al. indicated that the level of resection was not solely responsible for treatment success. While completely curing six patients by supratrigonal resection, there were three failures among 17 subtrigonal resections and half of the successful subtrigonal resections required self-catherization to support voiding of the ileocecal augmentate (263). A recent report on female sexuality after cystectomy and othotopic ileal neobladder (272) included eight patients. Pain was relieved in all eight patients, but only one patient regained a normal sexual life post-operatively. Selecting patients and technique. Bladder pain syndrome /Interstitial cystitis is benign and does not shorten life, so that operative procedures rank last in the therapeutic algorithm. However, severely refractory patients should not have to tolerate unsuccessful conservative treatments for years when surgical options are available. Detailed counselling and informed consent must precede any irreversible type of major surgery, which should only be undertaken by experienced surgeons. The choice of technique will be influenced by the experience of the surgeon. The appropriate extent of tissue resection should be based on the endoscopic and histopathological findings. Some surgeons recommend pre-operative cystoscopy and bladder capacity as a prognostic parameter for operative success (244). Responders and failures following orthotopic substitution differed in mean pre-operative bladder capacity (200 mL vs 525 mL, respectively) (253). These findings were supported by Peeker et al. (273), who found that patients with end-stage classic IC had excellent results following ileocystoplasty while patients with non-ulcer disease were not helped. These results have recently been confirmed by another report from the same institution. A retrospective analysis of 47 patients fulfilling the NIH criteria, who underwent reconstructive surgery using various techniques during 1978-2003 (274), resulted in complete symptom resolution in 32/34 patients with classic Hunner-type disease, but only 3/13 patients with

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non-ulcer disease. Cystectomy with formation of an ileal conduit stills ranks first in current US practice trends in surgical IC therapy (275). For cosmetic reasons, however, techniques of continent diversion are preferred, particularly in younger patients. After orthotopic bladder augmentation, particularly when removing the trigone, voiding may be incomplete and require intermittent self-catheterization. Patients considering these procedures should be advised and must be considered capable of performing, accepting and tolerating self-catheterization. For patients with BPS/IC who develop recurrent pain in the augmented bladder or continent pouch after enterocystoplasty or continent urinary diversion, Elzawahri (276) recommends retubularization of a previously used bowel segment to form a urinary conduit. For younger patients, it may be important to know that pregnancies with subsequent lower-segment Caesarean section after ileocystoplasty have been reported (277). Reconstructive surgery for refractory BPS/IC is an appropriate last resort only for well-selected patients with refractory end-stage disease. The decision to embark on major reconstructive surgery should be preceded by a thorough pre-operative evaluation, with an emphasis on assessment to determine the relevant disease location and subtype. A summary of the treatment options for BPS/IC, including a rating of the level of evidence and grade of recommendation (Table 9), is given in Tables 10 and 11. Figure 3 provides an algorithm for the diagnosis and therapy of BPS/IC based on the information discussed above. Table 9: Explanations of levels of evidence and grades of recommendation for treatment options for BPS/IC outlined in Tables 10 and 11 Level Type of evidence 1a Meta-analysis of randomized trials 1b At least one randomized trial 2a One well-designed controlled study w/o randomization 2b One other type of well-designed quasi-experimental study 3 Non-experimental study (comparative study, correlation study, case reports) 4 Expert committee, expert opinion Grade Nature of recommendation based on A Clinical studies of good quality and consistency including at least one randomized trial B Well-conducted clinical studies without randomized trials C Absence of directly applicable clinical studies of good quality Table 10: Medical treatment of BPS/IC LE GR Comment Analgesics 2b C Indications limited to cases awaiting further treatment Corticosteroids 3 C Corticosteroids not recommended as long-term treatment Hydroxyzine 1b A Standard treatment, even though limited efficacy shown in RCT Cimetidine 1b B Insufficient data Amitriptyline 1b A Standard treatment Sodium 1a A Standard treatment pentosanpolysulphate Data contradictory Antibiotics 1b A Limited role in the treatment of IC Prostaglandins 3 C Insufficient data on IC, adverse effects L-arginine 1b C Effect in IC uncertain Cyclosporin A 1b A RCT: superior to PPS but more adverse effects Duloxetin 2b C No effect, tolerability poor Oxybutynin/tolterodine 3 C Limited indication in IC Gabapentin 3 C Preliminary data so far Suplatast tosilate 3 C Preliminary data so far Quercetin 3 C Preliminary data so far RCT = randomized controlled trial; IC = interstitial cystitis; PPS = pentosanpolysulphate sodium; LE = level of evidence; GR = grade of recommendation.

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Table 11: Intravesical, interventional, alternative and surgical treatment of BPS/IC LE GRf Comment Intravesical anaesthesia 3 C Intravesical PPS 1b A Intravesical heparin 3 C Intravesical hyauronic acid 2b B Intravesical chondroitin 2b B sulphate Intravesical DMSO 1b A Intravesical Bacillus 1b Not recommended Calmette Guérin Intravesical clorpactin 3 Not recommended Obsolete Intravesical vanilloids 1b C Data contradictory Bladder distension 3 C Electromotive drug 3 B administration Transurethral resection NA A/B Hunner’s lesions only (coagulation and LASER) Nerve blockade/epidural 3 C For crisis intervention; affects pain pain pumps only Sacral neuromodulation 3 B Not recommended beyond clinical trials Bladder training 3 B Patients with little pain Manual and physical therapy 3 B Diet 3 C Acupuncture 3 C Data contradictory Hypnosis No data Psychological therapy 3 B Surgical treatment NA A Largely varying data ultima ratio, experienced surgeons PPS = pentosanpolysulphate sodium; DMSO = dimethyl sulphoxide; NA = type of evidence not applicable, since RCTs are unethical in such surgical procedures; LE = level of evidence; GR = grade of recommendation.

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Figure 3: Flowchart for the diagnosis and therapy of bladder pain syndrome/interstitial cystitis

2.7.15 References 1. Skene AJC. Diseases of the bladder and urethra in women. New York: William Wood 1887;167. 2. Hunner GL. A rare type of bladder ulcer in women: report of cases. Boston Med Surg J 1915;172:6604. 3. Hunner G. Elusive ulcer of the bladder: further notes on a rare type of bladder ulcer with report of 25 cases. Am J Obstet 1918;78:374-95. 4. Hand JR. Interstitial cystitis: report of 223 cases (204 women and 19 men). J Urol 1949;61:291. 5. Messing EM, Stamey TA. Interstitial cystitis: early diagnosis, pathology, and treatment. Urology 1978;12(4):381-92. http://www.ncbi.nlm.nih.gov/pubmed/213864 6. Fall M, Johansson SL, Aldenborg F. Chronic interstitial cystitis: a heterogeneous syndrome. J Urol 1987;137(1):35-8. http://www.ncbi.nlm.nih.gov/pubmed/3795363 7. Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, van Kerrebroeck P, Victor A, Wein A. The standardisation of terminology of lower urinary tract function: report from the Standardisation Subcommitte of the International Continence Society. Am J Obstet Gynecol 2002;187(1):116-26. http://www.ncbi.nlm.nih.gov/pubmed/12114899 8. van de Merwe JP, Nordling J, Bouchelouche P, Bouchelouche K, Cervigni M, Daha LK, Elneil S, Fall M, Hohlbrugger G, Irwin P, Mortensen S, van Ophoven A, Osborne JL, Peeker R, Richter B, Riedl C, Sairanen J, Tinzl M, Wyndaele JJ. Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an ESSIC poposal. Eur Urol 2008;53(1):60-7. http://www.ncbi.nlm.nih.gov/pubmed/17900797 9. Gillenwater JY, Wein AJ. Summary of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases Workshop on Interstitial Cystitis, National Institutes of Health, Bethesda, Maryland, August 28-29,1987. J Urol 1988;140(1):203-6. http://www.ncbi.nlm.nih.gov/pubmed/3379688

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Kontturi MJ, Hellstrom PA, Tammela TL, Lukkarinen OA. Colocystoplasty for the treatment of severe interstitial cystitis. Urol Int 1991;46(1):50-4. http://www.ncbi.nlm.nih.gov/pubmed/2024372 Seddon JM, Best L, Bruce AW.Intestinocystoplasty in treatment of interstitial cystitis. Urology 1977;10(5):431-5. http://www.ncbi.nlm.nih.gov/pubmed/919133 Leong CH. Use of the stomach for bladder replacement and urinary diversion. Ann R Coll Surg Engl 1978;60(4):283-9. http://www.ncbi.nlm.nih.gov/pubmed/666231 Singla A, Galloway N. Early experience with the use of gastric segment in lower urinary tract reconstruction in adult patient population. Urology 1997;50(4):630-5. http://www.ncbi.nlm.nih.gov/pubmed/9338749 Dounis A, Gow JG.Bladder augmentation-a long-term review. Br J Urol 1979;51(4):264-8. http://www.ncbi.nlm.nih.gov/pubmed/466001 Linn JF, Hohenfellner M, Roth S, Dahms SE, Stein R, Hertle L, Thüroff JW, Hohenfellner R. Treatment of interstitial cystitis: comparison of subtrigonal and supratrigonal cystectomy combined with orthotopic bladder substitution. J Urol 1998;159(3):774-8. http://www.ncbi.nlm.nih.gov/pubmed/9474146 Chakravarti A, Ganta S, Somani B, Jones MA. Caecocystoplasty for intractable interstitial cystitis: long-term results. Eur Urol 2004 Jul;46(1):114-7. http://www.ncbi.nlm.nih.gov/pubmed/15183556 Blaivas JG, Weiss JP, Desai P, Flisser AJ, Stember DS, Stahl PJ. Long-term followup of augmentation enterocystoplasty and continent diversion in patients with benign disease. J Urol 2005;173(5): 1631-4. http://www.ncbi.nlm.nih.gov/pubmed/15821519 Navalón Verdejo P, Ordoño Domínguez F, De la Torre Abril L, Sánchez Ballester F, Escudero JJ, Ramos de Campos M, Ramada Benlloch F. [Orthotopic bladder substitution in the treatment of interstitial cystitis.] Arch Esp Urol 2005;58(7):605-10. [article in Spanish] http://www.ncbi.nlm.nih.gov/pubmed/16294782 Bejany DE, Politano VA. Ileocolic neobladder in the woman with interstitial cystitis and a small contracted bladder. J Urol 1995;153(1):42-3. http://www.ncbi.nlm.nih.gov/pubmed/7966787 Nurse DE, McCrae P, Stephenson TP, Mundy AR.The problems of substitution cystoplasty. Br J Urol 1988;61(5):423-6. http://www.ncbi.nlm.nih.gov/pubmed/3395801 Lotenfoe RR, Christie J, Parsons A, Burkett P, Helal M, Lockhart JL. Absence of neuropathic pelvic pain and favorable psychological profile in the surgical selection of patients with disabling interstitial cystitis. J Urol 1995;154(6):2039-42. http://www.ncbi.nlm.nih.gov/pubmed/7500453 Hughes OD, Kynaston HG, Jenkins BJ, Stephenson TP, Vaughton KC. Substitution cystoplasty for intractable interstitial cystitis. Br J Urol 1995;76(2):172-4. http://www.ncbi.nlm.nih.gov/pubmed/7663907 Nurse DE, Parry JR, Mundy AR. Problems in the surgical treatment of interstitial cystitis. Br J Urol 1991;68(2):153-4. http://www.ncbi.nlm.nih.gov/pubmed/1822961 Volkmer BG, Gschwend JE, Herkommer K, Simon J, Küfer R, Hautmann RE. Cystectomy and orthotopic ileal neobladder: the impact on female sexuality. J Urol 2004;172(6 Pt 1):2353-7. http://www.ncbi.nlm.nih.gov/pubmed/15538266 Peeker R, Aldenborg F, Fall M. The treatment of interstitial cystitis with supratrigonal cystectomy and ileocystoplasty: difference in outcome between classic and nonulcer disease. J Urol 1998; 159(5):1479-82. http://www.ncbi.nlm.nih.gov/pubmed/9554337 Rössberger J, Fall M, Jonsson O, Peeker R. Long-term results of reconstructive surgery in patients with bladder pain syndrome/interstitial cystitis: subtyping is imperative. Urology 2007;70(4):638-42. http://www.ncbi.nlm.nih.gov/pubmed/17991529 Gershbaum D, Moldwin R. Practice trends for the management of interstitial cystitis. Urology 2001;57(6 Suppl 1):119. http://www.ncbi.nlm.nih.gov/pubmed/11378100

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Elzawahri A, Bissada NK, Herchorn S, Aboul-Enein H, Ghoneim M, Bissada MA, Finkbeiner A, Glazer AA. Urinary conduit formation using a retubularized bowel from continent urinary diversion or intestinal augmentations: ii. Does it have a role in patients with interstitial cystitis?. J Urol 2004;171(4):1559-62. http://www.ncbi.nlm.nih.gov/pubmed/15017220 Shaikh A, Ahsan S, Zaidi Z. Pregnancy after augmentation cystoplasty. J Pak Med Assoc 2006;56(10):465-7. http://www.ncbi.nlm.nih.gov/pubmed/17144396

Figure 4: An algorithm for diagnosing and managing scrotal pain

Scrotal Pain Physical examination Ultrasound

Intra-testicular lesion

Further analysis

Hydro/spermatocele Variocele

Surgical repair

Epididymo-orchitis

Antibiotics

Post-surgery vasectomy or hernia repair

Neuromuscular dysfunction?

Pelvic floor muscle dysfunction Myofascial triggerpoint (TrP)

PFM therapy TrP therapy

If treatment has no effect or If no pathology is found

Refer to a pain team

2.8 Scrotal pain Acute scrotal pain is a well-known urological emergency, while chronic scrotal pain is a common reason for men to contact their general practitioners. However, although chronic scrotal pain is not life-threatening and does not require immediate action, it has a considerable effect on a patient’s quality of life. The prevalence of chronic scrotal pain is unknown. A physical examination should always be done in patients with scrotal pain. Gentle palpation of each component of the scrotum is performed to search for masses and for painful spots. A DRE is done to look for prostate abnormalities and examine the pelvic floor muscles. Scrotal ultrasound has limited value in finding the cause of the pain (1). If physical examination is normal, ultrasound is sometimes performed to reassure the patient that there is no tumour in the testis. Ultrasound can be used to diagnose hydroceles, spermatoceles, cysts and varicoceles. The urine should be analysed. Magnetic resonance imaging and computed tomography scans may be used to help with assessment (2). The ilioinguinal and genitofemoral nerves are the most prominent afferent nerves for the scrotum (3). The pudendal nerve supplies the skin of the perineum. 2.8.1 Management of different conditions Intra-testicular lesion. Proceed with further analysis. If tumour is suspected, orchiectomy should be performed. Hydro/spermatocele. Painful fluid-filled spaces in the scrotum can be removed surgically. Varicocele. When localization of the pain and the pattern of aggravation in standing position are clear, correction can be performed.

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Epididymo-orchitis. An infection of the testis or epididymis is usually an acute problem. Chronic epididymitis has been discussed as an entity in literature. The nature of such a chronic inflammation can be infective or based on an obstruction of the vas deferens. For treatment, antibiotics should be tried first for a longer period, up to 3 months, and when needed combined with anti-inflammatory drugs (4). Post-surgical procedures. Procedures, such as vasectomy and hernia repair, may be complicated by scrotal pain. Scrotal pain after vasectomy occurs in about 15-19% (5,6) and is caused by congestion of the vas deferens and testis. Although antibiotics can be used, the results remain unclear. A spermatic cord blockade is also an option (7). Surgical options for both vasectomy and hernia repair include removal of the epididymis, with recent results varying from 43-62% (6,8). Results for denervation of the spermatic cord are reported to be as high as 96% for complete pain relief (9). In post-vasectomy pain, a vasovasostomy might help to overcome the obstruction and thereby improve the pain (10). Pelvic floor muscle dysfunction. At rectal examination, the pelvic floor muscles may be overactive, which means they contract when relaxation is needed, sometimes painfully. An overactive pelvic floor should be treated by physiotherapy (11-13). (See Chapter 6 on Pelvic floor function and dysfunction.) Myofascial trigger points is a type of end-stage surmenage of muscles. Pain in the scrotum can be the result of trigger points in the pelvic floor, but also in the lower abdominal musculature. Treatment consists of applying pressure to the trigger point and stretching the muscle (14,15). (See Chapter 6 on Pelvic floor function and dysfunction.) If no pathology is found, or when specific therapy has no effect, the patient should be referred to a multidisciplinary pain team or pain centre (16). Recommendations for the treatment of scrotal pain syndrome are listed in Table 12. Table 12: Treatment of scrotal pain syndrome LE GR • Orchiectomy 1a A • Excision 3 B • Antibiotics 3 C • Surgical intervention 3 C • Pelvic floor muscle 1b A therapy LE = level of evidence; GR = grade of recommendation. 2.8.2 1.

2.

3.

4.

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Comment In case of intratesticular tumour Hydrocele or varicocele For up to 3 months Epididymectomy, denervation spermatic cord. Vaso-vasostomy Including trigger point treatment

References van Haarst EP, van Andel G, Rijcken TH, Schlatmann TJ, Taconis WK. Value of diagnostic ultrasound in patients with chronic scrotal pain and normal findings on clinical examination. Urology 1999;54(6):1068-72. http://www.ncbi.nlm.nih.gov/pubmed/10604710 Lapointe SP, Wei DC, Hricak H, Varghese SL, Kogan BA, Baskin LS. Magnetic resonance imaging in the evaluation of congenital anomalies of the external genitalia. Urology 2001;58(3):452-6. http://www.ncbi.nlm.nih.gov/pubmed/11549498 Rab M, Ebmer AJ, Dellon AL. Anatomic variability of the ilioinguinal and genitofemoral nerve: implications for the treatment of groin pain. Plast Reconstr Surg 2001;108(6):1618-23. http://www.ncbi.nlm.nih.gov/pubmed/11711938 Nickel JC. Chronic epididymitis: a practical approach to understanding and managing a difficult urologic enigma. Rev Urol 2003;5(4):209-15. http://www.ncbi.nlm.nih.gov/pubmed/16985840 Leslie TA, Illing RO, Cranston DW, Guillebaud J. The incidence of chronic scrotal pain after vasectomy: a prospective audit. BJU Int 2007;100(6):1330-3. http://www.ncbi.nlm.nih.gov/pubmed/17850378

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6.

7.

8. 9.

10.

11.

12.

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14.

15.

16.

2.9

Nariculam J, Minhas S, Adeniyi A, Ralph DJ, Freeman A. A review of the efficacy of surgical treatment for and pathological changes in patients with chronic scrotal pain. BJU Int 2007;99(5):1091-3. http://www.ncbi.nlm.nih.gov/pubmed/17244279 Yamamoto M, Hibi H, Katsuno S, Miyake K. Management of chronic orchialgia of unknown etiology. Int J Urol 1995;2(1):47-9. http://www.ncbi.nlm.nih.gov/pubmed/7542163 Granitsiotis P, Kirk D. Chronic testicular pain: an overview. Eur Urol 2004;45(4):430-6. http://www.ncbi.nlm.nih.gov/pubmed/15041105 Heidenreich A, Olbert P, Engelmann UH. Management of chronic testalgia by microsurgical testicular denervation. Eur Urol 2002;41(4):392-7. http://www.ncbi.nlm.nih.gov/pubmed/12074809 Nangia AK, Myles JL, Thomas AJ Jr. Vasectomy reversal for the post-vasectomy pain syndrome: a clinical and histological evaluation. J Urol 2000;164(6):1939-42. http://www.ncbi.nlm.nih.gov/pubmed/11061886 Cornel EB, van Haarst EP, Schaarsberg RW, Geels J. The effect of biofeedback physical therapy in men with Chronic Pelvic Pain Syndrome Type III. Eur Urol 2005;47(5):607-11. http://www.ncbi.nlm.nih.gov/pubmed/15826751 Hetrick DC, Glazer H, Liu YW, Turner JA, Frest M, Berger RE. Pelvic floor electromyography in men with chronic pelvic pain syndrome: a case-control study. Neurourol Urodyn 2006;25(1):46-9. http://www.ncbi.nlm.nih.gov/pubmed/16167354 Rowe E, Smith C, Laverick L, Elkabir J, Witherow RO, Patel A. A prospective, randomized, placebo controlled, double-blind study of pelvic electromagnetic therapy for the treatment of chronic pelvic pain syndrome with 1 year of followup. J Urol 2005;173(6):2044-7. http://www.ncbi.nlm.nih.gov/pubmed/15879822 Anderson RU, Wise D, Sawyer T, Chan C. Integration of myofascial trigger point release and paradoxical relaxation training treatment of chronic pelvic pain in men. J Urol 2005;174(1):155-60. http://www.ncbi.nlm.nih.gov/pubmed/15947608 Srinivasan AK, Kaye JD, Moldwin R. Myofascial dysfunction associated with chronic pelvic floor pain: management strategies. Curr Pain Headache Rep 2007;11(5):359-64. http://www.ncbi.nlm.nih.gov/pubmed/17894926 Messelink EJ. The pelvic pain centre. World J Urol 2001;19(3):208-12. http://www.ncbi.nlm.nih.gov/pubmed/11469609

Urethral pain syndrome

Figure 5: An algorithm for diagnosing and managing urethral pain syndrome

Urethral pain syndrome Detailed micturition history Physical examination including urethral palpation Urine culture Uroflow

Urethro-cystoscopy

Antibiotics

Extended urine cultures

Alpha-blockers

Urine microscopy

NSAID

Further infestigation?

Urodynamics?

Acupuncture, other trials If treatment has no effect

Refer to a pain team

Urethral pain syndrome is a less well-defined entity and scientific studies are scant. Positive diagnostic signs are urethral tenderness or pain on palpation and a slightly inflamed urethral mucosa found during endoscopy. Hypotheses about the aetiology include concealed infections of the periurethral glands or dsucts, according to the anatomical description by Huffman (1), and oestrogen deficiency. Others consider urethral syndrome to be a less severe form of ‘early’ BPS/IC (2). In clinical practice, the diagnosis of urethral pain syndrome is commonly given to patients who present with the symptoms of dysuria (with or without frequency, nocturia, urgency and urge incontinence) in

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the absence of evidence of urinary infection. The ‘absence of urinary infection’ cause diagnostic problems as the methods typically used to identify urinary infection are extremely insensitive. Dysuria is pain or discomfort experienced in association with micturition. The classical symptom of a burning sensation in the urethra during voiding caused by infection is well known. The external dysuria experienced by women with vaginitis when urine passes over the labia is less appreciated. Biochemical testing and microbiological culture of urine is important in assessing lower urinary tract symptoms and has been reviewed in some detail in the elderly (3). There is confusion about the concept of significant bacteriuria. This may be accepted as 105 colonyforming units (CFU) of a single species in asymptomatic women. However, it may be as low as 102 CFU of a single species of a known urinary pathogen in symptomatic women. Many automated culture systems have a sensitivity of 104 CFU, while urinary leucocyte esterase and nitrite tests are correlated only with cultures as high as 105 CFU (4). In addition, many laboratory culture systems detect only just over 50% of infections in midstream urine specimens from genuinely infected patients (4). A narrow spectrum of aetiological agents causes 85-90% of cases of acute, uncomplicated cystitis in women. Nearly one-third of acutely dysuric women with urinary tract infections caused by Escherichia coli, Staphylococcus saprophyticus or Proteus spp. have midstream colony counts in the range of 102-104 bacteria/ mL. Investigators have also identified causative organisms by more invasive techniques, such as culturing specimens obtained by catheterization or suprapubic aspiration. Failing to identify an organism does not mean that it is not present. Although rarely included, proper manual urine microscopy using a haemocytometer should be part of a definitive work-up. Nowadays, most laboratories screen urine in wells using inverted microscopes or rely on robotic detection of pyuria, which are both insensitive methods. This is regrettable because studies have shown that significant pyuria is a nearly universal indicator of urinary tract infection, although it is not specific for differentiating cystitis from urethritis, particularly urethritis due to Chlamydia trachomatis. In relation to the latter, dysuria also merits the microscopic examination of a urethral smear after it has been Gram stained. If present, a purulent urethral exudate will be obvious, although a causative micro-organism will be identified in less than 50% of cases. The expression ‘non-specific urethritis’ is apposite and honestly states our current ignorance. Urethral trauma arising from intercourse may cause pain and dysuria. This condition used to be called ‘honeymoon cystitis’, and friction and trauma to the urethra may be the cause in the absence of infection. Women with pelvic floor dysfunction sometimes describe similar symptoms, as do post-menopausal women, in whom trauma is associated with oestrogen deficiency, loss of lubrication and vaginal dryness. Unless a thorough assessment is carried out, bearing in mind the comments described above, the diagnosis of urethral pain syndrome does not seem credible. There are no data available to answer the inevitable question, ’how common is dysuria in the presence of negative rigorous investigation of the bladder and urethra?’ 2.9.1 Treatment There is no consensus on treatment. Management may require a multidisciplinary approach. Various modalities including antibiotics, alpha-blockers, acupuncture and laser therapy have been proved successful. Psychological support is important (5). An algorithm for diagnosing and managing urethral pain syndrome is given in Figure 5. 2.9.2 1.

2.

3.

4.

5.

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References Huffman JW. The detailed anatomy of the paraurethral ducts in the adult human female. Am J Obstet Gynec.1948;55:86-101. http://www.ncbi.nlm.nih.gov/pubmed/18918954 Parsons CL, Zupkas P, Parsons JK. Intravesical potassium sensitivity in patients with interstitial cystitis and urethral syndrome. Urology 2001;57(3):428-32. http://www.ncbi.nlm.nih.gov/pubmed/11248610 Gray RP, Malone-Lee J. Review: urinary tract infection in elderly people - time to review management?. Age & Ageing 1995;24(4):341-5. http://www.ncbi.nlm.nih.gov/pubmed/7484494 Pappas PG. Laboratory in the diagnosis and management of urinary tract infections. Med Clin North Am 1991;75(2):313-25. http://www.ncbi.nlm.nih.gov/pubmed/1996036 Kaur H, Arunkalaivanan AS. Urethral pain syndrome and its management. Obstet Gynecol Surv 2007;62(5):348-51. http://www.ncbi.nlm.nih.gov/pubmed/17425813

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3. PELVIC PAIN IN GYNAECOLOGICAL PRACTICE 3.1

Introduction

The approach to pelvic pain presenting to the gynaecologist relies upon the same principles, namely to discover remediable causes and treat them using the most effective available therapies. However, the greatest therapeutic challenge will be provided by the 30% of patients in whom no cause can be found (1).

3.2

Clinical history

It is essential to start by taking a detailed medical history. The nature, frequency and site of the pain, and its relationship to precipitating factors and the menstrual cycle, may provide vital clues to the aetiology. A detailed menstrual and sexual history, including any history of sexually transmitted diseases and vaginal discharge is mandatory. Discrete inquiry about previous sexual trauma may be appropriate.

3.3

Clinical examination

Abdominal and pelvic examination will exclude any gross pelvic pathology (tumours, scarring and reduced uterine mobility), as well as demonstrating the site of tenderness if present. Abnormalities in muscle function should also be sought. 3.3.1 Investigations Vaginal and endocervical swabs to exclude infection are mandatory and cervical cytology screening is advisable. Pelvic ultrasound scanning provides further information about pelvic anatomy and pathology. Laparoscopy is the most useful invasive investigation to exclude gynaecological pathology (2) and to assist in the differential diagnosis (3).

3.4

Dysmenorrhoea

Pain in association with menstruation may be primary or secondary. Primary dysmenorrhoea classically begins at the onset of ovulatory menstrual cycles and tends to decrease following childbirth (4). Explanation and reassurance may be helpful, together with the use of simple analgesics progressing to the use of non-steroidal anti-inflammatory drugs (NSAIDs), which are particularly helpful if they are started before the onset of menstruation. NSAIDs are effective in dysmenorrhoea probably because of their effects on prostaglandin synthetase. Suppression of ovulation using the oral contraceptive pill reduces dysmenorrhoea dramatically in most cases and may be used as a therapeutic test. Because of the chronic nature of the condition, potentially addictive analgesics should be avoided. Secondary dysmenorrhoea suggests the development of a pathological process and it is essential to exclude endometriosis (5) and pelvic infection.

3.5

Infection

A history of possible exposure to infection should be sought and it is mandatory in all cases to obtain swabs to exclude chlamydia and gonorrhoea, as well as vaginal and genital tract pathogens (6). Patient’s sexual contacts need to be traced in all cases with a positive culture. If there is any doubt about the diagnosis, laparoscopy may be very helpful. Primary herpes simplex infection may present with severe pain (7), associated with an ulcerating lesion and inflammation, which may lead to urinary retention (8). Hospitalization and opiates may be needed to achieve adequate analgesia. 3.5.1 Treatment Treatment of infection depends on the causative organisms. Subclinical chlamydial infection may lead to tubal pathology. Screening for this organism in sexually active young women may reduce the incidence of subsequent subfertility. Chronic pelvic inflammatory disease is no longer common in developed countries, but still poses a significant problem with chronic pain in the Third World.

3.6 Endometriosis The incidence of endometriosis is rising in the developed world. The precise aetiology is still a source of debate, but an association with nulliparity is well accepted. The condition may be suspected from a history of secondary dysmenorrhoea and often dyspareunia, as well as the finding of scarring in the vaginal fornices on vaginal examination, with reduced uterine mobility and adnexal masses. Laparoscopy is the most useful diagnostic tool (9, 10). Endometriotic lesions affecting the urinary bladder or causing ureteric obstructions can occur, as well as lesions affecting the bowel, which may lead to rectal bleeding in association with menstruation.

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3.6.1 Treatment As in primary dysmenorrhoea, analgesics and NSAIDs are helpful in easing pain at the time of menstruation. Hormone treatment with progestogens or the oral contraceptive pill may halt progress of endometriosis, but is not curative. A temporary respite may be obtained by using luteinizing hormone releasing hormone (LHRH) analogues to create an artificial menopause, though the resulting oestrogen deficiency may have marked long-term side effects, such as reduced bone density and osteoporosis in those taking more than six months worth of treatment. These drugs are used prior to surgery to improve surgical outcome and reduce surgical complications. Surgery for endometriosis is challenging and the extensive removal of all endometriotic lesions is essential. The best results are achieved laparoscopically, by highly trained and skilled laparoscopic surgeons, in specialist centres (11). A multidisciplinary team will be required for the treatment of extensive disease, including a pain management team. The pain associated with endometriosis is often not proportionate to the extent of the condition and, even after extensive removal of the lesions and suppression of the condition, the pain may continue.

3.7 Gynaecological malignancy The spread of gynaecological malignancy of the cervix, uterine body or ovary will cause pelvic pain depending on the site of spread. Treatment is of the primary condition, but all physicians dealing with pelvic pain must be fully aware of the possibility of gynaecological malignancy.

3.8

Injuries related to childbirth

Tissue trauma and soft tissue injuries occurring at the time of childbirth may lead to CPP related to the site of injury. Dyspareunia is a common problem leading to long-term difficulties with intercourse and female sexual dysfunction (12). Denervation of the pelvic floor with re-innervation may also lead to dysfunction and pain. Hypo-oestrogenism, as a result of breast feeding, may also contribute to pelvic floor pain and dysfunction. Vulval pain and psychosexual problems are discussed extensively in other sections of this text. Post-menopausal oestrogen deficiency may lead to pain associated with intercourse, which will respond to hormone replacement therapy.

3.9

Conclusion

Once all the above conditions have been excluded, the gynaecologist may well be left with patients with unexplained pelvic pain. It is imperative to consider pain associated with the urinary and gastrointestinal tract at the same time. For example, patients with bladder pain quite often present with dyspareunia due to bladder base tenderness. Previously, pelvic congestion has been cited as a course of pelvic pain of unknown aetiology, but this diagnosis is not universally recognised (13, 14). As previously stated in dealing with pelvic pain, the best results will be obtained from a multidisciplinary approach that considers all possible causes.

3.10

REFERENCES

1.

Newham AP, van der Spuy ZM, Nugent F. Laparoscopic findings in women with pelvic pain. S Afr Med J 1996;86 (9 Suppl):1200-3. http://www.ncbi.nlm.nih.gov/pubmed/9180785 Howard FM. The role of laparoscopy as a diagnostic tool in chronic pelvic pain. Ballieres Best Pract Res Clin Obstet Gynaecol 2000;14(3):467-94. http://www.ncbi.nlm.nih.gov/pubmed/10962637 Porpora MG, Gomel V. The role of laparoscopy in the management of pelvic pain in women of reproductive age. Fertil Steril 1997;68(5):765-79. http://www.ncbi.nlm.nih.gov/pubmed/9389799 Visner SL, Blake RL Jr. Physician’s knowledge and treatment of primary dysmenorrhoea. J Fam Pract 1985;21(6):462-6. http://www.ncbi.nlm.nih.gov/pubmed/3934322 Porpora MG, Konincks PR, Piazze J, Natili M, Colagrande S, Cosmi EV. Correlation between endometriosis and pelvic pain. J AM Assoc Gynecol Laparosc 1999;6(4):429-34. http://www.ncbi.nlm.nih.gov/pubmed/10548700 Ness RB, Soper DE, Holley RL, Peipert J, Randall H, Sweet LL, Sondheimer SJ, Hendrix SL, Amortegui A, Trucco G, Souger T, LA JR, Hillier SL, Bass DC, Kelsey K. Effectiveness of inpatient and outpatient strategies for women with pelvic inflammatory disease. AM J Obstet Gynecol 2002;186(5):929-37. http://www.ncbi.nlm.nih.gov/pubmed/12015517

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8. 9.

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12. 13.

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Corey L, Adams HC, Brown ZA, Holmes KK. Genital herpes simplex infections: clinical manifestations cause and complications. Ann Intern Med 1983;98(6):958-72. http://www.ncbi.nlm.nih.gov/pubmed/6344712 Robertson DH, McMillan A, Young H. In: Clinical practice in sexually transmissible disease. Edinburgh: Churchill Livingstone, 1989; p. 333. Fauconnier A, Chapron C, Dubuisson JB, Viera M, Doussett B, Breart G. Relation between pain symptoms and the anatomic location of deep infiltrating endometriosis. Fertil Steril 2002;78(4):719-26. http://www.ncbi.nlm.nih.gov/pubmed/12372446 Goldstein DP, De Cholnoky C, Emans SJ. Adolescent endometriosis. J Adolesc Health Care 1980;1(1):37-41. http://www.ncbi.nlm.nih.gov/pubmed/6458589 Redwine DB, Wright JT. Laparoscopic treatment of complete obliteration of the cul-de-sac associated with endometriosis: long-term follow-up of en bloc resection. Fertil Steril 2001;76(2):358-65. http://www.ncbi.nlm.nih.gov/pubmed/11476786 Osborne JL. Presentation to the European Society of Female Urology. Verona, Italy, Oct 2001. Beard RW, Kennedy RG, Gangar KF, Stones RW, Rogers V, Reginald PW, Anderson M. Bilateral oophorectomy and hysterectomy in the treatment of intractable pelvic pain associated with pelvic ongestion. Br J Obstet Gynaecol 1991;98(10):988-92. http://www.ncbi.nlm.nih.gov/pubmed/1751445 Foong LC, Gamble J, Sutherland IA, Beard RW. Altered peripheral vascular response of women with and without pelvic pain due to congestion. Br J Obstet Gynaecol 2000;107(2):157-64. http://www.ncbi.nlm.nih.gov/pubmed/10688497

4. NEUROLOGICAL ASPECTS 4.1 Physiology of the urogenital system The fused somatic and autonomic innervation of the pelvic organs reflects the human need to integrate urogenital functions into our social existence. Proper bladder control is essential for everyday life, while sexual behaviour is an activity upon which depend intimate relationships and the continuation of the species. Physiological functioning of the bladder and sexual organs therefore requires intact innervation, which extends from the frontal lobes of the cortex to the distant pelvic plexi. The integration of the sympathetic, parasympathetic and somatic innervation in both female and male urogenital tracts is complex. Sympathetic innervation arises from the thoracolumbar outflow, while parasympathetic outflow and somatic innervation originate from the sacral segments of the spinal cord. Afferent nerves travel retrogradely with all three innervating systems. Integration of inputs from the different levels of central and peripheral innervation occurs in plexi, from which nerves arise to innervate pelvic organs. The sacral (predominantly somatic) and the pelvic (predominantly parasympathetic) plexus are intimately linked, with sympathetic connections from the superior and inferior hypogastric plexus. The sacral plexus innervates the perineum, uterus in the female and the penis in the male through the pudendal nerve. The parasympathetic fibres arise from S2 to S4 to synapse with the ganglia in the pelvic plexus, which are located in the adventitia around the bladder base and in the bladder wall, and from which comes visceral innervation to the bladder and the internal genital organs. The superior hypogastric plexus (sympathetic), situated at the sacral promontory, is the origin of the left and right hypogastric nerves.

4.2 Physiology of the bladder The urinary bladder is a reservoir whose functions are simply storage and emptying. However, these functions are only accomplished by an extensive and complex innervation that co-ordinates the activity of the striated muscles of the pelvic floor and the various effector organs making up the lower urinary tract (LUT) (1). ­­ 4.2.1 Bladder filling Most of the time, the bladder is a low-pressure storage system, which accommodates urine entering from the ureters. The walls of the ureters contain smooth muscle arranged in spiral, longitudinal and circular bundles. They pass obliquely through the bladder wall thereby preventing reflux of urine into the ureters during a bladder contraction. Under normal circumstances, urine entering the bladder does not cause an increase in intravesical pressure. The smooth muscle of the bladder wall (the detrusor muscle) exhibits plasticity when stretched. The relationship between detrusor pressure and bladder filling can be studied by performing subtracted cystometry,

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where the pressure difference between two fluid-filled catheters inserted into the bladder and the rectum is determined. A plot of these values against the volume of fluid infused is seen in Figure 6. In health, the detrusor pressure remains almost flat, as fluid fills the bladder that can normally accommodate around 500mL. Detrusor muscle fibres condense in the region of the bladder neck, forming a well-defined circular collar in the male, and an obliquely/ longitudinally orientated muscle coalescing into the urethral wall in the female. The bladder neck therefore forms a proximal sphincter, which is more evident in the male than in the female, and which is thought to be important in preventing retrograde ejaculation. Striated muscle comprises the external urethral sphincter, which forms a U-shape around the urethra with some fibres completely encircling it anteriorly, so that as the muscle contracts, the urethra becomes occluded. During the storage phase, continence is maintained by the high resistance offered by the bladder neck and urethra, together with the integrity of the external urethral sphincter (Figure 7). Tonic firing of pudendal motor units of the external urethral sphincter and pelvic floor ensure that a higher pressure is maintained within the urethra than within the bladder. Furthermore, dampening of the parasympathetic innervation of the detrusor by the activation of sympathetic efferents via a sacral to thoracolumbar intersegmental reflex pathway (2) prevents the bladder from contracting spontaneously or involuntarily, the so-called ‘storage reflex’. This reflex not only inhibits the detrusor, but also causes contraction of the bladder neck and the proximal urethra. The situation is reversed when micturition is initiated (see below). 4.2.2 Afferent innervation of the bladder Sensations of bladder fullness are conveyed to the spinal cord in the pelvic and hypogastric nerves (3). The afferent components of these nerves contain myelinated ( Aδ) and unmyelinated (C) axons. The Aδ fibres respond to passive distension and active contraction (3) and thus convey information about bladder filling. The C-fibres, insensitive to bladder filling under physiological conditions (therefore termed ‘silent’ C-fibres) respond primarily to noxious stimuli such as chemical irritation of the urothelium (4) or cooling (5). The cell bodies of both these classes of axons are located in the dorsal root ganglia (DRG) at the level of S2 – S3 and T11 – L2 spinal segments. Bladder afferent activity enters the spinal cord through the dorsal horn and ascends rostrally to higher brain centres involved in bladder control (see below). In the urinary bladder, sensory nerves have been identified in the suburothelial layer (predominantly in the bladder neck) as well as in the detrusor muscle (6-9). They form a plexus in the suburothelium with some terminal fibres possibly projecting into the urothelium (10-12). Afferent fibres also originate from the trigone and urethra and run in the hypogastric and pudendal nerves respectively. The response of the bladder to stretch has been extensively investigated and recently a population of cells located in the suburothelial layer of the bladder, called myofibroblasts (13), have been identified. They may act as stretch sensory receptors. 4.2.3 Efferent innervation of the bladder The LUT receives innervation from both the parasympathetic and the sympathetic branches of the autonomic nervous system. The pelvic nerves (arising from the parasympathetic pelvic plexus) cause contraction of the detrusor which effects bladder emptying, whereas parasympathetic innervation of the outflow tract exerts an inhibitory effect resulting in relaxation of the bladder neck and urethra (14). The sympathetic fibres are derived from the T11-T12 and L1-L2 in the spinal cord and run through either the inferior mesenteric ganglia or the hypogastric nerve, or pass through the paravertebral chain to enter the pelvic nerves at the base of the bladder and the urethra. The predominant effect of the sympathetic innervation is inhibition of the parasympathetic pathways at local or spinal level and mediation of contraction of the outflow tract. The somatic nerve supply to the pelvic floor musculature and part of the urethra originates at S2 – S4 and is conveyed peripherally by the pudendal nerves. A distinct, medially placed motor nucleus at the same spinal level (Onuf’s nucleus) supplies axons that innervate the external urethral sphincter. 4.2.4 Central control of micturition Efficient storage and emptying of the bladder requires co-ordinated action of the detrusor and outflow tract. Storage control is achieved in infancy, but voiding is determined by the perceived state of bladder fullness and the social environment (15). The spinal reflexes involved in storage and micturition are relatively simple and are controlled by higher brain centres. Functional brain imaging has shown that a wide complex of brain networks control the processes of bladder storage (16,17) and voiding (18,19), which ultimately results in the activation or inhibition of the pontine micturition centre. It is from here that direct pathways descend to the sacral spinal cord and modulate the parasympathetic outflow to the detrusor and co-ordinate the somatic innervation to the external urethral sphincter (20). A desire to void is generated when the bladder volume reaches capacity (approximately 500 mL in humans) (21), but a micturition reflex is only triggered if higher cortical function assesses the situation as appropriate for voiding. Complete emptying is ensured by the resultant detrusor contraction, which is

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maintained throughout voiding (achieved by the detrusor’s unique ability to sustain near-maximal force generation in the face of significant length change [22]), and concomitant relaxation of the outflow tract. 4.2.5 Physiology of the genital organs The female reproductive organs are comprised of the vagina and vulva, important for sexual function, and the ovaries and uterus, necessary for ovulation and reproduction. The uterus is made up of a fibromuscular lower body or cervix and a muscular upper body, which is lined by a hormonally sensitive endometrial layer. The latter responds to the complex monthly hormonal cycle mediated by the hypothalamic-pituitary-ovarian axis acting in tandem with neurological control. Innervation. Female reproductive organs are innervated in a topographic fashion by afferents which pass retrogradely to the pelvic or hypogastric plexus (23). The afferent nerves contribute to uterine and vaginal perceptions (nociception) that are modified by the reproductive status (24). These plexi communicate with the higher brain centres (the hypothalamus (25), the hippocampus and the limbic system) via the spinal cord, dorsal column nuclei and the solitary nucleus. The vagina, a highly expandable fibromuscular tube, receives sensory fibres from the pudendal nerve (the perineal and posterior labial branches) and the ilioinguinal nerve. The blood vessels of the smooth muscle of the vaginal walls are supplied by autonomic fibres from the inferior hypogastric plexuses. The clitoris, which is considered homologous to the penis, is also composed of erectile tissue with two miniature corpora cavernosa. Covered with a prepuce, the free end of the clitoris, the glans, is highly sensitive to sexual stimulation. Sexual excitement induces vascular smooth muscle relaxation, (26) mediated by substances such as vasoactive intestinal peptide (VIP) (27) and nitric oxide, and resulting in increased pelvic blood flow, clitoral and labial engorgement and transudative vaginal lubrication. This sexual response is due, as in the male, to parasympathetic activity, and at orgasm, there is repeated contraction of the perineal skeletal muscle, supplied by the perineal branch of the pudendal nerve. Women with complete spinal cord injury at the mid-thoracic level show perceptual responses to vaginal and/or cervical self-stimulation (e.g. pain suppression and sexual response, including orgasm), with increased activity in the solitary tract nucleus (28). Menstruation. Animal studies have shown that the rat uterus is directly innervated by both autonomic and sensory nerves, including adrenergic (29) and cholinergic (30), as well as by different peptidergic fibres containing VIP, substance P, calcitonin-gene-related peptide and galanin (31,32). Uterine innervation undergoes profound remodelling during puberty, pregnancy and after delivery. However, the extent to which uterine innervation may change during the menstrual cycle is uncertain (33,34). The human uterus is under direct control of the hormonal cycle, which influences the innervation of the uterine arteries (cholinergic, adrenergic and peptidergic), and regulates the spontaneous contractile activity of the smooth muscle of vessel walls, as well as the motor responses of these tissues to different vasoactive substances (35). A hormonal disturbance may cause dysfunctional bleeding by changing vessel growth as well as vascular and myometrial smooth muscle activity (36). An example of the latter is primary dysmenorrhoea, when there is an increased secretion of vasopressin (35), which acts on type V1 vasopressin receptors of the uterus, causing myometrial hyperactivity and vasoconstriction, with resultant uterine ischemia and pain. Pregnancy and parturition. In the pregnant uterus, the motor and sensory innervation undergoes a profound denervation process, although the changes do not affect all types of nerves. Immunocytochemical studies have indicated that myometrial and perivascular VIP-containing fibres disappear at the end of pregnancy (37). In contrast, SP-containing primary afferent neurons do not degenerate during pregnancy (38). At the end of pregnancy, the numbers of both myometrial and perivascular adrenergic nerves are decreased in the rat (39,40) in the guinea pig (41,42), and in humans (43). The whole autonomic uterine innervation therefore undergoes substantial remodelling during pregnancy. Urogenital pain. The innervation of the pelvis shows great convergence, demonstrating the existence of extensive cross-system, viscero-visceral interactions within the CNS, which, while organized for coherent bodily functioning, serve as a substrate by which pathophysiology in one organ can influence physiology and responses to pathophysiology in other organs (24). Some cross-system effects reported in the literature include bladder inflammation, reducing the rate of uterine contractions and the effects of drugs on the uterus (44) and colon inflammation, producing signs of inflammation in an otherwise healthy bladder and uterus. The pathophysiology of one pelvic organ influences the physiology of another is poorly understood, but improved knowledge and understanding of the convergence of peripheral and central innervation of the pelvis may have considerable clinical relevance.

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Conclusion. The rich and complex innervation of the bladder and genital organs, which enables their physiological function, appears also to be a potential substrate for neural pain. Perhaps pain results when autonomic innervation becomes ‘confused’. Figure 6: Effector organs making up the lower urinary tract (LUT). This is a representation of the female LUT. In the male, the prostate gland is situated around the external urethral sphincter. (With permission of Mr. Vinal Kalsi).

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Figure 7: Subtraction cystometry showing typical bladder function.

Pabd = intra-abdominal pressure measured with a rectal catheter; Pves = measured intravesical pressure; Pdet = detrusor pressure; Pdet = Pves-Pabd; Vinfus = infusion volume, 50 mL/min. The detrusor pressure remains less than 10 cmH20 until the first desire to void (FD) is reached, which is accompanied by a small rise in the pressure tracing. There is a concomitant rise in vesical pressure; however, there is no rise in intra-abdominal pressure. The pressure rise is due to contraction of the detrusor; however, it is small due to the compliant properties of the bladder. The normal desire to void (ND) is soon accompanied by cystometric capacity (about 500mL), at which time a void will be initiated. The undulations seen on the traces are a result of interference due to respiration.

4.3 Sexual dysfunction in men and women Various classifications of sexual dysfunction have been proposed, the most recent being one which included hypoactive sexual desire, or disorders of sexual desire, sexual arousal, orgasms or sexual pain (45). Many of these disorders are common amongst the general population: the Male Massachusetts study showing an increasing prevalence of ED with age so that of a group of men aged 60-70 almost 60% had ED to a greater or lesser extent (46). The prevalence of FSD has been estimated to be between 25%-63%, the figure depending on the definition used and population studies. Amongst groups of patients with neurological disease the prevalence of all types of disorder is even higher, although precise figures are not known. Neurological causes of sexual dysfunction include cortical disease, spinal cord trauma, stroke, epilepsy, multiple sclerosis, radical pelvic surgery and many more conditions. As the aetiology is diverse, so is the pathophysiology with damage to the thoraco-lumbar outflow in men during extensive surgery affecting ejaculation to damage of the hypothalamus and pituitary, following head injury, resulting in hypopituitarism and a concomitant de-sensitisation of the genital region. The treatment in men and women with neurological or non-neurological disease includes pelvic floor exercises and electrical stimulation feedback with cognitive therapy. Male sexual dysfunction is discussed in detail within these guidelines. Female sexual dysfunction is less easy to treat, but is affected by problems in the male, and it is now recommended that evaluation of the female should be addressed within the context of the couple in a sexual

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medicine clinic. Identifying and treating general medical conditions is vital to the effective management of both men and women. In addition to neurological related dysfunction in young women, pelvic floor dysfunction, as a consequence of childbirth, must be taken into account as the importance of the menopause in the older woman. Despite the fact that hormone replacement therapy has been used extensively and effectively, there is still a small sub-set of women in whom this is not enough. In this group the libido is affected greatly and the use of testosterone products have been found to be important. Pharmacotherapy, like the PDE-5 inhibitors in men, has not been found to be useful in women.

4.4

References

1.

de Groat WC, Booth AM. Physiology of the urinary bladder and urethra. Ann Intern Med 1980;92 (2 Pt 2):312-5. http://www.ncbi.nlm.nih.gov/pubmed/6243894 de Groat WC, Lalley PM. Reflex firing in the lumbar sympathetic outflow to activation of vesical afferent fibres. J Physiol 1972;226(2):289-309. http://www.ncbi.nlm.nih.gov/pubmed/4508051 Janig, W and Morrison, JF, Functional properties of spinal visceral afferents supplying abdominal and pelvic organs, with special emphasis on visceral nociception. Prog Brain Res 1986;67:87-114. http://www.ncbi.nlm.nih.gov/pubmed/3823484 Habler HJ, Janig W, Koltzenburg M. Activation of unmyelinated afferent fibres by mechanical stimuli and inflammation of the urinary bladder in the cat. J Physiol 1990;425:545-62. http://www.ncbi.nlm.nih.gov/pubmed/2213588 Fall M, Lindstrom S, Mazieres L. A bladder-to-bladder cooling reflex in the cat. J Physiol 1990;427:281-300. http://www.ncbi.nlm.nih.gov/pubmed/2213600 Gosling JA, Dixon JS. Sensory nerves in the mammalian urinary tract. An evaluation using light and electron microscopy. J Anat 1974;117(Pt 1):133-44. http://www.ncbi.nlm.nih.gov/pubmed/4844655 Smet PJ, Moore KH, Jonavicius J. Distribution and colocalization of calcitonin gene-related peptide, tachykinins, and vasoactive intestinal peptide in normal and idiopathic unstable human urinary bladder. Lab Invest 1997;77(1):37-49. http://www.ncbi.nlm.nih.gov/pubmed/9251677 Avelino A, Cruz C, Nagy I, Cruz F. Vanilloid receptor 1 expression in the rat urinary tract. Neuroscience 2002;109(4):787-98. http://www.ncbi.nlm.nih.gov/pubmed/11927161 Yiangou Y, Facer P, Ford A, Brady C, Wiseman O, Fowler CJ, Anand P. Capsaicin receptor VR1 and ATP-gated ion channel P2X3 in human urinary bladder. BJU Int 2001;87(9):774-9. http://www.ncbi.nlm.nih.gov/pubmed/11412212 Birder LA, Kanai AJ, de Groat WC, Kiss S, Nealen ML, Burke NE, Dineley KE, Watkins S, Reynolds IJ, Caterina MJ, Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. Proc Natl Acad Sci USA 2001;98(23):13396-401. http://www.ncbi.nlm.nih.gov/pubmed/11606761 Lazzeri M, Vannucchi G, Zardo C, Spinelli M, Beneforti P, Turini D, Faussone-Pellegrini MS. Immunohistochemical evidence of vanilloid receptor 1 in normal human urinary bladder urothelium. Eur Urol 2004;46(6):792-9. http://www.ncbi.nlm.nih.gov/pubmed/15548449 Gabella G, Davis C. Distribution of afferent axons in the bladders of rats. J Neurocytol 1998;27(3): 141-55. http://www.ncbi.nlm.nih.gov/pubmed/10640174 Wiseman OJ, Fowler CJ, Landon DN. The role of the human bladder lamina propria myofibroblast. BJU Int 2003;91(1):89-93. http://www.ncbi.nlm.nih.gov/pubmed/12614258 Burnstock G. Innervation of bladder and bowel. Ciba Found Symp 1990;151:2-18; discussion 18-26. http://www.ncbi.nlm.nih.gov/pubmed/1977565 Kavia RB, Dasgupta R, Fowler CJ. Functional imaging and the central control of the bladder. J Comp Neurol 2005;493(1):27-32. http://www.ncbi.nlm.nih.gov/pubmed/16255006 Athwal BS, Berkley KJ, Hussain I, Brennan, A, Craggs M, Sakakibara R, Frackowiak RS, Fowler CJ. Brain responses to changes in bladder volume and urge to void in healthy men. Brain 2001;124(Pt 2): 369-77. http://www.ncbi.nlm.nih.gov/pubmed/11157564

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16.

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24. 25.

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Matsuura S, Kakizaki H, Mitsui T, Shiga T, Tamaki N, Koyanagi T. Human brain region response to distention or cold stimulation of the bladder: a positron emission tomography study. J Urol 2002;168(5):2035-9. http://www.ncbi.nlm.nih.gov/pubmed/12394703 Blok BF, Willemsen AT, Holstege G. A PET study on brain control of micturition in humans. Brain 1997;120(Pt 1):111-21. http://www.ncbi.nlm.nih.gov/pubmed/9055802 Blok BF, Sturms LM, Holstege G. Brain activation during micturition in women. Brain 1998; 121(Pt 11):2033-42. http://www.ncbi.nlm.nih.gov/pubmed/9827764 Blok BF. Central pathways controlling micturition and urinary continence. Urology 2002;59 (5 Suppl 1):13-7. http://www.ncbi.nlm.nih.gov/pubmed/12007517 Wyndaele JJ. Normality in urodynamics studied in healthy adults. J Urol 1999;161(3):899-902. http://www.ncbi.nlm.nih.gov/pubmed/10022710 Uvelius B, Gabella G. Relation between cell length and force production in urinary bladder smooth muscle. Acta Physiol Scand 1980;110(4):357-65. http://www.ncbi.nlm.nih.gov/pubmed/7234441 Anaf V, Simon P, El Nakadi I, Fayt I, Buxant F, Simonart T, Peny MO, Noel JC. Relationship between endometriotic foci and nerves in rectovaginal endometriotic nodules. Hum Reprod 2000;15(8): 1744-50. http://www.ncbi.nlm.nih.gov/pubmed/10920097 Berkley KJ. A life of pelvic pain. Physiol Behav 2005;86(3):272-80. http://www.ncbi.nlm.nih.gov/pubmed/16139851 Akaishi T, Robbins A, Sakuma Y, Sato Y. Neural inputs from the uterus to the paraventricular magnocellular neurons in the rat. Neurosci Lett 1988;84(1):57-62. http://www.ncbi.nlm.nih.gov/pubmed/3347371 Berman JR, Adhikari SP, Goldstein I. Anatomy and physiology of female sexual function and dysfunction: classification, evaluation and treatment options. Eur Urol 2000;38(1):20-9. http://www.ncbi.nlm.nih.gov/pubmed/10859437 Levin RJ. VIP, vagina, clitoral and periurethral glans–an update on human female genital arousal. Exp Clin Endocrinol 1991;98(2):61-9. http://www.ncbi.nlm.nih.gov/pubmed/1778234 Whipple B, Komisaruk BR. Brain (PET) responses to vaginal-cervical self-stimulation in women with complete spinal cord injury: preliminary findings. J Sex Marital Ther 2002;28(1):79-86. http://www.ncbi.nlm.nih.gov/pubmed/11928182 Sjoberg NO. Dysmenorrhea and uterine neurotransmitters. Acta Obstet Gynecol Scand 1979;87:57-9. http://www.ncbi.nlm.nih.gov/pubmed/37691 Stjernquist M, Owman CO. Cholinergic and adrenergic neural control of smooth muscle function in the non-pregnant rat uterine cervix. Acta Physiol Scand 1985;124(3):429-36. http://www.ncbi.nlm.nih.gov/pubmed/4050475 Papka RE, Cotton JP, Traurig HH. Comparative distribution of neuropeptide tyrosine-, vasoactive intestinal polypeptide-, substance P-immunoreactive, acetylcholinesterase-positive and noradrenergic nerves in the reproductive tract of the female rat. Cell Tissue Res 1985 242(3):475-90. http://www.ncbi.nlm.nih.gov/pubmed/2416449 Shew RL, Papka RE, McNeill DL. Galanin and calcitonin gene-related peptide immunoreactivity in nerves of the rat uterus: localization, colocalization, and effects on uterine contractility. Peptides 1992;13(2):273-9. http://www.ncbi.nlm.nih.gov/pubmed/1384006 Sjoberg NO. New considerations on the adrenergic innervation of the cervix and uterus. Acta Obstet Gynecol Scand 1969;48 (Suppl 3):28+. http://www.ncbi.nlm.nih.gov/pubmed/5380821 Zoubina EV, Fan Q, Smith PG. Variations in uterine innervation during the estrous cycle in rat. J Comp Neurol 1998;397(4):561-71. http://www.ncbi.nlm.nih.gov/pubmed/9699916 Akerlund M. Vascularization of human endometrium. Uterine blood flow in healthy condition and in primary dysmenorrhoea. Ann N Y Acad Sci 1994;734:47-56. http://www.ncbi.nlm.nih.gov/pubmed/7978951

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36.

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Proctor ML, Latthe PM, Farquhar CM, Khan KS, Johnson NP. Surgical interruption of pelvic nerve pathways for primary and secondary dysmenorrhoea. Cochrane Database Syst Rev 2005(4):CD001896. http://www.ncbi.nlm.nih.gov/pubmed/16235288 Stjernquist M, Alm P, Ekman R, Owman C, Sjoberg NO, Sundler F. Levels of neural vasoactive intestinal polypeptide in rat uterus are markedly changed in association with pregnancy as shown by immunocytochemistry and radioimmunoassay. Biol Reprod 1985;33(1):157-63. http://www.ncbi.nlm.nih.gov/pubmed/4063437 Traurig H, Saria A, Lembeck F. Substance P in primary afferent neurons of the female rat reproductive system. Naunyn Schmiedebergs Arch Pharmacol 1984;326(4):343-6. http://www.ncbi.nlm.nih.gov/pubmed/6207443 Moustafa, FA, Changes in cholinergic and noradrenergic nerves in the pregnant and postpartum uterus of the albino rat and guinea pig. Acta Anat (Basel) 1988;132(4):310-6. http://www.ncbi.nlm.nih.gov/pubmed/3195314 Haase, EB, Buchman J, Tietz AE, Schramm LP. Pregnancy-induced uterine neuronal degeneration in the rat. Cell Tissue Res 1997;288(2):293-306. http://www.ncbi.nlm.nih.gov/pubmed/9082965 Thorbert G, Alm P, Owman,C, Sjoberg NO, Sporrong B. Regional changes in structural and functional integrity of myometrial adrenergic nerves in pregnant guinea-pig, and their relationship to the localization of the conceptus. Acta Physiol Scand 1978;103(2):120-31. http://www.ncbi.nlm.nih.gov/pubmed/676764 Alm P, Owman C, Sjoberg NO, Thorbert G. Uptake and metabolism of [3H]norepinephrine in uterine nerves of pregnant guinea pig. Am J Physiol 1979;236(5):C277-C285. http://www.ncbi.nlm.nih.gov/pubmed/443367 Wikland M, Lindblom B, Dahlstrom A, Haglid KG. Structural and functional evidence for the denervation of human myometrium during pregnancy. Obstet Gynecol 1984;64(4):503-9. http://www.ncbi.nlm.nih.gov/pubmed/6384845 Dmitrieva N, Johnson OL, Berkley KJ, Bladder inflammation and hypogastric neurectomy influence uterine motility in the rat. Neurosci Lett 2001;313(1-2):49-52. http://www.ncbi.nlm.nih.gov/pubmed/11684337 Levin RJ. The physiology of sexual arousal in the human female: a recreational and procreational synthesis. Arch Sex Behav 2002;31(5):405-11. http://www.ncbi.nlm.nih.gov/pubmed/12238607 Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetss Male Ageing Study. J Urol 1994;151(1):54-61. http://www.ncbi.nlm.nih.gov/pubmed/8254833

5 NEUROGENIC CONDITIONS 5.1

Introduction

It is clearly important for the patient to have been thoroughly examined by a urologist or gynaecologist and local pelvic pathology excluded. Once a structural cause has been eliminated, a neurological opinion is often sought, with the prime aim of the neurologist being to exclude any form of conus or sacral root pathology. MRI is the investigation of choice to show both neural tissue and surrounding structures. If all examinations and investigations fail to reveal an abnormality, the diagnosis is likely to be one of the focal pain syndromes. These are persistent or recurrent or episodic pains referred to specific pelvic organs in the proven absence of infection, malignancy or other obvious pathology (see Table 1). Although these are well-recognized conditions, their pathophysiology is not understood. However, it seems likely that the problems relate in some way to the combined visceral, autonomic and somatic innervation of the pelvic organs.

5.2 Pudendal nerve entrapment Chronic compression of the pudendal nerve in the ischiorectal fossa may result in a perineal pain located either anteriorly in the vagina or vulval region, or posteriorly in the anorectal region. The ICS has used the following definition, ‘perineal pain is felt: in the female, between the posterior fourchette (posterior lip of the introitus) and the anus, and in the male, between the scrotum and the anus’ (1). The pain may include unpleasant sensations of numbness or a burning sensation, and may be exacerbated by sitting and relieved by standing. Neurological examination of the perineum is normal. If tested,

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the sacral reflexes are present and anal sphincter tone is normal. Neurophysiological examination is said to be helpful is some cases; sacral reflex latency (using electrical stimulation of the dorsal nerve of the clitoris and recording muscle activity in the perineum) and the pudendal nerve distal motor latency using the St Marks Stimulator has been recommended. These investigations require specialist neurophysiological expertize. Pudendal nerve neuropathy is likely to be a probable diagnosis if the pain is unilateral, has a burning quality and is exacerbated by unilateral rectal palpation of the ischial spine, with delayed pudendal motor latency on that side only. However, such cases account for only a small proportion of all those presenting with perineal pain. Proof of diagnosis rests on pain relief following decompression of the nerve in Alcock’s canal and is rarely achieved. The value of the clinical neurophysiological investigations is debatable; some centres in Europe claim that the investigations have great sensitivity (1,2), while other centres, which also have a specialized interest in pelvic floor neurophysiology, have not identified any cases. Further information may be gained by a diagnostic nerve block or MRI investigation.

5.3 Other neurogenic conditions Other pelvic floor clinical neurophysiological investigations are more helpful in identifying changes of denervation and re-innervation. Lesions causing such disorders are usually associated with bladder and/or sexual dysfunction rather than isolated urogenital pain. A major defect of the clinical neurophysiological investigations currently available is that they examine mostly large myelinated nerve fibre function rather than the unmyelinated and small myelinated fibres, which subserve autonomic innervation, pelvic organ sensation and pain (3).

5.4

References

1.

Amarenco G, Kerdraon J. Pudendal nerve terminal sensitive latency: technique and normal values. J Urol 1999;161(1):103-6. http://www.ncbi.nlm.nih.gov/pubmed/10037379 Robert R, Prat-Pradal D, Labat JJ, Bensignor M, Raoul S, Rebai R, Leborgne J. Anatomic basis of chronic perineal pain: role of the pudendal nerve. Surg Radiol Anat 1998;20(2):93-8. http://www.ncbi.nlm.nih.gov/pubmed/9658526 Lee JC, Yang CC, Kromm BG, Berger RE. Neurophysiologic testing in chronic pelvic pain syndrome: a pilot study. Urology 2001;58(2):246-50. http://www.ncbi.nlm.nih.gov/pubmed/11489711

2.

3.

6. PELVIC FLOOR FUNCTION AND DYSFUNCTION 6.1

Introduction

The pelvic floor is made up of muscles and fascia. The muscles usually function as a composite, though the anterior and posterior components may act in isolation. The pelvic floor has three functions: support, contraction and relaxation.

6.2 Function In its resting state, the pelvic floor supports the bladder and the urethra in the anterior compartment, the uterus and the vagina in the middle compartment, and the rectum and the anus in the posterior compartment. The integrity of the support function depends on the anatomical position of the muscles, on the resting ‘tone’ and on the integrity of the fascia (1). As with all skeletal muscles, tone is maintained by the efferent nerve fibres, and may vary with hormonal status (menstrual cycle, pregnancy, and menopause). The support activated during a rise in intra-abdominal pressure is different from that at rest. When intra-abdominal pressure rises, the pelvic floor muscles must respond with a contraction occurring simultaneously or before the pressure rise. The latter is termed an anticipatory ‘response’ or feed-forward loop (2). Electromyography recordings show tonic motor unit activity at rest, with phasic recruitment of large motor units in response to coughing. A contraction of the pelvic floor muscles results in an inward movement of the perineum and an upward movement of the pelvic organs. In many situations, other muscles such as the abdominal muscles, the adductor muscles and the gluteal muscles also contract. There are two types of contraction that can be distinguished: a voluntary contraction, resulting from impulses arising in the cerebral cortex, and a reflex contraction. These contractions not only maintain support of the pelvic organs, they close the urethra, anus and vagina, thus avoiding loss of urine or stool, and affording women a defensive mechanism. Additionally, detrusor inhibition occurs in parallel with pelvic floor muscle contraction.

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A contraction of the pelvic floor muscles must have sufficient strength. Strength results from muscle capacity and neurogenic drive, reflected in the frequency of excitation and the number of activated motor units. An increase in muscle strength is achieved through the recruitment of more motor units. A contraction must be rapidly effective and remain so for a certain period (endurance). Pelvic floor contractions play an important role in sexual function. During the arousal phase, pelvic floor muscle contractions are used to increase vasocongestion. During the last phase of the sexual response cycle, a series of involuntary contractions is associated with the physical sensations of orgasm (3). Pelvic floor muscle relaxation results in a decrease or termination of the squeezing of the urethra, vagina and anus. The perineum and the pelvic organs return to their anatomical resting position. Pelvic floor muscle relaxation is the result of inhibition of tonically active motor units. Relaxation of the pelvic floor muscles is needed for voiding, defaecation and for sexual intercourse.

6.3

Dysfunction

Pelvic floor dysfunction should be classified according to ‘The standardisation of terminology of pelvic floor muscle function and dysfunction’ (4). This is an international multidisciplinary report from the ICS. As in all ICS standardization documents, this is based on the triad of symptom, sign and condition. Symptoms are what the patient tells you; signs are found by physical examination. By palpation of the pelvic floor muscles, the contraction and relaxation are qualified. The voluntary contraction can be absent, weak, normal or strong. The voluntary relaxation can be absent, partly or completely. The involuntary contraction and relaxation is absent or present. Based on these signs, pelvic floor muscles can be classified as follows: • non-contracting pelvic floor • non-relaxing pelvic floor • non-contracting, non-relaxing pelvic floor. • • • •

Based on symptoms and signs, the following conditions are possible: normal pelvic floor muscles overactive pelvic floor muscles underactive pelvic floor muscles non-functioning pelvic floor muscles.

• • •

An example is as follows: Symptom: pain in the perineal region Sign non-relaxing pelvic floor (no relaxation, neither voluntary nor involuntary) Condition: overactive pelvic floor muscles.

An underactive pelvic floor means that the muscles do not contract when they need to. In practice, this leads to incontinence of urine or stool. An overactive pelvic floor means that the pelvic floor muscles do not relax when they should. This may result in complaints like low flow rates and constipation (5). Another symptom of overactivity is CPP and more specific dyspareunia. Overactivity tends to develop over a protracted period, with many causes. In most cases, there is the problem of limited access to a toilet on demand, leading to postponement of voiding by contraction of the pelvic floor muscles. When they do eventually have the time to void, detrusor power is lacking. They start to use abdominal straining which results, through the guarding reflex, in contraction of the pelvic muscles (6). Why an overactive pelvic floor causes pain has only partly been elucidated (7). A muscle that is continuously contracting will ache. Nerves that pass through the pelvic floor may be compressed, and vessels to the penis and scrotum may be obstructed. Both mechanisms will lead to pelvic pain. A contracting pelvic floor will increase afferent input to the sacral spinal cord, the pons and the cerebral cortex. In response, the CNS may modify efferent signals to the pelvis. This change in efferent activity may further aggravate the situation (8).

6.4

Myofascial trigger points

Repeated or chronic muscular overload can activate trigger points in the muscle. Trigger points are defined as hyperirritable spots associated with a hypersensitive palpable nodule in a taut band (9). Trigger points are painful on compression and give rise to characteristic referred pain and motor dysfunction. They prevent full lengthening of the muscles, they weaken the muscle and they lead to pain that is very recognisable for the patient. Pain as a result of these trigger points is aggravated by specific movements and alleviated by certain positions. Patients know what activities and postures influence the pain. Trigger points can be located within the pelvic floor muscle (10). In a case of pelvic floor muscle trigger points, a patient will sit down cautiously,

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often on one buttock. Rising after a period of sitting will cause pain. Pain will be aggravated by pressure on the trigger point (e.g. pain related to sexual intercourse). Pain will also get worse after sustained or repeated contractions (e.g. pain related to voiding or defecation). On physical examination, trigger points can be palpated and compression will give local and referred pain. In patients with CPP, trigger points are often found in muscles related to the pelvis like abdominal, gluteal and piriformis muscle.

6.5

Therapy

Treating pelvic floor overactivity should be considered in the management of CPP (11). There are a number of methods, taught by specialized physiotherapists, which can be used to improve the function and co-ordination of the pelvic floor muscles. The use of biofeedback by means of pelvic floor muscle electromyography should be considered because it might help the patient to understand the dysfunction of the pelvic floor muscles. This understanding will improve the result of the treatment. Central trigger points are treated by stretching the muscle, which inactivates them. However, trigger points lying in the attachment of the muscle to the bone respond better to direct manual therapy. Muscle exercises are helpful, e.g. voluntary contractions followed by complete relaxation. Pressure on the trigger points and subsequent release is also effective (12,13). Stretching of the muscle will be more effective after pain relief by direct pressure on the trigger point. Injecting the trigger points with a local anaesthetic will show that the trigger points are really causing the pain; its will give an acute relief of pain and will unblock the muscle so that stretching becomes possible.

6.6

References

1.

Olsen AL, Smith VJ, Bergstrom JO, Colling JC, Clark AL. Epidemiology of surgically managed pelvic organ prolapse and urinary incontinence. Obstet Gynecol 1997;89(4):501-6. http://www.ncbi.nlm.nih.gov/pubmed/9083302 Constantinou CE, Govan DE. Spatial distribution and timing of transmitted and reflexly generated urethral pressures in healthy women. J Urol 1982;127(5):964-9. http://www.ncbi.nlm.nih.gov/pubmed/7201031 Epstein M. Physiology of sexual function in women. In: Epstein M, ed. Clinics in obstetrics and gynaecology. London: WB Saunders, 1980; p. 7. Messelink EJ, Benson T, Berghmans B et al. Standardisation of terminology of pelvic floor muscle function and dysfunction: report from the pelvic floor clinical assessment group of the International Continence Society. 2005;24, pp. 374-380. https://www.icsoffice.org/ASPNET_Membership/Membership/Portal.aspx?RedirectUrl=documents/ Search/Index.asp Kaplan SA, Santarosa RP, D’Alisera PM, Fay BJ, Ikeguchi EF, Hendricks J, Klein L, Te AE. Pseudodyssynergia (contraction of the external sphincter during voiding) misdiagnosed as chronic nonbacterial prostatitis and the role of biofeedback as a therapeutic option. J Urol 1997;157(6): 2234-7. http://www.ncbi.nlm.nih.gov/pubmed/9146624 Messelink EJ. The overactive bladder and the role of the pelvic floor muscles. BJU Int 1999;83(Suppl 2):31-5. http://www.ncbi.nlm.nih.gov/pubmed/10210602 Howard FM. Pelvic floor pain syndrome. In: Howard FM, ed. Pelvic Pain. Diagnosis and Management. Philadelphia: Lippincott Williams & Wilkins, 2000; pp. 429-432. Zermann DH, Ishigooka M, Doggweiler R, Schmidt RA. Chronic prostatitis: a myofascial pain syndrome? Infect Urol 1999;12:84-6. Carter J.E. Abdominal wall and pelvic myofascial trigger points. In: Howard FM, ed. Pelvic Pain. Diagnosis and Management. Lippincott Williams & Wilkins: Philadelphia, 2000, pp. 314-358 Slocumb JC. Neurological factors in chronic pelvic pain: trigger points and the abdominal pelvic pain syndrome. Am J Obstet Gynaecol 1984;149(5):536543. http://www.ncbi.nlm.nih.gov/pubmed/6234807 Glazer HI, Rodke G, Swencionis C, Hertz R, Young AW. Treatment of vulvar vestibulitis syndrome with electromyographic biofeedback of pelvic floor musculature. J Reprod Med 1995;40:283290. http://www.ncbi.nlm.nih.gov/pubmed/7623358 Anderson RU, Wise D, Sawyer T, Chan C. Integration of myofascial trigger point release and paradoxical relaxation training treatment of chronic pelvic pain in men. J Urol 2005;174(1):155160. http://www.ncbi.nlm.nih.gov/pubmed/15947608 Srinivasan AK, Kaye JD, Moldwin R. Myofascial dysfunction associated with chronic pelvic floor pain: management strategies. Curr Pain Headache Rep 2007;11(5):359-64. http://www.ncbi.nlm.nih.gov/pubmed/17894926

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7. PSYCHOLOGICAL FACTORS IN PERSISTENT CHRONIC PELVIC PAIN 7.1

Introduction

This section describes the evidence for psychological factors, which play a part in the development or maintenance of persistent pelvic pain, in adjustment to pain, and in treatments including psychologically-based treatments. The function of pain, particularly acute pain, is to demand action to stop or minimize damage, and to protect the injured part to promote healing. When pain persists without ongoing damage or disease, or after the damage has healed, it appears to have no such function. However, it can disrupt daily life and cause distress, particularly since the person with pain tends to use the acute pain model, and to fear damage, disease, and prolonged suffering. Cognitive and emotional processes are integral in pain processing (1,2). Psychological and social factors are involved as risk factors for the development of persistent pain from acute pain, in adaptation to pain, and in the decision to seek and to adhere (or not) to recommended treatment for the pain.

7.2 Psychological models of pain A fully integrated model of pain, as described above, with changes in excitatory and inhibitory mechanisms at peripheral and central level, and changes in cortical and subcortical processing of pain, but not defined by tissue damage or disease severity, does not correspond well with the model of somatization, or somatoform pain. This model assumes that pain can be partitioned into distinct biological and psychological processes which, added together, constitute the presenting complaint, and that absence of significant physical signs constitutes evidence for substantial psychological causation (3,4). This has been a particularly prominent model in pelvic pain, at least in women. In fact, multiple models co-exist, often poorly specified. One model, unsubstantiated by psychiatric diagnostic systems, rules that pain is inauthentic if it is not supported by clinical signs and that the pain is therefore a covert expression of distress or psychological disorder. This model relies on a dualism, which has no place in scientific medicine and is unacceptable to most patients. Another model, commoner in psychodynamically informed systems, constructs pain (perhaps without physical signs, but not defined by their absence) as an expression of an unconscious conflict or source of distress. Several models are compatible with our understanding of physiological processes as it has developed since Melzack and Wall’s (1965) work (1). Psychophysiological reactivity, built on stress models, describes the activation of systems for defence against physical or psychological stress. Prolonged stress leads to repeated alerting and depletion of systems involved. This was demonstrated by Flor et al. (1992) (5), using electromyography in back muscles, in response to psychological/social stressors. This may be a mechanism for the production of pain in pelvic floor muscles, even if it is not the primary cause of pelvic pain. Pelvic floor overactivity is now the subject of investigation and treatment attempts (see Sections 2.5 and 6.5). In addition, Link et al. (2007) (6) have proposed an association between trauma (sexual and physical abuse in childhood) and bladder activity and urinary symptoms, presumably mediated by stress mechanisms. The cognitive-behavioural model classically took pain as a starting point, and described modulation of the experience of pain, and reaction to it, in terms of cognition, emotion and behaviour. There are reliable associations between certain beliefs or types of belief, and associated behaviour and/or emotions, including extensive evidence for the importance of psychological factors in determining the level of pain experienced, levels of disability and restriction due to pain, levels of distress, and extent of healthcare use (2,7), demonstrated either in specific pain problems, such as back pain or fibromyalgia, or for mixed persistent pain populations, but with few studies in pelvic pain populations. Psychological factors are better researched and described than social factors, and both suffer from overlapping constructs which neither fall into clear hierarchies of organization nor map well on to processes and pathways in the brain. Among the better established ones are attention (8) and fear and associated avoidance patterns (9). The cognitive and behavioural model is compatible with the psychophysiological reactivity model. More recently, it has been extended by reference to neurotransmitters common to pain or to other symptoms, including urinary symptoms (10) and to mood pathways; and to dysregulation across multiple systems producing a range of ‘medically unexplained symptoms’, which concomitantly occur with mood disorders at a higher level than chance in individuals and in their first-degree relatives (11,12). Psychological models, particularly cognitive and behavioural models, when integrated with a biomedical model, are described as biopsychosocial models.

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7.3

Methodology

Both PubMed and PsychInfo were searched to access trials published in psychology journals not covered by medical databases, with a search covering the last 10 years, since psychological trials tend to take longer to run and to reach publication than medical and other clinical trials. The Cochrane database was also searched.

7.4 Psychological factors in assessment of pelvic pain A careful review by Savidge and Slade (1997) (13) of CPP in women identifies as problematic the notion that women without physical findings to which pain can be causally attributed differ in psychological characteristics from women with physical findings. They critically examine the methodologies of studies purporting to show such differences, and the bias introduced by sampling and by unsuitable measures; they argue for better methodology in replication of these studies, particularly those sampling life events, and for greater use of idiographic methods. However, the report of anxiety, depression, and sexual problems is sufficiently common for these to be important in assessment and in planning treatment. Distress, described in the patient’s terms or within a psychodiagnostic framework, is best understood in the context of pain and of the meaning of pain to the individual. 7.4.1 Psychological risk factors in the development of pelvic pain and adaptation to it There is one systematic review (14) of risk factors for CPP in women: there appears to be no equivalent systematic review of pelvic pain in men. For non-cyclical pelvic pain in women, Latthe et al. drew on 40 studies (n = 20,040). Of the 48 risk factors included in the studies, pain was associated with (biomedical factors) pelvic pathology, miscarriage, and heavy menstrual flow; and (psychological factors): • lifetime drug and alcohol abuse (OR 4.61, 95%; CI 1.09-19.38) • sexual or physical abuse (OR 1.51-3.49) • psychological problems: anxiety (OR 2.28; 95% CI 1.41-3.70); depression (OR 2.69; 95% CI 1.863.88); multiple somatic problems (OR 4.83; 95% CI 2.50-9.33 and OR 8.01; 95% CI 5.16-12.44): the terms ‘hysteria’ and ‘psychosomatic symptoms’ are used but can best be understood as multiple somatic symptoms not associated with or indicative of any serious disease process. Personality variables, length of education, and marital status were not reliably associated with pelvic pain in women. Interrelationships, such as between history of sexual abuse and depression, for instance, cannot be disentangled from the studies available. A meta-analysis (15) confirms the reported association in retrospective studies between the report of childhood sexual abuse by adults and persistent pain; often this concerns childhood sexual abuse and pelvic pain (16). However, these studies are retrospective; interestingly, Latthe et al. (14) found poor quality papers were more likely to report this association than better quality ones. The only prospective investigation into the relationship between childhood sexual abuse, physical abuse, or neglect, and ‘medically unexplained pain’ including pelvic pain, used court records concerning sexual abuse before the age of 11 to establish a definite history, comparing those with such a history with demographically matched classmates (17). It concluded that physically and sexually abused individuals were not at risk for increased pain symptoms. Although those individuals with pain problems as adults were more likely to report earlier sexual or physical abuse or neglect, this did not correspond with the established early history of abuse. The correlation between childhood victimization and pain symptoms is less straightforward than previously thought, and may be more about retrospective explanatory frameworks used by women for pain which is ‘medically unexplained’ than about occurrence or extent of abuse. In particular, findings of depression and/or post-traumatic stress disorder in adult women reporting childhood sexual abuse are common, with or without pain. Disentangling the influences and inferences requires prospective study or suitable comparison groups. See Savidge and Slade (1997) (13) for an excellent critique. Within pelvic pain populations, worthwhile studies can be done without comparison. For example, Poleshuck et al. (2005) (18) found that, in women with pelvic pain attending a clinic, the report of physical or sexual abuse in childhood was associated with greater psychological distress than in women without, but there were no differences in pain experience, or physical or social function. In summary, women with pelvic pain often have other ‘medically unexplained’ symptoms, and current or a lifetime anxiety and depression disorder; they may have a history of physical or sexual abuse in childhood but the significance of this for pelvic pain is unclear. The report of pelvic pain appears to be more common after rape (19), and recent sexual assault should be considered, particularly if the woman expresses distress. No studies were found of sexual or physical abuse in childhood and pelvic pain in men. 7.4.2 Anxiety Findings of anxiety are common in samples of women with CPP (20), as are above-threshold scores on screening instruments for post-traumatic stress disorder (21). In the latter study, higher post-traumatic stress disorder scores were associated with and contributed

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up to 10% unique variance to poorer health status and more surgery visits. However, anxiety is likely to refer to pain being caused by fears of missed pathology, particularly cancer, and to uncertainties about treatment and the likely prognosis, treated or untreated. Medical consultations and investigations are particular sources of anxiety, but also a focus of hopes of progress towards resolution of the problem. In a study of women with pelvic pain (22), laparoscopy was followed by a substantial reduction in pain, the size of which was predicted by beliefs about pain and about the seriousness of the woman’s condition. Women with higher levels of pain at baseline and higher estimates of the seriousness of their condition reported greater pain reduction. However, anxieties are not only about the possibility of serious pathology. Stones et al. (2000) reported that women with pelvic pain usually understand that nothing life-threatening has been or is likely to be found, but still want a diagnosis or explanation of the pain (23). Evidence from in-depth studies of women with pelvic pain underline the fact that they want to be assessed in terms of the effects of pain on their lives, to feel understood and have the pain legitimized. They hope for an explanation, and reassurance about the cause of pain and about the possibilities of treating it (24). When they feel disbelieved, and the emphasis is on the absence of physical findings rather than on their experience of pain, they are likely to feel invalidated and to drop out of treatment dissatisfied (25). There appear to be no similar studies of men’s concerns when consulting for persistent pelvic pain. 7.4.3 Depression and catastrophizing Depression or depressed mood is also commonly found in both men and women with persistent pelvic pain (10), and has been reliably associated with urological symptoms (not necessarily painful) (10). However, this association may be no greater than in other persistent pain groups (26), when the comparison group is from a pain sample not from the healthy population. In addition, there is an important methodological question to be asked of any study using diagnostic or standard assessment instruments, which is how symptoms have been attributed, many of which in depression are understood as neurovegetative signs. The core of clinical depression is negativity about the self. This describes relatively few people with persistent pain, who characteristically state that it is pain, not the self, at the base of their problem (27). Stones et al. (2000) suggested that ‘psychological distress may be a consequence and not a cause of persistent pain: while identification of depression is important as part of treatment, caution is required before attribution of causality’ (p. 416) (23). Psychological factors contributing to adjustment to CPP/prostatitis in men was investigated in a large North American cohort study (28). Overall pain severity, sensory and affective aspects of pain was predicted by catastrophizing, particularly the helplessness dimension; pain distress was also predicted by depression. Impact of pain on activity was predicted by urinary symptoms, pain, and taking pain-contingent rest. An earlier study (28) has shown the importance of pain and depression for predicting lower quality of life in men with chronic prostatitis/pelvic pain. 7.4.4 Impact of pain The impact of pain has been investigated almost entirely in terms of sexual problems. Women with pelvic pain reported these at a higher rate than did patients with other chronic pain disorders in a small UK study (29), with most reporting loss of interest in sex, dyspareunia, and pain following sexual intercourse. A much larger sample of women seeking healthcare, three-quarters for pelvic pain, yielded significantly lower quality of life scores than age-sex norms and widespread dissatisfaction with sexual activities, which was attributed to the pelvic problems (30). A small study of men with CPP (31) showed that pain severity predicted poorer sexual functioning, although this was less important than relationship variables. There are short measures available to assess the impact of pain on the patient’s life. The Brief Pain Inventory (www.mdanderson.org/pdf/bpisf.pdf) consists of four 0 to 10 numerical scales for pain (current, average, worst, least) and seven scales for interference with specific aspects of life: general activity, mood, walking ability, normal work, relationships with other people, sleep, and enjoyment of life (32). A higher total score indicates greater pain and interference by pain with life. The EuroQoL is a quality-of-life scale (www.euroqol.org) available in various European languages and free for non-commercial use (33). It provides questions asking about mobility, self-care, pain, usual activities, and psychological status. There are also two questions on the impact of urinary symptoms and one on quality of life within the NIH Chronic Prostatitis Symptom Scale, CPSI (34).

7.5 Summary: assessment recommendations (Table 13) A psychologist (or equivalent) is not required for this level of assessment, but access to regular discussion with a psychologist enables the clinician to interpret better the results of assessment.

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7.5.1 Anxiety It is important to obtain the patient’s view of what is wrong or of what the patient is worried might be causing pain and other symptoms. Investment in establishing a trusting therapeutic relationship with the patient pays off when these questions are asked. Howard et al. (2003) suggest asking the patient, ‘what do you believe or fear is the cause of your pain?’ (35). Investigations and results of examination should be explained clearly, in terms of what they can show, what they did or didn’t show, and how this helps the investigations, attempts at diagnosis, or plans for treatment. This requires an adequate model of pain. Brief reassurance alone provides (at best) short-term relief of anxiety, after which the patient returns to seek help with the problem and the anxiety. 7.5.2 Depression If the patient admits a depressed mood and attributes it to pain, it may be that the patient is interpreting information about and experience of pain and other symptoms in catastrophic ways. Good information can counteract this (as in anxiety). It may also be that the pain has had a serious impact on the patient’s life; roles and satisfactions are lost because of pain, but can return with effective treatment. Encouragement to consider how to recover valued activities, with or without some pain relief, is helpful but the patient may require advice on how to do this from a pain management team. 7.5.3 Sexual and physical abuse in childhood It is important to consider the possibility of physical and sexual abuse when taking the history, but disclosure can be difficult before a therapeutic relationship is established. It is not clear that pain, which the patient attributes to childhood sexual or physical abuse, should be managed any differently. Any disclosure of current physical or sexual abuse should be referred immediately to appropriate health, social or welfare services.

7.6 Psychological factors in treatment of pelvic pain (Table 14) Untreated, there is a significant likelihood of symptom improvement. A follow-up study of women with pelvic pain referred to a clinic showed that 25% reported recovery (nearly half of them total recovery) over the 3 to 4 intervening years. However, neither pain nor distress at baseline, nor intervention received, was found to be associated with recovery (36). Other sections cover the various physical (surgical, pharmacological, physiotherapeutic) interventions for male and female pelvic pain, and their outcomes. Psychological interventions may be directed: 1. At the pain itself, with the intended outcome of pain reduction and consequent reduction of impact of pain on life, or; 2. At adjustment to pain, with the intended outcome of improved mood and function and reduced healthcare use, with or without pain reduction. The first category of interventions includes relaxation and biofeedback methods of controlling and decreasing pain by reducing muscle tension. Such methods are being applied to pelvic floor retraining, both in men (37,38) and women, sometimes alongside other physical therapies (see Section 6.5). The only RCT has been of a specific type of cognitively enhanced physical therapy applied to overall muscle tension, not to the pelvic floor. This Norwegian study (39) tested ‘mensendieck somatocognitive therapy’ combined with normal gynaecological treatment versus gynaecological treatment alone in women with CPP. Pain was reduced by 50% and motor function improved by 10 hours of physical therapy, with particular attention to tension and relaxation, and the thoughts and emotions that interfere with balanced posture and movement. In the second category of interventions (see above), multicomponent pain management, involving education, physical retraining, behavioural change and increasing activity, relaxation, and cognitive therapy, is often applied to mixed groups of chronic pain patients, including those with pelvic pain, but there have been no RCTs of pelvic pain groups. There is a systematic review and meta-analysis (40), showing good outcome for mixed or back pain groups across pain experience, mood, coping, and activity. There is no reason to believe this does not apply to pelvic pain patients, but a trial of pelvic pain management alone is lacking. The Cochrane database holds one systematic review and meta-analysis of treatments for pelvic pain, excluding pain due to endometriosis, irritable bowel syndrome, and chronic pelvic inflammatory disease (41). Treatment inclusion was broad: medical, surgical, physical, psychological, lifestyle, and complementary and alternative. Outcomes were mainly pain scores, quality of life and use of resources, including health care resources. This review, updated in 2005, includes 14 treatment trials covering pharmacotherapy; surgery; chiropractic; magnet therapy; counselling, psychoeducation, reassurance, and emotional disclosure; and a multicomponent pain management programme. Most trials were small, so the review covers 1,133 patients in all. Nine were of good methodological quality, but outcomes were mainly change in pain and other symptoms, with few including scales for mood (2), pain beliefs (1) or impact of pain (2). From a psychological point of view, a minority of the trials in the Cochrane systematic review is of interest. The authors conclude in favour of educational counselling combined with ultrasound scan, which

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improved pain and mood; and a multidisciplinary rehabilitative approach, including surgery, pharmacotherapy, physiotherapy, and psychosocial intervention, which improved function but not pain. A selective serotonin reuptake inhibitor antidepressant made no improvement in pain but improved function. Consultation using a photograph taken during laparoscopy had no effect; emotional disclosure (a stress reduction method) through writing brought about very small improvement in some pain scores. It is regrettable that outcome measures correspond relatively poorly between studies with broadly similar aims, i.e. to restore the patient to a more normal lifestyle and better physical and psychological health. In the systematic review, the outcomes of pharmacotherapy trials and surgical and physical therapy trials are percentage pain reduction, self-rated pain score, physician-rated pain, and symptom scores, urinary measures such as peak flow rate (for persistent pelvic pain in men), pelvic tenderness (women); and uptake of further treatment following the trial treatment. A few studies included quality of life, but none measured mood change. Mood change is a particular issue since, intentionally or not, any intervention, and even a good consultation can bring about cognitive, emotional, and/or behavioural change. Enabling the patient to understand what is causing the pain, and therefore the implications of the pain for everyday life and longerterm life goals, can be a major influence on the patient’s successful management of pain. Furthermore, if all treatments sampled the same domains of pain in their evaluation, comparison across treatments, by medical personnel and by patients, would be more easily achieved (42). Table 13: Psychological factors in the assessment of CPP Assessment LE GR • Anxiety about cause of pain:’ 1a C • ‘Are you worried about what might be causing your pain? • Depression attributed to pain: 1a C ask ‘How has the pain affected your life?’ ‘How does the pain make you feel emotionally?’ • Multiple physical symptoms/ 1a C general health • History of sexual or physical 1a C abuse LE = level of evidence; GR = grade of recommendation.

Comment Studies of women only: men’s anxieties not studied Studies of women only: men’s anxieties not studied

Current/recent abuse may be more important

Table 14: Treatment factors in the management of CPP Treatment LE GR • Tension-reduction; relaxation, 1b A for pain reduction • Multidisciplinary pain (1a) (A) management for well-being LE = level of evidence; GR = grade of recommendation.

Comment Relaxation +/- biofeedback +/physical therapy; mainly male pelvic pain Pelvic pain patients treated within larger group: no specific pelvic pain trials

7.7

References

1.

Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965;150(699):971-9. http://www.ncbi.nlm.nih.gov/pubmed/5320816 Chapman CR, Gavrin J. Suffering: the contributions of persistent pain. Lancet 1999;353(9171):2233-7. http://www.ncbi.nlm.nih.gov/pubmed/10393002 Grace VM. Pitfalls of the medical paradigm in chronic pelvic pain. Baillieres Best Pract Res Clin Obstet Gynaecol 2000;14(3):525-39. http://www.ncbi.nlm.nih.gov/pubmed/10962640 Sharpe M, Carson A. ‘Unexplained’ somatic symptoms, functional syndromes, and somatization: do we need a paradigm shift? Ann Intern Med 2001;134(9 Pt 2):926-30. http://www.ncbi.nlm.nih.gov/pubmed/11346330 Flor H, Birbaumer N, Schugens MM, Lutzenberger W. Symptom-specific psychophysiological responses in chronic pain patients. Psychophysiol 1992;29:452-60. http://www.ncbi.nlm.nih.gov/pubmed/1410176

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Link CL, Lutfey KE, Steers WD, McKinlay JD. Is abuse causally related to urologic symptoms? Results from the Boston Area Community Health (BACH) Survey. Eur Urol 2007;52(2):397-406. http://www.ncbi.nlm.nih.gov/pubmed/17383083 Keefe FJ, Rumble ME, Scipio CD, Giordano LA, Perri LM. Psychological aspects of persistent pain: current state of the science. J Pain 2004;5(4):195-211. http://www.ncbi.nlm.nih.gov/pubmed/15162342 Eccleston C, Crombez G. Pain demands attention: a cognitive-affective model of the interruptive function of pain. Psychol Bull 1999;125(3):356-66. http://www.ncbi.nlm.nih.gov/pubmed/10349356 Vlaeyen JW, Linton SJ. Fear–avoidance and its consequences in chronic musculoskeletal pain: a state of the art. Pain 2000;85(3):317-32. http://www.ncbi.nlm.nih.gov/pubmed/10781906 Fitzgerald MP, Link CL, Litman HJ, Travison TG, McKinlay JB. Beyond the lower urinary tract: the association of urological and sexual symptoms with common illnesses. Eur Urol 2007;52(2):407-15. http://www.ncbi.nlm.nih.gov/pubmed/17382458 Schur EA, Afari N, Furberg H, Olarte M, Goldberg J, Sullivan PF, Buchwald D. Feeling bad in more ways than one: comorbidity patterns of medically unexplained and psychiatric conditions. J Gen Intern Med 2007;22(6):818-21. http://www.ncbi.nlm.nih.gov/pubmed/17503107 Warren JW, Jackson TL, Langenberg P, Meyers DJ, Xu J. Prevalence of interstitial cystitis in firstdegree relatives of patients with interstitial cystitis. Urology 2004;63(1):17-21. http://www.ncbi.nlm.nih.gov/pubmed/14751339 Savidge CJ, Slade P. Psychological aspects of chronic pelvic pain. J Psychosom Res 1997;42(5): 433-44. http://www.ncbi.nlm.nih.gov/pubmed/9194016 Latthe P, Mignini L, Gray R, Hills R, Khan K. Factors predisposing women to chronic pelvic pain: systematic review. BMJ 2006;332(7544):749-55. http://www.ncbi.nlm.nih.gov/pubmed/16484239 Davis DA, Luecken LJ, Zautra AJ. Are reports of childhood abuse related to the experience of chronic pain in adulthood? A meta-analytic review of the literature. Clin J Pain 2005;21(5):398-405. http://www.ncbi.nlm.nih.gov/pubmed/16093745 Hilden M, Schei B, Swahnberg K, Halmesmaki E, Langhoff-Roos J, Offerdal K, Pikarinen U, Sidenius K, Steingrimsdottir T, Stoum-Hinsverk H, Wigma B. A history of sexual abuse and health: a Nordic multicentre study. BJOG 2004;111(10):1121-7. http://www.ncbi.nlm.nih.gov/pubmed/15383115 Raphael KG, Widom CS, Lange G. Childhood victimization and pain in adulthood: a prospective investigation. Pain 2001;92(1-2):283-93. http://www.ncbi.nlm.nih.gov/pubmed/11323150 Poleshuck EL, Dworkin RH, Howard FM, Foster DC, Shield CG, Giles DE, Tu X. Contributions of physical and sexual abuse to women’s experiences with chronic pelvic pain. J Reprod Med 2005;50(2):91-100. http://www.ncbi.nlm.nih.gov/pubmed/15755045 Chandler HK, Ciccone DS, Raphael KG. Localization of pain and self-reported rape in a female community sample. Pain Med 2006;7(4):344-52. http://www.ncbi.nlm.nih.gov/pubmed/16898946 Zondervan KT, Yudkin PL, Vessey MP, Jenkinson CP, Dawes MG, Barlow DH, Kennedy SH. The community prevalence of chronic pelvic pain in women and associated illness behaviour. B J Gen Pract 2001;51(468):541-7. http://www.ncbi.nlm.nih.gov/pubmed/11462313 Meltzer-Brody S, Leserman J, Zolnoun D, Steege J, Green E, Teich A. Trauma and posttraumatic stress disorder in women with chronic pelvic pain. Obstet Gynecol 2007;109(4):902-8. http://www.ncbi.nlm.nih.gov/pubmed/17400852 Elcombe S, Gath D, Day A. The psychological effects of laparoscopy on women with chronic pelvic pain. Psychol Med 1997;27(5):1041-50. http://www.ncbi.nlm.nih.gov/pubmed/9300510 Stones RW, Selfe SA, Fransman S, Horn SA. Psychosocial and economic impact of chronic pelvic pain. Baillieres Best Pract Res Clin Obstet Gynaecol 2000;14(3):415-31. http://www.ncbi.nlm.nih.gov/pubmed/10962635

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Price J, Farmer G, Harris J, Hope T, Kennedy S, Mayou R. Attitudes of women with chronic pelvic pain to the gynaecological consultation: a qualitative study. BJOG 2006;113(4):446–52. http://www.ncbi.nlm.nih.gov/pubmed/16489938 McGowan L, Luker K, Creed F, Chew-Graham CA. ‘How do you explain a pain that can’t be seen?’: the narratives of women with chronic pelvic pain and their disengagement with the diagnostic cycle. B J Health Psychol 2007;12(Pt 2):261-74. http://www.ncbi.nlm.nih.gov/pubmed/17456285 Heinberg LJ, Fisher BJ, Wesselman U, Reed J, Haythornthwaite JA. Psychological factors in pelvic/ urogenital pain: the influence of site of pain versus sex. Pain 2004;108(1-2):88-94. http://www.ncbi.nlm.nih.gov/pubmed/15109511 Pincus T, Williams A. Models and measurements of depression in chronic pain. J Psychosom Res 1999;47(3):211-9. http://www.ncbi.nlm.nih.gov/pubmed/10576470 Tripp DA, Curtis Nickel J, Landis JR, Wang YL, Knauss JS, CPCRN Study Group. Predictors of quality of life and pain in chronic prostatitis/chronic pelvic pain syndrome: findings from the National Institutes of Health Chronic Prostatis Cohort Study. BJU Int 2004;94(9):1279-82. http://www.ncbi.nlm.nih.gov/pubmed/15610105 Collett BJ, Cordle J, Steward R, Jagger C. A comparative study of women with chronic pelvic pain, chronic nonpelvic pain and those with no history of pain attending general practitioners. Br J Obset Gynaecol 1998;105(1):87-92. http://www.ncbi.nlm.nih.gov/pubmed/9442168 Kuppermann M, Learman LA, Schembri M, Gregorich S, Jacoby A, Jackson RA, Gates E, Wassel-Fyr C, Lewis J, Washington AE. Effect of noncancerous pelvic problems on health-related quality of life and sexual functioning. Obstet Gynecol 2007;110(3):633-42. http://www.ncbi.nlm.nih.gov/pubmed/17766611 Smith KB, Tripp D, Pukall C, Nickel JC. Predictors of sexual and relationship functioning in couples with Chronic Prostatities/Chronic Pelvic Pain Syndrome. J Sex Med 2007;4(3):734-44. http://www.ncbi.nlm.nih.gov/pubmed/17451490 Tan G, Jensen MP, Thornby JI, Shanti BF. Validation of the Brief Pain Inventory for chronic nonmalignant pain, J Pain 2004;5(2):133-7. http://www.ncbi.nlm.nih.gov/pubmed/15042521 Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol group. Ann Med 2001;33(5):337-43. http://www.ncbi.nlm.nih.gov/pubmed/11491192 Turner JA, Ciol MA, Von Korff M, Berger R. Validity and responsiveness of the national institutes for health chronic prostatitis symptom index. J Urol 2003;169(2):580-3. http://www.ncbi.nlm.nih.gov/pubmed/12544311 Howard FM. Chronic pelvic pain. Obstet Gynecol 2003;101(3):594-611. http://www.ncbi.nlm.nih.gov/pubmed/12636968 Weijenborg PTM, Greeven A, Dekker FW, Peters AW, ter Kuile MM. Clinical course of chronic pelvic pain in women. Pain 2007;132(Suppl 1):S117-S123. http://www.ncbi.nlm.nih.gov/pubmed/17689866 Anderson RU, Wise D, Sawyer T, Chan C. Integration of myofascial trigger point release and paradoxical relaxation training treatment of chronic pelvic pain in men. J Urol 2005;174(1):155-60. http://www.ncbi.nlm.nih.gov/pubmed/15947608 Cornel EB, van Haarst EP, Schaarsberg RW, Geels J. The effect of biofeedback physical therapy in men with chronic pelvic pain syndrome Type III. Eur Urol 2005;47(5):607-11. http://www.ncbi.nlm.nih.gov/pubmed/15826751 Haugstad GK, Haugstad TS, Kirste UM, Leganger S, Klemmetsen I, Malt UF. Mensendieck somatocognitive therapy as treatment approach to chronic pelvic pain: Results of a randomized controlled intervention study. Am J Obs Gynecol 2006;194(5):1303-10. http://www.ncbi.nlm.nih.gov/pubmed/16647914 Morley SJ, Eccleston C, Williams A. Systematic review and meta-analysis of randomised controlled trials of cognitive behaviour therapy and behaviour therapy for chronic pain in adults, excluding headache. Pain 1999;80(1-2):1-13. http://www.ncbi.nlm.nih.gov/pubmed/10204712 Stones W, Cheong YC, Howard FM. Interventions for treatment chronic pelvic pain in women. Cochrane Database Syst Rev 2005;(2):CD000387. http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD000387/frame.html

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Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz NP, Kerns RD, Stucki G, Allen RR, Bellamy N, Carr DB, Chandler J, Cowan P, Dionne R, Galer BS, Hertz S, Jadad AR, Kramer LD, Manning DC, Martin S, McCormick CG, McDermott MP, McGrath P, Quessy S, Rappaport BA, Robbins W, Robinson JP, Rothman M, Royal MA, Simon L, Stauffer JW, Stein W, Tollett J, Wernicke J, Witter J;IMMPACT. Topical review and recommendations: Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain 2005;113(1-2):9-19. http://www.ncbi.nlm.nih.gov/pubmed/15621359

8. GENERAL TREATMENT OF CHRONIC PELVIC PAIN There is very little specific evidence for the role of analgesic and co-analgesic drugs in CPP, with one systematic review in women suggesting that further research is required (1). As CPP is thought to be modulated by similar mechanisms to those of somatic, visceral and neuropathic pain, the evidence below has been derived from the general chronic pain literature. This section has divided the drugs into their broad classes for ease of reading and reference. Many of the agents will be familiar to chronic pain clinicians and their involvement with difficult cases will help in the development of individualized pain management plans. Some drugs discussed below are best used by clinicians experienced in their use. The use of drugs for specific urogenital conditions is covered by the guidelines for that condition. This chapter looks at the general considerations for patients within the commonly used drug classes. The evidence grading is the same as elsewhere in the EAU guidelines, looking at outcome of treatment. Recommendations are based on the likely benefit to a patient in terms of pain or improved quality of life rather than on the basis of disease modification. Table 15 provides an overview of available treatments together with evidence levels and graded recommendations.

8.1 Simple analgesics 8.1.1 Paracetamol Paracetamol should be considered on its own. It has analgesic and antipyretic activity and is used in acute and chronic painful conditions (2). There is evidence for its use in somatic pain and arthritic pain in particular (3,4) but the benefits are limited. There is little evidence about its role in CPP. 8.1.2 Acidic antipyretic analgesics The classical NSAIDs fall into this group and include salicylic acid. They are known to act on the cyclooxygenase (COX) enzyme. The early NSAIDs tended to have little selectivity for COX-2 over COX-1, and are therefore said to be associated with more side effects than the newer COX-2 selective inhibitors. The COX-1 enzyme is mainly involved in normal ‘housekeeping’ functions, such as mediating gastric mucosal integrity, and renal and platelet function. Blocking the COX-1 enzyme is the cause of the platelet, gastric and renal complications that can occur with NSAIDs. It has been suggested that the COX-2 enzyme is inducible as a result of tissue damage, and that it is the main enzyme involved in inflammation and peripheral sensitization of nociceptors. As a result, the analgesic efficacy of COX-2 selective drugs should be as good as that of the nonselective drugs. This, however, has been disputed (5). More recent studies and reviews including those form the European and US drug advisory bodies highlight the cardiovascular risks associated with COX-2 selective agents (6-8). The risk for cardiac risk is clear for COX-2 agents and classical NSAIDs may also be incriminated (9). Thus, selective COX-2 agents should not be prescribed in patients with increased risk of cardiovascular disease including congestive cardiac failure. There is very little evidence for NSAIDs to be used in the management of CPP and even less evidence for COX-2 selective drugs. Most analgesic studies have investigated dysmenorrhoea, in which NSAIDs were found to be superior to placebo and possibly paracetamol (10). For practical purposes the NSAIDs may be divided into: • non-selective, low potency (e.g. salicylic acid, ibuprofen, mefenamic acid) • non-selective, high potency (e.g. ketoprofen, diclofenac, ketorolac) • COX-2 selective drugs (e.g. celecoxib, etoricoxib).

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8.1.3 Guidelines for use of NSAIDs and COX-2 selective agents • Non-selective, low potency NSAIDs should be used in the first instance. They are most likely to be of help if there is an inflammatory component to the pain. More potent NSAIDs should be reserved for those conditions in which the low potency drugs have been tried and failed to produce significant benefit. • COX-2 selective drugs should be used with caution as an alternative to the non-selective drugs where there is an increased risk of gastric complications. They should be avoided in patients with known cardiovascular disease. • NSAIDs should be taken with food and consideration must be given to the use of gastric protective agents. • The benefits of the NSAIDs must be demonstrated to outweigh the risks. • All NSAIDs are contraindicated in active gastrointestinal ulceration/bleeding and renal disease. They may exacerbate asthma and produce fluid retention. • Even if stronger analgesics such as opioids are added, the NSAIDs can be continued as they are likely to have a synergistic action improving pain control above and beyond that obtained with opioids alone (11). • Paracetamol should be considered as an alternative to, or given with, NSAIDs as it is well tolerated with few side effects.

8.2 Neuropathic analgesics 8.2.1 Tricyclic antidepressants There is very little evidence in CPP for tricyclic antidepressants in humans. What data is available includes these drugs as options in treatment (12-14). A study in cats does suggest that tricyclics may have a role in the management of cystitis (15). Most studies involve neuropathic pain. If there is a suggestion of nerve injury or central sensitization, the algorithm outlined in Figure 8 should be considered. Saarto and Wiffen (16) reviewed antidepressants for neuropathic pain. They concluded that tricyclics are effective for neuropathic pain with limited evidence for the selective serotonin reuptake inhibitor antidepressant drugs and insufficient evidence for other antidepressants. The study suggests that HIV-related pain does not respond and further work is required with regard to more specific conditions. Tricyclic antidepressants tend to be used in lower dosages than those required for treating depression. Amitriptyline is used up to a dose of 150 mg once daily. 8.2.2 Anticonvulsants These drugs have been used in the management of pain for many years. Whereas there is little evidence to support the use of anticonvulsants in the management of genitourinary pain, they should be considered if there is a suggestion of neuropathic pain or central sensitization. There is no role for these drugs in acute pain (17). Gabapentin has been introduced for pain management and has undergone a systematic review by Wiffen (18). It is said to have fewer serious side effects compaired to the older anticonvulsants and in some countries is licensed for use in chronic neuropathic pain. There are claims that it produces a more natural sleep state at night than antidepressants. The evidence (for neuropathic pain) does not demonstrate any superiority for gabapentin over carbamazepine (17). The numbers needed to harm (for minor harm) is 2.5 for gabapentin and 3.7 for carbamazepine. Many practitioners, however, would not use carbamazepine as a first-line anticonvulsant in pain management because of its potentially serious side effects (blood, hepatic or skin disorders). Carbamazepine and other anticonvulsants (e.g. phenytoin or valproate) have been used for neuropathic pain but are best reserved for practioners familiar with their use. 8.2.3 N-methyl-D-aspartate (NMDA) antagonists The NMDA receptor channel complex is known to be an important channel for the development and maintenance of chronic pain. It is felt to be particularly important when there is evidence of central sensitization and opioid tolerance (19-23). These are the phenomena that alter signal transmission within the nervous system so that non-painful stimuli may become painful (allodynia) and pain from a painful stimulus is magnified (hyperalgesia). NMDA antagonists have been used in the management of neuropathic pain (24). Ketamine has been useful in several chronic pain states including peripheral neuropathies with allodynia, stump and phantom pain, central pain, and cancer-related pain, with and without a neurological component, but its long-term role remains unclear (25). Ketamine has been used as a general anaesthetic for over 30 years. It has also been used as an intravenous analgesic in burns units and accident and emergency units. Ketamine is thought to act primarily at the NMDA receptor, though it may also have action at sodium channels and opioid (kappa and mu) receptors

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(23). Difficult urogenital pains may therefore be helped by ketamine if there is evidence of nerve injury or central sensitization. Ketamine is not licensed for use in chronic pain and like the opioids has been used as a street drug of addiction. Ketamine should only be started by an experienced practitioner trained in its use. Similar care to that of opioids must be taken if a patient is to be managed at home. 8.2.4 Sodium channel blockade In a significant number of patients with urogenital pain, nerve injury and neuropathic changes are thought to play a role. These may be associated with a reduction in some sodium channels and the development of novel sodium channels. As a result, injured afferents become prone to generating more prolonged and higher frequency discharges, with a reduced refractory period. These changes in the characteristics of sodium channels are thought to underlie the mechanisms of mechanosensitivity, thermosensitivity and chemosensitivity (26). They may be involved in some visceral hyperalgesia. Human studies have demonstrated that intravenous lidocaine reduces neuropathic pain and sensory phenomena, such as allodynia (27). A positive lidocaine challenge may be followed by repeated infusions of lidocaine and the benefit from a single infusion may be prolonged. A role for the oral analogue, mexiletine, has also to be defined (28); a positive response to intravenous lidocaine does not always indicate that mexiletine will work. Challapalli et al. have reviewed the role of local anaesthetic agents in neuropathic pain. They are safe and better than placebo and as effective as other analgesics. Further research is needed into specific painful conditions and outcome measures to assess whether pain relief is clinically significant (29). Again, these agents are being used outside their licence and are best instituted by clinicians familiar with them.

8.3 Opioids There is now a general acceptance that opioids have a role in the management of chronic non-malignant pain (30). Studies have tended to be short term and a systematic review concluded that further research is required into the long-term use of opioids (31). The use of opioids in urogenital pain is poorly defined. Their use in neuropathic pain remains equivocal but a meta-analysis suggests clinically important benefits (32). The authors emphasize that more research is needed ino long-term outcomes and side effects. There is also evidence suggesting that opioids may produce different responses with different types of pain (33). Generally, slow-release preparations are preferred for chronic pain. Side effects are common but rarely serious. If, however, a particular agent causes side effects and clinical benefit, rotating to another opioid may be beneficial. Titrating the dose should be closely monitored to assess both benefit and side effects. Rotating from one opioid to another also requires close monitoring as there are no exact dose equivalents. General guidelines for the use of opioids in chronic pain have been published (34,35). The following guidelines are suggested, but the clinician involved should be familiar with the use of opioids in non-malignant pain. 8.3.1 Guidelines for the use of opioids in chronic/non-acute urogenital pain 1. 2. 3. 4. 5. 6.

All other reasonable treatments must have been tried and failed. The decision to instigate long-term opioid therapy should be made by an appropriately trained specialist in consultation with another physician (preferably the patient’s family doctor). Where there is a history or suspicion of drug abuse, a psychiatrist or psychologist with an interest in pain management and drug addiction should be involved. The patient should undergo a trial of opioids. The dose required needs to be calculated by careful titration. The patient should be made aware (and possibly give written consent): I. That opioids are strong drugs and associated with addiction and dependency. II. The opioids will normally only be prescribed from one source (preferably the family doctor). III. The drugs will be prescribed for fixed periods of time and a new prescription will not be available until the end of that period. IV. The patient will be subjected to spot urine and possibly blood checks to ensure that the drug is being taken as prescribed and that non-prescribed drugs are not being taken. V. Inappropriate aggressive behaviour associated with demanding the drug will not be accepted. VI. Hospital specialist review will normally occur at least once a year. VII. The patient may be requested to attend a psychiatric/psychology review. VIII. Failure to comply with the above may result in the patient being referred to a drug dependency agency and the use of therapeutic, analgesic opioids being stopped.

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7.

Morphine is the first-line drug, unless there are contraindications to morphine or special indications for another drug. The drug should be prescribed in a slow-release/modified release form. Shortacting preparations are undesirable and should be avoided where possible. Parenteral dosing is undesirable and should be avoided where possible.

8.3.2 Morphine There is no compelling evidence that one opiate is better than another. Morphine is the traditional gold standard and the opioid many physicians are most familiar with. In an acute situation, the daily morphine requirement may be calculated by titration of rapid-release morphine. In chronic pain situations, starting with a low dose of slow-release morphine and titrating the dose every 3 days to 1 week is adequate. 8.3.3 Transdermal fentanyl Transdermal fentanyl is used when oral absorption is restricted or when the patient suffers with intolerable side effects from other opioids. Patients with rapid bowel transit times (e.g. iliostomy) may find transdermal preparations beneficial. Patches are generally changed every 72 hours. 8.3.4 Methadone Methadone is a strong analgesic with a long track record of use. It has opioid and NMDA-antagonistic activity (24). It is suggested that further work is needed to look at its role in neuropathic pain (33). Its use is supported as a fourth-line agent in treating neuropathic pain in a consensus document by the Canadian Pain Society (36). Rotating from other opioids to methadone is not an exact science because dosing ratios are not clearly understood (37). Metabolite accumulation and cardiac side effects can be a problem. A practitioner familiar with its use as an analgesic should prescribe methadone. 8.3.5 Oxycodone A slow-release preparation is available with evidence suggesting its benefit in neuropathic pain. Evidence suggests that oxycodone has benefits over morphine in some experimentally induced visceral pains (38). The pharmacology of oxycodone is different to morphine in experimental neuropathic states (39). An RCT has also demonstrated a role for oxycodone in neuropathic pain (diabetic neuropathy) (40). 8.3.6 Other opioids and opioid-like agents Other opioids are available as slow- or modified-release preparations. They may be useful for opiate rotation if side effects or tolerance is a problem. Buprenorphine and pentazocine both have agonist and antagonist properties and can induce withdrawal symptoms in patients used to opioids. Naloxone may only partly reverse respiratory depression. Buprenorphine topical patches are now available and may offer a similar advantage to topical fentanyl. Codeine and dihydrocodeine are effective for the relief of mild-to-moderate pain. They are limited by side effects (notably constipation) and genetic variance of metabolism that affects analgesic efficacy. Approximately 10% of individuals will not effectively metabolize codeine resulting in inadequate analgesia (41). Tramadol produces analgesia by two mechanisms, an opioid effect and an enhancement of serotoninergic and adrenergic pathways (42,43). It has fewer typical opioid side effects (especially less respiratory depression, less constipation and less addiction potential) and is available in a slow-release preparation. A Cochrane review suggests that there is a role for tramadol in neuropathic pain management (44).

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Figure 8: Guidelines for the use of neuropathic analgesics

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Table 15: General treatment of CPP Type of pain LE GRf Comment Paracetamol for 1b A Benefit is limited and based on arthritic somatic pain pain COX-2 antagonists 1b A Avoid in patients with cardiovascular risk factors NSAIDs 1a B Better than placebo but unable to for dysmenorrhoea distinguish between agents Tricyclic antidepressants 1a A Neuropathic pain Tricyclic antidepressants 3 C Evidence suggests pelvic pain is similar to neuropathic pain Anticonvulsants 1a A For neuropathic pain Gabapentin Opioids 1a A Limited long-term data for chronic non Should only be used by clinicians malignant pain experienced in their use Opioids 1a A Benefit is probably clinically significant for neuropathic pain Caution with use, as above COX = cyclo-oxygenase; NSAID = non-steroidal anti-inflammatory drug; LE = level of evidence; GR = grade of recommendation. .

8.4

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43.

44.

McQuay H. Opioids in pain management. Lancet 1999;353(9171):2229-32. http://www.ncbi.nlm.nih.gov/pubmed/10393001 Kalso E, Edwards JE, Moore RA, McQuay HJ. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain 2004;s112(3):372-80. http://www.ncbi.nlm.nih.gov/pubmed/15561393 Eisenberg E, McNicol E, Carr DB. Opioids for neuropathic pain. Cochrane Database Syst Rev. 2006;(3):CD006146. http://www.ncbi.nlm.nih.gov/pubmed/16856116 Lemberg K, Kontinen VK, Viljakka K, Kylänlahti I, Yli-Kauhaluoma J, Kalso E. Morphine, oxycodone, methadone and its enantiomers in different models of nociception in the rat. Anaesth Analg 2006;102(6):1768-74. http://www.ncbi.nlm.nih.gov/pubmed/16717324 Kalso E, Allan L, Dellemijn PL, Faura CC, Ilias WK, Jensen TS, Perrot S, Plaghki LH, Zenz M. Recommendations for using opioids in chronic non-cancer pain. Eur J Pain 2003;7(5):381-6. http://www.ncbi.nlm.nih.gov/pubmed/12935789 The Pain Society, Recommendations for the appropriate use of opioids for persistent non-cancer pain. A consensus statement prepared on behalf of the Pain Society, the Royal College of Anaesthetists, the Royal College of General Practitioners and the Royal College of Psychiatrists. London: The Pain Society, 2004. http://www.britishpainsociety.org/book_opioid_main.pdf Moulin DE, Clark AJ, Gilron I, Ware MA, Watson CP, Sessle BJ, Coderre T, Morley-Forster PK, Stinson J, Boulanger A, Peng P, Finley GA, Taenzer P, Squire P, Dion D, Cholkan A, Gilani A, Gordon A, Henry J, Jovey R, Lynch M, Mailis-Gagnon A, Panju A, Rollman GB, Velly A; Canadian Pain Society. Pharmacological management of chronic neuropathic pain–consensus statement and guidelines from the Canadian Pain Society. Pain Res Manag 2007;12(1):13-21. http://www.ncbi.nlm.nih.gov/pubmed/17372630 Fredheim OM, Borchgrevink PC, Klepstad P, Kaasa S, Dale O. Long term methadone for chronic pain: a pilot study of pharmacokinetic aspects. Eur J Pain 2007;11(6):599-604. http://www.ncbi.nlm.nih.gov/pubmed/17113329 Staahl C, Dimcevski G, Andersen SD, Thorsgaard N, Christrup LL, Arendt-Nielsen L, Drewes AM. Differential effect of opioids in patients with chronic pancreatitis: an experimental pain study. Scand J Gastroenterol 2007;42(3):383-90. http://www.ncbi.nlm.nih.gov/pubmed/17354119 Nielsen CK, Ross FB, Lotfipour S, Saini KS, Edwards SR, Smith MT. Oxycodone and morphine have distinctly different pharmacological profiles: radioligand binding and behavioural studies in two rat models of neuropathic pain. Pain 2007;132(3):289-300. http://www.ncbi.nlm.nih.gov/pubmed/17467904 Watson CP, Moulin D, Watt-Watson J, Gordon A, Eisenhoffer J. Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy. Pain 2003;105(1-2): 71-8. http://www.ncbi.nlm.nih.gov/pubmed/14499422 Mikus G, Weiss J. Influence of CYP2D6 genetics on opioid kinetics, metabolism and response. Curr Pharmacogenomics 2005;3(1):43-52. Sagata K, Minami K, Yanagihara N, Shiraishi M, Toyohira Y, Ueno S, Shigematsu A. Tramadol inhibits norepinephrine transporter function at desipramine-binding sites in cultured bovine adrenal medullary cells. Anaesth Analg 2002;94(4):901-6. http://www.ncbi.nlm.nih.gov/pubmed/11916794 Desmeules JA, Piguet V, Collart L, Dayer P. Contribution of monoaminergic modulation to the analgesic effect of tramadol. Br J Clin Pharmacol 1996;41(1):7-12. http://www.ncbi.nlm.nih.gov/pubmed/8824687 Hollingshead J, Dühmke RM, Cornblath DR. Tramadol for neuropathic pain. Cochrane Database Syst Rev 2006;(3):CD003726. http://www.ncbi.nlm.nih.gov/pubmed/16856016

8.5 Nerve blocks Neural blockade for pain management is usually carried out by a consultant in pain medicine with an anaesthetic background. Textbooks have been written on the techniques employed and individual specialists using neural blockade must be well versed in assessment of the patient, the indications for specific procedures, and the general and specific risks associated with the procedures, as well as possible advantages. Procedures may be performed for diagnostic reasons, therapeutic benefit or possibly both. Diagnostic

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blocks can be difficult to interpret and a clear understanding of the many mechanisms by which a block may be acting must be understood. Temporary but consistent responses to nerve blocks may lead a specialist to proceed with a neurolytic nerve block or to a pulsed radiofrequency neuromodulation procedure. Neurolytic nerve blocks are rarely indicated for a benign process, and to proceed with a neurolytic nerve block may result in disastrous results. Published guidelines emphasize that all nerve blocks should be performed with appropriate attention to safety, including the presence of skilled support staff and appropriate monitoring and resuscitation equipment. The use of block needles, nerve location devices and imaging (i.e. X-ray image intensifier, ultrasound or computerized tomography) appropriate for the procedure is essential. The evidence base for nerve blocks is not strong (1-5), but suggests that: • Peripheral nerve blocks, such as ilioinguinal/iliohypogastric/genitofemoral, may be useful in the management of neuropathic pain associated with nerve damage, such as following hernia repairs. • Blocks around the spermatic cord may be useful diagnostically prior to testicular denervation. • Lumbar (L1) sympathetic blocks may be helpful in the management of testicular pain, renal pain and possibly a range of pelvic pain conditions with afferents that pass via the L1 level. • Pudendal nerve blocks may be useful in the management of pudendal nerve injury related pain and possibly pelvic floor muscle spasm. Where pudendal neuralgia is suspected, pudendal nerve blocks may have a diagnostic role. Multiple other nerves close to the pudendal nerve may also be associated with neuropathic symptoms and differential nerve blocks using neurotracing may be of help in understanding the process’. • Pre-sacral blocks and the ganglion Impar block may have a role in the management of pelvic pathology, particularly cancer pain. • Sacral root nerve blocks may be helpful in the diagnosis of those conditions that might respond to sacral root stimulation. The above list is not exhaustive and readers are advised to look at the major textbooks in this area (6). 8.5.1 1.

6.

References Kennedy EM, Harms BA, Starling JR. Absence of maladaptive neuronal plasticity after genitofemoralilioinguinal neurectomy. Surgery 1994;116(4):665-70; discussion 670-1. http://www.ncbi.nlm.nih.gov/pubmed/7940164 Yamamoto M, Hibi H, Katsuno S, Miyake K. Management of chronic orchialgia of unknown etiology. Int J Urol 1995;2(1):47-9. http://www.ncbi.nlm.nih.gov/pubmed/7542163 Calvillo O, Skaribas IM, Rockett C. Computed tomography-guided pudendal nerve block. A new diagnostic approach to long-term anoperineal pain: a report of two cases. Reg Anaesth Pain Med 2000;25(4):420-3. http://www.ncbi.nlm.nih.gov/pubmed/10925942 Kovacs P, Gruber H, Piegger J, Bodner G. New, simple, ultrasound-guided infiltration of the pudendal nerve: ultrasonographic technique. Dis Colon Rectum 2001;44(9):1381-5. http://www.ncbi.nlm.nih.gov/pubmed/11584221 McDonald JS, Spigos DG. Computed tomography-guided pudendal block for treatment of pelvic pain due to pudendal neuropathy. Obstet Gynecol 2000;95(2):306-9. http://www.ncbi.nlm.nih.gov/pubmed/10674599 Baranowski AP, Fall M, Abrams P, eds. Urogenital Pain in Clinical Practice. Taylor and Francis, 2007.

8.6

Transcutaneous electrical nerve stimulation (TENS)

2.

3.

4.

5.

The rationale behind using surface electrical nerve stimulation to relieve pain is the stimulation of myelinated afferents and thus activation of segmental inhibitory circuits. Urinary frequency may also be reduced. The favoured explanation of transcutaneous electrical nerve stimulation (TENS) draws on the gate-control theory of pain (1). Nevertheless, TENS may directly elicit reflex effects and influence autonomous functions. For example, relaxation of the bronchial muscles (2), the coronary arteries (3) and the urinary bladder have been observed in response to TENS (4). TENS involves the use of a pulse generator with an amplifier and electrodes. The pulses may be delivered continuously or as trains of varying duration. Continuous stimulation seems to be preferable when treating pain. The stimulation pulses used may have different properties. Square-wave pulses are notably effective in activating the nerve fibres and are most frequently used. Biphasic pulses are preferable as the zero net charge flow of this pulse helps to reduce electrochemical reactions at the electrode contact sites. Nevertheless, technical simplification has led to the use of unipolar rectangular pulses in many devices, apparently with few complications. The stimulus intensity required to activate a peripheral nerve varies with the pulse duration. In

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terms of charge transfer for a threshold effect, short pulses (0.1 ms) are most effective, but at the expense of higher pulse amplitudes (5). For most applications of nerve stimulation, the pulse frequency is a crucial variable. The frequencies used during TENS vary widely, from 1 Hz to 100 Hz. There are no systematic evaluation data to guide optimal electrical settings for TENS in urological practice. Standard electrodes are made of carbon rubber. These are strong, flexible, durable and cheap, but must be attached by adhesive tape. Self-adhesive electrodes have been developed. These are especially advantageous for people with sensitive skin, but they are expensive. The size of the electrode has a bearing on the current density – a minimum of 4 cm2 has been recommended for TENS (6). The electrode-skin impedance should be reduced by application of a generous layer of electrolyte gel to promote good contact under the entire electrode. The stimulus intensity required to elicit sensory appreciation varies between individuals. The maximum tolerable intensity just below pain threshold should be used. While it is plausible that electrode positioning will affect the result of treatment, this property has not been evaluated. In BPS/IC, suprapubic (7,8), vaginal-anal (4,9) and tibial nerve sites (10,11) have been tested, all with some success. Counselling of the patient before the start of the treatment is necessary. A specially trained nurse with the time necessary to communicate the technical instructions is a good option. The patient should be confident with the feeling of strong stimulation and view self-treatment without fear. The induction time for TENS to produce analgesia varies widely. The effect is cumulative. Since onset and progression are usually rather slow in IC, the standard recommendation so far has been 0.5-2 hours of treatment twice daily. The duration of an individual treatment session depends on the severity of pain. 8.6.1 Results of suprapubic TENS in BPS/IC Observations are scant. In the largest study published so far, 60 patients, 33 with classic IC and 27 with nonulcer disease, were treated by suprapubic TENS (6). The electrodes were positioned about 10-15 cm apart, immediately above the pubic symphysis. They were attached by a long strip of adhesive tape going halfway around the body to enable the patient to be ambulant during stimulation. Follow-up ranged from 9 months to 17 years. Patients who responded reported more marked effects on bladder pain than on micturition frequency. Of the patients with classic IC, 54% were helped by the treatment. The outcome of TENS was less favourable in non-ulcer IC. Of 27 patients with non-ulcer IC, only 26% benefited from the treatment. The present experience of electrical stimulation is based on open studies. There are difficulties in designing controlled studies of TENS, since the treatment is based on administration of stimulation of high intensity, at specific sites, over a very long period of time. Another problem is that it is not possible to measure pain precisely. Therefore, it is difficult to assess the efficacy of TENS in BPS/IC with accuracy. Several controlled studies of post-operative pain have shown TENS to be superior to sham stimulation (12). TENS has also been shown to reduce the amount of halothane required to maintain adequate anaesthesia during hand surgery in unconscious patients, in whom psychological influences have been eliminated (13). The beneficial effect of TENS on classic IC clearly exceeds the level of the placebo effect observed in drug studies of IC (54% versus 13-20%) (14,15).

8.7 Sacral neuromodulation in pelvic pain syndromes Sacral neuromodulation (SNS) has been shown to have benefits in patients with refractory motor urge incontinence (16,17), urinary retention, and CPP (18-20). Neuropathic pain and complex regional pain syndromes may also be treated successfully with neurostimulation applied to dorsal columns and peripheral nerves (21). The mechanisms of action are the subject of many hypotheses, with very little evidence to support any particular one. The hypotheses include: • blocking of pain transmission by direct effects in the spinothalamic tracts • activation of descending inhibitory pathways • effects on central sympathetic systems • segmental inhibition through coarse fibre activation and brain stem loops • inhibition by increasing gamma-aminobutyric acid levels in the dorsal horn • thalamocortical mechanisms masking the nociceptive input (21,22). Sacral root neuromodulation was introduced in the mid-1980s as a means of regaining bladder control in the face of disturbed function (23). Based on the neurophysiology of the bladder and urethra, it is a minimally invasive tool that bridges the gap between conservative options and invasive surgical procedures. The data on clinical applications are drawn exclusively from observational studies. Sacral root neuromodulation draws on the observation that electrical stimulation of sacral nerves modulates neural reflexes of the pelvis (24). Acceptable application of the stimuli is the challenge. Neurostimulation of S3 or S4 sacral nerves using a transforamenal approach is a viable option for patients with refractory urinary voiding disorders.

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Recently, SNS has also been investigated in IC. In an initial report on six patients (25), percutaneous neurostimulation significantly improved frequency, pain and urgency towards normal values, while urinary markers for IC were normalized. Maher et al. (26) reported a favourable response with significant improvement in pelvic pain, daytime frequency, nocturia, urgency and voided volume in 15 women with IC. Because pelvic pain syndromes are viewed as a manifestation of disturbed neural function, patients with refractory pelvic floor dysfunction and pelvic pain have been treated with SNS and benefit has been reported (27). Sacral neuromodulation for CPP has been based on promising data from pilot studies and prospective, placebo-controlled studies are now justified. 8.7.1 1. 2.

3.

4.

5.

6.

7.

8.

9. 10.

11.

12.

13.

14.

15.

16.

References Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965;150(699):971-9. http://www.ncbi.nlm.nih.gov/pubmed/5320816 Sovijarvi AR, Poppius H. Acute bronchodilating effect of transcutaneous nerve stimulation in asthma. A peripheral reflex or psychogenic response. Scand J Respir Dis 1977;58(3):164-9. http://www.ncbi.nlm.nih.gov/pubmed/302028 Mannheimer C, Carlsson CA, Vedin A, Wilhelmsson C. Transcutaneous electrical nerve stimulation (TENS) in angina pectoris. Pain 1986;26(3):291-300. http://www.ncbi.nlm.nih.gov/pubmed/3534690 Fall M, Carlsson CA, Erlandson BE. Electrical stimulation in interstitial cystitis. J Urol 1980;123(2): 192-5. http://www.ncbi.nlm.nih.gov/pubmed/6965508 Fall M, Lindström S. Electrical stimulation. A physiologic approach to the treatment of urinary incontinence. Urol Clin North Am 1991;18(2):393-407. http://www.ncbi.nlm.nih.gov/pubmed/2017820 Fall M, Lindstrom S. Transcutaneous electrical nerve stimulation in classic and nonulcer interstitial cystitis. Urol Clin North Am 1994;21(1):131-9. http://www.ncbi.nlm.nih.gov/pubmed/8284836 Fall M. Conservative management of chronic interstitial cystitis: transcutaneous electrical nerve stimulation and transurethral resection. J Urol 1985;133(5):774-8. http://www.ncbi.nlm.nih.gov/pubmed/3872946 Fall M. Transcutaneous electrical nerve stimulation in interstitial cystitis. Update on clinical experience. Urology 1987;29(4 Suppl):40-2. http://www.ncbi.nlm.nih.gov/pubmed/3494331 Eriksen BC. Painful bladder disease in women: effect of maximal electric pelvic floor stimulation. Neurourol Urodynam 1989;8:362-3. Geirsson G, Wang YH, Lindstrom S, Fall M. Traditional acupuncture and electrical stimulation of the posterior tibial nerve. A trial in chronic interstitial cystitis. Scand J Urol Nephrol 1993;27(1):67-70. http://www.ncbi.nlm.nih.gov/pubmed/8493470 McGuire EJ, Zhang SC, Horwinski ER, Lytton B. Treatment of motor and sensory detrusor instability by electrical stimulation. J Urol 1983;129(1):78-9. http://www.ncbi.nlm.nih.gov/pubmed/6600794 Woolf CJ. Segmental afferent fibre-induced analgesia: transcutaneous electrical nerve stimulation (TENS) and vibration. In: Melzack R, Wall PD, eds. Textbook of Pain. 2nd ed. Edinburgh: ChurchillLivingstone, pp. 884-894. Bourke DL, Smith BA, Erickson J, Gwartz B, Lessard L. TENS reduces halothane requirements during hand surgery. Anaesthesiology 1984;61(6):769-72. http://www.ncbi.nlm.nih.gov:80/pubmed/6391280 Mulholland SG, Hanno P, Parsons CL, Sant GR, Staskin DR. Pentosan polysulfate sodium for therapy of interstitial cystitis. A double-blind placebo-controlled clinical study. Urology 1990;35(6):552-8. http://www.ncbi.nlm.nih.gov/pubmed/1693797 Holm-Bentzen M, Jacobsen F, Nerstrom B, Lose G, Kristensen JK, Pedersen RH, Krarup T, Feggetter J, Bates P, Barnard R et al. A prospective double-blind clinically controlled multicenter trial of sodium pentosanpolysulfate in the treatment of interstitial cystitis and related painful bladder disease. J Urol 1987;138(3):503-7. http://www.ncbi.nlm.nih.gov/pubmed/2442415 Kennedy EM, Harms BA, Starling JR. Absence of maladaptive neuronal plasticity after genitofemoralilioinguinal neurectomy. Surgery 1994;116(4):665-70; discussion 670-1. http://www.ncbi.nlm.nih.gov/pubmed/7940164

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17.

18.

19.

20.

21.

22.

23. 24.

25.

26.

27.

88

Janknegt RA, Hassouna MM, Siegel SW, Schmidt RA, Gajewski JB, Rivas DA, Elhilali MM, Milam DC, van Kerrebroeck PE, Dijkema HE, Lycklama a Nyeholt AA, Fall M, Jonas U, Catanzaro F, Fowler CJ, Oleson KA. Long-term effectiveness of sacral nerve stimulation for refractory urge incontinence. Eur Urol 2001;39(1):101-6. http://www.ncbi.nlm.nih.gov/pubmed/11173947 Paszkiewicz EJ, Siegel SW, Kirkpatrick C, Hinkel B, Keeisha J, Kirkemo A. Sacral nerve stimulation in patients with chronic, intractable pelvic pain. Urology 2001;57(6 Suppl 1):124. http://www.ncbi.nlm.nih.gov/pubmed/11378113 Edlund C, Hellstrom M, Peeker R, Fall M. First Scandinavian experience of electrical sacral nerve stimulation in the treatment of the overactive bladder. Scand J Urol Nephrol 2000;34(6):366-76. http://www.ncbi.nlm.nih.gov/pubmed/11195901 Shaker HS, Hassouna M. Sacral root neuromodulation in idiopathic nonobstructive chronic urinary retention. J Urol 1998;159(5):1476-8. http://www.ncbi.nlm.nih.gov/pubmed/9554336 Kemler MA, Barendse GA, van Kleef M, de Vet HC, Rijks CP, Furnee CA, van den Wildenberg FA. Spinal cord stimulation in patients with chronic reflex sympathetic dystrophy. N Engl J Med 2000;343(9):618-24. http://www.ncbi.nlm.nih.gov/pubmed/10965008 Kemler MA, Barendse GA, van Kleef M, Egbrink MG. Pain relief in complex regional pain syndrome due to spinal cord stimulation does not depend on vasodilation. Anaesthesiology 2000;92(6):1653-60. http://www.ncbi.nlm.nih.gov/pubmed/10839916 Schmidt RA. Applications of neuromodulation. Urol Neurourol Urodyn 1988;7:585. Schmidt RA, Senn E, Tanagho EA. Functional evaluation of sacral nerve root integrity. Report of a technique. Urology 1990;35(5):388-92. http://www.ncbi.nlm.nih.gov/pubmed/2336766 Chai TC, Zhang C, Warren JW, Keay S. Percutaneous sacral third nerve root neurostimulation improves symptoms and normalizes urinary HB-EGF levels and antiproliferative activity in patients with interstitial cystitis. Urology 2000;55(5):643-6. http://www.ncbi.nlm.nih.gov/pubmed/10792070 Maher CF, Carey MP, Dwyer PL, Schluter PL. Percutaneous sacral nerve root neuromodulation for intractable interstitial cystitis. J Urol 2001;165(3):884-6. http://www.ncbi.nlm.nih.gov/pubmed/11176493 Aboseif S, Tamaddon K, Chalfin S, Freedman S, Kaptein J. Sacral neuromodulation as an effective treatment for refractory pelvic floor dysfunction. Urology 2002;60(1):52-6. http://www.ncbi.nlm.nih.gov/pubmed/12100921

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9. ABBREVIATIONS USED IN THE TEXT

This list is not comprehensive for the most common abbreviations

ABP BCG BPS BTX CBP CFU CNS COX CPP(S) CPSI CyA DMSO DRE ED EMDA EPS ESSIC FD GAG GI HBO IASP IC ICA ICDB ICS ICSI IL-6 I-PSS ISSVD LHRH LUT LUTS ND Nd-YAG NIDDK NIH NMDA NSAID PBS PCA PFM PPMT PPS PSA PUGO PVR RCT RTX SNS SPIN TENS TUNA TUR VAS VB2 VB3



acute bacterial prostatitis Bacillus Calmette-Guérin bladder pain syndrome Botulinum Toxin A chronic bacterial prostatitis colony-forming units central nervous system cyclo-oxygenase chronic pelvic pain (syndrome) chronic Prostatitis Symptom Index cyclosporin A dimethyl sulphoxide digital rectal examination erectile dysfunction electromotive drug administration expressed prostatic secretions European Society for the Study of IC/PBS first desire to void glycosaminoglycan gastrointestinal hyperbaric oxygen International Association for the Study of Pain interstitial cystitis Interstitial Cystitis Association Interstitial Cystitis Data Base International Continence Society Interstitial Cystitis Symptom Index (also known as the O’Leary Sant Symptom Index) interleukin-6 International Prostate Symptom Score International Society for the Study of Vulvovaginal Disease luteinizing hormone releasing hormone lower urinary tract lower urinary tract symptoms normal desire to void neodymium-yttrium-aluminium-garnet National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health N-methyl-D-aspartate non-steroidal anti-inflammatory drugs painful bladder syndrome prostate cancers pelvic floor muscles pre- and post-massage test pentosanpolysulphate sodium prostate specific antigen IASP special interest group, Pain of Urogenital Origin post-void residual urine randomized controlled trial resiniferatoxin sacral neuromodulation Specialists in Pain International Network transcutaneous electrical nerve stimulation transurethral needle ablation of the prostate transurethral resection visual analogue scale pre-prostatic massage urine post-prostatic massage urine

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VIP WBC WHO

vasoactive intestinal peptide white blood cells World Health Organization

Conflict of interest All members of the Chronic Pelvic Pain guidelines writing panel have provided disclosure statements of all relationships which they have and which may be perceived as a potential source of conflict of interest. This information is kept on file in the European Association of Urology Central Office database. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel - and meeting expenses. No honoraria or other reimbursements have been provided.

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Guidelines on

Urolithiasis H-G. Tiselius, P. Alken, C. Buck, M. Gallucci, T. Knoll, K. Sarica, Chr. Türk

© European Association of Urology 2009

TABLE OF CONTENTS 1.

page

Background 1.1 References

6 7

2. CLASSIFICATION 2.1 Categories of stone formers 2.2 Specific risk factors for stone formation 2.3 References

7 7 8 9

3. DIAGNOSTIC PROCEDURES 3.1 Diagnostic imaging 3.1.1 Allergy to contrast medium 3.1.2 Metformin 3.1.3 Reduced renal function 3.1.4 Untreated hyperthyroidism 3.1.5 References 3.2 Analysis of stone composition 3.2.1 References 3.3 Biochemical investigations 3.3.1 Analytical work-up in the acute phase 3.3.2 Analysis of urine in search for risk factors of stone formation 3.3.3 Comments on the analytical work-up 3.3.4 A simplified overview of the principles of analytical work-up in patients 3.3.5 References

9 9 10 10 10 11 11 12 13 13 13 14 15 17 18

4.

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STONE BURDEN 4.1 References

5. TREATMENT OF PATIENTS WITH RENAL COLIC 5.1 Pain relief 5.1.1 Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) 5.1.2 Prevention of recurrent episodes of renal colic 5.1.3 Effects of diclofenac on renal function 5.2 Spontaneous passage of stones 5.3 Medical expulsive treatment (MET) 5.4 References

21 21 21 21 22 22 22 22

6.

23 23

INDICATIONS FOR ACTIVE STONE REMOVAL 6.1 References

7. ACTIVE REMOVAL OF STONES IN THE KIDNEY 7.1 Extracorporeal shock-wave lithotripsy (ESWL) for removal of stones in the kidney 7.1.2 Factors of importance for the outcome of ESWL 7.1.2.1 Location of the stone mass 7.1.2.2 Stone burden 7.1.2.3 Composition and hardness of the stone 7.1.2.4 References 7.2 Percutaneous removal of renal stones 7.2.1 Complications 7.2.2 References 7.3 Retrograde removal of ureteral and renal stones (retrograde intrarenal surgery [RIRS]) 7.3.1 Standard endoscopic technique 7.3.2 Anaesthesia 7.3.3 Assessment of different devices 7.3.3.1 Ureteroscopes 7.3.3.2 Disintegration devices 7.3.3.3 Baskets and forceps 7.3.3.4 Dilatation, ureteral access sheaths and stenting 7.3.4 Clinical results

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7.3.4.1 Renal calculi 7.3.5. Complications 7.3.6. Conclusions 7.3.7 References 7.4 Open and laparoscopic surgery for removal of renal stones 7.4.1 Indications for open and laparoscopic surgery 7.4.2 Operative procedures 7.4.3 References 7.5 Chemolytic possibilities by percutaneous irrigation 7.5.1 Infection stones 7.5.2 Brushite stones 7.5.3 Cystine stones 7.5.4 Uric acid stones 7.5.5 Calcium oxalate and ammonium urate stones 7.5.6 References 7.6 Recommendations for removal of renal stones

35 36 36 37 42 42 42 43 45 45 45 45 45 46 46 47

8.

49

STAGHORN STONES

9. MANAGEMENT OF PATIENTS WITH STONES IN THE URETER. EAU/AUA 2007 GUIDELINE FOR THE MANAGEMENT OF URETERAL CALCULI 9.1 Introduction 9.2 Methodology 9.3 Results of the Outcomes Analysis 9.3.1 Observation and Medical Therapies Stone passage rates 9.3.1.1 Shock-wave Lithotripsy and Ureteroscopy 9.3.1.2 Efficacy Outcomes Stone-free rates 9.3.1.3 Procedure Counts 9.3.1.4 Complications 9.3.1.5 Other Surgical Interventions 9.4 The Index Patient 9.5 Treatment Guidelines for the Index Patient 9.5.1 For All Index Patients 9.5.2 For Ureteral Stones 10 mm 9.5.4 For Patients Requiring Stone Removal 9.6 Recommendations for the Pediatric Patient 9.7 Recommendations for the Nonindex Patient 9.8 Discussion 9.8.1 Medical Expulsive Therapy 9.8.2 Shock-wave Lithotripsy 9.8.3 Ureteroscopy 9.8.4 Percutaneous Antegrade Ureteroscopy 9.8.5 Laparoscopic and Open Stone Surgery 9.8.6 Special Considerations 9.8.6.1 Pregnancy 9.8.6.2 Pediatrics 9.8.6.3 Cystine Stones 9.8.6.4 Uric acid Stones 9.9 Research and Future Directions 9.10 Acknowledgements and Disclaimers 9.11 References

50 52 52 54 55 55 55 55 55 58 60 62 62 63 63 63 64 64 65 65 65 65 66 67 67 68 68 68 68 69 69 69 70 70

10. GENERAL RECOMMENDATIONS AND PRECAUTIONS FOR STONE REMOVAL 10.1 Infections 10.2 Aspects of anticoagulation and stone treatment 10.3 Pacemaker 10.4 Hard stones

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3

10.5 Radiolucent stones 10.6 Recommendations for special considerations in the removal of stones 10.7 References

76 76 76

11.

MANAGING SPECIAL PROBLEMS IN STONE REMOVAL 11.1 References

77 77

12. MANAGEMENT OF STONE PROBLEMS DURING PREGNANCY 12.1 Symptoms 12.2 Diagnostic evaluation 12.3. Management of the stone problem 12.3.1 Surgical management 12.3.2 Temporary urinary diversion 12.3.2.1 Percutaneous nephrostomy catheter 12.3.2.2 Internal ureteral stent 12.3.2.3 Ureteroscopy (URS) 12.4 Conclusions 12.5 References

79 79 80 80 81 81 81 81 81 82 82

13. MANAGEMENT OF STONE PROBLEMS IN CHILDREN 13.1 Investigations 13.1.1 Imaging 13.1.1.1 Ultrasound 13.1.1.2 Plain films (KUB) 13.1.1.3 Intravenous urography (IVU) 13.1.1.4 Helical computed tomogram (CT) 13.1.1.5 Magnetic resonance urography (MRU) 13.1.1.6 Nuclear imaging 13.1.2 Metaphylactic investigations 13.2 Stone removal 13.2.1 Endourological procedures 13.2.2 ESWL 13.2.3 Conclusions 13.2.4 Open or laparoscopic surgery 13.3 References

83 84 84 84 84 84 85 85 85 85 85 86 86 87 87 87

14. RESIDUAL FRAGMENTS 14.1 References

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STEINSTRASSE 15.1 References

16. INTERNAL STENTING – WHEN AND WHY 16.1 Introduction 16.2 Stents in the management of kidney stones 16.3 The use of stents in the ureter 16.3.1 Indications for stenting for urgent relief of obstruction 16.4 Stents in conjunction with ESWL therapy for ureteral stones 16.5 Stents in conjunction with ureteroscopy (URS) 16.6 References 17. RECURRENCE PREVENTIVE TREATMENT 17.1 Recurrence preventive treatment of patients with calcium stone disease 17.1.1 Drinking recommendations 17.1.2 Dietary recommendations 17.1.3 Pharmacological treatment 17.1.3.1 Thiazides and thiazide-like agents 17.1.3.2 Alkaline citrate 17.1.3.3 Orthophosphate 17.1.3.4 Magnesium

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17.1.3.5 Allopurinol 17.1.3.6 Pyridoxine 17.1.3.7 Management of patients with enteric hyperoxaluria 17.1.4 Recommendations 17.1.5 References 17.2 Medical treatment of patients with uric acid stone disease 17.2.1 Drinking an dietary recommendations 17.2.2 Pharmacological treatment 17.2.3 References 17.3 Medical treatment of cystine stone disease 17.3.1 Dietary recommendations 17.3.2 Drinking advice 17.3.3 Pharmacological treatment 17.3.4 References 17.4 Management of patients with infection stones 17.4.1 Pharmacological treatment of infection stone disease 17.4.2 References

101 101 101 102 103 108 108 108 109 110 110 110 110 111 111 111 112

18. ABBREVIATIONS USED IN THE TEXT 19. APPENDICES Appendix 1: Devices for endoscopic disintegration of stones Appendix 2: Approximate stone surface area with known diameters of the stone

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114 114 115

5

1. BACKGROUND The management of patients with urolithiasis is an important part of everyday urological practice. The optimal clinical management of urolithiasis requires knowledge of the diagnostic procedures, the rational treatment of acute stone colic, stone expulsion treatment, and the latest methods of stone removal. A basic understanding of the aetiology of stone formation and of metabolic risk evaluation are also essential, as they provide a sound basis on which to select appropriate measures to prevent stone recurrence. During the past few decades, the treatment of urolithiasis has been characterized by changes resulting from major technical achievements, improved understanding of the mechanisms of stone formation and advances in pharmacological treatment. These guidelines are based on published results. Some of the therapeutic principles are based on evidence from randomized or controlled studies; some statements are based on other types of study or on substantial clinical experience. According to the principles of the European Association of Urology (EAU) Guidelines Office, the scientific basis for recommendations or statements has been classified by level of evidence (LE) and grade of recommendation (GR) when appropriate. The criteria for LE and GR are given in Tables 1 and 2 (1). Table 1: Level of evidence (LE)* Level Type of evidence 1a Evidence obtained from meta-analysis of randomized trials 1b Evidence obtained from at least one randomized trial 2a Evidence obtained from one well-designed controlled study without randomization 2b Evidence obtained from at least one other type of well-designed quasi-experimental study 3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case reports 4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities modified from Sackett et al. (1) Table 2: Grade of recommendation (GR)* Grade Nature of recommendations A Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomized trial B Based on well-conducted clinical studies, but without randomized clinical trials C Made despite the absence of directly applicable clinical studies of good quality modified from Sackett et al. (1) In several statements, the methods considered have been assigned preference numbers, 1, 2, 3, etc, to indicate which treatment alternative was considered most appropriate or was preferred, according to the literature or consensus reached. If two procedures were considered equally useful, the same preference number is given. The preferred treatment alternative always has the preference number 1 For the management of patients with stones in the ureter (see Chapter 9), we refer to the 2007 Guideline for the Management of Ureteral Calculi, a document resulting from collaboration between the American Urological Association (AUA) and the EAU (2, 3; http://www.auanet.org/guidelines and http://www. uroweb.org/professional-resources/guidelines). An ‘index patient’ has been defined to describe the typical individual with a ureteral stone The index patient is a non-pregnant adult with a unilateral non-cystine/non-uric acid radiopaque ureteral stone without renal calculi requiring therapy whose contralateral kidney functions normally and whose medical condition, body habitus, and anatomy allow any one of the treatment options to be undertaken. Whenever possible, statements are graded as ‘standard’, ‘recommendation’ or ‘option’ to reflect the degree of flexibility in application. ‘Standard’ is the most rigid treatment policy; ‘recommendation’ has significantly less rigidity, and ‘option’ allows for the greatest flexibility. 1. STANDARD: the health outcomes of the alternative interventions are sufficiently well known to permit meaningful decisions, and there is virtual unanimity about which intervention is preferred.

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2. RECOMMENDATION: the health outcomes of the alternative interventions are sufficiently well known to permit meaningful decisions, and an appreciable, but not unanimous, majority agrees on which intervention is preferred. 3. OPTION: the health outcomes of the interventions are not sufficiently well known to permit meaningful decisions, or preferences are unknown or equivocal. It is not possible to translate these levels of grading to the grade of recommendations currently used by the EAU. However, the statements made in Chapter 9 will correspond, at least partly, to the preference numbers used in the other fields of urolithiasis discussed in this guideline. For all clinical problems, the recommendations in this guideline are supported by comments based on the most important publications or, when data from the literature are contradictory or lacking, by panel opinion. However, no attempt was made to perform a structural analysis of the available literature. Where recommendations are made, the main focus is on medical aspects. A discussion of the associated economic issues is beyond the scope of a European guideline document because of the wide geographical diversity of, and variation between, different financial systems in the European healthcare sector. The Panel is aware of the different treatment and technical facilities available geographically. Our intention has been to highlight the alternatives that appear most convenient for the patient in terms of low invasiveness and risk of complications; however, this does not mean that other methods are not applicable. When a certain form of therapy is not recommended, this has been specifically stated. This edition of Guidelines on Urolithiasis is an update of previously published documents (4–6).

1.1

REFERENCES

1. Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998. http://www.cebm.net/index.aspx?o=1025 [access date February 2009]. 2. Preminger GM, Tiselius HG, Assimos DG, Alken P, Buck AC, Gallucci M, Knoll T, Lingeman JE, Nakada SY, Pearle MS, Sarica K, Türk C, Wolf JS Jr; American Urological Association Education and Research, Inc; European Association of Urology. 2007 Guideline for the management of ureteral calculi. Eur Urol 2007;52(6):1610-31. http://www.ncbi.nlm.nih.gov/pubmed/18074433 3. Preminger GM, Tiselius HG, Assimos DG, Alken P, Buck C, Gallucci M, Knoll T, Lingeman JE, Nakada SY, Pearle MS, Sarica K, Türk C, Wolf JS Jr; EAU/AUA Nephrolithiasis Guideline Panel. 2007 guideline for the management of ureteral calculi. J Urol 2007;178(6):2418-34. http://www.ncbi.nlm.nih.gov/pubmed/17993340 4. Tiselius HG, Ackermann D, Alken P, Buck C, Conort P, Gallucci M. Guidelines on urolithiasis. In: EAU Guidelines. Edition presented at the 16th EAU Congress, Geneva, Switzerland, 2001. ISBN 90-806179-3-9. http://www.uroweb.org/nc/professional-resources/guidelines/online/?no_cache=1&view=archive 5. Tiselius HG, Ackermann D, Alken P, Buck C, Conort P, Gallucci M. Guidelines on urolithiasis. Eur Urol 2001;40(4):362-71. http://www.ncbi.nlm.nih.gov/pubmed/11713390 6. Tiselius HG, Ackermann D, Alken P, Buck C, Conort P, Gallucci M. Guidelines on urolithiasis. In: EAU Guidelines. Edition presented at the 22nd EAU Congress, Berlin, Germany, 2007. ISBN-13:978-90-70244-59-0. http://www.uroweb.org/nc/professional-resources/guidelines/online/

2. CLASSIFICATION 2.1

Categories of stone-forming patients

A system for categorizing stone-forming patients according to type of stone and severity of disease is shown in Table 3. These categories are useful when making decisions regarding the need for metabolic evaluation and medical treatment (1–4).

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Table 3: Categories of stone-forming patients

NON-CALCIUM STONES

CALCIUM STONES

Definition

Category

Infection stone: magnesium ammonium phosphate, carbonate apatite or ammonium uratea

INF

Uric acid/ammonium uratea/sodium urate stone

UR

Cystine stone

CY

First-time stone former without residual stone or fragments

So

First-time stone former with residual stone or fragments

Sres

Recurrent stone former with mild disease and without residual stone(s) or fragments

Rmo

Recurrent stone former with mild disease and with residual stone(s) or fragments

Rm-res

Recurrent stone former with severe disease with or without Rs residual stone(s) or fragments or with specific risk factors irrespective of otherwise defined category (Table 4) a Ammonium urate stones form when a urease-producing infection occurs in patients with urine that is supersaturated with uric acid/urate.

2.2

Specific risk factors for stone formation

Risk factors for stone formation are listed in Table 4. Table 4: Risk factors for recurrent stone formation • Onset of urolithiasis early in life ( i.e. below 25 years of age) • Stones containing brushite (calcium hydrogen phosphate; CaHPO4.2H2O) • Strong family history of stone formation • Only one functioning kidney (although only one kidney does not mean an increased risk of stone formation, these patients should be particularly considered for measures to prevent stone recurrence) • Diseases associated with stone formation - hyperparathyroidism - renal tubular acidosis (partial/complete) - cystinuria - primary hyperoxaluria - jejuno-ileal bypass - Crohn’s disease - intestinal resection - malabsorptive conditions - sarcoidosis • Medication associated with stone formation - calcium supplements - vitamin D supplements - acetazolamide - ascorbic acid in megadoses (> 4 g/day) - sulphonamides - triamterene - indinavir • Anatomical abnormalities associated with stone formation - tubular ectasia (medullary sponge kidney) - pelvo-ureteral junction obstruction - caliceal diverticulum, caliceal cyst - ureteral stricture

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- vesico-ureteral reflux - horseshoe kidney - ureterocele

2.3

REFERENCES

1.

Tiselius HG. Aetiological factors in stone formation. Ch 8. In: Davison AM, Cameron JS, Grunfeld J-P, Kerr DN, Ritz E, Winearls CG, eds. Oxford textbook of clinical nephrology. 3rd edn. Oxford: Oxford University Press, 2005, pp. 1201-1223. Tiselius HG. Etiology and investigation of stone disease. Curriculum in Urology. Eur Urol 1998;33:1-7. Tiselius HG. Epidemiology and medical management of stone disease. BJU Int 2003;91(8):758-67. http://www.ncbi.nlm.nih.gov/pubmed/12709088 Tiselius HG, Ackermann D, Alken P, Buck C, Conort P, Gallucci M. Guidelines on urolithiasis. Eur Urol 2001;40(4):362-71. http://www.ncbi.nlm.nih.gov/pubmed/11713390

2. 3. 4.

3. DIAGNOSTIC PROCEDURES 3.1

Diagnostic imaging

Stone disease often presents as an episode of acute stone colic. Patients with renal stone colic usually have characteristic loin pain, vomiting and mild fever, and possibly a history of stone disease. The clinical diagnosis should be supported by an appropriate imaging procedure, which will immediately inform the decision to take a conservative approach or consider another treatment. Imaging is imperative in patients with fever or a solitary kidney, and when the diagnosis LE = 4 of stone is in doubt GR = C LE = level of evidence; GR = grade of recommendation The diagnostic work-up of all patients with symptoms of urinary tract stones requires a reliable imaging technique (Table 5). For an acute stone colic, excretory urography (intravenous pyelography, IVP) has been the gold standard however, in recent years, unenhanced helical computed tomography (CT) has been introduced as a quick and contrast-free alternative (1-3). In randomized prospective studies, for patients with acute flank pain, the specificity and sensitivity of unenhanced helical CT was found to be similar (4, 5–9) or superior (10–11) to that obtained with urography. In selected cases, additional information regarding renal function may be obtained by combining CT with contrast infusion. Advantages of CT are the demonstration of uric acid and xanthine stones, which are radiolucent on plain films, and the ability to detect alternative diagnoses (7, 12). However, the advantage of a non-contrast imaging modality must be balanced against the higher radiation dose given to the patient during CT investigation (3, 5, 13). Furthermore, CT is less suited for follow-up after treatment of radiopaque stones. An alternative, commonly used, method for evaluating patients with acute flank pain is a plain film of the kidneys, ureters and bladder (KUB) combined with ultrasonography (US). Extensive experience shows that in a large proportion of patients these methods are sufficient for the diagnosis of a ureteral stone. Special examinations carried out in selected cases include retrograde pyelography, antegrade pyelography and scintigraphy. Table 5: Imaging modalities in the diagnostic work-up of patients with acute flank pain Preference number

Examination

LE

GR

References

Comment

1

Non-contrast CT

1

A

1–12

3.1

1

Excretory urography

Standard procedure

2

KUB + US

2a

3.1 B

6

3.1

LE = level of evidence; GR = grade of recommendation; CT = computed tomography; KUB = plain film of kidneys, ureters and bladder; US = ultrasonography. Although intravascular administration of contrast medium is usually the responsibility of the radiologist, injection of contrast medium is occasionally used as an auxiliary procedure for stone localization during shock-wave lithotripsy. Many urologists also take responsibility for the diagnostic radiological work-up

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of patients with stone problems. A basic understanding of the risks associated with the use of contrast medium and the precautions needed is therefore essential (Table 6). 3.1.1 Allergy to contrast medium When contrast medium needs to be adminstered to a patient who has had or who may be at risk of an allergic reaction to the medium, the following precautions must be taken (14, 15): • always use low-molecular non-ionic contrast medium • give a corticosteroid (e.g. prednisolone, 30 mg) between 12 hours and 2 hours before the contrast medium is injected. • combine corticosteroid with an intramuscular injection of an antihistamine agent (e.g. clemastine, 2 mg) given 1 hour prior to administration of the contrast medium. 3.1.2 Metformin Metformin, which is used to treat diabetes type II, may give rise to lactic acidosis in case of contrast-induced anuria (16–18). This unusual complication is caused by retention of dimethylbiguanide. Unfortunately, lactic acidosis is associated with high mortality and great care needs to be taken when using contrast medium in patients taking metformin, particularly when renal function is reduced (i.e. serum creatinine level > 130 μmol/L or > 1.50 mg/100 mL). According to the recommendations given by the European Society of Urogenital Radiology (14, 15), serum creatinine level should be measured in every patient with diabetes being treated with metformin. In addition, the following should be considered. • In patients who are being treated with metformin and have a normal serum creatinine, contrast medium can be administered, but the intake of metformin should be stopped for 48 hours from the time of the radiological examination and until the serum creatinine remains normal. • In patients with reduced renal function, metformin should be stopped and administration of contrast medium delayed until 48 hours have passed after the last intake of metformin. Treatment with metformin may resume 48 hours after the examination provided that serum creatinine remains at the pre-examination level. • When no information on renal function is available, alternative imaging techniques should be used. • When contrast medium has been given to a patient on metformin, for whom no information on the renal function is available, or who has reduced renal function, metformin must be stopped immediately and the patient hydrated so that diuresis is ≥ 100 ml/h during 24 hours. Serum creatinine, lactic acid and blood pH should be monitored. Symptoms of lactic acidosis are vomiting, somnolence, epigastric pain, anorexia, hyperpnoea, lethargy, diarrhoea and thirst. The investigative findings are a blood pH < 7.25 and serum lactic acid concentration > 5 mmol/L (16,17). 3.1.3 Reduced renal function Intravenous administration of contrast medium might result in a reduced renal perfusion and toxic effect on tubular cells. Vasoconstriction of glomerular afferent arterioles causes a reduced glomerular filtration rate (GFR) and increased renal vascular resistance. Nephrotoxicity caused by contrast medium is diagnosed by an increase of 25%, or at least 44 μmol/L, in the level of serum creatinine during the 3 days following intravascular administration of the agent, when there is no alternative explanation. Risk factors for development of reduced renal function The following risk factors should be noted before intravenous contrast medium is used: • increased serum creatinine • dehydration • age over 70 years • diabetes • congestive heart failure • concurrent treatment with nephrotoxic drugs, for example non-steroidal anti-inflammatory agents (NSAIDs) • aminoglycosides should be stopped for at least 24 hours before contrast medium is injected. Patients with multiple myeloma should be examined either after adequate hydration or using an alternative method. Avoid repeated injections of contrast medium at intervals less than 48 hours (see Section 3.1.2.) to 72 hours. Dosage of iodine Reduced renal function is defined as serum creatinine ≥ 140 μmol/L or GFR ≤ 70 mL/min. For a patient with GFR 80–120 mL/min, the dose of iodine should not exceed 80–90 g. When the GFR is

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reduced to 50–80 mL/min, the dose of iodine should not exceed the same amount as the GFR expressed in mL/min/1.73 m2 body surface area (12, 13). Useful formulae for calculating GFR and body surface area are given in Table 7 (19). For further advice regarding the appropriate dose of contrast medium, see the guidelines presented by the Radiological Society (20). In patients with a serum or plasma creatinine ≥ 140 μmol/L (1.6 mg/100 mL), hydration, before and after use of contrast medium, may be beneficial in order to prevent nephropathy. Administration of N-acetylcysteine, 600 mg twice on the day before injection of contrast medium has been recommended to prevent renal failure caused by contrast medium (21). 3.1.4 Untreated hyperthyroidism For patients in whom hyperthyroidism is suspected, the level of thyroid-stimulating hormone should be assessed before use of contrast medium. Contrast medium should not be given unless these patients are appropriately treated for hyperthyroidism. Table 6: General considerations regarding the use of contrast medium Contrast medium should not be given, or should be avoided, in the following circumstances • Patients with an allergy to contrast media

LE

GR

Selected references

Comment

–

–

14,15

3.1.1

• Serum or plasma creatinine > 150 μmol/L

4

C

15

3.1.1

• Patients receiving metformin

3

B

15–18

3.1.2

• Untreated hyperthyroidism

3

B

–

3.1.4

3

B

15

3.1.3

• Patients with myelomatosis LE = level of evidence; GR = grade of recommendation

Table 7: Formulae for calculating glomerular filtration rate (GFR) and body surface area (19) Men Women For patients < 20 years, the following formula should be used:

GFR = (140 – age) . kg/(0.82 . serum creatinine) GFR = (0.85 x (140 – age) . kg/(0.82 . serum creatinine) Body surface area = kg0.425 . height(cm)0.725 . 0.007184 GFR = creatinine clearance . 1.73m2 Creatinine clearance= (42.5 . height(cm)/serum creatinine) . (kg/70)0.07

3.1.5 1.

References Smith RC, Rosenfield AT, Choe KA, Essenmacher KR, Verga M, Glickman MG, Lange RC. Acute flank pain: comparison of non-contrast-enhanced CT and intravenous urography. Radiol 1995;194(3): 789-94. http://www.ncbi.nlm.nih.gov/pubmed/7862980 2. Smith RC, Verga M, McCarthy S, Rosenfield AT. Diagnosis of acute flank pain: value of unenhanced helical CT. AMJ Am J Roentgenol 1996;166(1):97-101. http://www.ncbi.nlm.nih.gov/pubmed/8571915 3. Kobayashi T, Nishizawa K, Watanabe J, Ogura K. Clinical characteristics of ureteral calculi detected by non-enhanced computerized tomography after unclear results of plain radiography and ultrasonography. J Urol 2003;170(3):799-802. http://www.ncbi.nlm.nih.gov/pubmed/12913701 4. Sudah M, Vanninen RL, Partanen K, Kainulainen S, Malinen A, Heino A, Ala-Opas M. Patients with acute flank pain: comparison of MR urography with unenhanced helical CT. Radiol 2002;223(1): 98-105. http://www.ncbi.nlm.nih.gov/pubmed/11930053 5. Homer JA, Davies-Payne DL, Peddinti BS. Randomized prospective comparison of non-contrast enhanced helical computed tomography and intravenous urography in the diagnosis of acute ureteric colic. Australas Radiol 2001;45(3):285-90. http://www.ncbi.nlm.nih.gov/pubmed/11531750 6. Shokeir AA, Abdulmaaboud M. Prospective comparison of non-enhanced helical computerized tomography and Doppler ultrasonography for the diagnosis of renal colic. J Urol 2001;165(4):1082-4. http://www.ncbi.nlm.nih.gov/pubmed/11257642

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7. Gray Sears CL, Ward JF, Sears ST, Puckett MF, Kane CJ, Amling CL. Prospective comparison of computerized tomography and excretory urography in the initial evaluation of asymptomatic microhematuria. J Urol 2002;168(6):2457-60. http://www.ncbi.nlm.nih.gov/pubmed/12441939 8. Miller OF, Rineer SK, Reichard SR, Buckley RG, Donovan MS, Graham IR, Goff WB, Kane CJ. Prospective comparison of unenhanced spiral computed tomography and intravenous urogram in the evaluation of acute flank pain. Urology 1998;52(6):982-7. http://www.ncbi.nlm.nih.gov/pubmed/9836541 9. Dalrymple NC, Verga M, Anderson KR, Bove P, Covey AM, Rosenfield AT, Smith RC. The value of unenhanced helical computerized tomography in the management of acute flank pain. J Urol 1998;159(3):735-40. http://www.ncbi.nlm.nih.gov/pubmed/9474137 10. Worster A, Preyra I, Weaver B, Haines T. The accuracy of noncontrast helical computed tomography versus intravenous pyelography in the diagnosis of suspected acute urolithiasis: a meta-analysis. Ann Emerg Med 2002;40(3):280-6. http://www.ncbi.nlm.nih.gov/pubmed/12192351 11. Shine S. Urinary calculus: IVU vs CT renal stone? A critically appraised topic. Abdom Imaging 2008;33(1):41-3. http://www.ncbi.nlm.nih.gov/pubmed/17786506 12. Mindelzun RE, Jeffrey RB. Unenhanced helical CT evaluating acute abdominal pain: a little more cost, a lot more information. Radiology 1997;205(1):43-5. http://www.ncbi.nlm.nih.gov/pubmed/9314959 13. Shinokara K. Editorial: Choosing imaging modality in 2003. J Urol 2003;170(3):803. http://www.ncbi.nlm.nih.gov/pubmed/12913702 14. Morcos SK, Thomsen HS, Webb JA; Contrast Media Safety Committee of the European Society of Urogenital Radiolology. Prevention of generalized reactions to contrast media: a consensus report and guidelines. Eur Radiol 2001;11(9):1720-8. http://www.ncbi.nlm.nih.gov/pubmed/11511894 15. Thomsen HS, Morcos SK. Contrast media and the kidney: European Society of Urogenital Radiology (ESUR) guidelines. Br J Radiol 2003;76(908):513-8. http://www.ncbi.nlm.nih.gov/pubmed/12893691 16. Nawaz S, Cleveland T, Gaines PA, Chan P. Clinical risk associated with contrast angiography in metformine treated patients: a clinical review. Clin Radiol 1998;53(5):342-4. http://www.ncbi.nlm.nih.gov/pubmed/9630271 17. McCartney MM, Gilbert FJ, Murchinson LE, Pearson D, McHardy K, Murray AD. Metformin and contrast media–a dangerous combination? Clin Radiol 1999;54(1):29-33. http://www.ncbi.nlm.nih.gov/pubmed/9915507 18. Thompson NW, Thompson TJ, Love MH, Young MR. Drugs and intravenous contrast media. BJU Int 2000;85(3):219-21. http://www.ncbi.nlm.nih.gov/pubmed/10671870 19. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16(1):31-41. http://www.ncbi.nlm.nih.gov/pubmed/1244564 20. ESUR Guidelines on Contrast Media. European Society of Urogenital Radiology. [access date February 2009]. http://www.esur.org/ESUR_Guidelines_NEW.6.0.html 21. Tepel M, Van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. Prevention of radiographiccontrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000;343(3): 180-4. http://www.ncbi.nlm.nih.gov/pubmed/10900277

3.2

Analysis of stone composition

Stones that pass spontaneously, are removed surgically, or excreted as fragments following disintegration, should be analysed to determine their composition (1–5). The preferred analytical procedures are X-ray crystallography and infrared spectroscopy. All patients should have at least one stone analysed. Repeated analysis is indicated when any changes in urine composition, as a result of medical treatment, dietary habits, environment or diseases, might have influenced stone composition. When stone(s) or stone material have not been retrieved, stone composition may be assessed using the following: • qualitative cystine tests (e.g. sodium nitroprusside test, Brand’s test (6), or any other cystine test)

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• bacteriuria/urine culture (in the case of a positive culture, ask for urease-producing micro-organisms) • microscopic examination of the urinary sediment to detect crystals of struvite or cystine • serum urate (in cases where a uric acid or urate stone is a possible alternative) • urine pH (low in patients with uric acid stones, high in patients with infection stones) • radiographic characteristics of the stone. An appropriate quantitative or semi-quantitative analysis of stone material should enable the main constituent(s) to be determined. The following calcium stones, which are not associated with infection, are referred to as radiopaque stones: • calcium oxalate - calcium oxalate monohydrate - calcium oxalate dihydrate • calcium phosphate - hydroxyapatite - carbonate apatite - octacalcium phosphate - brushite - whitlockite. The following stones, which are not associated with infection, are referred to as uric acid/urate stones: • uric acid • sodium urate. Infection stones have the following typical constituents: • magnesium ammonium phosphate • carbonate apatite. Less common stone constituents include 2,8-dihydroxyadenine, xanthine and various drug metabolites (e.g. sulphonamide, indinavir). Calcium stones, uric acid/urate stones, cystine stones and ammonium urate stones associated with infection are referred to as ‘stones with infection’. 3.2.1 References 1. Asper R. Stone analysis. Urol Res 1990;18(Suppl):S9-S12. http://www.ncbi.nlm.nih.gov/pubmed/2291252 2. Herring LC. Observations on the analysis of ten thousand urinary calculi. J Urol 1962;88:545-62. http://www.ncbi.nlm.nih.gov/pubmed/13954078 3. Daudon M, Jungers P. Clinical value of crystalluria and quantitative morphoconstitutional analysis of urinary calculi. Nephron Physiol 2004;98(2):31-6. http://www.ncbi.nlm.nih.gov/pubmed/15499212 4. Otnes B. Crystalline composition of urinary stones in Norwegian patients. Scand J Urol Nephrol 1983;17(1):85-92. http://www.ncbi.nlm.nih.gov/pubmed/6867630 5. Leusmann DB, Blaschke R, Schmandt W. Results of 5,035 stone analyses: a contribution to epidemiology of urinary stone disease. Scand J Urol Nephrol 1990;24(3):205-10. http://www.ncbi.nlm.nih.gov/pubmed/2237297 6. Brand E, Harris MH, Biloon S. Cystinuria: Excretion of cystine complex which decomposes in the urine with the liberation of cystine. J Clin Chem 1980;86:315.

3.3

Biochemical investigations

3.3.1

Analytical work-up in the acute phase (Table 8)

Table 8: Biochemical analyses recommended for patients with an acute stone episode All patients

Patients with fever Patients who vomit

Update MARCH 2008

Urinary sediment/dipstick test for: Red cells White cells, test for bacteriuria (nitrite) and urine culture in case of a positive reaction Serum creatinine to measure renal function C-reactive protein and blood cell count Serum/plasma sodium Serum/plasma potassium

13

Optional useful information a b

Approximate pH levela Serum/plasma calciumb All other examinations that might be necessary in case of intervention

Knowledge of pH might reflect the type of stone. This might be the only occasion on which patients with hypercalcaemia are identified.

3.3.2 Analysis of urine in search for risk factors for stone formation For an identification of metabolic risk factors for stone formation, an analytical programme for the different categories of stone formers is available (Table 9). Table 9: Analytical programme for patients with stone disease Category of stone former1

Blood analysis (serum/plasma)

Urine analysis follow-up

Prevention

INF

Creatinine

Culture, pH

Yes

UR

Creatinine, urate

Urate, pH

Yes

CY

Creatinine2

Cystine, pH

Yes

So

Yes (see Table 11)

Limited urine analysis (only fasting spot urine)

No

Sres

Yes (see Table 11)

Yes (see Table 11)

Yes

Rmo

Yes (see Table 11)

Limited urine analysis (only fasting spot urine)

No

Rm-res

Yes (see Table 11)

Yes (see Table 11)

Yes

Rs

Yes (see Table 11)

Yes (see Table 11)

Yes

1See

Table 3 in Chapter 2 for an explanation of the categories of stone formers. type of medical treatment being received by these patients will determine which other blood variables need to be included in the follow-up analysis. 2The

For each set of analyses, two urine collections are recommended. The urine collections are repeated when necessary (1–3). Several alternative collection options are feasible (Table 10). Table 10: Some alternatives for urine collection Alternative Timing of collection 1 Two 24-hour collections

2

One 24-hour collection

3

One 16-hour urine collection and one 8-hour urine collection

4

Spot urine sample

Description of collection Sample 1 collected in a bottle containing 30 mL of 6 mol/L hydrochloric acid Sample 2 collected in a bottle containing 30 mL of 0.3 mol/L sodium azide Sample collected in a bottle containing 30 mL of 6 mol/L hydrochloric acid Sample 1 collected between 06.00 and 22.00 hours in a bottle containing 20 mL of 6 mol/L hydrochloric acid Sample 2 collected between 22.00 and 06.00 hours in a bottle containing 10 mL of 0.3 mol/L sodium azide Excretion of each urine variable is related to creatinine level

Hydrochloric acid (HCl) prevents precipitation of calcium oxalate and calcium phosphate in the container during storage. In addition, HCl counteracts oxidation of ascorbate to oxalate. In acidified samples, uric acid precipitates and must be dissolved by alkalinization if urate excretion is of interest. Urate can be analysed in samples collected with sodium azide as preservative. For pH measurement, collection of urine without HCl is needed; a sample collected with sodium azide is useful. As urinary pH may alter during storage, a night-time sample in which pH is measured soon after urine collection is useful. A patient with uncomplicated stone disease is one who is either stone-free after the first stone episode or who has a history of mild recurrent disease with long intervals between stone episodes (categories So, Rmo; Table 3). The stone, blood (serum or plasma) and urine analyses recommended for these patients are shown in Table 11.

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Ideally, a fasting morning urine sample should be analysed. However, as it is not always easy to obtain this sample during routine clinical work, a spot urine sample can provide a rough guide to the need of further analyses. A patient with complicated stone disease has a history of frequent recurrences, with or without residual fragments or stones in the kidney, or the patient presents specific risk factors. First-time stone formers with residual fragments may also be considered in this category (categories: Rs, Sres, Rm-res; Table 3). The stone, blood and urine analyses recommended for these patients are shown in Table 11 (4–12). Urine collection should be postponed until at least 4 weeks after stone removal or after an episode of obstruction and should never be carried out in the presence of infection or haematuria. For special tests that might be required see Table 12 (13–18). Table 11. Analyses in patients with uncomplicated and complicated stone disease. For all patients Blood Urine Calcium Fasting morning spot urine or spot urine sample: Albumin1 pH Creatinine Leucocytes / Bacteria Urate2 Cystine test (when necessary) Additional analyses for patients with complicated calcium stone disease Urine collection during a defined period of time3 Preference Urine variable 1 Calcium 1 Oxalate 1 Citrate 1 Creatinine 1 Volume

Stone In every patient one stone should be analysed.

2 2 2 2 2 2

Urate 4 Magnesium 5 Phosphate 5,6 Urea 5,6 Sodium 4,6 Potassium 4,6

1.

 nalysis of calcium + albumin to correct for differences in calcium concentration attributable to albumin A binding, or direct analysis of ionized (free) calcium 2. Optional 3. 24-hour urine, 16-hour + 8-hour urine or any other collection period can be chosen provided normal excretion data are available (4–7). A spot urine sample can be used with creatinine-related variables (7). 4. As uric acid precipitates in acid solutions, urate has to be analysed in a sample that has not been acidified or following alkalinization to dissolve uric acid. When a 16-hour urine sample has been collected in a bottle with an acid preservative, the remaining 8 hours of the 24-hour period can be used to collect urine in a bottle with sodium azide for urate analysis. 5. Analysis of magnesium and phosphate is necessary to calculate estimates of supersaturation with calcium oxalate (CaOx) and calcium phosphate (CaP), for example AP(CaOx) index and AP(CaP) index (8–12). Formulae are given below. 6. Urea, phosphate, sodium and potassium measurements are useful for assessing the patient’s dietary habits. 3.3.3 Comments on the analytical work-up The purpose of analysing serum or plasma calcium is to identify patients with hyperparathyroidism or other conditions associated with hypercalcaemia. In the case of a high calcium concentration (> 2.60 mmol/L), the diagnosis of hyperparathyroidism should be established or excluded by repeated calcium analyses and assessment of the parathyroid hormone level (19–24). When a stone analysis has not been carried out, a high serum urate level together with a radiolucent stone support the suspicion of a uric acid stone. Although a uric acid stone is usually invisible on a plain film (KUB), it is clearly demonstrated with a CT examination. A spot morning urine sample should be used to measure pH (25). A pH above 5.8 in fasting morning urine raises the suspicion of incomplete or complete renal tubular acidosis (RTA) (26). In the same fasting morning or spot urine sample, bacteriuria and cystinuria can be excluded or confirmed (27).

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The aim of adding serum potassium to the analytical programme is to obtain further support for a diagnosis of suspected RTA. Hypokalaemic hypocitraturia might be one reason for therapeutic failures in patients treated with thiazides. The recommendation to collect two urine samples is based on observations that this approach will increase the likelihood of detecting urine abnormalities. Various collection periods (e.g. 24 hours, 16 hours, 17 hours, 12 hours, 4 hours, or even spot urine samples) are useful for this purpose, provided a set of normal values is available for the collection period (4–7). The urine sample used for analysis of calcium, oxalate, citrate and phosphate must be acidified, preferably with HCl, to: • maintain calcium, oxalate and phosphate in solution, during and after the collection period • prevent bacterial growth and the associated alteration of urine composition • prevent the in-vitro oxidation of ascorbate to oxalate (28, 29). The following urine variables can be analysed in the acidified sample: calcium, oxalate, citrate, magnesium, phosphate, urea, sodium, chloride and potassium. Although the creatinine concentration might be slightly altered, it must be assessed in the same sample when creatinine-related variables are used and also for conclusions on the completeness of the collection. Urate forms uric acid in the acidified urine and must therefore be analysed either following complete dissolution with alkali or in a urine sample that has not been acidified. Optional analysis of urea, phosphate and sodium helps to assess dietary factors of therapeutic significance. The protein intake can be derived from the urea excretion (Uurea, mmol/L) and urine volume in litres (V) as follows (30): Intake of protein (g) during the 24 h period = (Uurea (mmol/24 h) . 0.18) + 13 An estimate of the ion-activity products of calcium oxalate (AP[CaOx] index) and calcium phosphate, known as the AP[CaP] index, can be calculated as follows (31–37): AP[CaOx] index = 1.9 . Ca0.84 . Ox . Cit-0.22 . Mg-0.12 . V-1.03 In this formula, the urine volume (V) is expressed in litres (L). The urine variables Ca (calcium), Ox (oxalate), Cit (citrate), and Mg (magnesium) are expressed in millimoles (mmol) excreted during the collection period. The factor 1.9 is specific for the 24-hour period; for a 16-hour urine sample, this factor is 2.3. For other collection periods, consult reference 5. The AP[CaOx] index corresponds approximately to 108 . APCaOx (where APCaOx is the ion-activity product of calcium oxalate). The AP[CaP] index for a 24-hour urine sample is calculated as follows: AP[CaP] index = 2.7 . 10-3 . Ca1.07 . P0.70 . (pH - 4.5)6.8 . Cit-0.20 . V-1.31 The AP[CaP] index corresponds approximately to 1015 . APCaP (where APCaP is the ion-activity product of calcium phosphate). Factors for other collection periods can be found in reference 5. P is used for phosphate. A relationship between abnormalities in urine composition and severity of calcium stone formation has been demonstrated (38–44). Although individual abnormal urine variables might indicate a risk of stone formation, it is the concerted action of the various urine constituents that produces supersaturation and crystallization of the stone. Occasionally, it may be necessary to measure pH variation during the day or to make an acid loading for identification of disturbances in urine acidification. The principles for such a work-up are summarized in Table 12. Analytical findings in patients with incomplete and complete RTA are summarized in Table 13.

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Table 12: Additional analytical work-up in patients with calcium stone disease pH profile (13) Repeated measurements of pH during the 24-hour period •F  requent samples should be collected for immediate measurement of pH with pH paper or a glass electrode • Sampling every second hour or otherwise as appropriate Acid loading (14–18) This test is carried out together with blood sampling to show whether or not the patient has a complete or an incomplete acidification defect • Breakfast + ammonium chloride tablets (0.1 g/kg body weight), drink 150 mL • 09.00 Collect urine and measure pH, drink 150 mL • 10.00 Collect urine and measure pH, drink 150 mL • 11.00 Collect urine and measure pH, drink 150 mL • 12.00 Collect urine and measure pH, drink 150 mL • 13.00 Collect urine and measure pH, lunch Interpretation pH of 5.4 or lower indicates no renal tubular acidosis (RTA) Table 13: A  nalytical findings in patients with complete or incomplete distal renal tubular acidosis (RTA) (13) Test • Blood (pH) • Plasma bicarbonate • Plasma/serum potassium • Plasma/serum chloride • Urinary calcium • Urinary phosphate • Urinary citrate RTA = renal tubular acidosis

Incomplete RTA Low Low Low High High High Low

Complete RTA Normal Normal Normal Normal High High Low

3.3.4 A simplified overview of the principles of analytical work-up in patients Correct categorization of patients requires both information on the stone composition and an actual imaging procedure. If a reasonable assumption regarding the patient’s category can be made, the principles shown in Figure 1 can be applied to all patients. If this assumption is not possible, an alternative analytical approach must be used until more data have been collected.

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Figure 1. R  ecommendations regarding analysis of stones, blood and urine in different categories of stone forming patients

3.3.5 1.

2.

3.

4.

5.

18

References Hobarth K, Hofbauer J, Szabo N. Value of repeated analysis of 24-hour urine in recurrent calcium urolithiasis. Urology 1994;44(1):24-5; discussion 24-5. http://www.ncbi.nlm.nih.gov/pubmed/8042263 Hess B, Hasler-Strub U, Ackermann D, Jaeger P. Metabolic evaluation of patients with recurrent idiopathic calcium nephrolithiasis. Nephrol Dial Transplant 1997;12(7):1362-8. http://www.ncbi.nlm.nih.gov/pubmed/9249770 Straub M, Strohmaier WL, Berg W, Beck B, Hoppe B, Laube N, Lahme S, Schmidt M, Hesse A, Koehrmann KU. Diagnosis and metaphylaxis of stone disease. Consensus concept of the National Working Committee on Stone Disease for the upcoming German Urolithiasis Guideline. World J Urol 2005;23(5):309-23. http://www.ncbi.nlm.nih.gov/pubmed/16315051 Berg C, Larsson L, Tiselius HG. The composition of four-hour urine samples from patients with calcium oxalate stone disease. Br J Urol 1987;60(4):301-6. http://www.ncbi.nlm.nih.gov/pubmed/3690199 Tiselius HG. Solution chemistry of supersaturation. In: Coe FL, Favus MJ, Pak CYC, Parks HG, Preminger GM, eds. Kidney Stones: Medical and Surgical Management. Philadelphia: LippincottRaven, 1996, pp. 33-64.

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6.

Bek-Jensen H, Tiselius HG. Evaluation of urine composition and calcium salt crystallization properties in standardized volume-adjusted 12-h night urine from normal subjects and calcium oxalate stone formers. Urol Res 1997;25(5):365-72. http://www.ncbi.nlm.nih.gov/pubmed/9373919 7. Strohmaier WL, Hoelz K-J, Bichler KH. Spot urine samples for the metabolic evaluation of urolithiasis patients. Eur Urol 1997;32(3):294-300. http://www.ncbi.nlm.nih.gov/pubmed/9358216 8. Tiselius HG. An improved method for the routine biochemical evaluation of patients with recurrent calcium oxalate stone disease. Clin Chim Acta 1982;122(3):409-18. http://www.ncbi.nlm.nih.gov/pubmed/7105424 9. Tiselius HG. A simplified estimate of the ion-activity product of calcium phosphate in urine. Eur Urol 1984;10(3):191-5. http://www.ncbi.nlm.nih.gov/pubmed/6547093 10. Tiselius HG. Aspects on estimation of the risk of calcium oxalate crystallization in urine. Urol Int 1991;47(4):255-9. http://www.ncbi.nlm.nih.gov/pubmed/1781112 11. Tiselius HG. Risk formulas in calcium oxalate urolithiasis. World J Urol 1997;15(3):176-85. http://www.ncbi.nlm.nih.gov/pubmed/9228725 12. Tiselius HG. Metabolic evaluation of patients with stone disease. Urol Int 1997;59(3):131-41. http://www.ncbi.nlm.nih.gov/pubmed/9428428 13. Hesse A, Tiselius HG. Jahnen A. Urinary Stones: Diagnosis, Treatment and Prevention of Recurrence. Uric acid stones. New York: Karger, 1996, p. 52. 14. Backman U, Danielson BG, Johansson G, Ljunghall S, Wikström B. Incidence and clinical importance of renal tubular defects in recurrent renal stone formers. Nephron 1980;25(2):96-101. http://www.ncbi.nlm.nih.gov/pubmed/6243755 15. Knispel HH, Fitzner R, Kaiser M, Butz M. Acute acid load in recurrent oxalate stone formers. Urol Int 1988;43(2):93-6. http://www.ncbi.nlm.nih.gov/pubmed/3388639 16. Nutahara K, Higashihara E, Ishiii Y, Niijima T. Renal hypercalciuria and acidification defect in kidney stone patients. J Urol 1989;141(4):813-8. http://www.ncbi.nlm.nih.gov/pubmed/2926870 17. Osther PJ, Hansen AB, Rohl HF. Screening renal stone formers for distal renal tubular acidosis. Br J Urol 1989;63(6):581-3. http://www.ncbi.nlm.nih.gov/pubmed/2752250 18. Buckalew VM Jr. Nephrolithiasis in renal tubular acidosis. J Urol 1989;141(3 Pt 2):731-7. http://www.ncbi.nlm.nih.gov/pubmed/2645431 19. Halabe A, Sutton RA. Primary hyperparathyroidism and idiopathic hypercalciuria. Miner Electrolyte Metab 1987;13(4):235-41. http://www.ncbi.nlm.nih.gov/pubmed/3306315 20. Fuss M, Pepersack T, Corvilain J, Vandewalle JC, Van Geertruyden J, Simon J, Kinnaert P. Infrequency of primary hyperparathyroidism in renal stone formers. Br J Urol 1988;62(1):4-6. http://www.ncbi.nlm.nih.gov/pubmed/3408867 21. Broadus AE. Primary hyperparathyroidism. J Urol 1989;141(3 Pt 2):723-30. http://www.ncbi.nlm.nih.gov/pubmed/2918615 22. Thomas WC Jr. Urinary calculi in hypercalcemic states. Endocrinol Metab Clin North Am 1990;19(4):839-49. http://www.ncbi.nlm.nih.gov/pubmed/2081514 23. Rose GA. Primary hyperparathyroidism. In: Wickham JEA, Buck AC, eds. Renal Tract Stone. Edinburgh, UK: Churchill Livingstone,1990, pp. 401-413. 24. Alvarez-Arroyo MV, Traba ML, Rapado A, de la Piedra C. Role of citric acid in primary hyperparathyroidism with renal lithiasis. Urol Res 1992;20(1):88-90. http://www.ncbi.nlm.nih.gov/pubmed/1736494 25. Elliot JS, Sharp RF, Lewis L. Urinary pH. J Urol 1959;81(2):339-43. http://www.ncbi.nlm.nih.gov/pubmed/13631832 26. Chafe L, Gault MH. First morning urine pH in the diagnosis on renal tubular acidosis with nephrolithiasis. Clin Nephrol 1994;41(3):159-62. http://www.ncbi.nlm.nih.gov/pubmed/8187359 27. Brand E, Harris MM, Bildon S. Cystinuria: excretion of a cystine complex which decomposes in the urine with the liberation of free cystine. J Biol Chem 1930;86:315.

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28.

Brown JM, Chalmers AH, Cowley DM, McWhinney BC. Enteric hyperoxaluria and urolithiasis. N Engl J Med 1986;315(15):970-1. http://www.ncbi.nlm.nih.gov/pubmed/3762602 29. Wandzilak TR, D’Andre SD, Davis PA, Williams HE. Effect of high dose vitamin C on urinary oxalate levels. J Urol 1994;151(4):834-7. http://www.ncbi.nlm.nih.gov/pubmed/8126804 30. Mitch WE, Walser M. Nutritional therapy of the uremic patient. In: Brenner BM, Rector FC Jr, eds. The Kidney. Vol II. 3rd edn. Philadelphia: WB Saunders, 1986, pp. 1759-1790. 31. Eisenberger F, Bub P, Schmidt A. The fate of residual fragments after extracorporeal shock wave lithotripsy. J Endourol 1992;6:217-8. 32. Liedl B, Jocham D, Schuster C, Lunz C. Long-term results in ESWL-treated urinary stone patients. Abstract. Urol Res 1988;16:256. 33. Cicerello E, Merlo F, Gambaro G, Maccatrozzo L, Fandella A, Baggio B, Anselmo G. Effect of alkaline citrate therapy on clearance of residual renal stone fragments after extracorporeal shock wave lithotripsy in sterile calcium and infection nephrolithiasis patients. J Urol 1994;151(1):5-9. http://www.ncbi.nlm.nih.gov/pubmed/8254832 34. Fine JK, Pak YC, Preminger GM. Effect of medical management and residual fragments on recurrent stone formation following shock wave lithotripsy. J Urol 1995;153(1):27-32. http://www.ncbi.nlm.nih.gov/pubmed/7966783 35. Streem SB, Yost A, Mascha E. Clinical implications of clinically insignificant stone fragments after extracorporeal shock wave lithotripsy. J Urol 1996;155(4):1186-90. http://www.ncbi.nlm.nih.gov/pubmed/8632527 36. Zanetti G, Seveso M, Montanari E, Guarneri A, Del Nero A, Nespoli R, Trinchieri A. Renal stone fragments following shock wave lithotripsy. J Urol 1997;158(2):352-5. http://www.ncbi.nlm.nih.gov/pubmed/9224301 37. Pacik D, Hanak T, Kumstat P, Turjanica M, Jelinek P, Kladensky J. Effectiveness of SWL for lowerpole caliceal nephrolithiasis: evaluation of 452 cases. J Endourol 1997;11(5):305-7. http://www.ncbi.nlm.nih.gov/pubmed/9355942 38. Tiselius HG. Factors influencing the course of calcium oxalate stone disease. Eur Urol 1999;36(5): 363-70. http://www.ncbi.nlm.nih.gov/pubmed/10516443 39. Robertson WG. A risk factor model of stone formation. Front Biosci 2003;8:1330-8. http://www.ncbi.nlm.nih.gov/pubmed/12957848 40. Strauss AL, Coe FL, Deutsch L, Parks JH. Factors that predict the relapse of calcium nephrolithiasis during treatment. A prospective study. Am J Med 1982;72(1):17-24. http://www.ncbi.nlm.nih.gov/pubmed/7058820 41. Hsu TH, Streem SB. Metabolic abnormalities in patients with caliceal diverticular calculi. J Urol 1998;160(5):1640-2. http://www.ncbi.nlm.nih.gov/pubmed/9783922 42. Daudon M, Hennequin C, Boujelben G, Lacour B, Jungers P. Serial crystalluria determination and the risk of recurrence in calcium stone formers. Kidney Int 2005;67(5):1934-43. http://www.ncbi.nlm.nih.gov/pubmed/15840041 43. Tiselius HG, Bek-Jensen H, Fornander AM, Nilsson MA. Crystallization properties in urine from calcium oxalate stone formers. J Urol 1995;154(3):940-6. http://www.ncbi.nlm.nih.gov/pubmed/7637098 44. Raj GV, Auge BK, Assimos D, Preminger GM. Metabolic abnormalities associated with renal calculi in patients with horseshoe kidneys. J Endourol 2004;18(2):157-61. http://www.ncbi.nlm.nih.gov/pubmed/15072623

4. STONE BURDEN The size of a concrement (stone burden or stone size) can be expressed in different ways. In the literature, the largest diameter (i.e. the length of the stone as measured on the plain film) is most commonly used to describe stone size. Using length (l) and width (w), surface area (SA) can be estimated for most stones (1): SA = l . w . π . 0.25

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For a quick estimate of the stone SA, see Table A1 (Appendix 2). The SA can also be measured using computerized systems and from CT scans; however these procedures are not necessarily easy and the software not always available. Using SA, stone volume SV can be calculated as follows (2): SV = 0.6 . SA1.27 In this guideline, we have based our statements on stone SA in addition to largest stone diameter. With the more common use of CT, improved estimates of SV can be obtained using length (l), width (w) and depth (d): SV = l . w . d . π . 0.52

4.1

REFERENCES

1.

Tiselius HG, Andersson A. Stone burden in an average Swedish population of stone formers requiring active stone removal: how can the stone size be estimated in the clinical routine?. Eur Urol 2003;4(3):275-81. http://www.ncbi.nlm.nih.gov/pubmed/12600431 2. Ackermann D, Griffith DP, Dunthorn M, Newman RC, Finlayson B. Calculation of stone volume and urinary stone staging with computer assistance. J Endourol 1989;3:355-9.

5. TREATMENT OF PATIENTS WITH RENAL COLIC 5.1 Pain relief Pain relief is usually the therapeutic step that needs to be taken most urgently in patients with an acute stone episode (Table 14). Table 14: Pain relief for patients with acute stone colic Preference

Pharmacological agent

LE

GR

References

Comment

1

Diclophenac sodium

1b

A

1–4

5.1

1

Indomethacin Ibuprophen Hydromorphine hydrochloride+ atropine Methamizol Pentazocine Tramadol

4

C

2

LE = level of evidence; GR = grade of recommendation 5.1.1 Treatment using non-steroidal anti-inflammatory drugs (NSAIDs) Clinical trials have shown that NSAIDs (e.g. diclofenac) provide effective relief in patients who have acute stone colic’ (1–5). Moreover, the resistant index was reduced in patients with renal colic when NSAID treatment was given (6). Is it recommended that pain relief should be initiated with diclofenac whenever possible (Table 15) and an alternative drug used if the pain persists. Hydromorphone and other opiates are associated with an increased risk of vomiting, and should not be given without simultaneous administration of atropine. 5.1.2 Prevention of recurrent episodes of renal colic In a double-blind, placebo-controlled trial, recurrent pain episodes of stone colic were significantly fewer in patients treated with diclofenac, 50 mg tds, during the first 7 days. The effect was most pronounced in the first 4 treatment days (7). For patients who have ureteral stones that are expected to pass spontaneously, suppositories or tablets of diclofenac sodium, 50 mg bid, over 3–10 days, might be useful in reducing inflammation and the risk of recurrent pain. Facilitation of Stone passage might be facilitated by administration of alpha-blocking agents or,

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possibly, nifedipine (see Chapter 9 fore futher details). Alpha-receptor antagonists inhibit ureteral basal tone and peristaltic activity and dilate the lumen of the ureter. Calcium channel blocking agents reduce ureteral spasm and inhibit the fast peristaltic activity whereas the slow peristaltic activity remains unaffected. The patient should be instructed to sieve the urine to retrieve a concrement for analysis. Passage of the stone and restoration of normal renal function should be confirmed using appropriate methods. When pain relief cannot be achieved by medical means, drainage using stenting or percutaneous nephrostomy or by stone removal should be carried out. 5.1.3 Effects of diclofenac on renal function Diclofenac can affect renal function in patients with an already reduced function; however, there is no effect if the kidney are functioning normally (LE = 1b; GR = A) (8). Table 15: Recommendations and considerations regarding pain relief for the patient with renal colic Recommendations

LE

GR

Treatment should be started with an NSAID

1b

Diclofenac sodium affects GFR in patients with reduced 2a renal function, but not in patients with normal renal function Diclofenac sodium is recommended to counteract 1b recurrent pain after an episode of ureteral colic

Comment

A

Selected references 1-4

2a

8

5.1.3

A

7

5.1.2

5.1.1

GFR = glomerular filtration rate; GR = grade of recommendation; LE = level of evidence; NSAID = non-steroidal anti-inflammatory drug.

5.2

Spontaneous passage of stones

Most ureteral stones pass spontaneously. For further details, please see Chapter 6 and Chapter 9 (9, 10).

5.3

Medical expulsive treatment (MET)

The facilitation of ureteral stone passage is discussed in detail in Chapter 9 (9, 10).

5.4

REFERENCES

1.

Holmlund D, Sjödin J-G. Treatment of ureteral colic with indomethacin. J Urol 1978;120(6):676-7. http://www.ncbi.nlm.nih.gov/pubmed/366182 2. Lundstam SO, Leissner KH, Wåhlander LA, Kral JG. Prostaglandin-synthetase inhibition of diclofenac sodium in the treatment of renal colic: comparison with use of a narcotic analgesic. Lancet 1982;1(8281):1096-7. http://www.ncbi.nlm.nih.gov/pubmed/6122892 3. Lundstam SO, Wåhlander LA, Kral LG. Treatment of ureteral colic by prostaglandin-synthetase inhibition with diclofenac sodium. Curr Ther Res 1980;28:355-8. 4. Walden M, Lahtinen J, Elvander E. Analgesic effect and tolerance of ketoprofen and diclofenac in acute ureteral colic. Scand J Urol Nephrol 1993;27(3):323-5. http://www.ncbi.nlm.nih.gov/pubmed/8290910 5. Cohen E, Hafner R, Rotenberg Z, Fadilla M, Garty M. Comparison of ketorolac and diclofenac in the treatment of renal colic. Eur J Clin Pharmacol 1998;54(6):455-8. http://www.ncbi.nlm.nih.gov/pubmed/9776434 6. Shokeir AA, Abdulmaaboud M, Farage Y, Mutabagani H. Resistive index in renal colic: the effect of nonsteroidal anti-inflammatory drugs. BJU Int 1999;84(3):249-51. http://www.ncbi.nlm.nih.gov/pubmed/10468715 7. Laerum E, Ommundsen OE, Gronseth JE, Christiansen A, Fagertun HE. Oral diclofenac in the prophylactic treatment of recurrent renal colic. A double-blind comparison with placebo. Eur Urol 1995;28(2):108-11. http://www.ncbi.nlm.nih.gov/pubmed/8529732 8. Lee A, Cooper MG, Craig JC, Knight JF, Keneally JP. Effects of nonsteroidal anti-inflammatory drugs on postoperative renal function in adults with normal renal function. Cochrane Database Syst Rev 2007;18(2):CD002765. http://www.ncbi.nlm.nih.gov/pubmed/17443518

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9.

10.

Preminger GM, Tiselius HG, Assimos DG, Alken P, Buck C, Gallucci M, Knoll T, Lingeman JE, Nakada SY, Pearle MS, Sarica K, Türk C, Wolf JS Jr; American Urological Association Education and Research, Inc; European Association of Urology. 2007 guideline for the management of ureteral calculi. Eur Urol 2007;52(6):1610-31. http://www.ncbi.nlm.nih.gov/pubmed/18074433 Preminger GM, Tiselius HG, Assimos DG, Alken P, Buck C, Gallucci M, Knoll T, Lingeman JE, Nakada SY, Pearle MS, Sarica K, Türk C, Wolf JS Jr; EAU/AUA Nephrolithiasis Guideline Panel. 2007 guideline for the management of ureteral calculi. J Urol 2007;178(6):2418-34. http://www.ncbi.nlm.nih.gov/pubmed/17993340

6. INDICATIONS FOR ACTIVE STONE REMOVAL The size, site and shape of the stone at the initial presentation influence the decision for operative intervention (Table 16). The likelihood of spontaneous passage must also be evaluated. Spontaneous stone passage can be expected in up to 80% in patients with stones ≤ 4 mm in diameter. For stones with increasing diameters, the chance for spontaneous passage is decreased (1-4). In the stone interval 6-10 mm spontaneous passage is seen between 10 and 53% of patients (Chapter 9). The overall passage rate of ureteral stones is: • proximal ureteral stones: 25% • mid-ureteral stones: 45% • distal ureteral stones: 70%. For stones with a diameter exceeding 6–7 mm, removal is indicated. Studies have shown that asymptomatic stones in the kidney will eventually cause clinical problems (5). Small stones (< 6–7 mm) in a calix can cause considerable pain or discomfort (6–12). These stones should be removed using a minimally invasive technique. A narrow caliceal neck may require dilatation. Table 16: Indications for active stone removal Indications for considering active stone removal •S  tone diameter > 7 mm (because of the chance of spontaneous passage is very low) • Adequate pain relief cannot be achieved • Stone obstruction is associated with infection* • Risk of pyonephrosis or urosepsis* • Single kidneys with obstruction* • Bilateral obstruction*

LE 2a

GR B

4 4 4 4 4

B B B B B

Selected references 1–5

*D  iversion of urine with a percutaneous nephrostomy catheter or bypassing the stone with a stent are minimal requirements in these patients. LE = level of evidence; GR = grade of recommendation.

6.1

REFERENCES

1.

Sandegard E. Prognosis of stone in the ureter. Acta Chir Scand Suppl 1956;219:1-67. http://www.ncbi.nlm.nih.gov/pubmed/13394022 2. Morse RM, Resnick MI. Ureteral calculi: natural history and treatment in an era of advanced technology. J Urol 1991;145(2):263-5. http://www.ncbi.nlm.nih.gov/pubmed/1988715 3. Ibrahim AI, Shetty SD, Awad RM, Patel KP. Prognostic factors in the conservative treatment of ureteric stones. Br J Urol 1991;67(4):358-61. http://www.ncbi.nlm.nih.gov/pubmed/2032074 4. Miller OF, Kane CJ. Time to stone passage for observed ureteral calculi: a guide for patient education. J Urol 1999;162(3 Pt 1):688-90. http://www.ncbi.nlm.nih.gov/pubmed/10458343 5. Andersson L, Sylven M. Small renal caliceal calculi as a cause of pain. J Urol 1983;130(4):752-3. http://www.ncbi.nlm.nih.gov/pubmed/6887409

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6.

Psihramis KE, Dretler SP. Extracorporeal shock wave lithotripsy of caliceal diverticula calculi. J Urol 1987;138(4):707-11. http://www.ncbi.nlm.nih.gov/pubmed/3116280 7. Coury TA, Sonda LP, Lingeman JE, Kahnoski RJ. Treatment of painful caliceal stones. Urology 1988;32(2):119-23. http://www.ncbi.nlm.nih.gov/pubmed/3400135 8. Lee MH, Lee YH, Chen MT, Huang JK, Chang LS. Management of painful caliceal stones by extracorporeal shock wave lithotripsy. Eur Urol 1990;18(3):211-4. http://www.ncbi.nlm.nih.gov/pubmed/2261935 9. Hübner W, Porpaczy P. Treatment of caliceal calculi. Br J Urol 1990;66(1):9-11. http://www.ncbi.nlm.nih.gov/pubmed/2393803 10. Streem SB, Yost A. Treatment of caliceal diverticular calculi with extracorporeal shock wave lithotripsy: patient selection and extended follow-up. J Urol 1992;148(3 Pt 2):1043-6. http://www.ncbi.nlm.nih.gov/pubmed/1507327 11. Brandt B, Ostri P, Lange P, Kvist Kristensen J. Painful caliceal calculi. The treatment of small nonobstructing caliceal calculi in patients with symptoms. Scand J Urol Nephrol 1993;27(1):75-6. http://www.ncbi.nlm.nih.gov/pubmed/8493473

7. ACTIVE REMOVAL OF STONES IN THE KIDNEY 7.1

Extracorporeal shock-wave lithotripsy (ESWL) for removal of kidney stones

The introduction of ESWL during the early 1980s dramatically changed the management of urinary tract stones. The development of new lithotripters, modified indications and treatment principles have completely changed the treatment of kidney stones. Modern lithotripters are smaller and usually included in uroradiological tables, allowing application of not only ESWL but other diagnostic and ancillary procedures associated with ESWL. The latest-generation lithotripters are at least as effective as the first lithotripters, but are much cheaper and have greater versatility. Contraindications to the use of ESWL are few, but include: • pregnancy • severe skeletal malformations • severe obesity • aortic and/or renal artery aneurysms • uncontrolled blood coagulation • uncontrolled urinary tract infections (1, 2). ESWL can remove >90% of stones in adults (3-5). The success rate for ESWL depends on the efficacy of the lithotripter and upon: • size (volume), number, location and hardness of the stones • patient’s habitus • ambition and experience of the operator (6). Each of these factors has an important influence on retreatment rate and final outcome of ESWL. Techniques other than ESWL, usually involving a percutaneous approach, should be used to treat large, hard stones (see below) (3-5,7-17). Repeat treatment sessions The disintegrating power of ESWL is generally very good. There is concern about using ESWL for large stones because residual fragments are common so repeat treatment may be necessary, particularly with later generations of lithotripters, which have smaller focal volumes. It is important to limit the number of shock waves and the power used in repeat treatments to avoid causing renal tissue damage and bleeding complications (see below). The number of ESWL sessions should not exceed three to five. For more sessions, a percutaneous method might be a more rational option. In the case of infected stones or bacteriuria, antibiotics should be given before ESWL and continued for at least 4 days after treatment. LE = level of evidence; GR = grade of recommendation

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LE = 4 GR = C

There are no rules on how frequently ESWL sessions can be repeated. However, the interval between

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two successive sessions must be longer for electrohydraulic and electromagnetic lithotripsy than for treatments using piezoelectric equipment. The risk of damaging the renal tissue is greatest with treatments directed towards stones in the kidney. For stones in the ureter, rather than in the kidney, shorter intervals between treatment sessions are usually acceptable. Clinical experience supports this view. LE = level of evidence; GR = grade of recommendation

LE = 4 GR = C

A variety of lithotripters are in use, it is not possible to make a general recommendation regarding the interval needed between two treatments. This should be determined by the energy level used and the number of shock waves given (18). The number of shock waves that can be delivered at each session depends on the type of lithotripter and shock-wave power. There is no consensus on the maximum number of shock waves. However, as the shock-wave frequency increases, tissue damage increases (19). Stone disintegration improves at lower frequencies. The optimal shock wave frequency is 1.0-1.5 Hz (20). LE = 3 GR = C LE = level of evidence; GR = grade of recommendation Anatomical abnormalities Anatomical abnormalities may affect the outcome of ESWL. Malformations of the renal collecting system can cause stone formation, as they alter the mechanism of urine elimination and thus impair the passage of stone fragments. Auxiliary procedures are often needed in anatomical abnormalities (21-27). In 35,100 patients treated for kidney stones using ESWL, satisfactory disintegration was recorded in 32,255 (92%) (40-70). The stone-free rate in these patients was 70% with re-treatments in 10.5% (40-70) When results reported during the past 7 years were considered separately, the stone-free rates of 41- 90% corresponded with those reported for the Dornier HM3-lithotripter and for the second- and third-generation lithotripters. Patient selection, stone location, frequency of repeated treatment sessions, use of auxiliary procedures and the experience of the operator might explain the viriable outcome. In a prospective randomised trial comparing the Dornier HM3- and the Lithostar Plus lithotripter, the stone-free rates were 89% and 87%, respectively (32). Although the disintegrating capacity varies considerably between devices, late-generation lithotripters can treat kidney stones effectively. 7.1.2 Factors influencing the outcome of ESWL Studies using ESWL to remove kidney stones have reported stone-free rates of 66-99% inpatients who had stones ≤ 20 mm in diameter and 45-60% for stones > 20 mm in diameter (29-31). Similar results were seen with the Dornier HM3 lithotripter; stone-free rates were 75-89% for stones with a diameter ≤ 20 mm versus 39-63% for stones with a diameter ≥ 20 mm (28). Complications When ESWL is used to treat large (diameter >20 mm or SA > 300 mm2) renal stones, common complications can include: • pain • hydronephrosis • fever • occasional urosepsis, as a result of difficulties in the passage of stone particles, especially when disintegration is not sufficient (71-76). Stents A double-J stent reduces the obstructive and infective complications that can follow the use ESWL for large renal stones. Insertion of an internal stent before ESWL is recommended when stones with a diameter ≥ 20 mm (~300 mm2) are to be treated (77) LE = level of evidence; GR = grade of recommendation

LE = 3 GR = B

A recent randomised study reported that the routine use of internal stents before ESWL does not improve outcome in terms of stone-free rate (LE = 1b, GR = A) (78).

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The routine use of internal stents before ESWL does not improve outcome in terms of stone-free rate (78) LE = level of evidence; GR = grade of recommendation

LE = 1b GR = A

Stone particles may pass easily along stents while urine flows in and around the stent. This usually prevents obstruction and loss of ureteral contraction. Occasionally, stents do not efficiently draining purulent or mucoid material, thus leading to a risk of obstructive pyelonephritis. If fever lasts for a few days, a percutaneous nephrostomy tube is needed, even when ultrasound does not reveal any dilation. The following factors all influence the outcome of treatment: • location of stone mass (pelvic or caliceal) • total stone burden (number, weight or volume of stones) • state of contralateral kidney (e.g. is the other kidney absent or functionless • composition and hardness of the stone. 7.1.2.1 Location of stone mass The clearance rate for lower caliceal stones is less than that for stones located elsewhere in the kidney. The clearance rate for upper pole stones is faster than for stones in the lower pole. Many kidney stones are located in the lower calix. The best way to treat these stones is debatable. Most residual fragments are lodged in the lower caliceal system. These stones either originate in the lower pole calises or gravitate there from other locations. It is still unknown why stones preferentially develop in the lower pole calices, although the accumulation of fragments in this position is most probably due to the effect of gravity. In up to 35% of patients treated using ESWL, the lower calices are incompletely cleared of disintegrated stone material. Using geometrical observations of the anatomy of the lower calix, attempts have been made to explain the incomplete clearance of fragments and to predict the outcome of ESWL treatments; however, the results are contradictory. In the absence of a geometrical explanation, the size of the stones has been found to be the most important factor (79-83). Although the geometry of the lower calix system is important in the clearance of fragments, the discriminating power is not sufficiently strong to predict the outcome of ESWL or to selecting alternative methods for stone removal (35). Caliceal physiology is another important factor (84, 85). Several authors have shown that an increased stone-free rate can be obtained with percutaneous nephrolithotomy (PNL), particularly when the stones are large (diameter >20 mm or SA > 300 mm2).The morbidity associated with PNL undoubtedly need to be taken into account. For stones with a diameter of ≤ 20 mm (surface area ~ 300 mm2), ESWL is recommended, despite the lower clearance rate of fragments. A multi-centre randomised comparison between ESWL and ureteroscopic removal of stones from the lower calyceal system failed to show a significantly better result with uretoscopy (86) (LE = 1b; GR = A). Comparison between ESWL and ureteroscopic removal of stones from the lower calix system failed to show a difference (91) LE = level of evidence; GR = grade of recommendation

LE = 1b GR = A

7.1.2.2 Total stone burden Although problems associated with stone removal increase with stone volume, there is no clear critical size. Most consider a stone diameter of 20 mm as the practical upper limit for ESWL, though some centres treat larger stones successfully with ESWL (36, 87). It is difficult to provide specific guidelines on kidney stone removal, as residual fragments occur with stones less than 20 mm (300 mm2) wide, while very large stones can be disintegrated using only one ESWL session. These guidelines recommend ESWL as the first choice of treatment for stones with a diameter ≤ 20 mm (300 mm2). For stones with a diameter ≥20 mm (300 mm2), PNL could be considered, although ESWL may still be an option. For stones with an area > 40 x 30 mm (1200 mm2) the combination of PNL and ESWL (sandwich approach) carries success rates of 71-96% with acceptable morbidity and complications. The use of ESWL after PNL seems to be more effective than using PNL after ESWL. The risk of complications for either combined treatment or PNL alone is higher than for ESWL monotherapy. With a solitary kidney, it might be possible to try ESWL monotherapy first, even if the stone has an area > 40 x 30 mm (1200 mm2) (75). 7.1.2.3 Composition and hardness of the stone ESWL monotherapy of large calcium- or struvite-containing stones provides reasonable results for stone removal and complications (76). About 1% of patients treated for urinary tract stones by ESWL have cystine stones. A total of 76% of cystine stones have a maximum diameter > 25 mm (only 29% of all patients with stones have stones of this size). Up to 66% more ESWL sessions and shock waves are needed to achieve

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satisfactory results with large cystine stones than with other types of stone (88). Instead of multiple ESWL sessions, PNL (possibly combined with ESWL) is an effective treatment for all other cystine stones (88, 89). Note that smooth cystine stones are much more susceptible than rough stones to shock waves (90). Stone composition can be important in the disintegration and subsequent elimination of fragments. Stones made of uric acid and calcium oxalate dihydrate have a better coefficient of fragmentation than those made of calcium oxalate monohydrate and cystine; success rates for these two groups of stones were 38-81% and 60-63%, respectively (12). In cystine stones 20 mm, the stone-free rate dropped to 40% (13). For cystine stones >15 mm, monotherapy ESWL is currently not recommended. 7.1.2.4 References 1. Loughlin KR. Management of urologic problems during pregnancy. Urology 1994;44(2):159-69. http://www.ncbi.nlm.nih.gov/pubmed/8048189 2. Ignatoff JM, Nelson JB. Use of extracorporeal shock wave lithotripsy in a solitary kidney with renal artery aneurysm. J Urol 1993;149(2):359-60. http://www.ncbi.nlm.nih.gov/pubmed/8426419 3. Miller NL, Lingeman JE. Management of kidney stones. BMJ 2007;334(7591):468-72. http://www.ncbi.nlm.nih.gov/pubmed/17332586 4. Wen CC, Nakada SY. Treatment selection and outcomes: renal calculi. Urol Clin North Am 2007;34(3);409-19. http://www.ncbi.nlm.nih.gov/pubmed/17678990 5. Galvin DJ, Pearle MS. The contemporary management of renal and ureteric calculi. BJU Int 2006;98(6):1283-8. http://www.ncbi.nlm.nih.gov/pubmed/17125486 6. Logarakis NF, Jewett MAS, Luymes J, D’A Honey RJ. Variation in shock wave lithotripsy. J Urol 2000;163(3):721-5 http://www.ncbi.nlm.nih.gov/pubmed/10687964 7. Di Silverio F, Gallucci M, Alpi G. Staghorn calculi of the kidney: classification and therapy. Br J Urol 1990;65(5):449-52. http://www.ncbi.nlm.nih.gov/pubmed/2354308 8. Lam HS, Lingeman JE, Barron M, Newman DM, Mosbaugh PG, Steele RE, Knapp PM, Scott JW, Nyhuis A, Woods JR. Staghorn calculi: analysis of treatment results between initial percutaneous nephrostolithotomy and extracorporeal shock wave lithotripsy monotherapy with reference to surface area. J Urol 1992;147(5):1219-25. http://www.ncbi.nlm.nih.gov/pubmed/1569653 9. Lingeman JE, Newmann D, Mertz JH, Mosbaugh PG, Steele RE, Kahnoski RJ, Coury TA, Woods JR. Extracorporeal shock wave lithotripsy: the Methodist Hospital of Indiana experience. J Urol 1986;135(6):1134-7. http://www.ncbi.nlm.nih.gov/pubmed/3520015 10. Politis G, Griffith DP. ESWL: stone free efficacy based upon stone size and location. World J Urol 1987;5:225-8. 11. Lingeman JE, Coury TA, Newman DM, Kahnoski RJ, Mertz JH, Mosbaugh PG, Steele RE, Woods JR. Comparison of results and morbidity of percutaneous nephrostolithotomy and extracorporeal shock wave lithotripsy. J Urol 1987;138(3):485-90. http://www.ncbi.nlm.nih.gov/pubmed/3625845 12. Mays N, Challah S, Patel S, Palfrey E, Creeser R, Vadera P, Burney P. Clinical comparison of extracorporeal shock wave lithotripsy and percutaneous nephrolithotomy in treating renal calculi. BMJ 1988;297(6643):253-8. http://www.ncbi.nlm.nih.gov/pubmed/3416143 13. Graff J, Diederichs W, Schulze H. Long term follow-up in 1,003 extracorporeal shock wave lithotripsy patients. J Urol 1988;140(3):479-83. http://www.ncbi.nlm.nih.gov/pubmed/3411655 14. Hochey NM, Lingeman JE, Hutchinson CL. Relative efficacy of extracorporeal shock wave lithotripsy and percutaneous nephrolithotomy in the management of cystine calculi. J Endourol 1989;3:273-5. 15. Lingeman JE. Relative roles of extracorporeal shock wave lithotripsy and percutaneous nephrolithotomy. In: Lingeman JE, Newman DM, eds. Shock Wave Lithotripsy 2: Urinary and Biliary Lithotripsy. Vol 1. New York: Plenum Press, 1989, pp. 303-308. 16. Gallucci M, Alpi G, Cassanelli A et al. Six-year follow-up in patients treated with PCNL and ESWL for staghorn stones. J Endourol 1993;7(Suppl 1):S105.

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Tiselius HG, Ringdén I. Stone treatment index: a mathematical summary of the procedure for removal of stones from the urinary tract. J Endourol 2007;21(11):1261-70. http://www.ncbi.nlm.nih.gov/pubmed/18042012 18. Villanyi KK, Szekely JG, Farkas LM, Javor E, Pusztai C. Short term changes in renal function after extracorporeal shock wave lithotripsy in children. J Urol 2001;166(1):222-4. http://www.ncbi.nlm.nih.gov/pubmed/11435873 19. Pishchalnikov YA, McAteer JA, Williams JC Jr, Pishchalnikova IV, Vonderhaar RJ. Why stones break better at slow shock wave rates than at fast rates: in vitro study with a research electrohydraulic lithotripter. J Endourol 2006;20(8):537-41. http://www.ncbi.nlm.nih.gov/pubmed/16903810 20. Yilmaz E, Batislam E, Basar M, Tuglu D, Mert C, Basar H. Optimal frequency in extracorporeal shock wave lithotripsy: prospective randomized study. Urology 2005;66(6):1160-4. http://www.ncbi.nlm.nih.gov/pubmed/16360432 21. Locke DR, Newman RC, Steinbock GS, Finlayson B. Extracorporeal shock-wave lithotripsy in horseshoe kidneys. Urology 1990;35(5):407-11. http://www.ncbi.nlm.nih.gov/pubmed/2336770 22. Kunzel KH, Schlocker H, Janetschek G. Arterial blood supply of horseshoe kidneys with special reference to percutaneous lithotripsy. Urol 1988;27(4):240-5. http://www.ncbi.nlm.nih.gov/pubmed/3176212 23. Jones DJ, Wickham JE, Kellett MJ. Percutaneous nephrolithotomy for calculi in horseshoe kidneys. J Urol 1991;145(3):481-3. http://www.ncbi.nlm.nih.gov/pubmed/1997693 24. Holmes SA, Eardley I, Corry DA, Nockler I, Withfield HN. The use of extracorporeal shock wave lithotripsy for medullary sponge kidneys. Br J Urol 1992;70(4):352-4. http://www.ncbi.nlm.nih.gov/pubmed/1450839 25. Vandeursen H, Baert L. Prophylactic role of extracorporeal shock wave lithotripsy in the management of nephrocalcinosis. Br J Urol 1993;71(4):392-5. http://www.ncbi.nlm.nih.gov/pubmed/8499980 26. Montanari E, Guarneri A, Zanetti G, Nespoli R, Trinchieri A. ESWL in patients with renal transplant. In: Pak CYC, Resnick MI, Preminger GM, eds. Urolithiasis. Dallas: Millett the Printer, 1996, pp. 372-374. 27. Bierkens AF, Hendrikx AJ, Lemmens WA, Debruyne FM. Extracorporeal shock wave lithotripsy for large renal calculi: the role of ureteral stents. A randomized trial. J Urol 1991;145(4):699-702. http://www.ncbi.nlm.nih.gov/pubmed/2005681 28. Pearle MS, Clayman RV. Outcomes and selection of surgical therapies of stones in the kidney and ureter. In: Coe FL, Favus MJ, Paky CYC, Parks JH, Preminger G, eds. Kidney Stones: Medical and Surgical Management. Philadelphia: Lippincott-Raven, 1996, pp. 709-755. 29. Egilmez T, Tekin MI, Gonen M, Kilinc F, Goren R, Ozkardes H. Efficacy and safety of a new-generation shockwave lithotripsy machine in the treatment of single renal or ureteral stones: Experience with 2670 patients.J Endourol 2007;21(1):23-7. http://www.ncbi.nlm.nih.gov/pubmed/17263603 30. Abe T, Akakura K, Kawaguchi M, Ueda T, Ichikawa T, Ito H, Nozumi K, Suzuki K. Outcomes of shockwave lithotripsy for upper urinary-tract stones: A large scale study at a single institution. J Endourol 2005;19(7):768-73. http://www.ncbi.nlm.nih.gov/pubmed/16190825 31. Tolon M, Miroglu C, Erol H, Tolon J, Acar D, Bazmanoglu E, Erkan A, Amato S. A report on extracorporeal shock wave lithotripsy results on 1,569 renal units in an outpatient clinic. J Urol 1991;145(4):695-8. http://www.ncbi.nlm.nih.gov/pubmed/2005680 32. Graber SF, Danuser H, Hochreiter WW, Studer UE. A prospective randomized trial comparing 2 lithotripters for stone disintegration and induced renal trauma. J Urol 2003;169(1):54-7. http://www.ncbi.nlm.nih.gov/pubmed/12478101 33. Saita A, Bonaccorsi A, Aquilino M, Guzzardi F, Lazzara A, Motta M. ESWL: comparing two analgesic techniques. Our experience. Urol Int 2004;72(Suppl 1):46-7. http://www.ncbi.nlm.nih.gov/pubmed/15133334 34. Riedler I, Trummer H, Hebel P, Hubmer G. Outcome and safety of extracorporeal shock wave lithotripsy as first-line therapy of lower pole nephrolithiasis. Urol Int 2003;71(4):350-4. http://www.ncbi.nlm.nih.gov/pubmed/14646431

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35. Danuser H, Müller R, Desoeudres B, Dobry E, Studer UE. Extracorporeal shock wave lithotripsy of lower calix calculi: how much is treatment outcome influenced by the anatomy of the collecting system? Eur Urol 2007;52(2):539-46. http://www.ncbi.nlm.nih.gov/pubmed/17400366 36. Coz F, Orvieto M, Bustos M, Lyng R, Stein C, Hinrichs A, San Francisco I. Extracorporeal shockwave lithotripsy of 2000 urinary calculi with the Modulith SL-20: success and failure according to size and location of stones. J Endourol 2000;14(3):239-46. http://www.ncbi.nlm.nih.gov/pubmed/10795612 37. Lalak NJ, Moussa SA, Smith G, Tolley DA. The Dornier Compact Delta lithotripter: the first 500 renal calculi. J Endourol 2002;16(1):3-7. http://www.ncbi.nlm.nih.gov/pubmed/11890447 38. Ozgür A, Yalm Iker N. Extracorporeal shock wave lithotripsy of renal pelviv stones with PCK stonelith lithotripter. Int Urol Nephrol 2005;37(1):9-11. http://www.ncbi.nlm.nih.gov/pubmed/16132749 39. Sun XZ, Zhang ZW. Shock wave lithotripsy for uric acid stones. Asian J Surg 2006;29(1):36-9. http://www.ncbi.nlm.nih.gov/pubmed/16428097 40. Tan YM, Yip SK, Chong TW, Wong MY, Cheng C, Foo KT. Clinical experience and results of ESWL treatment for 3,093 urinary calculi with the Storz Modulith SL 20 lithotripter at the Singapore General Hospital. Scand J Urol Nephrol 2002;36(5):363-7. http://www.ncbi.nlm.nih.gov/pubmed/12487741 41. Lalak NJ, Moussa SA, Smith G, Tolley DA. The Dornier Compact Delta lithotripter: the first 500 renal calculi. J Endourol 2002;16(1):3-7. http://www.ncbi.nlm.nih.gov/pubmed/11890447 42. Kupeli B, Biri H, Sinik Z, Karaca K, Tuncayegin A, Karaoglan U, Bozkirli I. Extracorporeal shock wave lithotripsy for lower caliceal calculi. Eur Urol 1998;34(3):203-6. http://www.ncbi.nlm.nih.gov/pubmed/9732193 43. Fialkov JM, Hedican SP, Fallon B. Reassessing the efficacy of the Dornier MFL-5000 lithotriptor. J Urol 2000;164(3 Pt 1):640-3. http://www.ncbi.nlm.nih.gov/pubmed/10953115 44. Fuselier HA, Prats L, Fontenot C, Gauthier A Jr. Comparison of mobile lithotripters at one institution: Healthtronics Lithotron, Dornier MFL-5000 and Dornier Doli. J Endourol 1999;13(8):539-42. http://www.ncbi.nlm.nih.gov/pubmed/10597121 45. Cass AS. Comparison of first-generation (Dornier HM3) and second-generation (Medstone STS) lithotripters: treatment results with 145 renal and ureteral calculi in children. J Endourol 1996;10(6):493-9. http://www.ncbi.nlm.nih.gov/pubmed/8972780 46. Newman DM, Coury T, Lingeman JE, Mertz JH, Mosbaugh PG, Steele RE, Knapp PM. Extracorporeal shock wave lithotripsy experience in children. J Urol 1986;136(1 Pt 2):238-40. http://www.ncbi.nlm.nih.gov/pubmed/3723671 47. Kramolowsky EV, Willoughby BL, Loening SA. Extracorporeal shock wave lithotripsy in children. J Urol 1987;137(5):939-41. http://www.ncbi.nlm.nih.gov/pubmed/3573189 48. Kroovand RL, Harrison LH, McCullough DL. Extracorporeal shock wave lithotripsy in childhood. J Urol 1987;138(4 Pt 2):1106-8. http://www.ncbi.nlm.nih.gov/pubmed/3656568 49. Sigman M, Laudone VP, Jenkins AD, Howards SS, Riehle R Jr, Keating MA, Walker RD. Initial experience with extracorporeal shock wave lithotripsy in children. J Urol 1987;138(4):839-41. http://www.ncbi.nlm.nih.gov/pubmed/3656542 50. Mininberg DT, Steckler R, Riehle RA Jr. Extracorporeal shock-wave lithotripsy for children. Am J Dis Child 1988;142(3):279-82. http://www.ncbi.nlm.nih.gov/pubmed/3344713 51. Moosaad A, El-Salamouni T. Results of extracorporeal shock wave lithotripsy in young children. In: Lingeman JE, Newman DM, eds. Shock Wave Lithotripsy 2: Urinary and Biliary Lithotripsy. Vol 1. New York: Plenum Press, 1989, p. 243. 52. Nijman RJM, Ackaert K, Scholtmeijer RJ, Lock TW, Schroder FH. Long-term results of extracorporeal shock wave lithotripsy in children. J Urol 1989;142(2 Pt 2):609-11. http://www.ncbi.nlm.nih.gov/pubmed/2746787 53. Frick J, Kohle R, Kunit G. Experience with extracorporeal shock wave lithotripsy in children. Eur Urol 1988;14(3):181-3. http://www.ncbi.nlm.nih.gov/pubmed/3383928

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Bohle A, Knipper A, Thomas S. Extracorporeal shock wave lithotripsy in paediatric patients. Scan J Urol Nephrol 1989;23(2):137-40. http://www.ncbi.nlm.nih.gov/pubmed/2756359 55. Marberger M, Turk C, Steinkogler I. Piezoelectric extracorporeal shock wave lithotripsy in children. J Urol 1989;142(2 Pt 1):349-52. http://www.ncbi.nlm.nih.gov/pubmed/2746751 56. Thornhill JA, Moran K, Mooney EE, Sheehan S, Smith JM, Fitzpatrick JM. Extracorporeal shockwave lithotripsy monotherapy for paediatric urinary tract calculi. Br J Urol 1990;65(6):638-40. http://www.ncbi.nlm.nih.gov/pubmed/2372678 57. Mishriki SF, Wills MI, Mukherjee A, Frank JD, Feneley RC. Extracorporeal shock wave lithotripsy for renal calculi in children. Br J Urol 1992;69(3):303-5. http://www.ncbi.nlm.nih.gov/pubmed/1568104 58. Abara E, Merguerian PA, McLorie GA, Psihramis KE, Jewett MAS, Churchill BM. Lithostar extracorporeal shock wave lithotripsy in children. J Urol 1990;144(2 Pt 2):489-91. http://www.ncbi.nlm.nih.gov/pubmed/2374227 59. Vandeursen H, Devos P, Baert L. Electromagnetic extracorporeal shock wave lithotripsy in children. J Urol 1991;145(6):1229-31. http://www.ncbi.nlm.nih.gov/pubmed/2033698 60. Alkibay T, Tokucoglu H, Karaoglan U, Karabas O, Bozkirli L, Hasanoglu E. Clinical experience with Lithostar Plus in children. J Endourol 1992;6:407-9. 61. Myers DA, Mobley TB, Jenkins JM, Grine WB, Jordan WR. Pediatric low energy lithotripsy with the Lithostar. J Urol 1995;153(2):453-7. http://www.ncbi.nlm.nih.gov/pubmed/7815618 62. Lin CM. Extracorporeal shock wave lithotripsy in children: experience with the multifunctional lithotripter MFL 5000. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi 1992;33(5):357-62. http://www.ncbi.nlm.nih.gov/pubmed/1296446 63. Zanetti G, Montanari E, Guarneri A, Seveso M, Trinchieri A, Rovera F, Austoni E, Pisani E. Extracorporeal shock wave lithotripsy with MPL9000 for the treatment of urinary stones in paediatric patients. Arch Ital Urol Androl 1993;65(6):671-3. http://www.ncbi.nlm.nih.gov/pubmed/8312950 64. Elsobky E, Sheir KZ, Madbouly K, Mokhtar AA. Extracorporeal shock wave lithotripsy in children: experience using two second-generation lithotripters. BJU Int 2000;86(7):851-6. http://www.ncbi.nlm.nih.gov/pubmed/11069413 65. Drach GW, Dretler S, Fair W, Finlayson B, Gillenwater J, Griffith D, Lingeman J, Newman D. Report of the United States cooperative study of extracorporeal shock wave lithotripsy. J Urol 1986;135(6): 1127-33. http://www.ncbi.nlm.nih.gov/pubmed/3520014 66. Lingeman JE, Coury TA, Newman DM, Kahnoski RJ, Mertz JH, Mosbaugh PG, Steele RE, Woods JR. Comparison of results and morbidity of percutaneous nephrostolithotomy and extracorporeal shock wave lithotripsy. J Urol 1987;138(3):485-90. http://www.ncbi.nlm.nih.gov/pubmed/3625845 67. Rigatti P, Francesca F, Montorsi F, Consonni P, Guazzoni G, Di Girolamo V. Extracorporeal lithotripsy and combined surgical procedures in the treatment of renoureteral stone disease: our experience with 2,995 patients. World J Surg 1989;13(6):765-74. http://www.ncbi.nlm.nih.gov/pubmed/2623887 68. Portis AJ, Yan Y, Pattaras JG, Andreoni C, Moore R, Clayman RV. Matched pair analysis of shock wave lithotripsy effectiveness for comparison of lithotriptors. J Urol 2003;169(1):58-62. http://www.ncbi.nlm.nih.gov/pubmed/12478102 69. Graber SF, Danuser HJ, Hochreiter WW, Studer UE. A prospective randomized trial comparing 2 lithotriptors for stone disintegrations and induced renal trauma. J Urol 2003;169(1):54-7. http://www.ncbi.nlm.nih.gov/pubmed/12478101 70. Mobley TB, Myers DA, Grine WB, Jenkins JM, Jordan WR. Low energy lithotripsy with the Lithostar: treatment results of 19,962 renal and ureteral calculi. J Urol 1993;149(6):1419-24. http://www.ncbi.nlm.nih.gov/pubmed/8501779 71. Grasso M, Loisides P, Beaghler M, Bagley D. The case for primary endoscopic management of upper urinary tract calculi: I. A critical review of 121 extracorporeal shock-wave lithotripsy failures. Urology 1995;45(3):363-71. http://www.ncbi.nlm.nih.gov/pubmed/7879329

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72.

Murray MJ, Chandoke PS, Berman CJ, Sankey NE. Outcome of extracorporeal lithotripsy monotherapy for large renal calculi: effect of stone and collecting system surface areas and costeffectiveness of treatment. J Endourol 1995;9(1):9-13. http://www.ncbi.nlm.nih.gov/pubmed/7780436 73. Ackermann D, Claus R, Zehntner CH, Schreiber K. Extracorporeal shock wave lithotripsy for large renal stones. To what size is extracorporeal shock wave lithotripsy alone feasible? Eur Urol 1988; 15(1-2):5-8. http://www.ncbi.nlm.nih.gov/pubmed/3215235 74. Burns T, Stein J, Tauber R. Extracorporeal piezoelectric shock wave lithotripsy as mono- and multiple therapy of large renal calculi including staghorn stones in unanaesthetized patients under semiambulant conditions. Br J Urol 1995;75(4):435-40. http://www.ncbi.nlm.nih.gov/pubmed/7788251 75. Baltaci S, Köhle R, Kunit G, Joos H, Frick J. Long-term follow-up after extracorporeal shock wave lithotripsy of large kidney stones. Eur Urol 1992;22(2):106-11. http://www.ncbi.nlm.nih.gov/pubmed/1478223 76. Michaels EK, Fowler JE Jr. ESWL monotherapy for large volume renal calculi: efficacy and morbidity. Urology 1989;34(2):96-9. http://www.ncbi.nlm.nih.gov/pubmed/2669309 77. Sulaiman MN, Buchholz NP, Clark PB. The role of ureteral stent placement in the prevention of Steinstrasse. J Endourol 1999;13(3):151-5. http://www.ncbi.nlm.nih.gov/pubmed/10360492 78. Musa AA. Use of double-J stents prior to shock wave lithotripsy is not beneficial: results of a prospective randomized study. Int Urol Nephrol. 2008;40(1):19-22. http://www.ncbi.nlm.nih.gov/pubmed/17394095 79. Srivastava A, Zaman W, Singh V, Mandhani A, Kumar A, Sing U. Efficacy of extracorporeal shock wave lithotripsy for solitary lower caliceal stone: a statistical model. BJU Int 2004;93(3):364-8. http://www.ncbi.nlm.nih.gov/pubmed/14764139 80. Ather MH, Abid F, Akhtar S, Khawaja K. Stone clearance in lower pole nephrolithiasis after extracorporeal shock wave lithotrips–the controversy continues. BMC Urol 2003;3:1. http://www.ncbi.nlm.nih.gov/pubmed/12546707 81. Albala DM, Assimos DG, Clayman RV, Denstedt JD, Grasso M, Gutierrez-Aceves J, Khan RI, Leveillee RJ, Lingeman JE, Macaluso JN Jr, Munch LC, Nakada SY, Newman RC, Pearle MS, Preminger GM, Teichman J, Woods JR. Lower pole I: a prospective randomized trial of extracorporeal shock wave lithotripsy and percutaneous nephrolithotomy for lower pole nephrolithiasis–initial results. J Urol 2001;166(6):2072-80. http://www.ncbi.nlm.nih.gov/pubmed/11696709 82. Sorensen CM, Chandoke PS. Is lower pole caliceal anatomy predictive of extracorporeal shock wave lithotripsy success for primary lower pole kidney stones? J Urol 2002;168(6):2377-82. http://www.ncbi.nlm.nih.gov/pubmed/12441921 83. Sistla BW, Devasia A, Ganavaj I, Chacko NK, Kekre NS, Gopalarishnan G. Radiographic anatomical factors do not predict clearance of lower caliceal calculus by SWL. Proceedings 22nd World Congress on Endourology and SWL, India, 2004. J Endourol 2004;18(S1):Abstr 53. 84. Poulakis V, Dahm P, Witzsch U, de Vries R, Remplik J, Becht E. Prediction of lower pole stone clearance after shock wave lithotripsy using an artificial neural network. J Urol 2003;169(4):1250-6. http://www.ncbi.nlm.nih.gov/pubmed/12629337 85. Talic RF, El Faqih SR. Extracorporeal shock wave lithotripsy for lower pole nephrolithiasis: efficacy and variables that influence treatment outcome. Urol 1998;51(4):544-7. http://www.ncbi.nlm.nih.gov/pubmed/9586604 86. Pearle MS, Lingeman JE, Leveillee R, Kuo R, Preminger GM, Nadler RB, Macaluso J, Monga M, Kumar U, Dushinski J, Albala DM, Wolf JS Jr, Assimos D, Fabrizio M, Munch LC, Nakada SY, Auge B, Honey J, Ogan K, Pattaras J, McDougall EM, Averch TD, Turk T, Pietrow P, Watkins S. Prospective, randomized trial comparing shock wave lithotripsy and ureteroscopy for lower pole caliceal calculi 1 cm or less. J Urol 2005;173(6):2005-9. http://www.ncbi.nlm.nih.gov/pubmed/15879805 87. Rassweiler JJ, Renner C, Chaussy C, Thürhoff S. Treatment of renal stones by extracorporeal shockwave lithotripsy: an update. Eur Urol 2001;39(2):187-99. http://www.ncbi.nlm.nih.gov/pubmed/11223679 88. Katz G, Lencovsky Z, Pode D, Shapiro A, Caine M. Place of extracorporeal shock-wave lithotripsy (ESWL) in the management of cystine calculi. Urology 1990;36(2):124-8. http://www.ncbi.nlm.nih.gov/pubmed/2385879

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89. Cranidis AI, Karayannis AA, Delakas DS, Livadas CE, Anezinis PE. Cystine stones: the efficacy of percutaneous and shock wave lithotripsy. Urol Int 1996;56(3):180-3. http://www.ncbi.nlm.nih.gov/pubmed/8860740 90. Bhatta KM, Prien EL Jr, Dretler SP. Cystine calculi-rough and smooth: a new clinical distinction. J Urol 1989;142(4):937-40. http://www.ncbi.nlm.nih.gov/pubmed/2795746

7.2 Percutaneous removal of renal stones Most renal stones can be removed using percutaneous surgery. However, if ESWL is available, PNL should be used only when the outcome is likely to be less favourable after ESWL. Although PNL is minimally invasive, it is a surgical procedure and, to avoid complications, the patient’s anatomy must be considered. Pre-procedural KUB (plain abdominal film of the kidneys, ureters and bladder) and intravenous urography (IVU) or computed tomography (CT) scans can be used to plan access and determine likely success. For example, whether stones will respond poorly to ESWL (e.g. stones made of cystine, calcium oxalate monohydrate, brushite) or if fragments are unlikely to pass (e.g. large stones, stones in caliceal diverticulae or horseshoe kidneys). Pre-procedural sonography and fluoroscopy of the kidney and the surrounding structures are recommended: • t o determine the optimal access site and stone position in the kidney (ventral or dorsal) • t o ensure organs adjacent to the kidney (e.g. spleen, liver, large bowel, pleura, lungs) are not within the planned percutaneous path (1,2). Percutaneous puncture may be easier if a ureteral balloon catheter is used to dilate and opacify the collecting system. The catheter also prevents fragments falling into the ureter. The puncture can be made under combined ultrasound (US) and X-ray control or under biplanar fluoroscopy. Ultrasound makes it easier to identify, and therefore avoid damage to, neighbouring organs (3). In rare cases, where there are anatomical anomalies, CT-guided renal access may be an option (4). The access site used most often is the dorsal calix of the lower pole. In the least traumatic access, the puncture site on the skin lies in the extension of the long axis of the target calix and the puncture passes through the papilla. The absence of major blood vessels results in only minimal bleeding. This is the safest access point because it uses the infundibulum as a conduit to the pelvis. A subcostal or supracostal upper pole access has been used frequently with good success for the treatment of staghorn stones. Renal tract dilatation is possible using the Amplatz system, balloon or metallic dilators, with choice depending on experience, availability and costs. Although standard nephroscopes have shaft calibres of 24-30 F, ‘mini-perc’ instruments have smaller shaft calibres of 12-20 F and may therefore have a lower rate of tract dilation-related complications (e.g. bleeding or renal trauma). As treatment time increases with stone size, this method is recommended only for stones with a diameter < 20 mm (5). The value of mini-perc in adults has not been determined, but mini-perc is the method of choice for percutaneous stone removal in children (6-8). In lower pole stones, ESWL, PNL and flexible uretero-nephroscopy are competing procedures with different success and complication rates and patient acceptance (9-10) (LE = 1b; GR = A). In lower pole stones, ESWL, PNL and flexible uretero-nephroscopy are competing procedures with different success and complication rates and patient acceptance (9-10). LE = level of evidence; GR = grade of recommendation

LE = 1b GR = A

Stones can be extracted straightaway, or following disintegration by US-, electrohydraulic-, laseror hydro-pneumatic probes. Continuous removal of small fragments by suction or extraction is preferred to reduce the number of residual fragments. In complicated cases or when a second intervention is necessary, a self-retaining balloon nephrostomy tube tamponading the tract and maintaining access to the collecting system is used at the end of the procedure. In uncomplicated cases, tubeless percutaneous nephrolithotomy, with or without tract fulguration, application of a sealant or double-J stenting, is a safe alternative (8,11) (LE = 1b; GR = A). To reduce the number of residual fragments, small fragments should be continuously LE = 1b removed. In uncomplicated cases, tubeless percutaneous nephrolithotomy, with or without GR = A tract fulguration, application of a sealant or double-J stenting, is a safe alternative (8, 11). LE = level of evidence; GR = grade of recommendation 7.2.1 Complications Major, but rare, complications are lesions to adjacent organs, which can be avoided by US-guided puncture. Bleeding is generally avoided by an anatomically oriented access, as described above. Sepsis and ‘transurethral resection syndrome’ indicate a poor technique that has resulted in high pressure within the

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collecting system during manipulation. These problems can be avoided by using continuous flow instruments or an Amplatz system (1,8). Major bleeding during the procedure requires termination of the operation, placement of a nephrostomy tube, and secondary intervention at a later date. In most cases, venous bleeding stops when the nephrostomy tube is clamped for some hours. Persistent or late secondary bleeding is caused by an arterial injury and can be managed by angiographic super-selective embolisation. As with open surgery, percutaneous procedures have different degrees of difficulty. The procedure is more likely to be difficult when anatomical conditions limit the space available for the initial puncture, dilatation and instrumentation, such as stones in diverticula, stones completely filling the target calix, or a large stone burden caused by complete or partial staghorn stones. In these cases, only experienced surgeons should carry out the procedure. 7.2.2 References 1. Kim SC, Kuo RL, Lingeman JE. Percutaneus nephrolithotomy: an update. Curr Opin Urol 2003;13(3):235-41. http://www.ncbi.nlm.nih.gov/pubmed/12692448 2. Knoll T, Michel MS, Alken P. Surgical Atlas. Percutaneous nephrolithotomy: the Mannheim technique. BJU Int 2007;99(1):213-31. http://www.ncbi.nlm.nih.gov/pubmed/17227510 3. Osman M, Wendt-Nordahl G, Heger K, Michel MS, Alken P, Knoll T. Percutaneous nephrolithotomy with ultrasonography-guided renal access: experience from over 300 cases. BJU Int 2005;96(6):875-8. http://www.ncbi.nlm.nih.gov/pubmed/16153221 4. Matlaga BR, Shah OD, Zagoria RJ, Dyer RB, Streem SB, Assimos DG. Computerized tomography guided access for percutaneous nephrolithotomy. J Urol 2003;170(1):45-7. http://www.ncbi.nlm.nih.gov/pubmed/12796641 5. Lahme S, Bichler KH, Strohmaier WL, Gotz T. Minimally invasive PCNL in patients with renal pelvic and caliceal stones. Eur Urol 2001;40(6):619-24. http://www.ncbi.nlm.nih.gov/pubmed/11805407 6. Jackman SV, Hedican SP, Peters CA, Docimo SG. Percutaneous nephrolithotomy in infants and preschool age children: experience with a new technique. Urology 1998;52(4):697-701. http://www.ncbi.nlm.nih.gov/pubmed/9763096 7. Desai M, Ridhorkar V, Patel S, Bapat S, Desai M. Pediatric percutaneous nephrolithotomy: assessing impact of technical innovations on safety and efficacy. J Endourol 1999;13(5):359-64. http://www.ncbi.nlm.nih.gov/pubmed/10446796 8. Feng MI, Tamaddon K, Mikhail A, Kaptein JS, Bellman GC. Prospective randomized study of various techniques of percutaneous nephrolithotomy. Urology 2001;58(3):345-50. http://www.ncbi.nlm.nih.gov/pubmed/11549477 9. Pearle MS, Lingeman JE, Leveillee R, Kuo R, Preminger GM, Nadler RB, Macaluso J, Monga M, Kumar U, Dushinski J, Albala DM, Wolf JS Jr, Assimos D, Fabrizio M,Munch LC, Nakada SY, Auge B, Honey J, Ogan K, Pattaras J, McDougall EM, Averch TD, Turk T, Pietrow P, Watkins S. Prospective, randomized trial comparing shock wave lithotripsy and ureteroscopy for lower pole caliceal calculi 1 cm or less. J Urol 2005;173(6):2005-9. http://www.ncbi.nlm.nih.gov/pubmed/15879805 10. Albala DM, Assimos DG, Clayman RV, Denstedt JD, Grasso M, Gutierrez-Aceves J, Kahn RI, Leveillee RJ, Lingeman JE, Macaluso JN Jr, Munch LC, Nakada SY, Newman RC, Pearle MS, Preminger GM, Teichman J, Woods JR. Lower pole I: a prospective randomized trial of extracorporeal shock wave lithotripsy and percutaneous nephrostolithotomy for lower pole nephrolithiasis-initial results. J Urol 2001;166(6):2072-80. http://www.ncbi.nlm.nih.gov/pubmed/11696709 11. Desai MR, Kukreja RA, Desai MM, Mhaskar SS, Wani KA, Patel SH, Bapat SD. A prospective randomized comparison of type of nephrostomy drainage following percutaneous nephrostolithotomy: large bore versus small bore versus tubeless. J Urol 2004;172(2):565-7. http://www.ncbi.nlm.nih.gov/pubmed/15247731 12. Troxel SA, Low RK. Renal intrapelvic pressure during percutaneous neprolithotomy and its correlation with the development of postoperative fever. J Urol 2002;168(4 Pt 1):1348-51. http://www.ncbi.nlm.nih.gov/pubmed/12352390

7.3

Retrograde removal of ureteral and renal stones (retrograde intrarenal surgery [RIRS])

During the past 20 years, ureterorenoscopy (URS) has dramatically changed the management of ureteral calculi and is now used extensively in urology centres worldwide. URS is, however, a more invasive technique than ESWL, and the treatment of choice for ureteral stones is therefore controversial. For renal calculi, ESWL and

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PNL are the recommended primary treatment options. Following the wider availability and improvement of flexible URS, its value in removing renal calculi has to be determined. This latter procedure is termed retrograde intrarenal surgery (RIRS). 7.3.1

Standard endoscopic technique

Before URS, antibiotic prophylaxis should be administered to ensure sterile urine (4, 5). LE = 4 GR = C LE = level of evidence; GR = grade of recommendation The basic endoscopic technique has been standardised (1-3). • Fluoroscopic equipment must be available in the operating room. • Pre-operative imaging of urinary tract confirms location of stone and identifies anatomical abnormalities • Under general anaesthesia, spinal anaesthesia or intravenous sedation, place patient in lithotomy position. • Begin procedure using rigid or flexible cystoscopy. • Introduce a safety wire (usually an 0.035-inch, non-hydrophylic, floppy tip) under endoscopic and fluoroscopic control and secure it to drapes. • The safety guide wire prevents the risk of false passage if there is perforation. • Intramural ureteral dilatation is not routine, but depends on size of ureteroscope and width of ureter. • Retrograde access to upper urinary tract is usually obtained under video guidance, with a rigid ureteroscope alongside safety wire. • Flexible ureteroscopes are most easily introduced via an additional guidewire or through an ureteral access sheath, although last-generation scopes allow bare passage in experienced hands. • Endoscopic lithotripsy is based on the use of different devices to break the stone into dust or fragments small enough for extraction. The stone may be fragmented by ultrasonic lithotripsy, electrohydraulic lithotripsy (EHL), laser lithotripsy or ballistic (= pneumatic) lithotripsy. Lithotripsy devices are described in Appendix 1. Small stones and fragments are best retrieved with a basket or a forceps (6-9). Stone extraction with a basket without endoscopic visualisation of the stone (blind basketing) should not be performed (see Chapter 9). LE = level of evidence; GR = grade of recommendation

LE = 4 GR = C

Irrigation with a piston syringe is needed to ensure good direct vision. Take care to avoid high-pressure irrigation as this is associated with an increased complication rate. Stent placement at the end of the procedure is optional and debatable (10-16). Most urologists leave the stent for about 1 week, although there is no evidence regarding the optimal interval. Patients should be followed up by plain abdominal film (IVU), CT or US. 7.3.2 Anaesthesia Improvement of ureteroscopes and stone retrieval instruments has enabled ureteroscopic procedures for ureteral calculi to be carried out using sedation analgesia with similar success rates (88-97%) to those using general anaesthesia (17-19). URS is particularly useful for removal of distal ureteral stones in women (20). For treatment of renal calculi with flexible URS, general anaesthesia may help minimise movements of the kidney. 7.3.3 Assessment of different devices 7.3.3.1 Ureteroscopes Rigid and flexible ureteroscopes are available. In most cases, miniaturisation (and regular pre-stenting of the ureter) avoid the need to dilate the intramural ureter and associated complications (21-23). The small tip diameters (5.0-7.5 F) allow easier and safer progression of rigid ureteroscopes up to the proximal ureter. Flexible ureteroscopes (5-7.5 F) are suitable for access to the upper part of the ureter and renal collecting system, without dilatation of the intramural ureter in most cases (3, 24-27). In the lower ureter, a flexible ureteroscope is less suitable because of its tendency to fall back into the bladder. Current scopes provide higher tip deflections and are more durable than the older generation (28-30). 7.3.3.2 Disintegration devices Disintegration devices are discussed in Appendix 1. Holmium:yttrium aluminium garnet (Ho:YAG) laser lithotripsy is a reliable method for treating urinary calculi, regardless of hardness (31-34) and is the preferred method when carrying out flexible URS (3, 34-37). Ho:YAG laser lithotripsy is the preferred method when carrying out flexible URS (3, 34-37). LE = 3 GR = B/C LE = level of evidence; GR = grade of recommendation 34

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A 365 μm laser fibre is the best choice for ureteral stones.The 200 μm fibre preserves tip deflection of flexible ureterorenoscopes and allows fragmentation of intracaliceal calculi (38). If manipulated with care, laser lithotripsy is safe; however, significant side-effects may be more common with EHL (39-43). For distal ureteral stones, Ho:YAG lithotripsy give better stone-free results at 3 months than EHL (97% versus 87%, respectively) (39). Ballistic lithotripters (pneumatic or electropneumatic), using a 2.4 F probe in a semi-rigid ureteroscope, provide excellent fragmentation rates (90-96%). Low cost with simple and safe handling are major advantages of this type of device (44-46). Nevertheless, stone migration towards the renal pelvis from the mid- or proximal ureter may limit the use of ballistic lithotripsy (47,48). 7.3.3.3 Baskets and forceps Ureteroscopic removal of small ureteral stones with a basket or forceps is a relatively quick procedure with a lower morbidity rate than that associated with lithotripsy (8,9). Several new endoscopic stone retrieval baskets are available. Nitinol baskets preserve tip deflection of flexible ureterorenoscopes and the tipless LE = 2b/3 design reduces the risk of mucosa injury (38). Nitinol baskets are most suitable for use GR = B in flexible URS. LE = level of evidence; GR = grade of recommendation Nitinol baskets are more vulnerable than a stainless steel basket, and laser or EHL might break the wires of the basket (49,50). 7.3.3.4 Dilatation, ureteral access sheaths and stenting Attempts to modify the standard technique of dilatation and stenting have been carried out during recent years. The use of thin ureteroscopes has resulted in reduced dilatation (0-40%), operating time and post-operative ureteral stenting. Today, ureteral access sheaths are used widely to facilitate retrograde manipulation in the proximal ureter and the kidney. Available access sheaths (9-16 F) have a hydrophilic surface and are introduced via a guide wire with the tip placed in the proximal ureter. Operating time might be reduced for higher stone burdens where multiple ureter passages are necessary (51-53). Another advantage is the maintenance of a low-pressure irrigation system by continuous outflow through the sheath (54-55). First follow-up series indicate a low rate of ureteral strictures, comparable to sheathless URS (56). Stenting following uncomplicated URS is optional (see also Chapter 9). LE = 1a GR = A LE = level of evidence; GR = grade of recommendation Several randomised prospective trials have found that routine stenting after uncomplicated URS may not be necessary (10-16,57-60). Ureteric stenting is associated with lower urinary tract symptoms and pain that can, even if only temporary, reduce quality of life (58-64). In addition, complications associated with ureteral stenting, include: • stent migration • urinary tract infection • breakage • encrustation • obstruction. Moreover, ureteral stents increase the overall cost of URS. Unless a pull-string is attached to the distal end of the stent, secondary cystoscopy is required for stent removal (13). Indications for stenting after the completion of URS, including: • ureteral injury • stricture • solitary kidney • renal insufficiency • a large residual stone burden. 7.3.4 Clinical results 7.3.4.1 Renal calculi Current guidelines suggest ESWL is the therapy of first choice for intrarenal calculi ≤ 20 mm, with PNL used to treat larger stones (69,70). However, as the results using ESWL for lower pole stones are poor, the use of

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primary PNL might be justified for smaller calculi starting from ≥ 15 mm in this location (69-73). Flexible URS may offer an alternative to ESWL or PNL, but to date, this procedure has not been mentioned by most guidelines. Unfortunately, few comparative data are available on the use of flexible URS for renal calculi. The latest-generation ureterenoscopes allow access to almost all calices. Together with laser lithotripsy, ureteral access sheaths and nitional retrieval tools, enable the removal of most calculi. Stone-free rates for calculi ≤1.5 cm are 50-80% (51,74-78); larger stones can also be treated successfully. Flexible URS has been demonstrated to be an effective treatment for ESWL-refractory calculi (79-80). LE = level of evidence; GR = grade of recommendation

LE = 1b GR = A

Flexible URS has not been recommended as a first-line treatment for renal calculi, and there are no valid data to support such a recommendation. However, because using ESWL for lower pole stones has poor results, flexible URS could become a reliable first-line treatment for lower pole stones ≤ 1.5 cm. Some authors have reported the combination of flexible URS with ESWL or PNL to improve stonefree rates (81-82). The simultaneous use of flexible URS and PNL may offer an attractive approach to achieve complete stone-free states after one procedure and to avoid multiple percutaneous tracts. However, such an approach requires significant experience and equipment and is therefore not used routinely. 7.3.5. Complications A meta-analysis published by the EAU-AUA Guidelines panel has evaluated the most relevant complications of sepsis, Steinstrasse, stricture, ureteral injury and urinary tract infection (UTI). URS for ureteral calculi had minimal side-effects (65-66). Serious complications, including death and loss of kidney, were rare, and data from which to estimate their rates of occurrence were not available. Complication rates for the overall population by treatment, size, and location are shown in Table 5, Chapter 9 Significant acute complication rates of 11% and 9% have been reported for the proximal and distal ureters, respectively (65, 66). Ureteral strictures were the only long-term complication (estimated rate 1%). There is a pronounced relationship between the complication rate, equipment used, and/or expertise of the urologist (83). The overall complication rates reported in the recent literature are 5–9%, with a 1% rate of significant complications (7, 44, 46, 83-86). The major acute complication remains ureteral avulsion (44,87); autologous transplantation or uretero-ileoplasty are the methods of choice in these cases. Ureteral perforation at the site of the stone is the primary risk factor for stricture. Most perforations seen during the procedure are successfully treated with approximately 2 weeks of stenting (46,83,85). URS can also be applied when ESWL might be contraindicated or ill-advised. LE = 4 GR = C LE = level of evidence; GR = grade of recommendation URS can be carried out safely in patients for whom stopping anticoagulants is unsafe (42). In addition, the success of URS is not affected by patient habitus. Morbidly obese patients can be treated with success rates and complication rates similar to those in the general population (88, 89) and has been used safely during pregnancy (90-91). However, URS should be limited to carefully selected patients. Finally, in selected cases, URS can be used safely to treat bilateral ureteral stones simultaneously (92, 93). 7.3.6 Conclusions Improvements in the design of ureteroscopes, accessories and URS have significantly improved the successful removal of ureteral stones along with a decrease in morbidity (65,66). In experienced hands, the new generation of ureteroscopes can treat of proximal and distal ureteric stones. Flexible URS is an effective treatment for ESW-refractory renal calculi. Further studies are needed to determine whether flexible URS can be a first-line treatment of renal calculi where, depending on size and location, ESWL or PNL are currently procedures of first choice. For ureteric calculi, both ESWL and URS are acceptable alternatives. Although ESWL is less invasive and has the lowest complication rates, a stone-free state can be achieved faster using URS. For larger calculi, the stonefree rates achieved using URS might be advantageous. Randomised and prospective studies to compare all forms of stone removal for renal and ureteric calculi are needed.

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7.3.7 1.

References Elashry OM, Elbahnasy AM, Rao GS, Nakada SY, Clayman RV. Flexible ureteroscopy: Washington University experience with the 9.3F and 7.5F flexible ureteroscopes J Urol 1997;157(6):2074-80. http://www.ncbi.nlm.nih.gov/pubmed/9146583 2. Beiko DT, Denstedt JD. Advances in ureterorenoscopy. Urol Clin North Am 2007;34(3):397-408. http://www.ncbi.nlm.nih.gov/pubmed/17678989 3. Smith RD, Patel A. Impact of flexible ureterorenoscopy in current management of nephrolithiasis. Curr Opin Urol 2007;17(2):114-9. http://www.ncbi.nlm.nih.gov/pubmed/17285021 4. Knopf HJ, Graff HJ, Schulze H. Perioperative antibiotic prophylaxis in ureteroscopic stone removal. Eur Urol 2003;44(1):115-8. http://www.ncbi.nlm.nih.gov/pubmed/12814685 5. Grabe M. Perioperative antibiotic prophylaxis in urology. Curr Opin Urol 2001;11(1):81-5. http://www.ncbi.nlm.nih.gov/pubmed/11148751 6. Netto NR Jr, Claro Jde A, Esteves SC, Andrade EF. Ureteroscopic stone removal in the distal ureter. Why change?. J Urol 1997;157(6):2081-3. http://www.ncbi.nlm.nih.gov/pubmed/9146584 7. Harmon WJ, Sershon PD, Blute ML, Patterson DE, Segura JW. Ureteroscopy: current practice and long-term complications. J Urol 1997;157(1):28-32. http://www.ncbi.nlm.nih.gov/pubmed/8976208 8. Monga M. Accessory instrumentation for ureteroscopy. Curr Opin Urol 2004;14(2):107-9. http://www.ncbi.nlm.nih.gov/pubmed/15075839 9. Portis AJ, Rygwall R, Holtz C, Pshon N, Laliberte M. Ureteroscopic laser lithotripsy for upper urinary tract calculi with active fragment extraction and computerized tomography followup. J Urol 2006;175(6):2129-33. http://www.ncbi.nlm.nih.gov/pubmed/16697818 10. Byrne RR, Auge BK, Kourambas J, Munver R, Delvecchio F, Preminger GM. Routine ureteral stenting is not necessary after ureteroscopy and ureteropyeloscopy: a randomized trial. J Endourol 2002;16(1):9-13. http://www.ncbi.nlm.nih.gov/pubmed/11890453 11. Srivastava A, Gupta R, Kumar A, Kapoor R, Mandhani A. Routine stenting after ureteroscopy for distal ureteral calculi is unnecessary: results of a randomized controlled trial. J Endourol 2003;17(10): 871-4. http://www.ncbi.nlm.nih.gov/pubmed/14744352 12. Jeong H, Kwak C, Lee SE. Ureteric stenting after ureteroscopy for ureteric stones: a prospective randomized study assessing symptoms and complications. BJU Int 2004;93(7):1032-1034; discussion 1034-5. http://www.ncbi.nlm.nih.gov/pubmed/15142158 13. Damiano R, Autorino R, Esposito C, Cantiello F, Sacco R, de Sio M, D’Armiento M. Stent positioning after ureteroscopy for urinary calculi: the question is still open. Eur Urol 2004;46(3):381-7. http://www.ncbi.nlm.nih.gov/pubmed/15306112 14. Keeley FX Jr, Timoney AG. Routine stenting after ureteroscopy: think again. Eur Urol 2007;52(3):642-4. http://www.ncbi.nlm.nih.gov/pubmed/17275989 15. Nabi G, Cook J, N’Dow J, McClinton S. Outcomes of stenting after uncomplicated ureteroscopy: systematic review and meta-analysis. BMJ 2007;334(7593):572. http://www.ncbi.nlm.nih.gov/pubmed/17311851 16. Haleblian G, Kijvikai K, de la Rosette J, Preminger G. Ureteral stenting and urinary stone management: a systematic review. J Urol 2008;179(2):424-30. http://www.ncbi.nlm.nih.gov/pubmed/18076928 17. Miroglu C, Saporta L. Transurethral ureteroscopy: is local anesthesia with intravenous sedation sufficiently effective and safe? Eur Urol 1997;31(1):36-9. http://www.ncbi.nlm.nih.gov/pubmed/9032532 18. Cybulski PA, Joo H, Honey RJ. Ureteroscopy: anesthetic considerations. Urol Clin North Am 2004;31(1):43-7, viii. http://www.ncbi.nlm.nih.gov/pubmed/15040400 19. Rao MP, Kumar S, Dutta B, Vyas N, Nandy PR, Mahmood M, Dwivedi US, Singh DK, Singh PB. Safety and efficacy of ureteroscopic lithotripsy for ureteral calculi under sedoanalgesia–a prospective study. Int Urol Nephrol 2005;37(2):219-24. http://www.ncbi.nlm.nih.gov/pubmed/16142546

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20.

Yalçinkaya F, Topalo lu H, Ozmen E, Unal S. Is general anaesthesia necessary for URS in women? Int Urol Nephrol 1996;28(2):153-6. http://www.ncbi.nlm.nih.gov/pubmed/8836781 21. Ferraro RF, Abraham VE, Cohen TD, Preminger GM. A new generation of semirigid fiberoptic ureteroscopes. J Endourol 1999;13(1):35-40. http://www.ncbi.nlm.nih.gov/pubmed/10102126 22. Basillote JB, Lee DI, Eichel L, Clayman RV. Ureteroscopes: flexible, rigid, and semirigid. Urol Clin North Am 2004;31(1):21-32. http://www.ncbi.nlm.nih.gov/pubmed/15040398 23. Hubert KC, Palmer JS. Passive dilation by ureteral stenting before ureteroscopy: eliminating the need for active dilation. J Urol 2005;174(3):1079-80. http://www.ncbi.nlm.nih.gov/pubmed/16094062 24. Roberts JG, Goel M. Flexible ureterorenoscopy for the treatment of refractory upper urinary tract stones. BJU Int 2000;85(4):561-2. http://www.ncbi.nlm.nih.gov/pubmed/10766532 25. Dasgupta P, Cynk MS, Bultitude MF, Tiptaft RC, Glass JM. Flexible ureterorenoscopy: prospective analysis of the Guy’s experience. Ann R Coll Surg Engl 2004;86(5):367-70. http://www.ncbi.nlm.nih.gov/pubmed/15333176 26. Ankem MK, Lowry PS, Slovick RW, Munoz del Rio A, Nakada SY. Clinical utility of dual active deflection flexible ureteroscope during upper tract ureteropyeloscopy. Urology 2004;64(3):430-4. http://www.ncbi.nlm.nih.gov/pubmed/15351558 27. Troy AJ, Anagnostou T, Tolley DA. Flexible upper tract endoscopy. BJU Int 2004;93(5):671-9. http://www.ncbi.nlm.nih.gov/pubmed/15009087 28. Traxer O, Dubosq F, Jamali K, Gattegno B, Thibault P. New-generation flexible ureterorenoscopes are more durable than previous ones. Urology 2006;68(2):276-9. http://www.ncbi.nlm.nih.gov/pubmed/16904434 29. Monga M, Best S, Venkatesh R, Ames C, Lee C, Kuskowski M, Schwartz S, Vanlangendock R, Skenazy J, Landman J. Durability of flexible ureteroscopes: a randomized, prospective study. J Urol 2006;176(1):137-41. http://www.ncbi.nlm.nih.gov/pubmed/16753388 30. Seto C, Ishiura Y, Egawa M, Komatsu K, Namiki M. Durability of working channel in flexible ureteroscopes when inserting ureteroscopic devices. J Endourol 2006;20(3):223-6. http://www.ncbi.nlm.nih.gov/pubmed/16548735 31. Grasso M. Experience with the holmium laser as an endoscopic lithotrite. Urology 1996;48(2):199-206. http://www.ncbi.nlm.nih.gov/pubmed/8753729 32. Grasso M, Chalik Y. Principles and applications of laser lithotripsy: experience with the holmium laser lithotrite. J Clin Laser Med Surg 1998;16(1):3-7. http://www.ncbi.nlm.nih.gov/pubmed/9728123 33. Jeon SS, Hyun JH, Lee KS. A comparison of holmium:YAG laser with Lithoclast lithotripsy in ureteral calculi fragmentation. Int J Urol 2005;12(6):544-7. http://www.ncbi.nlm.nih.gov/pubmed/15985075 34. Gupta PK. Is the holmium:YAG laser the best intracorporeal lithotripter for the ureter?. A 3-year retrospective study. J Endourol 2007;21(3):305-9. http://www.ncbi.nlm.nih.gov/pubmed/17444776 35. Gould DL. Retrograde flexible ureterorenoscopic holmium-YAG laser lithotripsy: the new gold standard. Tech Urol 1998;4(1):22-4. http://www.ncbi.nlm.nih.gov/pubmed/9568772 36. Tawfiek ER, Bagley DH. Management of upper urinary tract calculi with ureteroscopic techniques. Urology 1999;53(1):25-31. http://www.ncbi.nlm.nih.gov/pubmed/9886583 37. Scarpa RM, De Lisa A, Porru D, Usai E. Holmium:YAG laser ureterolithotripsy. Eur Urol 1999;35(3): 233-8. http://www.ncbi.nlm.nih.gov/pubmed/10072626 38. Michel MS, Knoll T, Ptaschnyk T, Köhrmann KU, Alken P. Flexible ureterorenoscopy for the treatment of lower pole calix stones: influence of different lithotripsy probes and stone extraction tools on scope deflection and irrigation flow. Eur Urol 2002;41(3):312-6. http://www.ncbi.nlm.nih.gov/pubmed/12180234 39. Teichman JM, Rao RD, Rogenes VJ, Harris JM. Ureteroscopic management of ureteral calculi: electrohydraulic versus holmium:YAG lithotripsy. J Urol 1997;158(4):1357-61. http://www.ncbi.nlm.nih.gov/pubmed/9302119

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Santa-Cruz RW, Leveillee RJ, Krongrad A. Ex vivo comparison of four lithotripters commonly used in the ureter: what does it take to perforate? J Endourol 1998;12(5):417-22. http://www.ncbi.nlm.nih.gov/pubmed/9847062 41. Yeniyol CO, Ayder AR, Minareci S, Ciçek S, Süelözgen T. Comparision of intracorporeal lithotripsy methods and forceps use for distal ureteral stones: seven years experience. Int Urol Nephrol 2000;32(2):235-9. http://www.ncbi.nlm.nih.gov/pubmed/11229638 42. Watterson JD, Girvan AR, Cook AJ, Beiko DT, Nott L, Auge BK, Preminger GM, Denstedt JD. Safety and efficacy of holmium: YAG laser lithotripsy in patients with bleeding diatheses. J Urol 2002;168(2):442-5. http://www.ncbi.nlm.nih.gov/pubmed/12131284 43. Sofer M, Watterson JD, Wollin TA, Nott L, Razvi H, Denstedt JD. Holmium:YAG laser lithotripsy for upper urinary tract calculi in 598 patients. J Urol 2002;167(1):31-4. http://www.ncbi.nlm.nih.gov/pubmed/11743269 44. Puppo P, Ricciotti G, Bozzo W, Introini C. Primary endoscopic treatment of ureteric calculi. A review of 378 cases. Eur Urol 1999;36(1):48-52. http://www.ncbi.nlm.nih.gov/pubmed/10364655 45. Tan PK, Tan SM, Consigliere D. Ureteroscopic lithoclast lithotripsy: a cost-effective option. J Endourol 1998;12(4):341-4. http://www.ncbi.nlm.nih.gov/pubmed/9726400 46. Sözen S, Küpeli B, Tunc L, Senocak C, Alkibay T, Karao lan U, Bozkirli I. Management of ureteral stones with pneumatic lithotripsy: report of 500 patients. J Endourol 2003;17(9):721-4. http://www.ncbi.nlm.nih.gov/pubmed/14642029 47. Miroglu C, Horasanli K, Tanriverdi O, Altay B, Gumus E. Operative failure during ureteroscopic pneumatic lithotripsy: factors affecting successful outcome. Urol Int 2006;77(2):148-51. http://www.ncbi.nlm.nih.gov/pubmed/16888421 48. Tunc L, Kupeli B, Senocak C, Alkibay T, Sözen S, Karaoglan U, Bozkirli I. Pneumatic lithotripsy for large ureteral stones: is it the first line treatment? Int Urol Nephrol 2007;39(3):759-64. http://www.ncbi.nlm.nih.gov/pubmed/17318351 49. el-Gabry EA, Bagley DH. Retrieval capabilities of different stone basket designs in vitro. J Endourol 1999;13(4):305-7. http://www.ncbi.nlm.nih.gov/pubmed/10405911 50. Honeck P, Wendt-Nordahl G, Häcker A, Alken P, Knoll T. Risk of collateral damage to endourologic tools by holmium:YAG laser energy. J Endourol 2006;20(7):495-7. http://www.ncbi.nlm.nih.gov/pubmed/16859463 51. Kourambas J, Byrne RR, Preminger GM. Does a ureteral access sheath facilitate ureteroscopy? J Urol 2001;165(3):789-93. http://www.ncbi.nlm.nih.gov/pubmed/11176469 52. Monga M, Best S, Venkatesh R, Ames C, Lieber D, Vanlangendock R, Landman J. Prospective randomized comparison of 2 ureteral access sheaths during flexible retrograde ureteroscopy. J Urol 2004;172(2):572-3. http://www.ncbi.nlm.nih.gov/pubmed/15247733 53. L’esperance JO, Ekeruo WO, Scales CD Jr, Marguet CG, Springhart WP, Maloney ME, Albala DM, Preminger GM. Effect of ureteral access sheath on stone-free rates in patients undergoing ureteroscopic management of renal calculi. Urology 2005;66(2):252-5. http://www.ncbi.nlm.nih.gov/pubmed/16040093 54. Landman J, Venkatesh R, Ragab M, Rehman J, Lee DI, Morrissey KG, Monga M, Sundaram CP. Comparison of intrarenal pressure and irrigant flow during percutaneous nephroscopy with an indwelling ureteral catheter, ureteral occlusion balloon, and ureteral access sheath. Urology 2002;60(4):584-7. http://www.ncbi.nlm.nih.gov/pubmed/12385911 55. Rehman J, Monga M, Landman J, Lee DI, Felfela T, Conradie MC, Srinivas R, Sundaram CP, Clayman RV. Characterization of intrapelvic pressure during ureteropyeloscopy with ureteral access sheaths. Urology 2003;61(4):713-8. http://www.ncbi.nlm.nih.gov/pubmed/12670551 56. Delvecchio FC, Auge BK, Brizuela RM, Weizer AZ, Silverstein AD, Lallas CD, Pietrow PK, Albala DM, Preminger GM. Assessment of stricture formation with the ureteral access sheath. Urology 2003;61(3):518-22. http://www.ncbi.nlm.nih.gov/pubmed/12639636

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57. Cheung MC, Lee F, Leung YL, Wong BB, Chu SM, Tam PC. Outpatient ureteroscopy: predictive factors for postoperative events. Urology 2001;58(6):914-8. http://www.ncbi.nlm.nih.gov/pubmed/11744457 58. Netto NR Jr, Ikonomidis J, Zillo C. Routine ureteral stenting after ureteroscopy for ureteral lithiasis: is it really necessary? J Urol 2001;166(4):1252-4. http://www.ncbi.nlm.nih.gov/pubmed/11547052 59. Borboroglu PG, Amling CL, Schenkman NS, Monga M, Ward JF, Piper NY, Bishoff JT, Kane CJ. Ureteral stenting after ureteroscopy for distal ureteral calculi: a multi-institutional prospective randomized controlled study assessing pain, outcomes and complications. J Urol 2001;166(5):1651-7. http://www.ncbi.nlm.nih.gov/pubmed/11586195 60. Denstedt JD, Wollin TA, Sofer M, Nott L, Weir M, D’A Honey RJ. A prospective randomized controlled trial comparing nonstented versus stented ureteroscopic lithotripsy. J Urol 2001;165(5):1419-22. http://www.ncbi.nlm.nih.gov/pubmed/11342889 61. Hollenbeck BK, Schuster TG, Faerber GJ, Wolf JS Jr. Routine placement of ureteral stents is unnecessary after ureteroscopy for urinary calculi. Urology 2001;57(4):639-43. http://www.ncbi.nlm.nih.gov/pubmed/11306367 62. Chen YT, Chen J, Wong WY, Yang SS, Hsieh CH, Wang CC. Is ureteral stenting necessary after uncomplicated ureteroscopic lithotripsy?. A prospective, randomized controlled trial. J Urol 2002;167(5):1977-80. http://www.ncbi.nlm.nih.gov/pubmed/11956421 63. Chow GK, Patterson DE, Blute ML, Segura JW. Ureteroscopy: effect of technology and technique on clinical practice. J Urol 2003;170(1):99-102. http://www.ncbi.nlm.nih.gov/pubmed/12796655 64. Lingeman JE, Preminger GM, Berger Y, Denstedt JD, Goldstone L, Segura JW, Auge BK, Watterson JD, Kuo RL. Use of a temporary ureteral drainage stent after uncomplicated ureteroscopy: results from a phase II clinical trial. J Urol 2003;169(5):1682-8. http://www.ncbi.nlm.nih.gov/pubmed/12686808 65. Preminger GM, Tiselius HG, Assimos DG, Alken P, Buck C, Gallucci M, Knoll T, Lingeman JE, Nakada SY, Pearle MS, Sarica K, Türk C, Wolf JS Jr; EAU/AUA Nephrolithiasis Guideline Panel. 2007 guideline for the management of ureteral calculi. J Urol 2007;178(6):2418-34. http://www.ncbi.nlm.nih.gov/pubmed/17993340 66. Preminger GM, Tiselius HG, Assimos DG, Alken P, Buck C, Gallucci M, Knoll T, Lingeman JE, Nakada SY, Pearle MS, Sarica K, Türk C, Wolf JS Jr; American Urological Association Education and Research, Inc; European Association of Urology. 2007 guideline for the management of ureteral calculi. Eur Urol 2007;52(6):1610-31. http://www.ncbi.nlm.nih.gov/pubmed/18074433 67. Preminger GM, Assimos DG, Lingeman JE, Nakada SY, Pearle MS, Wolf JS Jr; AUA Nephrolithiasis Guideline Panel). AUA guideline on management of staghorn calculi: diagnosis and treatment recommendations. Chapter 1. J Urol 2005;173(6):1991-2000. http://www.ncbi.nlm.nih.gov/pubmed/15879803 68. Tiselius HG, Ackermann D, Alken P, Buck C, Conort P, Gallucci M; Working Party on Lithiasis, European Association of Urology. Guidelines on urolithiasis. Eur Urol 2001;40(4):362-71. http://www.ncbi.nlm.nih.gov/pubmed/11713390 69. Albala DM, Assimos DG, Clayman RV, Denstedt JD, Grasso M, Gutierrez-Aceves J, Kahn RI, Leveillee RJ, Lingeman JE, Macaluso JN Jr, Munch LC, Nakada SY, Newman RC, Pearle MS, Preminger GM, Teichman J, Woods JR. Lower pole I: a prospective randomized trial of extracorporeal shock wave lithotripsy and percutaneous nephrostolithotomy for lower pole nephrolithiasis-initial results. J Urol 2001;166(6):2072-80. http://www.ncbi.nlm.nih.gov/pubmed/11696709 70. Obek C, Onal B, Kantay K, Kalkan M, Yalçin V, Oner A, Solok V, Tansu N. The efficacy of extracorporeal shock wave lithotripsy for isolated lower pole calculi compared with isolated middle and upper caliceal calculi. J Urol 2001;166(6):2081-4. http://www.ncbi.nlm.nih.gov/pubmed/11696710 71. Riedler I, Trummer H, Hebel P, Hubmer G. Outcome and safety of extracorporeal shock wave lithotripsy as first-line therapy of lower pole nephrolithiasis. Urol Int 2003;71(4):350-454. http://www.ncbi.nlm.nih.gov/pubmed/14646431

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Pearle MS, Lingeman JE, Leveillee R, Kuo R, Preminger GM, Nadler RB, Macaluso J, Monga M, Kumar U, Dushinski J, Albala DM, Wolf JS Jr, Assimos D, Fabrizio M, Munch LC, Nakada SY, Auge B, Honey J, Ogan K, Pattaras J, McDougall EM, Averch TD, Turk T, Pietrow P, Watkins S. Prospective, randomized trial comparing shock wave lithotripsy and ureteroscopy for lower pole caliceal calculi 1 cm or less. J Urol 2005;173(6):2005-9. http://www.ncbi.nlm.nih.gov/pubmed/15879805 73. Preminger GM. Management of lower pole renal calculi: shock wave lithotripsy versus percutaneous nephrolithotomy versus flexible ureteroscopy. Urol Res 2006;34(2):108-11. http://www.ncbi.nlm.nih.gov/pubmed/16463145 74. Grasso M, Ficazzola M. Retrograde ureteropyeloscopy for lower pole caliceal calculi. J Urol 1999;162(6):1904-8. http://www.ncbi.nlm.nih.gov/pubmed/10569534 75. Hollenbeck BK, Schuster TG, Faerber GJ, Wolf JS. Flexible ureteroscopy in conjunction with in situ lithotripsy for lower pole calculi. Urology 2001;58(6):859-63. http://www.ncbi.nlm.nih.gov/pubmed/11744445 76. Auge BK, Dahm P, Wu NZ, Preminger GM. Ureteroscopic management of lower-pole renal calculi: technique of calculus displacement. J Endourol 2001;15(8):835-8. http://www.ncbi.nlm.nih.gov/pubmed/11724125 77. Stav K, Cooper A, Zisman A, Leibovici D, Lindner A, Siegel YI. Retrograde intrarenal lithotripsy outcome after failure of shock wave lithotripsy. J Urol 2003;170(6 Pt 1):2198-201. http://www.ncbi.nlm.nih.gov/pubmed/14634378 78. Jung H, Nørby B, Osther PJ. Retrograde intrarenal stone surgery for extracorporeal shock-wave lithotripsy-resistant kidney stones. Scand J Urol Nephrol 2006;40(5):380-4. http://www.ncbi.nlm.nih.gov/pubmed/17060084 79. Johnson GB, Portela D, Grasso M. Advanced ureteroscopy: wireless and sheathless. J Endourol 2006;20(8):552-5. http://www.ncbi.nlm.nih.gov/pubmed/16903813 80. Mariani AJ. Combined electrohydraulic and holmium:YAG laser ureteroscopic nephrolithotripsy of large (greater than 4 cm) renal calculi. J Urol 2007;177(1):168-73. http://www.ncbi.nlm.nih.gov/pubmed/17162030 81. Undre S, Olsen S, Mustafa N, Patel A. ‘Pass the ball!’ Simultaneous flexible nephroscopy and retrograde intrarenal surgery for large residual upper-pole staghorn stone. J Endourol 2004;18(9): 844-7. http://www.ncbi.nlm.nih.gov/pubmed/15659916 82. Marguet CG, Springhart WP, Tan YH, Patel A, Undre S, Albala DM, Preminger GM. Simultaneous combined use of flexible ureteroscopy and percutaneous nephrolithotomy to reduce the number of access tracts in the management of complex renal calculi. BJU Int 2005;96(7):1097-100. http://www.ncbi.nlm.nih.gov/pubmed/15659916 83. Geavlete P, Georgescu D, Nita G, Mirciulescu V, Cauni V. Complications of 2735 retrograde semirigid ureteroscopy procedures: a single-center experience. J Endourol 2006;20(3):179-85. http://www.ncbi.nlm.nih.gov/pubmed/16548724 84. Turk TM, Jenkins AD. A comparison of ureteroscopy to in situ extracorporeal shock wave lithotripsy for the treatment of distal ureteral calculi. J Urol 1999;161(1):45-6. http://www.ncbi.nlm.nih.gov/pubmed/10037364 85. Aridogan IA, Zeren S, Bayazit Y, Soyupak B, Doran S. Complications of pneumatic ureterolithotripsy in the early postoperative period. J Endourol 2005;19(1):50-3. http://www.ncbi.nlm.nih.gov/pubmed/15735383 86. Roberts WW, Cadeddu JA, Micali S, Kavoussi LR, Moore RG. Ureteral stricture formation after removal of impacted calculi. J Urol 1998;159(3):723-6. http://www.ncbi.nlm.nih.gov/pubmed/9474134 87. Martin X, Ndoye A, Konan PG, Feitosa Tajra LC, Gelet A, Dawahra M, Dubernard JM. [Hazards of lumbar ureteroscopy: apropos of 4 cases of avulsion of the ureter.] Prog Urol 1998;8(3):358-62. http://www.ncbi.nlm.nih.gov/pubmed/9689667 88. Dash A, Schuster TG, Hollenbeck BK, Faerber GJ, Wolf JS Jr. Ureteroscopic treatment of renal calculi in morbidly obese patients: a stone-matched comparison. Urology 2002;60(3):393-7. http://www.ncbi.nlm.nih.gov/pubmed/12350468 89. Andreoni C, Afane J, Olweny E, Clayman RV. Flexible ureteroscopic lithotripsy: first-line therapy for proximal ureteral and renal calculi in the morbidly obese and superobese patient. J Endourol 2001;15(5):493-8. http://www.ncbi.nlm.nih.gov/pubmed/11465328

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Watterson JD, Girvan AR, Beiko DT, Nott L, Wollin TA, Razvi H, Denstedt JD. Ureteroscopy and holmium:YAG laser lithotripsy: an emerging definitive management strategy for symptomatic ureteral calculi in pregnancy. Urology 2002;60(3):383-7. http://www.ncbi.nlm.nih.gov/pubmed/12350466 91. Lifshitz DA, Lingeman JE. Ureteroscopy as a first-line intervention for ureteral calculi in pregnancy. J Endourol 2002;16(1):19-22. http://www.ncbi.nlm.nih.gov/pubmed/11890444 92. Deliveliotis C, Picramenos D, Alexopoulou K, Christofis I, Kostakopoulos A, Dimopoulos C. Onesession bilateral ureteroscopy: is it safe in selected patients?. Int Urol Nephrol 1996;28(4):481-4. http://www.ncbi.nlm.nih.gov/pubmed/9119632 93. Hollenbeck BK, Schuster TG, Faerber GJ, Wolf JS Jr. Safety and efficacy of same-session bilateral ureteroscopy. J Endourol 2003;17(10):881-5. http://www.ncbi.nlm.nih.gov/pubmed/14744354

7.4

Open surgery for removal of renal stones

With advances in ESWL and endourological surgery (i.e. URS and PNL), the indications for open stone surgery have decreased markedly. Centres with the equipment, expertise and experience in surgical treatment of renal tract stones report that open surgery is needed in 1.0-5.4% of cases (1-5). Most cases requiring open surgery involve difficult stone situations, and urologists must therefore maintain their proficiency, skills and expertise in open renal and ureteral surgical techniques. However, with different treatment modalities now available for surgical management of stones, it can be debated whether or not open operation is appropriate in a particular case. These guidelines provide general principles for open surgery based on a consensus of opinion drawn from experience and bearing in mind the technical limitations of less invasive alternative approaches. An open surgical procedure may be preferred when the major stone volume is located peripherally in the calices, especially if several percutaneous accesses and several, probably unsuccessful, shock-wave sessions are likely to be needed for complete stone removal. However, many hospitals now have limited experience with open stone surgery and it may be advisable to send patients to a centre experienced in the use of extended pyelocalicotomy (6), anatrophic nephrolithotomy (7-10), multiple radial nephrotomy (11, 12) and renal surgery under hypothermia. Recently, intra-operative B-mode scanning and Doppler sonography (13, 14) have been used to identify avascular areas in the renal parenchyma close to the stone or dilated calices. This allows removal of large staghorn stones by multiple small radial nephrotomies without loss of kidney function. 7.4.1 Indications for open and laparoscopic surgery Indications for open stone surgery include: • complex stone burden • treatment failure of ESWL and/or PNL, or failed ureteroscopic procedure • intrarenal anatomical abnormalities: infundibular stenosis, stone in the caliceal diverticulum (particularly in an anterior calix), obstruction of the ureteropelvic junction, stricture • morbid obesity • skeletal deformity, contractures and fixed deformities of hips and legs • co-morbid medical disease • concomitant open surgery • non-functioning lower pole (partial nephrectomy), non-functioning kidney (nephrectomy) • patient choice following failed minimally invasive procedures; the patient may prefer a single procedure and avoid the risk of needing more than one PNL procedure • stone in an ectopic kidney where percutaneous access and ESWL may be difficult or impossible • cystolithotomy for giant bladder calculus • large stone burden in children; open stone surgery will provide easy access and requires only one anaesthetic procedure. 7.4.2 Operative procedures Operative procedures that can be carried out include: • simple and extended pyelolithotomy • pyelonephrolithotomy • anatrophic nephrolithotomy • ureterolithotomy • radial nephrolithotomy • pyeloplasty

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• •

partial nephrectomy and nephrectomy removal of calculus with re-implantation of the ureter (i.e. ureteroneocystotomy).

The superiority of open surgery over less invasive therapy, in terms of stone-free rates, is based on historical experience, but no comparative studies are available yet (15, 16) (LE 4). The superiority of open surgery over less invasive therapy, in terms of stone-free rates, is based on historical experience, but no comparative studies are available yet. LE = level of evidence; GR = grade of recommendation

LE = 4 GR = B

Open surgery for renal tract stones has become almost obsolete, with laparoscopic surgery increasingly replacing open surgery, in situations such as complex stone burden, failed previous ESWL and / or endourological procedures, anatomical abnormalities, or morbid obesity. Laparoscopic surgery was initially used for ablative surgery in renal cancer and correction of pelviureteric junction obstruction, but is now being used to remove both renal and ureteric stones. Many patients with impacted ureteric stones have been treated successfully using laparoscopic ureterolithotomy, with less than 2% being converted to open surgery. Laparosopic ureterolitothomy can be carried out using either retroperitoneal or transperitoneal access (17-22). Laparoscopic ureterolithotomy should be considered when other non-invasive or low-invasive procedures have failed (23-39). Laparoscopic (video-endoscopic) surgery may be useful, particularly for stones located in a ventral caliceal diverticulum (33). Laparoscopic surgery should be carried out only by surgeons trained in this technique and in wellequipped, dedicated centres. The advantages of laparoscopic surgery are low post-operative morbidity, reduced hospital stay and minimal blood loss. However, the procedure takes considerably longer than conventional surgery. When expertise is available, laparoscopic surgery should be considered before proceeding to open surgery (40). LE = level of evidence; GR = grade of recommendation

LE = 4 GR = C

7.4.3 References 1. Assimos DG, Boyce WH, Harrison LH, McCullough DL, Kroonvand RL,Sweat KR. The role of open stone surgery since extracorporeal shock wave lithotripsy. J Urol 1989;142(2 Pt 1):263-7. http://www.ncbi.nlm.nih.gov/pubmed/2746742 2. Segura JW. Current surgical approaches to nephrolithiasis. Endocrinol Metab Clin North Am 1990;19(4):919-35. http://www.ncbi.nlm.nih.gov/pubmed/2081519 3. Kane MT, Cohen AS, Smith ER, Lewis C, Reidy C. 1995 Commission on Dietetic Registration Dietetics Practice Audit. J Am Diet Assoc 1996;96(12):1292-301. http://www.ncbi.nlm.nih.gov/pubmed/8948396 4. Bichler KH, Lahme S, Strohmaier WL. Indications for open stone removal of urinary calculi. Urol Int 1997;59(2):102-8. http://www.ncbi.nlm.nih.gov/pubmed/9392057 5. Paik ML, Wainstein MA, Spirnak P, Hampel N, Resnick MI. Current indications for open stone surgery in the treatment of renal and ureteral calculi. J Urol 1998;159(2):374-8. http://www.ncbi.nlm.nih.gov/pubmed/9649242 6. Gil-Vernet J. New surgical concepts in removing renal calculi. Urol Int 1965;20(5):255-88. http://www.ncbi.nlm.nih.gov/pubmed/5863978 7. Smith MJ, Boyce WH. Anatrophic nephrotomy and plastic calyrhaphy. Trans Am Assoc Genitourin Surg 1967;59:18-24. http://www.ncbi.nlm.nih.gov/pubmed/6064524 8. Harrison LH. Anatrophic nephrolithotomy: Update 1978. In: Bonney WW, Weems WL, Donohue JP, eds. AUA Courses in Urology. Vol 1. Baltimore: Williams and Wilkins, 1978, pp. 1-23. 9. Boyce WH. Re: anatrophic nephrolithotomy: experience with a simplification of the Smith and Boyce technique. J Urol 1980;123(4):604. http://www.ncbi.nlm.nih.gov/pubmed/7365912 10. Resnick MI, Pounds DM, Boyce WH. Surgical anatomy of the human kidney and its application. Urology 1981;17:367-9. 11. Wickham JE, Coe N, Ward JP. One hundred cases of nephrolithotomy under hyporthermia. J Urol 1974;112(6):702-5. http://www.ncbi.nlm.nih.gov/pubmed/4436892

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12.

Sleight MW, Gower RL, Wickham JE. Intrarenal access. Urology 1980;15(5):475-7. http://www.ncbi.nlm.nih.gov/pubmed/7052711 13. Thüroff JW, Frohneberg D, Riedmiller R, Alken P, Hutschenreiter G, Thüroff S, Hohenfellner R. Localization of segmental arteries in renal surgery by Doppler sonography. J Urol 1982;127(5):863-6. http://www.ncbi.nlm.nih.gov/pubmed/7086985 14. Alken P, Thüroff JW, Riedmiller H, Hohenfellner R. Doppler sonography and B-mode ultrasound scanning in renal stone surgery. Urology 1984;23(5):455-60. http://www.ncbi.nlm.nih.gov/pubmed/6719663 15. Kane CJ, Bolton DM,Stoller ML. Current indications for open stone surgery in an endourological centre. Urology 1995;45(2):218-21. http://www.ncbi.nlm.nih.gov/pubmed/7855969 16. Sy FY, Wong MY, Foo KT. Current indications for open stone surgery in Singapore. Ann Acad Med Singapore 1999;28(2):241-4. http://www.ncbi.nlm.nih.gov/pubmed/10497675 17. Abreu SC, Gill IS. Advanced renal laparoscopy. BJU Int 2005;95(Suppl 2):114-9. http://www.ncbi.nlm.nih.gov/pubmed/15720345 18. Turk I, Dreger S, Roigas J, Fahlenkamp D, Schonberger B, Loening SA. Laparoscopic ureterolithotomy. Tech Urol 1998;4(1):29-34. http://www.ncbi.nlm.nih.gov/pubmed/9568774 19. Keeley FX, Gialas I, Pillai M, Chrisofos M, Tolley DA. Laparosopcic ureterolithotomy; the Edinburgh experience. BJU Int 1999;84(7):765-9. http://www.ncbi.nlm.nih.gov/pubmed/10532968 20. Gaur DD, Trivedi S, Prabhudesai MR, Madhusudhana HR, Gopichand M. Laparoscopic ureterolithotomy: technical considerations and long term follow up. BJU Int 2002;89(4):339-43. http://www.ncbi.nlm.nih.gov/pubmed/11872020 21. Flasko T, Holman E, Kovacs G, Tallai B, Toth C, Salah MA. Laparoscopic ureterolithotomy: the method of choice in selected cases. J Laparoendosc Adv Surg Tech A. 2005;15(2):149-52. http://www.ncbi.nlm.nih.gov/pubmed/15898906 22. Kijvikai K, Patcharatrakul S. Laparoscopic ureterolithotomy: its role and some controversial technical considerations. Int J Urol 2006;13(3):206-10. http://www.ncbi.nlm.nih.gov/pubmed/16643610 23. Wickham J. The surgical treatment of renal lithiasis. In: Urinary Calculous Disease. New York: Churchill Livingstone, 1979, pp. 145-198. 24. Gaur D, Trivedi S, Prabhudesai M, Madhusudhana HR, Gopichand M. Laparoscopic ureterolithotomy: Technical considerations and long-term follow up. BJU Int 2002;89(4):339-43. http://www.ncbi.nlm.nih.gov/pubmed/11872020 25. Hemal AK, Goel A, Goel R. Minimally invasive retroperitoneoscopic ureterolithotomy. J Urol 2003;169(2):480-2. http://www.ncbi.nlm.nih.gov/pubmed/12544292 26. Nouira Y, Kallel Y, Binous MY, Dahmoul H, Horchani A. Laparoscopic retroperitoneal ureterolithotomy: Initial experience and review of literature. J Endourol 2004;18(6):557-61. http://www.ncbi.nlm.nih.gov/pubmed/15333221 27. Flasko T, Holman E, Kovacs G, Tallai B, Toth C, Salah MA. Laparoscopic ureterolithotomy: the method of choice in selected cases. J Laparoendosc Adv Surg Tech A 2005;15(2):149-52. http://www.ncbi.nlm.nih.gov/pubmed/15898906 28. Goel A, Hemal AK. Upper and mid-ureteric stone: a prospective unrandomized comparison of retroperitoneoscopic and open ureterolithotomy. BJU Int 2001;88(7):679-82. http://www.ncbi.nlm.nih.gov/pubmed/11890236 29. Demirci D, Gülmez I, Ekmekçioglu O, Karacagil M. Retroperitoneoscopic ureterolithotomy for the treatment of ureteral calculi. Urol Int 2004;73(3):234-7. http://www.ncbi.nlm.nih.gov/pubmed/15539842 30. El-Feel A, Abouel-Fettough H, Abdel Hakim A. Laparoscopic transperitoneal ureterolithotomy. J Endourol 2007;21(1):50-4. http://www.ncbi.nlm.nih.gov/pubmed/17263607 31. Micali S, Moore RG, Averch TD, Adams JB, Kavoussi LR. The role of laparoscopy in the treatment of renal and ureteral stones. J Urol 1997;157(2):463-6. http://www.ncbi.nlm.nih.gov/pubmed/8996332 32. Raboy A, Ferzli GS, Loffreda R, Albert PS. Laparoscopic ureterolithotomy. Urology 1992;39(3):223-5. http://www.ncbi.nlm.nih.gov/pubmed/1532102

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Hemal AK, Goel A, Kumar M, Gupta NP. Evaluation of laparoscopic retroperitoneal surgery in urinary stone disease. J Endourol 2001;15(7):701-5. http://www.ncbi.nlm.nih.gov/pubmed/11697400 34. Feyaerts A, Rietbergen J, Navarra S, Vallancien G, Guillonneau B. Laparoscopic ureterolithotomy for ureteral calculi. Eur Urol 2001;40(6):609-13. http://www.ncbi.nlm.nih.gov/pubmed/11805405 35. Skrepetis K, Doumas K, Siafakas I, Lykourinas M. Laparoscopic versus open ureterolithotomy. A comparative study. Eur Urol 2001;40(1):32-6; discussion 37. http://www.ncbi.nlm.nih.gov/pubmed/11528174 36. McDougall EM, Clayman RV. Laparoscopic nephrectomy for benign disease: comparison of the transperitoneal and retroperitoneal approaches. J Endourol 1996;10(1):45-9. http://www.ncbi.nlm.nih.gov/pubmed/8833728 38. Goel A, Hemal AK. Upper and mid-ureteric stones: a prospective unrandomized comparison of retroperitoneoscopic and open ureterolithotomy. BJU Int 2001;88(7):679-82. http://www.ncbi.nlm.nih.gov/pubmed/11890236 39. Brunet P, Meria P, Mahe P, Danjou P. Laparoscopically-assisted percutaneous nephrolithotomy for the treatment of anterior calyceal diverticula. BJU Int 2000;86(9):1088-9. http://www.ncbi.nlm.nih.gov/pubmed/11119107 40. Marberger M. Urinary stones. Curr Opin Urol 1999;9(4):315-7. http://www.ncbi.nlm.nih.gov/pubmed/10459467

7.5

Chemolytic dissolution of stones using percutaneous irrigation

Chemolytic dissolution of stones or stone fragments is a useful adjunct to ESWL, PNL, URS or open surgery to achieve more complete elimination of small residual stones or fragments. The combined treatment of ESWL and chemolysis is a particularly low-invasive option for patients who have partial or complete infection staghorn stones. Oral chemolytic treatment is an alternative for removing uric acid stones. In percutaneous chemolysis, at least two nephrostomy catheters should be used to allow irrigation of the renal collecting system, while preventing chemolytic fluid draining into the bladder and reducing the risk of increased intrarenal pressure. For a large stone burden, use a double-J stent to protect the ureter during the procedure (1,2). 7.5.1 Infection stones Stones composed of magnesium ammonium phosphate and carbonate apatite can be dissolved using a 10% solution of hemiacidrin (Renacidin) (pH 3.5-4) or Suby’s G solution. Under antibiotic prophylaxis, the chemolytic solution is allowed to flow in through one nephrostomy catheter and out through another. The contact surface area between the stone or the stone remnants and the chemolytic agent is increased using ESWL. The time required for dissolution depends on stone burden and chemical composition, but several weeks of chemolysis combined with ESWL are needed to dissolve a complete staghorn stone. The major advantage of this approach is that it can be carried out without anaesthesia and may therefore be an option for high-risk patients or for patients in whom anaesthesia or other surgical procedures must be avoided (3-13). Hemiacidrin and Suby’s G solution carry a risk of cardiac arrest due to hypermagnesaemia if there is leakage and magnesium is absorbed. These solutions should be used only when there is good evidence that the renal tract has healed following surgery. They should never be infused in the immediate post-operative stage. 7.5.2 Brushite stones Brushite is also soluble in the acid solutions hemiacidrin and Suby’s G solution. Chemolytic dissolution should be considered in patients who have residual brushite fragments after other stone-removing procedures. 7.5.3 Cystine stones Cystine is soluble in an alkaline environment, e.g. 0.3 or 0.6 mol/L trihydroxymethyl aminomethan (THAM) solution (pH range 8.5-9.0), or N-acetylcysteine (200 mg/L). These solutions can be used to improve elimination of fragments and stone residuals from the collecting system. Percutaneous chemolysis is a useful method for complete stone clearance together with other stone-removing techniques (14-18). 7.5.4 Uric acid stones A high concentration of urate and a low pH are the determinants of uric acid stone formation. Percutaneous chemolysis can be achieved using THAM solutions. Oral chemolysis is, however, the preferred option. It involves lowering the urate concentration using allopurinol and a high fluid intake and increasing the pH to alkali (19-21).

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Uric acid stones can also be removed using oral chemolysis involving an alkali and allopurinol. Further details of this regimen are given in Section 17.2. 7.5.5 Calcium oxalate and ammonium urate stones No physiologically useful chemolytic agents are available for dissolving calcium oxalate or ammonium urate stones (22). The presence of calcium oxalate in an infection stone markedly reduces the stone’s solubility in hemiacidrin (6). 7.5.6 1.

References Tiselius HG, Hellgren E, Andersson A, Borrud-Ohlsson A, Eriksson L. Minimally invasive treatment of infection staghorn stones with shock wave lithotripsy and chemolysis. Scand J Urol Neprol 1999; 33(5):286-90. http://www.ncbi.nlm.nih.gov/pubmed/10572989 2. Fahlenkamp C, Brien G, Bick C, Suckow B, De Temple R, Otting U, Schöpke W. [Lokale Chemolitholyse von Harnsteinen] Zeitschrift fur Klinische Medizin 1989;44:913-6. [article in German] [Local chemolysis of urinary stones] 3. Sheldon CA, Smith AD. Chemolysis of calculi. Urol Clin North Am 1982;9(1):121-30. http://www.ncbi.nlm.nih.gov/pubmed/7080280 4. Griffith DP. Ureteral calculi. In: Kandel B, Harrison LH, McCullough DL, eds. State of the Art Extracorporeal Shock Wave Lithotripsy. New York: Plenum Press, 1987, pp. 281-310. 5. Lingeman JE. Staghorn calculi. In: Kandel B, Harrison LH, McCullough DL, eds. State of the Art Extracorporeal Shock Wave Lithotripsy. New York: Plenum Press, 1987, pp. 311-353. 6. Wall I, Tiselius HG, Larsson L. Hemiacidrin–a useful component in the treatment of infection renal stones. Eur Urol 1988;15(1):26-30. http://www.ncbi.nlm.nih.gov/pubmed/3215233 7. Rodman JS, Reckler JM, Israel AR. Hemiacidrin irrigations to dissolve stone remnants after nephrolithotomy. Problems with solution flow. Urology 1981;18(2):127-30. http://www.ncbi.nlm.nih.gov/pubmed/7269011 8. Weirich W, Haas H, Alken P. [Perkutane Chemolyse von Struvit-Steinen bei Nierenbecken-und Kelchhalsobstruktion] Akt Urol 1982;13:256-8. [article in German] [Percutaneous chemolyses of struvitestones in renal-pelvic and caliceal obstruction] 9. Klein RS, Cattolica EV, Rankin KN. Hemiacidrin renal irrigation: complications and successful management. J Urol 1982;128(2):241-2. http://www.ncbi.nlm.nih.gov/pubmed/7109081 10. Dretler SP, Pfister RC. Primary dissolution therapy of struvite calculi. J Urol 1984;131(5):861-3. http://www.ncbi.nlm.nih.gov/pubmed/6708214 11. Fam B, Rossier AB, Yalla S, Berg S. The role of hemiacidrin in the management of renal stones in spinal cord injury patients. J Urol 1976;116(6):696-8. http://www.ncbi.nlm.nih.gov/pubmed/1003633 12. Burns JR, Joseph DB. Combination therapy for a partial staghorn calculus in an infant. J Endourol 1993;7(6):469-71. http://www.ncbi.nlm.nih.gov/pubmed/1003633 13. Levy DA, Resnick MI. Management of urinary stones in the patient with spinal cord injury. Urol Clin North Am 1993;20(3):435-42. http://www.ncbi.nlm.nih.gov/pubmed/8351769 14. Kachel TA, Vijan SR, Dretler SP. Endourological experience with cystine calculi and a treatment algorithm. J Urol 1991;145(1):25-8. http://www.ncbi.nlm.nih.gov/pubmed/1984093 15. Tseng CH, Talwalkar YB, Tank ES, Hatch T, Alexander SR. Dissolution of cystine calculi by pelvocaliceal irrigation with tromethamine-E. J Urol 1982;128(6):1281-4. http://www.ncbi.nlm.nih.gov/pubmed/7154186 16. Weirich W, Ackermann D, Riedmiller H, Alken P. [Auflösung von Cystin-Steinen mit N-Acetylcystein nach perkutaner Nephrostomie.] Akt Urol 1981;12:224-6. [article in German] [Dissolution of cystine calculi with N-acetylcysteine following percutaneous nephrostomy] 17. Smith AD, Lange PH, Miller RP, Reinke DB. Dissolution of cystine calculi by irrigation with acetylcysteine through percutaneous nephrostomy. Urology 1979;13(4):422-3. http://www.ncbi.nlm.nih.gov/pubmed/433056 18. Schmeller NT, Kersting H, Schüller J, Chaussy C, Schmiedt E. Combination of chemolysis and shock wave lithotripsy in the treatment of cystine renal calculi. J Urol 1984;131(3):434-8. http://www.ncbi.nlm.nih.gov/pubmed/6699980

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19.

Sharma SK, Indudhara R. Chemodissolution of urinary uric acid stones by alkali therapy. Urol Int 1992;48(1):81-6. http://www.ncbi.nlm.nih.gov/pubmed/1317980 20. Rodman JS, Williams JJ, Peterson CM. Dissolution of uric acid calculi. J Urol 1984;131(6):1039-44. http://www.ncbi.nlm.nih.gov/pubmed/6726897 21. Lee YH, Chang LS, Chen MT, Huang JK. Local chemolysis of obstructive uric acid stones with 0,1 M THAM and 0,02% chlorhexidine. Urol Int 1993;51(3):147-51. http://www.ncbi.nlm.nih.gov/pubmed/8249225 22. Oosterlinck W, Verbeeck R, Cuvelier C, Vergauwe D. Rationale for local toxicity of calcium chelators. Urol Res 1992;20(1):19-21. http://www.ncbi.nlm.nih.gov/pubmed/1736482

7.6

Recommendations for removal of renal stones

The options for kidney stone removal are ESWL, PNL, RIRS with a flexible ureteroscope, video-endoscopic laparoscopic or open surgery. For any given stone situation, a method offering low invasiveness and morbidity should be selected. More than 20 years of experience with low-invasive methods have shown that open surgery is necessary only in exceptional cases, mainly for patients in whom anatomical reconstruction is needed. Videoendoscopic retroperitoneal or laparoscopic surgery is not a standard procedure for removing kidney stones. However, this technique should be considered as an alternative before choosing open surgery, and has advantages in some types of reconstructive surgery. For small stones (maximum diameter ≤ 20 mm or a surface area of ~300 mm2), ESWL is the standard procedure because it is non-invasive, has a low rate of complications, and (at least in adults) avoids the need for regional or general anaesthesia. Debate continues about whether large renal stones are best treated with ESWL or with PNL. Although large stones can be treated successfully with ESWL, ESWL has sometimes to be repeated and residual fragments are relatively common. Although PNL is faster at debulking stone than ESWL, it must be emphasised that considerable expertise and experience is required to clear stones completely from the caliceal system. Unless a meticulous technique is used, residual fragments may remain. There is a low risk that residual fragments can develop into new stones. However, a follow-up programme is needed because patients with stone disease have an inherent tendency to new stone formation. Residual fragments of infection stones, which are associated with the most pronounced risk of recurrent stone formation, can be eliminated with PNL, with or without percutaneous chemolysis. Such a step might also be used as an auxiliary procedure for cystine stones. For uric acid stones, oral chemolysis is the treatment of choice. However, the combination of stone disintegration and chemolysis can increase the rate of dissolution and may be considered for removal of large uric acid stones. An overview of treatment recommendations according to size and stone type is shown in Tables 17-22. Table 17: A  ctive removal of radiopaque (calcium) renal stones with a largest diameter < 20 mm (surface area ~ ≤ 300 mm2) Preference (decreasing order) 1 2 3 4 5

Procedure ESWL, also including piezolithotripsy PNL RIRS Laparoscopic surgery Open surgery

LE 1b 1b 2a 2a 4

GR A A C C C

LE = level of evidence; GR = grade of recommendation Infection stones are also radiopaque and usually contain calcium in the form of carbonate apatite and hydroxyapatite. These stones should be treated in the same way as sterile calcium stones, provided there is no obstruction and that a symptomatic infection has been adequately treated. For all patients with infection stones, recent history of urinary tract infection or bacteriuria, LE = 4 antibiotic prophylaxis should be started before the stone-removing procedure and continued GR = C least 4 days afterwards. LE = level of evidence; GR = grade of recommendation

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Table 18: A  ctive removal of uric acid renal stones with a largest diameter < 20 mm (surface area ~ ≤ 300 mm2) Preference

Procedure

LE

GR

1

Oral chemolysis

2a

B

2

ESWL (including piezolithotripsy) + oral chemolysis

2a

B

LE = level of evidence; GR = grade of recommendation; ESWL = extracorporeal shock-wave lithotripsy For patients with uric acid stones and a percutaneous nephrostomy catheter in place, stone disintegration with ESWL can advantageously be combined with percutaneous chemolysis (see Section 7.5). Table 19: Active removal of cystine stones with a largest diameter ≤ 20 mm (surface area ~ ≤ 300 mm2) Preference

Procedure

LE

GR

1 1 2 3 4

ESWL (including piezolithotripsy) PNL RIRS Laparoscopic surgery Open surgery

2a 2a 4 4 4

B B C C C

LE = level of evidence; GR = grade of recommendation; ESWL = extracorporeal shock-wave lithotripsy Table 20: A  ctive removal of radiopaque (calcium) renal stones with a largest diameter > 20 mm (surface area > 300 mm2) Preference

Procedure

LE

GR

1 2 3 4 4

PNL ESWL (including piezolithotripsy) PNL + ESWL (including piezolithotripsy) Laparoscopic surgery Open surgery

1b 1b 2b 4 4

A A B C C

LE = level of evidence; GR = grade of recommendation; ESWL = extracorporeal shock-wave lithotripsy Table 21: A  ctive removal of uric acid renal stones with a largest diameter > 20 mm (surface area ~ > 300 mm2) Preference

Procedure

LE

GR

1

Oral chemolysis

2a

B

2

ESWL (including piezolithotripsy) + oral chemolysis

2a

B

3

PNL

3

C

3 Percutaneous + chemolysis 3 C LE = level of evidence; GR = grade of recommendation; ESWL = extracorporeal shock-wave lithotripsy For patients with uric acid stones and a percutaneous nephrostomy catheter in place, stone isintegration with ESWL combined with percutaneous chemolysis is a good alternative to quickly dissolve the stone material (see Section 7.5).

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Table 22: Active removal of cystine stones with a largest diameter > 20 mm (surface area > 300 mm2) Preference 1 1 1 2 3 3

Procedure Percutaneous nephrolithotomy PNL+ ESWL (including piezolithotripsy) PNL+ chemolysis ESWL (including piezolithotripsy) + chemolysis Laparoscopic surgery Open surgery

LE 2a 2a 3 3 4 4

GR B B C C C C

LE = level of evidence; GR = grade of recommendation; ESWL = extracorporeal shock-wave lithotripsy Patients for whom ESWL-treatment of stones (with a diameter exceeding 20 mm ~300 mm2) LE = 3 is scheduled should have an internal stent to avoid problems related to Steinstrasse. GR = B LE = level of evidence; GR = grade of recommendation

8. STAGHORN STONES A staghorn stone is defined as a stone with a central body and at least one caliceal branch. A partial staghorn stone fills only part of the collecting system. A complete staghorn stone fills all the calices and the renal pelvis. Patients with staghorn stones can usually be treated according to the principles given for large stones (diameter > 20 mm / 300 mm2) (see Chapter 7). LE = level of evidence; GR = grade of recommendation

LE = 1b GR = A/B

In patients with small staghorn stones and a non-dilated system, repeated ESWL sessions with a stent can be a reasonable treatment alternative. Nephrectomy should be considered in the case of a non-functioning kidney. In selected cases with infection, cystine, uric acid and calcium phosphate stones, the combined use of ESWL or other stone-removing procedures, with chemolysis may be useful. The principles of chemolytic treatment are discussed in Chapter 7.

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9. MANAGEMENT OF PATIENTS WITH STONES IN THE URETER.

2007 Guideline for the Management of Ureteral Calculi

European Association of Urology and American Urological Association Education and Research, Inc.

EAU/AUA Nephrolithiasis Guideline Panel

Members: Glenn M. Preminger, M.D., Co-Chair Hans-Göran Tiselius, M.D., Ph.D., Co-Chair Dean G. Assimos, M.D., Vice Chair Peter Alken, M.D., Ph.D. Colin Buck, M.D., Ph.D. Michele Gallucci, M.D., Ph.D. Thomas Knoll, M.D., Ph.D. James E. Lingeman, M.D. Stephen Y. Nakada, M.D. Margaret Sue Pearle, M.D., Ph.D. Kemal Sarica, M.D., Ph.D. Christian Türk, M.D., Ph.D. J. Stuart Wolf, Jr., M.D.

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Consultants: Hanan S. Bell, Ph.D. Patrick M. Florer AUA and EAU Staff: Gunnar Aus, M.D., Ph.D., EAU Guidelines Office Chair Heddy Hubbard, Ph.D. Edith Budd Karin Plass Michael Folmer Katherine Moore Medical Writing Assistance: Diann Glickman, PharmD

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The Management of Ureteral Calculi: Diagnosis and Treatment Recommendations TABLE OF CONTENTS

page

9.1 Introduction 9.2 Methodology 9.3 Results of the Outcomes Analysis 9.3.1 Observation and Medical Therapies Stone passage rates 9.3.1.1 Shock-wave Lithotripsy and Ureteroscopy 9.3.1.2 Efficacy Outcomes Stone-free rates 9.3.1.3 Procedure Counts 9.3.1.4 Complications 9.3.1.5 Other Surgical Interventions 9.4 The Index Patient 9.5 Treatment Guidelines for the Index Patient 9.5.1 For All Index Patients 9.5.2 For Ureteral Stones 10 mm 9.5.4 For Patients Requiring Stone Removal 9.6 Recommendations for the Pediatric Patient 9.7 Recommendations for the Nonindex Patient 9.8 Discussion 9.8.1 Medical Expulsive Therapy 9.8.2 Shock-wave Lithotripsy 9.8.3 Ureteroscopy 9.8.4 Percutaneous Antegrade Ureteroscopy 9.8.5 Laparoscopic and Open Stone Surgery 9.8.6 Special Considerations 9.8.6.1 Pregnancy 9.8.6.2 Pediatrics 9.8.6.3 Cystine Stones 9.8.6.4 Uric acid Stones 9.9 Research and Future Directions 9.10 Acknowledgements and Disclaimers 9.11 References

52 52 54 55 55 55 55 55 58 60 62 62 63 63 63 64 64 65 65 65 65 66 67 67 68 68 68 68 69 69 69 70 70

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9.1

Introduction

The American Urological Association (AUA) Nephrolithiasis Clinical Guideline Panel was established in 1991. Since that time, the Panel has developed three guidelines on the management of nephrolithiasis, the most recent being a 2005 update of the original 1994 Report on the Management of Staghorn Calculi (1). The European Association of Urology (EAU) began their nephrolithiasis guideline project in 2000, yielding the publication of Guidelines on Urolithiasis, with updates in 2001 and 2006 (2). While both documents provide useful recommendations on the management of ureteral calculi, changes in shock-wave lithotripsy (SWL) technology, endoscope design, intracorporeal lithotripsy techniques, and laparoscopic expertise have burgeoned over the past five to ten years. Under the sage leadership of the late Dr. Joseph W. Segura, the AUA Practice Guidelines Committee suggested to both the AUA and the EAU that they join efforts in developing the first set of internationally endorsed guidelines focusing on the changes introduced in ureteral stone management over the last decade. We therefore dedicate this report to the memory of Dr. Joseph W. Segura whose vision, integrity, and perseverance led to the establishment of the first international guideline project. This joint EAU/AUA Nephrolithiasis Guideline Panel (hereinafter the Panel) performed a systematic review of the English language literature published since 1997 and a comprehensively analyzed outcomes data from the identified studies. Based on their findings, the Panel concluded that when removal becomes necessary, SWL and ureteroscopy (URS) remain the two primary treatment modalities for the management of symptomatic ureteral calculi. Other treatments were reviewed, including medical expulsive therapy (MET) to facilitate spontaneous stone passage, percutaneous antegrade ureteroscopy, and laparoscopic and open surgical ureterolithotomy. In concurrence with the previously published guidelines of both organizations, open stone surgery is still considered a secondary treatment option. Blind basketing of ureteral calculi is not recommended. In addition, the Panel was able to provide some guidance regarding the management of pediatric patients with ureteral calculi. The Panel recognizes that some of the treatment modalities or procedures recommended in this document require access to modern equipment or presupposes a level of training and expertise not available to practitioners in many clinical centers. Those situations may require physicians and patients to resort to treatment alternatives. This article will be published simultaneously in European Urology and The Journal of Urology. The Panel believes that future collaboration between the EAU and the AUA will serve to establish other internationally approved guidelines, offering physician and patient guidance worldwide.

9.2

Methodology

The Panel initially discussed the scope of the guideline and the methodology, which would be similar to that used in developing the previous AUA guideline. All treatments commonly employed in the United States and/ or Europe were included in this report except for those that were explicitly excluded in the previous guideline or newer treatments for which insufficient literature existed. In the analysis, patient data were stratified by age (adult versus child), stone size, stone location, and stone composition. Later, however, the data were found to be insufficient to allow analysis by composition. The outcomes deemed by the Panel to be of particular interest to the patient included the following: stone-free rate, number of procedures performed, stone-passage rate or probability of spontaneous passage, and complications of treatment. The Panel did not examine economic effects, including treatment costs. Outcomes were stratified by stone location (proximal, mid, and distal ureter) and by stone size (dichotomized as 10 mm for surgical interventions, and 5 mm for medical interventions and observation where possible; exceptions were made when data were reported, for example as 10 mm). The mid ureter is the part of the ureter that overlies the bony pelvis, i.e., the position of the ureter that corresponds to the sacroiliac joint; the proximal ureter is above and the distal ureter is below. Treatments were divided into three broad groups: 1. Observation and medical therapy 2. Shock-wave lithotripsy and ureteroscopy 3. Open surgery, laparoscopic stone removal, or percutaneous antegrade ureteroscopy. The review of the evidence began with a literature search and data extraction. Articles were selected from a database of papers derived from MEDLINE searches dealing with all forms of urinary tract stones. This database was maintained by a Panel chair. The abstract of each paper was independently reviewed by an American and a European Panel member, and articles were selected for data extraction if any panel member felt it might have useful data. Additional articles were suggested by Panel members or found as references in review articles. In total, 348 citations entered the extraction process. An American and a European Panel member each independently extracted data from each article onto a standardized form. The team members reconciled the extractions, and the data were entered into a Microsoft Access® (Microsoft, Redmond, WA)

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database. The Panel scrutinized the entries, reconciled the inconsistencies in recording, corrected the extraction errors, and excluded some articles from further analysis for the following reasons: 1. The article was included in the previous guideline. 2. The article did not provide usable data on the outcomes of interest. 3. Results for patients with ureteral stones could not be separated from results for those with renal stones. 4. The treatments used were not current or were not the focus of the analysis. 5. The article was a review article of data reported elsewhere. 6. The article dealt only with salvage therapy. A total of 244 of the 348 articles initially selected had extractable data. Articles excluded from evidence combination remained candidates for discussion in the text of the guideline. The goal was to generate outcomes tables comparing estimates of outcomes across treatment modalities. To generate an outcomes table, estimates of the probabilities and/or magnitudes of the outcomes are required for each intervention. Ideally, these are derived from a synthesis or combination of the evidence. Such a combination can be performed in a variety of ways depending on the nature and quality of the evidence. For this report, the Panel elected to use the Confidence Profile Method (3), which provides methods for analyzing data from studies that are not randomized controlled trials (RCTs). The Fast*Pro computer software4 was used in the analysis. This program provides posterior distributions from meta-analyses from which the median can be used as a best estimate, and the central 95% of the distribution serves as a confidence interval (CI). Statistical significance at the p 10 mm

2 15

76% (36-97)%

5 73

78% (61-90)%

41 6428

82% (79-85)%

16 2242

81% (77-85)%

Proximal ureter < 10 mm

14 886

90% (85-93)%

9 243

80% (73-85)%

Proximal ureter > 10 mm

11 293

68% (55-79)%

8 230

79% (71-87)%

Distal Ureter

Mid Ureter

Proximal Ureter

G = Number of Groups/Treatment arms extracted; P = Number of Patients in those groups

Table 1. Stone-Free Rates for SWL and URS in the Overall Population

Stone Free Rates after Primary/First Treatment Distal Ureter - SWL Distal Ureter - URS Distal Ureter < 10 mm - SWL Distal Ureter < 10 mm - URS Distal Ureter > 10 mm - SWL Distal Ureter > 10 mm - URS Mid Ureter - SWL Mid Ureter - URS Mid Ureter < 10 mm - SWL Mid Ureter < 10 mm - URS Mid Ureter > 10 mm - SWL Mid Ureter > 10 mm - URS Proximal Ureter - SWL Proximal Ureter - URS Proximal Ureter < 10 mm - SWL Proximal Ureter < 10 mm - URS Proximal Ureter > 10 mm - SWL Proximal Ureter > 10 mm - URS 0%

20%

40%

60%

80%

100%

Figure 1. Stone-Free Rates for SWL and URS in the Overall Population Estimated Occurrence Rate with 95% CI CI=confidence interval

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This analysis shows that overall, for stones in the proximal ureter (n=8,670), there was no difference in stone-free rates between SWL and URS. However, for proximal ureteral stones 10 mm (n=523), URS had superior stone-free rates. This difference arises because the stone-free rate for proximal ureteral stones treated with URS did not vary significantly with size, whereas the stone-free rate following SWL negatively correlated with stone size. For all distal stones, URS yields better stone-free rates overall and in both size categories. For all mid-ureteral stones, URS appears superior, but the small number of patients may have prevented results from reaching statistical significance. Unfortunately, RCTs comparing these treatments were generally lacking, making an accurate assessment impossible. However, the posterior distributions resulting from the meta-analysis can be subtracted, yielding a distribution for the difference between the treatments. If the CI of this result does not include zero, then the results may be considered to be statistically significantly different. This operation is mathematically justifiable but operationally risky: if the patients receiving different treatments are different or if outcome measures are different, results may be meaningless. Nonetheless, the Panel performed the comparison and found that URS stone-free rates were significantly better than SWL rates for distal ureteral stones 10 mm and for proximal ureteral stones >10 mm. The stone-free rate for mid-ureteral stones was not statistically significantly different between URS and SWL. The results with URS using a flexible ureteroscope for proximal ureteral stones appear better than those achieved with a rigid device, but not at a statistically significant level. Stone-free results for pediatric patients are shown in Table 2 and Figure 2. The very small number of patients in most groups, particularly for URS, makes comparisons among treatments difficult. However, it does appear that SWL may be more effective in the pediatric subset than in the overall population, particularly in the mid and lower ureter. Table 2. Stone-Free Rates for SWL and URS, Pediatric Population

PediatricPopulation

AUA / EAU Ureteral Stones Guideline Panel Stone Free Rate - Primary Treatments or First Treatment SWL

URS

G/P 8 229

Med / 95% Cl 80% (68-90)%

G/P 9 151

Med / 95% Cl 92% (86-96)%*

Distal ureter < 10 mm

5 135

86% (78-92)%

2 29

86% (72-98)%

Distal ureter > 10 mm

2 26

(58-97)% 3 11

80% (52-96)%

Distal Ureter

83%

33

82% (63-94)%

Mid ureter < 10 mm

4 16

80% (41-98)%

Mid ureter > 10 mm

1 6

96% (67-100)%

1 5

78% (37-99)%

7 101

81% (69-90)%

5 18

57% (25-85)%

Proximal ureter < 10 mm

5 43

89% (72-98)%

Proximal ureter > 10 mm

3 16

63% (21-94)%

Mid Ureter

Proximal Ureter

6

G = Number of Groups/Treatment arms extracted; P = Number of Patients in those groups

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Figure 2. Stone-Free Rates for SWL and URS, Pediatric Population

Stone Free Rates after Primary/First Treatment Pediatric Patients Distal Ureter - SWL Distal Ureter - URS Distal Ureter < 10 mm - SWL Distal Ureter < 10 mm - URS Distal Ureter > 10 mm - SWL Mid Ureter - SWL Mid Ureter - URS Mid Ureter < 10 mm - SWL Mid Ureter > 10 mm - SWL Mid Ureter > 10 mm - URS Proximal Ureter - SWL Proximal Ureter - URS Proximal Ureter < 10 mm - SWL Proximal Ureter > 10 mm - SWL 0%

20%

40%

60%

80%

100%

Estimated Occurrence Rate with 95% CI CI=confidence interval

9.3.1.3 Procedure Counts Procedure counts were captured as three types: 1. Primary procedures – the number of times the intended procedure was performed. 2. Secondary procedures – the number of times an alternative stone removal procedure(s) was performed. 3. Adjunctive procedures – additional procedures performed at a time other than when the primary or secondary procedures were performed; these could include procedures related to the primary/ secondary procedures such as stent removals as well as procedures performed to deal with complications; most adjunctive procedures in the data presented represent stent removals. It is likely that many stent-related adjunctive procedures were underreported, and thus the adjunctive procedure count may be underestimated. As mentioned in Chapter 2, it was not possible to perform a meta-analysis or to test for statistically significant differences between treatments due to the lack of variance data, and only weighted averages could be computed. The procedure count results for the overall population are shown in Table 3 and Figure 3. Figure 3 results are presented as stacked bars.

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Table 3. Procedure Counts for SWL and URS in the Overall Population Overall Population

Procedure Counts Grps/Pts

# Procs

Grps/Pts

# Procs

Grps/Pts

# Procs

Grps/Pts

# Procs

Grps/Pts

SWL Distal Ureter

Primary 48/7117 1.22

# Procs

Grps/Pts

# Procs

URS

Secondary 30/5069 0.12

Adjunctive 0.03 15/3875

Primary 1.04 56/5308

Secondary 0.03 25/5124

Adjunctive 0.36 24/2848

Distal ureter < 10 mm

16/1618

1.34

5/170

0.12

12/1117

1.01

6/492

0.05

4/305

0.88

Distal ureter > 10 mm

11/951

1.44

3/1026

0.10

5/231

1.02

1/69

0.14

1/110

1.00

10/291

1.11

9316

0.18

25/686

1.04

15/934

0.07

8/357

0.09

Mid ureter < 10 mm

2/31

1.29

4/32

1.00

2/34

0.34

1/7

1.14

Mid ureter > 10 mm

3/53

1.76

2/18

1.00

1/35

0.31

1/5

0.02

37/5902

1.31

20/2131

0.07

13/1329

0.24

42/1634

1.02

27/1831

0.26

14/1159

0.17

Proximal ureter < 10 mm

16/1243

1.26

5/150

0.14

3/114

0.77

6/68

1.00

4/62

0.39

3/27

0.52

Proximal ureter > 10 mm

10/409

1.49

5/83

0.21

4/45

0.56

5/137

1.07

1/130

0.13

1/11

0.21

Mid Ureter

Proximal Ureter

4/241

0.23

Figure 3. Procedure Counts for SWL and URS in the Overall Population

Procedures per Patient Distal Ureter - SWL Distal Ureter - URS Distal Ureter < 10 mm - SWL Distal Ureter < 10 mm - URS Distal Ureter > 10 mm - SWL Distal Ureter > 10 mm - URS Mid Ureter - SWL Mid Ureter - URS Mid Ureter < 10 mm - SWL Mid Ureter < 10 mm - URS Mid Ureter > 10 mm - SWL Mid Ureter > 10 mm - URS Proximal Ureter - SWL Proximal Ureter - URS Proximal Ureter < 10 mm - SWL Proximal Ureter < 10 mm - URS Proximal Ureter > 10 mm - SWL Proximal Ureter > 10 mm - URS 0.0

0.5

1.0

1.5

2.0

2.5

3.0

Weighted Mean Procedures per Patient Primary Procedures Secundary Procedures Adjunctive Procedures

Procedure count results for pediatric patients are shown in Table 4 and Figure 4. Again, the numbers of patients with available data were small and did not support meaningful comparisons among treatments.

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Table 4. Procedure Counts for SWL and URS in the Pediatric Population, All Locations Pediatric Population

Procedure Counts Grps/Pts

# Procs

Grps/Pts

# Procs

Grps/Pts

# Procs

Grps/Pts

# Procs

Grps/Pts

SWL Distal Ureter

Primary 7/212 1.38

Distal ureter < 10 mm

5/135

1.42

Distal ureter > 10 mm

4/26

1.42

# Procs

Grps/Pts

# Procs

URS

Secondary 4/98 0.08

Adjunctive 0.07 2/43

Primary 1.05 10/185

Secondary 0.09 7/190

Adjunctive 0.72 5/96

1/14

0.36

2/63

1.00

4/131

0.11

1/5

0.78

1/9

0.11

4/32

1.44

4/18

1.00

2/12

0.17

2/12

0.75

Mid ureter < 10 mm

3/16

1.50

1/7

1.00

1/7

0.14

1/7

0.71

Mid ureter > 10 mm

1/6

1.33

1/5

1.00

1/5

0.20

1/5

0.20

5/83

1.28

3/38

0.05

1/5

0.00

6/27

1.00

7/38

0.34

1/9

1.00

Proximal ureter < 10 mm

5/43

1.19

1/3

0.00

1/3

0.00

1/9

1.00

2/18

0.33

1/9

1.00

Proximal ureter > 10 mm

4/16

1.38

2/2

0.00

2/2

0.00

Mid Ureter

Proximal Ureter

Figure 4. Procedure Counts for SWL and URS in the Pediatric Population, All Locations

Procedures per Patient - Pediatric Patients Distal Ureter - SWL Distal Ureter - URS Distal Ureter < 10 mm - SWL Distal Ureter < 10 mm - URS Distal Ureter > 10 mm - SWL Mid Ureter - SWL Mid Ureter - URS Mid Ureter < 10 mm - SWL Mid Ureter < 10 mm - URS Mid Ureter > 10 mm - SWL Mid Ureter > 10 mm - URS Proximal Ureter - SWL Proximal Ureter - URS Proximal Ureter < 10 mm - SWL Proximal Ureter < 10 mm - URS Proximal Ureter > 10 mm - SWL 0.0

0.5

1.0

1.5

2.0

2.5

Weighted Mean Procedures per Patient Primary Procedures Secundary Procedures Adjunctive Procedures

9.3.1.4 Complications The articles were extracted for various complications; however, the Panel believes the following are the most relevant: 1. Sepsis 2. Steinstrasse 3. Stricture 4. Ureteral injury 5. Urinary tract infection (UTI) Serious complications, including death and loss of kidney, were sufficiently rare that data were not available to estimate their rates of occurrence. Other complications are listed in Chapter 3. The complication rates for the overall population by treatment, size, and location are shown in Table 5.

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Table 5. Complications Occurrence Rates with SWL and URS, Overall Population SWL URS Groups/Patients Med/95% CI Groups/Patients Med/95% CI Distal Ureter Sepsis 6 3% 7 2% 2019 (2 - 5)% 1954 (1 - 4)% Steinstrasse

1 26

4% (0 - 17)%



Stricture

2 609

0% (0 - 1)%

16 1911

1% (1 - 2)%

Ureteral Injury

1 45

1% (0 - 5)%

23 4529

3% (3 - 4)%

UTI

3 87

4% (1 - 12)%

3 458

4% (2 - 7)%

Mid Ureter Sepsis

2 398

5% (0 - 20)%

4 199

4% (1 - 11)%



Steinstrasse

1 37

8% (2 - 20)%



1 43

1% (0 - 6)%



Stricture

Ureteral Injury

7 326

4% (2 - 7)%

10 514

6% (3 - 8)%

UTI

1 37

6% (1 - 16)%

1 63

2% (0 - 7)%

Proximal Ureter Sepsis

5 704

3% (2 - 4)%

8 360

4% (2 - 6)%

Steinstrasse

3 235

5% (2 - 10)%

1 109

0% (0 - 2)%



Stricture

2 124

2% (0 - 8)%

8 987

2% (1 - 5)%

Ureteral Injury

2 124

2% (0 - 8)%

10 1005

6% (3 - 9)%

UTI

5 360

4% (2 - 7)%

2 224

4% (1 - 8)%



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Table 6 summarizes complications for all pediatric groups. Since there are few groups and patients, it was not possible to stratify data by stone size or location. The reported frequencies of pain may be inaccurate because of inconsistent reporting.

Table 6. Complication Occurrence Rates - Overall, Pediatric Population

Complications of Treatment- PEDIATRIC SWL Bleeding Overall Significant complications Pain Retention Sepsis Skin Stricture Ureteral Obstruction UTI Infection Stent Migration Ureteral Injury Ureteral Obstruction UTI Stricture Other Long Term CX

URS

Groups/Patient

Med / 95% Cl

Groups/Patient

2

5%

1

Med / 95% Cl 17%

206

(0-24)%

66

(9-27)%

1

1%

5

5%

38

(0-6)%

65

(1-14)%

3

18%

3

5%

106

(9-30)%

98

(1-13)%

1

2%

1

4%

63

(0-7)%

26

(0-17)%

2

4%

3

3%

101

(1-12)%

73

(0-9)%

1

0%

168

(0-1)%

1

1%

25

(0-9)%

4

2%

283

(1-6)%

2

2%

63

(0-9)% 2

6%

91

(2-13)%

1

5%

25

(0-17)%

6

6%

216

(3-10)%

1

1%

26

(0-9)%

1

2%

12

(0-19)%

5

5%

106

(2-11)%

1

12%

43

(5-24)%

G = number of groups/treatment arms extracted; P = number of patients in those groups.

9.3.1.5 Other Surgical Interventions Small numbers of studies reported on open surgery, laparoscopic stone removal, and percutaneous antegrade ureteroscopy. Because these procedures are usually reserved for special cases, the reported data should not be used to compare procedures with each other or with SWL or URS. As expected, these more invasive procedures yielded high stone-free rates when used. A single pediatric report provided procedure counts for two patients who had one open procedure each. Two studies reported stone-free rates for children with open procedures (n=five patients); the computed stone-free rate was 82% (95% CI: 43% to 99%).

9.4

The Index Patient

In constructing these guidelines, an “index patient” was defined to reflect the typical individual with a ureteral stone whom a urologist treats. The following definition was created.

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The index patient is a nonpregnant adult with a unilateral noncystine/nonuric acid radiopaque ureteral stone without renal calculi requiring therapy whose contralateral kidney functions normally and whose medical condition, body habitus, and anatomy allow any one of the treatment options to be undertaken.

9.5

Treatment Guidelines for the Index Patient

9.5.1

For All Index Patients

Standard: Patients with bacteriuria should be treated with appropriate antibiotics. [Based on Panel consensus/Level IV] Untreated bacteriuria can lead to infectious complications and possible urosepsis if combined with urinary tract obstruction, endourologic manipulation, or SWL. Urine culture prior to intervention is recommended; screening with dipsticks might be sufficient in uncomplicated cases (2). In case of suspected or proven infection, appropriate antibiotic therapy should be administered before intervention (6). Standard: Stone extraction with a basket without endoscopic visualization of the stone (blind basketing) should not be performed. [Based on Panel consensus/Level IV] Before the availability of modern ureteroscopes, extraction of distal ureteral stones with a basket with or without fluoroscopy was common. This procedure is, however, associated with an obvious risk of injury to the ureter. It is the expert opinion of the Panel that blind stone extraction with a basket should not be performed, and that intraureteral manipulations with a stone basket should always be performed under direct ureteroscopic vision. Fluoroscopic imaging of the stone alone is not sufficient. 9.5.2

For Ureteral Stones 10 mm) compared with smaller stones (78% versus 91%, respectively). Ureteroscopic treatment of distal ureteral stones is uniformly associated with high success rates and low complication rates. An overall stone-free rate of 94% was achieved with either a rigid or semirigid ureteroscope, with little drop off in stone-free rates when treating larger stones. On the other hand, flexible URS was less successful than rigid or semirigid URS for distal ureteral stones, particularly those >10 mm, likely due to difficulty maintaining access within the distal ureter with a flexible ureteroscope. A number of adjunctive measures have contributed to the enhanced success of ureteroscopic management of ureteral calculi. Historically, stones in the proximal ureter have been associated with lower success rates than those in the mid and distal ureter, in part because the proximal ureter is more difficult to access and stone fragments often become displaced into the kidney where they may be difficult to treat. Improved flexible ureteroscopes and greater technical skill, along with the introduction of devices to prevent stone migration (48,49) have improved the success of treating proximal ureteral stones. Although the efficacy of URS for the treatment of ureteral calculi has been amply shown, the need for a ureteral stent with its attendant morbidity has biased opinion towards SWL in some cases. Clearly, SWL is associated with fewer postoperative symptoms and better patient acceptance than URS. However, a number of recent prospective, randomized trials have shown that for uncomplicated URS, the ureter may be left unstented without undue risk of obstruction or colic requiring emergent medical attention (10,14-19). Ureteroscopy can also be applied when SWL might be contraindicated or ill-advised. Ureteroscopy can be performed safely in select patients in whom cessation of anticoagulants is considered unsafe (50). In addition, URS has been shown to be effective regardless of patient body habitus. Several studies have shown that morbidly obese patients can be treated with success rates and complication rates comparable to the general population (51,52). Finally, URS can be used to safely simultaneously treat bilateral ureteral stones in select cases (53-55). 9.8.4 Percutaneous Antegrade Ureteroscopy Percutaneous antegrade removal of ureteral stones is a consideration in selected cases, for example, for the treatment of very large (>15 mm diameter) impacted stones in the proximal ureter between the ureteropelvic junction and the lower border of the fourth lumbar vertebra (30,56). In these cases with stone-free rates between 85% and 100%, its superiority to standard techniques has been evaluated in one prospective randomized (57) and in two prospective studies (28,30). In a total number of 204 patients, the complication rate was low, acceptable, and not specifically different from any other percutaneous procedure. Percutaneous antegrade removal of ureteral stones is an alternative when SWL is not indicated or

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has failed (58) and when the upper urinary tract is not amenable to retrograde URS; for example, in those with urinary diversion (29) or renal transplants (59). 9.8.5 Laparoscopic and Open Stone Surgery Shock-wave lithotripsy, URS, and percutaneous antegrade URS can achieve success for the vast majority of stone cases. In extreme situations or in cases of simultaneous open surgery for another purpose, open surgical ureterolithotomy might rarely be considered (60,61). For most cases with very large, impacted, and/ or multiple ureteral stones in which SWL and URS have either failed or are unlikely to succeed, laparoscopic ureterolithotomy is a better alternative than open surgery if expertise in laparoscopic techniques is available. Both retroperitoneal and transperitoneal laparoscopic access to all portions of the ureter have been reported. Laparoscopic ureterolithotomy in the distal ureter is somewhat less successful than in the middle and proximal ureter, but the size of the stone does not appear to influence outcome. Although highly effective, laparoscopic ureterolithotomy is not a first-line therapy in most cases because of its invasiveness, attendant longer recovery time, and the greater risk of associated complications compared to SWL and URS. 9.8.6 Special Considerations 9.8.6.1 Pregnancy Renal colic is the most common nonobstetric cause of abdominal pain in pregnant patients requiring hospitalization. The evaluation of pregnant patients suspected of having renal colic begins with ultrasonography, as ionizing radiation should be limited in this setting. If the US examination is unrevealing and the patient remains severely symptomatic, a limited intravenous pyelogram may be considered. A typical regimen includes a preliminary plain radiograph (KUB) and two films, 15 minutes and 60 minutes following contrast administration. Noncontrast computed tomography is uncommonly performed in this setting because of the higher dose of radiation exposure. Magnetic resonance imaging can define the level of obstruction, and a stone may be seen as a filling defect. However, these findings are nonspecific. In addition, there is a paucity of experience with using this imaging modality during pregnancy (62). Once the diagnosis has been established, these patients have traditionally been managed with temporizing therapies (ureteral stenting, percutaneous nephrostomy), an approach often associated with poor patient tolerance. Further, the temporizing approach typically requires multiple exchanges of stents or nephrostomy tubes during the remainder of the patient’s pregnancy due to the potential for rapid encrustation of these devices. A number of groups have now reported successful outcomes with URS in pregnant patients harboring ureteral stones. The first substantial report was by Ulvik, et al (63) who reported on the performance of URS in 24 pregnant women. Most patients had stones or edema, and there were no adverse sequelae associated with ureteroscopic stone removal. Similar results have been reported by Lifshitz and Lingeman (64) and Watterson et al (65) who found that the ureteroscopic approach was both diagnostic and therapeutic in pregnant patients with very low morbidity and the need for only short-term ureteral stenting, if at all, afterwards. When intracorporeal lithotripsy is necessary during ureteroscopic treatment of calculi in pregnant patients, the holmium laser has the advantage of minimal tissue penetration, thereby theoretically limiting risk of fetal injury. 9.8.6.2 Pediatrics Both SWL and URS are effective treatment alternatives for stone removal in children. Selection of the most appropriate treatment has to be based on the individual stone problem, the available equipment and the urologist’s expertise in treating children. Children appear to pass stone fragments after SWL more readily than adults (66-71). Ureteroscopy may be used as a primary treatment or as a secondary treatment after SWL in case of poor stone disintegration. Less efficient SWL disintegration might be seen in children with stones composed of cystine, brushite and calcium oxalate monohydrate or when anatomic abnormalities result in difficulties in fluoroscopic or ultrasonographic visualization of the stone (72-74). One of the main problems with pediatric URS is the size of the ureteroscope relative to the narrow intramural ureter and the urethral diameter. This problem has lately been circumvented by the use of smaller ureteroscopes, for example, mini or needle instruments as well as small flexible semirigid or rigid ureteroscopes and pediatric (6.9 Fr) cystoscopes. With the availability of 4.5 and 6.0 Fr semirigid ureteroscopes, a 5.3 Fr flexible ureteroscope and a holmium:YAG laser energy source, instrument-related complications have become uncommon (73-75). However, the utilization of proper technique remains the most important factor for generating successful outcomes in this population. Percutaneous stone removal is also possible in pediatric patients with comparable indications to those in adults. Such an approach might be considered for stone removal in children with a malformation of the lower urinary tract.

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9.8.6.3 Cystine Stones Individuals with cystinuria are considered nonindex patients by the Panel for a variety of reasons. There are limited data regarding treatment outcomes in this group (76-83). In vitro studies also show that these stones are commonly resistant to SWL, although the degree of resistance may be variable (77,78). The structural characteristics of these stones are thought to contribute to their decreased SWL fragility. In addition, some of these stones may be barely opaque on standard imaging or fluoroscopy, potentially compromising shock-wave focusing. In contrast to SWL, technology currently utilized for intracorporeal lithotripsy during URS, including the holmium laser, ultrasonic and pneumatic devices, can readily fragment cystine stones (81). Certain imaging characteristics may predict SWL outcomes for this patient group. Bhatta and colleagues reported that cystine stones having a rough-appearing external surface on plain film imaging were more apt to be fragmented with shock-wave energy than those with a smooth contour (82). Kim and associates reported that the computed tomography attenuation coefficients of the latter were significantly higher than the rough-type stones (83). Other types of stones with higher attenuation values have also been demonstrated to be resistant to shock-wave fragmentation (84). Patients with this rare genetic disorder typically have their first stone event early in life, are prone to recurrent stones, and are consequently subject to repetitive removal procedures. In addition, patients with cystinuria are at risk for developing renal insufficiency over time (85,86). Prophylactic medical therapy and close follow-up can limit recurrence. 9.8.6.4 Uric acid Stones Uric acid calculi are typically radiolucent, thus limiting the ability to treat such patients using in situ SWL. However, this approach may be possible with devices that use US if the stone can indeed be localized. When properly targeted, these stones fragment readily with SWL. Uric acid stones have lower computed tomography attenuation values, and can usually be distinguished from calcium, cystine, and struvite calculi (87). The presence of a low attenuation or a radiolucent stone, particularly in a patient with a low urinary pH, should lead the clinician to suspect this diagnosis. Manipulation of the urinary pH with oral potassium citrate, sodium citrate, or sodium bicarbonate to a level ranging from 6.0 to 7.0 may obviate the need for surgical intervention. Moreover, this medical treatment may allow stone dissolution in patients whose symptoms are controllable, should prevent the development of future uric acid stones, and has also been shown to enhance stone clearance with SWL (88). Medical expulsive therapy may be administered concomitantly. Ureteroscopy is a very effective method of treating patients who are not candidates for observation (89).

9.9

Research and Future Directions

Ten years have elapsed since the last publication of the AUA guidelines, and one year since the EAU recommendations on ureteral stones. Extensive cooperation between AUA and EAU Panel members has produced this unique collaborative report. This venture should provide the foundation for future collaborative efforts in guideline development. The Panel encountered a number of deficits in the literature. While the management of ureteral stones remains commonly needed, few RCTs were available for data extraction. The data were inconsistent, starting from the definition of stone sizes and ending with variable definitions of a stone-free state. These limitations hinder the development of evidence-based recommendations. To improve the quality of research, the Panel strongly recommends the following: • conducting RCTs comparing interventional techniques like URS and SWL • conducting pharmacological studies of stone-expulsion therapies as double-blinded RCTs • reporting stone-free data without inclusion of residual fragments • using consistent nomenclature to report stone size, stone location, stone-free rates, time point when stone-free rate is determined, or method of imaging to determine stone-free rate • reporting data stratified by patient/stone characteristics, such as patient age, stone size, stone location, stone composition, gender, body mass index, and treatment modality • reporting all associated treatments including placement of ureteral stents or nephrostomies • using standardized methods to report acute and long-term outcomes • developing methods to predict outcomes for SWL, URS, and MET • providing measures of variability such as standard deviation, standard error, CI, or variance with corresponding average patient numbers • reporting raw data to facilitate meta-analyses The Panel suggests focusing on the following issues in future investigations: • investigating the proposed current efficacy problems of second and third generation shock-wave machines and developing approaches to improve SWL

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• •

•

determining the safety of each technique with respect to acute and long-term effects investigating the promising medical stone expulsion in basic research studies and in clinical trials to unravel the underlying mechanisms and to optimize the treatment regimens addressing issues such as patient preferences, quality of life, and time until the patient completed therapy when evaluating treatment strategies. To date, only a few studies have addressed patient preference.90-92 although largely dependent on different health systems, addressing cost-effectiveness

9.10

Acknowledgements and Disclaimers

•

The supporting systematic literature review and data analysis, and the drafting of this document were conducted by the EAU/AUA Nephrolithiasis Guideline Panel (hereinafter the Panel). Each association selected a Panel chair who in turn appointed the Panel members, urologists with specific expertise in this disease. The mission of the Panel was to develop either analysis- or consensus-based recommendations, depending on the type of evidence available and Panel processes to support optimal clinical practices in the management of ureteral calculi. This document was submitted to 81 urologists and other health care professionals for peer review. After revision of the document based upon the peer review comments, the guideline was submitted for approval to the Practice Guidelines Committee of the AUA and the Guidelines Office of the EAU. Then it was forwarded to the AUA Board of Directors and the EAU Board for final approval. Funding of the Panel and of the PGC was provided by the AUA and the EAU, although Panel members received no remuneration for their work. Each member of the PGC and of the Panel furnished a current conflict of interest disclosure to the AUA. The final report is intended to provide medical practitioners with a current understanding of the principles and strategies for the management of ureteral calculi. The report is based on an extensive review of available professional literature as well as clinical experience and expert opinion. Some of the medical therapies currently employed in the management of ureteral calculi have not been approved by the US Food and Drug Administration for this specific indication. Thus, doses and dosing regimens may deviate from that employed for the Food and Drug Adminstration-approved indications, and this difference should be considered in the risk-versus-benefit assessment. This document provides guidance only, and does not establish a fixed set of rules or define the legal standard of care. As medical knowledge expands and technology advances, this guideline will change. Today it represents not absolute mandates but provisional proposals or recommendations for treatment under the specific conditions described. For all these reasons, the guideline does not preempt physician judgment in individual cases. Also, treating physicians must take into account variations in resources, and in patient tolerances, needs and preferences. Conformance with the guideline reflected in this document cannot guarantee a successful outcome.

9.11

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27. Damiano R, Autorino R, Esposito C, Cantiello F, Sacco R, de Sio M, D’Armiento M. Stent positioning ureteroscopy for urinary calculi: the question is still open. Eur Urol 2004;46(3):381-7; discussion 387-8. http://www.ncbi.nlm.nih.gov/pubmed/15306112 28. Maheshwari PN, Oswal AT, Andankar M, Nanjappa KM, Bansal M: Is antegrade ureteroscopy better than retrograde ureteroscopy for impacted large upper ureteral calculi? J Endourol 1999;13(6):441-4. http://www.ncbi.nlm.nih.gov/pubmed/10479011 29. el-Nahas AR, Eraky I, el-Assmy AM, Shoma AM, el-Kenaey MR, Abdel-Latif M, Mosbah A, Abol-Enein H, Shaaban AA, Mohsen T, el-Kappany HA. Percutaneous treatment of large upper tract stones after urinary diversion. Urology 2006;500-4. http://www.ncbi.nlm.nih.gov/pubmed/16979745 30. Kumar V, Ahlawat R, Banjeree GK, Bhaduria RP, Elhence A, Bhandari M: Percutaneous ureterolitholapaxy: the best bet to clear large bulk impacted upper ureteral calculi. Arch Esp Urol 1996; 49(1):86-91. http://www.ncbi.nlm.nih.gov/pubmed/8678608 31. Skreptis K, Doumas K, Siafakas I, Lykourinas M. Laparoscopic versus open ureterolithotomy. A comparative study. Eur Urol 2001;40(1):32-6. http://www.ncbi.nlm.nih.gov/pubmed/11528174 32. Goel A, Hemal AK. Upper and mid-ureteric stones: a prospective unrandomized comparison of retroperitoneoscopic and open ureterolithotomy. BJU Int 2001;88(7):679-82. http://www.ncbi.nlm.nih.gov/pubmed/11890236 33. Pearle MS, Pierce HL, Miller GL, Summa JA, Mutz JM, Petty BA, Roehrborn CG, Kryger JV, Nakada SY. Optimal method of urgent decompression of the collecting system for obstruction and infection due to ureteral calculi. J Urol 1998;160(4):1260-4. http://www.ncbi.nlm.nih.gov/pubmed/9751331 34. Gravina GL, Costa AM, Ronchi P, Galatioto GP, Angelucci A, Castellani D, Narcisi F, Vicentini C. Tamsulosin treatment increases clinical success rate of single extracorporeal shock wave lithotripsy of renal stones. Urology 2005;66(1):24-8. http://www.ncbi.nlm.nih.gov/pubmed/15992885 35. Resim S, Ekerbicer HC, Ciftci A. Role of tamsulosin in treatment of patients with steinstrasse developing after extracorporeal shock wave lithotripsy. Urology 2005;66(5):945-8. http://www.ncbi.nlm.nih.gov/pubmed/16286100 36. Borghi L, Meschi T, Amato F, Novarini A, Giannini A, Quarantelli C, Mineo F. Nifedipine and methylprednisolone in facilitating ureteral stone passage: a randomized, double-blind, placebocontrolled study. J Urol 1994;152(4):1095-8. http://www.ncbi.nlm.nih.gov/pubmed/8072071 37. Porpiglia F, Destefanis P, Fiori C, Fontana D. Effectiveness of nifedipine and deflazacort in the management of distal ureter stones. Urology 2000;56(4):579-82. http://www.ncbi.nlm.nih.gov/pubmed/11018608 38. Dellabella M, Milanese G, Muzzonigro G. Randomized trial of the efficacy of tamsulosin, nifedipine and phloroglucinol in medical expulsive therapy for distal ureteral calculi. J Urol 2005;174(1):167-72. http://www.ncbi.nlm.nih.gov/pubmed/15947613 39. Yilmaz E, Batislam E, Basar MM, Tuglu D, Ferhat M, Basar H. The comparison and efficacy of 3 different alpha1-adrenergic blockers for distal ureteral stones. J Urol 2005;173(6):2010-2. http://www.ncbi.nlm.nih.gov/pubmed/15879806 40. Carol PR, Shi RY. Genetic toxicity of high energy shockwaves: assessment using the induction of mutations or micronuclei in Chinese hamster ovary. J Urol 1986;135:292a. 41. Chaussy CG, Fuchs GJ. Extracorporeal shock wave lithotripsy of distal-ureteral calculi: is it worthwhile? J Endourol 1987;1:1. 42. Erturk E, Herrman E, Cockettt AT. Extracorporeal shock wave lithotripsy for distal ureteral stones. J Urol 1993;149(6):1425-6. http://www.ncbi.nlm.nih.gov/pubmed/8501780 43. Miller K, Bachor R, Haumann R. Extracorporeal shock wave lithotripsy in the prone position: technique, indications, results. J Endourol 1988;2:113. 44. Vieweg J, Weber HM, Miller K, Hautmann R. Female fertility following extracorporeal; shock wave lithotripsy of distal ureteral calculi. J Urol 1992;148(3 Pt 2):1007-10. http://www.ncbi.nlm.nih.gov/pubmed/1507317 45. Francesca F, Scattoni V, Nava L, Pompa P, Grasso M, Rigatti P. Failures and complications of transurethral ureteroscopy in 297 cases: conventional rigid instruments vs. small caliber semirigid ureteroscopes. Eur Urol 1995;28(2):112-5. http://www.ncbi.nlm.nih.gov/pubmed/8529733

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Yaycioglu O, Guvel S, Kilinc F, Egilmez T and Ozakardes H: Results with 7.5F versus 10F rigid ureteroscopes in treatment of ureteral calculi. Urology 2004;64(4):643-6. http://www.ncbi.nlm.nih.gov/pubmed/15491688 47. Johnson DB and Pearle MS: Complications of ureteroscopy. Urol Clin North Am 2004:31(1):157-71. http://www.ncbi.nlm.nih.gov/pubmed/15040412 48. Dretler SP. Prevention of retrograde stone migration during ureteroscopy. Nat Clin Pract Urol 2006; 3(2):60-1. http://www.ncbi.nlm.nih.gov/pubmed/16470185 49. Desai MR, Patel SB, Desai MM, Kukreja R, Sabnis RB, Desai RM, Patel SH. The Dretler stone cone: a device to prevent ureteral stone migration – the initial clinical experience. J Urol 2002;167(5):1985-8. http://www.ncbi.nlm.nih.gov/pubmed/11956424 50. Watterson JD, Girvan AR, Cook AJ, Beilo DT, Nott L, Auge BK, Preminger GM, Denstedt JD. Safety and efficacy of holmium: YAG laser lithotripsy in patients with bleeding diatheses. J Urol 2002;168(2):442-5. http://www.ncbi.nlm.nih.gov/pubmed/12131284 51. Dash A, Schuster TG, Hollenbeck BK, Faerver GJ, Wolf JS Jr. Ureteroscopic treatment of renal calculi in morbidly obese patients: a stone-matched comparison. Urology 2002;60(3):393-7. http://www.ncbi.nlm.nih.gov/pubmed/12350468 52. Andreoni C, Afane J, Olweny E, Clayman RV. Flexible ureteroscopic lithotripsy: first-line therapy for proximal ureteral and renal calculi in the morbidly obese and superobese patient. J Endourol 2001;15(5):493-8 http://www.ncbi.nlm.nih.gov/pubmed/11465328 53. Deliveliotis C, Picramenos D, Alexopoulou K, Christofis I, Kostakopoulos A, Dimopoulos C. Onesession bilateral ureteroscopy: is it safe in selected patients? Int Urol Nephrol 1996;28(4):481-4. http://www.ncbi.nlm.nih.gov/pubmed/9119632 54. Hollenbeck BK, Schuster TG, Faerber GJ, Wolf JS Jr. Safety and efficacy of same-session bilateral ureteroscopy. J Endourol 2003;17(10):881-5. http://www.ncbi.nlm.nih.gov/pubmed/14744354 55. Bilgasem S, Pace KT, Dyer S, Honey RJ. Removal of asymptomatic ipsilateral renal stones following rigid ureteroscopy for ureteral stones. J Endourol 2003;17(6):397-400. http://www.ncbi.nlm.nih.gov/pubmed/12965066 56. Goel R, Aron M, Kesarwani PK, Dogra PN, Hermal AK, Gupta NP. Percutaneous antegrade removal of impacted upper-ureteral calculi: still the treatment of choice in developing countries. J Endourol 2005; 19(1):54-7. http://www.ncbi.nlm.nih.gov/pubmed/15735384 57. Karami H, Arbab AH, Hosseini SJ, Razzaghi MR, Simaei NR: Impacted upper-ureteral calculi>1 cm: bind access and totally tubeless percutaneous antegrade removal or retrograde approach? J Endourol 2006;20(9):616-9. http://www.ncbi.nlm.nih.gov/pubmed/16999610 58. El-Assmy A, El-Nahas AR, Mohsen T, Eraky I, El-Kenawy MR, Shaban AA, Sheir KZ. Extracorporeal shock wave lithotripsy of upper urinary tract calculi in patients with cystectomy and urinary diversion. Urology 2005;66(3):510-3. http://www.ncbi.nlm.nih.gov/pubmed/16140067 59. Rhee BK, Bretan PN Jr, Stoller ML. Urolithiasis in renal and combined pancreas/renal transplant recipients. J Urol 1999;161(5):1458-62. http://www.ncbi.nlm.nih.gov/pubmed/10210372 60. Kane CJ, Bolton DM, Stoller ML. Current indications for open stone surgery in an endourology center. Urology 1995;45(2):218-21. http://www.ncbi.nlm.nih.gov/pubmed/7855969 61. Bichler KH, Lahme S, Strohmaier WL. Indications for open removal of urinary calculi. Urol Int 1997;59(2):102-8. http://www.ncbi.nlm.nih.gov/pubmed/9392057 62. Spencer JA, Chahal R, Kelly A, Taylor K, Eardley I, Lloyd SN. Evaluation of painful hydronephrosis in pregnancy: magnetic resonance urographic patterns in physiological dilatation versus calculus obstruction. J Urol 2004;171(1):256-60. http://www.ncbi.nlm.nih.gov/pubmed/14665888 63. Ulvik NM, Bakke A, Høisaeter PA. Ureteroscopy in pregnancy. J Urol 1995;154(5):1660-3. http://www.ncbi.nlm.nih.gov/pubmed/7563314

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Lifshitz DA, Lingeman JE. Ureteroscopy as a first-line intervention for ureteral calculi in pregnancy. J Endourol 2002;16(1):19-22. http://www.ncbi.nlm.nih.gov/pubmed/11890444 65. Watterson JD, Girvan AR, Beiko DT, Nott L, Wollin TA, Razvi H, Denstedt JD. Ureteroscopy and holmium:YAG laser lithotripsy: an emerging definitive management strategy for symptomatic ureteral calculi in pregnancy. Urology 2002;60(3):383-7. http://www.ncbi.nlm.nih.gov/pubmed/12350466 66. Lahme S. Shockwave lithotripsy and endourological stone treatment in children. Urol Res 2006;34(2):112-7. http://www.ncbi.nlm.nih.gov/pubmed/16446980 67. Desai M. Endoscopic management of stones in children. Curr Opin Urol 2005;15(2):107-12. http://www.ncbi.nlm.nih.gov/pubmed/15725934 68. Van Savage JG, Palanca LG, Andersen RD, Rao GS, Slaughenhoupt BL. Treatment of distal ureteral stones in children: similarities to the American Urological Association guidelines in adults. J Urol 2000;164(3 Pt 2):1089-93. http://www.ncbi.nlm.nih.gov/pubmed/10958749 69. Slavkovic A, Radovanovic M, Vlajkovic M, Novakovic D, Djordjevic N, Stefanovic V. Extracorporeal shock wave lithotripsy in the management of pediatric urolithiasis. Urol Res 2006;34(5):315-20. http://www.ncbi.nlm.nih.gov/pubmed/16868754 70. Kuvezdiç H, Tucak A, Periç N, Prliç D, Zoriç I, Galiç, R. ESWL treatment of urinary stones in children – the overview of 14 years of experience. Coll Antropol 2003;27(1):71-5. http://www.ncbi.nlm.nih.gov/pubmed/12955895 71. Tan AH, Al-Omar M, Watterson JD, Nott L, Denstedt JD, Razvi H. Results of shockwave lithotripsy for pediatric urolithiasis. J Endourol 2004;18(6):527-30. http://www.ncbi.nlm.nih.gov/pubmed/15333214 72. Thomas JC, DeMarco RT, Donohoe JM, Adams MC, Brock JW III, Pope JC IV. Pediatric ureteroscopic stone management. J Urol 2005;174(3):1072-4. http://www.ncbi.nlm.nih.gov/pubmed/16094060 73. Raza A, Smith G, Moussa S, Tolley D. Ureteroscopy in the management of pediatric urinary tract calculi. J Endourol 2005;19(2):151-8. http://www.ncbi.nlm.nih.gov/pubmed/15798409 74. Tan AH, Al-Omar M, Denstedt JD, Razvi H. Ureteroscopy for pediatric urolithiasis: an evolving firstline therapy. Urology 2005;65(1):153-6. http://www.ncbi.nlm.nih.gov/pubmed/15667882 75. El-Assmy A, Hafez AT, Eraky I, El-Nahas AR, El-Kappany HA. Safety and outcome of rigid ureteroscopy for management of ureteral calculi in children. J Endourol 2006;20(4):252-5. http://www.ncbi.nlm.nih.gov/pubmed/16646651 76. Slavkoviç A, Radovanoviç M, Siriç Z, Vlajkoviç M, Stefanoviç V: Extracorporeal shock wave lithotripsy for cystine urolithiasis in children: outcome and complications. Int Urol Nephrol 2002;34(4):457-61. http://www.ncbi.nlm.nih.gov/pubmed/14577484 77. Katz G, Kovalski N, Landau EH. Extracorporeal shock wave lithotripsy for treatment of ureterolithiasis in patients with cystinuria. Br J Urol 1993;72(1):13-6. http://www.ncbi.nlm.nih.gov/pubmed/8149169 78. Chow GK, Streem SB. Contemporary urological intervention for cystinuric patients: immediate and long-term impact and implications. J Urol 1998;160(2):341-4. http://www.ncbi.nlm.nih.gov/pubmed/9679873 79. Wu TT, Hsu TH, Chen MT, Chang LS/ Efficacy of in vitro stone fragmentation by extracorporeal, electrohydraulic, and pulsed-dye lithotripsy. J Endourol 1993;7(5):391-3. http://www.ncbi.nlm.nih.gov/pubmed/8298621 80. Williams JC Jr, Saw KC, Paterson RF, Hatt EK, McAteer JA, Lingeman JE. Viability of renal stone fragility in shock wave lithotripsy. Urology 2003;61(6):1092-6. http://www.ncbi.nlm.nih.gov/pubmed/12809867 81. Rudnick DM, Bennett PM, Dretler SP. Retrograde renoscopic fragmentation of moderate sized (1.53.0) renal cystine stones. J Endourol 1999;13(7):483-5. http://www.ncbi.nlm.nih.gov/pubmed/10569520 82. Bhatta KM, Prien EL Jr, Dretler SP. Cystine calculi – rough and smooth: a new clinical distinction. J Urol 1989;142(4):937-40. http://www.ncbi.nlm.nih.gov/pubmed/2795746

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83. Kim SC, Hatt EK, Lingeman JE, Nadler RB, McAteer JA, Williams JC Jr. Cystine helical computerized tomography characterization of rough and smooth calculi in vitro. J Urol 2005;174(4 Pt 1):1468-70. http://www.ncbi.nlm.nih.gov/pubmed/16145473 84. Saw KC, McAteer JA, Fineberg NS, Monga AG, Chua GT, Lingeman JE, Williams JC Jr. Calcium tone fragility is predicted by helical CT attenuation values. J Endourol 2000;14(6):471-4. http://www.ncbi.nlm.nih.gov/pubmed/10954300 85. Assimos DG, Leslie SW, Ng C, Streem SB, Hart LJ. The impact of cystinuria on renal function. J Urol 2002;168(1):27-30. http://www.ncbi.nlm.nih.gov/pubmed/12050485 86. Worcester EM, Coe FL, Evan AP, Parks JH. Reduced renal function and benefits of treatment of cystinuria vs other forms of nephrolithiasis. BJU Int 2006;97(6):1285-90. http://www.ncbi.nlm.nih.gov/pubmed/16686727 87. Nakada SY, Hoff DG, Attai S, Heisey D, Blankenbaker D, Pozniak M. Determination of stone composition by noncontrast spiral computed tomography in the clinical setting. Urology 2000;55(6):816-9. http://www.ncbi.nlm.nih.gov/pubmed/10840083 88. Ngo TC, Assimos DG, Uric acid nephrolithiasis: recent progress and future directions. Rev Urol 2007;9(1):17-27. http://www.ncbi.nlm.nih.gov/pubmed/17396168 89. Teichman JM, Vassar GJ, Bishoff JT, Bellman GC. Holmium:YAG lithropsy yields smaller fragments than lithoclast, pulsed dye laser or electrohydraulic lithotripsy. J Urol 1998;159(1):17-23. http://www.ncbi.nlm.nih.gov/pubmed/9400428 90. Pearle MS, Nadler R, Bercowsky E, Chen C, Dunn M, Figenshau RS, Hoenig DM, McDougall EM, Mutz J, Nakada SY, Shalhav AL, Sundaram C, Wolf JS Jr, Clayman RV. Prospective randomized trial comparing shock wave lithotripsy and ureteroscopy for management of distal ureteral calculi. J Urol 2001;166(4):1255-60. http://www.ncbi.nlm.nih.gov/pubmed/11547053 91. Hoskins DH et al: In: Urolithiasis 2000: Proceedings of the Ninth International Symposium on Urolithiasis. South Africa: University of Capetown 2000. 92. Rodgers AL, Hibbert BE, Hess B, Khan SR, Preminger GM. Urolithiasis 2000: Proceedings of the Ninth International Symposium on Urolithiasis. South Africa: University of Capetown 2000; p. 667.

10. GENERAL RECOMMENDATIONS AND PRECAUTIONS FOR STONE REMOVAL 10.1

Infections

A test should be carried out in All patients in whom stone removal is planned, should be tested for bacteriuria. For uncomplicated cases, dipsticks might be sufficient for screening, in others, urine culture is necessary. Where there is clinically significant infection and obstruction, several days of drainage, viaa stent or a percutaneous nephrostomy, should precede active intervention for stone removal.

10.2

Anticoagulation and stone treatment

Patients with bleeding diathesis or who are receiving anticoagulations should be referred to an internist for appropriate therapeutic measures before, and during, the stone-removing procedure. In patients with an uncorrected bleeding diathesis, the following are generally contraindicated: • extracorporeal shock-wave lithotripsy (ESWL) • percutaneous nephrolithotomy with or without lithotripsy (PNL) • open surgery (1, 2). Although ESWL is feasible and safe after correction of the underlying coagulopathy (3–5), ureterorenoscopy migh offer an alternative approach, which is associated with less morbidity. The used of the holmium (Ho:YAG) laser, in combination with contemporary small-calibre ureteroscopes, is safe in these patients . Furthermore, ureteroscopic Ho:YAG laser lithotripsy, without the need for pre-operative correction of the haemostatic parameters, limits the risk of thromboembolic complications and avoids the costs associated with an extended hospital stay.

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To decrease bleeding complications, electrohydraulic lithotripsy must be avoided (6, 7). LE = 4 GR = C LE = level of evidence; GR = grade of recommendation

10.3 Pacemaker Patients who have a pacemaker can be treated with ESWL; however, it is recommended that the patient’s cardiologist is consulted before ESWL is undertaken. Patients with implanted cardioverter defibrillators must be managed with special care, as some devices need to be deactivated during ESWL; however, this might not be necessary with the use of new-generation lithotripters (8).

10.4

Hard stones

Stones composed of brushite or calcium oxalate monohydrate are particularly hard. Percutaneous removal of these stones might be appropriate, particularly if they are large. Chemolytic treatment of brushite stone fragments is possible; this is important as a this type of stone is associated with a high recurrence rate. There are two types of cystine stone: those that respond well to ESWL and those that respond poorly (9). PNL, which avoids subjecting the renal tissue to too much shock-wave energy, is the best alternative for efficient removal of large ESWL-resistant stones.

10.5

Radiolucent stones

Uric acid concrements can be localized using US, or intravenous or retrograde administration of contrast medium. Only uric acid stones, not sodium urate or ammonium urate stones, can be dissolved by oral chemolysis.

10.6

Recommendations for special considerations in the removal of stones

Table 23 summarizes recommendations for special considerations. Table 23: Recommendations for special considerations Special considerations

LE

GR

In the presence of a positive urine culture, positive dip-stick test or suspicion of an infective 3 component, treatment with antibiotics should precede stone removal Salicylates should be stopped 10 days before planned stone removal 3

B

ESWL and PNL are contraindicated in pregnant women

4

C

ESWL is possible in patients with a pacemaker

4

C

B

GR = grade of recommendation; ESWL = extracorporeal shock-wave lithotripsy; LE = level of evidence; PNL = percutaneous nephrolithotomy.

10.7

REFERENCES

1. Rassweiler JJ, Renner C, Chaussy C, Thüroff S. Treatment of renal stones by extracorporeal shockwave lithotripsy: an update. Eur Urol 2001;39(2):187-99. http://www.ncbi.nlm.nih.gov/pubmed/11223679 2. Klingler HC, Kramer G, Lodde M, Dorfinger K, Hofbauer J, Marberger M. Stone treatment and coagulopathy. Eur Urol 2003;43(1):75-9. http://www.ncbi.nlm.nih.gov/pubmed/12507547 3. Becopoulos T, Karayannis A, Mandalaki T, Karafoulidou A, Markakis C. Extracorporeal lithotripsy in patients with hemophilia. Eur Urol 1988;14(4):343-5. http://www.ncbi.nlm.nih.gov/pubmed/3169076 4. Ruiz Marcellán FJ, Mauri Cunill A, Cabré Fabré P, Argentino Gancedo Rodríguez V, Güell Oliva JA, Ibarz Servio L, Ramón Dalmau M. [Extracorporeal shockwave lithotripsy in patients with coagulation disorders]. Arch Esp Urol 1992;45(2):135-7. http://www.ncbi.nlm.nih.gov/pubmed/1567255 5. Ishikawa J, Okamoto M, Higashi Y, Harada M. Extracorporeal shock wave lithotripsy in von Willebrand’s disease. Int J Urol 1996;3(1):58-60. http://www.ncbi.nlm.nih.gov/pubmed/8646601 6. Watterson JD, Girvan AR, Cook AJ, Beiko DT, Nott L, Auge BK, Preminger GM, Denstedt JD. Safety and efficacy of holmium:YAG laser lithotripsy in patients with bleeding diatheses. J Urol 2002;168(2):442-5. http://www.ncbi.nlm.nih.gov/pubmed/12131284

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7. Kuo RL, Aslan P, Fitzgerald KB, Preminger GM. Use of ureteroscopy and holmium:YAG laser in patients with bleeding diatheses. Urology 1998;52(4):609-13. http://www.ncbi.nlm.nih.gov/pubmed/9763079 8. Kufer R, Thamasett S, Volkmer B, Hautmann RE, Gschwend JE. New-generation lithotripters for treatment of patients with implantable cardioverter defibrillator: experimental approach and review of literature. J Endourol 2001;15(5):479-84. http://www.ncbi.nlm.nih.gov/pubmed/11465325 9. Bhatta KM, Prien EL Jr, Dretler SP. Cystine calculi: two types. In: Lingeman JE, Newman DM, eds. Shock Wave Lithotripsy 2: Urinary and Biliary Lithotripsy. Vol 1. New York: Plenum Press, 1989, pp. 55-59.

11. MANAGING SPECIAL PROBLEMS in stone removal Caliceal diverticulum stones are treated using ESWL, PNL (if possible) or RIRS. Diverticular stones can also be removed using video-endoscopic retroperitoneal surgery. The principles of video-endoscopic surgery are outlined elsewhere (1-5). If there is a narrow communication between the diverticulum and the renal collecting system, well-disintegrated stone material will remain in the original position. These patients may become asymptomatic as a result of stone disintegration only. Horseshoe kidneys can be treated in line with the stone treatment options described above (6) However, as the kidney lies anteriorly, ESWL is commonly carried out with the patient in the prone position (i.e. with shock-wave entrance from the abdominal side). Stones in transplanted kidneys: ESWL and PNL are recommended for the removal of stones in transplanted kidneys. For pelvic kidneys, ESWL or video-endoscopic laparoscopic surgery is recommended. For obese patients, the options are ESWL, PNL or open surgery. Stones formed in a continent reservoir present a varied and often difficult problem (7–14). Each stone problem must be considered and treated individually. Patients with obstruction of the ureteropelvic junction: when the outflow abnormality is corrected, stones can be removed with either percutaneous endopyelotomy (15–35) or open reconstructive surgery. Transureteral endopyelotomy with Ho:YAG laser endopyelotomy can also be used to correct this abnormality. Incision with an Acucise balloon catheter might also be considered, provided the stones can be prevented from falling into the pelvo-ureteral incision (36–39).

11.1

REFERENCES

1. Raboy A, Ferzli GS, Loffreda R, Albert PS. Laparoscopic ureterolithotomy. Urology 1992;39(3):223-5. http://www.ncbi.nlm.nih.gov/pubmed/1532102 2. Gaur DD. Retroperitoneal endoscopic ureterolithotomy: our experience in 12 patients. J Endourol 1993;7(6):501-3. http://www.ncbi.nlm.nih.gov/pubmed/8124346 3. Gaur DD. Retroperitoneal laparoscopic ureterolithotomy. World J Urol 1993;11(3):175-7. http://www.ncbi.nlm.nih.gov/pubmed/8401638 4. Gaur DD, Agarwal DK, Purohit KC, Darshane AS. Retroperitoneal laparoscopic pyelolithotomy. J Urol 1994;151(4):927-9. http://www.ncbi.nlm.nih.gov/pubmed/8126827 5. Escovar Diaz P, Rey Pacheco M, Lopez Escalante JR, Rodriguez Cordero M, la Riva Rodriguez F, Gonzalez Zerpa RD, Garcia JL, Cuervo R. [Ureterolitotomia laparoscopia.] Arch Esp Urol 1993;46(7):633-7. [article in Spanish] [Laparoscopic urelithotomy] http://www.ncbi.nlm.nih.gov/pubmed/8239742 6. Locke DR, Newman RC, Steinbock GS, Finlayson B. Extracorporeal shock wave lithotripsy in horseshoe kidney. Urology 1990;35(5):407-11. http://www.ncbi.nlm.nih.gov/pubmed/2336770

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7. Chen KK, Chang LS, Chen MT, Lee YH. Electrohydraulic lithotripsy for stones in Kock pouch. Eur Urol 1989;16(2):110-3. http://www.ncbi.nlm.nih.gov/pubmed/2714327 8. Weinerth JL, Webster GD. Experience with management of stones formed within Kock pouch continent urinary diversions. J Endourol 1990;4:149-54. 9. Khatri VP, Walden T, Pollack MS. Multiple large calculi in a continent urinary reservoir: a case report. J Urol 1992;148(3 Pt 2):1129-30. http://www.ncbi.nlm.nih.gov/pubmed/1507351 10. Chin JL, Denstedt JD. Massive calculi formation in Indiana continent urinary reservoir: pathogenesis and management problems. J Stone Dis 1992:4:323-7. 11. Terai A, Arai Y, Kawakita M, Okada Y, Yoshida O. Effect of urinary intestinal diversion on urinary risk factors for urolithiasis. J Urol 1995;153(1):37-41. http://www.ncbi.nlm.nih.gov/pubmed/7966785 12. Cohen TD, Streem SB, Lammert G. Long-term incidence and risks for recurrent stones following contemporary management of upper tract calculi in patients with a urinary diversion. J Urol 1996;155(1):62-5. http://www.ncbi.nlm.nih.gov/pubmed/7490899 13. Terai A, Ueda T, Kakehi Y, Terachi T, Arai Y, Okada Y, Yoshida O. Urinary calculi as a late complication of the Indiana continent urinary diversion: comparison with the Kock pouch procedure. J Urol 1996;155(1):66-8. http://www.ncbi.nlm.nih.gov/pubmed/7490900 14. Assimos DG. Nephrolithiasis in patients with urinary diversion. J Urol 1996;155(1):69-70. http://www.ncbi.nlm.nih.gov/pubmed/7490901 15. Ramsay JW, Miller RA, Kellett MJ, Blackford HN, Wickham JE, Whitfield HN. Percutaneous pyelolysis: indications, complications and results. Br J Urol 1984;56(6):586-8. http://www.ncbi.nlm.nih.gov/pubmed/6534471 16. Brannen GE, Bush WH, Lewis GP. Endopyelotomy for primary repair of ureteropelvic junction obstruction. J Urol 1988;139(1):29-32. http://www.ncbi.nlm.nih.gov/pubmed/3336099 17. Payne SR, Coptcoat MJ, Kellett MJ, Wickham JE. Effective intubation for percutaneous pyelolysis. Eur Urol 1988,14(6):477-81. http://www.ncbi.nlm.nih.gov/pubmed/3181229 18. Baba S, Masuda T, Yoshimura K, Ohkuma K, Ido K, Sugiura K, Tazaki H. Percutaneous transperitoneal endopyelotomy and ureteroplasty in pelvic kidney associated with ureteral calculus. J Endourol 1990;4:253-8. 19. Kuenkel M, Korth K. Endopyelotomy: long term follow-up of 143 patients. J Endourol 1990;4:109-16. 20. Gelet A, Martin X, Dessouki T. Ureteropelvic invagination: reliable technique of endopyelotomy. J Endourol 1991;5:223-4. 21. Cassis AN, Brannen GE, Bush WH, Correa RJ, Chambers M. Endopyelotomy: review of results and complications. J Urol 1991;146(6):1492-5. http://www.ncbi.nlm.nih.gov/pubmed/1942325 22. Motola JA, Badlani GH, Smith AD. Results of 212 consecutive endopyelotomies: an 8-year followup. J Urol 1993;149(3):453-6. http://www.ncbi.nlm.nih.gov/pubmed/8437245 23. Klahr S, Chandhoke P, Clayman RV. Review: obstructive uropathy - renal effects and endosurgical relief. J Endourol 1993;7(5):395-8. http://www.ncbi.nlm.nih.gov/pubmed/8298622 24. Motola JA, Fried R, Badlani GH, Smith AD. Failed endopyelotomy: implications for future surgery on the ureteropelvic junction. J Urol 1993;150(3):821-3. http://www.ncbi.nlm.nih.gov/pubmed/8345591 25. Gerber GS, Lyon ES. Endopyelotomy: patient selection, results and complications. Urology 1994;43(1):2-10. http://www.ncbi.nlm.nih.gov/pubmed/8284881 26. Nakamura K, Baba S, Tazaki H. Endopylotomy in horseshoe kidneys. J Endourol 1994;8(3):203-6. http://www.ncbi.nlm.nih.gov/pubmed/7951285 27. Bagley DH, Liu JB, Goldberg BB, Grasso M. Endopyelotomy: importance of crossing vessels demonstrated by endoluminal ultrasonography. J Endourol 1995;9(6):465-7. http://www.ncbi.nlm.nih.gov/pubmed/8775076

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28. Danuser H, Ackermann DK, Bohlen D, Studer UE. Endopyelotomy for primary ureteropelvic junction obstruction: risk factors determine the success rate. J Urol 1998;159(1):56-61. http://www.ncbi.nlm.nih.gov/pubmed/9400436 29. Van Cangh PJ. Editorial. Endopyelotomy - a panacea for ureteropelvic junction obstruction?. J Urol 1998;159(1):66. http://www.ncbi.nlm.nih.gov/pubmed/9400438 30. Gallucci M, Alpi G, Ricciuti GP, Cassanelli A, Persechino F, Di Silverio F. Retrograde cold-knife endopyelotomy in secondary stenosis of the ureteropelvic junction. J Endourol 1991;5:49-50. 31. Chowdhury SD, Kenogbon J. Rigid ureteroscopic endopyelotomy without external drainage. Endourol 1992;6:357-60. 32. Chandhoke PS, Clayman RV, Stone AM, McDougall EM, Buelna T, Hilal N, Chang M, Stegwell MJ. Endopyelotomy and endoureterotomy with the acucise ureteral cutting balloon device: preliminary experience. J Endourol 1993;7(1);45-51. http://www.ncbi.nlm.nih.gov/pubmed/8481721 33. McClinton S, Steyn JH, Hussey JK. Retrograde balloon dilatation for pelviureteric junction obstruction. Br J Urol 1993;71(2):152-5. http://www.ncbi.nlm.nih.gov/pubmed/8461946 34. Gerber GS, Lyon ES. Endopyelotomy: patient selection, results and complications. Urology 1994;43(1):2-10. http://www.ncbi.nlm.nih.gov/pubmed/8284881 35. Bolton DM, Bogaert GA, Mevorach RA, Kogan BA, Stoller ML. Pediatric ureteropelvic junction obstruction treated with retrograde endopyelotomy. Urology 1994;44(4):609-13. http://www.ncbi.nlm.nih.gov/pubmed/7941208 36. Gelet A, Combe M, Ramackers JM, Ben Rais N, Martin X, Dawahra M, Marechal JM, Dubernard JM. Endopyelotomy with the Acucise cutting balloon device. Early clinical experience. Eur Urol 1997;31(4):389-93. http://www.ncbi.nlm.nih.gov/pubmed/9187895 37. Faerber GJ, Richardson TD, Farah N, Ohl DA. Retrograde treatment of ureteropelvic junction obstruction using the ureteral cutting balloon catheter. Urol 1997;157(2):454-8. http://www.ncbi.nlm.nih.gov/pubmed/8996330 38. Conlin MJ, Bagley DH. Ureteroscopic endopyelotomy at a single setting. J Urol 1998;159(3):727-31. http://www.ncbi.nlm.nih.gov/pubmed/9474135 39. Nakada SY, Wolf JS Jr, Brink JA, Quillen SP, Nadler RB, Gaines MV, Clayman RV. Retrospective analysis of the effect of crossing vessels on successful retrograde endopyelotomy outcomes using spiral computerized tomography angiography. J Urol 1998;159(1):62-5. http://www.ncbi.nlm.nih.gov/pubmed/9400437

12. MANAGEMENT OF STONE PROBLEMS DURING PREGNANCY Urolithiasis during pregnancy, though rare, presents diagnostic and therapeutic challenges.. The incidence of urolithiasis has been reported to be 0.026 – 0.53%. When compared to non-pregnant age-matched controls, pregnant women do not have an elevated incidence of urolithiasis. No major differences in stone composition have been found when comparing pregnant women to the general population (1–6). Stones may be present in both kidneys with an equal frequency, and ureteral stones are twice as common as renal calculi. Symptomatic stone disease presents in the second or third trimester in 80–90% of women. Stones affect the two kidneys with equal frequency, although physiological hydronephrosis of pregnancy more commonly affects the right side (7). Management of these patients can pose significant and multiple challenges to the patient, obstetrician and urologist, but fortunately a considerable number of the symptomatic stones (70–80%) pass spontaneously. Obstetricians should be aware of the symptoms, the practical diagnosis and the risks associated with urolithiasis (8).

12.1

Symptoms

Generally, pregnant women present with symptoms of urolithiasis in the second or third trimesters. If signs such as flank pain with tenderness, haematuria and/or unresolved bacteriuria are present, urinary calculi must

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be considered. This is important because the obstetric complications associated with urolithiasis potentially include preterm labour and premature rupture of membranes. Failure to diagnose and manage urinary stones promptly during pregnancy might have adverse consequences for mother and child (9).

12.2

Diagnostic evaluation

As a consequence of the normal physiological changes occurring during pregnancy, the diagnosis of urolithiasis is often difficult as, in addition to maternal renal functional status and stone-related factors (number, size, location and configuration), imaging is essential for diagnosis and appropriate treatment planning. The most important factor complicating the radiological evaluation of stone disease in pregnancy is of the potential damage that can be caused by exposing the fetus to radiation, including teratogenesis, carcinogenesis, and mutagenesis. The risk of damage depends on gestational age and the amount of radiation delivered. Ultrasonography (US) (using the change in resistive index and transvaginal US when LE = 1a necessary) has become the primary radiological diagnostic tool. GR = A LE = level of evidence; GR = grade of recommendation The value of US is limited value in cases of acute obstruction because of poor sound transmission through gas and bone and the, operator-dependent, ability of US to differentiate between physiological dilation of pregnancy and ureteral. A limited excretory urogram or magnetic resonance imaging may be carried out in particularly complicated cases. Other diagnostic modalities used to diagnose the presence of the stone(s) and assess the degree of obstruction in pregnant women include: • transvaginal/endoluminal US (evaluation of possible stones at the vesicoureteral junction) • magnetic resonance urography (MRU), avoiding ionizing radiation and administration of iodinated contrast medium, which should be reserved for complex cases when US fails to provide a diagnosis • more recently, gadolinium-enhanced breath-hold gradient-echo MR excretory urography (MREU).

12.3

Management of the stone problem

Following a correct diagnosis: In 70–80% of patients, stones will pass spontaneously. LE = 1a GR = A Preference Conservative management with bed rest, appropriate hydration and analgesia should be the first-line treatment for all pregnant women with non1 complicated urolithiasis.

LE = 4 GR = C

If spontaneous passage of the stones does not occur or if complications develop (commonly the induction of premature labour), established treatment options should be considered. Preference An internal stent or percutaneous nephrostomy catheter are suggested firstline treatment alternatives. 2

LE = 4 GR = C

Preference URS, although more invasive, has been accepted as a minimally invasive treatment alternative (9–13). 3

LE = 1b GR = A

LE = level of evidence; GR = grade of recommendation Stone-related pain during pregnancy has been managed using acetaminophen and narcotic analgesics with no known teratogenic effects. Although no drug is absolutely free of risk during pregnancy, these drugs appear to be associated with minimal risk when used judiciously under medical supervision. Aspirin and NSAIDs can be used, while being aware of their non-teratogenic adverse effects (14, 15). In recent years, epidural blocks have been commonly used to reduce maternal pain, and their safety for mother and foetus are well accepted, provided maternal hypotension is avoided. Although this approach is used infrequently, it may be helpful for selected patients who fail more conservative expectant management and when operative intervention is not possible (e.g. because of patient refusal, absence of equipment or lack of endourological expertise) (16).

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12.3.1 Surgical management Despite the commonly accepted success of conservative management, surgical intervention might be needed in certain situations such as for instance when there is febrile urinary tract infection, pyonephrosis, sepsis, obstruction of a solitary kidney, intractable pain, nausea or vomiting. A team including a urologist, obstetrician and anaesthesiologist should make a develop an appropriate management plan based on the patient’s wishes and her comfort level. 12.3.2 Temporary urinary diversion Decompression of the renal collecting system using a percutaneous nephrostomy tube or an internal ureteral stent was first suggested by Meares in 1978. The efficacy of these procedures is established, however, each has its own advantages and disadvantages. 12.3.2.1 Percutaneous nephrostomy catheter This widely accepted approach is routinely carried out with local anaesthesia under US guidance. Increasing experience has shown that the percutaneous approach has certain advantages over retrograde stent placement: • In most cases, only local anaesthesia is needed to place the tube under US guidance in acutely ill or septic patients, providing immediate urine drainage and culture to determine organism-specific antibiotic therapy. • This approach may provide access PNL, which might be required post partum and at the same time manipulation of the obstructed ureter. The potential risks of perforation and infection are avoided. • The percutaneous approach enables immediate confirmation and continuous supervision of drainage. Failure to drain is easily identified and appropriately managed. • Subsequent percutaneous chemolytic irrigation of the renal collecting system might be useful for dissolution of uric acid, cystine, or struvite stones (17). The disadvantages of external tubes are the inconvenience of dealing with a collection device, the risk for accidental dislodgement and bacterial colonization. Also, insertion of a percutaneous nephrostomy catheter might be complicated by significant bleeding as as result of tract creation and dilatation. 12.3.2.2 Internal ureteral stent Drainage of the obstructed renal collecting system can be accomplished using an internal ureteral stent inserted under local or general anaesthesia with transabdominal US guidance or limited fluoroscopy, or without imaging procedures. Stent insertion is routinely carried out by most urologists and the equipment should be readily available at most centres (18). However, stent-related irritative lower urinary tract symptoms and rapid encrustation, which may be attributed to hypercalciuria, hyperuricosuria or infection that occur during pregnancy, are well-known problems associated with this approach. Internal stents may also be associated with increased analgesic requirements and decreased overall quality of life. Some investigators therefore recommend hydration, dietary calcium restriction and antibiotics as well as frequent stent replacement at intervals of 4–8 weeks. Infection and migration are other complications of internal stents and it has therefore been advocated that ureteral stent placement is reserved for the later stages (> 22 weeks) of pregnancy. The choice between these methods is based on the factors discussed above (21–23). When conservative management fails and urinary diversion is needed, both LE = 3 nephrostomy tube placement and internal ureteral insertion are appropriate GR = B alternatives. LE = level of evidence; GR = grade of recommendation 12.3.2.3 Ureteroscopy (URS) The use of flexible and thin ureteroscopes for diagnostic and therapeutic purposes in a less invasive and traumatic manner has led several urologists to consider this method as first-line treatment for pregnant women who have failed conservative management. However, ureteroscopic management during pregnancy should be planned and performed at an experienced urological centre under close obstetric and anaesthetic surveillance. General anaesthesia might be needed for URS, and it is important to always be aware of the potential risk of ureteral perforation and sepsis. The intervention should be carried out by an experienced urologist. The anatomical distortion of the bladder and distal ureter, particularly during the third trimester, can make semi-rigid URS more difficult. Stone manipulation at or near term should therefore be discouraged. Most distal-ureteral stones can be retrieved with a stone basket, but some may require fragmentation, which can be accomplished safely with a pulsed-dye laser, Ho:YAG laser or pneumatic lithotripsy (24, 25).

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The most important contraindications to URS during pregnancy are: • inexperience • inadequate endoscopic instruments • stones with a diameter > 1 cm • multiple calculi • transplanted kidney • sepsis (because of the higher risk of complications). Caution must be exercised when performing URS during pregnancy with a solitary kidney. Ureteroscopy in experienced hands can be an effective treatment alternative to removal of ureteral stones during pregnancy (LE = 1b; GR = B). ESWL and percutaneous nephrolithotripsy (PNL) are contraindicated in pregnancy, LE = 4b as there are established and obvious risks associated with exposing the foetus to GR = C radiation as well as shock waves. LE = level of evidence; GR = grade of recommendation

12.4

Conclusions

Urolithiasis in pregnancy remains a diagnostic and therapeutic challenge. Although US is the method of choice for the practical and safe evaluation of a pregnant woman, a limited intravenous urography, isotope renography or MREU is useful for delineating the level and grade of obstruction in case of hydronephrosis. Depending on the stage of the pregnancy, degree of pain and presence of certain complications (e.g. obstruction, urosepsis and renal functional deterioration), conservative management with bed rest, hydration and analgesia will result in spontaneous passage of the stone in two-thirds of patients. If conservative treatment fails, temporary urinary diversion with percutaneous nephrostomy or an internal stent may be appropriate. However, developments in diagnostic technology and endoscopic instrumentation during the last 5 years, have made it possible to use high-quality imaging and small-calibre ureteroscopes. Endoscopy is therefore a feasible and safe approach both for diagnostic and therapeutic purposes, but should be carried out only in centres with sufficient experience. ESWL in pregnancy remains an absolute contraindication.

12.5

REFERENCES

1. Gorton E, Whitfield H. Renal calculi in pregnancy. BJU 1997;80(1):4-9. http://www.ncbi.nlm.nih.gov/pubmed/9240217 2. Drago JR, Rohner TJ, Chez RA. Management of urinary calculi in pregnancy. Urology 1982;20(6): 578-81. http://www.ncbi.nlm.nih.gov/pubmed/7179620 3. McAleer S, Loughlin K. Nephrolithiasis and pregnancy. Curr Opin Urol 2004;14(2):123-7. http://www.ncbi.nlm.nih.gov/pubmed/15075842 4. Swanson SK, Heilman RL, Eversman WG. Urinary tract stones in pregnancy. Surg Clin North Am 1995;75(1):123-42. http://www.ncbi.nlm.nih.gov/pubmed/7855714 5. Smith CL, Kristensen C, Davis M, Abraham PA. An evaluation of the physicochemical risk for renal stone disease during pregnancy. Clin Nephrol 2001;55(3):205-11. http://www.ncbi.nlm.nih.gov/pubmed/11316240 6. Jarrard DJ, Gerber GS, Lyon ES. Management of acute ureteral obstruction in pregnancy utilizing ultrasound-guided placement of ureteral stents. Urology 1993;42(3):263-7. http://www.ncbi.nlm.nih.gov/pubmed/8379026 7. Biyani CS, Joyce AD. Urolithiasis in pregnancy I: pathophysiology, fetal considerations, and diagnosis. BJU Int 2002;89(8):811-8;quiz i-ii. http://www.ncbi.nlm.nih.gov/pubmed/11972502 8. Hendricks SK, Ross SO, Krieger JN. An algorithm for diagnosis and therapy of management and complications of urolithiasis during pregnancy. Surg Gynecol Obstet 1991;172(1):49-54. http://www.ncbi.nlm.nih.gov/pubmed/1985341 9. Stothers L, Lee LM. Renal colic in pregnancy. J Urol 1992;148(5):1383-7. http://www.ncbi.nlm.nih.gov/pubmed/1433534 10. Parulkar BG, Hopkins TB, Wollin MR, Howard PJ Jr, Lal A. Renal colic during pregnancy: a case for conservative treatment. J Urol 1998;159(2):365-8. http://www.ncbi.nlm.nih.gov/pubmed/9649240

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Lewis DF, Robichaux AG 3rd, Jaekle RK, Marcum NG, Stedman CM. Urolithiasis in pregnancy. Diagnosis, management and pregnancy outcome. J Reprod Med. 2003;48(1):28-32. http://www.ncbi.nlm.nih.gov/pubmed/12611091 12. Cormier CM, Canzoneri BJ, Lewis DF, Briery C, Knoepp L, Mailhes JB. Urolithiasis in pregnancy: current diagnosis, treatment, and pregnancy complications. Obstet Gynecol Surv 2006;61(11): 733-41. http://www.ncbi.nlm.nih.gov/pubmed/17044950 13. Denstedt JD, Razvi H. Management of urinary calculi during pregnancy. J Urol 1992;148(3 Pt 2): 1072–4. http://www.ncbi.nlm.nih.gov/pubmed/1507335 14. McCombs J, Cramer MK. Pregnancy and lactation: therapeutic considerations. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 4th edn. Norwalk: Appleton & Lange, 1999, pp. 1298-1312. 15. Evans MI, Johnson MP, Yaron Y, Drugan A, eds. Prenatal Diagnosis: Genetics, Reproductive Risks, Testing, and Management. New York: McGraw Hill, 2006, pp. 142-143. 16. Scherer R, Holzgreve W. Influence of epidural analgesia on fetal and neonatal well-being. Eur J Obstet Gynecol Reprod Biol 1995;59(Suppl):S17-S29. http://www.ncbi.nlm.nih.gov/pubmed/7556818 17. Biyani CS, Joyce AD. Urolithiasis in pregnancy II: management. BJU Int 2002;89(8):819-23. http://www.ncbi.nlm.nih.gov/pubmed/11972503 18. Tiselius HG, Ackermann D, Alken P, Buck C, Conort P, Gallucci M. Guidelines on urolithiasis. In: EAU Guidelines. Edition presented at the 16th EAU Congress, Geneva, Switzerland 2001. ISBN 90-8061793-9. [Access date November 2008] http://www.uroweb.org/nc/professional-resources/guidelines/online/?no_cache=1&view=archive 19. Pais VM Jr, Payton AL, LaGrange CA. Urolithiasis in pregnancy. Review. Urol Clin North Am 2007;34(1):43-52. http://www.ncbi.nlm.nih.gov/pubmed/17145360 20. Goldfarb R, Neerhut G, Lederer E. Management of acute hydronephrosis of pregnancy by ureteral stenting: risk of stone formation. J Urol 1989;141(4):921-2. http://www.ncbi.nlm.nih.gov/pubmed/2926891 21. Juan YS, Wu WJ, Chuang SM, Wang CJ, Shen JT, Long CY, Huang CH. Management of symptomatic urolithiasis during pregnancy. Kaohsiung J Med Sci 2007;23(5):241-6. http://www.ncbi.nlm.nih.gov/pubmed/17525006 22. Joshi HB, Adams S, Obadeyi OO, Rao PN. Nephrostomy tube or ‘JJ’ ureteric stent in ureteric obstruction: assessment of patient perspectives using quality-of-life survey and utility analysis. Eur Urol 2001;39(6):695-701. http://www.ncbi.nlm.nih.gov/pubmed/11464060 23. Mokhmalji H, Braun PM, Portillo JM, Siegsmund M, Alken P, Köhrmann KU. Percutaneous nephrostomy versus ureteral stents for diversion of hydronephrosis caused by stones: a prospective, randomized clinical trial. J Urol 2001;165(4):1088-92. http://www.ncbi.nlm.nih.gov/pubmed/11257644 24. Lifshitz DA, Lingeman JE. Ureteroscopy as a first line intervention for ureteral calculi in pregnancy. J Endourol 2002;16(1):19-22. http://www.ncbi.nlm.nih.gov/pubmed/11890444 25. Watterson JD, Girvan AR, Beiko DT, Nott L, Wollin TA, Razvi H, Denstedt JD. Ureteroscopy and holmium:YAG laser lithotripsy: an emerging definitive management strategy for symptomatic ureteral calculi in pregnancy. Urology 2002;60(3):383-7. http://www.ncbi.nlm.nih.gov/pubmed/12350466

13. MANAGEMENT OF STONE PROBLEMS IN CHILDREN In addition to the global increase in the rates of urolithiasis in developed countries, there has been a shift in the age group experiencing a first stone episode (1–3). More than 1% of all urinary stones have been registered in patients 10 mm or for impacted stones, calcium oxalate monohydrate and cystine stones, or stones in children with unfavourable anatomy and in whom localization difficulties exist. Compared to adults, children pass stone fragments easily and the need for a stent is rare. If the stone burden is so large, that a ureteral stent is required, alternative procedures should be considered. Although internal stents are seldom needed following ESWL-treatment of upper tract stones, ureteral pre-stenting appeared to have decreased the stone-free rate after the initial treatment and retreatments of 12–14% were recorded (23, 31, 37). 13.2.3 Conclusions Among the available treatment strategies of paediatric urinary calculi, ESWL is the method of choice for smaller stones (diameters < 20 mm, surface area ~ < 300 mm2). The successful stone-free rates emphasize the efficacy of this treatment modality when combined with judicious use of auxiliary procedures. Where appropriate, ESWL is a safe and highly effective treatment alternative for the management of stones in children. However, satisfactory outcomes with reasonable low complication rates can be achieved only with adequate experience. Particular attention should be paid to residual fragments, especially in children with predisposing metabolic, as well as anatomical, disorders. 13.2.4 Open or laparoscopic surgery The rate of open procedures in stone patients has dropped significantly in all age groups, including children. Open surgery, if required, may be replaced by laparoscopic procedures. Indications for surgery include failure of primary therapy for stone removal (38), abnormal position of the kidney (39), or an additional target of therapy apart from stone removal (e.g. treatment of stones in a primary obstructive megaureter) (40) (LE = 4; GR = C).

13.3

REFERENCES

1. Reis-Santos JM. Age of first stone episode. In: Rodgers AL, Hibbert BE, Hess B, Khan SR, Preminger GM, eds. Urolithiasis. Cape Town: University of Cape Town, 2000, pp. 375-378. 2. Robertson WG, Whitfield H, Unwin RJ, Mansell MA, Neild GH. Possible causes of the changing pattern of the age of onset of urinary stone disease in the UK. In: Rodgers AL, Hibbert BE, Hess B, Khan SR, Preminger GM, eds. Urolithiasis. Cape Town: University of Cape Town, 2000, pp. 366-368. 3. Hesse A, Brandle E, Wilbert D, Kohrmann KU, Alken P. Study on the prevalence and incidence of urolithiasis in Germany comparing the years 1979 vs. 2000. Eur Urol 2003; 44(6):709-13. http://www.ncbi.nlm.nih.gov/pubmed/14644124 4. Djelloul Z, Djelloul A, Bedjaoui A, Kaid-Omar Z, Attar A, Daudon M, Addou A. [Urinary stones in Western Algeria: study of the composition of 1,354 urinary stones in relation to their anatomical site and the age and gender of the patients.] Prog Urol 2006;16(3):328-35. http://www.ncbi.nlm.nih.gov/pubmed/16821346 5. Sarica K. Pediatric urolithiasis: etiology, specific pathogenesis and medical treatment. Urol Res 2006;34(2):96-101. http://www.ncbi.nlm.nih.gov/pubmed/16432692 6. Sayasone S, Odermatt P, Khammanivong K, Phomluangsyl S, Vinhl CV, Thin HM, Strobeli M. Bladder stones in childhood: a descriptive study in a rural setting in Saravan Province, Lao PDR1. Southeast Asian J Trop Med Public Health 2004;35(2):50-2. http://www.ncbi.nlm.nih.gov/pubmed/15906634

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7.

Stamatelou KK, Francis ME, Jones CA, Nyberg LM, Curhan GC. Time trends in reported prevalence of kidney stones in the United States: 1976-1994. Kidney Int 2003;63(5):1817-23. http://www.ncbi.nlm.nih.gov/pubmed/12675858 8. Straub M, Strohmaier WL, Berg W, Beck B, Hoppe B, Laube N, Lahme S, Schmidt M, Hesse A, Koehrmann KU. Diagnosis and metaphylaxis of stone disease. Consensus concept of the National Working Committee on Stone Disease for the upcoming German Urolithiasis Guideline. World J Urol 2005;23(5):309-23. http://www.ncbi.nlm.nih.gov/pubmed/16315051 9. Sternberg K, Greenfield SP, Williot P, Wan J. Pediatric stone disease: an evolving experience. J Urol 2005;174(4 Pt 2):1711-4. http://www.ncbi.nlm.nih.gov/pubmed/16148688 10. Palmer LS. Pediatric urologic imaging Urol Clin North Am 2006;33(3):409-23. http://www.ncbi.nlm.nih.gov/pubmed/16829274 11. Darge K, Heidemeier A. [Modern ultrasound technologies and their application in pediatric urinary tract imaging.] Radiologe 2005;45(12):1101-11. http://www.ncbi.nlm.nih.gov/pubmed/16086170 12. Pepe P, Motta L, Pennisi M, Aragona F. Functional evaluation of the urinary tract by color-Doppler ultrasonography (CDU) in 100 patients with renal colic. Eur J Radiol 2005;53(1):131-5. http://www.ncbi.nlm.nih.gov/pubmed/15607864 13. Oner S, Oto A, Tekgul S, Koroglu M, Hascicek M, Sahin A, Akhan O. Comparison of spiral CT and US in the evaluation of pediatric urolithiasis. JBR -BTR 2004; 87(5):219-23. http://www.ncbi.nlm.nih.gov/pubmed/15587558 14. Palmer JS, Donaher ER, O’Riordan MA, Dell KM. Diagnosis of pediatric urolithiasis: role of ultrasound and computerized tomography. J Urol 2005; 174(4 Pt 1):1413-6. http://www.ncbi.nlm.nih.gov/pubmed/16145452 15. Riccabona M, Lindbichler F, Sinzig M. Conventional imaging in paediatric uroradiology. Eur J Radiol 2002;43(2):100-9. http://www.ncbi.nlm.nih.gov/pubmed/12127207 16. Chateil JF, Rouby C, Brun M, Labessan C, Diard F. [Practical measurement of radiation dose in pediatric radiology: use of the dose surface product in digital fluoroscopy and for neonatal chest radiographs.] J Radiol 2004; 85(5 Pt 1):619-25. http://www.ncbi.nlm.nih.gov/pubmed/15205653 17. Thomson JM, Glocer J, Abbott C, Maling TM, Mark S. Computed tomography versus intravenous urography in diagnosis of acute flank pain from urolithiasis: a randomized study comparing imaging costs and radiation dose Australas Radiol 2001;45(3):291-7. http://www.ncbi.nlm.nih.gov/pubmed/11531751 18. Cody DD, Moxley DM, Krugh KT, O’Daniel JC, Wagner LK, Eftekhari F. Strategies for formulating appropriate MDCT techniques when imaging the chest, abdomen, and pelvis in pediatric patients AJR Am J Roentgenol 2004;182(4):849-59. http://www.ncbi.nlm.nih.gov/pubmed/15039151 19. Leppert A, Nadalin S, Schirg E, Petersen C, Kardorff R, Galanski M et al. Impact of magnetic resonance urography on preoperative diagnostic workup in children affected by hydronephrosis: should IVU be replaced? J Pediatr Surg 2002;37(10):1441-5. http://www.ncbi.nlm.nih.gov/pubmed/12378450 20. Hesse A, Kruse R, Geilenkeuser WJ, Schmidt M. Quality control in urinary stone analysis: results of 44 ring trials (1980-2001). Clin Chem Lab Med 2005;43(3):298-303. http://www.ncbi.nlm.nih.gov/pubmed/15843235 21. Sternberg K, Greenfield SP, Williot P, Wan J. Pediatric stone disease: an evolving experience. J Urol 2005;174(4 Pt 2):1711-4;discussion 1714. http://www.ncbi.nlm.nih.gov/pubmed/16148688 22. Jackman SV, Hedican SP, Peters CA, Docimo SG. Percutaneous nephrolithotomy in infants and preschool age children: experience with a new technique. Urology 1998;52(4):697-701. http://www.ncbi.nlm.nih.gov/pubmed/9763096 23. Lahme S. Shockwave lithotripsy and endourological stone treatment in children. Urol Res 2006; 34(2):112-7. http://www.ncbi.nlm.nih.gov/pubmed/16446980 24. Gedik A, Orgen S, Akay AF, Sahin H, Bircan MK. Semi-rigid ureterorenoscopy in children without ureteral dilatation. Int Urol Nephrol 2008;40(1):11-4. http://www.ncbi.nlm.nih.gov/pubmed/17653831

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25. Gupta PK. Is the holmium:YAG laser the best intracorporeal lithotripter for the ureter?. A 3-year retrospective study. J Endourol 2007;21(3):305-9. http://www.ncbi.nlm.nih.gov/pubmed/17444776 26. Desai M. Endoscopic management of stones in children. Curr Opin Urol 2005;15(2):107-12. http://www.ncbi.nlm.nih.gov/pubmed/15725934 27. Dogan HS, Tekgül S. Management of pediatric stone disease. Curr Urol Rep 2007;8(2):163-73. http://www.ncbi.nlm.nih.gov/pubmed/17303023 28. Sarica K, Erturhan S,Yurtseven C,Yagci F. Effect of potassium citrate therapy on stone recurrence and regrowth after extracorporeal shockwave lithotripsy in children. J. Endourol 2006:20(11):875-9. http://www.ncbi.nlm.nih.gov/pubmed/17144854 29. Rizvi S, Nagvi S, Hussain Z, Hashmi A, Hussain M, Zafar MN, Sultan S, Mehdi H. Management of pediatric urolithiasis in Pakistan: experience with 1,440 children. J Urol 2003;169(2):634-7. http://www.ncbi.nlm.nih.gov/pubmed/12544331 30. Schultz-Lampel D, Lampel A. The surgical management of stones in children. BJU Int 2001;87(8): 732-40. http://www.ncbi.nlm.nih.gov/pubmed/11350428 31. Landau EH, Gofrit ON, Shapiro A, Meretyk S, Katz G, Shenfeld OZ, Golijanin D, Pode D. Extracorporeal shockwave lithotripsy is highly effective for ureteral calculi in children. J Urol 2001;165(6 Pt 2):2316-9. http://www.ncbi.nlm.nih.gov/pubmed/11371970 32. Tan AH, Al-Omar M, Watterson JD, Nott L, Denstedt JD, Razvi H. Results of shockwave lithotripsy for pediatric urolithiasis. J Endourol 2004;18(6):527-30. http://www.ncbi.nlm.nih.gov/pubmed/15333214 33. Frick J, Sarica K, Kohle R, Kunit G. Long-term follow-up after extracorporeal shock wave lithotripsy in children. Eur Urol 1991;19(3):225-9. http://www.ncbi.nlm.nih.gov/pubmed/1855529 34. Sarica K, Küpeli S, Sarica N, Gögüs O, Kiliç S, Saribas S. Long-term follow-up of renal morphology and function in children after lithotripsy. Urol Int 1995;54(2):95-8. http://www.ncbi.nlm.nih.gov/pubmed/7747366 35. Muslumanoglu AY, Tefekli A, Sarilar O, Binbay M, Altunrende F, Ozkuvanci U. Extracorporeal shockwave lithotripsy as the first line treatment alternative for urinary tract stones in children: a large scale retrospective analysis. J Urol 2003;170(6 Pt 1):2405-8. http://www.ncbi.nlm.nih.gov/pubmed/14634438 36. Braun MP, Seif C, Jueneman KP, Alken P. Urolithiasis in children. Int Braz J Urol 2002;28(6); 539-44. http://www.ncbi.nlm.nih.gov/pubmed/15748404 37. Erdenetsesteg G, Manohar T, Singh H, Desai MR. Endourologic management of pediatric urolithiasis: proposed clinical guidelines. J Endourol 2006;20(10):737-48. http://www.ncbi.nlm.nih.gov/pubmed/17094748 38. Casale P, Grady RW, Joyner BD, Zeltser IS, Kuo RL, Mitchell ME. Transperitoneal laparoscopic pyelolithotomy after failed percutaneous access in the pediatric patient. J Urol 2004;172(2):680-3. http://www.ncbi.nlm.nih.gov/pubmed/15247760 39. Holman E, Toth C. Laparoscopically assisted percutaneous transperitoneal nephrolithotomy in pelvic dystopic kidneys: experience in 15 successful cases J Laparoendosc Adv Surg Tech A 1998;8(6): 431-5. http://www.ncbi.nlm.nih.gov/pubmed/9916597 40. Hemal AK, Ansari MS, Doddamani D, Gupta NP. Symptomatic and complicated adult and adolescent primary obstructive megaureter-indications for surgery: analysis, outcome, and follow-up. Urology 2003;61(4):703-7. http://www.ncbi.nlm.nih.gov/pubmed/12670547

14. RESIDUAL FRAGMENTS Residual fragments are commonly seen after ESWL, and most frequently present in the lower calix, following the disintegration of large stones. However, residual fragments may occur following ESWL for all sizes of stones. Different imaging techniques have variable degrees of sensitivity. Computed tomography CT or tomographic examinations demonstrate small fragments better than a standard plain abdominal film of the

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kidneys, ureters and bladder (KUB). A CT scan can also demonstrate uric acid concrements, which are otherwise radiolucent. Reports on residual fragments therefore vary between institutions, depending on which imaging method has been used. However, there are no data in the literature demonstrating the clinical value of being able to detect very small concretions, visible only on CT scan. Moreover, CT examinations are not universally available. The Panel recommends that the selection of a stone-removing procedure should be based on the findings of a good-quality KUB and that CT examination is necessary only for uric acid stones. • Stone residuals with a diameter ≤4 mm should be called residual fragments. • Residuals with a diameter ≥5 mm should be called residual stones. The clinical problem of asymptomatic stone residuals in the kidney is related to the risk of developing new stones from such nidi. Patients with residual fragments or stones should be followed up regularly to LE = 4 monitor the course of their disease. GR = C LE = level of evidence; GR = grade of recommendation Identification of biochemical risk factors and appropriate stone prevention is LE = 1b particularly indicated in patients with residual fragments or stones (35). GR = A LE = level of evidence; GR = grade of recommendation In symptomatic patients, it is important to rule out obstruction, or to treat this problem if it is present, and to take the therapeutic steps necessary to eliminate symptoms. In asymptomatic patients where the stone is unlikely to pass, treat according to the relevant stone situation. For well-disintegrated stone material residing in the lower calix, LE = 1a consider inversion therapy during high diuresis and mechanical percussion (38). GR = A LE = level of evidence; GR = grade of recommendation The risk of recurrence in patients with residual fragments after treatment of infection stones is well recognized. In a 2.2 year follow-up of 53 patients, 78% of patients with stone fragments 3 months after treatment experienced stone progression. The stone-free rate was 20%, the remaining 2% had stable desease (1). The term ‘clinically insignificant residual fragments’ (CIRF) was introduced for calcium stone residual fragments. The role of CIRF has been a matter of concern and debate (2–13). Most studies on the long-term course of the disease in patients with residual fragments are restricted to 1–6 years; the longest followup period was reported by Yu et al. (14). After 6.3 years, stone growth was observed in 26% of patients and recurrent stone formation in 15%. During a follow-up of 7– 96 months (average 3.4 years), the residual fragments had increased in size in 37% of patients; a new stone-removing procedure was undertaken in 22% of patients (15). Data from 104 patients with residual fragments showed that, in 40%, the size of the residual fragments had decreased or remained stable, while in 5% stone growth was seen during a mean follow-up of 1.2 years (16); by 2 years of follow-up, further intervention was needed in 9.3% of patients. In a 4-year followup of patients with residual fragments < 4 mm, there was obvious increase in size in 37% and a need for retreatment in 12% (17) . It is assumed that the percentage of stone-free patients is overestimated. The potential for new stone formation should therefore be considered in patients who have been treated with ESWL. •R  eported stone recurrences were 8.4% after 1 year, 6.2% after 1.6 years , 9.7% after 3.3 years, 20% after 3.5 years and 7% after 3.6 years (18). • In a Japanese report, the recurrence rates were 6.7%, 28.0% and 41.8% after 1, 3 and 5 years, respectively (19). •F  or a group of Swedish patients with calcium stones, a 20% risk of recurrent stone formation was recorded during the first 4 years after ESWL. Twenty-five per cent of patients with infection stones had formed new stones after 2 years. The greatest risk was seen in patients with stones containing a high content of calcium phosphate (20). • In a neural network analysis, an increased stone size was noted in 48% of patients with residual fragments followed up for 3.5 years; however, none of the identified risk factors for stone growth was found to be individually predictive for continuing stone formation (37). For a kidney with stones or fragments in the lower caliceal system and with no functioning parenchyma in that part, lower pole resection is an alternative to ESWL (21). For stones in the upper and middle calyces, URS with contact disintegration is another option. Percutaneous chemolysis can be used for stone fragments composed of magnesium ammonium phosphate, carbonate apatite, uric acid, cystine

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and brushite. For stones with a largest diameter ≤ 20 mm (~300 mm2), internal ureteral stenting before ESWL is recommended to avoid problems with an accumulation of stones obstructing the ureter, known as a Steinstrasse (see Chapter 15) (22–34). The risk of developing a Steinstrasse is particularly high for stones located in the renal pelvis (36). Table 24 summarizes the recommendations for the treatment of residual fragments. Table 24: Recommendations for the treatment of residual fragments Residual fragments, stones (largest diameter) < 4–5 mm > 6–7 mm

14.1

Symptomatic residuals

Asymptomatic residuals

Stone removal Stone removal

Reasonable follow-up Consider appropriate method for stone removal

REFERENCES

1.

Beck EM, Riehle RA Jr. The fate of residual fragments after extracorporeal shock wave lithotripsy monotherapy of infection stones. J Urol 1991;145(1):6-9. http://www.ncbi.nlm.nih.gov/pubmed/1984100 2. Eisenberger F, Bub P, Schmidt A. The fate of residual fragments after extracorporeal shock wave lithotripsy. J Endourol 1992;6:217-8. 3. Liedl B, Jocham D, Schuster C, Lunz C. Long-term results in ESWL-treated urinary stone patients. Urol Res 1988;16:256. Abstract. 4. Cicerello E, Merlo F, Gambaro G, Maccatrozzo L, Fandella A, Baggio B, Anselmo G. Effect of alkaline citrate therapy on clearance of residual renal stone fragments after extracorporeal shock wave lithotripsy in sterile calcium and infection nephrolithiasis patients. J Urol 1994;151(1):5-9. http://www.ncbi.nlm.nih.gov/pubmed/8254832 5. Fine JK, Pak YC, Preminger GM. Effect of medical management and residual fragments on recurrent stone formation following shock wave lithotripsy. J Urol 1995;153(1):27-32. http://www.ncbi.nlm.nih.gov/pubmed/7966783 6. Streem SB, Yost A, Mascha E. Clinical implications of clinically insignificant stone fragments after extracorporeal shock wave lithotripsy. J Urol 1996;155(4):1186-90. http://www.ncbi.nlm.nih.gov/pubmed/8632527 7. Zanetti G, Seveso M, Montanari E, Guarneri A, Del Nero A, Nespoli R, Trinchieri A. Renal stone fragments following shock wave lithotripsy. J Urol 1997;158(2):352-5. http://www.ncbi.nlm.nih.gov/pubmed/9224301 8. Pacik D, Hanak T, Kumstat P, Turjanica M, Jelinek P, Kladensky J. Effectiveness of SWL for lowerpole caliceal nephrolithiasis: evaluation of 452 cases. J Endourol 1997;11(5):305-7. http://www.ncbi.nlm.nih.gov/pubmed/9355942 9. Segura JW. The definition of success. Arch Esp Urol 1991;44:1023-4. 10. Krings F, Tuerk C, Steinkogler I, Marberger M. Extracorporeal shock wave lithotripsy retreatment (‘stirup’) promotes discharge of persistent caliceal stone fragments after primary extracorporeal shock wave lithotripsy. J Urol 1992;148(3 Pt 2):1040-1;discussion 1041-2. http://www.ncbi.nlm.nih.gov/pubmed/1507326 11. Yu CC, Lee YH, Huang JK, Chen MT, Chen KK, Lin AT, Chang LS. Long-term stone regrowth and recurrence rates after extracorporeal shock wave lithotripsy. Br J Urol 1993;72(5 Pt 2):688-91. http://www.ncbi.nlm.nih.gov/pubmed/8281395 12. Carlson KJ, Dretler SP, Roth RA, Hatziandreu E, Gladstone K, Mulley AG Jr. Extracorporeal shock wave lithotripsy and percutaneous nephrostolithotomy for urinary calculi: comparison of immediate and long-term effects. J Stone Dis 1993;5(1):8-18. http://www.ncbi.nlm.nih.gov/pubmed/10148257 13. Sabnis RB, Naik K, Patel SH, Desai MR, Bapat SD. Extracorporeal shock wave lithotripsy for lower calyceal stones: can clearance be predicted? Br J Urol 1997;80(6):853-7. http://www.ncbi.nlm.nih.gov/pubmed/9439396 14. Yu CC, Lee YH, Huang JK, Chen MT, Chen KK, Lin AT, Chang LS. Long-term stone regrowth and recurrence rates after extracorporeal shock wave lithotripsy. Br J Urol 1993;72(5 Pt 2):688-91. http://www.ncbi.nlm.nih.gov/pubmed/8281395 15. Candau C, Saussine C, Lang H, Roy C, Faure F, Jacqmin D. Natural history of residual renal stone fragments after ESWL. Eur Urol 2000;37(1):18-22. http://www.ncbi.nlm.nih.gov/pubmed/10671779

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16.

Tiselius HG. Comprehensive metabolic evaluation of stone formers is cost effective. In: Rodgers AL, BE Hibbert, B Hess, SR Khan, GM Preminger, eds. Urolithiasis. Cape Town: University of Cape Town, 2000, pp. 349-355. 17. Chen RN, Streem SB. Extracorporeal shock wave lithotripsy for lower pole calculi: long-term radiographic and clinical outcome. J Urol 1996;156(5):1572-5. http://www.ncbi.nlm.nih.gov/pubmed/8863540 18. Lahme S, Wilbert DM, Bichler KH. (Significance of ‘clinically insignificant residual fragments’ [CIRF] after ESWL) Urologe 1997 May;36(3):226-30. http://www.ncbi.nlm.nih.gov/pubmed/9265342 19. Kamihira O, Ono Y, Katoh N, Yamada S, Mizutani K, Ohshima S. Long-term stone recurrence rate after extracorporeal shock wave lithotripsy. J Urol 1996;156(4):1267-71. http://www.ncbi.nlm.nih.gov/pubmed/8808851 20. Tiselius HG. Recurrent stone formation in patients treated with extracorporal shock wave lithotripsy. J Stone Dis 1992;4:152-7. 21. Rose MB, Follows OJ. Partial nephrectomy for stone disease. Br J Urol 1977;49(7):605-10. http://www.ncbi.nlm.nih.gov/pubmed/597695 22. Miller K, Bachor R, Hautmann R. Percutaneous nephrolithotomy and extracorporeal shock wave lithotripsy versus ureteral stent and ESWL for the treatment of large renal calculi and staghorn calculi–a prospective randomized study: preliminary results. J Endourol 1988;2:131-5. 23. Recker F, Konstantinidis K, Jaeger P, Knonagel H, Alund G, Hauri D. [The staghorn calculus: anatrophic nephrolithotomy versus percutaneous litholapxy and extracorporeal shockwave therapy versus extracorporeal shockwave lithotripsy monotherapy. A report of over 6 years’ experience.] Urologe A 1989;28(3):152-7. [article in German] http://www.ncbi.nlm.nih.gov/pubmed/2741262 24. Chen AS, Saltzman B. Stent use with extracorporeal shock wave lithotripsy. J Endourol 1993;7(2): 155-62. http://www.ncbi.nlm.nih.gov/pubmed/8518830 25. Marberger M, Hofbauer J. Problems and complications in stone disease. Curr Opin Urol 1994;4:234-8. 26. Lennon GM, Thornhill JA, Grainger R, McDermott TE, Butler MR. Double pigtail ureteric stent versus percutaneous nephrostomy: effects on stone transit and ureteric motility. Eur Urol 1997;31(1):24-9. http://www.ncbi.nlm.nih.gov/pubmed/9032530 27. Ackermann D, Claus R, Zehntner C, Scheiber K. Extracorporeal shock wave lithotripsy for large renal stones. To what size is extracorporeal shock wave lithotripsy alone feasible?. Eur Urol 1988;15(1-2): 5-8. http://www.ncbi.nlm.nih.gov/pubmed/3215235 28. Cohen ES, Schmidt JD. Extracorporeal shock wave lithotripsy for stones in solitary kidney. Urology 1990;36(1):52-4. http://www.ncbi.nlm.nih.gov/pubmed/2368232 29. Shabsigh R, Gleeson MJ, Griffith DP. The benefits of stenting on a more-or-less routine basis prior to extracorporeal shock wave lithotripsy. Urol Clin North Am 1988;15(3):493-7. http://www.ncbi.nlm.nih.gov/pubmed/3407040 30. Saltzman B. Ureteral stents. Indications, variations and complications. Urol Clin North Am 1988;15(3):481-91. http://www.ncbi.nlm.nih.gov/pubmed/3043868 31. Constantinides C, Recker F, Jaeger P, Hauri D. Extracorporeal shock wave lithotripsy as monotherapy of staghorn renal calculi. 3 years of experience. J Urol 1989;142(6):1415-8. http://www.ncbi.nlm.nih.gov/pubmed/2585613 32. Anderson PA, Norman RW, Awad SA. Extracorporeal shock wave lithotripsy experience with large renal calculi. J Endourol 1989;3:31-6. 33. Pode D, Shapiro A, Verstandig A, Pfau A. Use of internal polyethylene ureteral stents in extracorporeal shock wave lithotripsy of staghorn calculi. Eur Urol 1987;13(3):174-5. http://www.ncbi.nlm.nih.gov/pubmed/3609094 34. Sulaiman MN, Buchholz NP, Clark PB. The role of ureteral stent placement in the prevention of Steinstrasse. J Endourol 1999;13(3):151-5. http://www.ncbi.nlm.nih.gov/pubmed/10360492 35. Kang DE, Maloney MM, Haleblian GE, Springhart WP, Honeycutt EF, Eisenstein EL, Marguet CG, Preminger GM. Effect of medical management on recurrent stone formation following percutaneous nephrolithotomy. J Urol 2007;177(5):1785-8; discussion 1788-9. http://www.ncbi.nlm.nih.gov/pubmed/17437820

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36.

Soyupek S, Arma an A, Koflar A, Serel TA, Hoflcan MB, Perk H, Oksay T. Risk factors for the formation of a steinstrasse after shock wave lithotripsy. Urol Int 2005;74(4):323-5. http://www.ncbi.nlm.nih.gov/pubmed/15897697 37. Michaels EK, Niederberger CS, Golden RM, Brown B, Cho L, Hong Y. Use of a neural network to predict stone growth after shock wave lithotripsy. Urology 1998;51(2):335-8. http://www.ncbi.nlm.nih.gov/pubmed/9495724 38. Chiong E, Hwee ST, Kay LM, Liang S, Kamaraj R, Esuvaranathan K. Randomized controlled study of mechanical percussion, diuresis, and inversion therapy to assist passage of lower pole renal calculi after shock wave lithotripsy. Urology 2005;65(6):1070-4. http://www.ncbi.nlm.nih.gov/pubmed/15922429

15. STEINSTRASSE A Steinstrasse or fragment column in the ureter is an accumulation of gravel that does not pass within a reasonable period of time and that interferes with the passage of urine (1). As internal ureteral stents are now commonly inserted before ESWL for large renal stones, the frequency of Steinstrasse has decreased. In all patients with signs of infection, antibiotics must be given and adequate drainage provided as soon as possible. Insertion of a percutaneous nephrostomy catheter usually results in passage of the fragments (2). For distally located accumulations of fragments, ureteroscopy (URS) might be useful to remove the leading stone fragment by contact disintegration. Treatment recommendations are summarized in Table 25. Table 25: Recommended treatment of Steinstrasse Position Proximal ureter

Obstructed and/or of stone symptomatic LE GR 1. PN 4 C 1. Stent 1. URS 1. ESWL Mid-ureter 1. ESWL 1. PN 4 C 2. URS 1. Stent 1. URS 1. ESWL Distal ureter 1. ESWL 1. PN 4 C 1. URS 1. Stent 1. URS 1. ESWL LE = level of evidence; GR = grade of recommendation; ESWL = extracorporeal shockwave lithotripsy; PN = percutaneous nephrostomy catheter; URS = ureteroscopy

15.1

Unobstructed 1. ESWL 2. URS

REFERENCES

1.

Tolley DA. Consensus of lithotriptor terminology. World J Urol 1993;11(1):37-42. http://www.ncbi.nlm.nih.gov/pubmed/8490666 2. Griffith DP. Ureteral calculi. In: Kandel LB, Harrison LH, McCullough DL, eds. State of the Art Extracorporeal Shock Wave Lithotripsy. Mt Kisco, New York: Futura Publishing, 1987, pp. 281-310.

16. INTERNAL STENTING – WHEN AND WHY 16.1

Introduction

Stents were introduced into clinical urological practice in the 1970s (1, 2). The internal ureteral stent is made of flexible, synthetic polymers and constructed and designed to be retained in situ. The stent has become an important device in the urologist’s armamentarium to assist and maintain drainage of the upper urinary tract in

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the face of obstruction or anticipated obstruction (3). As the renal calculus is the most commonest cause of upper urinary tract obstruction, the ureteric stent has become almost a sine qua non in the surgical management of upper tract renal and ureteral calculi in conjunction with extra- and intra-corporeal stone removal/disintegration. Although stent insertion for the immediate relief of significant and serious obstruction caused by a calculus is unquestionable, and placement of a stent in the ureter following ureteroscopic procedures was considered to be mandatory, a revised approach in some circumstances is now being considered on the basis of experience. No stent is ideal and the surgeon must be to be familiar with indications for usage, selection, modes of insertion and potential complications. Even though retrograde insertion of the stent is the usual method, a percutaneous antegrade approach through the loin under X-ray or ultrasound (US) control might, in some circumstances, be undertaken. Although both techniques are within the expertize of a competent, trained urological surgeon, the percutaneous antegrade method is often and most commonly performed by radiologists.

16.2

Stents in the management of kidney stones

Extracorporeal shock-wave lithotripsy (ESWL) or percutaneous nephrolithotomy (PNL) is the treatment of choice for renal calculi (see Chapter 7 for principles of active removal). Most simple renal calculi (80–85%) can be treated with SWL, while PNL is the treatment of choice for complex renal calculi (4, 5). With stones > 20 mm in diameter, the placement of a stent before ESWL was recommended to obviate the possible obstruction by a Steinstrasse. It was reported that the peri-operative placement of double-J stents can significantly reduce post ESWL morbidity and does not impede passage of the disintegrated stone fragments (6). In any case, this becomes almost obligatory when treating stones in a solitary kidney, where the avoidance of risk of obstruction by even small fragments is particularly relevant. There is little or no reason to leave a stent in situ after PNL because all disintegrated stone material is captured and removed at operation and the kidney drained by a nephrostomy tube. However, with bimodal therapy for staghorn stones, where PNL is followed by ESWL for residual fragments, internalized stenting prevents obstruction if stone fragments fall into the ureter before ESWL and prevents subsequent formation of an obstructing Steinstrasse. Technological advances of flexible, miniaturized ureteroscopes facilitates the treatment of simple renal calculi, with stone-free rates similar to those obtained using SWL and without the morbidity that accompanies PNL. The placement of a stent might be indicated in this situation; the decision to stent is a matter of clinical judgement and individual circumstances.

16.3

The use of stents in the ureter

The size, character and location of stones in the ureter determine management. The criteria that apply to the spontaneous passage of a stone are well documented and form the basis of expectant treatment. Likewise, ureteral obstruction by a stone, unlikely to pass, requires intervention to remove the stone and relieve obstruction. The two competing approaches to the interventional management of stones in the ureter are ESWL and/or ureteroscopic (URS) stone removal/disintegration. The relative advantages, benefits and results of the two are discussed elsewhere (7). Indications for the insertion of a stent together with SWL or URS and the relief of obstruction need to be defined (8). 16.3.1 Indications for stenting for urgent relief of obstruction The indications for stenting for urgent relief of obstruction are: • infection with urinary tract obstruction • urosepsis • intractable pain and/or vomiting • obstruction in a solitary or transplanted kidney • bilateral obstructing stones • ureteral calculus obstruction in pregnancy, pending definitive therapy in the post-partum period. A randomized controlled trial showed that ureteral catheters, ureteral stents and percutaneous nephrostomy tubes were equally effective for decompressing the urinary tract (9; Chapter 9). For decompression of the renal collecting system ureteral catheters, stents LE = 1b and percutaneous nephrostomy catheters are apparently equally effective GR = A LE = level of evidence; GR = grade of recommendation

16.4

Stents in conjunction with ESWL therapy for ureteral stones

The assumption that a stent in the ureter contributed to more efficient fragmentation of the stone with ESWL led to the routine pre-treatment placement of an internal stent. Several studies, including randomized

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controlled trials, in large numbers of patients have now shown that there was no difference in stone-free rates between stented and non-stented patients (10). In fact, stenting was seen to be significantly associated with a decreased stone-free rate (11). Indeed, stenting has several disadvantages. It makes a non-invasive procedure into an invasive one, causes undesirable side effects, and increases the cost of treatment. The recommendation, therefore, is that stent insertion before SWL for obstructing ureteral stones ≤2 cm provides no advantage and is unnecessary.

16.5

Stents in conjunction with URS

Routine placement of a stent has been considered to be an integral adjunct to URS, and was undertake to prevent: • obstruction • renal pain caused by oedema as a result of balloon dilatation • trauma of instrumentation • stone manipulation and disintegration. Several prospective, randomized, controlled trials comparing non-stented versus stented ureteroscopic lithotripsy have shown significantly more morbidity with regard to haematuria, flank and abdominal pain, dysuria and hospital stay in the stented patients (12–14). In a non-randomized study, up to 80% of participants experienced urinary symptoms and pain associated with indwelling ureteral stents, which interfered with daily activites and resulted in a reduced quality of life (15). A recent study has also reported that an indwelling ureteral stent can impair the quality of sexual life in both male and female patients (16). In a metaanalysis of nine randomized controlled trials of stenting versus non-stenting after URS in 831 patients, Nabi et al. (17) reported that the incidence of irritative lower urinary tract symptoms was significantly higher in the stented patients, while there were no differences in stone-free rates, urinary tract infection rates, requirements for analgesia or long-term ureteric stricture formation. It is therefore recommended that ureteric stents are not necessary following uncomplicated URS for stones.

16.6

REFERENCES

1.

Finney RP. Experience with new double J ureteral catheter stent. 1978. J Urol 2002;167(2 Pt 2):11358; discussion 1139. http://www.ncbi.nlm.nih.gov/pubmed/11905888 Hepperlen JR, Mardis HK, Kammandel H. Self-retained internal ureteral stents: a new approach. J Urol 1978;119(6):731-4. http://www.ncbi.nlm.nih.gov/pubmed/77917 Saltzman B. Ureteral stents. Indications, variations, and complications. Urol Clin North Am 1988;15(3):481-91. http://www.ncbi.nlm.nih.gov/pubmed/3043868 Lingeman JE, Coury TA, Newman DM, Kahnoski RJ, Mertz JH, Mosbaugh PG, Steele RE, Woods JR. Comparison of results and morbidity of percutaneous nephrostolithotomy and extracorporeal shock wave lithotripsy. J Urol 1987;138(3):485-90. http://www.ncbi.nlm.nih.gov/pubmed/3625845 Miller NL, Lingeman JE. Management of kidney stones. BMJ 2007;334(7591):468-72. http://www.ncbi.nlm.nih.gov/pubmed/17332586 Libby JM, Meacham RB, Griffith DP. The role of silicone ureteral stents in extracorporeal shock wave lithotripsy of large renal calculi. J Urol 1988;139(1):15-7. http://www.ncbi.nlm.nih.gov/pubmed/3275796 Tiselius HG. Removal of ureteral stones with extracorporeal shock wave lithotripsy and ureteroscopic procedures. What can we learn from the literature in trems of results and treatment efforts?. Urological Reseach 2005;33:185-90 Vieweg J, Teh C, Freed K, Leder RA, Smith RH, Nelson RH, Preminger GM. Unenhanced helical computerized tomography for the evaluation of patients with acute flank pain. J Urol 1998;160 (3 Pt 1):679-84. http://www.ncbi.nlm.nih.gov/pubmed/9720520 Pearle MS, Pierce HL, Miller GL, Summa JA, Mutz JM, Petty BA, Roehrborn CG, Kryger JV, Nakada SY. Optimal method of urgent decompression of the collecting system for obstruction and infection due to ureteral calculi. J Urol 1998;160(4):1260-4. http://www.ncbi.nlm.nih.gov/pubmed/9751331 El-Assmy A, El-Nahas AR, Sheir KZ. Is pre-shock wave lithotripsy stenting necessary for ureteral stones with moderate or severe hydronephrosis. J Urol 2006;176(5):2059-62;discussion 2062. http://www.ncbi.nlm.nih.gov/pubmed/17070256

2.

3.

4.

5. 6.

7.

8.

9.

10.

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11. Abdel-Khalek M, Sheir K, Elsobky E, Showkey S, Kenawy M. Prognostic factors for extracorporeal shock-wave lithotripsy of ureteric stones--a multivariate analysis study. Scand J Urol Nephrol 2003;37(5):413-8. http://www.ncbi.nlm.nih.gov/pubmed/14594691 12. Denstedt JD, Wollin TA, Sofer M, Nott L, Weir M, D’A Honey RJ. A prospective randomized controlled trial comparing nonstented versus stented ureteroscopic lithotripsy. J Urol 2001;165(5):1419-22. http://www.ncbi.nlm.nih.gov/pubmed/11342889 13. Jeong H, Kwak C, Lee SE. Ureteric stenting after ureteroscopy for ureteric stones: a prospective randomised study assessing symptoms and complications. BJU Int 2004;93(7):1032-4; discussion 1034-5. http://www.ncbi.nlm.nih.gov/pubmed/15142158 14. Al-Ba’adani T, Ghilan A, El-Nono I, Alwan M, Bingadhi A. Whether post-ureteroscopy stenting is necessary or not? Saudi Med J 2006;27(6):845-8. http://www.ncbi.nlm.nih.gov/pubmed/16758048 15 Joshi HB, Newns N, Stainthorpe A, McDonagh RP, Keeley, FX Jr, Timoney AG. Ureteral stent symptom questionnaire: development and validation of a multidimensional quality of life measure. J Urol 2003;169(3):1060-4. http://www.ncbi.nlm.nih.gov/pubmed/12576846 16. Sighinolfi MC, Micali S, DeStefani S, Mofferdin A, Grande A, Giacometti M, Ferrari N, Rivalta M, Bianchi G. Indwelling ureteral stents and sexual health: a presspective, multivariate analysis. J Urol 2007:178(1):229-31. http://www.ncbi.nlm.nih.gov/pubmed/17499774 17. Nabi G, Cook J, N’Dow J, McClinton S.Outcomes of stenting after uncomplicated ureteroscopy: systematic review and meta-analysis. BMJ 2007;334(7593):572. http://www.ncbi.nlm.nih.gov/pubmed/17311851

17. RECURRENCE PREVENTIVE TREATMENT 17.1

Recurrence preventive treatment of patients with calcium stone disease

Table 24 summarizes various therapeutic tools, which aim to reduce the risk of recurrent calcium stone formation. The levels of evidence (LE) and the grades of recommendation (GR) refer to the effects on stone formation reported in the literature. The description of biochemical effects enables the most appropriate treatment to be selected in patients with known abnormalities in urine composition. Table 24: Dietary and pharmacological treatment regimens for prevention of recurrent calcium stone formation Treatment Biochemical effects Increased fluid intake Dilution of urine Reduced intake of oxalate Reduced excretion of oxalate Reduced intake of animal protein Reduced excretion of: • Calcium • Oxalate • Urate Increased excretion of: • Citrate • Increased pH Reduced intake of sodium Reduced excretion of calcium Increased excretion of citrate Increased intake of fibres Increased intake of vegetables, provided there is a simultaneous adequate intake of calcium Avoid excessive intake of vitamin C Reduced urinary oxalate Thiazide Reduced excretion of calcium Potassium citrate Increased excretion of citrate Inreased urine pH Increased inhibition of crystal 96

References 6, 7

LE GR 1b A

28

1b

A

28

1b

A

12, 13 36

2b 3

B B

18 52-63, 67 70, 71

2b B 1a A 1b A

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growth and crystal agglomeration. Potassium magnesium citrate Inreased urine pH 73 Increased excretion of citrate Increased inhibition of crystal growth and crystal agglomeration Reduced supersaturation with CaOx as a result of increased urinary magnesium Increased inhibition of CaP crystal growth and aggregation Allopurinol (in patients with Reduces urinary urate 98 hyperuricuric calcium Decreased risk of calcium oxalate oxalate stone formation) crystal formation Pyridoxine In patients with primary 103 hyperoxaluria: reduced excretion of oxalate

1b A

1b A

3 C

Abnormal crystalluria is a common finding in patients with recurrent calcium stone disease. Compared to non-stone formers, stone-forming patients have been shown to have more, larger, and aggregated crystals (1). Moreover, crystalluria found in early morning urine samples seems to predict the risk of recurrent stone formation (2). The abnormal crystalluria can cause: • A small urine volume • Increased excretion of urine variables important for increasing the ion-activity products of calcium oxalate/calcium phosphate, or, • Reduced activity of inhibitors of crystal growth and crystal agglomeration. These factors have been extensively reported in a large number of articles and the issue has been previously comprehensively summarized (3-5). It is axiomatic that without sufficiently supersaturated urine there can be no crystal formation and accordingly no stone formation. It therefore seems essential to make the relevant corrections of urine composition in order to counteract critical supersaturation and pathological crystallization. The treatment recommendations, which are based on assumed or demonstrated abnormalities, should be adapted to the severity of the disease to avoid overtreatment and obtain reasonable patient compliance. 17.1.1 Drinking recommendations An inverse relationship between high fluid intake and stone formation has been demonstrated (6, 7). The general recommendation for calcium stone formers is to maintain a high urine flow by a generous intake of fluids. The aim should be to obtain a 24-hour urine volume of at least 2 L (LE 1b; GR A). Although most beverages can be drunk to increase fluid intake and help prevent stone formation, grapefruit juice has been shown to be associated with an increased risk of stone formation (8) (LE 3; GR C). The presence of citrate appears to be the important determinant of the effect of fruit juices. In the presence of hydrogen ions, the net result is neutralization. However, with potassium, pH and citrate are increased. For this reason, orange juice is beneficial but not cranberry juice (9,10). Although grapefruit juice has a high potassium content, its effect on calcium oxalate supersaturation is counteracted by a high supply of oxalate (11). 17.1.2 Dietary recommendations Diet should be of a ‘common sense’ type, i.e. a mixed balanced diet with contributions from all food groups, but without excesses of any kind (12). Fruits, vegetables and fibres: Fruit and vegetable intake should be encouraged because of the beneficial effects of fibre (13). The alkaline content of a vegetarian diet also gives rise to a desirable increase in urinary pH (12). Oxalate: An excessive intake of oxalate-rich products should be limited or avoided to prevent an oxalate load. This includes fruit and vegetable rich in oxalate such as wheat bran. This is particularly important in patients in whom an high oxalate excretion has been demonstrated. The following products have a high content of oxalate (14): • Rhubarb, 530 mg oxalate/100 g • Spinach, 570 mg oxalate/100 g • Cocoa, 625 mg oxalate/100 g • Tea leaves, 375-1450 mg oxalate/100 g • Nuts, 200-600 mg oxalate/100 g.

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Vitamin C is a precursor of oxalate, but its role as a risk factor in calcium oxalate stone formation remains controversial. Some studies have shown that a daily intake of up to 4 g might be allowed without risk (15-17). However, a recent study demonstrated a significantly increased risk in stone formation for men taking 1 g/ day or more of vitamin C compared to men taking less than 90 mg (18). It therefore seems justified to advise calcium oxalate stone formers to avoid excessive intake of vitamin C. The allowed amount is not obvious but a daily intake of more than 500 mg (11) to 1 g (18) should probably be avoided. Animal protein should not be ingested in excessive amounts (19-25), and it is recommended that animal protein intake is limited to to 0,8-1 g/kg body weight. An excessive consumption of animal protein gives rise to several unfavourable effects on stone formation, such as hypocitraturia, low pH, hyperoxaluria and hyperuricosuria. Moreover, an increased resorption of bone increases urinary calcium (26). Calcium intake should not be restricted unless there are very strong reasons because of the inverse relationship between dietary calcium and calcium stone formation (27). The minimum daily requirement for calcium is 800 mg and the general recommendation is 1,000 mg/day. Calcium supplements are not recommended except in cases of enteric hyperoxaluria, when additional calcium should be ingested with meals to bind intestinal oxalate. Sodium: A high consumption of sodium brings about several changes in urine composition. Calcium excretion is increased by reduced tubular reabsorption. Urinary citrate is reduced due to loss of bicarbonate. The risk of forming sodium urate crystals is increased and the effect of thiazide in reducing urinary calcium is counteracted by a high sodium intake. The combined restriction of sodium and animal protein in a randomized study resulted in a reduced rate of calcium stone formation (28). The daily sodium intake should not exceed 3 g. Urate: The intake of food particularly rich in urate should be restricted in patients with hyperuricosuric calcium oxalate stone disease (29-34), as well as in patients with uric acid stone disease. The intake of urate should not exceed 500 mg/day. Examples of food rich in urate (21) include: • Calf thymus, 900 mg urate/100 g • Liver, 260-360 mg urate/100 g • Kidneys, 210-255 mg urate/100 g • Poultry skin, 300 mg urate/100 g • Herring with skin, sardines, anchovies, sprats, 260-500 mg urate/100 g. In patients with an expected low risk of recurrent stone formation (S or Rm), advice on fluid intake and diet may be sufficient to prevent stone recurrence. The positive effect of such a regimen has been referred to as the ‘stone clinic effect’. 17.1.3 Pharmacological treatment The general opinion is that any treatment aiming at correction of abnormalities in urine composition and elimination of risk factors of pathological crystallization should always start by giving patients advice regarding dietary and drinking habits. In case pharmacological treatment is considered (following prior unsuccessful therapeutic approaches) adequate patient education regarding drinking and dietary recommendations is even more imminent since treatment outcome will largely depend on patient compliance. In this respect, it is essential to choose the most appropriate form of treatment. The ideal pharmacological agent should halt the formation of calcium stones, be free of side effects and be easy to administer. These aspects are all of utmost importance in order to achieve a reasonably good compliance. The recommendations given in this guideline document are based on what has been published in this field. An extensive review and interpretation of literature results were carried out by the European Urolithiasis Research group at a Consensus Conference in Mannheim, Germany in 1996, and have subsequently been referred to in several publications (37-41). The ensuing recommendations are to a large extent still highly relevant. It seems logical and theoretically most attractive to administer pharmacological agents in a selective way with the aim of correcting one or several biochemical abnormalities. It needs to be emphasized, however, that there is no absolute consensus on such a view (42, 43, 11). The pharmacological agents most commonly used for patients with recurrent calcium stone formation are thiazides, potassium citrate, orthophosphate, magnesium and allopurinol. The scientific basis of these forms of treatment is briefly summarized below. 17.1.3.1 Thiazides and thiazide-like agents Hydrochlorothiazide, bendroflumethiazide, trichlorothiazide and the non-thiazide indapamide have been used for recurrence prevention in patients with calcium stone disease. The purpose of thiazide treatment is to reduce

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the excretion of calcium in hypercalciuric patients, but it has been stated that calcium reduction is also seen in patients with normocalciuria (20). The hypocalciuric action of thiazides is thought to be mediated by increased reabsorption of calcium in the proximal as well as in the distal parts of the nephron (20,44). It has, moreover, been suggested that thiazides might decrease the excretion of oxalate, possibly by a reduced intestinal absorption of calcium (45-47), but recent studies have shown that such an effect is unlikely to occur. However, a thiazide-induced reduction in urinary oxalate is not a consistent finding in the clinical studies. There is more than 35 years of clinical experience with thiazides as a method for stone prevention. Following the initial report by Yendt in 1970 (48), a large number of reports have been published, most of which support a reduced rate of recurrent stone formation. The clinical effect of thiazide treatment has accordingly been evaluated in 10 randomized studies, four of which included placebo-treated patients. Although two short-term placebo-controlled studies (49,50) failed to confirm a positive effect of thiazides, a significantly reduced recurrence rate was recorded in three 3-year follow-up studies (51-55). A similar result was also obtained in three groups of patients treated with thiazides between 2.3 and 4.3 years, in comparison with conservatively treated patients (56,57). A significantly reduced rate of stone formation was also noted when a thiazide was given intermittently to recurrent stoneformers (58). A reduced rate of recurrence was also observed in several other studies which compared treated patients with those not given any pharmacological agent (58-62). In some other studies, the results were less convincing (63,64). The convincing positive effect of thiazide treatment was further supported by a meta-analysis based on randomized trials. This analysis showed significantly better results with active treatment than with placebo or no treatment (p < 0.02) (65). The major drawback of thiazide treatment is the occurrence of side effects. The unmasking of normocalcaemic hyperparathyroidism, development of diabetes and gout, as well as erectile dysfunction, contribute to a limited tolerance and a high drop-out rate. Compliance is usually in the range of only 50-70%. Whether or not thiazide treatment should be reserved only for patients with hypercalciuria, or used also in patients without this abnormality, cannot be definitely concluded from the various studies. Suffice it to mention that of the randomized studies, three studies selected hypercalciuric patients (55-57) and all three showed a significantly positive effect of thiazides. In the other seven randomized trials, in which no selection was made, a significant effect was reported in five. Due to the frequent occurrence of hypercalciuria also in an unselected group of stone formers, there is no strong scientific basis for a recommendation in this regard. It is our opinion, however, that the major indication for choosing a thiazide or a thiazide-like agent should be hypercalciuria. In the absence of high calcium excretion, other forms of treatment may be better first-choice alternatives. As in all situations when pharmacological treatment is considered, a judgment must be made between the benefits and risks of the medication. According to these considerations, treatment with thiazide is usually reserved for patients with a high excretion of calcium (i.e. more than 6.5-7 mmol/24 hours or more than 4.5-5 mmol/16 hours). Hydrochlorothiazide is usually administered at a dosage of 25-50 mg once or twice daily. The thiazideinduced loss of potassium should be substituted by giving either potassium citrate 3.5-7 mmol twice daily or another potassium salt. It has been shown, however, that potassium citrate was superior to potassium chloride in this regard (66). Hypocitraturia associated with hypokalaemia is thought to explain therapeutic failures in thiazide-treated patients. 17.1.3.2 Alkaline citrate Treatment with alkaline citrate is commonly used as a method to increase urinary citrate in patients with hypocitraturia. A low citrate excretion is a well-recognized and common finding in patients with calcium stone disease. The role of citrate is important because of its complex formation with calcium. This chelation reduces the ion-activity products of both calcium oxalate and calcium phosphate. Moreover, citrate is an inhibitor of growth and aggregation/agglomeration of these crystals (67). Administration of an alkaline salt brings about an increased pH and an increased excretion of citrate. There are also reports of favourable clearance of residual fragments during treatment with alkaline citrate (see below). Although the general principle is to give citrate preparations, it is the alkalinization of the tubular cells that is the most important factor that results in an increased citrate excretion, with only a small fraction of the administered citrate being excreted in urine. The alkalinizing agents used to prevent recurrent calcium stone formation are sodium potassium citrate, potassium citrate, sodium citrate, potassium magnesium citrate, potassium bicarbonate and sodium bicarbonate. Alkaline citrate has been used in four randomized studies. Potassium citrate was used in two studies (68, 69), sodium potassium in one study (70) and sodium magnesium citrate in another study (71). In the two studies of potassium citrate, a significantly reduced recurrence rate was recorded. A favourable effect was also reported with potassium magnesium citrate, whereas no effect was noted with sodium potassium citrate

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compared with an untreated group. Other non-randomized studies with alkaline citrate have shown a variable outcome. However, the general impression is that potassium citrate (68, 69, 72-77) has a greater potential for preventing recurrence than sodium potassium citrate (39, 70, 78, 79). This observation is also supported by the different effects of potassium citrate and sodium citrate on urine composition (80). Although potassium magnesium citrate appears efficient in prevention of recurrent stone formation, this agent is not yet generally available. Further studies are necessary to show whether this preparation is superior to potassium citrate. Whether or not alkaline citrate preparations should be reserved for patients with hypocitraturia or used in a non-selective way has not been appropriately addressed in any study. An attempt to compare literature data has suggested a trend towards selective treatment (81). In a meta-analysis of randomized trials, it was not possible to adequately analyse the therapeutic outcome (65). The usefulness of alkaline citrate as a way of increasing stone clearance after SWL has been studied by several groups. It was accordingly shown that sodium potassium citrate (82), as well as potassium citrate (77, 83), increased the clearance of stone fragments. According to preliminary and unpublished data from a European multicentre investigation, this effect has not been confirmed. The frequency of side effects is fairly high and compliance with alkaline citrate administration was shown to be no better than approximately 50%. Because of the many effects on calcium oxalate and calcium phosphate crystallization and stone formation, treatment with alkaline citrate, nevertheless, can be recommended as a treatment for preventing recurrent stones. The recommended agent is potassium citrate. Although it is likely that this form of treatment is most beneficial for patients with a low citrate excretion, so far there is no solid evidence in the literature to support this assumption and further studies are necessary. The risk of forming calcium phosphate stones as a result of the increased pH is theoretical, but there are only occasional reports of such an outcome. 17.1.3.3 Orthophosphate The theoretical rationale for giving orthophosphate to patients with recurrent calcium oxalate stone formation is to reduce the excretion of calcium and increase the excretion of pyrophosphate. Pyrophosphate is an inhibitor of both calcium oxalate and calcium phosphate crystal growth. The effect on urinary calcium is assumed to be mediated by formation of 1,25 (OH)2-vitamin D with an associated decreased absorption of calcium and reduced bone resorption. Administration of orthophosphate (neutral) has been reported to also increase urinary citrate. There are only a few studies in the literature that deal with the effect of orthophosphate on stone formation. In a randomized, placebo-controlled study on potassium acid phosphate given during a period of 3 years, stone formation increased in the orthophosphate-treated group (84). The rate of stone formation during 3 years of treatment with phosphate was also studied in two randomized studies (52, 53). The number of patients in each of these studies was small and there were no statistically significant differences between treated and untreated patients. In some, less well-controlled, studies (85, 86), it was also not possible to confirm a reliable effect of phosphate treatment. A reduced rate of stone formation was, however, noted by others (87, 88). In reviews of the literature results, there is a lack of scientific evidence that phosphate is effective in preventing calcium stone formation (65, 89). Although patient compliance with treatment is reported as good, side effects such as diarrhoea, abdominal cramps, nausea and vomiting are common. Moreover, a possible effect on parathyroid hormone must be considered. It is possible that the pattern of side effects is favourably affected by slow-release potassium phosphate (90). The effect of phosphate administration on calcium phosphate stone formation has not been elucidated. In conclusion, there is only very weak evidence that orthophosphate significantly reduces calcium oxalate stone formation. Although this form of treatment may be a possible option in patients with absorptive hypercalciuria, so far there is insufficient evidence to recommend its use. 17.1.3.4 Magnesium An increased excretion of magnesium might reduce the ion-activity product of calcium oxalate and inhibit the growth of calcium phosphate crystals. There are also observations of an increased excretion of citrate following administration of magnesium (91). Magnesium is also considered important for the transformation between various calcium phosphate crystal phases. A high urinary concentration of magnesium is thus thought to decrease the risk of brushite formation. Magnesium oxide, magnesium hydroxide, potassium magnesium citrate and magnesium aspartate have been used. The effect of potassium magnesium citrate is discussed above regarding alkaline citrate. There are two randomized studies on the clinical effects of magnesium, one in which treatment with magnesium hydroxide was compared with a placebo control group (92) and one with magnesium oxide and

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untreated controls (52). None of them showed a statistically significant effect on stone formation despite followup periods of 4 and 3 years, respectively. The positive effects of magnesium administration reported previously (93, 94) have not been confirmed by recent controlled studies (65, 89). Thus, there is insufficient evidence to recommend magnesium as monotherapy in calcium stone prevention. 17.1.3.5 Allopurinol Treatment with allopurinol to counteract the formation of calcium oxalate stones was introduced following demonstration of a relationship between hyperuricosuria and calcium oxalate stone formation (95). The effect of allopurinol on calcium oxalate stone formation may be mediated through: • Reduced salting-out effect • Decreased risk of uric acid or urate crystals as promoters of calcium oxalate precipitation • Complex formation between colloidal urate and macromolecular inhibitors, and/or • Reduced excretion of oxalate. It should also be mentioned that allopurinol may influence crystallization by its antioxidative properties. Allopurinol has been used clinically to treat patients both with, and without, hyperuricosuria. In a placebo-controlled randomized study of allopurinol-treated, hyperuricosuric, calcium-oxalate stone formers, 75% of patients given allopurinol were free of recurrent stone formation compared with 45% in the placebo group (96). This effect was statistically significant. Three other randomized studies compared treatment with allopurinol and placebo or no treatment (96-98) in patients not selected because of hyperuricosuria. No significant difference was found between treated and untreated patients in any of these studies. In a long-term follow-up of non-selected, calcium oxalate stone formers treated with 300 mg of allopurinol daily, no effect was found on stone formation (97). A similar result was recorded in another Swedish study (98). These results are in contrast to those obtained in patients treated for hyperuricosuria (99,100). Allopurinol tolerance is usually good, but severe side effects have been reported with high doses. There is no information on compliance. The results indicate that allopurinol might be useful for treating patients with hyperuricosuric calcium oxalate stone formation. However, it cannot be recommended for patients with other biochemical abnormalities. 17.1.3.6 Pyridoxine Theoretically, administration of pyridoxine (vitamin B6) might favourably influence the endogenous production of oxalate. This may be explained by an increased transamination of glyoxylate due to the action of the co-enzyme pyridoxal phosphate. Pyridoxine has successfully been used together with orthophosphate in the treatment of patients with primary hyperoxaluria (101), as well as patients with idiopathic hyperoxaluria (102). There are no controlled studies to support the use of pyridoxine in patients with idiopathic calcium oxalate stone disease. Due to the rarity, and severity, of primary hyperoxaluria, there are no randomized studies on the efficacy of pyridoxine. Several reports confirm, however, that a fraction of patients with Type 1 hyperoxaluria responds favourably to large doses of pyridoxine. Because of the lack of other effective forms of treatment, it is definitely worthwhile trying pyridoxine therapeutically, with the aim of reducing oxalate excretion in patients with primary hyperoxaluria Type I. 17.1.3.7 Management of patients with enteric hyperoxaluria Enteric hyperoxaluria is a particularly problematic condition encountered in patients with intestinal malabsorption of fat. This abnormality, which is associated with a high risk of stone formation is for example seen after intestinal resection, following jejunoileal bypass for treatment of obesity, in Crohn’s disease and in pancreas insufficiency. The intestinal loss of fatty acids is combined with a loss of calcium. The normal complex formation between oxalate and calcium is therefore disturbed and oxalate absorption is dramatically increased. In addition to the ensuing hyperoxaluria, these patients usually present with hypocitraturia because of loss of alkali. Urine pH is usually low and so are urinary calcium and the urine volume. All these abnormalities contribute to particularly high levels of supersaturation with calcium oxalate, crystalluria and stone formation. To prevent recurrence, it is essential to reduce the hyperabsorption of oxalate and correct any other urine abnormalities. A restricted intake of oxalate-rich foods should be combined with calcium supplements to enable calcium oxalate complex formation in the intestine (103). Calcium should therefore be given at meal times. Other oxalate-binding agents might also be useful, such as the marine colloid, Oxabsorb (104). An increased fluid intake is of course desirable, but its efficacy is often low because of the intestinal loss of water and increased diarrhoea. Administration of alkaline citrate is recommended to raise urinary pH and citrate (105). The diet should be restricted with regard to fat (106).

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17.1.4. Recommendations Although there is no place for monotherapy with magnesium salts, a combination with thiazides might prove useful, but there is so far insufficient scientific evidence for this approach (107). Nevertheless, this alternative is mentioned because of its possible role in prevention of brushite stones. It has been assumed that oxalate is more powerful than calcium in affecting supersaturation with calcium oxalate, but recent observations have indicated that calcium and oxalate influence the supersaturation with approximately equal power (108). It is therefore essential to correct abnormalities of both variables. In patients with incomplete distal renal tubular acidosis, the treatment of choice appears to be potassium citrate, a regimen that has a positive effect on the acidosis, citrate excretion and stone formation (109). There is no absolute consensus that a selective treatment is better than a non-selective treatment for recurrence prevention in idiopathic calcium stone disease. An analysis of data from the literature, however, has suggested a slight difference in favour of treatment directed towards individual biochemical abnormalities (43). Recommendations for a selective therapeutic approach are given in Table 27. In the absence of any common biochemical risk factors, it was shown that a water load had a positive effect on supersaturation and crystallization (110). It is generally considered that dietary and drinking advice should always be considered first and that pharmacological alternatives should be added only if the the first step fails or if there are specific reasons for starting pharmacological treatment from the beginning. It is essential to note, however, that pharmacological treatment always should be combined with appropriate changes in dietary and drinking habits. For patients with mild recurrent calcium stone disease and without residual stones or fragments (So, Rmo), it seems sufficient to give the patient general advice regarding dietary and fluid intake. For patients with a similar history of stone formation but with residual stones or fragments in the kidneys (Sres, Rm-res), it might be worthwhile applying a more aggressive treatment based on urinary findings as this approach has resulted in effective counteraction of active stone formation and growth of residuals (106). For patients in category Rs it is logical to take appropriate steps to stop or efficiently counteract recurrent stone formation, irrespective of whether or not the patient has residual stone-fragments (Table 28). Table 27: Suggested treatment for patients with specific abnormalities in urine composition Urinary risk factor Suggested treatment Hypercalciuria Thiazide + potassium citrate Hyperoxaluria Oxalate restriction Hypocitraturia Potassium citrate Enteric hyperoxaluria Potassium citrate Calcium supplement Oxalate absorption High excretion of sodium Restricted intake of salt Small urine volume Increased fluid intake Urea level indicating a high Avoid excessive intake of animal Intake of animal protein protein Distal renal tubular acidosis Potassium citrate Primary hyperoxaluria Pyridoxine No abnormality identified High fluid intake LE = Level of evidence; GR = grade of recommendation

LE GR 1a A 2b A 1b A 3-4 C 2 B 3 B 1b A 1b A 1b A 2b 3 2b

B B B

Table 28: When should calcium stone formers be offered recurrence preventive treatment and how? Category Analysis of urinary risk factors Recurrence prevention So No General advice Sres Yes* Specific advice, with or without a pharmacological agent Rmo No General advice Rm-res Yes* Specific advice, with or without a pharmacological agent Rs Yes Specific advice, with or without a pharmacological agent * Optional procedure that is recommended if it is likely that the information obtained can be useful for designing the subsequent treatment.

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17.1.5 References 1. Azoury R, Robertson WG, Garside J. Observations on in vitro and in vivo calcium oxalate crystalluria in primary calcium stone formers and normal subjects. Br J Urol 1987;59(3):211-3. http://www.ncbi.nlm.nih.gov/pubmed/3567480 2. Daudon M, Hennequin C, Boujelben G, Lacour B, Jungers P. Serial crystalluria determination and the risk of recurrence in calcium stone formers. Kidney Int 2005;67(5):1934-43. http://www.ncbi.nlm.nih.gov/pubmed/15840041 3. Hess B, Kok D. Nucleation, growth and aggregation of stone-forming crystals. In: Coe FL, Favus MJ, Pak CYC, Parks JH, Preminger GM, eds. Kidney Stones. Medical and Surgical Management. Philadelphia: Lippincott-Raven, 1996, pp. 3-32. 4. Tiselius HG. Solution chemistry of supersaturation. In: Coe FL, Favus MJ, Pak CYC, Parks JH, Preminger GM, eds. Kidney Stones. Medical and Surgical Management. Philadelphia: LippincottRaven, 1996, pp. 33-64. 5. Lieske JC, Coe FL. Urinary inhibitors and renal stone formation. In: Coe FL, Favus MJ, Pak CYC, Parks JH, Preminger GM, eds. Kidney Stones. Medical and Surgical Management. Philadelphia: Lippincott-Raven, 1996, pp. 65-114. 6. Borghi L, Meschi T, Amato F, Briganti A, Novarini A, Giannini A. Urine volume, water and recurrences in idiopathic calcium nephrolithiasis: a 5-year randomized prospective study. J Urol 1996;155(3): 839-43. http://www.ncbi.nlm.nih.gov/pubmed/8583588 7. Curhan GC, Willett WC, Speizer FE, Spiegelman D, Stampfer MJ. Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Ann Intern Med 1997;126(7): 497-504. http://www.ncbi.nlm.nih.gov/pubmed/9092314 8. Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Beverage use and risk for kidney stones in women. Ann Intern Med 1998;128(7):534-40. http://www.ncbi.nlm.nih.gov/pubmed/9518397 9. Wabner CL. Pak CY. Effect of orange juice consumption on urinary stone risk factors. J Urol 1993;149(6):1405-8. http://www.ncbi.nlm.nih.gov/pubmed/8501777 10. Gettman MT, Ogan K, Brinkley LJ, Adams-Huet B, Pak CY, Pearle MS. Effect of cranberry juice consumption on urinary stone risk factors. J Urol 2005;174(2):590-4. http://www.ncbi.nlm.nih.gov/pubmed/16006907 11. Park S, Pearle MS. Pathophysiology and management of calcium stones. Urol Clin North Am 2007;34(3):323-34. http://www.ncbi.nlm.nih.gov/pubmed/17678983 12. Hess B, Mauron H, Ackermann D, Jaeger P. Effects of a ‘common sense diet’ on urinary composition and supersaturation in patients with idiopathic calcium urolithiasis. Eur Urol 1999;36(2):136-43. http://www.ncbi.nlm.nih.gov/pubmed/10420035 13. Ebisuno S, Morimoto S, Yasukawa S, Ohkawa T. Results of long-term rice bran treatment on stone recurrence in hypercalciuric patients. Br J Urol 1991;67(3):237-40. http://www.ncbi.nlm.nih.gov/pubmed/1902388 14. Hesse A, Tiselius HG, Jahnen A. Urinary Stones: Diagnosis, Treatment and Prevention of Recurrence. In: Uric acid stones. New York: Karger, 1996, p. 62. 15. Wandzilak TR, D’Andre SD, Davis PA, Williams HE. Effect of high dose vitamin C on urinary oxalate levels. J Urol 1994;151(4):834-7. http://www.ncbi.nlm.nih.gov/pubmed/8126804 16. Sutton RA, Walker VR. Enteric and mild hyperoxaluria. Miner Electrolyte Metab 1994;20(6):352-60. http://www.ncbi.nlm.nih.gov/pubmed/7783697 17. Auer BL, Auer D, Rodger AL. The effects of ascorbic acid ingestion on the biochemical and physicochemical risk factors associated with calcium oxalate kidney stone formation. Clin Chem Lab Med 1998;36(3):143-7. http://www.ncbi.nlm.nih.gov/pubmed/9589801 18. Taylor EN, Stampfer MJ, Curhan GC. Dietary factors and the risk of incident kidney stones in men: new insights after 14 years of follow-up. J Am Soc Nephrol 2004;15(12):3225-32. http://www.ncbi.nlm.nih.gov/pubmed/15579526 19. Robertson WG. Diet and calcium stones. Miner Electrolyte Metab 1987;13(4):228-34. http://www.ncbi.nlm.nih.gov/pubmed/3306314 20. Yendt ER. Commentary: Renal calculi–twenty years later. J Lithotripsy Stone Dis 1990;2:164-72.

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Iguchi M, Umekawa T, Ishikawa Y, Katayama Y, Kodama M, Takada M, Katoh Y, Kataoka K, Kohri K, Kurita T. Dietary intake and habits of Japanese renal stone patients. J Urol 1990;143(6):1093-5. http://www.ncbi.nlm.nih.gov/pubmed/2342165 22. Kok DJ, Iestra JA, Doorenbos CM, Papapoulos SE. The effects of dietary excesses in animal protein and sodium on the composition and the crystallization kinetics of calcium oxalate monohydrate in urines of healthy men. J Clin Endocrinol Metab 1990;71(4):861-7. http://www.ncbi.nlm.nih.gov/pubmed/2401715 23. Goldfarb S. The role of diet in the pathogenesis and therapy of nephrolithiasis. Endocrinol Metab Clin North Am 1990;19(4):805-20. http://www.ncbi.nlm.nih.gov/pubmed/2081512 24. Hughes J, Norman RW. Diet and calcium stones. CMAJ 1992;146(2):137-43. http://www.ncbi.nlm.nih.gov/pubmed/1310430 25. Holmes RP, Goodman HO, Hart LJ, Assimos DG. Relationship of protein intake to urinary oxalate and glycolate excretion. Kidney Int 1993;44(2):366-72. http://www.ncbi.nlm.nih.gov/pubmed/8377380 26. Fellström B, Danielson BG, Karlström B, Lithell H, Ljunghall S, Vessby B, Wide L. Effects of high intake of dietary animal protein on mineral metabolism and urinary supersaturation of calcium oxalate in renal stone formers. Br J Urol 1984;56(3):263-9. http://www.ncbi.nlm.nih.gov/pubmed/6544608 27. Curhan GC, Willett WC, Speizer FE, Spiegelman D, Stampfer MJ. Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Ann Intern Med. 1997;126(7):497-504. http://www.ncbi.nlm.nih.gov/pubmed/9092314 28. Borghi L, Schianchi T, Meschi T, Guerra A, Allegri F, Maggiore U, Novarini A. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria.N Engl J Med 2002;346(2):77-84. http://www.ncbi.nlm.nih.gov/pubmed/11784873 29. Coe FL. Hyperuricosuric calcium oxalate nephrolithiasis. Adv Exp Med Biol 1980;128:439-50. http://www.ncbi.nlm.nih.gov/pubmed/7424690 30. Pak CY, Holt K, Britton F, Peterson R, Crowther C, Ward D. Assessment of pathogenetic roles of uric acid, monopotassium urate, monoammonium urate and monosodium urate in hyperuricosuric calcium oxalate nephrolithiasis. Miner Electrolyte Metab 1980;4:130-6. 31. Hofbauer J, Zechner O. Impact of allopurinol treatment on the prevention of hyperuricosuric calcium oxalate lithiasis. Eur Urol 1988;15(3-4):227-9. http://www.ncbi.nlm.nih.gov/pubmed/3215256 32. Sarig S. The hyperuricosuric calcium oxalate stone former. Miner Electrolyte Metab 1987;13(4):251-6. http://www.ncbi.nlm.nih.gov/pubmed/3306317 33. Zechner O. Hyperuricosuric calcium oxalate lithiasis. In: Wickham JEA, Buck AC, eds. Renal Tract Stone. Churchill Livingstone: Edinburgh, 1990, pp. 285-293. 34. Ettinger B. Hyperuricosuric calcium stone disease. In: Coe FL, Favus MJ, Pak CYC, Parks JH, Preminger GM, eds. Kidney Stones: Medical and Surgical Management. Lippincott-Raven: Philadelphia, 1996, pp. 851-858. 35. Hesse A, Tiselius HG, Jahnen A. Urinary Stones: Diagnosis, Treatment and Prevention of Recurrence. In: Uric acid stones. New York: Karger, 1996, p. 88. 36. Siener R, Hesse A. The effect of different diets on urine composition and the risk of calcium oxalate crystallisation in healthy subjects. Eur Urol 2002;42(3):289-96. http://www.ncbi.nlm.nih.gov/pubmed/12234515 37. Tiselius HG, Ackermann D, Alken P, Buck C, Conort P, Gallucci M. Guidelines on urolithiasis. In: EAU Guidelines. Edition presented at the 16th EAU Congress, Geneva, Switzerland, 2001. ISBN 90-806179-3-9. Access date November 2008. http://www.uroweb.org/nc/professional-resources/guidelines/online/?no_cache=1&view=archive 38. Tiselius HG, Ackermann D, Alken P, Buck C, Conort P, Gallucci M. Guidelines on urolithiasis. In: EAU Guidelines. Edition presented at the 21st EAU Congress, Berlin, Germany, 2007. ISBN 978-90-7024459-0. Access date November 2008. http://www.uroweb.org/nc/professional-resources/guidelines/online/ 39. Tiselius HG. Epidemiology and medical management of stone disease. BJU Int 2003;91(8):758-67. http://www.ncbi.nlm.nih.gov/pubmed/12709088 40. Tiselius HG, Ackermann D, Alken P, Buck C, Conort P, Gallucci M; Working Party on Lithiasis, EuropeanAssociation of Urology. Guidelines on urolithiasis. Eur Urol 2001;40(4):362-71. http://www.ncbi.nlm.nih.gov/pubmed/11713390

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Tiselius HG and Advisory Board of European Urolithiasis Research and EAU Health Care Office Working Party for Lithiasis. Possibilities for preventing recurrent calcium stone formation: principles for the metabolic evaluation of patients with calcium stone disease. BJU Int 2001;88(2):158-68. http://www.ncbi.nlm.nih.gov/pubmed/11446874 42. Pak CYC. Comprehensive evaluation is not cost-effective for the work-up of calcium stone formers. In: AL Rodgers, BE Hibbert, B Hess, SR Khan, GM Preminger, eds. Urolithiasis. Cape Town: University of Cape Town, 2000, pp. 356-359. 43. Tiselius HG. Comprehensive metabolic evaluation of stone formers is cost effective. In: Urolithiasis. AL Rodgers, BE Hibbert, B Hess, SR Khan, GM Preminger (eds). Cape Town: University of Cape Town, 2000, pp. 349-355. 44. Constanzo LS, Windhager EE. Calcium and sodium transport by the distal convoluted tubule of the rat. Am J Physiol 1978;235(5):F492-F506. http://www.ncbi.nlm.nih.gov/pubmed/727266 45. Cohanim M, Yendt ER. Reduction of urinary oxalate during long-term thiazide therapy in patients with calcium urolithiasis. Invest Urol 1980;18(2):170-3. http://www.ncbi.nlm.nih.gov/pubmed/7410033 46. Ehrig U, Harrison JE, Wilson DR. Effect of long term thiazide therapy on intestinal calcium absorption in patients with recurrent renal calculi. Metabolism 1974;23(2):139-49. http://www.ncbi.nlm.nih.gov/pubmed/4810806 47. Zerwekh JE, Pak CY. Selective effects of thiazide therapy on serum 1 alpha, 25-dihydroxyvitamin D and intestinal calcium absorption in renal and absorptive hypercalciuras. Metabolism 1980;29(1):13-7. http://www.ncbi.nlm.nih.gov/pubmed/7351872 48. Yendt ER. Renal calculi. CMAJ 1970;102(5):479-89. http://www.ncbi.nlm.nih.gov/pubmed/5438766 49. Wolf H, Brocks P, Dahl C. Do thiazides prevent recurrent idiopathic renal calcium oxalate stones? Proc Eur Dial Transplant Assoc 1983;20:477-80. http://www.ncbi.nlm.nih.gov/pubmed/6361755 50. Scholz D, Schwille PO, Sigel A. Double-blind study with thiazide in recurrent calcium lithiasis. J Urol 1982;128(5):903-7. http://www.ncbi.nlm.nih.gov/pubmed/7176047 51. Laerum E, Larsen S. Thiazide prophylaxis of urolithiasis. A double-blind study in general practice. Acta Med Scand 1984;215(4):383-9. http://www.ncbi.nlm.nih.gov/pubmed/6375276 52. Wilson DR, Strauss AL, Manuel MA. Comparison of medical treatments for the prevention of recurrent calcium nephrolithiasis. Urol Res 1984;12:39-40. 53. Robertson WG, Peacock M, Selby PL, Williams RE, Clark P, Chisholm GD, Hargreaves TB, Rose MB, Wilkinson H. A multicentre trial to evaluate three treatments for recurrent idiopathic calcium stone disease–a preliminary report. In: Schwille PO, Smith LH, Robertson WG, Vahlensieck W, eds. Urolithiasis and Related Clinical Research. New York: Plenum Press, 1985, pp. 545-548. 54. Ettinger B, Citron JT, Livermore B, Dolman LI. Chlorthalidone reduces calcium oxalate calculous recurrences but magnesium hydroxide does not. J Urol 1988;139(4):679-84. http://www.ncbi.nlm.nih.gov/pubmed/3280829 55. Ohkawa M, Tokunaga S, Nakashima T, Orito M, Hisazumi H. Thiazide treatment for calcium urolithiasis in patients with idiopathic hypercalciuria. Br J Urol 1992;69(6):571-6. http://www.ncbi.nlm.nih.gov/pubmed/1638340 56. Borghi L, Meschi T, Guerra A, Novarini A. Randomized prospective study of a nonthiazide diuretic, indapamide, in preventing calcium stones recurrences. J Cardiovasc Pharmacol 1993;22(6):S78-S86. http://www.ncbi.nlm.nih.gov/pubmed/7508066 57. Ahlstrand C, Sandwall K, Tiselius HG. Prophylactic treatment of calcium stone formers with hydrochlorothiazide and magnesium. In: HG Tiselius, ed. Renal Stones–Aspects on Their Formation, Removal and Prevention. Proceedings of the Sixth European Symposium on Urolithiasis 1995. Edsbruk: Akademitryck AB, 1996, pp. 195-197. 58. Ala-Opas M, Elomaa I, Porkka L, Alfthan O. Unprocessed bran and intermittent thiazide therapy in prevention of recurrent urinary calcium stones. Scand J Urol Nephrol 1987;21(4):311-4. http://www.ncbi.nlm.nih.gov/pubmed/2832935 59. Coe FL, Kavalach AG. Hypercalciuria and hyperuricosuria in patients with calcium nephrolithiasis. New Eng J Med 1974;291(25):1344-50. http://www.ncbi.nlm.nih.gov/pubmed/4610395

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Birkenhäger JC, Juttman JR, Lockefeer JHM. Do thiazides prevent recurrent idiopathic renal calcium stones? Lancet 1981(8246);578-89. http://www.ncbi.nlm.nih.gov/pubmed/6116016 61. Ljunghall S, Backman U, Danielson BG, Fellström B, Johannson G, Wikström B. Long-term treatment with bendroflumethiazide for prevention of renal stones: clinical experiences. In: Urolithiasis Clinical and Basic Research. New York: Plenum Press, 1981, pp. 241-244. 62. Ahlstrand C, Tiselius HG, Larsson L, Hellgren E. Clinical experience with long-term bendroflumethiazide treatment in calcium oxalate stone formers. Br J Urol 1984;56(3):255-62. http://www.ncbi.nlm.nih.gov/pubmed/6399984 63. Marangella M, Vitale C, Bagnis C, Bruno M, Ramello A. Idiopathic calcium nephrolithiasis. Nephron 1999;81(Suppl 1):38-44. http://www.ncbi.nlm.nih.gov/pubmed/9873213 64. Pak CY, Peters P, Hurt G, Kadesky M, Fine M, Reisman D, Splann F Carmela C, Freeman A, Britton F, Sakhaee K, Breslau NA. Is selective therapy of recurrent nephrolithiasis possible? Am J Med 1981;71(4):615-22. http://www.ncbi.nlm.nih.gov/pubmed/7282750 65. Pearle MS, Roehrborn CG, Pak CY. Meta-analysis of randomized trials for medical prevention of calcium oxalate nephrolithiasis. J Endourol 1999;13(9):679-85. http://www.ncbi.nlm.nih.gov/pubmed/10608521 66. Nicar MJ, Peterson R, Pak CY. Use of potassium citrate as potassium supplement during thiazide therapy of calcium nephrolithiasis. J Urol 1984;131(3):430-3. http://www.ncbi.nlm.nih.gov/pubmed/6699979 67. Tiselius HG, Berg C, Fornander AM, Nilsson MA. Effects of citrate on the different phases of calcium oxalate crystallisation. Scanning Microsc 1993;7(1):381-9. http://www.ncbi.nlm.nih.gov/pubmed/8316807 68. Barcelo B, Wuhl O, Servitge E, Rousaud A, Pak CY. Randomized double-blind study of potassium citrate in idiopathic hypocitraturic calcium nephrolithiasis. J Urol 1993;150(6):1761-4. http://www.ncbi.nlm.nih.gov/pubmed/8230497 69. Tuncel A, Biri H, Küpeli B, Tan Ö, Sen I. Efficiency of long-term potassium citrate treatment in patients with idiopathic calcium oxalate stone disease. In: Sarica K, Kyagci F, Erbagci A and Inal Y, eds. Urolithiasis. Proceedings of the 2nd Eurolithiasis Society Meeting. Gaziantep, Turkey: ReTa, 2003, p. 273. 70. Hofbauer J, Höbarth K, Szabo N, Marberger M. Alkali citrate prophylaxis in idiopathic recurrent calcium oxalate urolithiasis–a prospective randomized study. Br J Urol 1994;73(4):362-5. http://www.ncbi.nlm.nih.gov/pubmed/8199822 71. Ettinger B, Pak CY, Citron JT, Thomas C, Adams-Huet B, Vangessel A. Potassium-magnesium citrate is an effective prophylaxis against recurrent calcium oxalate nephrolithiasis. J Urol 1997;158(6): 2069-73. http://www.ncbi.nlm.nih.gov/pubmed/9366314 72. Lee YH, Huang WC, Tsai JY, Huang JK. The efficacy of potassium citrate based medical prophylaxis for preventing upper urinary tract calculi: a midterm follow-up study. J Urol 1999;161(5):1453-7. http://www.ncbi.nlm.nih.gov/pubmed/10210371 73. Pak CY, Fuller C. Idiopathic hypocitraturic calcium-oxalate nephrolithiasis successfully treated with potassium citrate. Ann Int Med 1986;104(1):33-7. http://www.ncbi.nlm.nih.gov/pubmed/3940503 74. Pak CY, Peterson R. Successful treatment of hyperuricosuric calcium oxalate nephrolithiasis with potassium citrate. Arch Intern Med 1986;146(5):863-7. http://www.ncbi.nlm.nih.gov/pubmed/3963975 75. Preminger GM, Harvey JA, Pak CY. Comparative efficacy of ‘specific’ potassium citrate therapy versus conservative management in nephrolithiasis of mild to moderate severity. J Urol 1985;134(4):658-61. http://www.ncbi.nlm.nih.gov/pubmed/3897582 76. Whalley NA, Meyers AM, Martins M, Margolius LP. Long-term effects of potassium citrate therapy on the formation of new stones in groups of recurrent stone formers with hypocitraturia. Br J Urol 1996;78(1):10-4. http://www.ncbi.nlm.nih.gov/pubmed/8795392 77. Soygur T, Akbay A, Kupeli S. Effect of potassium citrate therapy on stone recurrence and residual fragments after shockwave lithotripsy in lower caliceal calcium oxalate urolithiasis: a randomized controlled trial. J Endourol 2002;16(3):149-52. http://www.ncbi.nlm.nih.gov/pubmed/12028622

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Berg C, Larsson L, Tiselius HG. The effects of a single evening dose of alkaline citrate on urine composition and calcium stone formation. J Urol 1992;148(3 Pt 2):979-85. http://www.ncbi.nlm.nih.gov/pubmed/1507355 79. Jendle-Bengten C, Tiselius HG. Long-term follow-up of stone formers treated with a low dose of sodium potassium citrate. Scand J Urol Nephrol 2000;34(1):36-41. http://www.ncbi.nlm.nih.gov/pubmed/10757268 80. Sakhaee K, Nicar M, Hill K, Pak CY. Contrasting effects of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stone-forming salts. Kidney Int 1983;24(3): 348-52. http://www.ncbi.nlm.nih.gov/pubmed/6645208 81. Tiselius HG. Stone incidence and prevention. Braz J Urol 2000;26:452-62. 82. Cicerello E, Merlo F, Gambaro G, Maccatrozzo L, Fandella A, Baggio B, Anselmo G. Effect of alkaline citrate therapy on clearance of residual renal stone fragments after extracorporeal shock wave lithotripsy in sterile calcium and infection nephrolithiasis patients. J Urol 1994;151(1):5-9. http://www.ncbi.nlm.nih.gov/pubmed/8254832 83. Fine JK, Pak CY, Preminger GM. Effect of medical management and residual fragments on recurrent stone formation following shock wave lithotripsy. J Urol 1995;153(1):27-32. http://www.ncbi.nlm.nih.gov/pubmed/7966783 84. Ettinger B. Recurrent nephrolithiasis: natural history and effect of phosphate therapy. A double-blind controlled study. Am J Med 1976;61(2):200-6. http://www.ncbi.nlm.nih.gov/pubmed/782240 85. Palmqvist E, Tiselius HG. Phosphate treatment of patients with renal calcium stone disease. Urol Int 1988;43(1):24-8. http://www.ncbi.nlm.nih.gov/pubmed/3376359 86. Tiselius HG, Sandvall K. How are urine composition and stone disease affected by therapeutic measures at an outpatient stone clinic? Eur Urol 1990;17(3):206-12. http://www.ncbi.nlm.nih.gov/pubmed/2351189 87. Smith LH, Werness PG, VanDenBerg CJ, Wilson DM. Orthophosphate treatment in calcium urolithiasis. Scand J Urol Nephrol Suppl 1980;53:253-63. http://www.ncbi.nlm.nih.gov/pubmed/6938002 88. Backman U, Danielson BG, Ljunghall S. In: Njursten–Etiologi, Utredning, Behandling. Malmö, Sweden: Ferrosan, 1983, pp. 169-173. [article in Swedish] [Stones - etiology, investigation and treatment] 89. Churchill DN. Medical treatment to prevent recurrent calcium urolithiasis. A guide to critical appraisal. Miner Electrolyte Metab 1987;13(4):294-304. http://www.ncbi.nlm.nih.gov/pubmed/3627054 90. Breslau NA, Heller HJ, Reza-Albarran AA, Pak CY. Physiological effects of a slow release potassium phosphate for absorptive hypercalciuria: a randomized double-blind trial. J Urol 1998;160(3 Pt 1): 664-8. http://www.ncbi.nlm.nih.gov/pubmed/9720517 91. Schwartz BF, Bruce J, Leslie S, Stoller ML. Rethinking the role of urinary magnesium in calcium urolithiasis. J Endourol 2001;15(3):233-5. http://www.ncbi.nlm.nih.gov/pubmed/11339386 92. Ettinger B, Citron JT, Livermore B, Dolman LI. Chlorthalidone reduces calcium oxalate calculous recurrence but magnesium hydroxide does not. J Urol 1988;139(4):679-84. http://www.ncbi.nlm.nih.gov/pubmed/3280829 93. Johansson G, Backman U, Danielson BG, Fellström B, Ljunghall S, Wikström B. Effects of magnesium hydroxide in renal stone disease. J Am Coll Nutr 1982;1(2):179-85. http://www.ncbi.nlm.nih.gov/pubmed/6764473 94. Prien EL Sr, Gershoff SF. Magnesium oxide - pyridoxine therapy for recurrent calcium oxalate calculi. J Urol 1974;112(4):509-12. http://www.ncbi.nlm.nih.gov/pubmed/4414543 95. Favus MJ, Coe FL. The effects of allopurinol treatment on stone formation in hyperuricosuric calcium oxalate stone-formers. Scand J Urol Nephrol 1980;53:265-71. http://www.ncbi.nlm.nih.gov/pubmed/6938003 96. Miano L, Petta S, Galatioto GP, Gullucci M. A placebo controlled double-blind study of allopurinol in severe recurrent idiopathic renal lithiasis. In: Schwille PO, Smith LH, Robertson WG, Vahlensieck W, eds. Urolithiasis and Related Clinical Research. New York: Plenum Press, 1985, pp. 521-524. 97. Tiselius HG, Larsson L, Hellgren E. Clinical results of allopurinol treatment in prevention of calcium oxalate stone formation. J Urol 1986;136(1):50-3. http://www.ncbi.nlm.nih.gov/pubmed/3712614

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Fellström B, Backman U, Danielson BG, Holmgren K, Johannson G, Lindsjo M, Ljunghall S, Wikström B. Allopurinol treatment of renal calcium stone disease. Br J Urol 1985;57(4):375-9. http://www.ncbi.nlm.nih.gov/pubmed/4027505 99. Coe FL, Raisen L. Allopurinol treatment of uric-acid disorders in calcium-stone formers. Lancet 1973;1(7795):129-31. http://www.ncbi.nlm.nih.gov/pubmed/4118468 100. Coe FL. Uric acid and calcium oxalate nephrolithiasis. Kidney Int 1983;24(3):392-403. http://www.ncbi.nlm.nih.gov/pubmed/6645213 101. Milliner DS, Eickholt JT, Bergstralh EJ, Wilson DM, Smith LH. Results of long-term treatment with orthophosphate and pyridoxine in patients with primary hyperoxaluria. N Engl J Med 1994;331(23):1553-8. http://www.ncbi.nlm.nih.gov/pubmed/7969325 102. Mitwalli A, Ayiomamitis A, Grass L, Oreopoulos DG. Control of hyperoxaluria with large doses of pyridoxine in patients with kidney stones. Int Urol Nephrol 1988;20(4):353-9. http://www.ncbi.nlm.nih.gov/pubmed/3170105 103. Takei K, Ito H, Masai M, Kotake T. Oral calcium supplement decreases urinary oxalate excretion in patients with enteric hyperoxaluria. Urol Int 1998;61(3):192-5. http://www.ncbi.nlm.nih.gov/pubmed/9933846 104. Lindsjö M, Fellström B, Ljunghall S, Wikström B, Danielson BG. Treatment of enteric hyperoxaluria with calcium-containing organic marine hydrocolloid. Lancet 1989;2(8665):701-4. http://www.ncbi.nlm.nih.gov/pubmed/2570957 105. Nordenvall B, Backman L, Burman P, Larsson L, Tiselius HG. Low-oxalate, low-fat dietary regimen in hyperoxaluria following jejunoileal bypass. Acta Chir Scand 1983;149(1):89-91. http://www.ncbi.nlm.nih.gov/pubmed/6837228 106. Kang DE, Maloney MM, Haleblian GE, Springhart WP, Honeycutt EF, Eisenstein EL, Marguet CG, Preminger GM. Effect of medical management on recurrent stone formation following percutaneous nephrolithotomy. J Urol 2007;177(5):1785-8; discussion 1788-9. http://www.ncbi.nlm.nih.gov/pubmed/17437820 107. Ahlstrand C, Sandvall K, Tiselius HG. Prophylactic treatment of calcium stone formers with hydrochlorothiazide and magnesium. In: Tiselius HG, ed. Renal Stones-Aspects on their Formation, Removal and Prevention. Proceedings of the Sixth European Symposium on Urolithiasis. Linköping: University Hospital, 1995, pp. 195-197. 108. Pak CY, Adams-Huet B, Poindexter JR, Pearle MS, Peterson RD, Moe OW. Rapid Communication: relative effect of urinary calcium and oxalate on saturation of calcium oxalate. Kidney Int 2004;66(5):2032-7. http://www.ncbi.nlm.nih.gov/pubmed/15496176 109. Preminger GM, Sakhaee, K, Skurla C, Pak CY. Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal renal tubular acidosis. J Urol 1985;134(1):20-3. http://www.ncbi.nlm.nih.gov/pubmed/4009822 110. Borghi L, Guerra A, Meschi T, Briganti A, Schianchi T, Allegri F, Novarini A. Relationship between supersaturation and calcium oxalate crystallization in normals and idiopathic calcium oxalate stone formers. Kidney Int 1999;55(3):1041-50. http://www.ncbi.nlm.nih.gov/pubmed/10027942

17.2

Medical treatment of patients with uric acid stone disease

Uric acid stones form in urine highly supersaturated with uric acid. The most common abnormality is a low urine pH often occurring with a small urine volume. These two abnormalities provide the basis for precipitation of uric acid, even in patients with a normal urate excretion. A typical example is the patient with ileostomy with loss of both alkali and fluid. The high excretion of urate seen in patients with disturbed purine metabolism can result in a critical supersaturation with reasonably normal pH and volume (1). 17.2.1 Drinking and dietary recommendations Fluid intake should be adjusted to allow for a 24-hour urine flow of approximately 2-2.5 L (2-5). The intake of animal protein should not exceed 0.8 g/kg /day (6-7). 17.2.2 Pharmacological treatment Alkalinization of urine is mandatory and should preferably be carried out with potassium citrate. The pH should be increased to a level above 6.5 and the general recommendation is to obtain a pH in the range 6.5-7.2 (2,3,5). The dose should be adjusted to obtain a pH in the range between 6.1 and 7.0 (3). There might be a risk of calcium phosphate stone formation if the pH is raised to higher levels, although such a complication seems

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to be less common than expected. Although both sodium bicarbonate and sodium citrate can be used to obtain an alkaline pH (1 g of sodium bicarbonate corresponds to 12 mmol and the recommended dose is 1 g x 3) the preferred agent is potassium citrate. This is because the solubility of potassium urate is greater than that of sodium urate (10, 11) and potassium does not increase the excretion of calcium. For further alkalinization, it has been suggested that acetazolamide or topiratmate might be considered (8, 9), but with this therapy the risk of calcium phosphate stones is more pronounced because of the simultaneous decrease in citrate excretion. A reduced excretion of urate is accomplished with allopurinol and this agent should be used when the 24-hour urate excretion exceeds 4 mmol (12). It is interesting to know that a combination of alkali, allopurinol and a high fluid intake can be used to dissolve uric acid stones. The pharmacological treatment of patients with uric stone disease is outlined in Table 29. Table 29: Pharmacological treatment of uric acid stone disease Objective Therapeutic measures Ref Prevention Urine dilution 2-5 A high fluid intake; 24-hour urine volume exceeding 2-2.5 L Alkalinization 8-11 Potassium citrate 3-7 mmol x 2-3 In patients with a high serum or urine level of urate 12 Allopurinol 300 mg x 1 Medical Urine dilution dissolution of A high fluid intake; 24-hour urine volume exceeding 2-2.5L uric acid Alkalinization 13,14 stones Potassium citrate 6-10 mmol x 2-3 Always reduce urate excretion Allopurinol 300 mg x 1 LE = level of evidence; GR = grade of recommendation

LE GR 3 B 2b

B

3

B

4 C 1b A 4 C

17.2.3 References 1. Tiselius HG. Aettiological factors in stone formation. In: Davison AM, Cameron JS, Grunfeld J-P, Kerr DN, Ritz E, Winearls CG, eds. Oxford Textbook of Clinical Nephrology. 3rd edn. Oxford: Oxford University Press, 2005, pp. 1201-1223. 2. Rodman JS, Sosa E, Lopez ML. Diagnosis and treatment of uric acid calculi. In: Coe FL, Favus MJ, Pak CYC, Parks JH, Preminger GM, eds. Kidney Stones. Medical and Surgical Management. Philadelphia: Lippincott-Raven, 1996, pp. 973-989. 3. Low RK, Stoller ML. Uric acid-related nephrolithiasis. Urol Clin North Am 1997;24(1):135-48. http://www.ncbi.nlm.nih.gov/pubmed/9048857 4. Shekarriz B, Stoller ML. Uric acid nephrolithiasis: current concepts and controversies. J Urol 2002;168(4 Pt 1):1307-14. http://www.ncbi.nlm.nih.gov/pubmed/12352383 5. Hesse A, Tiselius HG, Jahnen A. Urinary Stones: Diagnosis, Treatment and Prevention of Recurrence. Uric acid stones. Basel: Karger, 2002:73-91. 6. Cameron MA, Sakhaee K. Uric acid nephrolithiasis. Urol Clin North Am 2007;34(3):335-46. http://www.ncbi.nlm.nih.gov/pubmed/17678984 7. Food and Nitrition Board. 2002 Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein and Amino Acids. Washington DC: The National Academies Press, 2002, pp. 589-786. http://books.nap.edu/catalog/10490.html 8. Coe FL, Evan A, Worcester E. Kidney stone disease. J Clin Invest 2005;115(10):2598-608. http://www.ncbi.nlm.nih.gov/pubmed/16200192 9. Welch BJ, Graybeal D, Moe OW, Maalouf NM, Sakhaee K. Biochemical and stone-risk profiles with topiramate treatment. Am J Kidney Dis 2006;48(4):555-63. http://www.ncbi.nlm.nih.gov/pubmed/16997051 10. Pak CY, Waters O, Arnold L, Holt K, Cox C, Barolla D. Mechanism for calcium urolithiasis among patients with hyperuricosuria: supersaturation of urine with respect to monosodium urate. J Clin Invest 1977;59(3):426-31. http://www.ncbi.nlm.nih.gov/pubmed/14173

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11.

12.

13.

14.

17.3

Wilcox WR, Khalaf A, Weinberger A, Kippen I, Klinenberg JR. Solubility of uric acid and monosodium urate. Med Biol Eng 1972;10(4):522-31. http://www.ncbi.nlm.nih.gov/pubmed/5074854 Pak CY, Sakhaee K, Fuller C. Successful management of uric acid nephrolithiasis with potassium citrate. Kidney Int 1986;30(3):422-8. http://www.ncbi.nlm.nih.gov/pubmed/3784284 Mattle D, Hess B. Preventive treatment of nephrolithiasis with alkali citrate--a critical review. Urol Res 2005;33(2):73-9. http://www.ncbi.nlm.nih.gov/pubmed/15875173 Shekarriz B, Stoller ML. Uric acid nephrolithiasis: current concepts and controversies. J Urol 2002;168(4 Pt 1):1307-14. http://www.ncbi.nlm.nih.gov/pubmed/12352383

Medical treatment of cystine stone disease

17.3.1 Dietary recommendations Although a diet low in methionine theoretically might be of value for reducing urinary excretion of cystine, such a step is unlikely to result in reasonable compliance by the patient and this regimen is not usually used or recommended. A restricted intake of sodium is, however, probably more effective in reducing urinary cystine. The recommendation given is to avoid a daily consumption of sodium above 2 g (1). 17.3.2 Drinking advice A high diuresis is of fundamental importance. The aim is to dilute the urine so that supersaturation with cystine is decreased below the solubility product of cystine, or at least below its formation product. In general, the goal is a 24-hour urine volume of at least 3 L (2, 3). To reach this goal, a considerable fluid intake evenly distributed during the day is necessary. A more accurate recommendation of the size of urine volume needed can be obtained by knowing the ion-activity product of cystine, which can be calculated from the cystine concentration and the pH (4). 17.3.3 Pharmacological treatment The solubility of cystine increases in alkaline urine, but a substantial increment in solubility does not occur unless the pH is above 7.5. The rule of thumb is that the solubility of cystine is approximately 250 mg/L (1 mmol/L) at pH 7, 500 mg (2 mmol/L) at pH 7.5 and 750 mg (3 mmol/L) at pH 8 (2). To alkalinize the urine, potassium citrate is the best alternative. Sodium bicarbonate, sodium citrate or sodium potassium citrate should not be given because of the undesirable effect of sodium on the excretion of cystine (1). A typical dose of potassium citrate is 20-25 mmol per day given three times a day, but the required dose has to be determined by the effect this regimen has on urinary pH. The administration of acetazolamide can be used to improve the alkalinization (5). When the combined effects of a high diuresis and alkalinization are not enough to prevent stone formation, complex formation by chelating agents is necessary (2, 6, 7). Thiol compounds, such as D-penicillamine (8,9) and α-mercaptopropionyl glycine (tiopronin) (8-10), are most commonly used. The latter compound seems to be associated with fewer side effects than penicillamine. The recommended daily dosage is 10-15 mg/kg (or 750 mg/day), but the daily required dose might be in the range 250-2000 mg. For pencillamine, the daily dose is 1-2 g. A third alternative is captopril (an angiotensin-converting enzyme inhibitor). Positive effects on urinary cystine and stone formation have been reported with a daily dose of 75-100 mg (1, 11, 12). Administration of thiols always should be accompanied by pyridoxine to avoid vitamin B6-deficiency. The recommended dose is 50 mg/day. Patients who are treated with thiols should regularly be examined with analysis of blood haemoglobin, white blood cells and thromocytes. Moreover, the urine should be checked for proteinuria. The treatment of patients with cystine stone disease is outlined in Table 30. Table 30: Pharmacological treatment of patients with cystine stone disease Therapeutic measures Urine dilution A high fluid intake should be recommended so that the 24-h urine volume exceeds 3000 mL. To achieve this goal, the intake should be at least 150 ml/h Alkalinization For patients with a cystine excretion below 3 mmol/24h:

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References 1-3

LE GR 3 B

1-3

3

B

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Potassium citrate 3-10 mmol x 2-3 should be given to achieve a pH > 7.5 Complex formation with cystine For patients with a cystine excretion above 3 mmol/24 or when other 1-7 measures are insufficient Tiopronin (α-mercapto-propionyl glycine), 250-2000 mg/day or Captopril, 75-150 mg LE = level of evidence; GR = grade of recommendation

3

B

17.3.4 References 1. Ng CS, Streem SB. Contemporary management of cystinuria. J Endourol 1999;13(9):645-51. http://www.ncbi.nlm.nih.gov/pubmed/10608516 2. Biyani CS, Cartledge JJ. Cystinuria–Diagnosis and Management. EAU-EBU Update Series 4, issue 5. 2006:175-83. http://journals.elsevierhealth.com/periodicals/eeus/issues/contents 3. Dent CE, Senior B. Studies on the treatment of cystinuria. Br J Urol 1955;27(4):317-32. http://www.ncbi.nlm.nih.gov/pubmed/13276628 4. Tiselius HG. Solution chemistry of supersaturation. In: Coe FL, Favus MJ, Pak CYC, Parks HG, Preminger GM, eds. Kidney Stones: Medical and Surgical Management. Philadelphia: LippincottRaven, 1996, pp. 33-64. 5. Freed SZ. The alternating use of an alkalizing salt and acetazolamide in the management of cystine and uric acid stones. J Urol 1975;113(1):96-9. http://www.ncbi.nlm.nih.gov/pubmed/1113405 6. Rogers A, Kalakish S, Desai RA, Assimos DG. Management of cystinuria. Urol Clin North Am 2007;34(3):347-62. http://www.ncbi.nlm.nih.gov/pubmed/17678985 7. Chow GK, Streem SB. Contemporary urological intervention for cystinuric patients: immediate and long-term impact and implications. J Urol 1998;160(2):341-4. http://www.ncbi.nlm.nih.gov/pubmed/9679873 8. Crawhall JC, Scowen EF, Watts RW. Effect of penicillamine on cystinuria. BMJ 1963;1(5330):588-90. http://www.ncbi.nlm.nih.gov/pubmed/14023737 9. Halperin EC, Their SO, Rosenberg LE. The use of D-penicillamine in cystinuria: efficacy and untoward reactions. Yale J Biol Med 1981;54(6):439-46. http://www.ncbi.nlm.nih.gov/pubmed/7342491 10. Barbey F, Joly D, Rieu P, Méjean A, Daudon M, Jungers P. Medical treatment of cystinuria: critical reappraisal of long-term results. J Urol 2000;163(5):1419-23. http://www.ncbi.nlm.nih.gov/pubmed/10751848 11. Streem SB, Hall P. Effect of captopril on urinary cystine excretion in homozygous cystinuria. J Urol 1989;142(6):1522-4. http://www.ncbi.nlm.nih.gov/pubmed/2685368 12. Akakura K, Egoshi K, Ueda T, Nozumi K, Kotake T, Masai M, Ito H. The long-term outcome of cystinuria in Japan. Urol Int 1998;61(2):86-9. http://www.ncbi.nlm.nih.gov/pubmed/9873246

17.4

Management of patients with infection stones

17.4.1 Pharmacological treatment of infection stone disease The pharmacological treatment of patients with infection stone disease is outlined in Table 31. The definition of infection stones is stones composed of magnesium ammonium phosphate and carbonate apatite. These stones are caused by urease-producing micro-organisms. It is fundamental that the renal collecting system is cleared of stone material to prevent recurrence in patients with infection stone disease. It is fundamental that the renal collecting system is cleared from stone material. LE = 3 GR = C

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Table 31: Pharmacological treatment of infection stone disease Therapeutic measures References Stone removal 1 Surgical removal of the stone material as completely as possible Antibiotic treatment Short-term antibiotic course 2 Long-term antibiotic course Acidification Ammonium chloride 1 g x 2-3 4 Methionine 500 mg 1-2 x 3 3 Urease inhibition 5, 6 In very selected cases with severe infections, treatment with acetohydroxamic acid (Lithostat) might be a therapeutic option LE = level of evidence; GR = grade of recommendation

LE GR 4 C

3 3

B B

3 B 3 B 1b A

17.4.2 References 1. Wilson DM. Clinical and laboratory approaches for evaluation of nephrolithiasis. J Urol 1989;141(3 Pt 2):770-4. http://www.ncbi.nlm.nih.gov/pubmed/2918617 2. Wong HY, Riedl CR, Griffith DP. Medical management and prevention of struvite stones. In: Coe FL, Favus MJ, Pak CYC, Parks JH, Preminger GM, eds. Kidney Stones: Medical and Surgical Management. Philadelphia: Lippincott-Raven, 1996, pp. 941-50. 3. Jarrar K, Boedeker RH, Weidner W. Struvite stones: long term follow up under metaphylaxis. Ann Urol (Paris) 1996;30(3):112-17. http://www.ncbi.nlm.nih.gov/pubmed/8766146 4. Wall I, Tiselius HG. Long-term acidification of urine in patients treated for infected renal stones. Urol Int 1990;45(6):336-41. http://www.ncbi.nlm.nih.gov/pubmed/2288050 5. Griffith DP, Gleeson MJ, Lee H, Longuet R, Deman E, Earle N. Randomized double-blind trial of Lithostat (acetohydroxamic acid) in the palliative treatment of infection induced urinary calculi. Eur Urol 1991;20(3):243-7. http://www.ncbi.nlm.nih.gov/pubmed/1726639 6. Williams JJ, Rodman JS, Peterson CM. A randomized double blind study of acetohydroxamic acid in struvite nephrolithiasis.N Engl J Med 1984;311(12):760-4. http://www.ncbi.nlm.nih.gov/pubmed/6472365

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18. ABBREVIATIONS USED IN THE TEXT

This list is not comprehensive for the most common abbreviations

APCaOx ion-activity product of calcium oxalate APCaP ion-activity product of calcium phosphate AP(CaOx) index approximate estimate of APCaOx AP(CaP) index approximate estimate of APCaP AUA American Urological Association Ca calcium CaHPO42H2O calcium hydrogen phosphate CaOx calcium oxalate CaP calcium phosphate CI confidence interval CIs credible intervals CIRF clinically insignificant residual fragments Cit citrate CT computed tomography CY cystine stone EAU European Association of Urology EHL electrohydraulic lithotripsy ESWL extracorporeal shock-wave lithotripsy, also including piezolithotripsy GFR glomerular filtration rate GR grade of recommendation HCl hydrochloric acid Ho:YAG holmium:yttrium aluminium garnet INF infection stone IVP intravenous pyelography IVU Intravenous urography KUB plain abdominal film of the kidneys, ureters and bladder LE level of evidence l length (of stone) MET medical expulsive therapy Mg magnesium MREU MR excretory urography MRU Magnetic resonance urography Nd: YAG frequency doubled laser NH4Cl ammonium chloride NSAID non-steroidal anti-inflammatory drug Ox oxalate PNL percutaneous nephrolithotomy with or without lithotripsy RIRS retrograde intrarenal surgery Rmo recurrent stone former with mild disease and without residual stone(s) or stone fragments Rm-res recurrent stone former with mild disease with residual stone(s) or stone fragments Rs recurrent stone former with severe disease with or without residual stone(s) or fragments or with specific risk factors irrespective of otherwise defined category RTA renal tubular acidosis SA stone surface area So first time stone former without residual stone or stone fragments Sres first time stone former with residual stone or stone fragments SWL shock-wave lithotripsy THAM trihydroxymethyl aminomethan UR uric acid/sodium urate/ammonium urate stone URS ureteroscopy US ultrasonography UTI urinary tract infection V urine volume w width (of stone)

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19. APPENDICES APPENDIX 1: Devices for endoscopic disintegration of stones BALLISTIC LITHOTRIPSY Ballistic lithotripsy involves a device in which alternating compression caused by air or electromechanical forces is transmitted to a metal rod. Pulses drive a metallic bullet that bumps the end of the rod against the stone. Rods are 2.4-6 F in diameter and can be used through a semi-rigid ureteroscope and all rigid endoscopes. A similar effect is obtained by alternating mechanical displacement. ULTRASONIC LITHOTRIPSY These commercially available units consist of a power generator, an US transducer and a probe, forming the sonotrode. A piezoceramic element in the handle of the sonotrode is stimulated to resonate, and this converts electrical energy into US waves (at a frequency of 23,000- 27,000 Hz). The US waves are transmitted along the hollow metal probe to create a vibrating action at its tip. When the vibrating tip is brought into contact with the surface of a stone, the calculus can be disintegrated. The probes, which are available in sizes 10 F and 12 F, are passed through the straight working channel of a rigid ureteroscope or nephroscope. Suction tubing can be connected to the end of the sonotrode. ELECTROHYDRAULIC LITHOTRIPSY The electrohydraulic lithotripsy (EHL) unit has a probe, a power generator and a foot pedal. The probe consists of a central metal core and two layers of insulation with another metal layer between them. Probes are flexible and available in many sizes for use in rigid and flexible nephroscopes. The electrical discharge is transmitted to the probe where it generates a spark at the tip. The intense heat produced in the immediate area surrounding the tip results in a cavitation bubble, which produces a shock wave that radiates spherically in all directions. EHL will effectively fragment all kinds of urinary stones, including very hard stones composed of cystine, uric acid and calcium oxalate monohydrate. Recently, a 1.6 F EHL probe was developed. It has been quite successful in fragmenting ureteral and intrarenal stones. It has superior flexibility compared to the laser fibre. LASER LITHOTRIPSY Today, neodymium:yttrium-aluminium-garnet (Nd:YAG) or holmium:YAG (Ho:YAG) lasers are used as sources for laser lithotripsy units. The reported results indicate that the Ho:YAG efficacy is superior to the Nd:YAG and does effectively fragment all types of urinary stones, wherever they are located and whatever their composition, including cystine stones. The Ho:YAG system produces light of 2100 nm, with a tissue penetration of less than 0.5 mm and complete absorption in water. The Nd:YAG is used frequency-doubled and produces light of 1064 nm, with a tissue penetration of 4 mm. Fibres for ureteroscopy are available for both lasers at 200 and 365 µm in diameter. In combination with the actively deflectable, flexible ureteroscope, the Ho:YAG laser has proven to be ideally suited for fragmenting stones in the upper ureter. Potential complications of the Ho:YAG laser when used to fragment ureteral stones include possible perforation of the ureteral wall and consecutive formation of strictures.

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14

16

19

21

24

26

28

31

33

35

38

40

42

45

47

49

52

54

6 4.7 9.4

7 5.5 11.0

8 6.3 12.6

9 7.1 14.1

10 7.9 15.7

11 8.6 17.3

12 9.4 18.8

13 10.2 20.4

14 11.0 22.0

15 11.8 23.6

16 12.6 25.1

27

18 14.1 28.3

30

17 13.3

19 14.9

20 15.7 31.4

21 16.5 33.0

22 17.3 34.5

23 18.1 36.1





































57

16

12

5 3.9 7.9



24 18.8 37.7

13

4 3.1 6.3 9.4





9

3 2.4 4.7 7.1



75

72

69

66

63

60

57

53

50

47

44

41

38

35

31

28

25

22

19

6

2 1.6 3.1 4.7

4



3

3

2

1 0.8 1.6 2.4

1

Width mm

Length mm

92

82

71

61

51

41

31

20

10

13

88

75

63

50

38

25

13

16

93

80

67

53

40

27

13

17

89

75

60

45

30

15

19

94

79

63

47

31

16

20

86

69

52

35

17

22

90

72

54

36

18

23

94

75

57

38

19

24

98

79

59

39

20

25

99 104 108 113 118

82

66

49

33

16

21

99 104 110 115 121 126 132 137

85

71

57

42

28

14

18

94 100 107 113 119 126 132 138 144 151 157

82

71

59

47

35

24

12

15

99 106 113 120 127 134 141 148 155 162 170 177

88

77

66

55

44

33

22

11

14

94 102 110 118 126 133 141 149 157 165 173 181 188 196

85

75

66

57

47

38

28

19

9

12

95 104 112 121 130 138 147 155 164 173 181 190 199 207 216

86

78

69

60

52

43

35

26

17

9

11

94 104 113 122 132 141 151 160 170 179 188 198 207 217 226 236

86

79

71

63

55

47

39

31

24

16

8

10

99 110 121 132 143 154 165 176 187 198 209 220 231 242 253 264 275

92 102 112 122 133 143 153 163 173 184 194 204 214 225 235 245 255

85

78

71

64

57

49

42

35

28

21

14

7

9

94 106 118 130 141 153 165 177 188 200 212 224 236 247 259 271 283 294

88

82

75

69

63

57

50

44

38

31

25

19

13

6

8

99 113 127 141 155 170 184 198 212 226 240 254 268 283 297 311 325 339 353

93 107 120 133 147 160 173 187 200 214 227 240 254 267 280 294 307 320 334

88 100 113 126 138 151 163 176 188 201 214 226 239 251 264 276 289 301 314

82

77

71

66

60

55

49

44

38

33

27

22

16

11

5

7

99 115 132 148 165 181 198 214 231 247 264 280 297 313 330 346 363 379 396 412

94 110 126 141 157 173 188 204 220 236 251 267 283 298 314 330 345 361 377 393

89 104 119 134 149 164 179 194 209 224 239 254 268 283 298 313 328 343 358 373

85

80

75

71

66

61

57

52

47

42

38

33

28

24

19

14

9

5

6

94 113 132 151 170 188 207 226 245 264 283 301 320 339 358 377 396 414 433 452 471

90 108 126 144 162 181 199 217 235 253 271 289 307 325 343 361 379 397 415 433 451

86 104 121 138 155 173 190 207 225 242 259 276 294 311 328 345 363 380 397 414 432

82

79

75

71

67

63

59

55

51

47

43

39

35

31

27

24

20

16

12

8

4

5

APPENDIX 2: Approximate stone surface area with known diameters of the stone

An approximate estimate of the stone surface area (mm2) can be extracted from the length and width on the KUB. The calculated surface area for any combination of stone diameters up to 25 mm is shown in Table A1.

Table A1: Approximate stone surface area (mm2) calculated from the length and width of the stone

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Conflict of interest All members of the Urolithiasis Guidelines writing panel have provided disclosure statements on all relationships that they have and that might be perceived to be a potential source of conflict of interest. This information is kept on file in the European Association of Urology Central Office database. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

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Guidelines on

Renal Transplantation T. Kälble, A. Alcaraz, K. Budde, U. Humke, G. Karam, M. Lucan, G. Nicita, C. Süsal

© European Association of Urology 2009

TABLE OF CONTENTS 1.

page

INTRODUCTION 1.1 Reference

6 6

2. KIDNEY DONATION 2.1 Ethical issues in transplantation 2.1.1 Primary ethical principles 2.1.1.1 Beneficence: doing good, avoiding harm, autonomy, fairness 2.1.2 Deceased donor organ donation 2.1.2.1 Deceased organ donor 2.1.2.2 Allocation of deceased donor organs 2.1.3 Living-organ donors 2.1.4 References 2.2 Policies to increase the supply and use of deceased donors 2.2.1 Donor cards 2.2.2 Improved organisation and resources 2.2.3 ‘Opting-out’ legislation 2.2.4 Non-heart-beating donor (NHBD) 2.2.5 Elderly donors 2.2.6 References 2.3 Policies to enhance living donation 2.3.1 Medical methods to increase the number of living donations 2.3.1.1 Acceptance of grafts with anatomical anomalies 2.3.1.2 Laparoscopic living-donor nephrectomy (LLDN) 2.3.1.3 References 2.3.1.4 ABO-incompatible donors 2.3.1.5 Cross-match-positive living-donor kidney transplants 2.3.1.6 Living unrelated kidney donation 2.3.1.7 ‘Non-directed‘ living-donor transplantation 2.3.1.8 Payment to living donors from a central organisation 2.3.1.9 References 2.3.2 Ethical ways of showing appreciation for organ donation 2.3.2.1 Donor ‘medal of honour’ 2.3.3 Organisational ways to encourage organ donation 2.3.3.1 Cross-over transplantation or paired kidney exchange 2.3.3.2 Medical leave for organ donation 2.3.4 References 2.4 Kidney donor selection and refusal criteria 2.4.1 Introduction 2.4.2 Infections 2.4.3 Special exceptions for infections 2.4.4 Malignant tumours 2.4.5 Special exceptions for malignant tumours 2.4.6 Vascular conditions and renal function 2.4.7 Marginal donors 2.4.8 One graft or two grafts per recipient 2.4.9 References 2.5 Explantation technique 2.5.1 Technique of deceased donor organ recovery 2.5.2 The living donor 2.5.2.1 Evaluation 2.5.2.2 Choice of kidney 2.5.2.3 Pre-operative management 2.5.2.4 Surgical alternatives in live-donor nephrectomy 2.5.2.5 Post-operative care 2.5.3 References 2.6 Organ preservation 2.6.1 Kidney storage solutions 2.6.2 Methods of kidney preservation

2

7 7 7 7 7 7 7 7 8 9 9 10 10 10 11 11 11 12 12 13 13 14 14 15 15 15 15 17 17 17 17 17 17 18 18 18 19 19 19 19 20 20 21 22 22 23 23 24 24 24 25 26 28 28 28

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2.6.3 2.6.4

Duration of organ preservation References

29 29

3. KIDNEY RECIPIENT 3.1 Pre-transplant therapy 3.1.1 Abnormal urogenital tract 3.1.2 Urinary diversion 3.1.3 Indications for pre-transplant nephrectomy 3.1.4 References 3.2 Selection and refusal criteria 3.2.1 Contraindications 3.2.1.1 Malignancy 3.2.1.2 Infection 3.2.1.3 Other contraindications for transplantation 3.2.2 Co-morbidity 3.2.2.1 Cardiac disease 3.2.2.2 Peripheral artery disease, cerebral occlusive vascular disease 3.2.2.3 Diabetes mellitus 3.2.2.4 Obesity 3.2.2.5 Coagulopathies 3.2.2.6 Other diseases with potential influence on post-transplant outcome 3.2.3 Age 3.2.4 Recurrence risk (original renal disease) 3.2.5 Patients with a previous transplant 3.2.6 References 3.3 Transplantation in pregnancy 3.3.1 Planning pregnancy 3.3.2 Graft survival 3.3.3 Care during pregnancy 3.3.4 Immunosuppressive treatment 3.3.5 Follow-up 3.3.6 References

29 30 30 30 30 31 32 32 32 32 33 33 33 33 34 34 34 35 35 35 36 36 41 41 41 41 42 42 42

4. TRANSPLANTATION TECHNIQUES 4.1 Transplant preparation and transplant techniques in adults 4.2 Early complications 4.2.1 General complications 4.2.1.1 Wall abscesses 4.2.1.2 Haemorrhage 4.2.1.3 Haematuria 4.2.1.4 Incisional hernia 4.2.2 Urinary fistulae 4.2.2.1 Management 4.2.3 Arterial thrombosis 4.2.3.1 Treatment 4.2.4 Venous thrombosis 4.3 Late complications 4.3.1 Ureteral stenosis 4.3.2 Reflux and acute pyelonephritis 4.3.3 Kidney stones 4.3.4 Renal artery stenosis 4.3.5 Arterio-venous fistulae and Pseudo aneurysms after renal biopsy 4.3.6 Lymphocele 4.4. References 4.5 Kidney transplantation in abnormal urinary tract 4.5.1 References

43 43 45 45 45 45 45 45 45 45 45 46 46 46 46 46 47 47 47 47 48 51 52

5. MATCHING OF DONORS AND RECIPIENTS 5.1 Histocompatibility (HLA) matching 5.1.1 Practical aspects of HLA-testing

52 52 52

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3

5.2 5.3 5.4 5.5

Cross-matching Pre-existing HLA-specific antibodies 5.3.1 Eurotransplant Acceptable Mismatch (AM) programme ABO compatibility References

53 53 54 54 54

6. IMMUNOSUPPRESSION AFTER KIDNEY TRANSPLANTATION 6.1 Introduction 6.2 Primary immunosuppressive phrophylaxis 6.2.1 Calcineurin-inhibitors (CNIs) 6.2.1.1 Cyclosporine A 6.2.1.2 Tacrolimus 6.2.1.3 Summary 6.2.2 Mycophenolates 6.2.3 Azathioprine 6.2.4 Steroids 6.2.5 Inhibitors of the mammalian target of rapamycin (m-TOR) 6.2.5.1 Side-effects 6.2.5.2 Comparison of pharmokinetics and licensed use 6.2.5.3 Conversion from CNIs to m-TOR inhibitors 6.2.6 T-cell depleting induction therapy 6.2.7 Interleukin-2 receptor antibodies 6.2.8 References

55 55 55 55 55 56 56 57 58 58 58 58 59 59 59 60 60

7. IMMUNOLOGICAL COMPLICATIONS 7.1 Introduction 7.2 Hyper-acute rejection (HAR) 7.2.1 Prevention 7.3 Acute allograft rejection 7.3.1 Treatment of T-cell mediated acute rejection 7.3.2 Treatment of acute humoral rejection (AHR) 7.4 Chronic allograft dysfunction (interstitial fibrosis and tubular atrophy [IF/TA]) 7.4.1 Diagnosis and treatment 7.5 References

65 65 66 67 67 68 68 69 69 69

8. MALIGNANCY 8.1 Transmission of a donor neoplasia to the recipient 8.2 Prior malignancy in the recipient 8.3 ‘De-novo’ tumour in the recipient 8.3.1 Skin cancer and Kaposi’s sarcoma 8.3.2 Lymphatic disease 8.3.3 Gynaecological cancers 8.3.4 Prostate cancer 8.3.5 Bowel cancer 8.3.6 Urothelial tumours 8.3.7 Renal tumours 8.3.8 Chest X-ray 8.4 References

72 72 73 74 74 74 75 75 75 75 75 75 76

9

78 78 78

ANNUAL SCREENING 9.1 Recommendations for annual screening 9.2 References

10. GRAFT AND PATIENT SURVIVAL 10.1 Deceased and living donors 10.1.1 Graft survival 10.1.2 Patient survival 10.2 Age of donor and recipient 10.2.1 Donor’s age 10.2.2 Recipient’s age

4

78 79 79 81 82 82 82

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10.3 10.4 10.5 10.6 10.7 10.8

HLA-matching Immunosuppresion Number of transplantations Cold ischaemia time Time on dialysis References

11

ABBREVIATIONS USED IN THE TEXT

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82 83 84 85 86 86 88

5

1. INTRODUCTION Most renal transplantation centres in Europe were founded by urologists. However, many of them are becoming part of transplant centres run by general transplant surgeons. This is a main reason why it is important to present current knowledge about renal transplantation in these European Association of Urology (EAU) guidelines. As renal transplantation is very much an interdisciplinary field, the Guidelines Group contains not only urologists but also an immunologist (Prof. Dr. Süsal) and a nephrologist (Prof. Dr. Budde). Besides medical and technical aspects, the Guidelines Group has also considered ethical, social and political aspects. This was necessary because of the still-increasing gap between ‘supply’ and ‘demand’ for kidney transplants, and the large differences in organ donation rates between several European countries, suggesting European countries can learn from each other on how to increase organ donation rates. There are few prospective randomised studies for most sections of the Guidelines, and sometimes none. Thus, the grades of recommendation, which are evidence-based, seldom exceed grade C. Instead, the Guidelines are well supported by a wealth of clinical experience based on several decades of work in renal transplantation, as in, for example, technical aspects of transplantation and explantation. A level of evidence (LE) and/or grade of recommendation (GR) have been assigned where possible (1). The aim of grading recommendations is to provide transparency between the underlying evidence and the recommendation given. Publication history information: The Renal Transplantation Guidelines were first published in 2003, with a partial update in 2004 followed by this full text update in 2009. Additionally, a quick reference guide is available. All texts can be viewed and downloaded for personal use at the society website: http://www.uroweb.org/professional-resources/ guidelines/. Levels of evidence and grade of guideline recommendations* Table 1: Level of evidence Level Type of evidence 1a Evidence obtained from meta-analysis of randomised trials 1b Evidence obtained from at least one randomised trial 2a Evidence obtained from one well-designed controlled study without randomisation 2b Evidence obtained from at least one other type of well-designed quasi-experimental study 3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case reports 4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities Table 2: Grade of recommendation Grade Nature of recommendations A Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomised trial B Based on well-conducted clinical studies, but without randomised clinical trials C Made despite the absence of directly applicable clinical studies of good quality *modified from Sackett et al. (1)

1.1

REFERENCE

1.

Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998. http://www.cebm.net/index.aspx?o=1025 [accessed February 2009].

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2. KIDNEY DONATION 2.1

Ethical issues in transplantation

2.1.1 Primary ethical principles A number of primary principles are widely accepted as forming the bedrock of medical ethics (1-4). Conflict in an individual case often arises in trying to adhere to all these principles at the same time. 2.1.1.1 Beneficence: doing good, avoiding harm, autonomy, fairness A central tenet of medical ethics is the obligation to strive at all times to do good for the patient. Although no physical good will accrue to a donor, it is generally accepted that the psychosocial benefits to the living donor justify the risks involved (5). Making sure there is an appropriate balance between benefit and harm is an important clinical judgement. A high standard of donor assessment and risk limitation is therefore of paramount importance before living kidney donation can take place (6). Individuals are said to have ‘decision-making capacity’ if they able to understand relevant information, consider its implications, and come to a communicable decision. A donor’s decision to donate should be respected. The principle of justice is very important in kidney distribution, where demand far outstrips supply, which means there is a ranking system for allocating organs in an order of priority that can be morally justified. In transplantation, scarce resources usually have to be carefully allocated to recipients chosen from a larger pool of the population. 2.1.2 Deceased donor organ donation There has been an increase in living-donor organ procurement in recent years. Most organs still come from deceased donors, brain-dead donors, and organs from the non-heart beating donor (NHBD) procurement programme, now used by several transplant centres. However, this resource base is shrinking. Together with an ever-increasing rise in potential recipients, this causes considerable pressure on the transplantation programme. 2.1.2.1 Deceased organ donor In most countries, obtaining consent to proceed with organ donation is a major challenge. The process of gaining formal consent from relatives or from the patient during life can be defined as ‘opting in’ to a donor scheme. Unless consent is expressly given, the presumption is that consent is withheld. In some European countries, the opposite situation applies. Consent is presumed unless the patient has specifically opted out before death. This type of legislation can increase organ donation. For example, in Spain, this approach has produced a national network of medical teams dedicated to obtaining the maximum number of donors and greatly increasing organ transplantation (7). 2.1.2.2 Allocation of deceased donor organs Who ‘owns’ deceased donor organs and who makes the decision regarding allocation are both issues in need of clarification (8-10). However, there is a general presumption that the State holds the responsibility for allocation or disposal of donated organs, which is then delegated to the appropriate transplant team (11). It is considered unacceptable that deceased donor donation and allocation should depend upon the personal attributes of the recipient, e.g. race, religion or wealth. In kidney transplantation, the European healthcare systems attempt to maximise benefits by distributing kidneys on the basis of (HLA) matching. Potential recipients are allocated points for waiting time, matchability and sensitisation. Kidney distribution systems should be transparent and regularly audited. 2.1.3 Living-organ donors The ethical approach to organ donation is guided mainly by those rules that seek to be charitable. Living-donor transplant has been regarded as a regrettable necessity because of the success of living-donor transplant (as judged by graft and patient survival) and the scarcity of deceased donor organs (12). The chronic shortage of deceased donor organs has led to a more general acceptance of living-donor transplants. The physical and psychosocial well-being of the donor are of primary importance. Each donor should have an advocate (i.e. a psychiatrist and nephrologist from the donor evaluation team) to provide unbiased advice on the donation process and there should be separation of the recipient and donor teams.

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Kidneys can be accepted from related and unrelated donors, including spouses, friends, and acquaintances or altruistic donors (anonymous donors) or paired kidney donation (see Section 2.3.3.1). The donor must be given a psychosocial evaluation by a mental health professional, who has no relationship with the recipient, to assess the donor’s ability to make his or her decision. The donor’s confidentiality must be protected and the evaluation must be carried out in the absence of the recipient. If a translator is necessary, the translator must be unknown to both the recipient and donor. The donor should be told about the benefits to the recipient’s health (physical and mental) and the risks to the donor’s health (physical and mental). The donor’s motivation should be assessed. Coercion and secondary gain (monetary or other personal gain) should be excluded. Outcomes should be discussed, psychological benefits after a successful transplantation (increased self-esteem) and resentment or depression after an unsuccessful transplantation. Recommendations • It is the right of individuals to donate as well as to receive an organ • Commercially motivated renal transplantation is unacceptable. It has been widely prohibited by law and is strongly opposed by the International Society of Transplantation • With the increasing success of living-donor transplants, as judged by graft and patient survival, and with the scarcity of deceased donor organs, living-donor transplants should be encouraged. The appeal of using living donors in renal transplantation is partly due to the ongoing shortage of deceased donors • The altruistic living donor must give informed consent, which can only be obtained if he or she has a proper understanding of the risk involved • A patient should be treated as an ‘end’, and not as a ‘means’. Respect for dignity, integrity and authenticity of the person are basic human rights • Living unrelated donors should only be accepted after the local ethical committee has given permission according to the rules of the country in which the donation is taking place Because ethical values cannot be measured using the ‘scientific’ basis of levels of evidence, grades of recommendation are not given 2.1.4 1. 2. 3. 4. 5.

6.

7.

8. 9.

10.

11. 12.

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References Gillon R (ed). Philosophical medical ethics. Chichester: John Wiley, 1993. Bierce A. The enlarged devil’s dictionary. London: Penguin, 1990. Boyd KM, Higgs R, Pinching AJ, eds. The new dictionary of medical ethics. London: BMJ Publishing, 1997. General Medical Council. Good medical practice. 2nd edn. London: GMC, 1998. de Graaf Olson W, Bogett-Dumlao A. Living donors’ perception of their quality of health after donation. Prog Transplant 2001;11(2):108-15. http://www.ncbi.nlm.nih.gov/pubmed/11871045 Reimer J, Rensing A, Haasen C, Philipp T, Pietruck F, Franke GH. The impact of living-related kidney transplantation on the donor’s life. Transplantation 2006;81(9):1259-60. http://www.ncbi.nlm.nih.gov/pubmed/16699453 Matesanz R, Miranda B. A decade of continuous improvement in cadaveric organ donation: the Spanish model. J Nephrol 2002;15(1):22-8. http://www.ncbi.nlm.nih.gov/pubmed/11936422 Andrews LB. My body, my property. Hastings Cent Rep 1986;16(5):28-38. http://www.ncbi.nlm.nih.gov/pubmed/3771198 Kreis H. The question of organ procurement: beyond charity. Nephrol Dial Transplant 2005;20(7): 1303-6. http://www.ncbi.nlm.nih.gov/pubmed/15919689 Spital AA, Taylor JS. Routine recovery of cadaveric organs for transplantation: consistent, fair, and life-saving. Clin J Am Soc Nephrol 2007;2(2):300-3. http://www.ncbi.nlm.nih.gov/pubmed/17699428 Dossetor JB. Ethics in Transplantation. In: Morris P Jr (ed). Kidney transplantation. 4th edn. Philadelphia: WB Saunders, 1994, pp 524-531. Sells RA, Johnson R, Hutchinson I. Recommendations on the use of living kidney donors in the United Kingdom. British Transplantation Society. Br Med J (Clin Res Ed) 1986;293(6541):257-8. http://www.ncbi.nlm.nih.gov/pubmed/3089478

Update march 2009

2.2 Policies to increase the supply and use of deceased donors Generally, the gap between supply and demand of kidneys has tended to stabilise in countries with a donation rate greater than 40 kidneys per million population (pmp), but has increased in countries with a lower donation rate. This is in spite of the trend for donation rates to increase (or stabilise) in Europe since 2001. Table 3 lists recent kidney transplant rates in different European countries (1). Table 3: Kidney transplant rates in 2007 (1) Country Austria (ET)* Belgium (ET)* Bulgaria Croatia (ET)* Cyprus Czech Republic Denmark (ST)** Estonia Finland (ST)** France Georgia Germany (ET)* Greece Hungary Iceland (ST)** Ireland Italy Latvia Lithuania Luxembourg (ET)* Malta Moldova Netherlands (ET)* Norway (ST)** Poland Portugal Romania Slovak Republic Slovenia (ET)* Spain Sweden (ST)** Switzerland Ukraine United Kingdom

Deceased donor kidneys (pmp) 37.2 40.3 1.5 13.8 25.7 35.2 21 38.6 31.8 42.3 0 27 9.2 26.2 0 31.9 26.1 31.3 24.4 25 12.5 0 26.6 36.8 17 40.8 3.33 36.8 14.9 45.9 27.9 21.6 1.2 20.1

Living-donor kidney (pmp) 7.5 4 2.2 4.5 51.4 3.3 10.2 3.7 1 3.7 1.8 6.9 7.9 1.7 22.4 1.2 1.7 0.4 2.7 – 5 0.6 21.8 18.2 0.6 3.5 7.23 2.6 – 3 13.4 13.2 1.6 13.4

Total kidneys (pmp) 44.7 44.3 3.7 18.3 77.1 38.5 31.2 42.3 32.8 46 1.8 33.9 17.1 27.9 22.4 33.1 27.8 31.7 27.1 25 17.5 0.6 48.4 55 17.6 44.38 10.56 39.4 14.9 48.9 41.3 34.8 2.8 33.5

pmp = per million population. * ET = Country member of the Eurotransplant. ** ST = Country member of the Scandia Transplant. The data suggest that a donation rate of 40 pmp per year should be achievable by any single country in Europe, especially with so many sociocultural similarities. However, the act of donation is complex, depending on many factors and interactions, few of which have been proven useful individually or are generally applicable throughout the European Union. Although it is relatively easy to set a minimum standard for organ donation, it is more difficult to recommend specific, donor-promoting activities for individual countries and professional organisations. However, a few options are described below. 2.2.1 Donor cards Some countries such as the UK require donors to ‘opt in’. Others, such as Belgium and Denmark, ‘presume consent‘ and allow individuals who do not want to be donors to ‘opt out’.

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9

Many countries have publicity schemes encouraging the general population to carry donor cards or register their wish to donate (opting-in) on a computerised donor register. This helps to reduce the risk of donation being refused by the family. In the UK, 15.1 million individuals are registered on the ‘opting-in’ computer, while 5-10% of the population prefer to carry donor cards (2). However, the efficiency of this ‘opt-in’ system in creating donors is lower than in countries with a presumed consent. Opt-in systems require continuous publicity to increase the number of opted-in donors and transplant centres. Intensive care physicians and transplant co-ordinators also need to access the register routinely to identify potential deceased donors. Recommendation GR • In all countries without presumed consent law, efforts should be increased to recruit donors C through an opting-in register or by carrying donor cards GR = grade of recommendation 2.2.2 Improved organisation and resources Services must be better organised and resourced to increase deceased donor donation. The ability to achieve more than 25 donors pmp increases with the number of intensive care beds. High-donating countries with better-resourced intensive care units (e.g. Spain, France, Belgium) have increased the number of staff responsible for donation (transplant co-ordinators) and given them proper financial support. Successful education programmes, such as European Donor Hospital Education Programme (EDHEP) (3) or institutional audits, such as Donor Action, have increased and maintained the awareness of intensive care physicians for the need for deceased donor donation and supported them in approaching donor families to discuss donation. Transplant co-ordinators are responsible for liaising with coroners and public relations, particularly avoiding adverse publicity. Recommendation GR • Professional organisations within countries should, where necessary, put pressure on C government health departments to maintain enough intensive care beds, create a cadre of national transplant co-ordinators, and fund and deploy educational programmes for intensive care physicians GR = grade of recommendation 2.2.3 ‘Opting-out’ legislation The introduction of opting-out legislation results in increased rates of deceased donor donation. All European countries with more than 30 kidney donors pmp per annum (see Table 3) have opting-out legislation. Adverse publicity results in a ‘soft’ presumed consent in most countries, which also takes the family’s views into account. Countries with informed consent do not usually perform as well, with the USA producing the highest kidney donation rate of 24 donors pmp through the United Network for Organ Sharing/The Organ Procurement and Transplantation Network (UNOS/OPT) (4, 5). Recommendations • A recommendation cannot be made about something as fundamental as changing the law on deceased donor donation • However, presumed consent with an opting-out law is desirable 2.2.4 Non-heart-beating donor (NHBD) Non-heart-beating donors provide an important opportunity to decrease the deceased donor shortage of kidneys, even though NHBD kidneys are suboptimal organs due to the increased risk of delayed graft function and primary non-function. However, the long-term viability of NHBD kidneys in strictly selected donors has been improved by the use of a continuous perfusion machine on the cadaver before harvesting (6). A continuous perfusion machine can be used to assess NBHD kidney viability. Flow measurements and urinary enzyme excretion (7) are predictors of viability. Presumed consent legislation would allow many more NHBD kidneys because rapid intra-arterial cold perfusion of a recently deceased person would normally be allowed before family members arrive at the hospital. However, under informed consent law, perfusion of a cadaver without relatives’ permission is an unwarranted assault. In contrast, under presumed consent, a coroner is able to give permission for perfusion without requiring the relatives’ consent, so allowing the use of NHBD to be expanded significantly.

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Update march 2009

Recommendations GR • Greater use of NHBDs should be made B • Transplant staff should create policies for recently dead admissions to casualty departments B to be used as NHBDs • Local coroners should be consulted regarding the legal implications B GR = grade of recommendation. 2.2.5 Elderly donors The use of kidneys from elderly donors (> 60 years) is increasing. In countries such as Spain, it represents 40% of total kidney transplants. Long-term survival of kidneys is similar to the transplants performed with non-expanded criteria donors (8). After 6 months’ post transplant, patients who have been transplanted have a better survival rate than patients remaining on dialysis. Kidney transplants from donors older than 70 years carry a higher risk of graft loss and mortality, especially when transplanted to recipients under 60 years (9). Recommendations GR • The use of carefully selected donors over 60 years should be maintained and encouraged as B a continuing source of deceased donor kidneys • Donors over 70 should be evaluated on an individual basis, taking into account that better B results are obtained when transplanted to patients older than 60 years GR = grade of recommendation. 2.2.6 1. 2. 3. 4. 5. 6.

7.

8.

9.

References Transplant Procurement Management. www.tpm.org NHS Organ Donor Register. http://www.uktransplant.org.uk/ukt/statistics/statistics.jsp European Donor Hospital Education Programme. http://www10.gencat.net/catsalut/ocatt/en/htm/fun_prm_edh.htm United Network for Organ Sharing. http://www.unos.org/ The Organ Procurement and Transplantation Network. http://www.optn.org Bagul A, Hosgood SA, Kaushik M, Kay MD, Waller HL, Nicholson ML. Experimental renal preservation by normothermic resuscitation perfusion with autologous blood. Br J Surg 2008;95 (1):111-8. http://www.ncbi.nlm.nih.gov/pubmed/17696214 Balupuri S, Buckley P, Snowden C, Mustafa M, Sen B, Griffiths P, Hannon M, Manas D, Kirby J, Talbot D. The trouble with kidneys derived from the non heart-beating donor: a single centre 10-year experience. Transplantation 2000;69(5):842-6. Cadaveric donor\Balupuri S Transp 2000.htm http://www.ncbi.nlm.nih.gov/pubmed/10755537 Merion RM, Ashby VB, Wolfe RA, Distant DA, Hulbert-Shearon TE, Metzger RA, Ojo AO, Port FK. Deceased-donor characteristics and the survival benefit of kidney transplantation. JAMA 2005;294(21):2726-33. Cadaveric donor\jama-ojo.pdf http://www.ncbi.nlm.nih.gov/pubmed/16333008 Chavalitdhamrong D, Gill J, Takemoto S, Madhira BR, Cho YW, Shah T, Bunnapradist S. Patient and graft outcomes from deceased kidney donors age 70 years and older: an analysis of the Organ Procurement Transplant Network/United Network of Organ Sharing database. Transplantation 2008;85(11):1573-9. http://www.ncbi.nlm.nih.gov/pubmed/18551062

2.3 Policies to enhance living donation Kidney transplants from living donors offer a better graft and patient survival than those from deceased donors (1). Two major recent developments have led to the increased acceptance of living kidney donation: • Kidney transplant results have improved so that more patients with end stage renal disease (ESRD) have opted for transplant rather than dialysis • As the number of deceased donor kidneys has not increased, the number of living donors has increased. It is also likely that laparoscopic donor nephrectomy (less time off work, shorter hospital stay) has helped recruit living donors.

Update march 2009

11

The USA have greatly improved the supply of kidney transplants by recruiting more than 50% of total donations from consanguineous and non-consanguineous donors (i.e. living unrelated donors, which make up 40% transplants from living donors) (2, 3). In contrast, in Europe, living-donor transplants make up only 15% of transplantations. However, there is a clear trend for an increase in the living-donor rate, especially in the Scandinavian countries, The Netherlands and Cyprus (see Table 3). Living-donor rates can be improved at different stages in the referral process and in more general ways (Table 4). Table 4: Ways of improving the living donation rate During referral process • Nephrologists, at non-transplanting as well as transplanting centres, should be encouraged to discuss openly living donation with families of patients suffering ESRD, preferably before the patient begins dialysis. This results in pre-dialysis transplantation, increased transplant rates and better use of dialysis resources • Counselling (e.g. by senior nurse practitioners or living-donor co-ordinators) should be available to discuss screening tests, provide information packs, and arrange reimbursement of necessary donor expenses allowed in law • If legally permitted, living unrelated donors should be encouraged More general methods • Medical methods, such as laparoscopic harvesting, paired kidney exchange, transplantation of grafts with anatomical abnormalities (vascular, urinary tract fusion), reversal of a positive cross-match by treatment with plasmapheresis, and intravenous immunoglobulin administration • Ethical methods, such as showing appreciation for organ donation • Organisational methods, such as medical leave for organ donation and reimbursement of all costs to the donor Recommendations GR • Living donation in Europe should be encouraged. There is a widening gap between donation C and demand for kidney transplants, with not enough deceased donors. There is, however, an increase in living donors. In the USA, the number of kidneys from living donors is nearly the number of kidneys from deceased donors. • Organ donation should be considered a charitable gift. Society can express gratitude to organ C donors for their gift as with charitable contributions, without jeopardising its altruistic basis (e.g. ‘Medal of Honor’, limited reimbursement, medical leave, priority access to organ for transplant, donor insurance). • All nephrologists who care for ESRD patients should explore the living donor option with the family when a patient first presents with ESRD ESRD = end stage renal disease; GR = grade of recommendation 2.3.1 Medical methods to increase number of living donations 2.3.1.1 Acceptance of grafts with anatomical anomalies The use of grafts with anatomical anomalies is considered a relative contraindication by most experienced transplantation centres because of the shortage of living donors. Anatomical anomalies include renal cysts, uretero-pelvic junction obstruction, solitary stones > 1 cm, duplex ureteral system and multiple arteries and veins. However, retrospective reports have suggested that grafts with multiple renal artery or vein anomalies, such as circumaortic or retroaortic renal vein, do not carry an increased risk of complications in experienced hands (4). If the donor has a good immunological correspondence with the recipient, but an abnormal kidney, which is the only kidney available, and if the recipient on haemodialysis has a poor status, the abnormal kidney should be transplanted leaving the donor with the best one. A laparoscopic right kidney donor nephrectomy is as safe as a left nephrectomy. A recent prospective trial showed no differences in complication rates and graft survival between left- and right-sided donor nephrectomy (5). Recommendations GR • Multiple renal artery or grafts with anatomical anomalies are not absolute contraindications. C Decisions should be made on an individual basis

12

Update march 2009

•

 aparoscopic right kidney nephrectomy is as safe as left nephrectomy in terms of L complications and graft survival GR = grade of recommendation

A

2.3.1.2 Laparoscopic living-donor nephrectomy (LLDN) Laparoscopic living-donor nephrectomy (LLDN) is an alternative surgical method that has increased the rate of living donations. It is becoming the preferred technique for living-donor renal transplantation. In the USA, laparoscopic donor nephrectomies are more common than open surgery donor nephrectomies. In Europe, although increasing, fewer laparoscopic nephrectomies are performed than open procedures (6). There is a good evidence base for LLDN, including three systematic reviews, which have compared its safety and efficacy to the ‘gold standard’ of open donor nephrectomy, at least seven randomised control trials (level of evidence: 1-2), five prospective non-randomised studies (level of evidence: 2), and several retrospective studies (7-9). Compared to open live donor nephrectomy (OLDN), LLDN shows similar rates for graft function, rejection rate, urological complications, and patient and graft survival. However, measures for analgesic requirements, pain, hospital stay, and time to return to work are significantly better for a laparoscopic procedure. In terms of donor safety, the historical mortality rate is 0.03% with open donor nephrectomy, a rate unchanged by the introduction of LLDN (10, 11). The data about potential mortality should be included in all informed consent. In addition, LLDN does not affect the long-term risk of developing ESRD (12). However, the laparoscopic approach takes longer and requires additional resources. Nevertheless, the shorter hospital stay and more rapid return to work may compensate for the initial higher costs. In addition, the number of live kidney donations has increased by more than 100% in many institutions since the introduction of the laparoscopic approach. Overall, laparoscopic nephrectomy offers donors less post-operative pain, shorter convalescence, and better cosmetic results, compared to traditional open donation. In experienced hands, this procedure is accomplished without increased risk to the donor’s safety or allograft function. As with OLDN, LLDN should be considered the gold standard of treatment. Table 5: Laparoscopic live donor nephrectomy: advantages and disadvantages Advantages • Less post-operative pain • Minimal surgical scarring • Rapid return to full activities and work (about 4 weeks) • Shorter hospital stay • Magnified view of renal vessels

Disadvantages • Graft loss or damage during ‘learning curve’ • Pneumoperitoneum may compromise renal blood flow • Longer operative time

Recommendations GR • Laparoscopic nephrectomy offers equal urological complications, graft function and graft A survival than open nephrectomy, with less post-operative morbidity, shorter convalescence and better cosmetic results • Laparoscopic nephrectomy increases the number of individuals willing to donate. It should C be used only by appropriately trained and experienced surgeons. GR = grade of recommendation 2.3.1.3 References 1. Knight RJ, Burrows L, Bodian C. The influence of acute refection on long-term renal allograft survival: a comparison of living and cadaveric donor transplantation. Transplantation 2001;72(1):69-76. Living donor\comparison LD vs CD 2001.pdf http://www.ncbi.nlm.nih.gov/pubmed/11468537 2. United Network for Organ Sharing. http://www.unos.org/ 3. The Organ Procurement and Transplantation Network. http://www.optn.org

Update march 2009

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4.

5.

6.

7.

8.

9.

10.

11.

12.

Hsu TH, Su LM, Ratner LE, Trock BJ, Kavoussi LR. Impact of renal artery multiplicity on outcomes of renal donors and recipients in laparoscopic donor nephrectomy. Urology 2003;61(2):323-7. http://www.ncbi.nlm.nih.gov/pubmed/12597939 Minnee RC, Bemelman WA, Maartense S, Bemelman FJ, Goume DJ, Idu MM. left or right kidney in hand-assisted donor nephrectomy? A randomised controlled trial. Transplantation 2008;85(2):203-8. http://www.ncbi.nlm.nih.gov/pubmed/18212624 Kok NH, Weimar W, Alwayn IP, Ijzermans JN. The current practice of live donor nephrectomy in Europe. Transplantation 2006;82(7):892-7. http://www.ncbi.nlm.nih.gov/pubmed/17038903 Shokeir AA. Open versus laparoscopic live donor nephrectomy: a focus on the safety of donors and the need for a donor registry. J Urol 2007;178(5):1860-6. http://www.ncbi.nlm.nih.gov/pubmed/17868736 Tooher RL, Rao MM. Scott DE, Wall DR, Francis DMA, Bridgewater FH, Maddern GJ. A systematic review of laparoscopic live-donor nephrectomy. Transplantation 2004;78(3):404-14. http://www.ncbi.nlm.nih.gov/pubmed/15316369 Giessing M. Laparoscopic living-donor nephrectomy. Nephrol Dial Transplant 2004;19(Suppl 4): iv36-40. http://www.ncbi.nlm.nih.gov/pubmed/15240847 Matas AJ, Bartlett ST, Leichtman AB, Delmonico FL. Morbidity and mortality after living kidney donation, 1999-2001: Survey of United States Transplant Centers. Am J Transplant 2003;3(7):830-4. http://www.ncbi.nlm.nih.gov/pubmed/12814474 Hadjianastassious VG, Johnson RJ, Rudge CJ, Mamode N. 2509 living donor nephrectomies, morbidity and mortality, including the UK introduction of laparoscopic donor surgery. Am J Transplant 2007;7(11):2532-7. http://www.ncbi.nlm.nih.gov/pubmed/17868058 Fehrman-Ekholm I, Dunér F, Brink B, Tydén G, Elinder CG. No evidence of accelerated loss of kidney function in living kidney donors: results from a cross-sectional follow-up. Transplantation 2001;72(3):444-9. http://www.ncbi.nlm.nih.gov/pubmed/11502974

2.3.1.4 ABO-incompatible donors ABO incompatibility was once a contraindication for renal transplantation, but this is no longer the case because of new techniques (antibody adsorption columns) (1) and new immunosuppressive tools (e.g. anti-CD20 monoclonal antibody, rituximab) (2). This has increased the opportunities for organ donation. Successful transplantation case studies have been reported in living donors against a blood group barrier, with retrospective studies showing similar outcomes to those of blood-group-compatible transplants (3, 4). Limitations of the current reports are the small patient numbers, relatively short follow-up periods and differences in treatment protocols (5, 6). Further investigation is ongoing (7-10). Current reports indicate that ABO-incompatible transplantation require a more intense and more costly immunosuppressive therapy (11-13) (level of evidence: 3). Until more long-term data are available, and key issues of the treatment protocol are solved, this procedure remains experimental and should only be performed as part of a scientific trial. Patients should be counselled on the potential risks (more intense immunosuppression, lack of long-term outcome data) and benefits (immediate availability of a living donor). Other transplantation methods should be considered, such as crossover transplantation, which allows timely transplantation using standard immunosuppressive protocols (level of evidence: 3). Recommendations GR • ABO-incompatible transplantation is a promising procedure undergoing clinical evaluation C • Due to its experimental nature, it should be performed in experienced centres under C scientific documentation • Patients should be counselled about potential risks and alternatives C GR = grade of recommendation 2.3.1.5 Cross-match-positive living-donor kidney transplants This was previously thought to be a contraindication. However, several pilot studies (11-14) have reported successful transplantion with acceptable short-term results, using extensive antibody elimination strategies (e.g. plasmapheresis), intravenous application of immunoglobulins, and a more intense immunosuppression with antibody induction and the use of B-cell depleting agents (e.g. anti-CD20 antibody rituximab). (Level of evidence: 3) 14

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Due to lack of standardized treatment protocols and paucity of long-term results of larger cohorts this procedure remains experimental and should only be performed as part of a scientific trial. Patients should be counselled adequately on the potential risks. Alternative ways for transplanting highly immunised patients (e.g. Eurotransplant Acceptable Missmatch programme , cross-over transplantation ) should be considered to allow a timely transplantation of these patients with standard immunosuppressive protocols (15, level of evidence: 4). Recommendation GR • Transplantation of cross-match positive living donors is an experimental procedure, which C should only be performed in scientific trials. Patients should be counselled about risks and potential alternatives. GR = grade of recommendation 2.3.1.6 Living unrelated kidney donation In many countries in Europe, altruistic non-consanguineous kidney donation is allowed legally, provided checks are made for altruistic motivation and financial gain excluded (15, 16). The results are comparable to related living donation (level of evidence: 3). Recommendation GR • Living related and unrelated donation should be encouraged within national laws B GR = grade of recommendation 2.3.1.7 ‘Non-directed’ living-donor transplantation ‘Non-directed’ living-donor transplantation between an altruistic donor and a recipient unknown to the donor is being performed in a few centres worldwide (17-19). Though controversial, there seem no moral or social reasons to exclude such truly altruistic donors (16, 20). However, there are ethical and legal concerns about this type of donation (21), which at the moment make it difficult to recommend in these guidelines. 2.3.1.8 Payment to living donors from a central organisation Although paying living donors to donate organs from a central organisation would be a potential way of increasing organ availability in an era of organ shortage (22), it is generally agreed that the payment of living donors to donate organs is ethically unjustifiable (23, 24). It is strongly recommended that all organ donors have adequate lifelong access to medical care for the prevention of renal failure and potential side-effects of organ donation (15, 16). The cornerstone of clinical transplantation has been the altruistic donation of kidneys from living relatives. The gift of a transplant is priceless and societies that support transplantation have generally refused to give a monetary value to a transplantable organ or tissue. In Europe, it is illegal to make a payment for living related organs and The World Health Organization (WHO) has stated that the body and its parts cannot be the subject of commercial transactions, and all giving and receiving of payments should be prohibited (24) (level of evidence: 4). Recommendations GR • Legislation in every European country forbids payment for organs C • Donation of an organ should remain a gift of live without any financial impetus C GR = grade of recommendation 2.1.3.9 References 1. Kumlien G, Ullström L, Losvall A, Persson LG, Tydén G. Clinical experience with a new apheresis filter that specifically depletes ABO blood group antibodies. Transfusion 2006;46(9):1568-75. http://www.ncbi.nlm.nih.gov/pubmed/16965585 2. Becker YT, Samaniego-Picota M, Sollinger HW. The emerging role of rituximab in organ transplantation. Transpl Int 2006;19(8):621-8. http://www.ncbi.nlm.nih.gov/pubmed/16827678 3. Ichimaru N, Takahara S. Japan’s experience with living-donor kidney transplantation across ABO barriers. Nat Clin Pract Nephrol 2008;4(12): 682-92. http://www.ncbi.nlm.nih.gov/pubmed/18941430 4. Genberg H, Kumlien G, Wennberg L, Berg U, Tydén G. ABO-incompatible kidney transplantation using antigen-specific immunoadsorption and rituximab: a 3-year follow-up. Transplantation 2008;85(12):1745-54. http://www.ncbi.nlm.nih.gov/pubmed/18580466

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Thielke J, Kaplan B, Benedetti E. The role of ABO-incompatible living donors in kidney transplantation: state of the art. Semin Nephrol 2007;27(4):408-13. http://www.ncbi.nlm.nih.gov/pubmed/17616273 Gloor JM, Stegall MD. ABO incompatible kidney transplantation. Curr Opin Nephrol Hypertens 2007;16(6):529-34. http://www.ncbi.nlm.nih.gov/pubmed/18089966 Wilpert J, Geyer M, Pisarski P, Drognitz O, Schulz-Huotari C, Gropp A, Goebel H, Gerke P, Teschner S, Walz G, Donauer J. On-demand strategy as an alternative to conventionally scheduled posttransplant immunoadsorptions after ABO-incompatible kidney transplantation. Nephrol Dial Transplant 2007;22(10):3048-51. http://www.ncbi.nlm.nih.gov/pubmed/17623716 Tydén G, Donauer J, Wadström J, Kumlien G, Wilpert J, Nilsson T, Genberg H, Pisarski P, Tufveson G. Implementation of a protocol for ABO-incompatible kidney transplantation–a three-center experience with 60 consecutive transplantations. Transplantation 2007 May 15;83(9):1153-5. http://www.ncbi.nlm.nih.gov/pubmed/17496528 Wilpert J, Geyer M, Teschner S, Schaefer T, Pisarski P, Schulz-Huotari C, Gropp A, Wisniewski U, Goebel H, Gerke P, Walz G, Donauer J. ABO-incompatible kidney transplantation-proposal of an intensified apheresis strategy for patients with high initial isoagglutinine titers. J Clin Apher 2007;22(6):314-22. http://www.ncbi.nlm.nih.gov/pubmed/18095303 Tanabe K. Double-filtration plasmapheresis. Transplantation 2007;84(12 Suppl):S30-S32. http://www.ncbi.nlm.nih.gov/pubmed/18162985 Grim SA, Pham T, Thielke J, Sankary H, Oberholzer J, Benedetti E, Clark NM. Infectious complications associated with the use of rituximab for ABO-incompatible and positive cross-match renal transplant recipients. Clin Transplant 2007;21(5):628-32. http://www.ncbi.nlm.nih.gov/pubmed/17845637 Warren DS, Zachary AA, Sonnenday CJ, King KE, Cooper M, Ratner LE, Shirey RS, Haas M, Leffell MS, Montgomery RA. Successful renal transplantation across simultaneous ABO incompatible and positive crossmatch barriers. Am J Transplant 2004;4(4):561-8. http://www.ncbi.nlm.nih.gov/pubmed/15023148 Dean PG, Gloor JM, Stegall MD. Conquering absolute contraindications to transplantation: positivecrossmatch and ABO-incompatible kidney transplantation. Surgery 2005;137(3):269-73. http://www.ncbi.nlm.nih.gov/pubmed/15746773 West-Thielke P, Herren H, Thielke J, Oberholzer J, Sankary H, Raofi V, Benedetti E, Kaplan B. Results of positive cross-match transplantation in African American renal transplant recipients. Am J Transplant 2008;8(2):348-54. http://www.ncbi.nlm.nih.gov/pubmed/18190659 Delmonico F; Council of the Transplantation Society. Report of the Amsterdam Forum On the Care of the Live Kidney Donor: Data and Medical Guidelines. Transplantation 2005;79(6 Suppl):S53-S66. http://www.ncbi.nlm.nih.gov/pubmed/15785361 Ethics Committee of the Transplantation Society. The consensus statement of the Amsterdam Forum on the Care of the Live Kidney Donor. Transplantation 2004;78(4):491-2. http://www.ncbi.nlm.nih.gov/pubmed/15446304 Lennerling A, Fehrman-Ekholm I, Nordén G. Nondirected living kidney donation: experiences in a Swedish Transplant Centre. Clin Transplant 2008;22(3):304-8. http://www.ncbi.nlm.nih.gov/pubmed/18499902 Segev DL, Montgomery RA. Regional and racial disparities in the use of live non-directed kidney donors. Am J Transplant 2008;8(5):1051-5. http://www.ncbi.nlm.nih.gov/pubmed/18416741 Jendrisak MD, Hong B, Shenoy S, Lowell J, Desai N, Chapman W, Vijayan A, Wetzel RD, Smith M, Wagner J, Brennan S, Brockmeier D, Kappel D. Altruistic living donors: evaluation for nondirected kidney or liver donation. Am J Transplant 2006;6(1):115-20. http://www.ncbi.nlm.nih.gov/pubmed/16433765 Mueller PS, Case EJ, Hook CC. Responding to offers of altruistic living unrelated kidney donation by group associations: an ethical analysis. Transplant Rev (Orlando) 2008;22(3):200-5. http://www.ncbi.nlm.nih.gov/pubmed/18631879 Hilhorst MT, Kranenburg LW, Zuidema W, Weimar W, Ijzermans JN, Passchier J, Busschbach JJ. Altruistic living kidney donation challenges psychosocial research and policy: a response to previous articles. Transplantation 2005;79(11):1470-4. http://www.ncbi.nlm.nih.gov/pubmed/15940033

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Delmonico FL, Dew MA. Living donor kidney transplantation in a global environment. Kidney Int 2007;71(7):608-14. http://www.ncbi.nlm.nih.gov/pubmed/17290291 International Summit on Transplant Tourism and Organ Trafficking. The Declaration of Istanbul on organ trafficking and transplant tourism. Kidney Int 2008;74(7):854-9. http://www.ncbi.nlm.nih.gov/pubmed/18810784 World Health Assembly Resolution 57.18. Human organ and tissue transplantation, 22 May 2004. http://www.who.int/gb/ebwha/pdf_files/WHA57/A57_R18-en.pdf.

2.3.2 Ethical ways of showing appreciation for organ donation 2.3.2.1 Donor ‘medal of honour’ Organ procurement organisations could have ceremonies which recognise and honour organ donation. A donor ‘medal of honour’, given by a top official of a country, would effectively express appreciation and gratitude on behalf of the whole community to the living donors and families of deceased donors (1, 2). Policymakers, ethicists and the transplant community cannot agree on whether giving benefits to the families of organ donors would increase organ availability (3) (level of evidence 4). Because of the lack of evidence, no general recommendation can be made on whether or not to provide incentives for living donors or families of deceased donors. 2.3.3 Organisational ways to encourage organ donation 2.3.3.1 Cross-over transplantation or paired organ exchange A cross-over renal transplantation or a paired kidney exchange transplant is an exchange between two or more couples, who are prevented by ABO incompatibility or positive cross-match from donating their kidneys to their preferred recipients. The problem may be solved by exchanging the living donor kidneys between pairs of couples to achieve a cross-match negative or ABO-compatible combination. The inclusion criteria should favour the exchange of equivalent kidneys in size and age. A programme of cross-over kidney transplantation allows an exchange of organs between two living donors (4), or in some countries, from one living donor and one deceased donor (5). By using paired kidney exchange, the recipients are able to benefit from living donation. Paired kidney exchange also reduces the duration of dialysis before transplantation and expands the pool of living donors (6). Graft survival rates of paired kidney exchange are similar to directed, compatible live donor transplants (7) (level of evidence: 3). Recommendation GR • Paired kidney exchange if permitted by national law is a way of increasing the number of C kidney transplants GR = grade of recommendation 2.3.3.2 Medical leave for organ donation No-one should have to incur a personal expense for donating an organ (8). Many countries legally provide 30-days’ paid medical leave to all employees who donate an organ for transplantation (9). The American Society of Transplantation has recommended living donors should be given leave from employment similar to parental leave granted for a new baby (level of evidence: 3). Recommendations GR • The health and well-being of living donors should be monitored in a follow-up register to B document any long-term medical problems due to donation B • There should be a national insurance plan that provides life and disability insurance for B all living donors GR = grade of recommendation 2.3.4 1. 2. 3.

References H.R. 708. Gift of life Congressional Medal Act of 2001 (U.S. Rep. P. Srak, Calif.). S. 235. Gift of life Congressional Medal Act of 2001 (U.S. Sen. W. Frist, Tenn.). Bryce CL, Siminoff LA, Ubel PA, Nathan H, Caplan A, Arnold RM. Do incentives matter?. Providing benefits to families of organ donors. Am J Transplant 2005;5(12):2999-3008. http://www.ncbi.nlm.nih.gov/pubmed/16303016

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Ross LF, Rubin DT, Siegler M, Josephson MA, Thistlethwaite JR Jr, Woodle ES. Ethics of a pairedkidney-exchange-program. N Engl J Med 1997;336(24):1752-5. http://www.ncbi.nlm.nih.gov/pubmed/9180096 Delmonico FL, Morrissey PE, Lipkowitz GS, Stoff JS, Himmelfarb J, Harmon W, Pavlakis M, Mah H, Goguen J, Luskin R, Milford E, Basadonna G, Chobanian M, Bouthot B, Lorber M, Rohrer RJ. Donor kidney exchanges. Am J Transplant 2004;4(10):1628-34. http://www.ncbi.nlm.nih.gov/pubmed/15367217 de Klerk M, Witvliet MD, Haase-Kromwijk BJ, Claas FH, Weimar W. A highly efficient living donor kidney exchange program for both blood type and crossmatch incompatible donor-recipient combinations. Transplantation 2006;82(12):1616-20. http://www.ncbi.nlm.nih.gov/pubmed/17198246 Montgomery RA, Zachary AA, Ratner LE, Segev DL, Hiller JM, Houp J, Cooper M, Kavoussi L, Jarret T, Burdick J, Maley WR, Melancon JK, Kozlowski T, SimpkinsCE, Phillips M, Desai A, Collins V, Reeb B, Kraus E, Rabb H, Leffel MS, Warren DS. Clinical results from transplanting incompatible live kidney donor/recipient pairs using kidney paired donation. JAMA 2005;294(13):1655-93. http://www.ncbi.nlm.nih.gov/pubmed/16204665 Abecassis M, Adams M, Adams P, Arnold RM, Atkins CR, Barr ML, Bennett WM, Bia M, Briscoe DM, Burdick J, Corry RJ, Davis J, Delmonico FL, Gaston RS, Harmon W, Jacobs CL, Kahn J, Leichtman A, Miller C, Moss D, Newmann JM, Rosen LS, Siminoff L, Spital A, Starnes VA, Thomas C, Tyler LS, Williams L, Wright FH, Youngner S; The Live Organ Donor Consensus Group. Consensus statement on the live organ donor. JAMA 2000;284(22):2919-26. http://www.ncbi.nlm.nih.gov/pubmed/11187711 Organ Donor Leave Act, H.R. 457, Pub. L. No. 106-56. http://frwebgate.access.gpo.gov/cgibin/getdoc.cgi?dbname=106_cong_public_ laws&docid=f:publ056.106.pdf

Kidney donor selection and refusal criteria

2.4.1 Introduction A diagnosis of brain death is required in a comatose subject who may potentially be a deceased organ donor. The potential donor must be evaluated for any transmissible pathological condition and the quality of any organ(s) being considered for transplantation. The short-term results of transplants with kidneys from donors over 65 years old are almost similar to those with younger organs. However, long-term graft survival is lower (1). In addition, the main physiological risk factor in ‘older’ kidneys is a prolonged cold ischaemia time (2, 3). In keeping with these observations, the modern definition of a suitable donor places less emphasis on age and more on the physical condition of the donor, especially of the organ to be donated. The aim is to reduce the possibility of discarding usable organs. Thus, there are now no absolute age limits to donation. However, a short ischaemia time is mandatory, as well as careful donor selection, particularly because older donors have more co-morbidity. There is a similar trend towards extending the upper age donation limit in living donors to over 55 years (4). 2.4.2 Infections The potential donor must be checked for infectious diseases (Table 6): Table 6: Infections to be checked for in potential donor • • • • • • • •

Human immunodeficiency virus-1, -2 (HIV-1, HIV-2) Hepatis C Hepatitis B surface antigen (HBsAg), anti-HBc; acute hepatitis (liver enzymes) Cytomegalovirus (CMV) Epstein-Barr virus (EBV), only in paediatric recipients Active syphilis Viral infection, sepsis, tuberculosis, infections of unknown aetiology Family history of (or clinical signs that may be caused by) Creutzfeldt-Jacob disease

There is a high risk of HIV transmission from potential donors with suspected intravenous drug abuse. In addition, serology tests during the incubation period of HIV (2 months) or hepatitis (up to 6 months) may be negative, while large amounts of fluids administered during a resuscitation attempt can result in a normal serology due to dilution effects (5). Serological tests must therefore be repeated and additional tests done (e.g. polymerase chain reaction) to rule out infection.

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2.4.3 Special exceptions for infections Different circumstances apply when an organ recipient is already infected with HIV or hepatitis (Table 7). Table 7: Exceptions for organ recipients who already have infections HCV-positive donor • In an HCV-positive recipient, transplant is allowed following informed consent • In an HCV¬-negative recipient, there is a high risk of disease transmission. However, transplant may be possible in emergency situations following informed consent HBsAg-positive donor • In an HBsAg-positive recipient (if HDV antigen is negative), transplant is allowed after informed consent • In an HBsAg-negative recipient with high anti-HBs antibody titre and HBc positivity, transplant is allowed after informed consent • In an HBsAg-negative recipient with intermediate/high anti-HBs antibody titre alone (Hbc-antibody negative), transplantation may carry a higher risk but is allowed after informed consent • In an HBsAg-negative recipient with undetectable anti-Hbs antibody, transplant is allowed only in a life-saving situation, when HDV antigen is negative and following informed consent HBc-antibody-positive donor • In liver transplantation, there is a high risk (50%) of transmitting hepatitis B from an anti-HBc antibodypositive donor to the recipient. In this situation, liver transplantation is allowed after informed consent. Kidneys, heart and lungs carry a low, but not absent, risk of hepatitis B transmission, so kidney transplant is allowed in an HBsAg-positive recipient, or an HBsAg-negative recipient with anti-HBs antibody titre ≥10 mIU/mL, following informed consent • In an HBsAg-negative recipient with no anti-HBsAg antibody, only life-saving transplants are allowed, after informed consent 2.4.4 Malignant tumours A previous history of malignancy is not usually a contraindication for organ donation. However, there are some absolute contraindications that make a donor unsuitable for transplant. These are active cancer or a history of metastatic cancer (with a few exceptions, such as testicular cancer) and cancers with high recurrence rates, such as advanced breast carcinoma, melanoma, leukaemia, or lymphoma. In addition, when a potential donor has experienced a brain haemorrhage of unknown aetiology, metastasis must be excluded as a cause of intracranial bleeding. For example, the serum level of human chorionic gonadotropin must be measured to exclude chorioncarcinoma in female donors. With other cancers, if less than 10 years has elapsed since completion of treatment, a careful risk-benefit assessment must be done of the risk of disease transmission versus mortality on the waiting list. The donor shortage has led to many transplant programmes accepting donors after only 5 years’ absence of recurrent malignancy. So far, only a low incidence of donor-transmitted malignancies has been observed (6). Successful renal transplants have been performed with kidneys affected by small, low-grade renal carcinomas that were completely excised. Recipients of organs from donors with a history of malignancy must be informed and carefully monitored (7). 2.4.5 Special exceptions for malignant tumours For special exceptions in malignant tumours, see Section 8.1. 2.4.6 Vascular conditions and renal function Important risk factors for organ failure are a prolonged history of diabetes mellitus or serious hypertension with retinal vascular damage. Factors for excluding potential donors or for considering a donor as a single- rather than a multi-organ donor include: • Previous myocardial infarction • Coronary bypass and angina • Severe systemic vascular disease • Events of long-lasting hypotension • Oliguria • Long-lasting intensive care stay. A donor’s renal function should be evaluated at admission using creatinine clearance (Cockcroft-Gault formula), which corrects the serum creatinine value for age, body weight and sex (8). The urinary tract can

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also be assessed by 24-h proteinuria and ultrasound kidney imaging, particularly in elderly donors. In many transplant centres, a calculated creatinine clearance level of 50 mL/min is at the lower range for kidneys usable for two recipients, independent of the histology of the organ, but according to the history of the donor, while other centres evaluate glomerular sclerosis and arteriolar sclerosis from renal biopsy (9). Acute renal failure is not itself a contraindication. The kidneys may be used after careful assessment (level of evidence: 3). 2.4.7 Marginal donors The following criteria need to be considered in a marginal organ (10) (level of evidence: 3): • Age over 70 years without other risk factors. • Age between 60 and 70 years, with a history of diabetes mellitus, hypertension, clinical proteinuria up to 1 g/24 h, or retinal vascular changes. • Calculated creatinine clearance of 50 mL/min – the organs are still valuable for a single graft. • Calculated creatinine clearance < 50 mL/min – the organs should be used as dual graft or discarded if histologically abnormal. • Approximately 5-20% of glomerulosclerosis at biopsy with at least 25 glomeruli taken from both kidneys – the organs are still valuable for a single or double graft. • More than 20% glomerulosclerosis – an individual decision has to be made based on renal function. The true clinical meaning of each criterion is unknown because none of them have been rigorously validated and opinions differ over their individual value, as for example with pre-transplant renal biopsy (11, 12). 2.4.8 One graft or two grafts per recipient The rationale for dual marginal kidney transplantation is based on two conflicting concepts. Firstly, kidneys with a small nephron mass undergo hyperfiltration and glomerular hypertension, which causes progressive glomerulosclerosis (13). A single marginal kidney has a reduced renal mass and a suboptimal number of nephrons, which are further reduced by cold ischaemia time, transplant trauma and the potential nephrotoxicity of immunosuppressive therapy. Simultaneous transplantation of both kidneys to the same recipient may increase nephron mass and prevent kidney damage. Secondly, marginal kidneys have a functional reserve only verifiable after transplantation. In addition, the glomerular filtration rate of a transplanted kidney often increases post transplant (14-16). Dual transplantation is redundant because it shortens the organ pool. These two opposing concepts would seem to suggest that kidneys judged unsuitable based on function or histology should either both be transplanted into a single recipient or both be discarded (17). However, a prospective multicentre study (18) concluded that double-kidney transplants are safe, well tolerated, and result in no more surgical complications than single-graft operations. To date, the surgical technique for dual renal grafting has not been standardised (19, 20) (level of evidence: 3). Recommendations GR • Any brain death comatose subject should be considered a potential organ donor, without C age limits • Consensus for organ harvesting should be obtained from relatives or significant others according to local law and policies. Authorisation for explantation by the donor’s close relatives is always recommended, even if local legislation on organ donation presumes consent: - Contact between relatives and a well-trained, sensitive professional is very important in establishing favourable public opinion on organ donation - Individuals who objected to donation during life must always be excluded • Any donor organ affected by a potentially transmittable pathology (infections, neoplasias) B must be carefully evaluated considering the risk-benefit ratio for the recipient B • A good-quality organ must be guaranteed to the recipient and every transplant centre C must establish its own guidelines on organ acceptability. Organs from marginal donors can only be used after thorough assessment. The recipients need to be informed and must confirm their acceptance GR = grade of recommendation

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References Alexander JW, Bennett LE, Breen TJ. Effect of donor age on outcome of kidney transplantation. A two-year analysis of transplants reported to the United Network for Organ Sharing Registry. Transplantation 1994;57(6):871-6. http://www.ncbi.nlm.nih.gov/pubmed/8154034 Wyner LM, McElroy JB, Hodge EE, Peidmonte M, Novick AC. Use of kidneys from older cadaver donors for renal transplantation. Urology 1993;41(2):107-10. http://www.ncbi.nlm.nih.gov/pubmed/8497979 Cicciarelli J, Iwaki Y, Mendez R. The influence of donor age on kidney graft survival in the 1990s. Clin Transpl 1999:13:335-40. http://www.ncbi.nlm.nih.gov/pubmed/11038652 Kerr SR, Gillingham KJ, Johnson EM, Matas AJ. Living donors > 55 years: to use or not to use? Transplantation 1999;67(7) 999-1004. http://www.ncbi.nlm.nih.gov/pubmed/10221484 Scheinkestel CD, Tuxen DV, Cooper DJ, Butt W. Medical management of the (potential) organ donor. Anaesth Intensive Care 1995;23(1):51-9. http://www.ncbi.nlm.nih.gov/pubmed/7778748 Taioli E, Mattucci DA, Palmieri S, Rizzato L, Caprio M, Costa AN. A population-based study of cancer incidence in solid organ transplants from donors at various risk of neoplasia. Transplantation 2007;83(1):13-6. http://www.ncbi.nlm.nih.gov/pubmed/17220783 Penn I. Precautions to be taken to prevent transmission of neoplastic diseases in the grafting process. In: Organ and Tissue Transplantation in the European Union. London: Graham and Trotman, 1994: 33-41. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16(1):31-41. http://www.ncbi.nlm.nih.gov/pubmed/1244564 Karpinski J, Lajoie G, Cattran D, Fenton S, Zaltzman J, Cardella C, Cole E. Outcome of kidney transplantation from high-risk donors is determined by both structure and function. Transplantation 1999;67(8):1162-7. http://www.ncbi.nlm.nih.gov/pubmed/10232568 European best practice guidelines for renal transplantation (part 1). Transplantation Section II: Evaluation and selection of donors. Nephrol Dial Transplant 2000;15(Suppl 7):39-51. http://www.ndteducational.org/images/Renal%20Transplantation%201%20Section%20II.pdf Andres A, Herrero JC, Morales E, Praga M, Vazquez S, Vereda M, Cebrian P, Rodicio JL, Morales JM, Aguirre F, Diaz R, Polo G, Leiva O. The double or single renal graft depending on the percentage of glomerulosclerosis in the preimplant biopsy reduces the number of discarded kidneys from donors older than 60 years. Transplant Proc 1999;31(6):2285-6. http://www.ncbi.nlm.nih.gov/pubmed/10500580 Pokorna E, Vitko S, Chadimova M, Schuck O, Ekberg H. Proportion of glomerulosclerosis in procurement wedge renal biopsy cannot alone discriminate for acceptance of marginal donors. Transplantation 2000;69(1):36-43. http://www.ncbi.nlm.nih.gov/pubmed/10653377 Brenner BM, Cohen RA, Milford EL. In renal transplantation, one size may not fit all. J Am Soc Nephrol 1992;3(2):162-9. http://www.ncbi.nlm.nih.gov/pubmed/1391717 Halloran PF, Melk A, Barth C. Rethinking chronic allograft nephropathy: the concept of accelerated senescence. J Am Soc Nephrol 1999;10(1):167-81. http://www.ncbi.nlm.nih.gov/pubmed/9890324 Berardinelli L, Beretta C, Raiteri M, Pasciucco A, Carini M. Long-term results of 211 single necrokidney transplantations from extreme-age donors: why dual allograft?. Transplant Proc 2001;33(7-8):3774-6. http://www.ncbi.nlm.nih.gov/pubmed/11750606 Beckurts UT, Stippel D, Pollok M, Arns W, Weber M, Holscher AH. Single-centre experience with the ‘old for old’ program for renal transplantation. Transplant Proc 2001;33(7-8):3779-80. http://www.ncbi.nlm.nih.gov/pubmed/11750608 Alfrey EJ, Lee CM, Scandling JD, Witter MM, Carter JT, Markezich AJ, Salvatierra O, Dafoe DC. Expanded criteria for donor kidneys: an update on outcome in single versus dual kidney transplants. Transplant Proc 1997;29(8):3671-3. http://www.ncbi.nlm.nih.gov/pubmed/9414884

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Remuzzi G, Grinyo J, Ruggenenti P, Beatini M, Cole EH, Milford EL, Brenner BM. Early experience with dual kidney transplantation in adults using expanded donor criteria. Double Kidney Transplant Group (DKG). J Am Soc Nephrol 1999;10(12):2591-8. http://www.ncbi.nlm.nih.gov/pubmed/10589699 Dietl KH, Wolters H, Marschall B, Senninger N, Heidenreich S. Cadaveric ‘two-in-one’ kidney transplantation from marginal donors: experience of 26 cases after 3 years. Transplantation 2000;70(5):790-4. http://www.ncbi.nlm.nih.gov/pubmed/11003359 Lu AD, Carter JT, Weinstein RJ, Prapong W, Salvatierra O, Dafoe DC, Alfrey EJ. Excellent outcome in recipients of dual kidney transplants: a report of the first 50 dual kidney transplants at Stanford University. Arch Surg 1999;134(9):97l-5, discussion 975-6. http://www.ncbi.nlm.nih.gov/pubmed/10487592

Explantation technique

2.5.1 Technique of deceased donor organ recovery Each solid organ should be procured as quickly as possible to minimise ischaemic injury. Removal of the heart, lungs, liver and pancreas (Table 8) usually takes place before kidney retrieval (Table 7) (1-10) (level of evidence: 3). Continuous machine perfusion reduces injuries due to ischaemia or reperfusion and improves the immediate post-operative graft outcome (8-10) (level of evidence: 3). Table 8: Important considerations during removal of heart, lungs, liver and pancreas • •

Infuse 3L of UW (University of Wisconsin) solution into the aorta before organ recovery. Open Gerota’s fascia to expose the kidneys for surface cooling. While the heart is being removed and the cold perfusate is being infused, place ice slush into the abdominal cavity to provide surface cooling for the liver, kidneys and pancreas After the heart is removed and the liver is to be retrieved, careful attention should be given to ensure the following: • Do not extend the aortic cannula beyond the ostia of the renal arteries. This will avoid the risk of inadequate flushing of the kidneys, leading to unnecessary and harmful warm ischaemia • If the superior mesenteric artery is not being taken along the coeliac artery for the liver, the upper portion of the remaining aorta can be reclamped to allow continued perfusion of the kidneys and cooling during removal of the liver • If the superior mesenteric artery is taken with the liver and removed, it may not be possible to place a curved forceps in a tangential manner on the remaining segment of aorta. Although this would allow continued flushing of the kidneys, there is a risk of occluding the renal artery orifices, especially on the right side • During transection of the vena cava between the liver and the kidneys, take care to avoid injury to the right renal vein. The right renal vein can often extend superiorly before entering the vena cava and may be accidentally transected. Because a segment of infrahepatic vena cava is needed in liver transplantation, the kidney retrieval team must be instructed to leave an optimal amount of venal caval cuff to go with the liver to prevent injury to the right renal vein • The pancreas, if being retrieved, should be removed before the kidney. Again, injury to the left renal artery or vein can occur while the pancreas is dissected. Often the pancreas, and occasionally the kidneys, are recovered en bloc with the liver and then separated on the back table • It is unnecessary to perform extensive kidney mobilisation prior to kidney removal, especially in multiple organ recovery. Such retroperitoneal dissection may cause accidental injury to aberrant renal arteries, so causing incomplete perfusion and warm ischaemia of the kidneys (2-4) (level of evidence: 2a) Table 9: Important considerations in kidney retrieval •

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 issection is carried cephalad and kept as far posterior as possible; the line of dissection is D maintained at the level of the paraspinal muscles. Gerota’s fascia is kept attached to the kidneys. At the superior poles of the kidneys, the adrenal glands are left intact attached to the kidneys. The kidneys are removed en bloc without identification of the hilar structures On the back table, care must be taken to identify aberrant renal arteries, which may originate from the iliac arteries or distal or superior aorta. The aortic segment is left intact. The ureters are examined for length, numbers and size It is useful to rewash each kidney until the effluent is free of blood before packaging

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If the liver is not to be recovered, a double balloon perfusion cannula can be placed in the aorta for selective renal perfusion and a venting catheter is inserted into the lower vena cava to allow venous blood to be washed out Dissection of the kidneys can then proceed with mobilisation of the right colon, exposing the right kidney, the inferior vena cava and lower aorta. Identification and ligation of the inferior mesenteric artery and vein are performed, and the splanchnic nerves are divided, allowing mobilisation of the left mesocolon and exposure of the left kidney. The coeliac axis is identified, ligated and divided Mass clamping of the hepatoduodenal ligament can be performed to minimise flushing of the liver. In a donor < 3-4 years, the surgeon must make sure the aortic cannula does not occlude the renal artery orifices

Improvements in techniques for harvesting organs from non-heart beating donors (NBHDs) has allowed the use of organs that would otherwise not have been considered for transplantation. Reports of the satisfactory function of organs retrieved in this manner have been followed by the development of adequate methods of aortic infusion techniques (11-13). NHB donors accounted for 11,06% in EUROTRANSPLANT and for 6,5% in USA. (12-18). With the development of multiple organ recovery techniques (19), good co-ordination and co-operation between the various surgical teams involved are essential for the successful retrieval of transplantable organs (2, 19-21). Logistics and programming of organ explantation should routinely be done by the local transplant coordinator. Recommendations GR • Kidneys are the last organs to be recovered in multiple organ recovery. Appropriate C placement of the aortic cannula for the cold ‘in-situ’ flush is essential • After retrieval of the thoracic organs and liver, and if the pancreas is to be removed, the B kidney and pancreas should be recovered en bloc and separated on the back table • In multiple organ recovery, it is essential there is good co-ordination and co-operation C between the surgical teams GR = grade of recommendation 2.5.2 The living donor At present, 20% in EUROTRANSPLANT and 40% in USA of all kidney transplants are performed with living donors (14, 16) (level of evidence: 2a). In countries with low deceased donor rates, over 75% of kidney transplants are with living donors (22). Most living donors are family members, but there is an increasing number of genetically unrelated donors, who are ‘emotionally related’, such as spouses or friends. In 2005, in EUROTRANSPLANT, nearly 50% of living donors were not genetically related (42.2%). In the USA, 37.2% were unrelated living donors (14, 16) (level of evidence: 2a). Ethical guidelines mandate that the living donors have not been coerced and not been paid for their donation. Living donation should be considered a gift of extraordinary value and should be facilitated wherever a suitable donor is available (Table 10) (23-26) (level of evidence: 2b). Table 10: Advantages of living donation • • • • • •

Better results (both long- and short-term) compared to deceased donor grafts Consistent early function and easier management Avoidance of long waiting time for transplantation Less aggressive immunosuppressive regimens Emotional gain to donor Increases globally the kidney transplant rate

2.5.2.1 Evaluation Evaluation of a potential donor may be performed by an independent physician and consists of a complete history and physical examination, routine laboratory testing, and serological evaluation for Epstein-Barr virus (EBV), herpes virus, cytomegalovirus (CMV), human immunodeficiency virus (HIV) and hepatitis B and C viruses (HBV, HCV). Routine evaluation should also include urinalysis and culture, together with 24-h urine collection for creatinine clearance and protein excretion. A borderline hypertensive blood pressure should be measured on at least three, and as many as 10, separate occasions.

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Renal angiography is indicated only if spiral computed tomography (CT) scan with three-dimensional reconstruction or MRI angiography with reconstruction are not available. Donors are unsuitable for a variety of reasons (Table 11). Potential donors for siblings with diabetes should routinely undergo a 5-h glucose tolerance test and the 24-h urine specimen must be free of proteinuria. Unexplained microscopic haematuria may indicate underlying renal disease. A history of thromboembolism or thrombophlebitis places a potential donor at increased risk of pulmonary embolism and contraindicates donation, as does advanced heart disease or a history of malignant neoplasia. Obesity is a relative contraindication for any potential donor > 30% above ideal body weight. Table 11: Exclusion criteria for living donors Absolute contraindications • Age < 18 years • Uncontrolled hypertension • Diabetes mellitus • Proteinuria (> 300 mg/24 h) • Abnormal GFR for age • Microscopic haematuria • High risk of thromboembolism • Medically significant illness (chronic lung disease, recent malignant tumour, heart disease) • History of bilateral kidney stones • HIV positive Relative contraindications • Active chronic infection (e.g. tuberculosis, hepatitis B/C, parasites) • Obesity • Psychiatric disorders GFR = glomerular filtration rate; HIV = human immunodeficiency virus. Patients with psychiatric disorders should be fully evaluated by a psychiatrist to establish that the donor understands and agrees to the procedure. 2.5.2.2 Choice of kidney If examination of the donor’s vascular supply and drainage system reveals an abnormality, it must be decided whether the risks imposed on the donor or the recipient are too great. When one kidney is smaller or has a minor abnormality, the donor should always be left with the ‘better’ kidney. 2.5.2.3 Pre-operative management Pre-operative assessment by the anaesthesiologist and the pain management team is mandatory. 2.5.2.4 Surgical alternatives in live-donor nephrectomy There are several ways of harvesting kidneys from living donors (Table 12) (11-13, 21, 27-35). The method chosen will depend on the surgeon’s experience and preferred choice of operation. Table 12: Approaches for harvesting kidneys from living donors Approach • Classic transperitoneal • Sub- or supra-costal extraperitoneal • Dorsal lumbar • Laparoscopic

Description Through a midline or through a left or right subcostal incision Can be either left- or right-sided  erform incision either underneath the 12th rib, resecting the 12th rib, or P above the 12th rib (extraperitoneal, extrapleural) Can be transperitoneal or retroperitoneoscopic. The transperitoneal approach is more common in the USA and Scandinavia

The operative stages are similar to those in transperitoneal nephrectomy performed for malignant or benign conditions of the kidney. In 2.3% of cases, concomitant splenectomy is needed (11-13, 21, 28-35), due to injuries of the spleen that occur during colon dissection. In addition, the transperitoneal approach is accompanied by a significantly higher rate of intestinal complications, such as ileus (functional or even obstructive).

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Removal of the left kidney from a living donor is recommended because of the longer length of the left renal vein (36-38). Before starting the incision, the donor’s diuresis is increased, usually by giving mannitol, 25 g. Arterial spasm may be prevented with externally applied papaverine (39). Laparoscopic kidney removal (Table 13) is a less traumatic technique, entails less pain, a shorter hospital stay and may encourage more people to consider donation. Table 13: Special considerations during a laparoscopic procedure Patient’s preparation During organ harvesting, especially during dissection of the renal pedicle, the patient requires appropriate fluids and a mannitol infusion to maximise renal function during surgery and after transplantation (15-17, 40, 41) Patient’s position on Place the patient on the operative table in a left or right position with the operative table the kidney bridge. The left kidney is preferred for laparoscopic removal because it has a longer renal vein. On the right side, the liver may make dissection difficult in a transperitoneal approach Transperitoneal laparoscopic The transperitoneal approach offers more working space. The kidney approach is approached by dissecting the colon and peritoneum on different lengths. The approach to the renal artery is more complicated due to its position behind the renal vein. However, after detachment from vascular connections, the kidney can be more easily extracted through a lower umbilical incision Retroperitoneoscopic approach The retroperitoneal approach allows an easy, initial identification of the renal artery and a direct approach to the branches of renal vein. Its main drawback is the limited space for manoeuvre, which also makes it difficult to use endobags for a quick kidney extraction 2.5.2.5 Post-operative care Adequate post-operative analgesia is crucial in preventing post-operative complications, such as atelectasis and pneumonia (20, 21). Antibiotic prophylaxis should also be given. Subcutaneous heparin, the continuous use of leg stockings and sequential compression devices should be prescribed to prevent deep venous thrombosis of the lower limbs. Most patients tolerate oral feeding by post-operative day 2 or 3, and the donor can be discharged between post-operative days 2 to 6. Renal function should be assessed periodically after operation. Although donors experience a 25% increase in serum creatinine level, the creatinine level should return to near baseline within 3 months. There are no convincing data to suggest that living donors are at increased long-term risk because of kidney donation. Nevertheless, ongoing periodic long-term follow-up evaluation is recommended for donors. This can be performed by the donor’s personal physician (14-17, 40-43) (level of evidence: 2a). Recommendations GR • The use of living donors has been associated with higher success rates than seen with B deceased donor donation. Living donation allows some patients to avoid long waiting times and even dialysis • An independent assessment of the donor’s renal function by a nephrologist or a specialised B team is mandatory in all cases • It is advisable to obtain a psychiatric or independent medical evaluation of the donor’s B motivation, fitness, and his ability to understand the risks of the operation • It is the surgeon’s responsibility to ensure that the donor is medically, as well as B psychologically suitable, for the procedure; the donated organ is healthy; and the expectation of success in the recipient is reasonable • The donor should always be left with the ‘better’ kidney. Kidney removal through a B transperitoneal approach has a higher number of splenic and intestinal complications compared with other surgical alternatives • Open-donor nephrectomy should be performed by an extraperitoneal approach through B a subcostal or dorsal lumbotomy incision

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 aparoscopic donor nephrectomy (either trans- or retro-peritoneal) should only be performed B L by those trained in the procedure • Hand-assisted laparoscopic donor nephrectomy minimises warm ischaemia time compared B to classic laparoscopic procedures GR = grade of recommendation 2.5.3 1.

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References Brasile L, Stubenitsky BM, Booster MH, Lindell S, Araneda D, Buck C, Bradfield J, Haisch CE, Kootstra G. Overcoming severe renal ischemia: the role of ex vivo warm perfusion. Transplantation 2002;73(6):897-901. http://www.ncbi.nlm.nih.gov/pubmed/11923688 Boggi U, Vistoli F, Del Chiaro M, Signori S, Pietrabissa A, Costa A, Bartolo TV, Catalano G, Marchetti P, Del Prato S, Rizzo G, Jovine E, Pinna AD, Filipponi F, Mosca F. A simplified technique for the en bloc procurement of abdominal organs that is suitable for pancreas and small-bowel transplantation. Surgery 2004;135(6):629-41. http://www.ncbi.nlm.nih.gov/pubmed/15179369 Dalle Valle R, Capocasale E, Mazzoni MP, Busi N, Sianesi M. Pancreas procurement technique. Lessons learned from an initial experience. Acta Biomed 2006;77(3):152-6. http://www.ncbi.nlm.nih.gov/pubmed/17312985 Frilling A. [Standards of visceral organ procurement.] Zentralbl Chir 2003;128(10):804-15. [article in German] http://www.ncbi.nlm.nih.gov/pubmed/14763454 Hauet T, Han Z, Doucet C, Ramella-Virieux S, Hadj Aïssa A, Carretier M, Papadopoulos V. A modified University of Wisconsin preservation solution with high-Na+ low-K+ content reduces reperfusion injury of the pig kidney graft. Transplantation 2003;76(1):18-27. http://www.ncbi.nlm.nih.gov/pubmed/12865781 Nunes P, Mota A, Figueiredo A, Macário F, Rolo F, Dias V, Parada B. Efficacy of renal preservation: comparative study of Celsior and University of Wisconsin solutions. Transplant Proc 2007;39(8): 2478-9. http://www.ncbi.nlm.nih.gov/pubmed/17954152 Opelz G, Döhler B. Multicenter analysis of kidney preservation. Transplantation 2007;83(3):247-53. http://www.ncbi.nlm.nih.gov/pubmed/17297393 Balupuri S, Strong A, Hoernich N, Snowden C, Mohamed M, Manas D, Kirby J, Talbot D. Machine perfusion for kidneys: how to do it at minimal cost. Transpl Int 2001;14(2):103-7. http://www.ncbi.nlm.nih.gov/pubmed/11370162 Kwiatkowski A, Wszola M, Kosieradzki M, Danielewicz R, Ostrowski K, Domagala P, Lisik W, Nosek R, Fesolowicz S, Trzebicki J, Durlik M, Paczek L, Chmura A, Rowinski W. Machine perfusion preservation improves renal allograft survival. Am J Transplant 2007;7(8):1942-7. http://www.ncbi.nlm.nih.gov/pubmed/17617857 Maathuis MH, Manekeller S, van der Plaats A, Leuvenink HG, ‘t Hart NA, Lier AB, Rakhorst G, Ploeg RJ, Minor T. Improved kidney graft function after preservation using a novel hypothermic machine perfusion device. Ann Surg 2007;246(6):982-8, 989-91. http://www.ncbi.nlm.nih.gov/pubmed/18043100 Sanni AO, Wilson CH, Wyrley-Birch H, Vijayanand D, Navarro A, Gok MA, Sohrabi S, Jaques B, Rix D, Soomro N, Manas D, Talbot D. Non-heart-beating kidney transplantation: 6-year outcomes. Transplant Proc 2006;38(10):3396-7. http://www.ncbi.nlm.nih.gov/pubmed/17175282 Snoeijs MG, Dekkers AJ, Buurman WA, van den Akker L, Welten RJ, Schurink GW, van Heurn LW. In situ preservation of kidneys from donors after cardiac death: results and complications. Ann Surg 2007;246(5):844-52. http://www.ncbi.nlm.nih.gov/pubmed/17968178 Gok MA, Bhatti AA, Asher J, Gupta A, Shenton BK, Robertson H, Soomro NA, Talbot D. The effect of inadequate in situ perfusion in the non heart-beating donor. Transpl Int 2005;18(10):1142-6. http://www.ncbi.nlm.nih.gov/pubmed/16162100 Oosterlee A, Rahmel A, van Zwet W (eds). Annual report 2005. Eurotransplant International Foundation, Leiden: 2005. http://64.233.183.104/search?q=cache:N2A2NVhd1dsJ:www.eurotransplant.nl/files/annual_report/ AR2005_def.pdf+978-90-71658-25-9&hl=nl&ct=clnk&cd=1&gl=nl

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Dittrich S, Groneberg DA, von Loeper J, Lippek F, Hegemann O, Grosse-Siestrup C, Lange PE. Influence of cold storage on renal ischemia reperfusion injury after non-heart-beating donor explantation. Nephron Exp Nephrol 2004;96(3):e97-e102. http://www.ncbi.nlm.nih.gov/pubmed/15056986 Malaise J, Van Deynse D, Dumont V, Lecomte C, Mourad M, Dufrane D, Squifflet JP, Van Ophem D, Verschuren F, Meert P, Thys F, El Gariani A, Wittebole X, Laterre PF, Hantson P. Non-heart-beating donor, 10-year experience in a Belgian transplant center. Transplant Proc 2007;39(8):2578-9. http://www.ncbi.nlm.nih.gov/pubmed/17954180 Kootstra G, Daemen JH, Oomen AP. Categories of non-heart beating donors. Transplant Proc 1995;27(5):2893-5. http://www.ncbi.nlm.nih.gov/pubmed/7482956 Gok MA, Asher JF, Shenton BK, Rix D, Soomro NA, Jaques BC, Manas DM, Talbot D. Graft function after kidney transplantation from non-heartbeating donors according to Maastricht category. J Urol 2004;172(6 Pt 1):2331-4. http://www.ncbi.nlm.nih.gov/pubmed/15538260 Spital A, Jacobs CL. The beauty of the gift: the wonder of living organ donation. Clin Transplant 2007;21(4):435-40. http://www.ncbi.nlm.nih.gov/pubmed/17645701 Lucan M (ed). [Textbook of surgical urologic techniques.] Bucharest: Infomedica, 2001:528-36. [article in Romanian] Signori S, Boggi U, Vistoli F, Del Chiaro M, Pietrabissa A, Costa A, Vanadia Bartolo T, Coletti L, Gremmo F, Croce C, Morelli L, Mosca F. Regional procurement team for abdominal organs. Transplant Proc 2004;36(3):435-6. http://www.ncbi.nlm.nih.gov/pubmed/15110547 Lucan M. Five years of single-center experience with paired kidney exchange transplantation. Transplant Proc 2007;39(5):1371-5. http://www.ncbi.nlm.nih.gov/pubmed/17580142 Abouna GM. Ethical issues in organ and tissue transplantation. Exp Clin Transplant 2003;1(2):125-38. http://www.ncbi.nlm.nih.gov/pubmed/15859919 Banasik M. Living donor transplantation–the real gift of life. Procurement and the ethical assessment. Ann Transplant 2006;11(1):4-6. http://www.ncbi.nlm.nih.gov/pubmed/17025022 Kuss R, Bourget P. An illustrated history of organ transplantation: the great adventure of the century. Rueil-Malmaison, France: Laboratoires Sandoz, 1992. Moritsugu KP. Organ donation: the gift of life. J Am Diet Assoc 2007;107(1):15. http://www.ncbi.nlm.nih.gov/pubmed/17197259 Simforoosh N, Bassiri A, Ziaee SA, Tabibi A, Salim NS, Pourrezagholi F, Moghaddam SM, Maghsoodi R, Shafi H. Laparoscopic versus open live donor nephrectomy: the first randomized clinical trial. Transplant Proc 2003;35(7):2553-4. http://www.ncbi.nlm.nih.gov/pubmed/14612012 Brown SL, Biehl TR, Rawlins MC, Hefty TR. Laparoscopic live donor nephrectomy: a comparison of the conventional open approach. J Urol 2001;165(3):766-9. http://www.ncbi.nlm.nih.gov/pubmed/11176463 Buell JF, Edye M, Johnson M, Li C, Koffron A, Cho E, Kuo P, Johnson L, Hanaway M, Potter SR, Bruce DS, Cronin DC, Newell KA, Leventhal J, Jacobs S, Woodle ES, Bartlett ST, Flowers JL. Are concerns over right laparoscopic donor nephrectomy unwarranted?. Ann Surg 2001;233(5):645-51. http://www.ncbi.nlm.nih.gov/pubmed/11323503 El-Galley R, Hood N, Young CJ, Deierhoi M, Urban DA. Donor nephrectomy: a comparison of techniques and results of open, hand assisted and full laparoscopic nephrectomy. J Urol 2004;171(1):40-3. http://www.ncbi.nlm.nih.gov/pubmed/14665839 Ng CS, Abreu SC, Abou El-Fettouh HI, Kaouk JH, Desai MM, Goldfarb DA, Gill IS. Right retroperitoneal versus left transperitoneal laparoscopic live donor nephrectomy. Urology 2004;63(5):857-61. http://www.ncbi.nlm.nih.gov/pubmed/15134965 Handschin AE, Weber M, Demartines N, Clavien PA. Laparoscopic donor nephrectomy. Br J Surg 2003;90(11):1323-32. http://www.ncbi.nlm.nih.gov/pubmed/14598409

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Ratner LE, Montgomery RA, and Kavoussi LR. Laparoscopic live donor nephrectomy: a review of the first 5 years. Urol Clin North Am 2001;28(4):709-19. http://www.ncbi.nlm.nih.gov/pubmed/11791488 Ruiz-Deya G, Cheng S, Palmer E, Thomas, R. Slakey, D. Open donor, laparoscopic donor and hand assisted laparoscopic donor nephrectomy: a comparison of outcomes. J Urol 2001;166(4):1270-4. http://www.ncbi.nlm.nih.gov/pubmed/11547056 Dalla Valle R, Mazzoni MP, Capocasale E, Busi N, Pietrabissa A, Moretto C, Gualtierotti M, Massa M, Mosca F, Sianesi M. Laparoscopic donor nephrectomy: short learning curve. Transplant Proc 2006;38(4):1001-2. http://www.ncbi.nlm.nih.gov/pubmed/16757244 Berardinelli L. Technical problems in living donor transplantation. Transplant Proc 2005;37(6):2449-50. http://www.ncbi.nlm.nih.gov/pubmed/16182704 Desai MR, Ganpule AP, Gupta R, Thimmegowda M. Outcome of renal transplantation with multiple versus single renal arteries after laparoscopic live donor nephrectomy: a comparative study. Urology 2007;69(5):824-7. http://www.ncbi.nlm.nih.gov/pubmed/17482914 Ruszat R, Wyler SF, Wolff T, Forster T, Lenggenhager C, Dickenmann M, Eugster T, Gürke L, Steiger J, Gasser TC, Sulser T, Bachmann A. Reluctance over right-sided retroperitoneoscopic living donor nephrectomy: justified or not?. Transplant Proc 2007;39(5):1381-5. http://www.ncbi.nlm.nih.gov/pubmed/17580144 Sasaki TM, Finelli F, Bugarin E, Fowlkes D, Trollinger J, Barhyte DY, Light JA. Is laparoscopic donor nephrectomy the new criterion standard?. Arch Surg 2000;135(8):943-7. http://www.ncbi.nlm.nih.gov/pubmed/10922257 Azar SA, Nakhjavani MR, Tarzamni MK, Faragi A, Bahloli A, Badroghli N. Is living kidney donation really safe? Transplant Proc 2007;39(4):822-3. http://www.ncbi.nlm.nih.gov/pubmed/17524822 Hazebroek EJ, Gommers D, Schreve MA, van Gelder T, Roodnat JI, Weimar W, Bonjer HJ, IJzermans JN. Impact of intraoperative donor management on short-term renal function after laparoscopic donor nephrectomy. Ann Surg 2002;236(1):127-32. http://www.ncbi.nlm.nih.gov/pubmed/12131095 Goldfarb DA, Matin SF, Braun WE, Schreiber MJ, Mastroianni B, Papajcik D, Rolin HA, Flechner S, Goormastic M, Novick AC. Renal outcome 25 years after donor nephrectomy. J Urol 2001;166(6):2043-7. http://www.ncbi.nlm.nih.gov/pubmed/11696703 Gres P, Avances C, Iborra F, Mourad G, Guiter J. Long-term morbidity of living donor kidney harvesting. Prog Urol 2007;17(2):194-8. http://www.ncbi.nlm.nih.gov/pubmed/17489317

Organ preservation

2.6.1 Kidney storage solutions There is no agreement on which of the mechanisms listed in Table 14 is most important for post-ischaemic renal graft function (1-6). No storage solution combines all mechanisms. Previously, Euro-Collins was widely used, but is no longer recommended. Today, Celsior-solution, UW- (University of Wisconsin) and HTK(histidine-tryptophane-ketoglutarate) solution are equally effective and are standard for multi-organ or single kidney harvesting procedures (7-10) (level of evidence: 1b). For living donors, in whom a long cold ischaemia time is not expected, perfusion with crystalloid solution (e.g. Ringer-lactate) is sufficient. Table 14: Aims of modern kidney storage solutions* • Control of cell-swelling during hypothermic ischaemia • Maintenance of intra- and extra-cellular electrolyte gradient during ischaemia • Buffering acidosis • Providing energy reserve • Minimising oxidative reperfusion injury *From references 1-6. 2.6.2 Methods of kidney preservation There are two methods of kidney preservation: • Initial flushing with cold preservation solution followed by ice storage.

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 ontinuous pulsatile hypothermic machine-perfusion (clinical relevance for non heart-beating donors C and marginal donors).

2.6.3 Duration of organ preservation The duration of cold ischaemia should be as short as possible. Kidneys from the elderly (> 55 years) and marginal donors are more sensitive to ischaemia than young kidneys (level of evidence: 1b). Organ preservation relies mainly on hypothermia, which lowers the metabolic rate, conserves stores of adenosine triphosphate, and prevents formation of oxygen-free radicals during the reperfusion phase. Recommendations GR • University of Wisconsin (UW)-solution and histidine-tryptophane-ketoglutarate (HTK)-solution A are standard storage solutions and equally effective for both multiorgan-donors and kidney-only donors • Celsior-solution seems to be equally effective B • Keep cold and warm ischaemia times as short as possible for any renal transplant A GR = grade of recommendation 2.6.4 1.

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References Belzer FO, Ashby BS, Dunphy JE. 24-hour and 72-hour preservation of canine kidneys. Lancet 1967;2(7515):536-8. http://www.ncbi.nlm.nih.gov/pubmed/4166894 Collins GM, Bravo-Shugarman M, Terasaki Pl. Kidney preservation for transportation. Initial perfusion and 30 hours’ ice storage. Lancet 1969;2(7632):1219-22. http://www.ncbi.nlm.nih.gov/pubmed/4187813 Cofer JB, Klintmalm GB, Morris CV, Solomon H, Watemberg IA, Husberg BS, Jennings LW. A prospective randomized trial between Euro-Collins and University of Wisconsin solutions as the initial flush in hepatic allograft procurement. Transplantation 1992;53(5):995-8. http://www.ncbi.nlm.nih.gov/pubmed/1585493 Opelz G, Terasaki PI. Advantage of cold storage over machine perfusion for preservation of cadaver kidneys. Transplantation 1982;33(1):64-8. http://www.ncbi.nlm.nih.gov/pubmed/7039024 Buhl MR, Jorgensen S. Breakdown of 5’-adenine nucleotides in ischaemic renal cortex estimated by oxypurine excretion during perfusion. Scand J Clin Lab Invest 1975;35(3):211-17. http://www.ncbi.nlm.nih.gov/pubmed/1153918 Lam FT, Mavor AI, Potts DJ, Giles GR. Improved 72-hour renal preservation with phosphate-buffered sucrose. Transplantation 1989;47(5):767-71. http://www.ncbi.nlm.nih.gov/pubmed/2655211 Agarwal A, Murdock P, Fridell JA. Comparison of histidine-tryptophan ketoglutarate solution and University of Wisconsin solution in prolonged cold preservation of kidney allografts. Transplantation 2006;81(3):480-2. http://www.ncbi.nlm.nih.gov/pubmed/16477239 Booster MH, van der Vusse GJ, Wijnen RM, Yin M, Stubenitsky BM, Kootstra G. University of Wisconsin solution is superior to histidine tryptophanketoglutarate for preservation of ischemically damaged kidneys. Transplantation 1994;58(9):979-84. http://www.ncbi.nlm.nih.gov/pubmed/7974736 De Boer J, De Meester J, Smits JM, Groenewoud AF, Bok A, van der Velde O, Doxiadis II, Persijn GG. Eurotransplant randomized multicenter kidney graft preservation study comparing HTK with UW and Euro-Collins. Transpl Int 1999;12(6):447-53. http://www.ncbi.nlm.nih.gov/pubmed/10654357 Muhlbacher F, Langer F, Mittermayer C. Preservation solutions for transplantation. Transplant Proc 1999;31(5):2069-70. http://www.ncbi.nlm.nih.gov/pubmed/10455972

3. KIDNEY RECIPIENT Kidney transplantation prolongs life, reduces morbidity, improves quality of life, enables social and medical rehabilitation and reduces the costs associated with the medical care of patients with ESRD.

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Kidney transplantation is a surgical procedure, with inherent risks due to anaesthesia and the surgical procedure itself. In addition, the need for continuous immunosuppressive therapy may lead to immunosuppression-related side-effects. The pre-transplant evaluation evaluates potential contraindications and risk factors for transplantation (e.g. malignancy, ongoing infection) (level of evidence: 2b). Recommendation GR • Careful pre-operative work-up of all transplant candidates is mandatory to improve organ B and patient survival in the post-transplant period. The work-up should be repeated regularly GR = grade or recommendation

3.1 Pre-transplant therapy 3.1.1 Abnormal urogenital tract In patients, whose ESRD is caused by either a congenital (i.e. posterior urethral valve, spina bifida, prune belly syndrome, vesico-renal reflux, bladder exstrophy, VATER syndrome) or an acquired malformation (shrunken or neurogenic bladder, neurogenic) of the lower urinary tract, the abnormality should be corrected before transplantation (1-4). Avoid ureteral implantation in a fibrotic, thickened, bladder wall (e.g. following an urethral valve) because of the high risk of surgical complications and/or graft loss (1). In low-compliance bladders, pharmacological therapy (e.g. parasympathicolysis), with or without intermittent self-catheterisation, is necessary. If these methods fail, bladder augmentation is recommended. If catheterisation is not possible, supravesical urinary diversion is crucial. Anatomical or functional urological disorders do not seem to change the outcome of renal transplantation (level of evidence: 3). 3.1.2 Urinary diversion In patients with sphincter insufficiency (e.g. neurogenic bladder) or absent bladder, supravesical urinary diversions must be performed, such as conduits or continent catheterisable pouches. Artificial sphincters may be an alternative. In low-compliance bladders with intact sphincters, both bladder augmentation and continent pouches are successful alternatives (4-9). Most authors prefer to perform a supravesical urinary diversion at least 10-12 weeks before transplantation (6, 8). Bladder augmentation or conduit is possible following transplantation (6). Patients with conduits, augmented or abnormal bladders have an increased risk of urinary infection (1, 4-6). Results can be similar to those in the general population (7, 9-12) (level of evidence: 3). 3.1.3 Indications for pre-transplant nephrectomy Depending on the indication (Table 15), nephrectomy can be done by either an open or laparoscopic approach (level of evidence: 3-4). Table 15: Indications for pre-transplant nephrectomy Autosomal-dominant polycystic kidney disease (ADPKD) • Unilateral or bilateral nephrectomy is necessary if there is not enough space for the transplant kidney, or if there are complications, such as cyst infection, cyst rupture with/without haematuria, pain, or abdominal girth • Nephrectomy can be done before transplantation or simultaneously with similar complication rates and outcomes (2, 13, 14) Medically refractory hypertension • Bilateral nephrectomy usually results in less antihypertensive medications (15). It has become rare due to improved control of hypertension with better dialysis and drugs Chronically infected kidneys Suspected renal or urothelial cancer Urolithiasis • No strong evidence for removal of native kidneys in urolithiasis • Nephrectomy is necessary if there is a possible risk of infection due to stones

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Recommendations GR • In abnormal urogenital tract, meticulous pre-transplant work up is necessary, with B/C urodynamics being the key investigation • If pharmacological therapy or intermittent catheterisation fails or is not possible, urinary B/C diversion is necessary using catheterisable pouches, conduits or cystoplasties • ADPKD with insufficient space or complications, chronic infections, or kidneys with B/C suspected tumour growth have to be removed either pre-operatively or concomitant with transplantation GR = grade of recommendation 3.1.4 1.

2.

3.

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7. 8.

9.

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11.

12.

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References Adams J, Mehls O, Wiesel M. Pediatric renal transplantation and the dysfunctional bladder. Transplant Int 2004;17(10):596-602. http://www.ncbi.nlm.nih.gov/pubmed/15517166 Fuller TF, Brennan TV, Feng S, Kang S, Stock PG, Freise CE. End stage polycystic kidney disease: indications and timing of native nephrectomy relative to kidney transplantation. J Urol 2005;174(6):2284-8. http://www.ncbi.nlm.nih.gov/pubmed/16280813 Fusaro F, Zanon GF, Ferreli AM, Giuliani S, Zacchello G, Psserini-Glazel G, Rigamonti W. Renal transplantation in prune-belly syndrome. Transpl Int 2004;17(9):549-52. http://www.ncbi.nlm.nih.gov/pubmed/15517165 Hamdi M, Mohan P, Little DM, Hickey DP. Successful renal transplantation in children with spina bifida: long term single center experience. Pediat Transplant 2004;8(2):167-70. http://www.ncbi.nlm.nih.gov/pubmed/15049797 Hatch DA, Koyle MA, Baskin LS, Zaontz MR, Burns MW, Tarry WF, Barry JM, Belitsky P, Taylor RJ. Kidney transplantation in children with urinary diversion or bladder augmentation. J Urol 2001;165(6 Pt 2):2265-8. http://www.ncbi.nlm.nih.gov/pubmed/11371960 Koo HP, Bunchman TE, Flynn JT, Punch JD, Schwartz AC, Bloom DA. Renal transplantation in children with severe lower urinary tract dysfunction. J Urol 1999;161(1):240-5. http://www.ncbi.nlm.nih.gov/pubmed/10037414 Mendizabal S, Estornell F, Zamora I, Sabater A, Carcia Ibarra F, Simon J. Renal transplantation in children with severe bladder dysfunction. J Urol 2005;173(1):226-9. http://www.ncbi.nlm.nih.gov/pubmed/15592081 Power RE, O’Malley KJ, Little DM, Donovan MG, Creagh TA, Murphy DM, Hickey DP. Long-term followup of cadaveric renal transplantation in patients with spina bifida. J Urol 2002;167(2 Pt 1):477-9. http://www.ncbi.nlm.nih.gov/pubmed/11792900 Rigamonti W, Capizzi A, Zacchello G, Capizzi V, Zanon GF, Montini G, Murer L, Glazel GP. Kidney transplantation into bladder augmentation or urinary diversion: long-term results. Transplantation 2005;80(10):1435-40. http://www.ncbi.nlm.nih.gov/pubmed/16340788 Luke, PP, Herz DB, Bellinger MF, Chakrabarti P, Vivas CA, Scantlebury VP, Hakala TR, Jevnikar AM, Jain A, Shapiro R, Jordan ML. Long-term results of pediatric renal transplantation into a dysfunctional lower urinary tract. Transplantation 2003;76(11):1578-82. http://www.ncbi.nlm.nih.gov/pubmed/14702527 Nahas WC, Mazzucchi E, Arap MA, Antonopoulos IM, Neto ED, Ianhez LE, Arap S. Augmentation cystoplasty in renal transplantation: a good and safe option-experience with 25 cases. Urology 2002;60(5):770-4. http://www.ncbi.nlm.nih.gov/pubmed/12429293 Ozcan O, Tekgul S, Duzova A, Aki F, Yuksel S, Bakkaloglu A, Erkan I, Bakkaloglu M. How does the presence of urologic problems change the outcome of kidney transplantation in the pediatric age group. Transplant Proc 2006;38(2):552-3. http://www.ncbi.nlm.nih.gov/pubmed/16549172 Glassman DT, Nipkow L, Bartlett ST, Jacobs SC. Bilateral nephrectomy with concomitant renal graft transplantation for autosomal dominant polycystic kidney disease. J Urol 2000;164(3 Pt 1):661-4. http://www.ncbi.nlm.nih.gov/pubmed/10953121 Rozanski J, Kozlowska I, Myslak M, Domanski L, Sienko J, Ciechanowski K, Ostrowski M. Pretransplant nephrectomy in patients with autosomal dominant polycystic kidney disease. Transplant Proc 2005;37(2):666-8. http://www.ncbi.nlm.nih.gov/pubmed/15848495

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15.

Power RE, Calleary JG, Hickey DP. Pre-transplant bilateral native nephrectomy for medically refractory hypertension. Ir Med J 2001;94(7):214-6. http://www.ncbi.nlm.nih.gov/pubmed/11693214

3.2

Selection and refusal criteria

3.2.1 Contraindications 3.2.1.1 Malignancy Active malignancy is a contraindication for transplantation because immunosuppressive therapy may aggravate underlying malignancy, jeopardising the patient’s life and long-term success of the transplant (1-3). Patients with a history of malignancy should be cured (see Chapter 8 - Malignancy). 3.2.1.2 Infection Infections can be a major cause of morbidity and mortality in transplanted patients, especially under intense immunosuppressive therapy. As part of the pre-transplant work-up, carry out screening for infections to exclude any active infections, which might jeopardise the immediate outcome post transplant (1-3). In contrast, chronic infection does not cause an immediate post-operative risk. If chronic infection is detected, counsel the patient and treat it before transplantation or take prophylactic measures after transplantation. Screening for infections also documents the recipient’s infectious status in case of disease transmission from the donor. In cases of previous negative serology for CMV, HBV, HCV and HIV recipients, serology should be repeated at the time of transplantation. A record of the viral status before transplantation enables graft transmission of disease to be firmly excluded. Finally, the recipient’s infectious status may have implications for the allocation of organs (level of evidence: 3). If the patient’s history or physical examination suggests an underlying infection, a thorough examination should be instituted, which may involve physicians from other subspecialties, such as an ear, nose and throat specialist, dentist, dermatologist, urologist and gynaecologist, to firmly rule out infectious foci (1-3) ( level of evidence: 3). Important infections screened prior to transplantation are HBV, HCV, HIV, tuberculosis (TB), cytomegalovirus (CMV), and Treponema pallidum (1-3). Testing of HBV and HCV serology is particularly important, because viral hepatitis is the major cause of liver disease after renal transplantation and contributes to post-transplant morbidity and mortality (4, 5, 6) (level of evidence: 3). A liver biopsy may be needed to assess disease status in patients positive for HBV or HCV before transplantation. Consider antiviral therapy before transplantation according to current guidelines (7, 8, 9) (level of evidence: 3). The serological CMV status of all recipients should be determined (1-3) (level of evidence 3). Current immunosuppressive regimens are associated with a high incidence of potentially life-threatening CMV disease (4, 10) that is, however, preventable with the appropriate prophylactic strategy (level of evidence: 1a). HIV screening is recommended because active HIV disease is a contraindication for transplantation (1-3). However, retrospective studies show that renal transplantation can be successful in well-controlled (no detectable viral load) and treated HIV-positive recipients (3) (level of evidence: 3). A history of TB is important because adequate preventive measures (e.g. isoniazid prophylaxis; 11, 12) will avoid reactivation of TB under heavy post-transplant immunosuppression (level of evidence: 1a). Screening for TB requires a careful history and chest X-ray (1-3) (level of evidence: 3). Screening for T. pallidum has been previously recommended (1, 2). However, due to the low incidence of disease, it is not strongly recommended for all potential transplant candidates. A Treponema haemaglutination (TPHA)-test may be performed in populations with a higher risk for disease (level of evidence: 3). Screening for Epstein Barr virus (EBV) has been suggested in children and young adults (13), because of their higher risk for the development of EBV-related lymphoproliferative disease. General EBV screening is not recommended (level of evidence: 3) Recommendations GR • Active infection, which may exacerbate after transplantation causing life-threatening B infection, is a contraindication to transplantation • Carry out screening for viral and bacterial diseases in all transplant candidates B Screen all patients for HBV, HCV, HIV and CMV and TB (history and chest X-ray) • Routine screening examination of all patients in all subspecialties is not necessary B GR = grade of recommendation

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3.2.1.3 Other contraindications for transplantation Transplantation should be offered to patients with potential for long-term survival of the graft because of the scarcity of organs, the complexity of the transplant procedure, and increased mortality associated with the transplant procedure itself. A short life expectancy and conditions (e.g. severe psychiatric disease) that interfere with compliance are not acceptable risks for long-term success of transplantation. If there is non-compliance, a careful psychological examination should try to identify the underlying cause (14) and if possible institute an adequate treatment (15). Non-compliance is not a lifelong determinant of a personality and re-evaluation may be needed. Recommendation GR • In severe co-morbidity or non-compliance, a thorough and individual assessment should be C performed GR = grade of recommendation 3.2.2 Co-morbidity Due to the inherent risks of the surgical procedure, anesthesia and post transplant immunosuppressive therapy a careful evaluation of potential transplant recipients is very important, particularly a cardiovascular work-up to reduce early graft failure due to technical problems and to improve patient survival in the post-transplant period (1-3). 3.2.2.1 Cardiac disease Death with a functioning kidney allograft occurs frequently in kidney-transplanted patients, with cardiac death being the most important cause (16). Nevertheless, uraemic patients with cardiovascular disease are more likely to survive with a renal transplant compared to dialysis (17, 18). However, patients with cardiac diease have a higher peri-operative risk (19, 20). All candidates should therefore be given a careful history and physical examination for cardiac disease, including an electrocardiogram and chest X-ray (21) (level of evidence: 3). An additional, extensive, cardiac work-up is recommended for patients with a history of coronary heart disease, severe peripheral artery disease, or a history of stroke or severe occlusive cerebrovascular disease, and a long history of renal insufficiency/dialysis (22, 23), as well as for elderly and/or diabetic patients (22, 24, 25) (level of evidence: 3). The work-up includes (22, 23): • Echocardiography to detect valvular disease, cardiomyopathy, and systolic and/or diastolic left ventricular dysfunction (26). • Exercise electrocardiogram and/or exercise thallium scintigraphy or stress echocardiography in patients with a low exercise capacity (22, 23). • Coronary angiography in every suspicious case, especially in dialysis patients who are elderly and/or diabetic, or in patients with a long history of renal disease (27). Revascularisation, either surgical, or by coronary angioplasty, should be performed in every suitable transplant candidate (18, 24) before transplantation (level of evidence: 3) Recommendations GR • Pre-transplant work-up should focus on the presence of cardiac disease B • In patients with a high risk of cardiac disease, an extensive work-up is strongly B recommended to firmly rule out coronary artery disease • Perform any revascularisation before transplantation B GR = grade of recommendation 3.2.2.2 Peripheral artery disease, cerebral occlusive vascular disease Peripheral artery disease is common in uraemic patients (28). In potential kidney transplant recipients, very severe pelvic vessel disease may prohibit transplantation, be a significant cause of technical graft failure, and may enhance the risk of amputation. Cerebral vascular occlusion may lead to post-operative morbidity and mortality (29, 30). Evaluate the patient carefully for signs and symptoms of vascular occlusive disease. Pelvic radiography should be done routinely before transplantation (31, 32). If there is vascular calcification, signs and symptoms or risk factors (e.g. age, diabetes, length of time on dialysis) of vascular occlusive disease, perform a thorough work-

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up, including duplex ultrasonography of the peripheral and cerebral arteries (33), and/or non-contrast enhanced abdominal-pelvic CT scan. In selected patients, angiography and pre-transplant arterial repair can be indicated. Avoid contrast-enhanced magnetic resonance imaging (MRI) because of the risk of nephrogenic systemic fibrosis (34) (level of evidence: 3). Recommendation GR • During pre-transplant work-up, special attention should be paid to iliacal, peripheral and C cerebrovascular disease. Appropriate diagnostic and therapeutic measures are recommended GR = grade of recommendation 3.2.2.3 Diabetes mellitus Patients with diabetes mellitus have an increased mortality and reduced long-term graft outcome compared to non-diabetic patients following kidney transplantation (35). Nevertheless, diabetes mellitus itself is not a contraindication for kidney transplant (1-3). Furthermore, a kidney-only transplant or a combined kidneypancreas transplant will reduce the long-term morbidity and mortality of uraemic diabetic patients compared to dialysis (36, 37) (level of evidence: 3). Thus, kidney transplantation should be considered in every diabetic uraemic patient who has no other severe contraindication, especially cardiovascular disease. In patients with diabetes type I, a combined kidney-pancreas transplant is preferred because it improves blood glucose control and slows progression of cardiovascular disease (38, 39) (evel of evidence: 3). Because there is an exceptionally high incidence of cardiovascular disease in diabetic dialysis patients (2123), it is usually necessary to exclude patients with a high vascular risk using peripheral angiography or noninvasive imaging procedures (e.g. CT scan) (27). Bladder neuropathy is a common complication in diabetic patients (40) and a urological clinical work-up should be performed. In selected patients, an urodynamic examination is needed (level of evidence: 3). Recommendation GR • Patients with diabetes mellitus should be transplanted. They require an extensive B pre-transplant work-up GR = grade of recommendation 3.2.2.4 Obesity Overweight patients have a higher incidence of surgical and non-surgical complications (41, 42). Weight is a traditional risk factor for diabetes, hypertension and cardiovascular disease. However, renal transplantation provides a better survival and better quality of life in overweight dialysis patients (43, 44) (level of evidence: 3). There is not enough evidence to recommend exclusion based on body mass index (BMI). Recommendation GR • Obesity itself is not a contraindication for transplantation. However, a thorough C pre-transplant evaluation and attempt to reduce weight are recommended GR = grade of recommendation 3.2.2.5 Coagulopathies Coagulation disorders have a negative impact on post-transplant graft survival, leading to early graft thrombosis or post-transplant thrombotic complications (45, 46). Early post-transplant anticoagulation may prevent thrombosis and early graft loss (47, 48). As a consequence, a pre-transplant work-up should include the diagnosis of coagulopathies, especially in patients with recurrent shunt thrombosis or with a history of thrombotic events. In these patients, a careful pre-transplant assessment is mandatory, including ATIII, protein C, activated protein C resistance (Factor V Leiden), protein S, and anti-phospholipid antibodies (level of evidence: 3). Patients on anticoagulant treatment, e.g. warfarin, acetylsalicylic acid, clopidogrel, are not excluded from transplantation. During surgery, special precautions for anticoagulant use are needed. Recommendation GR • A careful examination of coagulopathies in patients at risk in order to prevent early C post-transplant thrombotic events is recommended GR = grade of recommendation

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3.2.2.6 Other diseases with potential influence on post-transplant outcome Some conditions or diseases may follow an aggravated clinical course after transplantation due to immunosuppressive therapy and/or may place the transplanted kidney at a higher risk for complications (1-3). Important examples are diverticulosis, with or without previous episodes of diverticulitis, cholecystolithiasis and hyperparathyroidism. Decisions for pre-transplant treatment should be made by a multidisciplinary team on an individual basis with appropriate patient counselling. (Level of evidence 4) Mental retardation and psychiatric diseases are not necessarily contraindications for transplantation (1-3). If the patient is able to understand the procedure and can adhere to the procedures and medication required, such patients are eligible for transplantation (level of evidence: 4). Recommendation GR • Diseases that might influence post-transplant course should be identified during C pre-transplant work-up and if possible treated before transplantation GR = grade of recommendation 3.2.3 Age Although there is no controversy about the fact that a kidney transplant offers improved survival and quality of life in younger patients with ESRD, an ongoing debate exists about kidney transplants in the elderly. Reduced mortality in patients over 65 years has been shown in transplanted patients compared to patients on the waiting list (35, 36) and reasonable outcomes have been reported for elderly transplant recipients (49, 50) (level of evidence: 3). However, a prolonged waiting time in this patient subgroup significantly decreases the beneficial clinical outcome and socio-economic advantages of transplantation (51, 52) Every effort should be taken to reduce waiting times in the elderly (over 65 years). Elderly transplant patients should be enrolled in special programmes such as the Eurotransplant (ET) Senior programme (50), as well as applying for livingdonor transplantation (level of evidence: 3). In elderly dialysis patients selected for kidney transplantation, special attention must be paid to concomitant cardiovascular disease and possible pre-existing cancer (53). Patients should be informed about the potential hazards of transplantation, including a high fatality rate in the first year after transplantation (and infection during the first year post-transplant (49, 50, 53-56) (level of evidence: 3). If there are any signs of age-related dementia, a psychological evaluation should be instituted. Recommendation GR • Although age itself is not a contraindication for transplantation, a thorough pre-transplant B evaluation is needed. A careful risk-benefit evaluation must be performed and the patient should be counselled on the increased risks associated with age GR = grade of recommendation 3.2.4 Recurrence risk (original renal disease) An histological recurrence of original renal disease is common in a transplanted kidney. Despite high recurrence rates in some diseases, overall graft loss due to recurrence is less than 10% after 10 years (57, 58). Higher recurrence rates have occurred in living related donors and living donation should therefore be critically discussed, especially in diseases with early and very high recurrence rates (level of evidence: 3). Some rare renal diseases with a high recurrence rate, which can lead to an immediate graft loss, are contraindications for transplant. They include light-chain deposit disease (LCDD), primary oxalosis, and anti-glomerular basement (anti-GBM) antibodies) (1-3). However, transplants may still be possible in some circumstances: • Patients with anti-GBM disease can be given a transplant after disappearance of anti-GBM antibodies (1-3) (level of evidence: 3). • In patients with primary oxalosis, combined liver-kidney transplantation is recommended (1-3) (level of evidence: 3). • In patients with amyloidosis or LCDD, no treatment guidelines exist. In this very rare group of patients, case reports and small case series describe successful chemotherapy or autologous stem cell transplantation, with or without kidney transplantation (59-61) (level of evidence: 3). In patients with systemic diseases (e.g. lupus, vasculitis, haemolytic uraemic syndrome), the underlying disease should be treated and the patient should be in remission before transplantation (1-3) (level of evidence: 3)

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For most patients with glomerulonephritis, no special precautions are recommended (1-3). Focal and segmental glomerulosclerosis (FSGS) may recur early after transplantation (62, 63) and may be treated with plasmapheresis and/or with anti-CD20 antibody (rituximab) (64, 65) When a previous graft has been lost because of recurrent glomerulonephritis, especially FSGS, the patient must be counselled on the higher risk of graft failure in a second transplant. However, successful long-term outcomes have occurred in these patients. (62, 63) (level of evidence: 3). Recommendations GR • Recurrence of the original disease is common, but graft loss due to recurrence is infrequent C • Only a few rare diseases with a high recurrence rate leading to early graft loss are a C contraindication for renal transplant • Patients with the risk of recurrent diseases should be counselled before transplantation, C especially before living related kidney transplant GR = grade of recommendation 3.2.5 Patients with a previous transplant Assess patients with a previous graft loss carefully for malignancy, cardiovascular disease (1-3) and for increased immunological risk because of the development of antibodies against the first graft (66). Gradually discontinue immunosuppression following graft failure, as continuous immunosuppressive therapy has a higher risk of complications under renal replacement therapy (67, 68) (level of evidence: 3). If the graft becomes symptomatic, perform graft nephrectomy immediately (69). Graft embolisation (70) may be an alternative. However, prophylactic transplantectomy does not seem to be beneficial (71-73). Take appropriate measures to avoid repeated alloantigen mismatches (level of evidence: 3). Patients with a previous non-renal organ transplant, who develop ESRD (74, 75), also benefit from renal transplantation, as there is a high risk of severe complications with a combination of ESRD and continuous immunosuppressive therapy (76) (level of evidence: 3) . Work-up should pay special attention to malignancy, cardiovascular disease, potential immunisation, and potential graft dysfunction of the previously transplanted organ, which may therefore require a combined transplant procedure (level of evidence: 3). Recommendation • Pre-transplant work-up for patients with retransplantation or previous non-renal transplantation should focus on the immunological risk, including a thorough analysis for the presence of anti-HLA antibodies 3.2.6 1.

2.

3.

4.

5. 6.

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References EBPG (European Expert Group on Renal Transplantation); European Renal Association (ERA-EDTA); European Society for Organ Transplantation (ESOT). European Best Practice Guidelines for Renal Transplantation (part 1). Nephrol Dial Transplant 2000;15(Suppl 7):1-85. http://www.ncbi.nlm.nih.gov/pubmed/11286185 Kasiske BL, Cangro CB, Hariharan S, Hricik DE, Kerman RH, Roth D, Rush DN, Vazquez MA, Weir MR; American Society of Transplantation. The evaluation of renal transplantation candidates: clinical practice guidelines. Am J Transplant 2001;1(Suppl 2):3-95. http://www.ncbi.nlm.nih.gov/pubmed/12108435 Knoll G, Cockfield S, Blydt-Hansen T, Baran D, Kiberd B, Landsberg D, Rush D, Cole E; Kidney Transplant Working Group of the Canadian Society of Transplantation. Canadian Society of Transplantation consensus guidelines on eligibility for kidney transplantation. CMAJ 2005;173(10):1181-4. http://www.ncbi.nlm.nih.gov/pubmed/16275969 Kotton CN, Fishman JA. Viral infection in the renal transplant recipient. J Am Soc Nephrol 2005;16(6):1758-74. http://www.ncbi.nlm.nih.gov/pubmed/15829710 Viral hepatitis guidelines in hemodialysis and transplantation. Am J Transplant 2004;4(Suppl 10):72-82. http://www.ncbi.nlm.nih.gov/pubmed/15504218 Barclay S, Pol S, Mutimer D, Benhamou Y, Mills PR, Hayes PC, Cameron S, Carman W. The management of chronic hepatitis B in the immunocompromised patient: recommendations from a single topic meeting. J Clin Virol 2008;41(4):243-54. http://www.ncbi.nlm.nih.gov/pubmed/18203658

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15. 16.

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22. 23.

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Broumand B, Hakemi MS, Sabet MS. Impact of hepatitis C virus infection on short-term outcomes in renal transplantation. Exp Clin Transplant 2004;2(2):242-5. http://www.ncbi.nlm.nih.gov/pubmed/15859935 Fabrizi F, Marzano A, Messa P, Martin P, Lampertico P. Hepatitis B virus infection in the dialysis population: current perspectives. Int J Artif Organs 2008;31(5):386-94. http://www.ncbi.nlm.nih.gov/pubmed/18609511 Okoh EJ, Bucci JR, Simon JF, Harrison SA. HCV in patients with end-stage renal disease. Am J Gastroenterol 2008;103(8):2123-34. http://www.ncbi.nlm.nih.gov/pubmed/18796105 Snydman DR. The case for cytomegalovirus prophylaxis in solid organ transplantation. Rev Med Virol 2006;16(5):289-95. http://www.ncbi.nlm.nih.gov/pubmed/16888821 Naqvi R, Akhtar S, Noor H, Saeed T, Bhatti S, Sheikh R, Ahmed E, Akhtar F, Naqvi A, Rizvi A. Efficacy of isoniazid prophylaxis in renal allograft recipients. Transplant Proc 2006;38(7):2057-8. http://www.ncbi.nlm.nih.gov/pubmed/16979998 Vikrant S, Agarwal SK, Gupta S, Bhowmik D, Tiwari SC, Dash SC, Guleria S, Mehta SN. Prospective randomized control trial of isoniazid chemoprophylaxis during renal replacement therapy. Transpl Infect Dis 2005;7(3-4):99-108. http://www.ncbi.nlm.nih.gov/pubmed/16390397 Okano M, Gross TG. Advanced therapeutic and prophylactic strategies for Epstein-Barr virus infection in immunocompromised patients. Expert Rev Anti Infect Ther 2007;5(3):403-13. http://www.ncbi.nlm.nih.gov/pubmed/17547505 Dobbels F, Van Damme-Lombaert R, Vanhaecke J, De Geest S. Growing pains: non-adherence with the immunosuppressive regimen in adolescent transplant recipients. Pediatr Transplant 2005;9(3): 381-90. http://www.ncbi.nlm.nih.gov/pubmed/15910397 Baines LS, Zawada ET Jr, Jindal RM. Psychosocial profiling: a holistic management tool for noncompliance. Clin Transplant 2005;19(1):38-44. http://www.ncbi.nlm.nih.gov/pubmed/15659132 Chang SH, Russ GR, Chadban SJ, Campbell SB, McDonald SP. Trends in kidney transplantation in Australia and New Zealand, 1993-2004. Transplantation 2007;84(5):611-8. http://www.ncbi.nlm.nih.gov/pubmed/17876274 Meier-Kriesche HU, Schold JD, Srinivas TR, Reed A, Kaplan B. Kidney transplantation halts cardiovascular disease progression in patients with end-stage renal disease. Am J Transplant 2004;4(10):1662-8. http://www.ncbi.nlm.nih.gov/pubmed/15367222 Jeloka TK, Ross H, Smith R, Huang M, Fenton S, Cattran D, Schiff J, Cardella C, Cole E. Renal transplant outcome in high-cardiovascular risk recipients. Clin Transplant 2007;21(5):609-14. http://www.ncbi.nlm.nih.gov/pubmed/17845634 Lentine KL, Brennan DC, Schnitzler MA. Incidence and predictors of myocardial infarction after kidney transplantation. J Am Soc Nephrol 2005;16(2):496-506. http://www.ncbi.nlm.nih.gov/pubmed/15615820 Kasiske BL, Maclean JR, Snyder JJ. Acute myocardial infarction and kidney transplantation. J Am Soc Nephrol 2006;17(3):900-7. http://www.ncbi.nlm.nih.gov/pubmed/16481414 Woo YM, McLean D, Kavanagh D, Ward L, Aitken S, Miller GJ, Egan P, Hughes K, Clark L, Carswell K, Morris ST, Northridge DB, Rodger RS, Jardine AG.The influence of pre-operative electrocardiographic abnormalities and cardiovascular risk factors on patient and graft survival following renal transplantation. J Nephrol 2002;15(4):380-6. http://www.ncbi.nlm.nih.gov/pubmed/12243367 Pilmore H. Cardiac assessment for renal transplantation. Am J Transplant 2006;6(4):659-65. http://www.ncbi.nlm.nih.gov/pubmed/16539621 Kasiske BL, Malik MA, Herzog CA. Risk-stratified screening for ischemic heart disease in kidney transplant candidates. Transplantation 2005;80(6):815-20. http://www.ncbi.nlm.nih.gov/pubmed/16210970 Lentine KL, Schnitzler MA, Brennan DC, Snyder JJ, Hauptman PJ, Abbott KC, Axelrod D, Salvalaggio PR, Kasiske B. Cardiac evaluation before kidney transplantation: a practice patterns analysis in Medicare-insured dialysis patients. Clin J Am Soc Nephrol 2008;3(4):1115-24. http://www.ncbi.nlm.nih.gov/pubmed/18417743

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26.

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28.

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40.

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Ohtake T, Kobayashi S, Moriya H, Negishi K, Okamoto K, Maesato K, Saito S. High prevalence of occult coronary artery stenosis in patients with chronic kidney disease at the initiation of renal replacement therapy: an angiographic examination. J Am Soc Nephrol 2005;16(4):1141-8. http://www.ncbi.nlm.nih.gov/pubmed/15743997 Sharma R, Chemla E, Tome M, Mehta RL, Gregson H, Brecker SJ, Chang R, Pellerin D. Echocardiography-based score to predict outcome after renal transplantation. Heart 2007;93(4):464-9. http://www.ncbi.nlm.nih.gov/pubmed/16980518 Witczak BJ, Hartmann A, Jenssen T, Foss A, Endresen K. Routine coronary angiography in diabetic nephropathy patients before transplantation. Am J Transplant 2006;6(10):2403-8. http://www.ncbi.nlm.nih.gov/pubmed/16952302 Snyder JJ, Kasiske BL, Maclean R. Peripheral arterial disease and renal transplantation. J Am Soc Nephrol 2006;17(7):2056-68. http://www.ncbi.nlm.nih.gov/pubmed/16775031 Oliveras A, Roquer J, Puig JM, Rodríguez A, Mir M, Orfila MA, Masramon J, Lloveras J. Stroke in renal transplant recipients: epidemiology, predictive risk factors and outcome. Clin Transplant 2003;17(1): 1-8. http://www.ncbi.nlm.nih.gov/pubmed/12588314 Lentine KL, Rey LA, Kolli S, Bacchi G, Schnitzler MA, Abbott KC, Xiao H, Brennan DC. Variations in the risk for cerebrovascular events after kidney transplant compared with experience on the waiting list and after graft failure. Clin J Am Soc Nephrol 2008;3(4):1090-101. http://www.ncbi.nlm.nih.gov/pubmed/18385393 Zeier M, Ritz E.Preparation of the dialysis patient for transplantation. Nephrol Dial Transplant 2002;17(4):552-6. http://www.ncbi.nlm.nih.gov/pubmed/11917044 Fritsche L, Budde K, Neumayer HH. Evaluating candidates for kidney transplantation: some recommendations still lack convincing clinical evidence. Nephrol Dial Transplant 2003;18(3):621-2. http://www.ncbi.nlm.nih.gov/pubmed/12584294 Aull-Watschinger S, Konstantin H, Demetriou D, Schillinger M, Habicht A, Hörl WH, Watschinger B. Pre-transplant predictors of cerebrovascular events after kidney transplantation. Nephrol Dial Transplant 2008;23(4):1429-35. http://www.ncbi.nlm.nih.gov/pubmed/18045824 Bhave G, Lewis JB, Chang SS. Association of gadolinium based magnetic resonance imaging contrast agents and nephrogenic systemic fibrosis. J Urol 2008;180(3):830-5. http://www.ncbi.nlm.nih.gov/pubmed/18635232 Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, Held PJ, Port FK. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999;341(23):1725-30. http://www.ncbi.nlm.nih.gov/pubmed/10580071 Merion RM, Ashby VB, Wolfe RA, Distant DA, Hulbert-Shearon TE, Metzger RA, Ojo AO, Port FK. Deceased-donor characteristics and the survival benefit of kidney transplantation. JAMA 2005;294(21):2726-33. http://www.ncbi.nlm.nih.gov/pubmed/16333008 Luan FL, Miles CD, Cibrik DM, Ojo AO. Impact of simultaneous pancreas and kidney transplantation on cardiovascular risk factors in patients with type 1 diabetes mellitus. Transplantation 2007;84(4):541-4. http://www.ncbi.nlm.nih.gov/pubmed/17713440 Reddy KS, Stablein D, Taranto S, Stratta RJ, Johnston TD, Waid TH, McKeown JW, Lucas BA, Ranjan D. Long-term survival following simultaneous kidney-pancreas transplantation versus kidney transplantation alone in patients with type 1 diabetes mellitus and renal failure. Am J Kidney Dis 2003;41(2):464-70. http://www.ncbi.nlm.nih.gov/pubmed/12552511 Becker BN, Odorico JS, Becker YT, Groshek M, Werwinski C, Pirsch JD, Sollinger HW. Simultaneous pancreas-kidney and pancreas transplantation. J Am Soc Nephrol 2001;12(11):2517-27. http://www.ncbi.nlm.nih.gov/pubmed/11675431 Fedele D. Therapy insight: sexual and bladder dysfunction associated with diabetes mellitus. Nat Clin Pract Urol 2005;2(6):282-90. http://www.ncbi.nlm.nih.gov/pubmed/16474810 Gore JL, Pham PT, Danovitch GM, Wilkinson AH, Rosenthal JT, Lipshutz GS, Singer JS. Obesity and outcome following renal transplantation. Am J Transplant 2006;6(2):357-63. http://www.ncbi.nlm.nih.gov/pubmed/16426321

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Pelletier SJ, Maraschio MA, Schaubel DE, Dykstra DM, Punch JD, Wolfe RA, Port FK, Merion RM. Survival benefit of kidney and liver transplantation for obese patients on the waiting list. Clin Transpl 2003:77-88. http://www.ncbi.nlm.nih.gov/pubmed/15387099 Schold JD, Srinivas TR, Guerra G, Reed AI, Johnson RJ, Weiner ID, Oberbauer R, Harman JS, Hemming AW, Meier-Kriesche HU. A ‘weight-listing’ paradox for candidates of renal transplantation? Am J Transplant 2007;7(3):550-9. http://www.ncbi.nlm.nih.gov/pubmed/17173655 Schnitzler MA, Salvalaggio PR, Axelrod DA, Lentine KL, Takemoto SK. Lack of interventional studies in renal transplant candidates with elevated cardiovascular risk. Am J Transplant 2007;7(3):493-4. http://www.ncbi.nlm.nih.gov/pubmed/17250551 Heidenreich S, Junker R, Wolters H, Lang D, Hessing S, Nitsche G, Nowak-Göttl U. Outcome of kidney transplantation in patients with inherited thrombophilia: data of a prospective study. J Am Soc Nephrol 2003;14(1):234-9. http://www.ncbi.nlm.nih.gov/pubmed/12506156 Kranz B, Vester U, Nadalin S, Paul A, Broelsch CE, Hoyer PF. Outcome after kidney transplantation in children with thrombotic risk factors. Pediatr Transplant 2006;10(7):788-93. http://www.ncbi.nlm.nih.gov/pubmed/17032424 Irish A. Hypercoagulability in renal transplant recipients. Identifying patients at risk of renal allograft thrombosis and evaluating strategies for prevention. Am J Cardiovasc Drugs 2004;4(3):139-49. http://www.ncbi.nlm.nih.gov/pubmed/15134466 Friedman GS, Meier-Kriesche HU, Kaplan B, Mathis AS, Bonomini L, Shah N, DeFranco P, Jacobs M, Mulgaonkar S, Geffner S, Lyman N, Paraan C, Walsh C, Belizaire W, Tshibaka M. Hypercoagulable states in renal transplant candidates: impact of anticoagulation upon incidence of renal allograft thrombosis. Transplantation 2001;72(6):1073-8. http://www.ncbi.nlm.nih.gov/pubmed/11579303 Rao PS, Merion RM, Ashby VB, Port FK, Wolfe RA, Kayler LK. Renal transplantation in elderly patients older than 70 years of age: results from the Scientific Registry of Transplant Recipients. Transplantation 2007;83(8):1069-74. http://www.ncbi.nlm.nih.gov/pubmed/17452897 Frei U, Noeldeke J, Machold-Fabrizii V, Arbogast H, Margreiter R, Fricke L, Voiculescu A, Kliem V, Ebel H, Albert U, Lopau K, Schnuelle P, Nonnast-Daniel B, Pietruck F, Offermann R, Persijn G, Bernasconi C. Prospective age-matching in elderly kidney transplant recipients–a 5-year analysis of the Eurotransplant Senior Program. Am J Transplant 2008;8(1):50-7. http://www.ncbi.nlm.nih.gov/pubmed/17973969 Meier-Kriesche HU, Kaplan B. Waiting time on dialysis as the strongest modifiable risk factor for renal transplant outcomes: a paired donor kidney analysis. Transplantation 2002;74(10):1377-81. http://www.ncbi.nlm.nih.gov/pubmed/12451234 Schold JD, Meier-Kriesche HU. Which renal transplant candidates should accept marginal kidneys in exchange for a shorter waiting time on dialysis? Clin J Am Soc Nephrol 2006;1(3):532-8. http://www.ncbi.nlm.nih.gov/pubmed/17699256 de Fijter JW. An old virtue to improve senior programs. Transpl Int 2008 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/18954372 Giessing M, Budde K, Fritsche L, Slowinski T, Tuerk I, Schoenberger B, Neumayer HH, Loening SA. ‘Old-for-old’ cadaveric renal transplantation: surgical findings, perioperative complications and outcome. Eur Urol 2003;44(6):701-8. http://www.ncbi.nlm.nih.gov/pubmed/14644123 Bentas W, Jones J, Karaoguz A, Tilp U, Probst M, Scheuermann E, Hauser IA, Jonas D, Gossmann J. Renal transplantation in the elderly: surgical complications and outcome with special emphasis on the Eurotransplant Senior Programme. Nephrol Dial Transplant 2008;23(6):2043-51. http://www.ncbi.nlm.nih.gov/pubmed/18203840 Bodingbauer M, Pakrah B, Steininger R, Berlakovich G, Rockenschaub S, Wekerle T, Muehlbacher F. The advantage of allocating kidneys from old cadaveric donors to old recipients: a single-center experience. Clin Transplant 2006;20(4):471-5. http://www.ncbi.nlm.nih.gov/pubmed/16842524 Briganti EM, Russ GR, McNeil JJ, Atkins RC, Chadban SJ. Risk of renal allograft loss from recurrent glomerulonephritis. N Engl J Med 2002;347(2):103-9. http://www.ncbi.nlm.nih.gov/pubmed/12110738

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Golgert WA, Appel GB, Hariharan S. Recurrent glomerulonephritis after renal transplantation: an unsolved problem. Clin J Am Soc Nephrol 2008;3(3):800-7. http://www.ncbi.nlm.nih.gov/pubmed/18272827 Leung N, Griffin MD, Dispenzieri A, Haugen EN, Gloor JM, Schwab TR, Textor SC, Lacy MQ, Litzow MR, Cosio FG, Larson TS, Gertz MA, Stegall MD. Living donor kidney and autologous stem cell transplantation for primary systemic amyloidosis (AL) with predominant renal involvement. Am J Transplant 2005;5(7):1660-70. http://www.ncbi.nlm.nih.gov/pubmed/15943624 Bergesio F, Ciciani AM, Manganaro M, Palladini G, Santostefano M, Brugnano R, Di Palma AM, Gallo M, Rosati A, Tosi PL, Salvadori M; Immunopathology Group of the Italian Society of Nephrology. Renal involvement in systemic amyloidosis: an Italian collaborative study on survival and renal outcome. Nephrol Dial Transplant 2008;23(3):941-51. http://www.ncbi.nlm.nih.gov/pubmed/17951308 Lorenz EC, Gertz MA, Fervenza FC, Dispenzieri A, Lacy MQ, Hayman SR, Gastineau DA, Leung N. Long-term outcome of autologous stem cell transplantation in light chain deposition disease. Nephrol Dial Transplant 2008;23(6):2052-7. http://www.ncbi.nlm.nih.gov/pubmed/18178602 Vincenti F, Ghiggeri GM. New insights into the pathogenesis and the therapy of recurrent focal glomerulosclerosis. Am J Transplant 2005;5(6):1179-85. http://www.ncbi.nlm.nih.gov/pubmed/15888021 Fine RN. Recurrence of nephrotic syndrome/focal segmental glomerulosclerosis following renal transplantation in children. Pediatr Nephrol 2007;22(4):496-502. http://www.ncbi.nlm.nih.gov/pubmed/17186280 Bayrakci US, Baskin E, Sakalli H, Karakayali H, Haberal M. Rituximab for post-transplant recurrences of FSGS. Pediatr Transplant 2008 Sep 4. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/18822107 Yabu JM, Ho B, Scandling JD, Vincenti F. Rituximab failed to improve nephrotic syndrome in renal transplant patients with recurrent focal segmental glomerulosclerosis. Am J Transplant 2008;8(1): 222-7. http://www.ncbi.nlm.nih.gov/pubmed/17979998 Arnold ML, Dechant M, Doxiadis II, Spriewald BM. Prevalence and specificity of immunoglobulin G and immunoglobulin A non-complement-binding anti-HLA alloantibodies in retransplant candidates. Tissue Antigens 2008;72(1):60-6. http://www.ncbi.nlm.nih.gov/pubmed/18588575 Smak Gregoor PJ, Zietse R, van Saase JL, op de Hoek CT, IJzermans JN, Lavrijssen AT, de Jong GM, Kramer P, Weimar W. Immunosuppression should be stopped in patients with renal allograft failure. Clin Transplant 2001;15(6):397-401. http://www.ncbi.nlm.nih.gov/pubmed/11737116 Marcén R, Teruel JL. Patient outcomes after kidney allograft loss. Transplant Rev (Orlando) 2008;22(1):62-72. http://www.ncbi.nlm.nih.gov/pubmed/18631859 Secin FP, Rovegno AR, del Rosario Brunet M, Marrugat RE, Dávalos Michel M, Fernandez H. Cumulative incidence, indications, morbidity and mortality of transplant nephrectomy and the most appropriate time for graft removal: only nonfunctioning transplants that cause intractable complications should be excised. J Urol 2003;169(4):1242-6. http://www.ncbi.nlm.nih.gov/pubmed/12629335 Delgado P, Diaz F, Gonzalez A, Sanchez E, Gutierrez P, Hernandez D, Torres A, Lorenzo V. Intolerance syndrome in failed renal allografts: incidence and efficacy of percutaneous embolization. Am J Kidney Dis 2005;46(2):339-44. http://www.ncbi.nlm.nih.gov/pubmed/16112054 Perl J, Bargman JM, Davies SJ, Jassal SV. Clinical outcomes after failed renal transplantation-does dialysis modality matter? Semin Dial 2008;21(3):239-44. http://www.ncbi.nlm.nih.gov/pubmed/18533967 Bennett WM. The failed renal transplant: in or out?. Semin Dial 2005;18(3):188-9. http://www.ncbi.nlm.nih.gov/pubmed/15934960 Langone AJ, Chuang P. The management of the failed renal allograft: an enigma with potential consequences. Semin Dial 2005;18(3):185-7. http://www.ncbi.nlm.nih.gov/pubmed/15934959

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Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, Arndorfer J, Christensen L, Merion RM. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003;349(10):931-40. http://www.ncbi.nlm.nih.gov/pubmed/12954741 Stratta P, Canavese C, Quaglia M, Balzola F, Bobbio M, Busca A, Franchello A, Libertucci D, Mazzucco G. Posttransplantation chronic renal damage in nonrenal transplant recipients. Kidney Int 2005;68(4):1453-63. http://www.ncbi.nlm.nih.gov/pubmed/16164622 Ojo AO.Renal disease in recipients of nonrenal solid organ transplantation. Semin Nephrol 2007;27(4):498-507. http://www.ncbi.nlm.nih.gov/pubmed/17616280

Transplantation in pregnancy

3.3.1 Planning pregnancy Chronic renal failure is often associated with sexual dysfunction and infertility. After kidney transplantation, sex life and fertility are improved (1). Both male and female patients should be counselled about the possibility of pregnancy. Ideally, pregnancy should be planned at a time of good general and graft health, usually not earlier or later than 1-2 years after transplant (2). In pregnancy occurring some years after transplantation, there is a risk that some chronic rejection and/or some deterioration of renal function may have developed. If graft function and immunosuppressive therapy are stabie, and there is no sign of rejection, hypertension, proteinuria, hydronephrosis or chronic infection, there is no significant difference in outcome between early, recommended, or late pregnancies (3) (level of evidence: 2a). Hydronephrosis makes pregnancy riskier because of the increased possibility of infection and lithiasis, which may also worsen in the last trimester. Early detection of pregnancy is important so that monitoring and adjustment of immunosuppressive therapy can begin as soon as possible. Recommendations GR • Pregnancy should be planned at a time of good general and graft health, when renal B function and immunosuppressive therapy are stable and there is no sign of rejection, hypertension, proteinuria, hydronephrosis or chronic infection • The second post-transplant year is the ideal period B GR = grade of recommendation 3.3.2 Graft survival Recently, the pregnancy rate in the kidney-transplanted population has increased from 2% to 5%. Successful gestations are common in female organ transplant recipients (4) (Table 16). Table 16: Factors that may affect a kidney graft during pregnancy • • • • •

Haemodynamic changes Hypertension Impairment of renal function (5-10) (level of evidence: 2a) Rejection (11) Urinary tract infections

Pregnancies in transplanted women are often unproblematic, but these patients should always be considered high risk and require shared care by an obstetrician, nephrologist and a urologist. Recommendations GR • After kidney transplantation pregnancy is possible and well tolerated for most patients with B normal graft function • However, pregnant transplanted women always must be considered at high risk and their B care requires the co-operation of the obstetrician, nephrologist and urologist GR = grade of recommendation 3.3.3 Care during pregnancy The care of a pregnant transplanted patient should focus on the risk factors mentioned in Table 16. This includes checking for bacterial urinary tract infection with monthly urine cultures and always treating bacteriuria, whether symptomatic or asymptomatic. Antibiotics agents should be chosen from the penicillin and cephalosporine families to avoid fetal and renal toxicity. Every urological endoscopy requires antibiotic

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protection. Viral infections may be transmitted to offspring. If this is CMV, the baby may be mentally retarded. Amniotic culture will reveal any fetal infections (12). Recommendation GR • Care during pregnancy should focus on control of proteinuria, hypertension (pre-eclampsia B affects 30% of patients), renal function, rejection and infection GR = grade of recommendation 3.3.4 Immunosuppressive treatment The common immunosuppressive treatment used during pregnancy is cyclosporine, with or without azathioprine and prednisone (6, 13). These drugs pass the placental barrier but apparently do not increase the risk of teratogenicity. Blood cyclosporine levels may change, and usually decrease, especially during the third trimester because of increased volume distribution and pharmacokinetic changes. Its dosage should usually be augmented. Recent papers suggest that the new drug tacrolimus (14, 15) (level of evidence: 3, 2b) used in kidney, heart and liver transplantation might also be safe. There are only sporadic reports on the effects of mycophenolate mofetil (MMF), which, like sirolimus, is contraindicated due to teratogenicity (16). Recommendations GR • Cyclosporine and tacrolimus do not seem to increase the risk of teratogenicity and they are B currently used with or without steroids and azathioprine • Treatment with mycophenolate (mycophenolate mofetil or mycophenolate sodium) or B m-TOR- Inhibitors (sirolimus or everolimus) is not recommended GR = grade of recommendation 3.3.5 Follow-up Rates of spontaneous (14%) or therapeutic (20%) abortions in transplanted women are similar to those in the general population. Although a vaginal delivery is not mechanically impaired by an abdominal graft, pre-term delivery and a high rate (50%) of Caesarean sections are observed, due to a high incidence of prematurity (uncontrolled hypertension, fetal distress, rupture of membranes weakened by steroid use). About 20% of babies have a low birthweight (mean birthweight 2.5 ± 0.67 vs normal birthweight 3.5 kg ± 0.53) (17, 18), but congenital abnormalities are no higher than in the general population. Breastfeeding is not suggested because of the baby’s risk of ingesting immunosuppressive agents. A close follow-up of the mother in the first three post-partum months is recommended, including weekly renal function tests. Delay vaccinations until the infant is 6 months old. There are few data on the growth, long-term outcome, or adult life of children born from kidney-transplanted mothers. Offspring are often born prematurely and have a reduced birthweight. Long-term studies on fetal exposure to immunosuppressive therapy have only recently begun. No other important data exist at present. Children of fathers in immunosuppressive treatment following kidney transplantation are clinically not different from those of the general population. They are aborted less often than fetuses of kidney-transplanted mothers. However, if the father is affected by hereditary disease, there is a higher risk of transmission. Recommendations GR • If there is no premature condition or fetal distress, vaginal delivery can be considered B • Breastfeeding is not recommended because of the potential risk of ingesting B immunosuppressive agents GR = grade of recommendation 3.3.6 1.

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References Pezeshki M, Taherian AA, Gharavy M, Ledger WL. Menstrual characteristics and pregnancy in women after renal transplantation. Int J Gynaecol Obstet 2004;85(2):119-25. http://www.ncbi.nlm.nih.gov/pubmed/15099772 Bar J, Ben-Rafael Z, Pados A, Orvieto R, Boner G, Hod M. Prediction of pregnancy outcome in subgroups of women with renal disease. Clin Nephrol 2000;53(6):437-44. http://www.ncbi.nlm.nih.gov/pubmed/10879663 Stratta P, Canavese C, Giacchino F, Mesiano P, Quaglia M, Rossetti M. Pregnancy in kidney transplantation: satisfactory outcomes and harsh realities. J Nephrol 2003;16(6):792-806. http://www.ncbi.nlm.nih.gov/pubmed/14736006

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Kok TP, Tan A, Koon TH, Vathsala A. Effect of pregnancy on renal graft function and maternal survival in renal transplant recipients. Transplant Proc 2002;34(4):1161-3. http://www.ncbi.nlm.nih.gov/pubmed/12072304 Hou S. Pregnancy in chronic renal insufficiency and end-stage renal disease. Am J Kidney Dis 1999;33(2):235-52. http://www.ncbi.nlm.nih.gov/pubmed/10023634 Fischer T, Neumayer HH, Fischer R, Barenbrock M, Schobel HP, Lattrell BC, Jacobs VR, Paepke S, von Steinburg SP, Schmalfeldt B, Schneider KT, Budde K. Effect of pregnancy on long-term kidney function in renal transplant recipients treated with cyclosporine and with azathioprine. Am J Transplant 2005;5(11):2732-9. http://www.ncbi.nlm.nih.gov/pubmed/16212634 Ehrich JHH, Loirat C, Davison JM, Rizzoni G, Wittkop B, Selwood NH, Mallick NP. Repeated successful pregnancies after kidney transplantation in 102 women (Report by the EDTA Registry). Nephrol Dial Transplant 1996;11(7):1314-7. http://www.ncbi.nlm.nih.gov/pubmed/8672028 Sturgiss SN, Davison JM. Effect of pregnancy on long-term function of renal allograft: an update. Am J Kidney Dis 1995;26(1):54-6. http://www.ncbi.nlm.nih.gov/pubmed/7611268 First Mr, Combs CA, Weislttel P, Miodovnik M. Lack of effect of pregnancy on renal allograft survival or function. Transplantation 1995;59(4):472-8. http://www.ncbi.nlm.nih.gov/pubmed/7878748 Rahamimov R, Ben-Haroush A, Wittemberg C, Mor E, Lustig S, Gafter U, Hod M, Bar J. Pregnancy in renal transplant recipients: long-term effect on patient and graft survival. A single center experience. Transplantation 2006;81(5):660-4. http://www.ncbi.nlm.nih.gov/pubmed/16534465 EBPG Expert Group on Renal Transplantation. European best practice guidelines for renal transplantation. Section IV: Long term management of the transplant recipient. IV.10. Pregnancy in renal transplant recipients. Nephrol Dial Transplant 2002;17(Suppl 4):50-5. http://www.ncbi.nlm.nih.gov/pubmed/12091650 Hagay ZJ, Biran G, Ornoy A, Reece EA. Congenital cytomegalovirus infection: along-standing problem still seeking a solution. Am J Obstet Gynecol 1996;174(1 Pt 1):241-5. http://www.ncbi.nlm.nih.gov/pubmed/8572014 Armenti VT, Moritz MJ, Davison JM. Drug safety issues in pregnancy following transplantation and immunosuppression: effects and outcomes. Drug Saf 1998;19(3):219-32. http://www.ncbi.nlm.nih.gov/pubmed/9747668 Kainz A, Harabacz I, Cowlrick IS, Gadgil SD, Hagiwara D. Review of the course and outcome of 100 pregnancies in 84 women treated with tacrolimus. Transplantation 2000;70(12):1718-21. http://www.ncbi.nlm.nih.gov/pubmed/11152103 Jain A, Venkataramanan R, Fung JJ, Gartner JC, Lever J, Balan V, Warty V, Starzl TE. Pregnancy after liver transplantation under tacrolimus. Transplantation 1997;64(4):559-65. http://www.ncbi.nlm.nih.gov/pubmed/9293865 Sifontis NM, Coscia LA, Costantinescu S, Lavelanet AF, Moritz MJ, Armenti VT. Pregnancy outcomes in solid organ transplant recipients with exposure to micophenolate mofetil or sirolimus. Transplantation 2006;82(12):1698-702. http://www.ncbi.nlm.nih.gov/pubmed/17198262 Davison JM, Milne JEC. Pregnancy and renal transplantation. Br J Urol 1997;80(Suppl 1):29-32. http://www.ncbi.nlm.nih.gov/pubmed/9240221 Sgro MD, Barozzino T, Mirghani HM, Sermer M, Moscato L, Akoury H, Koren G, Chitayat DA. Pregnancy outcome post renal transplantation. Teratology 2002;65(1):5-9. http://www.ncbi.nlm.nih.gov/pubmed/11835226

4. TRANSPLANTATION TECHNIQUES 4.1

Transplant preparation and transplant techniques in adults.

Transplant preparation is a crucial step in the transplantation process and should not be neglected. Key points of transplant preparation are listed in Table 17. The transplant procedure in adults, with special considerations, is detailed in Table 18.

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Table 17: Transplant preparation Kidney • • • Vein •

Place the kidney on a sterile iced bed Check for the absence of renal tumours Tie all that is cut near the hilus (lymphostasis)  he right kidney should be removed, together with the infra renal vena cava for lengthening the renal T vein on the back table (1)

Artery • Preserve the aortic patch and check the intima of the renal ostium • In severe atheroma in the ostium, remove the aortic patch • In multiple arteries, back table reconstruction could be necessary (2, 3) Ureter • Preserve peri-pyelic and proximal peri-ureteral fat in the ‘golden triangle’ • Check for double ureter Transplant biopsies • Use 16G or 18G automatic single-use needle • Systematic in some centres because it can be very important to follow the long-term histological modifications of the transplant Table 18: Transplant technique Transplant technique in adults Approach • Extra peritoneal approach of one iliac fossa • Transplantation is possible either into the contralateral or ipsilateral iliac fossa • Lymphostasis with clips or ligatures to avoid lymphocele is mandatory • Total mobilisation of the external iliac vein avoids traction on the venous anastomosis (sometimes ligation of the internal iliac vein is necessary particularly for right transplant with a short vein) • Minimal dissection of the iliac artery Vascular anastomosis • Generally external iliac vessels are used; avoid atheromatous plaques • Choose the sites of vascular anastomosis according to the length of each vessel to avoid plication or traction • Both anastomoses are performed with two halves of running non-absorbable monofil 6x0 or 5x0 sutures • Internal iliac artery should not be used except in specific situations Ureteral anastomosis • Extravesical implantation at the antero-lateral surface of the bladder is the method of choice. Suture the ureter to the bladder mucosa using two halves of running absorbable 6x0 or 5x0 sutures. This technique gives better results than open implantation to the bladder (4, 5) • A double J-stent may be placed to protect the anastomosis, particularly in cases of tricky anastomoses. Several transplant groups use a double J-stent routinely (6-8) and remove it 2-4 weeks later (level of evidence: 2b) • The uretero-ureteral anastomosis is an alternative to a very short or poorly vascularised transplant ureter. It is also used for a third transplant or in children (9). A double J-stent is absolutely necessary in these cases (level of evidence: 3) Special considerations Kidneys taken from children weighing < 15 kg • In adults, en-bloc transplantation should be performed, including the aorta and the inferior vena cava • The two ureters are anastomosed in double pant using the extra-vesical technique Vascular problems in the recipient • If the iliac arteries do not allow clamping, endarterectomy or a simultaneous vascular prosthesis has to be performed (10) • If a prosthetic replacement has been previously carried out, implant the renal artery into the prosthesis using a punch perforator (11) • If iliac vein and/or vena cava are thrombosed, native renal vein or superior mesenteric vein can be used. However, in most cases, transplantation must be stopped

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Paediatric recipient • Large kidneys must be placed in a higher position towards the lumbar fossa, using the aorta or the right common iliac artery and the inferior vena cava • Iliac fossa is an option for young recipients (12, 13) (level of evidence: 3)

Recommendations GR • It is essential not to neglect transplant preparation. This is a crucial step in the C transplantation process • Take care with lymphostasis into the recipient and during the graft preparation C • Vascular anastomosis sites should take into account the differences in vessel length C • Double J-stent may be used routinely C • Check the arterial and venous status before transplant C • Iliac fossa may be an alternative in children less than 20 kg provided the graft is small enough C GR = grade of recommendation

4.2

Early complications

4.2.1 General complications 4.2.1.1 Wall abscesses (5%) These are more common when the recipients are obese or old. Risk factors include diabetes, haematoma, obesity, rejection or over-immunosuppression (14, 15). Abscesses can be prevented by minimising electrocoagulation and using subcutaneous aspirational drainage in obese patients. A superficial abscess can be treated with a simple opening of the wound, while a deep abscess requires surgical drainage. It is important to look for urinary fistulae. 4.2.1.2 Haemorrhage Risk factors include acetylsalicylic acid, poorly prepared transplant hilus, multiple renal arteries, renal biopsies and hyper-acute rejection (HAR) (16-18). A large haematoma or active bleeding requires surgical drainage. Following drainage, the uretero-vesical anastomosis must be checked and a double J-stent may be inserted. 4.2.1.3 Haematuria After transplant biopsy, look for arterio-venous fistula (AVF) (19). Selective percutaneous embolisation is necessary for large AVF and for recurring haematuria. Clotting may cause ureteral obstruction, increasing the risk of haematuria. Dialysis may be necessary if ureteral stenting or percutaneous nephrostomy are ineffective. 4.2.1.4 Incisional hernia (3-5%) Risk factors include obesity, diabetes, haematoma, rejection and finally m-TOR inhibitors. Treat in a similar way to a ‘classical‘ incisional hernia with or without synthetic mesh (14, 20, 21). 4.2.2 Urinary fistulae Urinary fistulae are the most common early complication. They occur in 3-5% of cases in which a double J-stent has not been used (22-24). They can occur on the ureter, bladder or parenchyma. The most frequent cause is ischaemic necrosis of the ureter (23, 25). 4.2.2.1 Management If it is possible to localise the fistula, it is worth trying nephrostomy and/or a vesical catheter and double J-stent. Stented re-implantation is possible if necrosis is very distal and the ureter is long enough. Otherwise, uretero-ureteral anastomosis is performed using the patient’s original ureter (26). Vesical fistulae can be treated by suprapubic or transurethral catheter. Calyceal fistulae may be treated by double J-stent and vesical catheter. In most cases, polar nephrectomy and omental plasty are necessary (27). Recommendations GR • Use a short ureter and keep the peri-ureteral fat around the hilus (28) C • Avoid ligature of polar artery because of the risk of parenchymal and ureteral necrosis C • Prophylactic use of double J-stent remains controversial C GR = grade of recommendation 4.2.3 Arterial thrombosis The incidence of arterial thrombosis is 0.5% in the first post-operative week. Risk factors include atherosclerosis, unidentified intimal rupture, poor suture technique, kinking if the artery is longer than the vein

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or the anastomosis is incorrectly sited, multiple arteries (29) and paediatric transplants (30-32). It should be suspected if there is primary non-function or sudden anuria. It is diagnosed by Doppler or technetium scan and confirmed by CT scan. 4.2.3.1 Treatment Surgery is always necessary. A radiological thrombectomy may be carried out successfully within the first 12 h. However, tolerance to warm ischaemia is poor and most transplants have to be removed. Recommendations GR • Importance of procurement technique quality C • Preserve when possible the aortic patch; otherwise, use a punch perforator to create a C large arterial opening • Look for a possible intimal rupture before performing anastomosis C • Avoid plication of the artery C GR = grade of recommendation 4.2.4 Venous thrombosis Venous thrombosis is rare, occurring in 0.5% of kidney transplants in adults and in 2.5% in paediatric patients (32, 33). It is suspected by primary non-function, haematuria or anuria and is diagnosed by Doppler or technetium scan. Salvage thrombectomy has a very poor success rate and transplantectomy is often necessary. Recommendations GR • Lengthen the right renal vein with the infra renal vena cava C • Carry out a large venous anastomosis C • Avoid post-operative drop in blood pressure C • Check for hypercoagulation or Leiden factor V mutation if there is a history of thrombosis C GR = grade of recommendation

4.3

Late complications

4.3.1 Ureteral stenosis The renal calyces and pelvis are dilated and there is often an elevated creatinine level. These stenoses occur in 5% (range, 2-7.5%) of transplants (34, 35). They can present late between 1 and 10 years’ post transplant (36). There are three causes of ureteral dilatation: • Vesical high pressure with thickened bladder wall or urinary retention, which is treated by bladder drainage • Vesicorenal reflux, which is not an obstruction • Ureterovesical stenosis due to scar formation and/or poor surgical technique. These comprise 80% of ureteral stenoses. Most occur during the first year post transplant, although the risk of occurrence increases with time to 9% of transplant patients at 10 years. Risk factors include multiple arteries, donor’s age, delayed graft function, and CMV infection (34). Initial treatment involves percutaneous drainage and checking renal function to see if it has improved. Imaging should then be done to determine the level of stenosis, degree and length. Further treatment depends on the level of stenosis, degree and delay of occurrence. This can be endoscopic, either transurethral or percutaneous. The outcome of dilatation is better when the stenosis is early, distal and short (37-41). Treatment can also be with open surgery using an uretero-ureteral anastomosis to the patient’s ureter or a vesicopyelostomy. Recommendations GR • Use a short and well-vascularised ureter, surrounded by peri-ureteral fat • Do not narrow the anastomosis and the antireflux tunnel • Use of a double J-stent remains controversial • Yearly routine echography GR = grade of recommendation 4.3.2 Reflux and acute pyelonephritis Acute pyelonephritis is a rare complication (42, 43). Reflux in the renal cavity is more common (44). Reflux is found in up to 30% of cases after Leadbetter and in 80% after Lich-Gregoire if the submucosal tunnel is

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short and in 10% if the tunnel is long. In lower urinary tract infections, the risk of acute pyelonephritis is 80% with reflux and 10% without reflux. Every reflux complicated by acute pyelonephritis should be treated with an endoscopic injection. This has a success rate of 30-53% (45). If this fails, try using an uretero-ureteral anastomosis if the native ureter is not refluxive, or an ureterovesical re-implantation with a long tunnel if the original ureter is refluxive or non-usable. . Recommendations • The anti-reflux tunnel for the uretero-vesical anastomosis should be 3-4 cm long • Avoid lower urinary tract infections GR = grade of recommendation 4.3.3 Kidney stones Kidney stones may be transplanted with the kidney or may be acquired. The incidence is less than 1% of transplants (46, 47). The stones manifest themselves by haematuria, infection or obstruction. Diagnosis may require non-injected CT scan. Some stones are eliminated spontaneously, but if stones do need to be removed, there are several options (48): • The first step should be to try a double J-catheter or echo-guided percutaneous nephrostomy. • Calyceal and smaller renal stones should be treated by extracorporeal shock wave lithotripsy (ESWL). • Larger stones should be removed by percutaneous (49) or open nephrolithotomy. • Ureterolithiasis should be treated by ESWL (50) or by ureteroscopy (51). Recommendations • Treat hyperparathyroidism in the recipient • Use absorbable threads for the urinary anastomosis • Treat urinary obstructions and infections • Check calciuria 4.3.4 Renal artery stenosis Renal artery stenosis has an incidence of 10% (range, 2-38%). It is suspected when existing arterial hypertension becomes refractory to medical treatment and/or there is an increase in serum creatinine without hydronephrosis (52, 53). It is diagnosed by Doppler sonography showing high velocity > 2m/s. Treatment options include medical treatment and renal function follow-up, with interventional treatment indicated if the stenosis is > 70% (54). Transluminal dilatations, with or without stenting, give poorer results (70%) than surgery, but their simplicity makes them the first-line treatment for aligned and distal stenosis (33). Open surgery is reserved for plication or anastomotic stenosis, failure of percutaneous dilatation and involves resection with direct implantation. Repair with the saphenous vein must be avoided. Recommendations • Use aortic patch from the donor • Examine the artery intima, fix it or re-cut the artery when necessary • Keep a long left renal vein, and lengthen the right one with the vena cava • Avoid too tight anastomoses • Use punch perforator when aortic patch is absent 4.3.5 Arteriovenous fistulae and pseudo aneurysms after renal biopsy Arteriovenous fistulae are seen in 10% (range, 7-17%) of cases and are suggested by repeated haematuria (55, 56). Diagnosis is by Doppler ultrasound and is confirmed by MRI or by angiography. Angiography is also the first step in treatment. Fistulae may regress spontaneously (19), but when persistent haematuria or when diameter > 15 mm, selective embolisation should be used. Pseudo aneurysms are often due to mycotic infection (57) and can be fatal. Recommendation GR • Avoid very deep biopsy reaching the renal hilum C GR = grade of recommendation 4.3.6 Lymphocele Lymphocele comprises 1-20% of complications. It occurs secondary to insufficient lymphostasis of the iliac vessels and/or of the transplant kidney. Obesity and the use of some immunosuppressant agents such as

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m-TOR inhibitors are associated with a higher risk oh lymphocele (58-60). Generally, it is asymptomatic, but there may be pain caused by ureter compression or infection. No treatment is necessary for mild lymphocele or if there is no compression of the iliac vessels or the transplant ureter. Otherwise, laparoscopic marsupialisation is the treatment of choice. Open surgery is indicated when laparoscopy (61) is not available or dangerous (62). Recommendation GR • Strict lymphostasis should be maintained by clips or ligatures of the lymphatic vessels of C the transplant and during dissection of the iliac vessels GR = grade of recommendation

4.4

REFERENCES

1.

Barry JM, Fuchs EF. Right renal vein extension in cadaver kidney transplantation. Arch Surg 1978;113(3):300. http://www.ncbi.nlm.nih.gov/pubmed/346002 Brekke IB. Management of multiple renal transplant arteries. Transpl Int 1990;3(4):241. http://www.ncbi.nlm.nih.gov/pubmed/2076175 Bakirtas H, Guvence N, Eroglu M, Ure M, Ozok HU, Karabulut I, Gul O, Banli O. Surgical approach to cases with multiple renal arteries in renal transplantation. Urol Int 2006;76(2):169-72. http://www.ncbi.nlm.nih.gov/pubmed/16493221 Thrasher JB, Temple DR, Spees EK. Extravesical versus Leadbetter-Politano ureteroneocystostomy: a comparison of urological complications in 320 renal transplants. J Urol 1990;144(5):1105-9. http://www.ncbi.nlm.nih.gov/pubmed/2231880 Butterworth PC, Horsburgh T, Veitch PS, Bell PR, Nicholson ML. Urological complications in renal transplantation: impact of a change of technique. Br J Urol 1997;79(4):499-502. http://www.ncbi.nlm.nih.gov/pubmed/9126075 Benoit G, Blanchet P, Eschwege P, Alexandre L, Bensadoun H, Charpentier B. Insertion of a double pigtail ureteral stent for the prevention of urological complications in renal transplantation: a prospective randomized study. J Urol 1996;156(3):881-4. http://www.ncbi.nlm.nih.gov/pubmed/8709353 Nicol DL, P‘Ng K, Hardie DR, Wall DR, Hardie IR. Routine use of indwelling ureteral stents in renal transplantation. J Urol 1993;150(5 Pt 1):1375-9. http://www.ncbi.nlm.nih.gov/pubmed/8411403 Mangus RS, Haag BW. Stented versus nonstented extravesical ureteroneocystostomy in renal transplantation: a metaanalysis. Am J Transplant 2004;4(11):1889-96. http://www.ncbi.nlm.nih.gov/pubmed/15476491 Lapointe SP, Charbit M, Jan D, Lortat-Jacob S, Michel JL, Beurton D, Gagnadoux MF, Niaudet P, Broyer M, Révillon Y. Urological complications after renal transplantation using ureteroureteral anastomosis in children. J Urol 2001;166(3):1046-8. http://www.ncbi.nlm.nih.gov/pubmed/11490295 Pampaloni F, Sanchez LJ, Bencini L, Taddei G. Simultaneous aortoiliac reconstruction and renal transplantation: is it safe?. Chir Ital 2002;54(1):115-20. http://www.ncbi.nlm.nih.gov/pubmed/11942002 George P, Tan HP, Beebe H, Ratner LE. Successful renal transplantation after endovascular bifurcated stent graft repair of an abdominal aortic aneurysm. Transplantation 2001;72(3):533-4. http://www.ncbi.nlm.nih.gov/pubmed/11502990 Furness PD 3rd, Houston JB, Grampsas SA, Karrer FM, Firlit CF, Koyle MA. Extraperitoneal placement of renal allografts in children weighing less than 15 kg. J Urol 2001;166(3):1042-5. http://www.ncbi.nlm.nih.gov/pubmed/11490294 Humar A, Arrazola L, Mauer M, Matas AJ, Najarian JS. Kidney transplantation in young children: should there be a minimum age? Pediatr Nephrol 2001;16(12):941-5. http://www.ncbi.nlm.nih.gov/pubmed/11793077 Dean PG, Lund WJ, Larson TS, Prieto M, Nyberg SL, Ishitani MB, Kremers WK, Stegall MD. Woundhealing complications after kidney transplantation: a prospective, randomized comparison of sirolimus and tacrolimus. Transplantation 2004;77(10):1555-61. http://www.ncbi.nlm.nih.gov/pubmed/15239621 Humar A, Ramcharan T, Denny R, Gillingham KJ, Payne WD, Matas AJ. Are wound complications after a kidney transplant more common with modern immunosuppression? Transplantation 2001;72(12):1920-3. http://www.ncbi.nlm.nih.gov/pubmed/11773889

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Azar GJ, Zarifian AA, Frentz GD, Tesi RJ, Etheredge EE. Renal allograft rupture: a clinical review. Clin Transplant 1996;10(6 Pt 2):635-8. http://www.ncbi.nlm.nih.gov/pubmed/8996757 Osman Y, Shokeir A, Ali-el-Dein B et al. Vascular complications after live donor renal transplantation: study of risk factors and effects on graft and patient survival. J Urol 2003;169(3):859-62. http://www.ncbi.nlm.nih.gov/pubmed/12576799 Schwarz A, Gwinner W, Hiss M, Radermacher J, Mengel M, Haller H. Safety and adequacy of renal transplant protocol biopsies. Am J Transplant 2005;5(8):1992-6. http://www.ncbi.nlm.nih.gov/pubmed/15996250 Brandenburg VM, Frank RD, Riehl J. Color-coded duplex sonography study of arteriovenous fistulae and pseudoaneurysms complicating percutaneous renal allograft biopsy. Clin Nephrol 2002;58(6): 398-404. http://www.ncbi.nlm.nih.gov/pubmed/12508960 Flechner SM, Zhou L, Derweesh I, Mastroianni B, Savas K, Goldfarb D, Modlin CS, Krishnamurthi V, Novick A. The impact of sirolimus, mycophenolate mofetil, cyclosporine, azathioprine, and steroids on wound healing in 513 kidney-transplant recipients. Transplantation 2003;76(12):1729-34. http://www.ncbi.nlm.nih.gov/pubmed/14688524 Rogers CC, Hanaway M, Alloway RR Corticosteroid avoidance ameliorates lymphocele formation and wound healing complications associated with sirolimus therapy. Transplant Proc 2005;37(2):795-7. http://www.ncbi.nlm.nih.gov/pubmed/15848534 Gogus C, Yaman O, Soygur T, Beduk Y, Gogus O. Urological complications in renal transplantation: long-term follow-up of the Woodruff ureteroneocystostomy procedure in 433 patients. Urol Int 2002;69(2):99-101. http://www.ncbi.nlm.nih.gov/pubmed/12187037 Karam G, Maillet F, Parant S, Soulillou JP, Giral-Classe M. Ureteral necrosis after kidney transplantation: risk factors and impact on graft and patient survival. Transplantation 2004;78(5): 725-9. http://www.ncbi.nlm.nih.gov/pubmed/15371676 Secin FP, Rovegno AR, Marrugat RE, Virasoro R, Lautersztein GA, Fernandez H. Comparing Taguchi and Lich-Gregoir ureterovesical reimplantation techniques for kidney transplants. J Urol 2002;168(3):926-30. http://www.ncbi.nlm.nih.gov/pubmed/12187192 Shaul DB, Xie HW, Shimada H, Hardy BE, Anderson KD. Venous ischemia as a cause of ureteral necrosis in transplanted ureters. J Pediatr Surg 1999;34(11):1725-7. http://www.ncbi.nlm.nih.gov/pubmed/10591580 Li Marzi V, Filocamo MT, Dattolo E, Zanazzi M, Paoletti MC, Marzocco M, Villari D, Salvadori M, Nicita G. The treatment of fistulae and ureteral stenosis after kidney transplantation. Transplant Proc 2005;37(6):2516-7. http://www.ncbi.nlm.nih.gov/pubmed/16182729 Gutierrez-Calzada JL, Ramos-Titos J, Gonzalez-Bonilla JA, Garcia-Vaquero AS, Martin-Morales A, Burgos-Rodriguez R. Caliceal fistula formation following renal transplantation: management with partial nephrectomy and ureteral replacement. J Urol 1995;153(3 Pt 1):612-4. http://www.ncbi.nlm.nih.gov/pubmed/7861495 Salvatierra O, Olcott C, Amend WJ, Cochrum KC, Feduska NJ. Urological complications of renal transplantation can be prevented or controlled. J Urol 1977;177(4):421-4. http://www.ncbi.nlm.nih.gov/pubmed/321807 Lechevallier E, Bretheau D, Berland Y, Olmer M, Rampal M, Coulange C. [Outcome of kidney transplants with multiple arteries]. Prog Urol 1995;5(3): 370-6. [article in French] http://www.ncbi.nlm.nih.gov/pubmed/7670512 Adams J, Gudemann C, Tonshoff B, Mehls O, Wiesel M. Renal transplantation in small children--a comparison between surgical procedures. Eur Urol 2001;40(5):552-6. http://www.ncbi.nlm.nih.gov/pubmed/11752865 Irish AB, Green FR, Gray DW, Morris PJ. The factor V Leiden (R506Q) mutation and risk of thrombosis in renal transplant recipients. Transplantation 1997;64(4):604-7. http://www.ncbi.nlm.nih.gov/pubmed/9293873 Ismail H, Kalicinski P, Drewniak T, Smirska E, Kamiński A, Prokurat A, Grenda R, Szymczak M, Chrupek M, Markiewicz M. Primary vascular thrombosis after renal transplantation in children. Pediatr Transplant 1997;1(1):43-7. http://www.ncbi.nlm.nih.gov/pubmed/10084786

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Duckett T, Bretan PNJ, Cochran ST, Rajfer J, Rosenthal JT. Noninvasive radiological diagnosis of renal vein thrombosis in renal transplantation. J Urol 1991;146(2)403-6. http://www.ncbi.nlm.nih.gov/pubmed/1856941 Karam G, Hetet JR, Maillet F, Rigaud J, Hourmant M, Soulillou JP, Giral M. Late ureteral stenosis following renal transplantation: risk factors and impact on patient and graft survival. Am J Transplant 2006;6(2):352-6. http://www.ncbi.nlm.nih.gov/pubmed/16426320 Schwartz BF, Chatham JR, Bretan P, Goharderakhshan R, Stoller ML. Treatment of refractory kidney transplant ureteral strictures using balloon cautery endoureterotomy. Urology 2001;58(4):536-9. http://www.ncbi.nlm.nih.gov/pubmed/11597533 Faenza A, Nardo B, Catena F, Scolari MP, d’Arcangelo GL, Buscaroli A, Rossi C, Zompatori M. Ureteral stenosis after kidney transplantation. A study on 869 consecutive transplants. Transpl Int 1999;12(5):334-40. http://www.ncbi.nlm.nih.gov/pubmed/10551998 Bhagat VJ, Gordon RL, Osorio RW, LaBerge JM, Kerlan RK Jr, Melzer JS, Bretan PN, Wilson MW, Ring EJ. Ureteral obstructions and leaks after renal transplantation: outcome of percutaneous antegrade ureteral stent placement in 44 patients. Radiology 1998;209(1):159-67. http://www.ncbi.nlm.nih.gov/pubmed/9769827 Conrad S, Schneider AW, Tenschert W, Meyer-Moldenhauer WH, Huland H. Endo-urological coldknife incision for ureteral stenosis after renal transplantation. J Urol 1994;152(3):906-9. http://www.ncbi.nlm.nih.gov/pubmed/8051750 Dugardin F, Rigaud J, Drapier E, Maillet F, Hetet JF, Bouchot O, Karam G. [Endoscopic incision of uretero-vesical junction after renal transplantation]. Prog Urol 2003;13(3):523-6. [article in French] http://www.ncbi.nlm.nih.gov/pubmed/12940212 Faenza A, Nardo B, Catena F, Scolari MP, Buscaroli A, D‘Arcangelo GL. Ureteral stenosis after kidney transplantation: interventional radiology or surgery? Transplant Proc 2001;33(1-2):2045-6. http://www.ncbi.nlm.nih.gov/pubmed/11267618 Kristo B, Phelan MW, Gritsch HA, Schulam PG. Treatment of renal transplant ureterovesical anastomotic strictures using antegrade balloon dilation with or without holmium:YAG laser endoureterotomy. Urology 2003;62(5):831-4. http://www.ncbi.nlm.nih.gov/pubmed/14624903 Ranchin B, Chapuis F, Dawhara M, Canterino I, Hadj-Aïssa A, Saïd MH, Parchoux B, Dubourg L, Pouillaude JM, Floret D, Martin X, Cochat P. Vesicoureteral reflux after kidney transplantation in children. Nephrol Dial Transplant 2000;15(11):1852-8. http://www.ncbi.nlm.nih.gov/pubmed/11071977 Vianello A, Pignata G, Caldato C, Di Falco G, Calconi G, Fandella A, Rabassini A, Maresca MC.Vesicoureteral reflux after kidney transplantation: clinical significance in the medium to long-term. Clin Nephrol 1997;47(6):356-61 http://www.ncbi.nlm.nih.gov/pubmed/9202864 Ohba K, Matsuo M, Noguchi M, Nishikido M, Koga S, Kanetake H, Nazneen A, Liu D, Razzaque MS, Taguchi T. Clinicopathological study of vesicoureteral reflux (VUR)-associated pyelonephritis in renal transplantation. Clin Transplant 2004;18( Suppl 11):34-8. http://www.ncbi.nlm.nih.gov/pubmed/15191371 Mallet R, Game X, Mouzin M, Sarramon JP, Vaessen C, Malavaud B, Rischmann P. [Symptomatic vesicoureteral reflux in kidney transplantation: results of endoscopic injections of teflon and predictive factors for success]. Prog Urol 2003;13(4):598-601. [article in French] http://www.ncbi.nlm.nih.gov/pubmed/14650289 Abbott KC, Schenkman N, Swanson SJ, Agodoa LY. Hospitalized nephrolithiasis after renal transplantation in the United States. Am J Transplant 2003;3(4):465-70. http://www.ncbi.nlm.nih.gov/pubmed/12694070 Crook TJ, Keoghane SR. Renal transplant lithiasis: rare but time-consuming. BJU Int 2005;95(7): 931-3. http://www.ncbi.nlm.nih.gov/pubmed/15839905 Challacombe B, Dasgupta P, Tiptaft R, Glass J, Koffman G, Goldsmith D, Khan MS. Multimodal management of urolithiasis in renal transplantation. BJU Int 2005;96(3):385-9. http://www.ncbi.nlm.nih.gov/pubmed/16042735 Francesca F, Felipetto R, Mosca F, Boggi U, Rizzo G, Puccini R. Percutaneous nephrolithotomy of transplanted kidney. J Endourol 2002;16(4):225-7. http://www.ncbi.nlm.nih.gov/pubmed/12042104

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Klingler HC, Kramer G, Lodde M, Marberger M. Urolithiasis in allograft kidneys. Urology. Urology 2002;59(3):344-8. http://www.ncbi.nlm.nih.gov/pubmed/11880067 Henderson A, Gujral S, Mitchelmore AE, Keeley FXJ. Endo-urological techniques in the management of stent complications in the renal transplant patient. Transplant Int 2002;15(12):664-6. Epub 2002. http://www.ncbi.nlm.nih.gov/pubmed/12478416 Akbar SA, Jafri SZ, Amendola MA, Madrazo BL, Salem R, Bis KG. Complications of renal transplantation. Radiographics 2005;25(5):1335-56. http://www.ncbi.nlm.nih.gov/pubmed/16160115 Bruno S, Remuzzi G, Ruggenenti P. Transplant renal artery stenosis. J Am Soc Nephrol 2004;15(1):134-41. http://www.ncbi.nlm.nih.gov/pubmed/14694165 Spinosa DJ, Isaacs RB, Matsumoto AH, Angle JF, Hagspiel KD, Leung DA. Angiographic evaluation and treatment of transplant renal artery stenosis. Curr Opin Urol 2001;11(2):197-205. http://www.ncbi.nlm.nih.gov/pubmed/11224752 Ladinsky GA, Goral S. Macroscopic hematuria in a kidney transplant recipient: a rare cause. Am J Kidney Dis 2006;47(1):e3-e7. http://www.ncbi.nlm.nih.gov/pubmed/16377377 Taghavi M, Shojaee Fard A, Mehrsai R, Shadman M. Late onset anastomotic pseudoaneurysm of renal allograft artery: case report, diagnosis, and treatment. Transplant Proc 2005;37(10):4297-9. http://www.ncbi.nlm.nih.gov/pubmed/16387101 Laouad I, Buchler M, Noel C, Sadek T, Maazouz H, Westeel PF, Lebranchu Y. Renal artery aneurysm secondary to Candida albicans in four kidney allograft recipients. Transplant Proc 2005;37(6):2834-6. http://www.ncbi.nlm.nih.gov/pubmed/16182825 Goel M, Flechner SM, Zhou L, Mastroianni B, Savas K, Derweesh I, Patel P, Modlin C, Goldfarb D, Novick AC.The influence of various maintenance immunosuppressive drugs on lymphocele formation and treatment after kidney transplantation.J Urol 2004;171(5):1788-92. http://www.ncbi.nlm.nih.gov/pubmed/15076277 Valente JF, Hricik D, Weigel K, Seaman D, Knauss T, Siegel CT, Bodziak K, Schulak JA. Comparison of sirolimus vs. mycophenolate mofetil on surgical complications and wound healing in adult kidney transplantation. Am J Transplant 2003;3(9):1128-34. http://www.ncbi.nlm.nih.gov/pubmed/12919093 Vitko S, Margreiter R, Weimar W, Dantal J, Kuypers D, Winkler M, Øyen O, Viljoen HG, Filiptsev P, Sadek S, Li Y, Cretin N, Budde K; RAD B201 Study Group. Three-year efficacy and safety results from a study of everolimus versus mycophenolate mofetil in de novo renal transplant patients.Am J Transplant 2005;5(10):2521-30. http://www.ncbi.nlm.nih.gov/pubmed/16162203 Schips L, Lipsky K, Hebel P, Hutterer G, Gidaro S, Petritsch PH, Zigeuner RE. Laparoscopic fenestration of lymphoceles after kidney transplantation with diaphanoscopic guidance. Urology 2005;66(1):185-7. http://www.ncbi.nlm.nih.gov/pubmed/15992897 Fuller TF, Kang SM, Hirose R, Feng S, Stock PG, Freise CE. Management of lymphoceles after renal transplantation: laparoscopic versus open drainage. J Urol 2003;169(6):2022-5. http://www.ncbi.nlm.nih.gov/pubmed/12771709

Kidney transplantation in abnormal urogenital tract

The following points should be considered when performing kidney transplantation in the abnormal urogenital tract: • The technique used to implant transplant ureters in augmentations or conduits is the same as the method used with a patient’s own ureter, e.g. following cystectomy for bladder cancer (Bricker, Wallace). • In bladder augmentations or continent pouches, ureters are implanted by tunnel technique (GoodwinHohenfellner), or extravesically (favoured in most patients), e.g. using Lich Gregoir or Leadbetter methods (1-3). • In ureterocystoplasty, it is feasible to perform uretero-ureterostomy with one of the patient’s own ureters (1, 4). • In patients with continent ileocoecal pouches with umbilical stoma or ileocystoplasties/ileal neobladders, transplant kidneys must be placed on the contralateral left side with the transplant ureters, crossing the abdomen subsigmoidally (2, 3, 5) (level of evidence: 3-4.)

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4.5.1 1.

2.

3.

4.

5.

References Koo HP, Bunchman TE, Flynn JT, Punch JD, Schwartz AC, Bloom DA. Renal transplantation in children with severe lower urinary tract dysfunction. J Urol 1999;161(1):240-5. http://www.ncbi.nlm.nih.gov/pubmed/10037414 Riedmiller H, Gerharz EW, Kohl U, Weingartner K. Continent urinary diversion in preparation for renal transplantation: a staged approach. Transplantation 2000;70(12):1713-7. http://www.ncbi.nlm.nih.gov/pubmed/11152102 Sullivan ME, Reynard JM, Cranston DW. Renal transplantation into the abnormal lower urinary tract, BJU Int 2003;92(5):510-5. http://www.ncbi.nlm.nih.gov/pubmed/12930409 Nahas WC, Mazzucchi E, Arap MA, Antonopoulos IM, Neto ED, Ianhez LE, Arap S. Augmentation cystoplasty in renal transplantation: a good and safe option-experience with 25 cases. Urology 2002;60(5):770-4. http://www.ncbi.nlm.nih.gov/pubmed/12429293 Mendizabal S, Estornell F, Zamora I, Sabater A, Ibarra FG, Simon J. Renal transplantation in children with severe bladder dysfunction. J Urol 2005;173(1):226-9. http://www.ncbi.nlm.nih.gov/pubmed/15592081

5. MATCHING OF DONORS AND RECIPIENTS Recommendations GR • The ABO blood group and the HLA-A, -B, and -DR phenotypes should be determined for all B candidates awaiting kidney transplantation • To avoid hyper-acute rejection, a lymphocyte cross-match test must be performed before B each kidney and combined kidney/pancreas transplantation GR = grade of recommendation

5.1

Histocompatibility (HLA) matching

Histocompatibility (HLA) matching is still very important in kidney transplantation because transplant outcome correlates with the number of HLA mismatches (1, 2). HLA incompatibility can result in proliferation and activation of the recipient’s CD4+ and CD8+ T-cells with concomitant activation of B-cell allo-antibody production. This leads to cellular and humoral graft rejection. HLA antigens show remarkable polymorphism. Matching should concentrate on HLA antigens, which impact on rejection rates. The HLA-A, HLA-B, and HLA-DR phenotypes should be determined in all potential recipients and donors. Kidneys from deceased donors should preferentially be allocated to potential recipients with the lowest number of HLA mismatches. This is also true for living-donor transplantation, although HLAcompatibility is less important in living- than in deceased-donor kidney transplantation (3). In living-donor transplantation, other risk factors for graft rejection, e.g. cold ischaemia time, brain death and donor’s age, can be minimised. 5.1.1 Practical aspects of HLA-testing Laboratories that provide HLA-testing and cross-matching for a transplant centre must have a valid accreditation to ensure accuracy and reliability. They must follow the standards of national and international organisations, such as the European Federation for Immunogenetics. Other practical considerations include (4, 5): • Obtain cells for HLA-typing from the recipient’s peripheral blood using an appropriate anticoagulant, e.g. ammonium heparin, ethylene diamine tetra-acetic acid (EDTA) or acid-citrate-dextrose (ACD). Most HLA laboratories use 20 mL heparinised peripheral blood for serological HLA typing and 10 mL EDTA peripheral blood for molecular typing. • Type donors using lymphocytes from lymph nodes, spleen, or peripheral blood. • Use a comprehensive set of reagents capable of detecting all commonly occurring HLA antigens in the relevant ethnic group. • For HLA-A and HLA-B specificities, serological or molecular typing is accepted. For HLA-DR, only molecular typing is accepted. For reporting HLA antigens, the latest WHO nomenclature should be used (6). • Use family typing or DNA typing to detect possible homozygosity if the phenotype of a potential

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recipient shows fewer than six HLA-A, -B, -DR antigens.

5.2

Cross-matching

To avoid HAR, a cross-match test must be performed before each kidney and combined kidney/pancreas transplantation. Patients at risk are those who have HLA-specific allo-antibodies or have had an alloimmunising event, such as pregnancy, blood transfusion or a previous transplantation. The cross-match test detects preformed allo-antibodies in the recipient’s serum directed against lymphocytes of the potential donor. Routinely, a complement-dependent lymphocytotoxicity (CDC) assay is used. Crossmatches must be carried out using unseparated lymphocytes or T-enriched lymphocytes of the potential donor. B-cell cross-matches must be performed if required by the relevant transplantation programmes. T-lymphocytes express only HLA class I antigens. As B-lymphocytes express, besides HLA class I antigens also HLA class II antigens on their surface, a B-cell cross-match is considered to be more sensitive than a cross-match with T-lymphocytes. Spleen contains more B-lymphocytes than peripheral blood. A crossmatch with unseparated lymphocytes from spleen is therefore more sensitive than a cross-match with unseparated lymphocytes from peripheral blood. A positive T-cell cross-match is generally a contraindication to transplantation. A positive B-cell cross-match result can occur for different reasons, including anti-HLA class I/II antibodies or allo-antibodies, immune complexes, therapy with anti-B-cell agents (rituximab, alemtuzumab), and non-HLA allo-antibodies (not shown yet). For a positive B-cell cross-match, individual decisions should be made based on the recipient’s antibody status and immunological history. Sera obtained 14 days after a potentially sensitising event should be included in a final cross-match. Be aware of false-positive cross-match results, especially in autoimmune diseases, which often exhibit clinically irrelevant IgM auto-antibodies. Inactivation of IgM antibodies by serum treatment with dithiothreitol (DTT) can minimise false-positive cross-match results. However, be aware that IgM-anti-HLA allo-antibodies are also DTT-sensitive. Anti-HLA allo-antibodies of the IgM isotype are rare and a positive cross-match result due to IgM-anti-HLA is currently considered as potentially relevant. Flow cytometry cross-match may be used in presensitised recipients at high risk of antibody-mediated graft rejection. However, the great sensitivity of flow cytometric cross-match may exclude unnecessarily a high number of patients from transplantation (1, 7). An enzyme-linked immunosorbent assay (enzyme-linked immunosorbent assay, ELISA) cross-match test, which uses solid-phase technology to detect donor-specific anti-HLA antibodies, is being evaluated.

5.3 Pre-existing HLA-specific antibodies Sera from potential organ recipients should be screened for HLA-specific antibodies every 3 months or as stipulated by the national and/or international organ exchange organisations. Screening for HLA-specific antibodies should be carried out at 2 and 4 weeks after every immunising event, e.g. blood transfusion, transplantation, pregnancy, and graft explantation. The results of HLA-antibody testing in a recipient’s serum are expressed as the percentage of panel reactive antibodies (%PRA) and as the HLA specificity against which these antibodies react. To detect antibodies to HLA class II antigens, a technique must be used that distinguishes them from antibodies to HLA class I antigens. In the standard CDC assay, the panel of lymphocytes used cover most of the common HLA-alleles in the donor population and should optimally contain at least 50 different HLA-typed cells. As the assay is not sufficiently sensitive, clinically relevant anti-HLA class I and class II antibodies may go undetected in the traditional microlymphocytotoxicity assay (8). Non-complement fixing antibodies are not detected at all. More specific and sensitive solid-phase techniques have been developed, such as flow cytometry and ELISA, which use solubilised or recombinant HLA molecules instead of lymphocytes. Preformed non-HLA allo-antibodies may also influence graft outcome (9). Solid-phase assays are strictly HLA-specific and cannot detect non-HLA antibodies. It is not clear whether clinically relevant non-HLA antibodies are expressed on B-lymphocytes and can therefore be recognised by lymphocytotoxicity testing. No antibody screening methods can reliably detect all clinically relevant allo-antibodies, and a combination or alternate use of lymphocytotoxic and solid-phase antibody screening methods is therefore recommended (6). Presensitised patients with high PRA have two major disadvantages: • Due to an often positive cross-match, they generally wait longer for an organ than non-sensitised patients • Overlooked antibodies or higher alloreactivity in the cross-match may adversely affect the graft outcome.

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5.3.1 Eurotransplant Acceptable Mismatch (AM) programme Special efforts, such as the acceptable mismatch (AM) programme of Eurotransplant, have achieved successful transplantation in highly sensitised patients (PRA ≥ 85%) (10). A careful analysis of HLA antibody specificities is carried out to avoid unacceptable HLA antigens and to determine acceptable HLA antigens in potential donors, who are expected to give a negative cross-match result. Patients accepted for the AM programme of Eurotransplant are given high priority during organ allocation if the donor cross-match test is negative. 5.4 ABO compatibility Compatibility for ABO blood group antigens is of critical importance in kidney transplantation. Since blood group antigens can behave as strong transplant antigens (i.e. expression on renal vascular endothelium), incompatibility in the ABO antigen system between donor and recipient can cause early HAR and must be avoided. However, with the introduction of antibody elimination methods and anti-B cell agents, increasing numbers of centres are performing successful ABO-incompatible transplantations, even without splenectomy (11). Despite an elevated risk of post-transplant haemolytic disease due to resting donor B-cells in the graft, the kidneys of potential donors with blood group O can theoretically be transplanted in A, B, or AB recipients. To avoid an increasing imbalance between demand and supply in deceased-donor kidney transplantation in O recipients, ABO identity is demanded by several organ allocation organisations with a few exceptions, e.g. as in zero HLA-A+B+DR-mismatch kidneys. In living-donor transplantation, ABO compatibility is as acceptable as ABO identity.

5.5

REFERENCES

1.

CTS Collaborative Transplant Study. http://ctstransplant.org/protected/dataR/html_all/K-21111-0207.html Last accessed October 19, 2008. UNOS United Network for Organ Sharing. http://www.unos.org/ Last accessed October 13, 2008. Terasaki PI, Cecka JM, Gjertson DW, Takemoto S. High survival rates of kidney transplants from spousal and living unrelated donors. N Engl J Med 1995;333(6):333-6. http://www.ncbi.nlm.nih.gov/pubmed/7609748 EFI European Federation for Immunogenetics. Standards for histocompatibility testing. http://www.efiweb.eu/ [accessed October 13, 2008.] The British Transplantation Society. Towards standards for organ and tissue transplantation in the United Kingdom. http://www.bts.org.uk/Forms/Towards%20standards.pdf Last accessed October 13, 2008. The Anthony Nolan Trust. Nomenclature for factors of the HLA system, monthly updates 2006-2008. http://www.anthonynolan.org.uk/research/hlainformaticsgroup/updates/nomenclature-for-factors-ofthe-hla-system-monthly-updates-2006-2008.htm?knownurl=http%3a%2f%2fwww.anthonynolan.org. uk%2fresearch%2fhlainformaticsgroup%2fupdates%2f [accessed October 13, 2008] Christiaans MH, Overhof R, ten Haaft A, Nieman F, van Hooff JP, van den Berg-Loonen EM. No advantage of flow cytometry crossmatch over complement-dependent cytotoxicity in immunologically well-documented renal allograft recipients. Transplantation 1996;62(9):1341-7. http://www.ncbi.nlm.nih.gov/pubmed/8932282 Süsal C, Opelz G. Kidney graft failure and presensitization against HLA class I and class II antigens. Transplantation 2002;73(8):1269-73. http://www.ncbi.nlm.nih.gov/pubmed/11981420 Opelz G; Collaborative Transplant Study. Non-HLA transplantation immunity revealed by lymphocytotoxic antibodies. Lancet 2005;365(9470):1570-6. http://www.ncbi.nlm.nih.gov/pubmed/15866311 De Meester J, Doxiadis II, Persijn GG, Claas FH. Renal transplantation of highly sensitised patients via prioritised renal allocation programs. Shorter waiting time and above-average graft survival. Nephron 2002; 92(1):111-9. http://www.ncbi.nlm.nih.gov/pubmed/12187093 Segev DL, Simpkins CE, Warren DS, King KE, Shirey RS, Maley WR, Melancon JK, Cooper M, Kozlowski T, Montgomery RA. ABO incompatible high-titer renal transplantation without splenectomy or anti-CD20 treatment. Am J Transplant 2005;5(10):2570-5. http://www.ncbi.nlm.nih.gov/pubmed/16162210

2. 3.

4. 5.

6.

7.

8.

9.

10.

11.

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6. IMMUNOSUPPRESSION AFTER KIDNEY TRANSPLANTATION 6.1

Introduction

The principle underlying successful immunosuppression is ‘the balance of survival’. Practitioners must prescribe a dosage of drug high enough to suppress rejection without endangering the recipient’s health. Increased understanding of immune rejection has led to the development of safe modern immunosuppressives (1), which suppress sensitised lymphocyte activity against a transplant. Immunosuppression is particularly important during the initial post-transplant period when there is a high incidence of early post-transplant rejection. In later post-operative stages, ‘graft adaptation‘ occurs, resulting in the very low rejection rates seen in maintenance patients. Rejection prophylaxis should therefore be reduced over time by steroid tapering and gradual lowering of calcineurin inhibitor (CNI) (2, 3) (level of evidence: 1b). Non-specific side-effects of immunosuppression include a higher risk of malignancy and infection, particularly opportunistic infections (1-3). All immunosuppressants also have dose-dependant specific side-effects. Current immunosuppressive protocols aim to reduce drug-specific side-effects using a synergistic regimen (4). A truly synergistic regimen allows profound dose reductions of immunosuppressive drugs, so reducing side-effects, while still maintaining efficacy due to the synergistic effects of the immunosuppressants (level of evidence; 1b). Current standard initial immunosuppression provides excellent efficacy with good tolerability (5, 6). It is given to most patients and consists of: • CNIs (cyclosporine or tacrolimus) • Mycophenolate (MMF or enteric-coated mycophenolate sodium, EC-MPS) • Steroids (prednisolone or methylprednisolone) • With or without induction therapy. This multidrug regimen reflects today the standard of care for the majority of transplant recipients worldwide (5, 6) (level of evidence: 1b) This standard regimen is likely to change as new immunosuppressive drugs and new treatment regimens are developed (7). In addition, any initial drug regimen will need to be tailored to the individual needs of a patient as suggested by the appearance of side-effects, lack of efficacy or protocol-driven requirements (3, 4, 6).

6.2 Primary immunosuppressive phrophylaxis 6.2.1 Calcineurin inhibitors (CNIs) Both cyclosporine and tacrolimus have significant side-effects that are hazardous to the graft and patient (1-3) (8, 9). Most importantly, both are nephrotoxic (10, 11) (level of evidence: 1a), and long-term use is a major cause of chronic allograft dysfunction, eventually leading to graft loss or severe chronic kidney disease in recipients of non-renal organs (12). 6.2.1.1 Cyclosporine A Cyclosporine A micro-emulsion (CsA-ME; Neoral) has a better pharmacokinetic profile and appears to be more acceptable to patients compared to the previous formulation (Sandimmune) (1, 6, 13, 14). More importantly, the area under the absorption curve is higher with CsA-ME than with Sandimmune, enabling a reduction in the dosage of cyclosporine without affecting efficacy (8). CsA-ME treatment is also associated with a reduced rejection rate 1 year post transplant (8) (level of evidence: 1b). Although CsA-ME has proven efficacy and safety, it is a ‘critical-dose‘ drug, so that any deviations from exposure can lead to severe toxicity or failure of efficacy (13, 14). The demonstration of bioequivalence in healthy volunteers according to standard criteria is not sufficient evidence to support treatment of all renal allograft recipients with generic formulations of cyclosporine. Until more data are available, the patient and physician prescibing generic cyclosporine formulations must be aware of potential differences in exposure, maximal drug concentration, variability and food effects (15, 16). Precautions (e.g. close surveillance and determination of drug levels) should be instituted after conversion from one cyclosporine formulation to another (13, 14) (level of evidence: 2a). Pharmaceutical companies and researchers are asked to provide sufficient data on key pharmacokinetic

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parameters in target populations, including de-novo transplanted patients. Drug agencies should institute more stringent criteria for ‘critical dose’ drugs requesting approval (level of evidence: 4). Cyclosporine causes hypercholesterolaemia, hypertension, gum hypertrophy, constipation, hirsuitsm and acne (1-3, 8, 10) (level of evidence: 1a). Therapeutic drug monitoring is mandatory (17, 18) (level of evidence: 3) because of its narrow therapeutic window and the potential for drug-to-drug interaction. The drug level at 2 hours after intake (C2) may correlate better with exposure with retrospective studies suggesting a better correlation for C2 levels with outcome parameters (17, 18) (level of evidence: 3). However, no prospective comparative studies have been undertaken, and C2 levels alone may not adequately reflect cyclosporine exposure in the early post-transplant period (17, 18) (level of evidence: 2b). Furthermore, the determination of C2 levels may cause logistical problems. Most importantly, similiar overall outcomes were achieved with conventional monitoring strategies. In summary, both cyclosporine-monitoring strategies are useful for assessing cyclosporine exposure. The additional measurement of a trough level in C2-monitored patients or of a C2 level in trough-level monitored patients may provide a more accurate assessment of drug exposure (18) (level of evidence: 4). 6.2.1.2 Tacrolimus Tacrolimus is a more powerful immunosuppressive than cyclosporine, as indicated by its more potent prophylaxis of transplant rejection. However, its use is associated with diabetes, neurological sideeffects (tremor, headache), hair loss, gastrointestinal side-effects (e.g. diarrhoea, nausea, vomiting) and hypomagnesemia (1-3, 8, 10) (level of evidence: 1a). In combination with a mycophenolate, it may also more often cause over-immunosuppression, namely polyoma nephritis (19) (level of evidence: 1b). A new modified-release formulation (Advagraf), which allows once-daily dosing of tacrolimus (20, 21), has been approved in Europe, though not yet in the USA. Advagraf fulfils standard bioequivalence criteria, although it results in slightly lower exposure, lower peak levels and lower trough levels, which therefore require a higher dosage to maintain exposure (20-23) (level of evidence: 1b). Too low a level of exposure may be critical, especially early after transplantation. Both tacrolimus formulations provide effective rejection prophylaxis and overall similar outcomes compared to cyclosporine (22) (level of evidence: 1b). Because of its narrow therapeutic window and the potential for drugto-drug interaction, tacrolimus should be monitored using trough levels, which provide a reasonable estimate for exposure (20, 21) (level of evidence: 3). 6.2.1.3. Summary Meta-analysis of tacrolimus and cyclosporine has demonstrated similar outcomes with respect to overall patient and graft survival (8) (level of evidence: 1a). Some analyses have shown that tacrolimus provided better rejection prophylaxis and was associated with slightly better graft survival, when censored for death in some analysis. Renal function was favourable for tacrolimus-treated patients, but did not reach statistical significance in most analyses. Several more recent trials have confirmed that rejection prophylaxis is better with tacrolimus (22, 24, 25), but failed to show any benefit with respect to patient and graft survival. Thus, in summary, both CNIs can be used for the effective prevention of acute rejection (level of evidence: 1a). In case of specific side effects of a CNI (e.g. hirsutism, alopecia, gingival hyperplasia, diabetes, polyoma nephropathy) conversion to the other CNI can be a successful strategy to reduce side effects (26, 27) (level of evidence: 1b). Due to differences in the efficacy and safety profile, the choice of CNI should include the individual risks and benefits for each patient (level of evidence: 4). Despite their side-effects, CNIs have been a cornerstone of modern immunosuppresive regimens for more than 20 years because they have resulted in an exemplary improvement in kidney graft survival. This has led to success in pancreas, heart, liver, and lung transplantation (1) (level of evidence: 1a). Future protocols aim to minimise or even eliminate CNIs. However, until such strategies provide superior outcomes, CNIs remain the standard of care in the initial post-operative period (2, 3) (level of evidence: 1b). For severe CNI-related sideeffects, CNI withdrawal, replacement or profound reduction may be needed (10) (evidence level 2b). Special attention should be paid to maintenance patients, which may need less CNIs than previously thought (26, 28) (level of evidence: 1b). Recommendations GR • Rejection prophylaxis with CNIs represents current best practice pending publication of A long-term results using newer agents

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•

 he choice of CNI depends on the immunological risk, recipient characteristics, T concomitant immunosuppression and socio-economic factors • Blood-level monitoring of both cyclosporine and tacrolimus is mandatory to prevent under-immunosuppression (enhanced risk of rejection) and excessively high blood levels (resulting in a high risk of chronic side-effects, particularly nephrotoxicity) GR = grade of recommendation

A A

6.2.2 Mycophenolates The mycophenolates, MMF and EC-MPS, are based on mycophenalic acid (MPA), which inhibits inosine monophosphate dehydrogenase. This is the rate-limiting step for the synthesis of guanosine monophosphate in the de-novo purine pathway. As the function and proliferation of lymphocytes is more dependent on de-novo purine nucleotide synthesis compared to other cell types, inosine monophosphate dehydrogenase (IMPDH) inhibitors may provide a more specific lymphocyte-targeted immunosuppression (1). Mycophenolic acid is not nephrotoxic; however, it inhibits bone marrow function and may cause gastrointestinal side-effects particularly diarrhoea (29, 30). Both MPA formulations are equally effective with an almost identical safety profile (29) (level of evidence: 1b), though some prospective studies suggest a better gastrointestinal side-effect profile for EC-MPS in patients who have suffered from MMF-related gastrointestinaI complaints, although firm evidence from prospective randomised studies is lacking (31, 32) (level of evidence: 2a). The co-administration of mycophenolate with prednisolone and CNI has resulted in a profound reduction of biopsy-proven rejections (33) (level of evidence: 1b). A retrospective study Mycophenolate mofetil decreased the relative rate for chronic allograft rejection by 27% versus azathioprine, an effect independent of the reduction of acute cellular rejection in patients receiving MMF (33) (level of evidence: 3). Recent retrospective studies have suggested that MPA dose reductions are associated with inferior outcomes (31) (level of evidence: 3). Other side-effects include the potential for over-immunosuppression, especially a higher incidence of CMV infections and severe CMV disease, and a higher incidence of polyoma nephropathy, especially when mycophenolate is combined with tacrolimus (1-3) (level of evidence: 1b). Standard doses in combination with cyclosporine are MMF 1 g bid or EC-MPS 720 mg bid (level of evidence: 1b), although higher initial doses have been suggested, recently (34, 35) (level of evidence: 2b). MPA is not formally approved for use with tacrolimus, though this is the most frequently used drug combination in many countries worldwide (5). Despite its frequent use with tacrolimus, there is insufficient evidence to support the optimal dosage for this combination (34, 35). Tacrolimus has no influence on MPA exposure and leads to approximately 30% higher MPA exposure compared to cyclosporine (34, 35) (level of evidence: 2a). Most transplant centres use the same starting dose compared to cyclosporine-treated patients (35) (level of evidence: 2b), however dose reductions are frequent, especially because of gastrointestinal side-effects (35). After 6-12 months, most patients are treated with a daily dose of MMF, 1000-1500 mg, or EC-MPS, 720-1080 mg (22, 24, 25). Due to the high incidence of side effects, some centers perform a protocol-driven MPA dose reduction in tacrolimus treated patients (34, 35) (level of evidence: 3). Regular monitoring for polyoma is recommended in patients given MPA combined with tacrolimus (36, 37) (level of evidence: 3). Due to a higher incidence of CMV disease with MPA, either CMV prophylaxis or a pre-emptive strategy with regular screening for CMV viraemia should be instituted (37-40) (level of evidence: 1a). CMV prophylaxis with antiviral medications (e.g. valganciclovir) should be used routinely in CMV positive recipients and in CMV negative recipients of CMV positive organ transplants, because prophylaxis recently has been shown to reduce CMV disease, CMV-associated mortality in solid organ transplant recipients (40) and leads to better long-term graft survival in kidney allograft recipients (38) (level of evidence: 1a). The benefit for MPA drug monitoring is uncertain and currently not recommended for the majority of patients (34, 35, 41-44) (level of evidence: 1b). In maintenance patients, the potency of MPA can be used for successful steroid withdrawal in most patients (45, 46) (level of evidence: 1a) or for substantial dose reductions of nephrotoxic CNIs, which may lead to better renal function (2, 3, 28, 47) (level of evidence: 1b). Although there have been several studies of the potential for CNI-free protocols with MPA and steroids, complete CNI avoidance or withdrawal over the first 3 years has been associated with a substantially increased rejection risk and even worse outcomes in prospective randomised studies (47-49) (level of evidence: 1b). In contrast, CNI withdrawal under MPA and

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steroids appeared to be safe in long-term maintenance patients beyond 5 years’ post-transplant and resulted in improved renal function (50, 51) (level of evidence: 1b). It is under investigation whether or not early CNI withdrawal under combination therapy of MPA, steroids and m-TOR inhibitors is safe and efficacious. Recommendations GR • Mycophenolates are the current standard of care. The standard dose of MMF combined A with cyclosporine is 1 g bid or EC-MPS 720 mg bid • Combination therapy of mycophenolates with tacrolimus is not formally approved. Optimal A mycophenolate dosing is not yet clear, as tacrolimus-treated patients develop higher MPA exposure compared to cyclosporine-treated patients. The standard starting dose of MMF combined with tacrolimus is MMF 1 g bid or EC-MPS 720 mg bid. This dosage, which is applied in most centres, is often reduced resulting in 30-50% lower doses at 1 year • Mycophenolate drug monitoring cannot be recommended for all patients due to limited A evidence supporting its benefit GR = grade of recommendation 6.2.3 Azathioprine Mycophenolate is now routinely used as a primary therapy in place of azathioprine in most units worldwide. In comparison to azathioprione, MPA reduced rejection rates significantly in prospective randomised trials (1, 5, 6, 28, 29) (level of evidence: 1b). Although a recent, large, prospective study found that azathioprine may give acceptable results in a low-risk population (52) (level of evidence: 1b), azathioprine is usually reserved for patients who cannot tolerate MPA (5, 6). When added to dual therapy with cyclosporine and steroids, a metaanalysis found no significant benefit for azathioprine with respect to major outcome parameters (53) (level of evidence: 1a). Recommendations GR • Azathioprine may be used in a low-risk population as initial immunosuppression, especially A for those intolerant to MPA formulations • There is no firm evidence for the efficacy of azathiprine in combination therapy with CNIs A and steroids GR = grade of recommendation 6.2.4 Steroids Steroids have a large number of side-effects (1-3, 45, 54), especially with long-term use. Most practitioners still consider prednisolone to be a fundamental adjunct to primary immunosuppression (5), even though successful prednisolone withdrawal has been achieved in the vast majority of patients in many prospective, randomised trials (45, 46, 55, 56) (level of evidence: 1a). These trials suggest the risk of steroid withdrawal depends on the use of concomitant immunosuppressive medication, immunological risk, ethnicity, and time after transplantation. Although the risk of rejection diminishes over time, potential benefits may be less prominent after a prolonged steroid treatment peroid. (1-3, 45, 54, 57) (level of evidence: 3). Recommendations GR • Initial steroid therapy remains the standard in perioperative and early posttransplamt period. A • There is increasing evidence that steroids may be safely stopped in most patients after A 3-12 months on combination therapy with CNI and MPA • Steroid-free long-term therapy is inherently associated with a reduction of steroid-induced A side effects GR = grade of recommendation 6.2.5 Inhibitors of the mammalian target of rapamycin (m-TOR) The immunosuppressants, sirolimus and everolimus, inhibit the mammalian target of rapamycin (m-TOR) and suppress lymphocyte proliferation and differentiation. They inhibit both calcium-dependent and calciumindependent pathways and block cytokine signals for T-cell proliferation. Similar effects are seen on B-cells, endothelial cells, fibroblasts and tumour cells (1-3, 57-60). m-TOR inhibitors are as effective as MPA when combined with CNIs in preventing rejection (57-60) (level of evidence: 1b). 6.2.5.1 Side-effects m-TOR inhibitors exhibit dose-dependent bone marrow toxicity. Other potential side-effects include hyperlipidaemia, oedema, development of lymphoceles, wound-healing problems, pneumonitis, proteinuria, and impaired fertility (57-60) (level of evidence: 1b). When combined with CNIs, pneumocystis prophylaxis is

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mandated, e.g. low-dose cotrimoxazole (57-60) (level of evidence: 3). Most importantly, combination therapy with CNIs aggravate CNI-induced nephrotoxicity, although m-TOR inhibitors themself are non-nephrotoxic (5760) (level of evidence: 1b). Several studies suggest less favourable outcomes for this combination, especially if CNIs are maintained at standard dosages (57-61) (level of evidence: 3). CNI dosage should therefore be substantially reduced in combination therapy with m-TOR inhibitors, which seems to have no impact on effcacy, due to the highly synergisitic potential of this combination therapy (57-60) (level of evidence: 1b). 6.2.5.2 Comparison of pharmacokinetics and licensed use To date, no prospective comparative studies have been carried out on sirolimus and everolimus. Both m-TOR inhibitors have an almost identical side-effect profile and mainly differ in their pharmacokinetic properties (57-60). Sirolimus has a half-life of about 60 h, is given once a day and is licensed for prophylaxis of kidney recipients only. Everolimus has a half-life of about 24 h, is licensed for kidney and heart recipients and is given twice a day. Everolimus is licenced for use with cyclosporine (57-60) (level of evidence: 1b) and can be given simultaneously with cyclosporine, while sirolimus should be given 4 h after cyclosporine (57-60). Sirolimus is also licensed in combination therapy with steroids for cyclosporine withdrawal from combination therapy with cyclosporine (57-60) (level of evidence: 1b). Therapeutic monitoring of trough levels is recommended because of the narrow therapeutic window and the risk of drug-to-drug interactions (57-60) (level of evidence: 3). 6.2.5.3 Conversion from CNIs to m-TOR inhibitors Despite an encouraging earlier metaanalysis (60), recent studies suggest m-TOR inhibitors cannot replace CNIs in the initial phase after transplantation due to lower efficacy and a less favourable side-effect profile, particularly wound healing problems and lymphoceles (2, 3, 24, 57-60) (level of evidence: 1a). Other research suggests that m-TOR inhibitors can safely replace CNI at later stages, e.g. 3 months after transplantation, with improvements in renal function (2, 3, 57-60, 62) (level of evidence: 1a). However, especially early after transplantation, there is a slightly increased risk of rejection, which may be offset by the benefit of the nonnephrotoxic immunosuppression. Despite higher rejection rates, one study showed better long-term survival, better renal function and fewer malignancies under dual therapy with sirolimus and steroids compared to the more nephrotoxic therapy with cyclosporine, steroids and sirolimus. (2, 3, 57-60, 62) (level of evidence: 1b). Proteinuria and poor renal function are associated with inferior outcomes. Conversion from CNI is not advisable in patients with proteinuria > 800 mg/day (57-60, 63, 64, 65) (level of evidence: 1b). A cautious and individual approach should be followed in patients with GFR < 30 mL/min (57-60, 63-65) (level of evidence: 3). Due to an antiproliferative effect and a lower incidence of malignancy in sirolimus-treated patients, conversion from CNIs to m-TOR inhibitors may be beneficial for patients, who develop malignancy after transplantation, or who are at a high risk for the development of post-transplant malignancy (57-60, 66) (level of evidence: 3). However, no controlled trials have reported better outcomes after conversion. To date, only a few data on longterm follow-up of m-TOR-treated patients have been reported. Emerging side-effects including proteinuria (66, 67) and infertility (68) warrant an individual and cautious approach (level of evidence: 3). Recommendations GR • Acute rejection can be effectively prevented by m-TOR inhibitors, such as sirolimus and A everolimus, in combination with CNIs. This combination regimen is associated with enhanced nephrotoxicity and inferior outcomes. CNI dosage must be significantly reduced to prevent aggravated nephrotoxicity • Initial CNI-free combination therapy of m-TOR inhibitors with MPA and steroids is not A sufficient to effectively prevent acute rejection compared to a standard regimen • Use of m-TOR inhibitors is associated with impaired wound healing. Prophylactic surgical A measures must be implemented if patients receive m-TOR inhibitors during the peri-operative period • m-TOR inhibitors can safely replace CNIs beyond the early post-transplant period. They are A a valid alternative to CNIs when there are severe CNI related side-effects, e.g. nephrotoxicity • Blood levels of both sirolimus and everolimus must be measured at regular intervals A GR = grade of recommendation 6.2.6 T-cell depleting induction therapy Prophylactic immunosuppression in many countries, particularly the USA, featured the emergence of ‘induction’ treatments, using biological T-cell depleting agents. These include anti-thymocyte globulin (ATG), OKT3 and more recently an anti-CD52 antibody (Campath1-H) after renal transplantation (1, 5).

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Some centres use these agents to provide effective rejection prophylaxis while initiating CNIs after recovery of the graft from ischaemic injury, although evidence supporting this hypothesis is lacking (69, 70) (level of evidence: 1b). Graft rejection rates are initially lower with induction treatment (69, 70, 71); however, some studies suggest an increased rejection rate after cessation of lymphocyte depletion (70, 72). There is no evidence of better long-term graft survival in patients receiving induction therapy versus those who have not (70, 73-75) (level of evidence: 3). In contrast, it is well documented that induction therapies with T-cell depleting agents carry an increased risk of post-operative opportunistic infections and cancer, especially post-transplant lymphoproliferative disease (70, 73-75) (level of evidence: 3). Recommendations GR • Potential life-threatening side-effects of T-cell depleting biological induction therapy include B a higher incidence of severe opportunistic infections and malignancy, particularly post-transplant lymphoproliferative disease • Use of T-cell depleting antibodies has not been associated with improved outcomes in the B overall population • T-cell depleting antibodies should not be routinely used in a low-risk first-transplant recipient B • If such induction therapy is used, the increased risks of infection and cancer must be B explained to the patient before staring therapy GR = grade of recommendation 6.2.7 Interleukin-2 receptor antibodies Two high-affinity anti-interleukin-2 (IL-2) receptor monoclonal antibodies (daclizumab and basiliximab) are approved for rejection prophylaxis following organ transplantation (1, 70, 76-78). These agents are given in a short course during the post-transplantation period, are safe, and have been shown in randomised controlled trials to reduce the prevalence of acute cellular rejection by approximately 40% (70, 78) (level of evidence: 1a). Both antibodies appear to be equally efficacious, though no formal comparative study was performed. A meta-analysis has confirmed the efficacy, although no positive effect on patient or graft survival could be demonstrated (78) (level of evidence: 1a) although large retrospective cohort studies and a recent large prospective study suggest such a benefit (24, 70, 73, 75). The effect of these antibodies in combination with tacrolimus and/or mycophenolate was not investigated in the meta-analysis. Several recently published large controlled trials support the efficacy and safety of quadruple therapy with these agents (6, 22, 24, 25, 49, 55, 56, 70) (level of evidence: 1b). Interleukin-2 receptor antibodies may allow early steroid withdrawal (55, 56) (level of evidence: 1b), although higher rejection rates were described. Most importantly, IL-2 receptor antibodies allow a substantial reduction in CNIs, while maintaining excellent efficacy and renal function. (2, 3, 6 24, 47) (level of evidence: 1b). Recommendations GR • Use of IL-2R antibodies for preventing rejection is efficacious and safe, and effectively A reduces the rate of acute rejection, enabling CNI- and steroid sparing regimens • Formal evidence for improved patient and graft outcome is lacking, although recent large A clinical trials suggest such a benefit GR = grade of recommendation 6.2.8 1.

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Kliem V, Fricke L, Wollbrink T, Burg M, Radermacher J, Rohde F. Improvement in long-term renal graft survival due to CMV prophylaxis with oral ganciclovir: results of a randomized clinical trial. Am J Transplant 2008;8(5):975-83. http://www.ncbi.nlm.nih.gov/pubmed/18261177 Hodson EM, Jones CA, Strippoli GF, Webster AC, Craig JC. Immunoglobulins, vaccines or interferon for preventing cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev 2007;(2):CD005129. http://www.ncbi.nlm.nih.gov/pubmed/17443573 Hodson EM, Craig JC, Strippoli GF, Webster AC. Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev 2008;(2):CD003774. http://www.ncbi.nlm.nih.gov/pubmed/16235341 Arns W, Cibrik DM, Walker RG, Mourad G, Budde K, Mueller EA, Vincenti F. Therapeutic drug monitoring of mycophenolic acid in solid organ transplant patients treated with mycophenolate mofetil: review of the literature. Transplantation 2006;82(8):1004-12. http://www.ncbi.nlm.nih.gov/pubmed/17060847 Knight SR, Morris PJ. Does the evidence support the use of mycophenolate mofetil therapeutic drug monitoring in clinical practice? A systematic review. Transplantation 2008;85(12):1675-85. http://www.ncbi.nlm.nih.gov/pubmed/18580456 Oremus M, Zeidler J, Ensom MH, Matsuda-Abedini M, Balion C, Booker L, Archer C, Raina P. Utility of monitoring mycophenolic acid in solid organ transplant patients. Evid Rep Technol Assess (Full Rep) 2008;(164):1-131. http://www.ncbi.nlm.nih.gov/pubmed/18457479 van Gelder T, Silva HT, de Fijter JW, Budde K, Kuypers D, Tyden G, Lohmus A, Sommerer C, Hartmann A, Le Meur Y, Oellerich M, Holt DW, Tönshoff B, Keown P, Campbell S, Mamelok RD. Comparing mycophenolate mofetil regimens for de novo renal transplant recipients: the fixed-dose concentration-controlled trial. Transplantation 2008;86(8):1043-51. http://www.ncbi.nlm.nih.gov/pubmed/18946341 Pascual J, Quereda C, Zamora J, Hernández D; Spanish Group for Evidence-Based Medicine in Renal Transplantation. Updated metaanalysis of steroid withdrawal in renal transplant patients on calcineurin inhibitor and mycophenolate mofetil. Transplant Proc 2005;37(9):3746-8. http://www.ncbi.nlm.nih.gov/pubmed/16386525 Pascual J, Quereda C, Zamora J, Hernández D; Spanish Group for Evidence-Based Medicine in Renal Transplantation. Steroid withdrawal in renal transplant patients on triple therapy with a calcineurin inhibitor and mycophenolate mofetil: a meta-analysis of randomized, controlled trials. Transplantation 2004;78(10):1548-56. http://www.ncbi.nlm.nih.gov/pubmed/15599321 Ekberg H. Calcineurin inhibitor sparing in renal transplantation. Transplantation 2008;86(6):761-7. http://www.ncbi.nlm.nih.gov/pubmed/18813097 Abramowicz D, Del Carmen Rial M, Vitko S, del Castillo D, Manas D, Lao M, Gafner N, Wijngaard P; Cyclosporine Withdrawal Study Group. Cyclosporine withdrawal from a mycophenolate mofetilcontaining immunosuppressive regimen: results of a five-year, prospective, randomized study. J Am Soc Nephrol 2005;16(7):2234-40. http://www.ncbi.nlm.nih.gov/pubmed/15917338 Ekberg H, Grinyó J, Nashan B, Vanrenterghem Y, Vincenti F, Voulgari A, Truman M, Nasmyth-Miller C, Rashford M. Cyclosporine sparing with mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: the CAESAR Study. Am J Transplant 2007;7(3):560-70. http://www.ncbi.nlm.nih.gov/pubmed/17229079 Suwelack B, Gerhardt U, Hohage H. Withdrawal of cyclosporine or tacrolimus after addition of mycophenolate mofetil in patients with chronic allograft nephropathy. Am J Transplant 2004 Apr;4(4):655-62. http://www.ncbi.nlm.nih.gov/pubmed/15023160 Dudley C, Pohanka E, Riad H, Dedochova J, Wijngaard P, Sutter C, Silva HT Jr; Mycophenolate Mofetil Creeping Creatinine Study Group. Mycophenolate mofetil substitution for cyclosporine a in renal transplant recipients with chronic progressive allograft dysfunction: the ‘creeping creatinine’ study. Transplantation 2005;79(4):466-75. http://www.ncbi.nlm.nih.gov/pubmed/15729174

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Remuzzi G, Cravedi P, Costantini M, Lesti M, Ganeva M, Gherardi G, Ene-Iordache B, Gotti E, Donati D, Salvadori M, Sandrini S, Segoloni G, Federico S, Rigotti P, Sparacino V, Ruggenenti P. Mycophenolate mofetil versus azathioprine for prevention of chronic allograft dysfunction in renal transplantation: the MYSS follow-up randomized, controlled clinical trial. J Am Soc Nephrol 2007;18(6):1973-85. http://www.ncbi.nlm.nih.gov/pubmed/17460145 Kunz R, Neumayer HH. Maintenance therapy with triple versus double immunosuppressive regimen in renal transplantation: a meta-analysis. Transplantation. 1997;63(3):386-92. http://www.ncbi.nlm.nih.gov/pubmed/9039928 Rike AH, Mogilishetty G, Alloway RR, Succop P, Roy-Chaudhury P, Cardi M, Kaiser TE, Thomas M, Woodle ES. Cardiovascular risk, cardiovascular events, and metabolic syndrome in renal transplantation: comparison of early steroid withdrawal and chronic steroids. Clin Transplant 2008;22(2):229-35. http://www.ncbi.nlm.nih.gov/pubmed/18339144 Woodle ES, First MR, Pirsch J, Shihab F, Gaber AO, Van Veldhuisen P; Astellas Corticosteroid Withdrawal Study Group. A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy. Ann Surg 2008;248(4):564-77. http://www.ncbi.nlm.nih.gov/pubmed/18936569 Vincenti F, Schena FP, Paraskevas S, Hauser IA, Walker RG, Grinyo J; FREEDOM Study Group. A randomized, multicenter study of steroid avoidance, early steroid withdrawal or standard steroid therapy in kidney transplant recipients. Am J Transplant 2008;8(2):307-16. http://www.ncbi.nlm.nih.gov/pubmed/18211506 Kuypers DR. Benefit-risk assessment of sirolimus in renal transplantation. Drug Saf 2005;28(2):153-81. http://www.ncbi.nlm.nih.gov/pubmed/15691225 Augustine JJ, Bodziak KA, Hricik DE. Use of sirolimus in solid organ transplantation. Drugs 2007;67(3):369-91. http://www.ncbi.nlm.nih.gov/pubmed/17335296 Sánchez-Fructuoso AI. Everolimus: an update on the mechanism of action, pharmacokinetics and recent clinical trials. Expert Opin Drug Metab Toxicol 2008;4(6):807-19. http://www.ncbi.nlm.nih.gov/pubmed/18611120 Webster AC, Lee VW, Chapman JR, Craig JC. Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients: a systematic review and meta-analysis of randomized trials. Transplantation 2006;81(9):1234-48. http://www.ncbi.nlm.nih.gov/pubmed/16699448 Meier-Kriesche HU, Schold JD, Srinivas TR, Howard RJ, Fujita S, Kaplan B. Sirolimus in combination with tacrolimus is associated with worse renal allograft survival compared to mycophenolate mofetil combined with tacrolimus. Am J Transplant 2005;5(9):2273-80. http://www.ncbi.nlm.nih.gov/pubmed/16095509 Mulay AV, Cockfield S, Stryker R, Fergusson D, Knoll GA. Conversion from calcineurin inhibitors to sirolimus for chronic renal allograft dysfunction: a systematic review of the evidence. Transplantation 2006;82(9):1153-62. http://www.ncbi.nlm.nih.gov/pubmed/17102766 Abramowicz D, Hadaya K, Hazzan M, Broeders N, Hoang AD, Ghisdal L, Noel C, Wissing KM. Conversion to sirolimus for chronic renal allograft dysfunction: risk factors for graft loss and severe side effects. Nephrol Dial Transplant 2008;23(11):3727-9. http://www.ncbi.nlm.nih.gov/pubmed/18567692 Morath C, Arns W, Schwenger V, Mehrabi A, Fonouni H, Schmidt J, Zeier M. Sirolimus in renal transplantation. Nephrol Dial Transplant 2007;22(Suppl 8):viii61-viii65. http://www.ncbi.nlm.nih.gov/pubmed/17890266 Diekmann F, Budde K, Slowinski T, Oppenheimer F, Fritsche L, Neumayer HH, Campistol JM. Conversion to sirolimus for chronic allograft dysfunction: long-term results confirm predictive value of proteinuria. Transpl Int 2008;21(2):152-5. http://www.ncbi.nlm.nih.gov/pubmed/18005087 Campistol JM, Albanell J, Arns W, Boletis I, Dantal J, de Fijter JW, Mortensen SA, Neumayer HH, Øyen O, Pascual J, Pohanka E, Schena FP, Serón D, Sparacino V, Chapman JR. Use of proliferation signal inhibitors in the management of post-transplant malignancies–clinical guidance. Nephrol Dial Transplant 2007;22(Suppl 1):i36-i41. http://www.ncbi.nlm.nih.gov/pubmed/17456617

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Letavernier E, Legendre C. m-TOR inhibitors-induced proteinuria: mechanisms, significance, and management. Transplant Rev (Orlando) 2008;22(2):125-30. http://www.ncbi.nlm.nih.gov/pubmed/18631865 Huyghe E, Zairi A, Nohra J, Kamar N, Plante P, Rostaing L. Gonadal impact of target of rapamycin inhibitors (sirolimus and everolimus) in male patients: an overview. Transpl Int 2007;20(4):305-11. http://www.ncbi.nlm.nih.gov/pubmed/17326771 Mourad G, Garrigue V, Squifflet JP, Besse T, Berthoux F, Alamartine E, Durand D, Rostaing L, Lang P, Baron C, Glotz D, Antoine C, Vialtel P, Romanet T, Lebranchu Y, Al Najjar A, Hiesse C, Potaux L, Merville P, Touraine JL, Lefrancois N, Kessler M, Renoult E, Pouteil-Noble C, Cahen R, Legendre C, Bedrossian J, Le Pogamp P, Rivalan J, Olmer M, Purgus R, Mignon F, Viron B, Charpentier B. Induction vs. Noninduction in renal transplant recipients with tacrolimus-based immunosuppression. Transplantation 2001;72(6):1050-5. http://www.ncbi.nlm.nih.gov/pubmed/11579299 Nashan B. Antibody induction therapy in renal transplant patients receiving calcineurin-inhibitor immunosuppressive regimens: a comparative review. BioDrugs 2005;19(1):39-46. http://www.ncbi.nlm.nih.gov/pubmed/15691216 Mehrabi A, Mood ZhA, Sadeghi M, Schmied BM, Müller SA, Welsch T, Kuttymuratov G, Wente MN, Weitz J, Zeier M, Morath Ch, Riediger C, Schemmer P, Encke J, Büchler MW, Schmidt J. Thymoglobulin and ischemia reperfusion injury in kidney and liver transplantation. Nephrol Dial Transplant 2007;22(Suppl 8):viii54-viii60. http://www.ncbi.nlm.nih.gov/pubmed/17890265 Abramowicz D, Wissing M. Induction protocols: yesterday, today, and tomorrow. Transplant Proc 1999;31(1-2):1100-1. http://www.ncbi.nlm.nih.gov/pubmed/10083491 Cherikh WS, Kauffman HM, McBride MA, Maghirang J, Swinnen LJ, Hanto DW. Association of the type of induction immunosuppression with posttransplant lymphoproliferative disorder, graft survival, and patient survival after primary kidney transplantation. Transplantation 2003;76(9):1289-93. http://www.ncbi.nlm.nih.gov/pubmed/14627905 Meier-Kriesche HU, Arndorfer JA, Kaplan B. Association of antibody induction with short- and longterm cause-specific mortality in renal transplant recipients. J Am Soc Nephrol 2002;13(3):769-72. http://www.ncbi.nlm.nih.gov/pubmed/11856783 Opelz G, Naujokat C, Daniel V, Terness P, Döhler B. Disassociation between risk of graft loss and risk of non-Hodgkin lymphoma with induction agents in renal transplant recipients. Transplantation 2006;81(9):1227-33. http://www.ncbi.nlm.nih.gov/pubmed/16699447 Mottershead M, Neuberger J. Daclizumab. Expert Opin Biol Ther 2007;7(10):1583-96. http://www.ncbi.nlm.nih.gov/pubmed/17916050 Ramirez CB, Marino IR. The role of basiliximab induction therapy in organ transplantation. Expert Opin Biol Ther 2007;7(1):137-48. http://www.ncbi.nlm.nih.gov/pubmed/17150025 Webster AC, Playford EG, Higgins G, Chapman JR, Craig JC. Interleukin 2 receptor antagonists for renal transplant recipients: a meta-analysis of randomized trials. Transplantation 2004;77(2):166-76. http://www.ncbi.nlm.nih.gov/pubmed/14742976

7. IMMUNOLOGICAL COMPLICATIONS 7.1

Introduction

Immunological rejection is a common cause of early and late transplant dysfunction (1, 2). There is great variation in the timing and severity of rejection episodes and how they respond to treatment (Table 19). There are several main types of immunological reaction (Table 20). Table 19: Determining factors in rejection episodes and response to treatment (1-5) • • •

 egree of sensitisation to HLA, measured by the panel-reactive antibody (PRA) and specific anti-HLA D antibodies Degree of HLA-mismatch, particularly in sensitised recipients (1) History of previous rejection episodes

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• Previous transplantations, especially when graft loss has occurred due to acute rejection • Non-compliance with immunosuppressive treatment • Some virus infections, e.g. CMV CMV = cytomegalovirus. Table 20: Main types of rejection (1-7) Hyper-acute rejection (HAR) • Antibody-mediated rejection is caused by pre-formed anti-HLA or anti-AB (blood group) antibodies • Now rare due to donor-recipient ABO matching and routine pre-transplant cross-matching between donor cells and recipient serum Acute cellular rejection (ACR) • Much more common than HAR, occurring in 10-40% of transplants • Usually occurs from 5 days’ post transplant • Most likely within the first 3 months, though may occur after this time • Usually responds well to steroid bolus treatment Acute humoral rejection (AHR) • Much less frequent than ACR, occurring in 5-20% of transplants • Most likely within the first 3 months’ post transplant • Presence of certain histological features and/or positive C4d immunostaining and/or anti-HLA antibodies • Worse prognosis than ACR because more difficult to treat Chronic allograft rejection (CAR) • Rare, slowly progressive, immunological process • Certain non-specific histological features and/or anti-HLA antibodies • Requires clear strong evidence for a solely chronic immunological process The gold standard for the diagnosis of ACR, AHR and CAR is transplant biopsy (1, 2) (see below), which may demonstrate a mixed histological picture in many cases. The Banff criteria (6, 7) are uniform criteria applied to biopsy, which are updated regularly and are the basis for deciding prognosis and treatment (8) (level of evidence: 3). The term ‘IF/TA’ replaces the previously used terms ‘chronic allograft nephropathy’. This term was used to refer to chronic destruction of the graft associated with fibrosis and arteriosclerosis in renal biopsy and of uncertain aetiology. IF/TA is the common histological manifestation of some damage to the graft, where it is not possible to make a specific diagnosis of the underlying cause (6-9). IF/TA is probably the commonest histological feature in failed grafts and is present to some degree in the vast majority of grafts up to 10 years’ post transplant (9). ‘Chronic allograft dysfunction’ is the term used to refer to the chronic deterioration of graft function without histological evidence (level of evidence: 4).

7.2

Hyper-acute rejection (HAR)

Hyper-acute rejection (HAR) is the most dramatic and destructive immunological attack on the graft (1-5). It results from circulating, complement-fixing IgG antibody, specifically reactive against incompatible donor antigen, which engages with and destroys the vascular endothelium. It occurs in most ABO-incompatible grafts due to the presence of pre-existing IgM iso-antibodies against blood group antigens. In ABO-matched grafts, HAR is mediated by anti-donor HLA IgG antibodies (1-5) (level of evidence: 3). With the development of the cross-match test, HAR has become an extremely uncommon complication. The complement-dependent cytotoxicity test (CDC) is now universally employed in all transplant centres. Recently, newer techniques have been developed, allowing a more sensitive detection of specific anti-HLA antibodies (4, 5) (see Chapter 5). However, validation of these techniques is ongoing. If such diagnostic tests demonstrate the possibility of specific anti-HLA antibodies in the presence of a negative CDC cross-match, an individual decision has to be made whether to transplant or not (level of evidence: 4). Hyper-acute rejection is a rare complication usually seen at the time of surgery. Within minutes or hours of vascularisation, the kidney becomes mottled and then dark and flabby. Histology reveals generalised infarction of the graft (4). Delayed HAR may occur within a week of the transplant, and may be recognised by acute anuria, fever and a swollen graft. Hyper-acute rejection is treated by graft nephrectomy.

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7.2.1 Prevention Hyper-acute rejection can be prevented by the avoidance of an ABO-incompatible renal transplant and by performing a regular CDC cross-match before transplantation (level of evidence: 3). All patients registered for renal transplantation should have their serum screened for anti-HLA antibodies, which are particularly common after pregnancy, previous transplant, transplant rejection, and blood transfusions (4, 5, 10) (level of evidence: 3). Highly sensitised patients (> 50% PRA) should be considered for prioritisation in a points-based matching algorithm (10) (level of evidence: 3). In a national kidney-sharing programme, identification of the specificity of anti-HLA antibodies in highly sensitised patients and cross-matching allows the detection of acceptable and unacceptable antigens present in the donor (10). This information can be highlighted with the patient’s details on the transplant registry database, so preventing the unnecessary transport of kidneys to recipients with high antibody sensitivity (10) (level of evidence: 3). Recommendations GR • All recipients and donors must be tested for blood group antigens and blood group B incompatibility must be avoided, except intentional living-donor ABO-incompatible transplantation • All centres practising renal transplantation should have access to elective serological B profiling of all potential, and actual, waiting-list recipients to define the percentage and specificity of PRA and their isotypes, IgG or IgM • The laboratory service should provide a 24-h donor-recipient cross-matching service to be B able to quickly inform a surgeon of the CDC cross-match result before a deceased donor renal transplant (within 5 h) PRA = panel-reactive antibody; CDC = complement-dependent cytotoxicity (testing); GR = grade of recommendation

7.3

Acute allograft rejection

Acute allograft rejection can be classified into either T-cell mediated (acute cellular rejection, ACR) or antibodymediated (acute humoral rejection, AHR) according to the most recent Banff criteria (1-7). Tubulo-interstitial infiltrate of T-cells, macrophages, and to a lesser extent, neutrophils invading the tubular epithelium is a hallmark of T-cell mediated ACR. Humoral rejection commonly accompanies ACR and causes the same clinical signs. As in ACR, the diagnosis of AHR becomes apparent on renal allograft biopsy. It can be categorised into capillary or arterial antibodymediated rejection. During post-operative humoral rejection, antibodies are formed against donor antigen on the endothelium. In 20-25% of cases, these antibodies may be detected in the serum during rejection (4, 5). Acute humoral rejection is under-diagnosed (11, 12). On biopsy, the appearance may be of oedema and haemorrhage with focal necrosis. The C4d fraction of complement in renal biopsy is required for diagnosis according to the current Banff criteria (6, 7, 11, 12). Not surprisingly, the prognosis is poorer than when ACR occurs alone (4, 5, 11, 12) (level of evidence: 3). Because it is impossible to differentiate acute rejection solely on clinical indicators from other causes of renal dysfunction (e.g. acute tubular necrosis or CNI nephrotoxicity), a biopsy is necessary to correctly diagnose and treat the patient (1-6) (level of evidence: 3). If possible, all rejections must be verified by renal biopsy and graded according to the most recent Banff criteria, except when contraindications for a renal biopsy are present (6-8) (level of evidence: 3). Renal transplant biopsy should be conducted preferably under ultrasound control, using an automated needle biopsy system (e.g. tru-cut, biopsy gun) (13) (level of evidence: 3). Recommendations GR • Renal transplant practitioners must be continuously aware of the possibility of acute rejection, B particularly during the first 6 months after renal transplant • During hospitalisation, regular blood and urine samples should be taken for renal and B haematological studies in addition to regular ultrasound examinations • Rejection should be strongly suspected in any patient who suffers fever, graft tenderness, B or reduced urine output. In case of suspected acute rejection, other potential causes of graft dysfunction need to be ruled out immediately • All patients with suspected acute rejection episodes should undergo renal biopsy, which B should be graded according to the most recent Banff criteria. Only if contraindications to r enal biopsy are present, can ‘blind’ steroid bolus therapy be initiated. Steroid treatment for

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rejection may start before biopsy is performed There should be routine access to ultrasound-guided biopsy of the transplant and sufficient B expertise in the hospital pathology department to allow a clear-cut diagnosis of rejection or other type of allograft dysfunction • Staff and facilities on renal transplant units should be sufficiently equipped to admit a B patient with acute rejection immediately to allow rapid diagnosis and treatment • Patients who suffer ACR should be tested as soon as possible for anti-HLA IgG antibodies B reactive with the graft GR = grade of recommendation •

7.3.1 Treatment of T-cell mediated acute rejection As only a few randomised trials have investigated different treatment options for this clinical problem, therapy is mainly based on empirical experience than on clinical evidence (1-4, 14). Parenteral methylprednisolone (500 mg to 1 g) should be given intravenously as one pulse per day for 3 days (1-4) (level of evidence: 3). Anuria or a steep rise in the serum creatinine may indicate steroid-refractory rejection and the need for another 3-day course of pulsed methylprednisolone therapy (1-4) (level of evidence: 3). In addition, baseline immunosuppression should be re-evaluated to ensure adequate drug exposure (1-4) (level of evidence: 3). In severe rejection, a conversion from cyclosporine to tacrolimus should be considered (1-4) (level of evidence: 3). T-cell depleting biological agents, such as ALG or anti-CD3 monoclonal antibody (OKT3), may be considered in severe steroid-refractory cases (1-4, 14) (level of evidence: 1a). If biological agents are used, other immunological suppression should be reduced or stopped and daily T-cell monitoring should be done to minimise the dose of the biological agent (15, 16) (level of evidence: 4). Before immunosuppression is intensified, especially before the use of T-cell depleting agents, the prognosis of the graft should be critically assessed against the risks of the aggravated immunosuppression. The patient should be counselled adequately (level of evidence: 4). Recommendations GR • Treatment with steroid bolus therapy is recommended B • In severe or steroid-resistant rejection, consider intensified immunosuppression, including B high-dose steroid treatment, conversion to tacrolimus, and T-cell depleting agents GR = grade of recommendation 7.3.2 Treatment of acute humoral rejection (AHR) Acute humoral rejection is treated in a similar way as T-cell mediated rejection (4, 17) (level of evidence: 3). Treatment relies on retrospective studies and empirical treatment guidelines. Treatment with a steroid bolus (at least 3 days of 500 mg/day) and conversion to tacrolimus therapy with trough levels > 10 ng/mL are common (4, 17) (level of evidence: 3). Although T-cell depleting agents appear to have limited value, there are several retrospective case series and a small prospective trial in children and adolescents describing the successful use of the anti-CD20 antibody, rituximab (4, 17, 18) (level of evidence: 1b). However, no further prospective trials have been published and neither the dose, side-effects nor efficacy parameters have been evaluated in a larger cohort with adequate follow-up. Most centres also try to remove antibodies using plasmapheresis or immunoadsorption columns. Retrospective and prospective case series clearly suggest efficacy (4, 17, 19) (level of evidence: 1b), although details of the procedures vary widely. Some centres advocate intravenous immunoglobulin (20), which may modulate and/or suppress antibody production (4, 17, 20) (level of evidence: 3). Dosages vary widely from 0.2-2.0 g/kg bodyweight. No comparative studies have been published. Several regimens have proven efficacious in AHR. However, the lack of firm evidence does not permit evidence-based recommendations for treatment, except for a beneficial effect of early antibody removal. Recommendations GR • Treatment of AHR should include early antibody elimination B • In addition, steroid bolus therapy, conversion to tacrolimus, T-cell depleting agents and B intravenous immunoglobulin treatment are used frequently • Anti-CD20 (rituximab) may be efficacious. However, firm evidence on efficacy and B side-effects are lacking GR = grade of recommendation

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7.4

Chronic allograft dysfunction/interstitial fibrosis and tubular atrophy (IF/TA)

Many patients lose their grafts due to chronic allograft dysfunction (9). Histology will usually reveal a chronic process of IF/TA. An unknown, but rather small number of these patients will have ‘true’ immunological CAR (1, 2). IF/TA takes months or years to develop and is heralded by proteinuria and hypertension, with a simultaneous or delayed rise in serum creatinine level over months (9). It is likely that IF/TA is more common in patients who have had early attacks of ACR, which is a good reason for preventing acute cellular rejection. The main differential diagnoses are chronic nephrotoxicity, which is common in patients receiving CNIs, and pre-existing and/or aggravated chronic kidney damage from a marginal donor kidney (9). Histological features on biopsy are fibrosis, cortical atrophy, concentric intimal fibroplasia of larger arteries with capillary dilatation, arteriolar hyalinosis, and thickened split basement membranes. (Level of evidence: 3). 7.4.1 Diagnosis and treatment Diagnosis is by renal biopsy (5, 6). In patients diagnosed early, particularly if there is evidence for CNI toxicity, disease progression may be slowed by conversion to a CNI-free regimen (22-24) (level of evidence: level 1a). Conversion to m-TOR inhibitors is safe. Favourable outcomes have been observed without significant proteinuria (< 800 mg/day) (24, 25) (level of evidence: 1a). Alternatively, successful conversion to a MPA-based regimen has been described, especially in patients beyond the first 3 years’ post transplant (22, 23) level of evidence: 1b). If there is intolerance to m-TOR inhibitors or MPA, conversion to an azathioprine-based regimen may be successful, though the higher risk of rejection warrants close surveillance (26) (level of evidence: 1a). If the risk of rejection seems too high, another option is substantial reduction of CNI under the protection of MPA (21, 27) (level of evidence: 1b). In patients with proteinuria, intervention with an ACE inhibitor or angiotensin II receptor blocker (28) may slow down renal decompensation (level of evidence: 3). Other supportive measures include the treatment of hypertension, hyperlipidaemia, diabetes, anaemia, acidosis and bone disease (29-34) (level of evidence: 3). However, ultimately, the patient will require another transplant (if fit enough to go on the transplant waiting list) or dialysis therapy. Recommendations GR • During the years of follow-up after renal transplantation, regularly monitor serum creatinine, A creatinine clearance, blood pressure and urinary protein excretion • Changes in these parameters over time should trigger hospital admission for renal biopsy and further diagnostic work-up including a search for infectious causes and anti-HLA antibodies. An ultrasound of the graft should rule out obstruction and renal artery stenosis • If a specific cause for deteriorating renal function can be identified, appropriate treatment A should be instituted • If unspecific IF/TA is confirmed, begin appropriate medical treatment (e.g. control of A hypertension, proteinuria) • Supportive measures should aim to adequately treat the consequences of chronic kidney disease (e.g. anaemia, acidosis, bone disease) and cardiovascular risk factors (e.g. hyperlipidaemia, diabetes) • In patients with IF/TA under current CNI therapy and/or with histological signs suggestive for A CNI toxicity (e.g. arteriolar hyalinosis, striped fibrosis) without significant proteinuria (< 800 mg/day), conversion to an m-TOR inhibitor or substantial CNI reduction under MPA protection may be indicated. In chronic maintenance patients beyond 5 years, posttransplant CNI withdrawal under MPA and steroids is another safe option GR = grade of recommendation

7.5

REFERENCES

1.

Cornell LD, Smith RN, Colvin RB. Kidney transplantation: mechanisms of rejection and acceptance. Annu Rev Pathol 2008;3:189-220. http://www.ncbi.nlm.nih.gov/pubmed/18039144 Tomasoni S, Remuzzi G, Benigni A. Allograft rejection: acute and chronic studies. Contrib Nephrol 2008;159:122-34. http://www.ncbi.nlm.nih.gov/pubmed/18391589 Kuypers DR. Immunosuppressive drug therapy and subclinical acute renal allograft rejection: impact and effect. Transplantation 2008;85(7 Suppl):S25-S30. http://www.ncbi.nlm.nih.gov/pubmed/18401259 Gloor J, Cosio F, Lager DJ, Stegall MD. The spectrum of antibody-mediated renal allograft injury: implications for treatment. Am J Transplant 2008;8(7):1367-73. http://www.ncbi.nlm.nih.gov/pubmed/18510643

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Terasaki PI, Cai J. Human leukocyte antigen antibodies and chronic rejection: from association to causation. Transplantation 2008;86(3):377-83. http://www.ncbi.nlm.nih.gov/pubmed/18698239 Solez K, Colvin RB, Racusen LC, Sis B, Halloran PF, Birk PE, Campbell PM, Cascalho M, Collins AB, Demetris AJ, Drachenberg CB, Gibson IW, Grimm PC, Haas M, Lerut E, Liapis H, Mannon RB, Marcus PB, Mengel M, Mihatsch MJ, Nankivell BJ, Nickeleit V, Papadimitriou JC, Platt JL, Randhawa P, Roberts I, Salinas-Madriga L, Salomon DR, Seron D, Sheaff M, Weening JJ. Banff ‘05 Meeting Report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (‘CAN’). Am J Transplant 2007;7(3):518-26. http://www.ncbi.nlm.nih.gov/pubmed/17352710 Solez K, Colvin RB, Racusen LC, Haas M, Sis B, Mengel M, Halloran PF, Baldwin W, Banfi G, Collins AB, Cosio F, David DS, Drachenberg C, Einecke G, Fogo AB, Gibson IW, Glotz D, Iskandar SS, Kraus E, Lerut E, Mannon RB, Mihatsch M, Nankivell BJ, Nickeleit V, Papadimitriou JC, Randhawa P, Regele H, Renaudin K, Roberts I, Seron D, Smith RN, Valente M. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant 2008;8(4):753-60. http://www.ncbi.nlm.nih.gov/pubmed/17352710 Mengel M, Sis B, Halloran PF. SWOT analysis of Banff: strengths, weaknesses, opportunities and threats of the international Banff consensus process and classification system for renal allograft pathology. Am J Transplant 2007;7(10):2221-6. http://www.ncbi.nlm.nih.gov/pubmed/17848174 Najafian B, Kasiske BL. Chronic allograft nephropathy. Curr Opin Nephrol Hypertens 2008;17(2): 149-55. http://www.ncbi.nlm.nih.gov/pubmed/18277147 Doxiadis II, Duquesnoy RJ, Claas FH. Extending options for highly sensitized patients to receive a suitable kidney graft. Curr Opin Immunol 2005;17(5):536-40. http://www.ncbi.nlm.nih.gov/pubmed/16084709 Sis B, Campbell PM, Mueller T, Hunter C, Cockfield SM, Cruz J, Meng C, Wishart D, Solez K, Halloran PF. Transplant glomerulopathy, late antibody-mediated rejection and the ABCD tetrad in kidney allograft biopsies for cause. Am J Transplant 2007;7(7):1743-52. http://www.ncbi.nlm.nih.gov/pubmed/17564636 Colvin RB. Antibody-mediated renal allograft rejection: diagnosis and pathogenesis. J Am Soc Nephrol 2007;18(4):1046-56. http://www.ncbi.nlm.nih.gov/pubmed/17360947 Schwarz A, Gwinner W, Hiss M, Radermacher J, Mengel M, Haller H. Safety and adequacy of renal transplant protocol biopsies. Am J Transplant 2005;5(8):1992-6. http://www.ncbi.nlm.nih.gov/pubmed/15996250 Webster AC, Pankhurst T, Rinaldi F, Chapman JR, Craig JC. Monoclonal and polyclonal antibody therapy for treating acute rejection in kidney transplant recipients: a systematic review of randomized trial data. Transplantation 2006;81(7):953-65. http://www.ncbi.nlm.nih.gov/pubmed/16612264 Nashan B. Antibody induction therapy in renal transplant patients receiving calcineurin-inhibitor immunosuppressive regimens: a comparative review. BioDrugs 2005;19(1):39-46. http://www.ncbi.nlm.nih.gov/pubmed/15691216 Mehrabi A, Mood ZhA, Sadeghi M, Schmied BM, Müller SA, Welsch T, Kuttymuratov G, Wente MN, Weitz J, Zeier M, Morath Ch, Riediger C, Schemmer P, Encke J, Büchler MW, Schmidt J. Thymoglobulin and ischemia reperfusion injury in kidney and liver transplantation. Nephrol Dial Transplant 2007;22(Suppl 8):viii54-viii60. http://www.ncbi.nlm.nih.gov/pubmed/17890265 Venetz JP, Pascual M. New treatments for acute humoral rejection of kidney allografts. Expert Opin Investig Drugs 2007;16(5):625-33. http://www.ncbi.nlm.nih.gov/pubmed/17461736 Zarkhin V, Li L, Kambham N, Sigdel T, Salvatierra O, Sarwal MM. A randomized, prospective trial of rituximab for acute rejection in pediatric renal transplantation. Am J Transplant 2008;8(12):2607-17. http://www.ncbi.nlm.nih.gov/pubmed/18808404 Böhmig GA, Wahrmann M, Regele H, Exner M, Robl B, Derfler K, Soliman T, Bauer P, Müllner M, Druml W. Immunoadsorption in severe C4d-positive acute kidney allograft rejection: a randomized controlled trial. Am J Transplant 2007;7(1):117-21. http://www.ncbi.nlm.nih.gov/pubmed/17109725

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Glotz D, Antoine C, Julia P, Pegaz-Fiornet B, Duboust A, Boudjeltia S, Fraoui R, Combes M, Bariety J. Intravenous immunoglobulins and transplantation for patients with anti-HLA antibodies. Transpl Int 2004;17(1):1-8. http://www.ncbi.nlm.nih.gov/pubmed/14685653 Srinivas TR, Meier-Kriesche HU. Minimizing immunosuppression, an alternative approach to reducing side effects: objectives and interim result. Clin J Am Soc Nephrol 2008;3(Suppl 2):S101-S116. http://www.ncbi.nlm.nih.gov/pubmed/18308998 Suwelack B, Gerhardt U, Hohage H. Withdrawal of cyclosporine or tacrolimus after addition of mycophenolate mofetil in patients with chronic allograft nephropathy. Am J Transplant 2004;4(4): 655-62. http://www.ncbi.nlm.nih.gov/pubmed/15023160 Dudley C, Pohanka E, Riad H, Dedochova J, Wijngaard P, Sutter C, Silva HT Jr; Mycophenolate Mofetil Creeping Creatinine Study Group. Mycophenolate mofetil substitution for cyclosporine A in renal transplant recipients with chronic progressive allograft dysfunction: the ‘creeping creatinine’ study. Transplantation 2005;79(4):466-75. http://www.ncbi.nlm.nih.gov/pubmed/15729174 Mulay AV, Cockfield S, Stryker R, Fergusson D, Knoll GA. Conversion from calcineurin inhibitors to sirolimus for chronic renal allograft dysfunction: a systematic review of the evidence. Transplantation 2006;82(9):1153-62. http://www.ncbi.nlm.nih.gov/pubmed/17102766 Diekmann F, Budde K, Slowinski T, Oppenheimer F, Fritsche L, Neumayer HH, Campistol JM. Conversion to sirolimus for chronic allograft dysfunction: long-term results confirm predictive value of proteinuria. Transpl Int 2008;21(2):152-5. http://www.ncbi.nlm.nih.gov/pubmed/18005087 Kasiske BL, Chakkera HA, Louis TA, Ma JZ. A meta-analysis of immunosuppression withdrawal trials in renal transplantation. J Am Soc Nephrol 2000;11(10):1910-7. http://www.ncbi.nlm.nih.gov/pubmed/11004223 Frimat L, Cassuto-Viguier E, Charpentier B, Noël C, Provôt F, Rostaing L, Glotz D, Sraer JD, Bourbigot B, Moulin B, Lang P, Ducloux D, Pouteil-Noble C, Girardot-Seguin S, Kessler M. Impact of cyclosporine reduction with MMF: a randomized trial in chronic allograft dysfunction. The ‘reference’ study. Am J Transplant 2006;6(11):2725-34. http://www.ncbi.nlm.nih.gov/pubmed/17049060 Barama AA. Mechanisms and management of proteinuria in kidney transplant patients. Drugs 2008;68(Suppl 1):33-9. http://www.ncbi.nlm.nih.gov/pubmed/18442299 Shirali AC, Bia MJ. Management of cardiovascular disease in renal transplant recipients. Clin J Am Soc Nephrol 2008;3(2):491-504. http://www.ncbi.nlm.nih.gov/pubmed/18287250 Ambühl PM. Posttransplant metabolic acidosis: a neglected factor in renal transplantation? Curr Opin Nephrol Hypertens 2007;16(4):379-87. http://www.ncbi.nlm.nih.gov/pubmed/17565282 Winkelmayer WC, Chandraker A. Posttransplantation anemia: management and rationale. Clin J Am Soc Nephrol 2008;3(Suppl 2):S49-S55. http://www.ncbi.nlm.nih.gov/pubmed/18309003 Bia M. Evaluation and management of bone disease and fractures post transplant. Transplant Rev (Orlando) 2008;22(1):52-61. http://www.ncbi.nlm.nih.gov/pubmed/18631858 Bloom RD, Crutchlow MF. New-onset diabetes mellitus in the kidney recipient: diagnosis and management strategies. Clin J Am Soc Nephrol 2008;3(Suppl 2):S38-S48. http://www.ncbi.nlm.nih.gov/pubmed/18309002 Kasiske B, Cosio FG, Beto J, Bolton K, Chavers BM, Grimm R Jr, Levin A, Masri B, Parekh R, Wanner C, Wheeler DC, Wilson PW; National Kidney Foundation. Clinical practice guidelines for managing dyslipidemias in kidney transplant patients: a report from the Managing Dyslipidemias in Chronic Kidney Disease Work Group of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative. Am J Transplant 2004;4(Suppl 7):13-53. http://www.ncbi.nlm.nih.gov/pubmed/15027968

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8. MALIGNANCY There are three situations in which malignancy occurs in kidney transplant recipients: 1. Transmitted malignancy by the donor 2. Known or latent prior malignancy in the recipients 3. ‘De-novo‘ malignancies developed in the recipient after transplantation.

8.1

Transmission of a donor neoplasia to the recipient

The risk of a donor disease transmission is estimated at 0.2% (1) with increased use of older donors and marginal kidneys. Donors can be divided into three groups according to the risk of transmission of cancer: • Donors without cancer • Donors with a per-operative diagnosis of cancer • Donors with a history of cancer. However, even in the first situation, there remains a very small risk that donors may carry an infraclinical tumour, particularly of the prostate (2). Pre-operative suspicion of cancer was reported in 337 (4.4%) out of 7608 donors (3). Among them, there were 131 donors suitable for donation, who donated a total of 241 organs without any donor-related tumour transmission to the recipients. In 1069 donors with a history of cancer and no tumour transmission, the most common cancers were non-melanoma skin cancer (31%), central nervous system (CNS) tumours (25%), and uterine and cervical cancers (13%) (4). Melanoma and choriocarcinoma are the most aggressive donortransmitted malignancies (5). Individuals with active cancer or a history of metastatic cancer or who have had cancers with a high risk of recurrence (e.g. medulloblastoma and glioblastoma multiform) should not be donors (6). Occasionally, brain metastasis may masquerade as a primary brain tumour or cerebral haemorrhage and must be excluded as it is a contraindication for donation. However, a prior history of neoplasia is no longer an absolute contraindication for organ donation. Nonmelanoma low-grade skin cancer and selected CNS tumours that have not undergone surgical manipulation may also be acceptable. The following tumours are not contraindications to donation: • Basal cell carcinoma • Non-metastatic spinocellular carcinoma of the skin • Cervical carcinoma in situ • Carcinoma in situ of the vocal cords. There is no consensus on donors with transitional cell carcinoma of the bladder at the Ta G1 (TNM) stage. Screening for prostate cancer is different from country to country and is suggested only when there are reasons for such a test. Donors affected by certain low-grade (grades 1 and 2) brain tumours (Table 21) are suitable for kidney donation. Individuals affected by brain tumours of any grade who have undergone ventriculo-peritoneal shunting must be excluded because of the high risk of systemic dissemination of tumour cells through the shunt (level of evidence: 3). Table 21: Low-grade brain tumours that do not exclude organ donation • • • • • • • • • • • •

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Low-grade astrocytoma Pituitary adenomas Epidermoid cysts Colloid cysts of the third ventricle Pilocytic astrocytoma, ependymoma Low-grade oligodendroglioma (Schmidt A and B) Choroid plexus papilloma Ganglionic cell tumour (ganglioma, gangliocytoma) Benign meningioma Craniopharyngioma Haemangioblastoma (not associated with Von Hippel Lindau syndrome) Acoustic Schwannoma

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• •

Pineocytoma Well-differentiated teratoma

When a kidney has been transplanted from a donor with a post-transplant diagnosis of cancer, graft nephrectomy and suspension of immunosuppression are not always necessary. The risks and benefits should be discussed with the recipient. Due to a low risk of recurrence, kidneys with small renal cell carcinoma (RCC) can be considered for local excision and transplant after the recipient has given informed consent. The risk of RCC transmission to the contralateral kidney and/or to other organs is even lower; again, the patient’s informed consent is necessary (level of evidence: 4). Recommendations GR • Donors with active cancer or history of metastatic cancer and cancers with a high risk of C recurrence should not be considered as possible donors • A prior history of neoplasia is no longer an absolute contraindication for organ donation C GR = grade of recommendation

8.2 Prior malignancy in the recipient Any active tumour in the recipient is an absolute contraindication for kidney transplantation because of the risk of dissemination and fatal outcome. However, a previous history of cancer does not automatically exclude transplantation. It can be difficult to decide who should be considered as suitable for transplantation and particularly ‘when’. So far, clinical decision has been mainly based on the Cincinnati Registry, which essentially considers the type of tumour and the delay between its treatment and kidney transplantation. However, a better approach would be based on type of tumour, TNM stages, and the risk of recurrence after treatment. For most tumours, the waiting time for transplantation is 2 years on the Registry. However, a 2- year waiting period would eliminate only 13% of colorectal recurrences, 19% of breast cancer recurrences, and 40% of prostatic cancer recurrences (7, 8). In contrast, a 5-year waiting period would eliminate most recurrences, but this is not practical in the elderly (9) and unnecessary for most tumours. There is therefore not enough evidence to support a fixed waiting period before transplantation. Recipients who have tumours with a low recurrence rate can be considered for immediate transplantation after successful treatment of the tumour (e.g. incidental RCC, non-melanoma skin cancer and in-situ uterine/ cervical cancer). In the remaining cases, because of the risk of dormant metastases, the waiting period should be individualised according to the type and TNM stage and grade of the tumour, age and recipient’s general condition. Patients on the waiting list and after transplantation must be evaluated regularly to detect recurrence (level of evidence: 4). Modification of immunosuppression may be considered in these patients following a recent report that the use of m-TOR inhibitors is associated with a reduced incidence of malignancy (10), as is similarly a reduction in immunosuppressive therapy. Recommendations GR • Any active tumour in the recipient is an absolute contraindication for kidney transplantation C because of the risk of dissemination and fatal outcome • The waiting period before transplant in recipients with a history of malignancy depends on C the type, TNM stage and grade of the tumour, and recipient’s age and general health • Recipients with tumours that have a low recurrence rate can be considered for immediate C transplantation after successful treatment • Close follow-up is mandatory particularly after transplantation C GR = grade of recommendation Patients with ESRD on the waiting list for kidney transplantation will be ageing, and thus carry a higher, potential risk of latent neoplasia being activated following kidney transplantation. Candidates for kidney transplantation, particularly > 50 years old, should be screened for the presence of a pre-existing cancer (Table 22).

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Table 22: Screening of potential recipients for malignancy • • • • • • •

Exhaustive history and physical examination, including a dermatological examination Gynaecological examination: vaginal cytology and colposcopy, regardless of age Mammography in women over 40 years old or with a family history of breast cancer Prostate examination: prostate-specific antigen (PSA) levels and digital rectal examination (DRE) in men aged over 50 years. Faecal occult blood testing or colonoscopy according to current guidelines Chest X-ray Abdominal ultrasound to exclude renal cell carcinoma or other abdominal tumour

8.3

‘De-novo’ tumours in the recipient

The risk of cancer after kidney transplantation is several times higher than in the general population (11, 12). Post-transplantation cancer is one of the most common long-term causes of death; with up to 35% of heart transplant recipients dying of cancer (13). Most malignancy affects the skin (40%) or the lymphatic system (11%). Several factors contribute to the high prevalence of cancers in transplant recipients (Table 23). Annual screening is mandatory to detect a new cancer or co-morbidity. Table 23: Factors increasing risk of de-novo tumour in recipient • • • • •

Sun exposure: skin cancer Analgesic abuse: urothelial cancer Acquired multicystic renal disease: renal cancer Immunosuppressants, e.g. CNIs and lymphocyte-depleting antibodies Viral infections, e.g. EBV, herpes 8 virus, human papillomavirus, HBV, HCV, HEV

8.3.1 Skin cancer and Kaposi’s sarcoma The risk of skin cancer increases with age (> 50 years) (14), cyclosporine (10) and duration of immunosuppression. Its incidence rises with time to 5% at 5 years, 16% at 10 years and 52% at 20 years’ post transplant (15). Skin cancer represents 40-60% of post-transplantation tumours, with up to 50% of all skin cancers being squamous cell. The male-to-female ratio is 4.8 to 1.3 (16). It is closely linked to sun and ultraviolet exposure, the presence of HLA-B27 antigen and the degree of immunosuppression. Skin cancer often recurs, particularly in heart and kidney recipients (17). An annual dermatological examination and use of total sun block are recommended (18, 19) (level of evidence: 2a). The prevalence of Kaposi’s sarcoma ranges from 0.5% to 4%, depending on the country (20). It is associated with HHV8 positive serology. Screening for HHV8 in high-risk patients (Mediterranean countries) and prophylactic measures may be considered (21) (level of evidence: 3). The use of m-TOR inhibitors may be preferrable over CNIs, which seem to promote the appearance of Kaposi´s sarcoma (19) (level of evidence: 3) Recommendations GR • Oral and written information on the risk of skin cancer and protective measures should be C given • Dermatological examination before, and at least annually after, transplantation is mandatory C • The use of m-TOR inhibitors instead of CNIs is advised in patients with Kaposi´s sarcoma or a C history of Kaposi´s sarcoma GR = grade of recommendation 8.3.2 Lymphatic disease Post-transplantation lymphoproliferative disease (PTLD) is a life-threatening complication because of extranodal dissemination and a poor outcome (12, 22). The incidence (1-5%) has increased since the introduction of cyclosporine (23) and the induction regimen by ALG and OKT3 with a SIR (standardized incidence ratio) between 9 and 29 (24). The disease usually occurs within the first year after transplantation and is characterised by non-Hodgkin’s lymphomas and EBV-infected B-lymphocytes. Treatment involves reduction or even suspension of immunosuppressive therapy, with a remission rate of 50-68%. Anti-CD20 antibody therapy, with or without chemotherapy, and antiviral drugs (acyclovir, ganciclovir) may be helpful (25, 26) (level of evidence: 3).

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Recommendations GR • Use of induction therapy with T-cell depleting agents should be restricted whenever possible C • Clinical examination every 3 months during the first post-transplant year is advised for C young recipients and for patients who have received T-cell depleting agents GR = grade of recommendation 8.3.3 Gynaecological cancers Cervical cancer is 3 to 16 times more common in transplanted females compared to the general population. In 70% of cases, it will be in-situ carcinoma or cervical intraepithelial neoplasia (CIN). Cervical cancer appears to be arising from infection of the cervix with sexually transmitted oncogenic strains of human papillomavirus (HPV). Increased risk of cervical cancer in transplant recipients is due to re-activation of latent HPV in the immunosuppressed recipient. The prevalence of HPV in the cervix of transplanted females is almost 45%, though this figure is currently decreasing, as is also CIN prevalence (27). Data on successful HPV immunization are not available, but young female transplant recipients may benefit from HPV immunization. Annual colposcopy and cytology are required. Mammography and gynaecological ultrasound should be periodically performed, although formal evidence for this preventive strategy is lacking (28) (level of evidence 4). 8.3.4 Prostate cancer The prevalence of clinical prostatic adenocarcinoma in the male transplanted population is 0.3% to 1.8%. Prevalence increases with the age of the recipient and can reach 5.8% if PSA screening is performed in all males. All recipients over 50 years old should have an annual PSA test and DRE. Prostate serum antigen levels are not modified by kidney transplantation and most prostate cancers detected in transplanted patients are clinically localised (84%) at diagnosis (29) (level of evidence: 4). 8.3.5 Bowel cancer The association of colon cancer with kidney transplantation is much more controversial than for other cancers, even though an increased risk factor of 2.6 has been reported at 10 years’ post transplant.However, it is difficult to advise on the most appropriate method of follow-up and its frequency. An annual faecal blood test is acceptable and cost-effective, but not performed routinely worldwide. Colonoscopy every 5 years is also acceptable in the absence of other factors implying a high risk of colon cancer, despite the absence of data on screening in this population. A risk factor is the re-activation of CMV and EBV infections (28) (level of evidence: 4). 8.3.6 Urothelial tumours The incidence of urothelial tumours is three times higher than in the general population (29). Tumours are usually transitional cell neoplasia, though the incidences of bladder adenocarcinoma and nephrogenic adenoma have both increased. Urinary cytology is routinely performed in patients with microhaematuria, analgesic nephropathy, or a prior history of urothelial cancer, despite its poor sensitivity of 30%. Recipients with gross haematuria should undergo a detailed study of the whole urinary system, bladder, ureters and kidneys. 8.3.7 Renal tumours Renal cell carcinoma usually occurs in the patient’s own kidneys, but can also present in the graft. The prevalence ranges between 0.5% and 3.9%, which is 10 to 100 times greter than in the general population (29). The main risk factor is the presence of acquired chronic kidney disease (ACKD). Other risk factors include previous history of RCC, Von Hippel Landau disease and (perhaps) polycystic kidneys. The main histological patterns are RCC and tubulopapillary carcinoma (30). Annual ultrasound of the patient’s native kidneys and the graft is recommended (28, 29) (level of evidence: 4). Any renal solid tumour should be treated with retroperitoneoscopic or laparoscopic nephrectomy (level of evidence: 4). 8.3.8 Chest X-ray An annual chest X-ray is recommended in order to detect lung cancer and cardiothorarcic abnormalities (28) (level of evidence: 4).

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Recommendations grade B/C GR • The risk of cancer is several times greater in transplanted patients than in the general B/C population and is the main concern of the medical team in the long-term follow-up of all organ recipients • Screening should be carried out annually for cancers of the skin, lymphatic system and native B/C kidneys. For all other organs, screening should be the same as in the general population GR = grade of recommendation

8.4

REFERENCES

1.

Birkeland SA, Storm HH. Risk for tumor and other disease transmission by transplantation: a population-based study of unrecognized malignancies and other diseases in organ donors. Transplantation 2002;74(10):1409-13. http://www.ncbi.nlm.nih.gov/pubmed/12451241 Yin M, Bastacky S, Chandran U, Becich MJ, Dhir R. Prevalence of incidental prostate cancer in the general population: a study of healthy organ donors. J Urol 2008;179(3):892-5; discussion 895. http://www.ncbi.nlm.nih.gov/pubmed/18207193 Zucchini N, Fiorentino M, D‘Errico Grigioni A, Rizzato L, Venettoni S, Nanni Costa A, Grigioni WF; Italian Transplant Research Network. The Italian multiorgan donor cancer screening protocol: 20022005 experience. Transplantation 2008;85(8 Suppl):S57-S60. http://www.ncbi.nlm.nih.gov/pubmed/18425038 Kauffman HM, Cherikh WS, McBride MA, Cheng Y, Hanto DW. Deceased donors with a past history of malignancy: an organ procurement and transplantation network/united network for organ sharing update. Transplantation 2007;84(2):272-4. http://www.ncbi.nlm.nih.gov/pubmed/17667822 Buell JF, Trofe J, Hanaway MJ, Lo A, Rosengard B, Rilo H, Alloway R, Beebe T, First MR, Woodle ES. Transmission of donor cancer into cardiothoracic transplant recipients. Surgery 2001;130(4):660-6; discussion 666-8. http://www.ncbi.nlm.nih.gov/pubmed/11602897 Kauffman HM, McBride MA, Cherikh WS, Spain PC, Delmonico FL. Transplant tumor registry: donors with central nervous system tumors 1. Transplantation 2002;73(4):579-82. http://www.ncbi.nlm.nih.gov/pubmed/11889434 Penn I. Primary kidney tumors before and after renal transplantation. Transplantation 1995;59(4):4 80-5. http://www.ncbi.nlm.nih.gov/pubmed/7878750 Trivedi MH, Agrawal S, Muscato MS, Metzler MH, Marshall JB. High grade, synchronous colon cancers after renal transplantation: were immunosuppressive drugs to blame? Am J Gastroenterol 1999;94(11):3359-61. http://www.ncbi.nlm.nih.gov/pubmed/10566744 Sola R, Rodriguez S, Guirado L Löpez-Navidad A, Caballero F, Diaz M, Baro E, Paredes D. Renal transplant for recipients over 60 years old. Transplantation 2000;69(11):2460-1. http://www.ncbi.nlm.nih.gov/pubmed/10868662 Campistol JM, Eris J, Oberbauer R,.Friend P, Hutchison B, Morales JM, Claesson K, Stallone G, Russ G, Rostaing L, Kreis H, Burke JT, Brault Y, Scarola JA, Neylan JF. Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation. J Am Soc Nephrol 2006;17(2):581-9. http://www.ncbi.nlm.nih.gov/pubmed/16434506 Villeneuve PJ, Schaubel DE, Fenton SS, Shepherd FA, Jiang Y, Mao Y. Cancer incidence among Canadian kidney transplant recipients. Am J Transplant 2007;7(4):941-8. http://www.ncbi.nlm.nih.gov/pubmed/17331115 Kasiske BL, Snyder JJ, Gilbertson DT, Wang C. Cancer after kidney transplantation in the United States. Am J Transplant 2004;4(6):905-13. http://www.ncbi.nlm.nih.gov/pubmed/15147424 Roussel JC, Baron O, Perigaud C, Bizouarn P, Pattier S, Habash O, Mugniot A, Petit T, Michaud JL, Heymann MF, Treilhaud M, Trochu JN, Gueffet JP, Lamirault G, Duveau D, Despins P. Outcome of heart transplants 15 to 20 years ago: graft survival, post-transplant morbidity, and risk factors for mortality. J Heart Lung Transplant 2008;27(5):486-93. http://www.ncbi.nlm.nih.gov/pubmed/18442713

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

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14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

Naldi L, Fortina AB, Lovati S, Barba A, Gotti E, Tessari G, Schena D, Diociaiuti A, Nanni G, La Parola IL, Masini C, Piaserico S, Peserico A, Cainelli T, Remuzzi G. Risk of nonmelanoma skin cancer in Italian organ transplant recipients. A registry-based study. Transplantation 2000;70(10):1479-84. http://www.ncbi.nlm.nih.gov/pubmed/11118094 Bordea C, Wojnarowska F, Millard PR, Doll H, Welsh K, Morris PJ. Skin cancers in renal-transplant recipients occur more frequently than previously recognized in a temperate climate. Transplantation 2004;77(4):574-79. http://www.ncbi.nlm.nih.gov/pubmed/15084938 Kanitakis J, Alhaj-Ibrahim L, Euvrard S, Claudy A. Basal cell carcinomas developing in solid organ transplant recipients: clinicopathologic study of 176 cases. Arch Dermatol 2003;139(9):1133-7. http://www.ncbi.nlm.nih.gov/pubmed/12975154 Euvrard S, Kanitakis J, Decullier E, Butnaru AC, Lefrançois N, Boissonnat P, Sebbag L, Garnier JL, Pouteil-Noble C, Cahen R, Morelon E, Touraine JL, Claudy A, Chapuis F. Subsequent skin cancers in kidney and heart transplant recipients after the first squamous cell carcinoma. Transplantation 2006;81(8):1093-100. Ulrich C, Kanitakis J, Stockfleth E, Euvrard S. Skin cancer in organ transplant recipients--where do we stand today? Am J Transplant 2008;8(11):2192-8. http://www.ncbi.nlm.nih.gov/pubmed/18782290 Ulrich C, Degen A, Patel MJ, Stockfleth E. Sunscreens in organ transplant patients. Nephrol Dial Transplant 2008;23(6):1805-8. http://www.ncbi.nlm.nih.gov/pubmed/18492979 Munoz P, Alvarez P, de Ory F, Pozo F, Rivera M, Bouza E. Incidence and clinical characteristics of Kaposi sarcoma after solid organ transplantation in Spain: importance of seroconversion against HHV8. Medicine (Baltimore) 2002;81(4):293-304. http://www.ncbi.nlm.nih.gov/pubmed/12169884 Cattani P, Capuano M, Graffeo R, Ricci R, Cerimele F, Cerimele D, Nanni G, Fadda G. Kaposi‘s sarcoma associated with previous human herpesvirus 8 infection in kidney transplant recipients. J Clin Microbiol 2001;39(2):506-8. http://www.ncbi.nlm.nih.gov/pubmed/11158097 Opelz G, Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant 2004;4(2):222-30. http://www.ncbi.nlm.nih.gov/pubmed/14974943 Sheil AG, Disney AP, Mathew TH, Amiss N. De novo malignancy emerges as a major cause of morbidity and late failure in renal transplantation. Transplant Proc 1993;25(1 Pt 2):1383-4. http://www.ncbi.nlm.nih.gov/pubmed/8442150 Opelz G, Naujokat C, Daniel V, Terness P, Dohler B. Disassociation between risk of graft loss and risk of non-Hodgkin lymphoma with induction agents in renal transplant recipients. Transplantation 2006;81(9):1227-33. http://www.ncbi.nlm.nih.gov/pubmed/16699447 Lee JJ, Lam MS, Rosenberg A. Role of chemotherapy and rituximab for treatment of posttransplant lymphoproliferative disorder in solid organ transplantation. Ann Pharmacother 2007 Oct;41(10): 1648-59. http://www.ncbi.nlm.nih.gov/pubmed/17848421 Vasudev B, Hariharan S. Cancer after renal transplantation. Curr Opin Nephrol Hypertens 2007 Nov;16(6):523-8. http://www.ncbi.nlm.nih.gov/pubmed/18089965 Nordin P, Hansson BG, Hansson C, Blohmè I, Larkö O, Andersson K. Human papilloma virus in skin, mouth and uterine cervix in female renal transplant recipients with or without a history of cutaneous squamous cell carcinoma. Acta Derm Venereol 2007;87(3):219-22. http://www.ncbi.nlm.nih.gov/pubmed/17533486 Kasiske BL, Vasquez MA, Harmon WE, Brown RS, Danovitch GM, Gaston RS, Roth D, Scandling JD, Singer GG. Recommendations for the outpatient surveillance of renal transplant recipients. J Am Soc Nephrol 2000:11(Suppl 15);S1–S86. http://www.ncbi.nlm.nih.gov/pubmed/11044969 Muruve NA, Shoskes DA. Genitourinary malignancies in solid organ transplant recipients. Transplantation 2005;80(6):709-16. http://www.ncbi.nlm.nih.gov/pubmed/16210955 Wong G, Chapman JR. Cancers after renal transplantation. Transplant Rev (Orlando). 2008 Apr;22(2):141-9. http://www.ncbi.nlm.nih.gov/pubmed/18631867

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9. ANNUAL SCREENING The risk of cancer and cardiac disease is several-fold higher in transplanted patients than in the general population (1, 2). Cancer is a cause of significant morbidity and mortality in the transplanted population (1). Cardiovascular disease is the most frequent cause of death in renal allograft recipients (2, 3) (level of evidence: 3).

9.1

Recommendations for annual screening

The following recommendations can be made for annual screening of a transplant recipient. They include: • Lifelong regular post-transplant follow-up by an experienced and trained transplant specialist is strongly recommended at least every 6-12 months • More frequent follow-up visits (e.g. every 4-8 weeks) for renal function and immunosuppression and side-effects by a physician • Annual screening should include a dermatological examination, tumour screening (including a nodal examination, faecal occult screening, chest X-ray, gynaecological and urological examination), and an abdominal ultrasound, including ultrasound of the native and transplanted kidney) • Special attention during post-transplant care should also focus on proteinuria, recurrence of original disease • posttransplant care should aim to detect cardiac disease and cardiovascular risk factors. Cardiac exam and cardiac history should be taken, and if appropriate further diagnostic tests should be prompted to exclude the progression of cardiac disease • Blood pressure, blood glucose and blood lipids should be determined at appropriate intervals, and adequate measures to control this risk factors should be instituted. • The physician should also focus on the adequate prophylaxis, detetction and treatment of concomitant diseases (e.g. bone disease, anemia) and infections.

9.2

REFERENCES

1.

Shirali AC, Bia MJ. Management of cardiovascular disease in renal transplant recipients. Clin J Am Soc Nephrol 2008;3(2):491-504. http://www.ncbi.nlm.nih.gov/pubmed/18287250 Wong G, Chapman JR. Cancers after renal transplantation. Transplant Rev (Orlando) 2008;22(2): 141-9. http://www.ncbi.nlm.nih.gov/pubmed/18631867 Kasiske BL, Vasquez MA, Harmon WE, Brown RS, Danovitch GM, Gaston RS, Roth D, Scandling JD, Singer GG. Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation. J Am Soc Nephrol 2000;11(Suppl 15):S1–S86. http://www.ncbi.nlm.nih.gov/pubmed/11044969

2.

3.

10. GRAFT AND PATIENT SURVIVAL Recommendations • Graft survival following unselected kidney transplantation should be at least 85% after 1 year and 70% after 5 years (1,2) (Figure 1) • Patient survival following unselected kidney transplantation should be at least 90% after 1 year and 85% after 5 years (1,2) (Figure 2) LE = level of evidence; GR = grade of recommendation

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Figure 1: Improvement of graft survival following kidney transplantation during the last two decades

Reproduced from CTS Collaborative Transplant Study by kind permission of Prof. Dr. G. Opelz, Heidelberg, Germany. Figure 2: Improvement of patient survival following kidney transplantation during the last two decades

Reproduced from CTS Collaborative Transplant Study by kind permission of Prof. Dr. G. Opelz, Heidelberg, Germany. This general outcome following kidney transplantation depends on several criteria that are discussed below:

10.1

Deceased and living donors

10.1.1 Graft survival Graft survival after living-donor kidney transplantation is generally better than after deceased-donor kidney transplantation (Figure 3). A better selection of donors, absence of brain death and a shorter cold ischaemia time are the most likely explanations.

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Figure 3: Graft survival following deceased- and living-donor kidney transplantation

Reproduced from CTS Collaborative Transplant Study by kind permission of Prof. Dr. G. Opelz, Heidelberg, Germany. The 1-year graft survival of living-donor kidney is in mean 97% for HLA-identical siblings and 95% for 1-haplotype-identical related donors compared to 88% for deceased-donor kidneys (Figure 4). The 3-year graft survival of living-donor kidney is in mean 95% for HLA-identical siblings and 90% for 1-haplotype-identical related donors compared to 83% for deceased- donor kidneys (Figure 4). Figure 4: Graft survival following deceased- and living-donor kidney transplantation.

Reproduced from CTS Collaborative Transplant Study by kind permission of Prof. Dr. G. Opelz, Heidelberg, Germany. Excellent graft outcomes have been reported in unrelated living-donor transplantation, even if the donorrecipient pairs were poorly HLA-matched (3). CTS data show that poorly matched kidneys from unrelated living donors demonstrate a much better outcome than poorly matched kidneys from deceased donors. However, this difference almost disappears in donors aged between 15 and 45 years old (Figure 5). This suggests that a good outcome in unrelated living-donor transplantation may mainly be due to optimal selection of donors and

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absence of brain death. Figure 5: Graft survival in poorly HLA-matched deceased-donor and unrelated living-donor kidney transplantation

Reproduced from CTS Collaborative Transplant Study by kind permission of Prof. Dr. G. Opelz, Heidelberg, Germany. Husband-to-wife and wife-to-husband transplantations performed between 1991 and 2005 show virtually identical results with a 3-year graft survival of 87% (Figure 6). If a wife recipient has been pregnant, the outcome may be worse (3). Figure 6: Graft survival in living unrelated kidney transplantation

Reproduced from CTS Collaborative Transplant Study by kind permission of Prof. Dr. G. Opelz, Heidelberg, Germany. 10.1.2 Patient survival Nowadays, patient survival following living-donor kidney transplantation is about 98% after 1 year and 90% after 5 years. This is better than patient survival following deceased donor kidney transplantation with a 1-year

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survival rate of 95% and a 5-year survival rate of about 80% (1, 2).

10.2

Age of donor and recipient

10.2.1 Donor’s age The donor’s age has a highly significant influence on the outcome of kidney transplantation in deceaseddonor transplantation. With increasing age of donor (except in paediatric transplantation), there is a worsening of initial function, long-term function and survival rate. The 3-year graft-survival rate of a deceased-donor transplant is up to 20% higher for donors aged 18-30 years than for donors older than 70 years (Figure 7) (1, 2, 4). Figure 7: Impact of donor’s age on graft survival in deceased-donor kidney transplantation

Reproduced from CTS Collaborative Transplant Study by kind permission of Prof. Dr. G. Opelz, Heidelberg, Germany. Other than in deceased-donor transplantation, donor’s age appears to influence graft outcome only marginally in living-donor transplantation (4). The most likely interpretation of this difference is that living donors are selected for organ donation based on their general status of health whereas such selection is not made in the case of deceased donor transplantation. Furthermore, it is likely that the process of brain death, which is associated with the release of cytokines, chemokines, etc, further contributes to the lower success of grafts from elderly deceased donors. 10.2.2 Recipient’s age The recipient’s age has an important impact on transplant outcome (5). Five-year graft survival in recipients aged 18-34 years is 72% versus 59% in recipients more than 65 years old (2). Nevertheless, the transplantation of kidneys from old donors to old recipients is feasible with acceptable success rates (6). The importance of HLA-matching is not clear in this ‘old for old’ group.

10.3

HLA-matching

Despite impressive improvements in graft success rates in recent years (Figure 1), the ‘relative’ impact of HLA compatibility on graft outcome has not changed. Between 1995 and 2004, the relative risk for graft loss was 0.77 for 0-1 HLA-A+B+DR mismatches and 1.17 for 5-6 HLA-A+B+DR mismatches. These relative risk values were almost identical with the 0.76 and 1.16 values calculated for 0-1 and 5-6 mismatches, respectively, for transplantations between 1985 and 1994 (7, 8). According to UNOS, in patients transplanted between 1997 and 2005, recipients of 0 HLA-A+B+DR mismatched deceased-donor kidneys showed an 11% lower 5-year graft survival than recipients of 6 mismatched kidney transplants which is similar to the CTS data (Figure 8). Also similar to the findings in the CTS database, UNOS data confirm that graft outcome gradually worsens with every additional mismatch (2). HLA matching is still important even with ‘modern’ immunosuppressive agents such as tacrolimus, MMF,

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rapamycin, or IL-2 receptor antibodies (Figure 9). It is still debatable whether HLA-DR compatibility influences graft outcome more than compatibility for HLA-A+B. Figure 8: Impact of HLA compatibility on deceased-donor kidney graft survival

Reproduced from CTS Collaborative Transplant Study by kind permission of Prof. Dr. G. Opelz, Heidelberg, Germany. Figure 9: Impact of HLA compatibility on kidney graft survival under ‘modern-day’ immunosuppression

Reproduced from CTS Collaborative Transplant Study by kind permission of Prof. Dr. G. Opelz, Heidelberg, Germany. CYA = cyclosporine A; MPA = mycophenolate mofetil; RAPA = rapamycin.

10.4

Immunosuppression

Data from the CTS study clearly demonstrates the advantage of cyclosporine A-based immunosuppression. Graft-survival rates are about 15% superior to survival rates following immunosuppression without cyclosporine A (Figure 10). However, different combinations of ‘modern’ immunosuppressive drugs do not appear to result in major differences in graft outcome (Figure 11).

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Figure 10: Influence of cyclosporine A-based immunosuppression on kidney graft survival in first transplant recipients

Reproduced from CTS Collaborative Transplant Study by kind permission of Prof. Dr. G. Opelz, Heidelberg, Germany. FK: FK506; MMF: mycophenolate mofetil; CYA = cyclosporine A; AZA = azathioprine; STE = steroids Figure 11: Influence of different immunosuppressive agent combinations on graft survival following kidney transplantation

Reproduced from CTS Collaborative Transplant Study by kind permission of Prof. Dr. G. Opelz, Heidelberg, Germany. CYA = cyclosporine A; FK: FK506; AZA = azathioprine; MMF: mycophenolate mofetil.

10.5

Number of transplantations

The 4-year graft survival rate decreases by about 5% from the first to second and second to third transplantation. The 4-year graft survival rate for the first deceased-donor transplantation is 80% versus 75% for the second, 70% for the third and 63% for the fourth or more transplants (Figure 12). For living donors, the worsening of graft function between first and second transplantation is less marked (about 2%) (1).

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Figure 12: Number of transplantations and kidney graft survival

Reproduced from CTS Collaborative Transplant Study by kind permission of Prof. Dr. G. Opelz, Heidelberg, Germany. 10.6 Cold ischaemia time The success of unrelated living-donor kidney transplantation suggests that short cold ischaemia time plays an important role in kidney transplantation. However, according to CTS data, graft survival is influenced only marginally by ischaemia times up to 24 h (Figure 13) and that HLA matching has a significant effect on outcome, even with a short ischaemic preservation time (Figure 14). Compared to other preservation solutions, University of Wisconsin (UW) solution was associated with significantly better outcome in the CTS study with ischaemia > 24 h (7). Figure 13: Impact of cold ischaemia time on graft survival in deceased-donor kidney transplantation

Reproduced from CTS Collaborative Transplant Study by kind permission of Prof. Dr. G. Opelz, Heidelberg, Germany.

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Figure 14: HLA-match dependent impact of cold ischaemia time on graft survival in deceased-donor kidney transplantations performed between 1990 and 2005

Cold Ischemia − HLA-A+B+DR Mismatches 0-6 hrs

7-12 hrs

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13-18 hrs

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Patients 3-Yr Surv N % 280 2,197 502

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Patients 3-Yr Surv N % 6,542 28,637 4,488

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2

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Reproduced from CTS Collaborative Transplant Study by kind permission of Prof. Dr. G. Opelz, Heidelberg, Germany.

10.7

Time on dialysis

According to CTS data, graft outcome is best if the patient never received dialysis and diminishes with every additional year of dialysis treatment (Figure 15). These findings are in agreement with data from reports that underline the importance of pre-emptive transplantation (9). Figure 15: Impact of time on dialysis on graft survival in deceased-donor kidney transplantation

Reproduced from CTS Collaborative Transplant Study by kind permission of Prof. Dr. G. Opelz, Heidelberg, Germany.

10.8

REFERENCES

1.

CTS Collaborative Transplant Study. http://ctstransplant.org [accessed October 14, 2008.] UNOS United Network for Organ Sharing. http://www.unos.org/ [accessed October 14, 2008.] Terasaki PI, Cecka JM, Gjertson DW, Takemoto S. High survival rates of kidney transplants from spousal and living unrelated donors. N Engl J Med 1995;333(6):333-6. http://www.ncbi.nlm.nih.gov/pubmed/7609748

2. 3.

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4. 5.

6.

7. 8.

9.

CTS Collaborative Transplant Study Newsletter 1:2005. http://www.ctstransplant.org/public/newsletters.shtml#2005 [accessed October 14, 2008] Morris J, Johnson R J, Fuggle S, Belger MA, Briggs JD. Analysis of factors that affect outcome of primary cadaveric renal transplantation in the UK. Lancet 1999;354(9185):1147-52. http://www.ncbi.nlm.nih.gov/pubmed/10513707 Cohen B, Smits JM, Haase B, Persijn G, Vanrenterghem Y, Frei U. Expanding the donor pool to increase renal transplantation. Nephrol Dial Transplant 2005;20(1):34-41. http://www.ncbi.nlm.nih.gov/pubmed/15522904 Opelz G, Döhler B. Multicenter analysis of kidney preservation. Transplantation 2007;83(3):247-53. http://www.ncbi.nlm.nih.gov/pubmed/17297393 Opelz G, Döhler B. Effect of human leukocyte antigen compatibility on kidney graft survival: comparative analysis of two decades. Transplantation 2007;84(2):137-43. http://www.ncbi.nlm.nih.gov/pubmed/17667803 Maier-Kriesche HU, Schold JD. The impact of pretransplant dialysis on outcomes in renal transplantation. Semin Dial 2005;18(6):499-504. http://www.ncbi.nlm.nih.gov/pubmed/16398713

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11. ABBREVIATIONS USED IN THE TEXT This list may not include the most commonly known abbreviations

ABO ACD ACE ACKD ACR ADPKD AHG AHR ALG, ATG AM Anti-GBM AVF AZA BMI CAR CDC CMV CNIs CsA-ME CT CTS CYA DTT DRE EAU EBV EC EC-MPS EDTA EDHEP ELISA ESRD ESWL ET FSGS GFR GR HAR HbA1C HBcAb HBsAg HBV HCA hCG HCV HDV HEV HIV HLA HTK IF IL-2 IMPDH IVIG LCDD LE

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blood group system consisting of groups A, AB, B and O acid-citrate-dextrose angiotensin-converting enzyme acquired cystic kidney disease acute cellular rejection autosomal dominant polycystic kidney disease anti-human globulin acute humoral rejection anti-lymphocyte globulin acceptable mismatch anti-glomerular basement arterio-venous fistula azathioprine body mass index chronic allograft rejection complement-dependent cytotoxicity test cytomegalovirus Calcineurin-inhibitors cyclosporine A micro-emulsion computed tomography Collaborative Transplant Study cyclosporine A dithiothreitol (test) digital rectal examination European Association of Urology Epstein-Barr virus EuroCollins (solution) enteric-coated mycophenolate sodium ethylenediaminetetra-acetic acid European Donor Hospital Education Program enzyme-linked immunosorbent assay end stage renal disease extracorporeal shockwave lithotripsy Eurotransplant focal and segmental glomerulosclerosis glomerular filtration rate grade of recommendation hyper-acute rejection glycosylated haemoglobin hepatitis B core antibody hepatitis B surface antigen hepatitis B virus human leucocyte antigen human chorionic gonadotrophin hepatitis C virus hepatitis D virus hepatitis E virus human immunodeficiency virus human leukocyte antigen, histocompatibility antigen histidine-tryptophan-ketoglutarates interstitial fibrosis interleukin-2 inosine monophosphate dehydrogenase (inhibitors) intravenous immunoglobulin light-chain deposit disease level of evidence

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LLDN LURD MMF MPA MR MRT NHBD OKT3 OLDN PBS PRA PSA PTLD RAPA RCC ST STE TA TB UNOS/OPT UW VATER WHO

laparoscopic live donor nephrectomy living unrelated donor mycophenolate mofetil mycophenalic acid magnetic resonance magnetic resonance tomography non-heartbeating donor anti-CD3 monoclonal antibody open live donor nephrectomy phosphate-buffered sucrose panel-reactive antibody prostate-specific antigen post-transplantation lymphoproliferative disease rapamycin renal cell carcinoma Scandia Transplant steroids tubular atrophy Tuberculosis United Network for Organ Sharing/The Organ Procurement and Transplantation Network University of Wisconsin (solution) Vertebrae, Anus, Trachea, Esophagus, and Renal World Health Organization

Conflict of interest All members of the Renal Transplantation Guidelines writing panel have provided disclosure statements on all relationships that they have and that might be perceived to be a potential source of conflict of interest. This information is kept on file in the European Association of Urology Central Office database. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

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Guidelines on

Paediatric Urology S. Tekgül, H. Riedmiller, E. Gerharz, P. Hoebeke, R. Kocvara, R. Nijman, Chr. Radmayr, R. Stein

European Society for Paediatric Urology © European Association of Urology 2009

TABLE OF CONTENTS page 1.

Introduction 1.1 Reference

6 6

2.

Phimosis 2.1 Background 2.2 Diagnosis 2.3 Treatment 2.4 References

6 6 7 7 7

3. Cryptorchidism 3.1 Background 3.2 Diagnosis 3.3 Treatment 3.3.1 Medical therapy 3.3.1.1 Medical therapy for testicular descent 3.3.1.2 Medical therapy for fertility potential 3.3.2 Surgery Palpable testis Non-palpable testis 3.4 Prognosis 3.5 References

8 8 8 9 9 9 9 9 9 9 10 10

4. Hydrocele 4.1 Background 4.2 Diagnosis 4.3 Treatment 4.4 References

11 11 11 11 12

5. Acute scrotum in children 5.1 Background 5.2 Diagnosis 5.3 Treatment 5.3.1 Epididymitis 5.3.2 Testicular torsion 5.3.3 Surgical treatment 5.4 Prognosis 5.4.1 Fertility 5.4.2 Subfertility 5.4.3 Androgen levels 5.4.4 Testicular cancer 5.4.5 Nitric oxide 5.5 Perinatal torsion 5.6. References

12 12 12 13 13 13 13 13 13 14 14 14 14 14 14

6. Hypospadias 6.1 Background 6.1.1 Risk factors 6.2 Diagnosis 6.3 Treatment 6.3.1 Age at surgery 6.3.2 Penile curvature 6.3.3 Preservation of the well-vascularized urethral plate 6.3.4 Re-do hypospadias repairs 6.3.5 Urethral reconstruction 6.3.6 Urine drainage and wound dressing 6.3.7 Outcome 6.4 References

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7. Congenital penile curvature

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22 22 22 23

7.1 Background 7.2 Diagnosis 7.3 Treatment 7.4 References

8. Varicocele in children and adolescents 8.1 Background 8.2 Diagnosis 8.3 Therapy 8.4 References

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9. Micropenis 9.1 Background 9.2 Diagnosis 9.3 Treatment 9.4 References

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10. DAYTIME LOWER URINARY TRACT CONDITIONS 10.1 Background 10.2 Definition 10.2.1 Filling-phase dysfunctions 10.2.2 Voiding-phase (emptying) dysfunctions 10.3 Diagnosis 10.4 Treatment 10.4.1 Standard therapy 10.4.2 Specific interventions 10.5 References

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11. MONOSYMPTOMATIC ENURESIS 11.1 Background 11.2 Definition 11.3 Diagnosis 11.4 Treatment 11.4.1 Supportive treatment measures 11.4.2 Alarm treatment 11.4.3 Medication 11.5 References

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12. MANAGEMENT OF NEUROGENIC BLADDER IN CHILDREN 12.1 Background 12.2 Definition 12.3 Classification 12.4 Urodynamic studies 12.4.1 Method of urodynamic study 12.4.2 Uroflowmetry 12.4.3 Cystometry 12.5 Management 12.5.1 Investigations 12.5.2 Early management with clean intermittent catheterisation (CIC) 12.5.3 Medical therapy 12.5.3.1 Botulinum toxin injections 12.5.4 Management of bowel incontinence 12.5.5 Urinary tract infection 12.5.6 Sexuality 12.5.7 Bladder augmentation 12.5.8 Bladder outlet procedures 12.5.9 Continent stoma 12.5.10 Total bladder replacement

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12.5.11 Lifelong follow-up of neurogenic bladder patients 12.6 References

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13. Dilatation of the upper urinary tract (ureteropelvic junction and ureterovesical junction obstruction) 13.1 Background 13.2 Diagnosis 13.2.1 Antenatal ultrasound 13.2.2 Postnatal ultrasound 13.2.3 Voiding cystourethrogram (VCUG) 13.2.4 Diuretic renography 13.3 Treatment 13.3.1 Prenatal management 13.3.2 UPJ obstruction 13.4 Megaureter 13.5 Conclusion 13.6 References

41 41 41 42 42 42 42 43 43 43 43 43 43

14. Vesicoureteruc (VUR) VESICOURETERICReflux REFLUX (VUR) 14.1 Background 14.2 Classification 14.3 Diagnostic work-up 14.4 Treatment 14.4.1 Conservative approach 14.4.2 Interventional treatment 14.4.2.1 Open surgery 14.4.2.2 Laparoscopic reflux correction 14.4.2.3 Endoscopic therapy 14.5 Follow-up 14.6 References

44 44 45 45 46 46 46 46 46 46 47 47

15. URINARY STONE DISEASE 15.1 Background 15.2 Stone formation mechanism, diagnosis of causative factors and medical treatment for specific stone types 15.2.1 Calcium stones Hypercalcuria Hyperoxaluria Hypocitraturia 15.2.2 Uric acid stones 15.2.3 Cystine stones 15.2.4 Infection stones (struvite stones) 15.3 Clinical presentation 15.4 Diagnosis 15.4.1 Imaging 15.4.2 Metabolic evaluation 15.5 Management 15.5.1 Extracorporeal shockwave lithotripsy (ESWL) 15.5.2 Percutaneous nephrolithotomy 15.5.3 Ureteronoscopy 15.5.4 Open stone surgery 15.6 References

49 49

16. Obstructive pathology of renal duplication: ureterocele and ectopic ureter 16.1 Background 16.1.1 Ureterocele 16.1.2 Ectopic ureter 16.2 Classification 16.2.1 Ectopic ureterocele 16.2.2 Orthotopic ureterocele

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16.2.3 Caecoureterocle 16.3 Diagnosis 16.3.1 Ureterocele 16.3.2 Ectopic ureter 16.4 Treatment 16.4.1 Ureterocele 16.4.1.1 Early diagnosis 16.4.1.2 Re-evaluation 16.4.2 Ectopic ureter 16.5 References

60 60 60 60 60 60 61 61 61 61

17. DISORDERS OF SEX DEVELOPMENT 17.1 Background 17.2 The neonatal emergency 17.2.1 Family history and clinical examination 17.2.2 Choice of laboratory investigations 17.3 Gender assignment 17.4 Role of the paediatric urologist 17.4.1 Diagnosis 17.4.1.1 Clinical examination 17.4.1.2 Investigations 17.5 Management 17.5.1 Feminizing surgery 17.5.2 Masculinizing surgery 17.6 REFERENCES

62 62 63 63 64 64 64 64 64 65 65 65 65 66

18. Posterior urethral valves 18.1 Background 18.2 Classification 18.2.1 Urethral valve 18.3 Diagnosis 18.4 Treatment 18.4.1 Antenatal treatment 18.4.2 Postnatal treatment Bladder drainage Valve ablation Vesicostomy High diversion 18.5 References

67 67 67 67 67 68 68 68 68 68 68 68 70

19.

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Abbreviations used in the text

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1. INTRODUCTION A collaborative working group consisting of members representing the European Society for Paediatric Urology (ESPU) and the European Association of Urology (EAU) has gathered in an effort to produce the current update of the paediatric urology guidelines. The aim of this close collaboration between a subspecialty group and its parent specialty is to make a document available that may help to increase the quality of care for children with urological problems. The majority of urological clinical problems in children are distinct and in many ways different to those in adults. The aim of this work is to outline a practical and preliminary approach to paediatric urological problems. Complex and rare conditions that require special care with experienced doctors should be referred to designated centres where paediatric urology practice has been fully established and a multidisciplinary approach is available. For quite some time, paediatric urology has informally developed, expanded, matured and established its diverse body of knowledge and expertize and may now be ready to distinguish itself from its parent specialties. Thus, paediatric urology has recently emerged in many European countries as a distinct subspecialty of both urology and paediatric surgery, and presents a unique challenge in the sense that it covers a large area with many different schools of thought and a huge diversity in management. Knowledge gained by increasing experience, new technological advances and non-invasive diagnostic screening modalities has had a profound influence on treatment modalities in paediatric urology, a trend that is likely to continue in the years to come. We now have new techniques for the treatment of reflux, our techniques for the treatment of complex congenital anomalies have substantially improved and totally new technologies for bladder replacement and laparoscopic procedures have been developed. There is also an increasing body of knowledge in paediatric urology related to basic research. Paediatric urology covers a huge field within urology. The scope and complexity of paediatric urology practice continues to expand. Capturing the entire field of paediatric urology in a single guideline document was never an option, but we will keep on amending and adding on this document on a regular basis. This year there are two new chapters within the document and eight chapters have been revised. The guidelines were compiled by the collaborative working group and based on current literature following a systematic review using MEDLINE. Application of a structured analysis of the literature was not possible in many conditions due to a lack of well-designed studies. Whenever possible, statements have been classified in terms of level of evidence and grade of recommendation (1). Due to the limited availability of large randomized controlled trials – influenced also by the fact that a considerable number of treatment options relate to surgical interventions on a large spectrum of different congenital problems – this document will therefore largely be a consensus document. We hope that you will consider this document to be a valuable educational resource for your practice and that it will provide you with guidance in the care of your cases in paediatric urology.

1.1.

REFERENCE

1. Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998 http://www.cebm.net/index.aspx?o=1025 [access date February 2009].

2. PHIMOSIS 2.1

Background

At the end of the first year of life, retraction of the foreskin behind the glandular sulcus is possible in only about 50% of boys; this rises to approximately 89% by the age of 3 years. The incidence of phimosis is 8% in 6 to 7-year-olds and just 1% in males aged 16-18 years (1). The phimosis is either primary (physiological) with no sign of scarring, or secondary (pathological) to a scarring such as balanitis xerotica obliterans. Phimosis has to

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be distinguished from normal agglutination of the foreskin to the glans, which is a physiological phenomenon (2). The paraphimosis must be regarded as an emergency situation: retraction of a too narrow prepuce behind the glans penis into the glanular sulcus may constrict the shaft and lead to oedema. It interferes with perfusion distally from the constrictive ring and brings a risk of consecutive necrosis.

2.2

Diagnosis

The diagnosis of phimosis and paraphimosis is made by physical examination. If the prepuce is not retractable or only partly retractable and shows a constrictive ring on drawing back over the glans penis, a disproportion between the width of the foreskin and the diameter of the glans penis has to be assumed. In addition to the constricted foreskin, there may be adhesions between the inner surface of the prepuce and the glanular epithelium and/or a fraenulum breve. A fraenulum breve leads to a ventral deviation of the glans once the foreskin is retracted. If the tip remains narrow and glanular adhesions were separated, than the space is filled with urine during voiding causing the foreskin to balloon outward. The paraphimosis is characterized by retracted foreskin with the constrictive ring localized at the level of the sulcus, which prevents replacement of the foreskin over the glans.

2.3

Treatment

Treatment of phimosis in children is dependent on the parents’ preferences and can be plastic or radical circumcision after completion of the second year of life. Plastic circumcision has the objective of achieving a wide foreskin circumference with full retractability, while the foreskin is preserved (dorsal incision, partial circumcision). However, this procedure carries the potential for recurrence of the phimosis. In the same session, adhesions are released and an associated fraenulum breve is corrected by fraenulotomy. Meatoplasty is added if necessary. An absolute indication for circumcision is secondary phimosis. The indications in primary phimosis are recurrent balanoposthitis and recurrent urinary tract infections in patients with urinary tract abnormalities (3-6) (level of evidence: 2, grade B recommendation). Simple ballooning of the foreskin during micturition is not a strict indication for circumcision. Routine neonatal circumcision to prevent penile carcinoma is not indicated. Contraindications for circumcision are coagulopathy, an acute local infection and congenital anomalies of the penis, particularly hypospadias or buried penis, because the foreskin may be required for a reconstructive procedure (7, 8). Childhood circumcision has an appreciable morbidity and should not be recommended without a medical reason (9-12) (level of evidence: 2, grade B recommendation). As a conservative treatment option of the primary phimosis, a corticoid ointment or cream (0.05-0.1%) can be administered twice a day over a period of 20-30 days (13-16) (level of evidence: 1, grade A recommendation). This treatment has no side effects and the mean bloodspot cortisol levels are not significantly different from an untreated group of patients (17) (level of evidence: 1). Agglutination of the foreskin does not respond to steroid treatment (14) (level of evidence: 2). Treatment of paraphimosis consists of manual compression of the oedematous tissue with a subsequent attempt to retract the tightened foreskin over the glans penis. Injection of hyaluronidase beneath the narrow band may be helpful to release it (18) (level of evidence: 4, grade C recommendation). If this manoeuvre fails, a dorsal incision of the constrictive ring is required. Depending on the local findings, a circumcision is carried out immediately or can be performed in a second session.

2.4

REFERENCES

1. Gairdner D. The fate of the foreskin: a study of circumcision. Br Med J 1949;2(4642):1433-7. http://www.ncbi.nlm.nih.gov/pubmed/15408299 2. Oster J. Further fate of the foreskin. Incidence of preputial adhesions, phimosis, and smegma among Danish schoolboys. Arch Dis Child 1968;43(288):200-3. http://www.ncbi.nlm.nih.gov/pubmed/5689532 3. Wiswell TE. The prepuce, urinary tract infections, and the consequences. Pediatrics 2000;105(4 Pt 1): 860-2. http://www.ncbi.nlm.nih.gov/pubmed/10742334 4. Hiraoka M, Tsukahara H, Ohshima Y, Mayumi M. Meatus tightly covered by the prepuce is associated with urinary tract infection. Pediatr Int 2002;44(6):658-62. http://www.ncbi.nlm.nih.gov/pubmed/12421265 5. To T, Agha M, Dick PT, Feldman W. Cohort study on circumcision of newborn boys and subsequent risk of urinary tract infection. Lancet 1998;352(9143):1813-6. http://www.ncbi.nlm.nih.gov/pubmed/9851381 6. Herndon CDA, McKenna PH, Kolon TF, Gonzales ET, Baker LA, Docimo SG. A multicenter outcomes analysis of patients with neonatal reflux presenting with prenatal hydronephrosis. J Urol 1999;162(3 Pt 2):1203-8. http://www.ncbi.nlm.nih.gov/pubmed/10458467 Update march 2009

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7. Thompson HC, King LR, Knox E, Korones SB. Report of the ad hoc task force on circumcision. Pediatrics 1975;56(4):610-1. http://www.ncbi.nlm.nih.gov/pubmed/1174384 8. American Academy of Pediatrics. Report of the Task Force on Circumcision. Pediatrics 1989:84:38891. Erratum in: Pediatrics 1989;84(2):761. http://www.ncbi.nlm.nih.gov/pubmed/2664697 9. Griffiths DM, Atwell JD, Freeman NV. A prospective study of the indications and morbidity of circumcision in children. Eur Urol 1985;11(3):184-7. http://www.ncbi.nlm.nih.gov/pubmed/4029234 10. Christakis DA, Harvey E, Zerr DM, Feudtner C, Wright JA, Connell FA. A trade-off analysis of routine newborn circumcision. Pediatrics 2000;105(1 Pt 3):246-9. http://www.ncbi.nlm.nih.gov/pubmed/10617731 11. Ross JH. Circumcision: Pro and con. In: Elder JS, ed. Pediatric urology for the general urologist. New York: Igaku-Shoin, 1996, pp. 49-56. 12. Hutcheson JC. Male neonatal circumcision: indications, controversies and complications. Urol Clin N Amer 2004;31(3):461-7. http://www.ncbi.nlm.nih.gov/pubmed/15313055 13. Monsour MA, Rabinovitch HH, Dean GE. Medical management of phimosis in children: our experience with topical steroids. J Urol 1999;162(3 Pt 2):1162-4. http://www.ncbi.nlm.nih.gov/pubmed/10458456 14. Chu CC, Chen KC, Diau GY. Topical steroid treatment of phimosis in boys. J Urol 1999;162(3 Pt 1): 861-3. http://www.ncbi.nlm.nih.gov/pubmed/10458396 15. ter Meulen PH, Delaere KP. A conservative treatment of phimosis on boys. Eur Urol 2001;40(2):196-9; discussion 200. http://www.ncbi.nlm.nih.gov/pubmed/11528198 16. Elmore JM, Baker LA, Snodgrass WT. Topical steroid therapy as an alternative to circumcision for phimosis in boys younger than 3 years. J Urol 2002;168(4 Pt 2):1746-7; discussion 1747. http://www.ncbi.nlm.nih.gov/pubmed/12352350 17. Golubovic Z, Milanovic D, Vukadinovic V, Rakic I, Perovic S. The conservative treatment of phimosis in boys. Br J Urol 1996;78(5):786-8. http://www.ncbi.nlm.nih.gov/pubmed/8976781 18. DeVries CR, Miller AK, Packer MG. Reduction of paraphimosis with hyaluronidase. Urology 1996;48(3):464-5. http://www.ncbi.nlm.nih.gov/pubmed/8804504

3. CRYPTORCHIDISM 3.1

Background

At the age of 1 year, almost 1% of all full-term male infants are affected by this most common congenital anomaly associated with the genitalia of newborn males (1). Because knowledge of the location and existence of the testis directly influences clinical management, it seems appropriate to categorise the testes into palpable and non-palpable. Retractile testes do not need any form of treatment except observation as they can become ascendant. Retractile testes have completed their descent but may be found in the groin because of a strong cremasteric reflex (2). In the case of bilateral non-palpable testes and any suggestion of sexual differentiation problems, such as hypospadias, urgent endocrinological and genetic evaluation is mandatory (3) (level of evidence: 3, grade of recommendation: B).

3.2

Diagnosis

A physical examination is the only method of differentiating between palpable or non-palpable testes. There is no additional benefit in performing ultrasound, computed tomography (CT), magnetic resonance imaging (MRI) or angiography. Clinical examination includes a visual description of the scrotum and an examination of the child while supine and in crossed-leg position. The examiner should inhibit the cremasteric reflex with his non-dominant hand right above the symphysis in the groin region before touching, or reaching for, the scrotum. The groin

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region may be ‘milked’ towards the scrotum in an attempt to move the testis into the scrotum. This manoeuvre also makes it possible to differentiate between an inguinal testis and enlarged lymph nodes that could give the impression of an undescended testis. A retractile testis can generally be brought into the scrotum, where it will remain until a cremasteric reflex (touching the inner thigh skin) will retract it again into the groin (4). A unilateral non-palpable testis and an enlarged contralateral testis may suggest testicular absence or atrophy, but this finding is not specific and does not preclude surgical exploration. Specific visual attention should be given to the femoral, penile and perineal region in the case of an inguinal non-palpable testis to exclude an ectopic testis. There is no reliable examination to confirm or exclude an intra-abdominal, inguinal and absent/ vanishing testis (non-palpable testis), except for diagnostic laparoscopy (5) (level of evidence: 1b, grade of recommendation: A). Before instigating laparoscopic assessment, an examination under general anaesthesia is recommended because some originally non-palpable testes are palpable under anaesthetic conditions.

3.3

Treatment

If a testis has not descended by the age of 1 year, there is no benefit in waiting for a spontaneous descent. To prevent histological deterioration, treatment should be carried out and finished before 12-18 months of age (6). 3.3.1 Medical therapy 3.3.1.1 Medical therapy for testicular descent Medical therapy using human chorionic gonadotrophin (hCG) or gonadotrophin-releasing hormone (GnRH) is based on the hormonal dependence of testicular descent with success rates of a maximum of 20% (level of evidence: 1, grade of recommendation: C) (7, 8). Hormonal therapy for testicular descent has lower success rates the higher the undescended testis is located. Human chorionic gonadotrophin is used in a total dosage of 6.000-9.000 IU, given in four dosages within 2 to 3 weeks depending on weight and age and GnRH in a dosage of 1.2 mg/day divided into three dosages per day for 4 weeks using a nasal spray, respectively. 3.3.1.2 Medical therapy for fertility potential Medical treatment can be beneficial before (dosage as described above), or after (low intermittent dosages) surgical orchidolysis and orchidopexy (14) in terms of increasing the fertility index, which may act as a predictor for fertility later on in life (level of evidence 1b, grade of recommendation A). However, data from the long-term follow-up of the impact of hormonal treatment on fertility potential is still lacking. 3.3.2 Surgery Palpable testis. Surgery for the palpable testis includes orchidofuniculolysis and orchidopexy, via an inguinal approach, with success rates of up to 92% (9). It is important to remove and dissect all cremasteric fibres to prevent secondary retraction. Associated problems, such as an open processus vaginalis, must be carefully dissected and closed. It is recommended that the testis is placed in a subdartos pouch. With regard to sutures, there should either be no fixation sutures or they should be made between the tunica vaginalis and the dartos musculature. The lymph drainage of a testis that has undergone surgery for orchidopexy has been changed from iliac drainage to iliac and inguinal drainage (important in the event of later malignancy). Non-palpable testis. In the situation of a non-palpable testis, inguinal surgical exploration with the possibility of performing laparoscopy should be attempted. There is a significant chance of finding the testis via an inguinal incision, but in rare cases, it is necessary to search into the abdomen if there are no vessels or vas deferens in the groin. Laparoscopy is the most appropriate way of examining the abdomen for a testis. In addition, either removal or orchidolysis and orchiopexy can be performed via laparoscopic access (10). Before starting diagnostic laparoscopy, it is recommended that the child be examined again under general anaesthesia since a previous non-palpable testis might now be palpable under anaesthetic conditions. An intra-abdominal testis in a 10-year-old boy or older with a normal contralateral testis should be removed. In bilateral intra-abdominal testes, or in a boy younger than 10 years, a one-stage or two-stage Fowler-Stephens procedure can be performed. In the event of a two-stage procedure, the spermatic vessels are either laparoscopically clipped or coagulated proximal to the testis to allow development of the collateral vasculature (11). The second-stage procedure, in which the testis is brought directly over the symphysis and next to the bladder into the scrotum, can also be performed by laparoscopy 6 months later. The testicular survival rate in a one-stage procedure varies between 50% and 60%, with success rates rising up to 90% in a two-stage procedure (12). Microvascular autotransplantation can also be performed with 90% testicular survival rate. However, the procedure requires a very skilful and experienced surgical technique (13).

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3.4

Prognosis

Boys with one undescended testis have a lower fertility rate but the same paternity rate as boys with bilateral descended testes. Boys with bilateral undescended testes have both a lower fertility and paternity rate. Boys with an undescended testis have a 20-fold higher chance of developing testicular malignancy, a risk which is uninfluenced by any kind of treatment. Screening both during and after puberty is therefore recommended for these boys. A recent Swedish study followed up a cohort of nearly 17,000 men treated surgically for undescended testis for a total of almost 210,000 person-years. The study revealed that treatment for undescended testis before puberty decreases the risk of testicular cancer. The relative risk of testicular cancer among those who underwent orchiopexy before reaching 13 years of age was 2.23 as compared with the Swedish general population; for those treated at 13 years of age or older, the relative risk was 5.40 (15). In addition, an American group has published a systematic review and meta-analysis of the literature and concluded similarly that prepubertal orchiopexy may indeed decrease the risk of testicular cancer and that early surgical intervention is indicated in children with cryptorchidism (16). Boys with retractile testes do not need medical or surgical treatment but require close follow-up until puberty. Due to the lack of spontaneous testicular descent after the age of 1 year, and because of the potential loss of testicular quality, it is recommended that surgical orchidolysis and orchidopexy are performed at the latest by 12-18 months of age. To date, it seems that pre- or post-operative hormonal treatment may have a beneficial effect on fertility later in life.

3.5

REFERENCES

1.

Berkowitz GS, Lapinski RH, Dolgin SE, Gazella JG, Bodian CA, Holzman IR. Prevalence and natural history of cryptorchidism. Pediatrics 1993;92(1):44-9. http://www.ncbi.nlm.nih.gov/pubmed/8100060 2. Caesar RE, Kaplan GW. The incidence of the cremasteric reflex in normal boys. J Urol 1994;152(2 Pt 2):779-80. http://www.ncbi.nlm.nih.gov/pubmed/7912745 3. Rajfer J, Walsh PC. The incidence of intersexuality in patients with hypospadias and cryptorchidism. J Urol 1976;116(6):769-70. http://www.ncbi.nlm.nih.gov/pubmed/12377 4. Rabinowitz R, Hulbert WC Jr. Late presentation of cryptorchidism: the etiology of testicular re-ascent. J Urol 1997;157(5):1892-4. http://www.ncbi.nlm.nih.gov/pubmed/9112557 5. Cisek LJ, Peters CA, Atala A, Bauer SB, Diamond DA, Retik AB. Current findings in diagnostic laparoscopic evaluation of the nonpalpable testis. J Urol 1998;160(3 Pt 2):1145-9; discussion 1150. http://www.ncbi.nlm.nih.gov/pubmed/9719296 6. Huff DS, Hadziselimovic F, Snyder HM 3rd, Blythe B, Ducket JW. Histologic maldevelopment of unilaterally cryptorchid testes and their descended partners. Eur J Pediatr 1993;152 Suppl:S11-S14. http://www.ncbi.nlm.nih.gov/pubmed/8101802 7. Rajfer J, Handelsman DJ, Swerdloff RS, Hurwitz R, Kaplan H, Vandergast T, Ehrlich RM. Hormonal therapy of cryptorchidism. A randomized, double-blind study comparing human chorionic gonadotropin and gonadotropin-releasing hormone. N Engl J Med 1986;314(8):466-70. http://www.ncbi.nlm.nih.gov/pubmed/2868413 8. Pyorala S, Huttunen NP, Uhari M. A review and meta-analysis of hormonal treatment of cryptorchidism. J Clin Endocrinol Metab 1995;80(9):2795-9. http://www.ncbi.nlm.nih.gov/pubmed/7673426 9. Docimo SG. The results of surgical therapy for cryptorchidism: a literature review and analysis. J Urol 1995;154:1148-52. http://www.ncbi.nlm.nih.gov/pubmed/7637073 10. Jordan GH, Winslow BH. Laparoscopic single stage and staged orchiopexy. J Urol 1994;152(4): 1249-52. http://www.ncbi.nlm.nih.gov/pubmed/7915336 11. Bloom DA. Two-step orchiopexy with pelviscopic clip ligation of the spermatic vessels. J Urol 1991;145(5):1030-3. http://www.ncbi.nlm.nih.gov/pubmed/1673160 12. Radmayr C, Oswald J, Schwentner C, Neururer R, Peschel R, Bartsch G. Long-term outcome of laparoscopically managed nonpalpable testes. J Urol 2003;170(6 Pt 1):2409-11. http://www.ncbi.nlm.nih.gov/pubmed/14634439

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13.

Wacksman J, Billmire DA, Lewis AG, Sheldon CA. Laparoscopically assisted testicular autotransplantation for management of the intraabdominal undescended testis. J Urol 1996;156(2 Pt 2):772-4. http://www.ncbi.nlm.nih.gov/pubmed/8683780 14. Schwentner C, Oswald J. Kreczy A, Lunacek A, Bartsch G, Deibl M, Radmayr C. Neoadjuvant gonadotropin releasing hormone therapy before surgery may improve the fertility index in undescended testes – a prospective randomized trial. J Urol 2005;173(3): 974-7. http://www.ncbi.nlm.nih.gov/pubmed/15711353 15. Pettersson A, Richiardi L, Nordenskjold A, Kaijser M, Akre O. Age at surgery for undescended testis and risk of testicular cancer. N Engl J Med 2007;356(18):1835-41. http://www.ncbi.nlm.nih.gov/pubmed/17476009 16. Walsh T, Dall’Era M, Croughan M, Carroll P, Turek P. Prepubertal orchiopexy for cryptorchidism may be associated with a lower risk of testicular cancer. J Urol 2007;178: 1440-6; discussion 1446. http://www.ncbi.nlm.nih.gov/pubmed/17706709

4. HYDROCELE 4.1

Background

Hydrocele is defined as a collection of fluid between the parietal and visceral layer of tunica vaginalis (1). Pathogenesis of hydrocele is based on an imbalance between the secretion and reabsorption of this fluid. This is in contrast with inguinal hernia, which is defined as the protrusion of a portion of organs or tissues through the abdominal wall (2). Incomplete obliteration of the processus vaginalis peritonei results in formation of various types of communicating hydrocele alone or connected with other intrascrotal pathology (hernia). The exact time of obliteration of processus vaginalis is not known. It persists in approximately 80-94% of newborns and in 20% of adults (3). If complete obliteration of processus vaginalis occurs with patency of midportion, a hydrocele of the cord occurs. Scrotal hydroceles without associated patency of the processus vaginalis are encountered in newborns as well (4). Non-communicating hydroceles are found secondary to minor trauma, testicular torsion, epididymitis, varicocele operation or may appear as a recurrence after primary repair of a communicating hydrocele.

4.2

Diagnosis

The classic description of a communicating hydrocele is that of a hydrocele that vacillates in size, and is usually related to activity. It may be diagnosed by history; physical investigation and transillumination of the scrotum make the diagnosis in the majority of cases (5). If the diagnosis is that of a hydrocele, there will be no history of reducibility and no associated symptoms; the swelling is translucent, smooth and usually non-tender. If there are any doubts about the character of an intrascrotal mass, scrotal ultrasound should be performed and has nearly 100% sensitivity in detecting intrascrotal lesions. Doppler ultrasound studies help to distinguish hydroceles from varicocele and testicular torsion, although these conditions may also be accompanied by a hydrocele.

4.3

Treatment

In the majority of infants, the surgical treatment of hydrocele is not indicated within the first 12-24 months because of the tendency for spontaneous resolution (level of evidence: 4, grade C recommendation). Early surgery is indicated if there is suspicion of a concomitant inguinal hernia or underlying testicular pathology (6). The question of contralateral disease should be addressed by both history and examination at the time of initial consultation (5). Persistence of a simple scrotal hydrocele beyond 24 months of age may be an indication for surgical correction. However, there is no evidence that this type of hydrocele risks testicular damage. In the paediatric age group, the operation consists of ligation of patent processus vaginalis via inguinal incision and the distal stump is left open, whereas in hydrocele of the cord the cystic mass is excised or unroofed (1,5,6) (level of evidence: 4, grade C recommendation). In expert hands, the incidence of testicular damage during hydrocele or inguinal hernia repair is very low (0.3%) (level of evidence: 3, grade B recommendation). Sclerosing agents should not be used because of the risk of chemical peritonitis in communicating processus vaginalis peritonei (5,6) (level of evidence: 4, grade C recommendation). The scrotal approach (Lord or Jaboulay technique) is used in the treatment of a secondary non-communicating hydrocele.

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4.4

REFERENCES

1.

Kapur P, Caty MG, Glick PL. Pediatric hernias and hydroceles. Pediatric Clin North Am1998;45(4): 773-89. http://www.ncbi.nlm.nih.gov/pubmed/9728185 2. Barthold JS, Kass EJ. Abnormalities of the penis and scrotum. In: Belman AB, King LR, Kramer SA, eds. Clinical pediatric urology. 4th edn. London: Martin Dunitz, 2002, pp. 1093-1124. 3. Schneck FX, Bellinger MF. Abnormalities of the testes and scrotum and their surgical management. In: Walsh PC, Retik AB, Vaughan ED, Wein AJ, eds. Campbell’s urology. 8th edn. Philadelphia: WB Saunders, 2002, pp. 2353-94. 4. Rubenstein RA, Dogra VS, Seftel AD, Resnick MI. Benign intrascrotal lesions. J Urol 2004;171(5): 1765-72. http://www.ncbi.nlm.nih.gov/pubmed/15076274 5. Skoog SJ. Benign and malignant pediatric scrotal masses. Pediatr Clin North Am 1997;44(5):1229-50. http://www.ncbi.nlm.nih.gov/pubmed/9326960 6. Stringer MD, Godbole PP. Patent processus vaginalis. In: Gearhart JP, Rink RC, Mouriquand PD, eds. Pediatric urology. Philadelphia: WB Saunders, 2001, pp. 755-762.

5. Acute scrotum in children 5.1

Background

Acute scrotum is a paediatric urology emergency case, most commonly caused by torsion of the testis, torsion of the appendix testis and epididymitis/epididymo-orchitis (1-6). Other causes of acute scrotal pain are idiopathic scrotal oedema, mumps orchitis, varicocele, scrotal haematoma, incarcerated hernia, appendicitis or systemic disease (Henoch-Schönlein purpura) (7-19). Torsion of the testis occurs most often in the neonatal period and around puberty, while torsion of the appendix testes occurs over a wider age range. Acute epididymitis affects two age groups: below the age of 1 year and between 12 and 15 years (5, 20, 21). Acute epididymitis was found most often (37-64.6%) in boys with acute scrotum (1-4). One study predicted the incidence of epididymitis as about 1.2 per 1,000 male children per year (22).

5.2

Diagnosis

Patients usually present with scrotal pain. The duration of symptoms is shorter in testicular torsion (69% present within 12 hours) compared to torsion of the appendix testes (62%) and acute epididymitis (31%) (5, 6, 20). In the early phase, location of the pain can lead to the diagnosis. Patients with acute epididymitis experience a tender epididymitis, while patients with testicular torsion are more likely to have a tender testicle and patients with torsion of the appendix testis feel isolated tenderness of the superior pole of the testis (20). An abnormal position of the testis was more frequent in testicular torsion than in patients with epididymitis (20). Looking for the absence of the cremasteric reflex is a simple method with a sensitivity of 100% and specificity of 66% for the presence of testicular torsion (21, 23) (Level of evidence: 3; Grade of recommendation: C). Fever occurs often in epididymitis (11-19%). The classical sign of a ‘blue dot’ was found only in 10-23% patients with torsion of the appendix testis (4, 6, 21, 24). In many cases, it is not easy to determine the cause of acute scrotum based on history and physical examination alone (1-6, 21, 24). A positive urine culture is only found in a few patients with epididymitis (3, 21, 24, 25). It should be remembered that a normal urinalysis does not exclude epididymitis. Similarly, an abnormal urinalysis does not exclude testicular torsion. Doppler ultrasound is useful to evaluate an acute scrotum, with a sensitivity of 63.6-100% and a specificity of 97-100%, and a positive predictive value of 100% and negative predictive value 97.5% (26-31) (Level of evidence: 3; Grade of recommendation: C). The use of Doppler ultrasound may reduce the number of patients with acute scrotum undergoing scrotal exploration, but it is operator-dependent and can be difficult to perform in prepubertal patients (29, 32). It may also show a misleading arterial flow in the early phases of torsion and in partial or intermittent torsion: persistent arterial flow does not exclude testicular torsion. In a multicentre study of 208 boys with torsion of the testis, 24% patients had normal or increased testicular vascularization (29). Better results were reported using high-resolution ultrasonography (HRUS) for direct visualization of the spermatic cord twist with a sensitivity of 97.3% and a specificity of 99% (29, 33) (Level of

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evidence: 2; Grade of recommendation: C). Scintigraphy and, more recently, dynamic contrast-enhanced subtraction MRI of the scrotum also provide a comparable sensitivity and specificity to ultrasound (34-37). These investigations may be used when diagnosis is less likely and if torsion of the testis still cannot be excluded from history and physical examination. This should be done without inordinate delays for emergent intervention (24). The diagnosis of acute epididymitis in boys is mainly based on clinical judgement and adjunctive investigation. However, it should be remembered that findings of secondary inflammatory changes in the absence of evidence of an extra-testicular nodule by Doppler ultrasound might suggest an erroneous diagnosis of epididymitis in children with torsion of appendix testes (38). Prepubertal boys with acute epididymitis have an incidence of underlying urogenital anomalies of 25-27.6%. Complete urological evaluation in all children with acute epididymitis is still debatable (3, 21, 22).

5.3

Treatment

5.3.1 Epididymitis In prepubertal boys, the aetiology is usually unclear, with an underlying pathology of about 25%. A urine culture is usually negative, and unlike in older boys, a sexually transmitted disease is very rare. Antibiotic treatment, although often started, is not indicated in most cases unless urinalysis and urine culture show a bacterial infection (22,39). Epididymitis is usually self-limiting and with supportive therapy (i.e. minimal physical activity and analgesics) heals without any sequelae (Level of evidence: 3; Grade of recommendation: C). However, bacterial epididymitis can be complicated by abscess or necrotic testis and surgical exploration is required (40). Torsion of the appendix testis can be managed conservatively (Level of evidence: 4; Grade of recommendation: C). During the six-week-follow-up, clinically and with ultrasound, no testicular atrophy was revealed. Surgical exploration is done in equivocal cases and in patients with persistent pain (27). 5.3.2 Testicular torsion Manual detorsion of the testis is done without anaesthesia. It should initially be done by outwards rotation of the testis unless the pain increases or if there is obvious resistance. Success is defined as the immediate relief of all symptoms and normal findings at physical examination (41) (Level of evidence: 3; Grade of recommendation: C). Doppler ultrasound may be used for guidance (42). Bilateral orchiopexy is still required after successful detorsion. This should not be done as an elective procedure, but rather immediately following detorsion. One study reported residual torsion during exploration in 17 out of 53 patients, including 11 patients who had reported pain relief after manual detorsion (41, 43). 5.3.3 Surgical treatment Testicular torsion is an urgent condition, which requires prompt surgical treatment. The two most important determinants of early salvage rate of the testis are the time between onset of symptoms and the detorsion and degree of twisting of the cord (44). Severe testicular atrophy occurred after torsion for as little as 4 hours when the turn was more than 360°. In cases of incomplete torsion (180° to 360°), with symptom duration up to 12 hours, no atrophy was observed. However, an absent or severely atrophied testis was found in all cases of torsion of more than 360° and symptom duration of more than 24 hours (45). Early surgical intervention with detorsion (mean torsion time < 13 hours) was found to preserve fertility (46). Urgent surgical exploration is mandatory in all cases of testicular torsion within 24 hours of the onset of symptoms. In those patients with testicular torsion of more than 24 hours, semi-elective exploration is necessary (44,45) (Level of evidence: 3; Grade of recommendation: C). Until now, there is still controversy to carry out detorsion and to preserve the ipsilateral testis, or to perform an orchiectomy, in order to preserve contralateral function and fertility after testicular torsion of long duration (> 24 hours). A recent study in humans found that sperm quality was preserved in both orchiectomy and orchiopexy groups in comparison to control normal men, although orchiectomy resulted in better sperm morphology (47). During exploration, fixation of the contralateral testis is also performed. Recurrence after orchiopexy is rare (4.5%) and may occur several years after operation. There is no common recommendation about the preferred type of fixation and suture material; however, many urologists currently use a Dartos pouch orchiopexy (48). External cooling before exploration and several medical treatments seem effective in reducing ischaemia-reperfusion injury and preserving the viability of the torsed testis and the contralateral testis (49-53).

5.4

Prognosis

5.4.1 Fertility The results vary and are conflicting. In one study, unilateral torsion of the testis seriously intervened with

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subsequent spermatogenesis in about 50% of the patients and produced borderline impairment in another 20%. 5.4.2 Subfertility Subfertility is found in 36-39% of the patients after torsion. Semen analysis may be normal in only 5-50% in long-term follow-up (44). Early surgical intervention (mean torsion time < 13 hours) with detorsion was found to preserve fertility, but prolonged torsion periods (mean torsion time of 70 hours) followed by orchiectomy jeopardizes fertility (46). One study identified antisperm antibodies in the semen of patients with testicular torsion and correlated antibody levels with infertility, while other studies have failed to confirm these results (44,47). Anderson et al. found pre-existing contralateral testis abnormalities in biopsies performed at the time of surgery and did not detect any case of antisperm antibodies after testicular torsion (46). 5.4.3 Androgen levels A study in rats showed a long-term reduction in testicular androgen production after testicular torsion. This effect was considered to be caused by reperfusion/ oxidative stress in the testis (45). Even though the levels of FSH, LH and testosterone are higher in patients after testicular torsion compared to normal controls, endocrine testicular function remains in the normal range in patients after testicular torsion (47). 5.4.4 Testicular cancer There may be a 3.2-fold increased risk of developing a testis tumour 6-13 years after torsion. However, two of nine reported cases had torsion of a tumour- bearing testis and four had a tumour in the contralateral testis to the torsed testicle (44). 5.4.5 Nitric oxide A study in rats found that spermatic cord torsion did not lead to impairment in nitric oxide-mediated relaxant responses of the isolated penile bulb (54).

5.5

Perinatal torsion

Perinatal torsion of the testis most often occurs prenatally. After birth, perinatal torsion occurs in 25%, with bilateral perinatal torsion comprises 11-21% of all perinatal torsions (55). Most cases are extravaginal torsion in contrast to the usual intravaginal torsion, which occurs during puberty. Intrauterine torsion may presented as: present as: • Patients with a testicular nubbin • Patients with a small and hard testis • Patients with a normal-sized and hard testis • Patients with an acute scrotum. Torsion occurring in the postnatal period within the first month of life presents with signs of an acute scrotum. The clinical signs correlate well with surgical and histological findings and thus define the need and the urgency to explore the history (56). Doppler ultrasound can be an additional diagnosis tool. The sensitivity for diagnosis of torsion of the testis is high, though the specificity is unknown for neonates. Doppler ultrasound may also be used to exclude congenital testicular neoplasm (57). Neonates with acute scrotal signs as well as bilateral cases should be treated as surgical emergencies (56, 58). In cases of postnatal torsion, one study reported 40% of testes were salvaged with emergency exploration (59). The contralateral scrotum should also be explored because of the risk of asynchronous contralateral testicular torsion in as many as 33% of cases (58).

5.6.

References

1. Varga J, Zivkovic D, Grebeldinger S, Somer D. Acute scrotal pain in children–ten years’ experience. Urol Int 2007;78(1):73-7. http://www.ncbi.nlm.nih.gov/pubmed/17192737 2. Cavusoglu YH, Karaman A, Karaman I, Erdogan D, Aslan MK, Varlikli O, Cakmak O. Acute scrotum– etiology and management. Indian J Pediatr 2005;72(3):201-3. http://www.ncbi.nlm.nih.gov/pubmed/15812112 3. Sakellaris GS, Charissis GC. Acute epididymitis in Greek children: a 3-year retrospective study. Eur J Pediatr 2007;5. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/17786475

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4.

Klin B, Zlotkevich L, Horne T, Efrati Y, Serour F, Lotan G. Epididymitis in childhood: a clinical retrospective study over 5 years. IMAJ 2001;3:833-35. http://www.ima.org.il/imaj/dynamic/web/showArt.asp?id=543&nMonth=11&nYear=2001&sCat=Origin a%20l%20Articles&sJur=Vol%203.h 5. McAndrew HF, Pemberton R, Kikiros CS, Gollow I. The incidence and investigation of acute scrotal problems in children. Pediatr Surg Int 2002; 18(5-6): 435-7. http://www.ncbi.nlm.nih.gov/pubmed/12415374 6. Makela E, Lahdes-Vasama T, Rajakorpi H, Wikstrom S. A 19-year review of paediatric patients with acute scrotum. Scan J Surg 2007;96(1):62-6. http://www.ncbi.nlm.nih.gov/pubmed/17461315 7. Klin B, Lotan G, Efrati Y, Zlotkevich L, Strauss S. Acute idiopathic scrotal edema in children–revisited. J Pediatr Surg 2002;37(8);1200-2. http://www.ncbi.nlm.nih.gov/pubmed/12149702 8. van Langen AM, Gal S, Hulsmann AR, de Nef JJ. Acute idiopathic scrotal oedema: four cases and short review. Eur J Pediatr 2001;160(7):455-6. http://www.ncbi.nlm.nih.gov/pubmed/11475590 9. Hara Y, Tajiri T, Matsuura K, Hasegawa A. Acute scrotum caused by Henoch-Schonlein purpura. Int J Urology 2004;11(7):578-80. http://www.ncbi.nlm.nih.gov/pubmed/15242376 10. Singh S, Adivarekar P, Karmarkar SJ. Acute scrotum in children: a rare presentation of acute, nonperforated appendicitis. Pediatr Surg Int 2003;19(4):298-9. http://www.ncbi.nlm.nih.gov/pubmed/12682749 11. Bingol-Kologlu M, Fedakar M, Yagmurlu A, Dindar H, Gokcora IH. An exceptional complication following appendectomy: acute inguinal and scrotal suppuration. Int Urol Nephrol 2006;38(3-4):663-5. http://www.ncbi.nlm.nih.gov/pubmed/17160451 12. Ng KH, Chung YFA, Wilde CC, Chee C. An unusual presentation of acute scrotum after appendicitis. Singapore Med J 2002;43(7):365-6. http://www.ncbi.nlm.nih.gov/pubmed/12437045 13. Dayanir YO, Akdilli A, Karaman CZ, Sonmez F, Karaman G. Epididymoorchitis mimicking testicular torsion in Henoch-Schonlein purpura. Eur Radiol 2001;11(11):2267-9. http://www.ncbi.nlm.nih.gov/pubmed/11702171 14. Krause W. Is acute idiopathic scrotal edema in children a special feature of neutrophilic eccrine hidradenitis? Dermatology 2004;208(1):86. http://www.ncbi.nlm.nih.gov/pubmed/14730248 15. Diamond DA, Borer JG, Peters CA, Cilento BG Jr, Sorcini A, Kaefer M, Paltiel HJ. Neonatal scrotal haematoma: mimicker of neonatal testicular torsion. BJU Int 2003; 91:675-7. http://www.ncbi.nlm.nih.gov/pubmed/12699483 16. Vlazakis S, Vlahakis I, Kakavelakis KN, Charissis G. Right acute hemiscrotum caused by insertion of an inflamed appendix. BJU Int 2002;89(9):967-8. http://www.ncbi.nlm.nih.gov/pubmed/12010250 17. Ha TS, Lee JS. Scrotal involvement in childhood Henoch-Schonlein purpura. Acta Paediatr 2007;96(4):552-5. http://www.ncbi.nlm.nih.gov/pubmed/17306010 18. Myers JB, Lovell MA, Lee RS, Furness PD 3rd, Koyle M. Torsion of an indirect hernia sac causing acute scrotum. J Pediatr Surg 2004;39(1):122-3. http://www.ncbi.nlm.nih.gov/pubmed/14694389 19. Matsumoto A, Nagatomi Y, Sakai M, Oshi M. Torsion of the hernia sac within a hydrocele of the scrotum in a child. Int J Urol 2004;11(9):789-91. http://www.ncbi.nlm.nih.gov/pubmed/15379947 20. Sauvat F, Hennequin S, Slimane MAA, Gauthier F. [Age for testicular torsion?] Arch Pediatr 2002;9(12):1226-9. [article in French] http://www.ncbi.nlm.nih.gov/pubmed/12536102 21. Kadish HA, Bolte RG. A retrospective review of pediatric patients with epididymitis, testicular torsion, and torsion of testicular appendages. Pediatrics 1998;102(1 Pt 1):73-6. http://www.ncbi.nlm.nih.gov/pubmed/9651416 22. Somekh E, Gorenstein A, Serour F. Acute epididymitis in boys: evidence of a post-infectious etiology. J Urol 2004;171(1):391-4. http://www.ncbi.nlm.nih.gov/pubmed/14665940

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23. Nelson CP, Williams JF, Bloom DA. The cremaster reflex: a useful but imperfect sign in testicular torsion. J Pediatr Surg 2003; 38(8):1248-9. http://www.ncbi.nlm.nih.gov/pubmed/12891505 24. Mushtaq I, Fung M, Glasson MJ. Retrospective review of pediatric patients with acute scrotum. ANZ J Surg 2003;73(1-2):55-8. http://www.ncbi.nlm.nih.gov/pubmed/12534742 25. Murphy FL, Fletcher L, Pease P. Early scrotal exploration in all cases is the investigation and intervention of choice in the acute paediatric scrotum. Pediatr Surg Int 2006;22(5):413-6. http://www.ncbi.nlm.nih.gov/pubmed/16602024 26. Baker LA, Sigman D, Mathews RI, Benson J, Docimo SG. An analysis of clinical outcomes using color doppler testicular ultrasound for testicular torsion. Pediatrics 2000;105(3 Pt 1):604-7. http://www.ncbi.nlm.nih.gov/pubmed/10699116 27. Schalamon J, Ainoedhofer H, Schleef J, Singer G, Haxhija EQ, Hollwarth ME. Management of acute scrotum in children–the impact of Doppler ultrasound. J Pediatr Surg 2006;41(8):1377-80. http://www.ncbi.nlm.nih.gov/pubmed/16863840 28. Gunther P, Schenk JP, Wunsch R, Holland-Cunz S, Kessler U, Troger J Waag KL. Acute testicular torsion in children: the role of sonography in the diagnostic workup. Eur Radiol 2006;16(11):2527-32. http://www.ncbi.nlm.nih.gov/pubmed/16724203 29. Kalfa N, Veyrac C, Lopez M, Lopez C, Maurel A, Kaselas C, Sibai S, Arena F, Vaos G, Breaud J, Merrot T, Kalfa D, Khochman I, Mironescu A, Minaev S, Averous M, Galifer RB. Multicenter assessment of ultrasound of the spermatic cord in children with acute scrotum. J Urol 2007;177(1):297-301. http://www.ncbi.nlm.nih.gov/pubmed/17162068 30. Karmazyn B, Steinberg R, Kornreich L, Freud E, Grozovski S, Schwarz M, Ziv N, Livne P. Clinical and sonographic criteria of acute scrotum in children: a retrospective study of 172 boys. Pediatr Radiol 2005(3);35:302-10. http://www.ncbi.nlm.nih.gov/pubmed/15503003 31. Lam WW, Yap TL, Jacobsen AS, Teo HJ. Colour Doppler ultrasonography replacing surgical exploration for acute scrotum: myth or reality? Pediatr Radiol 2005;35(6):597-600. http://www.ncbi.nlm.nih.gov/pubmed/15761770 32. Pepe P, Panella P, Pennisi M, Aragona F. Does color Doppler sonography improve the clinical assessment of patients with acute scrotum? Eur J Radiol 2006;60(1):120-4. http://www.ncbi.nlm.nih.gov/pubmed/16730939 33. Kalfa N, Veyrac C, Baud C, Couture A, Averous M, Galifer RB. Ultrasonography of the spermatic cord in children with testicular torsion: impact on the surgical strategy. J Urol 2004;172(4 Pt 2):1692-5. http://www.ncbi.nlm.nih.gov/pubmed/15371792 34. Yuan Z, Luo Q, Chen L, Zhu J, Zhu R. Clinical study of scrotum scintigraphy in 49 patients with acute scrotal pain: a comparison with ultrasonography. Ann Nucl Med 2001;15(3):225-9. http://www.ncbi.nlm.nih.gov/pubmed/11545192 35. Nussbaum Blask, Bulas D, Shalaby-Rana E, Rushton G, Shao C, Majd M. Color Doppler sonography and scintigraphy of the testis: a prospective, comparative analysis in children with acute scrotal pain. Pediatr Emerg Care 2002;18(2):67-71. http://www.ncbi.nlm.nih.gov/pubmed/11973493 36. Paltiel HJ, Connolly LP, Atala A, Altiel AD, Zurakowski D, Treves ST. Acute scrotal symptoms in boys with an indeterminate clinical presentation: comparison of color Doppler sonography and scintigraphy. Radiology 1998;207:223-31. http://radiology.rsnajnls.org/cgi/content/abstract/207/1/223 37. Terai A, Yoshimura K, Ichioka K, Ueda N, Utsunomiya N, Kohei N, Arai Y, Watanabe Y. Dynamic contrast-enhanced subtraction magnetic resonance imaging in diagnostics of testicular torsion. Urology 2006;67(6):1278-82. http://www.ncbi.nlm.nih.gov/pubmed/16765192 38. Karmazyn B, Steinberg R, Livne P, Kornreich L, Grozovski S, Schwarz M, Nitza Z, Freud E. Duplex sonographic findings in children with torsion of the testicular appendages: overlap with epididymitis and epididymoorchitis. J Pediatr Surg 2006;41(3):500-4. http://www.ncbi.nlm.nih.gov/pubmed/16516624 39. Lau P, Anderson PA, Giacomantonio JM, Schwarz RD. Acute epididymitis in boys: are antibiotics indicated? Br J Urol 1997;79(5):797-800. http://www.ncbi.nlm.nih.gov/pubmed/9158522

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40.

Abul F, Al-Sayer H, Arun N. The acute scrotum: a review of 40 cases. Med Princ Pract 2005;14(3): 177-81. http://www.ncbi.nlm.nih.gov/pubmed/15863992 41. Cornel EB, Karthaus HF. Manual derotation of the twisted spermatic cord. BJU Int 1999;83(6): 672-4. http://www.ncbi.nlm.nih.gov/pubmed/10233577 42. Garel L, Dubois J, Azzie G, Filiatrault D, Grignon A, Yazbeck S. Preoperative manual detorsion of the spermatic cord with Doppler ultrasound monitoring in patients with intravaginal acute testicular torsion. Pediatr Radiol 2000;30(1):41-4. http://www.ncbi.nlm.nih.gov/pubmed/10663509 43. Sessions AE, Rabinowitz R, Hulbert WC, Goldstein MM, Mevorach RA. Testicular torsion: direction, degree, duration and disinformation. J Urol 2003;169(2):663-5. http://www.ncbi.nlm.nih.gov/pubmed/12544339 44. Visser AJ, Heyns CF. Testicular function after torsion of the spermatic cord. BJU Int 2003;92(3):200-3. http://www.ncbi.nlm.nih.gov/pubmed/12887467 45. Tryfonas G, Violaki A, Tsikopoulos G, Avtzoglou P, Zioutis J, Limas C, Gregoriadis G, Badouraki M. Late postoperative results in males treated for testicular torsion during childhood. J Pediatr Surg 1994;29(4):553-6. http://www.ncbi.nlm.nih.gov/pubmed/8014814 46. Anderson MJ, Dunn JK, Lishultz LI, Coburn M. Semen quality and endocrine parameters after acute testicular torsion. J Urol 1992;147(6):1545-50. http://www.ncbi.nlm.nih.gov/pubmed/1593686 47. Arap MA, Vicentini FC, Cocuzza M, Hallak J, Athayde K, Lucon AM, Arap S, Srougi M. Late hormonal levels, semen parameters, and presence of antisperm antibodies in patients treated for testicular torsion. J Androl 2007;28(4):528-32. http://www.ncbi.nlm.nih.gov/pubmed/17287456 48. Mor Y, Pinthus JH, Nadu A, Raviv G, Golomb J, Winkler H, Ramon J. Testicular fixation following torsion of the spermatic cord- does it guarantee prevention of recurrent torsion events? J Urol 2006;175(1):171-4. http://www.ncbi.nlm.nih.gov/pubmed/16406900 49. Haj M, Shasha SM, Loberant N, Farhadian H. Effect of external scrotal cooling on the viability of the testis with torsion in rats. Eur Surg Res 2007;39(3):160-9. http://www.ncbi.nlm.nih.gov/pubmed/17341878 50. Aksoy H, Yapanoglu T, Aksoy Y, Ozbey I, Turhan H, Gursan N. Dehydroepiandrosterone treatment attenuates reperfusion injury after testicular torsion and detorsion in rats. J Pediatr Surg 2007;42(10):1740-4. http://www.ncbi.nlm.nih.gov/pubmed/17923206 51. Akcora B, Altug ME, Kontas T, Atik E. The protective effect of darbepoetin alfa on experimental testicular torsion and detorsion injury. Int J Urol 2007;14(9):846-50. http://www.ncbi.nlm.nih.gov/pubmed/17760753 52. Yazihan N, Ataoglu H, Koku N, Erdemli E, Sargin AK. Protective role of erythropoietin during testicular torsion of the rats. World J Urol 2007;25(5):531-6. http://www.ncbi.nlm.nih.gov/pubmed/17690891 53. Unal D, Karatas OF, Savas M, Yeni E, Keser BS, Verit A, Erel O,Bitiren M. Protective effects of trimetazidine on testicular ischemia-reperfusion injury in rats. Urol Int 2007;78(4):356-62. http://www.ncbi.nlm.nih.gov/pubmed/17495496 54. Dokmeci D, Kanter M, Inan M, Aydogdu N, Basaran UN, Yalcin O, Turan FN. Protective effects of ibuprofen on testicular torsion/detorsion-induced ischemia/reperfusion injury in rats. Arch Toxicol 2007;81(9):655-63. http://www.ncbi.nlm.nih.gov/pubmed/17345063 55. Turner TT, Bang HJ, Lysiak JJ. Experimental testicular torsion: reperfusion blood flow and subsequent testicular venous plasma testosterone concentration. Urology 2005;65(2):390-4. http://www.ncbi.nlm.nih.gov/pubmed/15708073 54. Ozkan MH, Vural IM, Moralioglu S, Uma S, Sarioglu Y. Torsion/detorsion of the testis does not modify responses to nitric oxide in rat isolated penile bulb. Basic Clin Pharmacol Toxicol 2007;101(2):117-20. http://www.ncbi.nlm.nih.gov/pubmed/17651313 55. Yerkes EB, Robertson FM, Gitlin J, Kaefer M, Cain M, Rink RC. Management of perinatal torsion: today, tomorrow or never? J Urol 2005;174(4 Pt 2): 1579-83. http://www.ncbi.nlm.nih.gov/pubmed/16148656

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56. Cuervo JL, Grillo A, Vecchiarelli C, Osio C, Prudent L. Perinatal testicular torsion: a unique strategy. J Pediatr Surg 2007;42:699-703. http://www.ncbi.nlm.nih.gov/pubmed/17448769 57. van der Sluijs JW, den Hollander JC, Lequin MH, Nijman RM, Robben SG. Prenatal testicular torsion: diagnosis and natural course. An ultrasonographic study. Eur Radiol 2004;14(2):250-5. http://www.ncbi.nlm.nih.gov/pubmed/12955451 58. Baglaj M, Carachi R. Neonatal bilateral testicular torsion: a plea for emergency exploration. J Urol 2007;177(6):2296-9. http://www.ncbi.nlm.nih.gov/pubmed/17509343 59. Sorensen MD, Galansky SH, Striegl AM, Mevorach R, Koyle MA. Perinatal extravaginal torsion of the testis in the first month of life is a salvageable event. Urology 2003;62(1):132-4. http://www.ncbi.nlm.nih.gov/pubmed/12837441

6. Hypospadias 6.1

Background

Hypospadias can be defined as hypoplasia of the tissues forming the ventral aspect of the penis beyond the division of the corpus spongiosum. Hypospadias are usually classified based on the anatomical location of the proximally displaced urethral orifice: • Distal-anterior hypospadias (located on the glans or distal shaft of the penis and the most common type of hypospadias) • Intermediate-middle (penile) • Proximal-posterior (penoscrotal, scrotal, perineal). The pathology may be much more severe after skin release. 6.1.1 Risk factors Risk factors associated with hypospadias are likely to be genetic, placental and/or environmental (1) (Level of evidence: 2b): • Endocrine disorders can be detected in a very few cases. • Babies of young or old mothers and babies with a low birth weight have a higher risk of hypospadias. • A significant increase in the incidence of hypospadias over the last 20 years suggests a role for environmental factors (hormonal disruptors and pesticides) (2-5). The use of oral contraceptives during pregnancy has not been associated with an increased risk of hypospadias in the offspring (6) (Level of evidence: 2a; Grade of recommendation; B).

6.2

Diagnosis

Patients with hypospadias should be diagnosed at birth (except for the megameatus intact prepuce variant). Diagnosis includes a description of the local findings: • Position, shape and width of the orifice • Presence of atretic urethra and division of corpus spongiosum • Appearance of the preputial hood and scrotum • Size of the penis • Curvature of the penis on erection. The diagnostic evaluation also includes an assessment of associated anomalies, which are: • Cryptorchidism (in up to 10% of cases of hypospadias) • Open processus vaginalis or inguinal hernia (in 9-15%). Severe hypospadias with unilaterally or bilaterally impalpable testis, or with ambiguous genitalia, require a complete genetic and endocrine work-up immediately after birth to exclude intersexuality, especially congenital adrenal hyperplasia. Urine trickling and ballooning of the urethra requires exclusion of meatal stenosis. The incidence of anomalies of the upper urinary tract does not differ from the general population, except in very severe forms of hypospadias (2, 3).

6.3

Treatment

Differentiation between functionally necessary and aesthetically feasible operative procedures is important for therapeutic decision-making. The functional indications for surgery are:

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• Proximally located meatus • Ventrally deflected urinary stream • Meatal stenosis • Curved penis. The cosmetic indications, which are strongly linked to the psychology of the parent or future patient’s psychology, are: • Abnormally located meatus • Cleft glans • Rotated penis with abnormal cutaneous raphe • Preputial hood • Penoscrotal transposition • Split scrotum. As all surgical procedures carry the risk of complications, thorough pre-operative counselling of the parents is crucial. The therapeutic objectives are to correct the penile curvature, to form a neo-urethra of an adequate size, to bring the neomeatus to the tip of the glans, if possible, and to achieve an overall acceptable cosmetic appearance of the boy’s genitalia (2,3) (Level of evidence: 4; Grade of recommendation; C) (Figure 1). The use of magnifying spectacles and special fine synthetic absorbable suture materials (6/0-7/0) is required. As in any penile surgery, an exceptional prudence should be adopted with the use of cautery. Knowledge of a variety of surgical reconstructive techniques, wound care and post-operative treatment are essential for a satisfactory outcome. Pre-operative hormonal treatment with local or parenteral application of testosterone, dihydrotestosterone or beta-chorionic gonadotropin can be helpful in patients with a small penis or for repeat surgery. 6.3.1 Age at surgery The age at surgery for primary hypospadias repair is usually 6-18 (7) months (2) (Level of evidence: 4; Grade of recommendation; C). However, earlier repair between 4 and 6 months of age has been reported recently (Level of evidence: 3; Grade of recommendation; B) (8). 6.3.2 Penile curvature If present, penile curvature is often released by degloving the penis (skin chordee) and by excision of the connective tissue of the genuine chordee on the ventral aspect of the penis. The urethral plate has wellvascularized connective tissue and does not cause curvature in most cases. The residual chordee (curvature) is caused by corporeal disproportion and requires straightening of the penis, mostly using dorsal orthoplasty (modification of Nesbit dorsal corporeal plication) (9) (Level of evidence: 3; Grade of recommendation; B). 6.3.3 Preservation of the well-vascularized urethral plate The mainstay of hypospadias repair is preservation of the well-vascularized urethral plate and its use for urethral reconstruction has become the mainstay of hypospadias repair (10). If the urethral plate is wide, it can be tubularized following the Thiersch-Duplay technique. If the plate is too narrow to be simply tubularized, it is recommended that a midline-relaxing incision of the plate, followed by reconstruction according to the Snodgrass-Orkiszewski technique, is performed in distal hypospadias, as well as in proximal hypospadias (though the complication rate is higher) (7, 11-15). The onlay technique is preferred in proximal hypospadias and in cases of a plate that is unhealthy or too narrow. For distal forms of hypospadias, a range of other techniques is available (e.g. Mathieu, urethral advancement, etc) (12, 16) (Level of evidence: 2b; Grade of recommendation; B). If the continuity of the urethral plate cannot be preserved, a modification of the tubularized flap, such as a tube-onlay or an inlay-onlay flap, is used to prevent urethral stricture (17, 18) (Level of evidence: 3; Grade of recommendation; C). In this situation, as well as in severe scrotal or penoscrotal hypospadias, the Koyanagi technique or two-stage procedure may be an option (19-21). If preputial or penile skin is not available, or has signs of balanitis xerotica obliterans, a buccal mucosa graft is used in an onlay or two-stage repair (22-25) (Level of evidence: 3; Grade of recommendation; C). The use of inlay skin grafts may allow an increased number of single-stage repairs to be performed (26, 27). 6.3.4 Re-do hypospadias repairs For re-do hypospadias repairs, no definitive guidelines can be given. All the above-mentioned procedures are used in different ways and are often modified according to the individual needs of the patient.

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Figure 1: Algorithm for the management of hypospadias Hypospadias

Diagnosis at birth

Intersex

Paediatric urologist

No reconstruction

Reconstruction required

Preparation (foreskin, hormone therapy)

Distal

Proximal

Chordee

Urethral plate cut

TIP, Mathieu, MAGPI, King, advancement, etc.

Tube-onlay, inlay-onlay, Koyanagi, two-stage procedure (local skin, bucal mucosa)

No chordee

Urethral plate preserved

Onlay, TIP, two-stage procedure (local skin, buccal mucosa)

TIP = tubularized incised plate urethroplasty; MAGPI = meatal advancement and granulaplasty. 6.3.5 Urethral reconstruction Following formation of the neo-urethra, the procedure is completed by glansplasty and by reconstruction of the penile skin. If there is a shortage of skin covering, the preputial double-face technique or placement of the suture line into the scrotum may be used. In countries where circumcision is not routinely performed, preputial reconstruction can be considered. However, in the TIP repair, the parents should be advised that use of a preputial dartos flap reduces the fistula rate (11) (Level of evidence: 2; Grade of recommendation: B). 6.3.6 Urine drainage and wound dressing Urine is drained with a transurethral dripping stent, or with a suprapubic tube. Some surgeons use no drainage after distal hypospadias repair. Circular dressing with slight compression, as well as prophylactic antibiotics, are established procedures. A large variety of duration of stenting and dressing is described. No recommendation can be given due to the low level of evidence. 6.3.7 Outcome Adolescents, who have undergone hypospadias repair in childhood, have a slightly higher rate of dissatisfaction with penile size, but their sexual behaviour is not different from that in control subjects (28) (Level of evidence: 2a).

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6.4

References

1. Morera A, Valmalle A, Asensio M, Chossegros L, Chauvin M, Durand P, Mouriquand P. A study of risk factors for hypospadias in the Rhône-Alpes region (France). J Ped Urol 2006;2(3):169-77. http://www.ncbi.nlm.nih.gov/pubmed/18947603 2. Belman AB. Hypospadias and chordee. In: Belman AB, King LR, Kramer SA, eds. Clinical Pediatric Urology. 4th edn. London, Martin Dunitz, 2002, pp. 1061-1092. 3. Mouriquand OD, Mure PY. Hypospadias. In: Gearhart J, Rink R, Mouriquand PDE, eds. Pediatric Urology, Philadelphia, WB Saunders, 2001, pp. 713-728. 4. Wang Z, Liu BC, Lin GT, Lin CS, Lue TF, Willingham E, Baskin LS. Up-regulation of estrogen responsive genes in hypospadias: microarray analysis. J Urol 2007;177(5):1939-46. http://www.ncbi.nlm.nih.gov/pubmed/17437852 5. Weidner IS, Moller H, Jensen TK, Skakkebaek NE. Risk factors for cryptorchidism and hypospadias. J Urol 1999;161(5):1606-9. http://www.ncbi.nlm.nih.gov/pubmed/10210427 6. Wogelius P, Horvath-Puho E, Pedersen L, Norgaard M, Czeizel AE, Sorensen HT. Maternal use of oral contraceptives and risk of hypospadias–a population-based case-control study. Eur J Epidemiol 2006;21(10):777-81. http://www.ncbi.nlm.nih.gov/pubmed/17077991 7. Snodgrass WT, Yucel S. Tubularized incised plate for mid shaft and proximal hypospadias repair. J Urol 2007;177(2):698-702. http://www.ncbi.nlm.nih.gov/pubmed/17222659 8. Perlmutter AE, Morabito R, Tarry WF. Impact of patient age on distal hypospadias repair: a surgical perspective. Urology 2006;68(3):648-51. http://www.ncbi.nlm.nih.gov/pubmed/16979730 9. Baskin LS, Duckett JW, Ueoka K, Seibold J, Snyder HM 3rd. Changing concepts of hypospadias curvature lead to more onlay island flap procedures. J Urol 1994;151(1):191-6. http://www.ncbi.nlm.nih.gov/pubmed/8254812 10. Hollowell JG, Keating MA, Snyder HM 3rd, Duckett JW. Preservation of the urethral plate in hypospadias repair: extended applications and further experience with the onlay island flap urethroplasty. J Urol 1990;143(1): 98-100; discussion 100-1. http://www.ncbi.nlm.nih.gov/pubmed/2294275 11. El-Sherbiny MT, Hafez AT, Dawaba MS, Shorrab AA, Bazeed MA. Comprehensive analysis of tubularized incised-plate urethroplasty in primary and re-operative hypospadias. BJU Int 2004;93(7):1057-61. http://www.ncbi.nlm.nih.gov/pubmed/15142164 12. Germiyanoglu C, Nuhoglu B, Ayyildiz A, Akgul KT. Investigation of factors affecting result of distal hypospadias repair: comparison of two techniques. Urology 2006;68(1):182-5. http://www.ncbi.nlm.nih.gov/pubmed/16806428 13. Orkiszewski M, Leszniewski J. Morphology and urodynamics after longitudinal urethral plate incision in proximal hypospadias repairs: long-term results. Eur J Pediatr Surg 2004;14(1):35-8. http://www.ncbi.nlm.nih.gov/pubmed/15024677 14. Riccabona M, Oswald J, Koen M, Beckers G, Schrey A, Lusuardi L. Comprehensive analysis of six years experience in tubularized incised plate urethroplasty and its extended application in primary and secondary hypospadias repair. Eur Urol 2003;44(6):714-9. http://www.ncbi.nlm.nih.gov/pubmed/14644125 15. Snodgrass W, Koyle M, Manzoni G, Hurwitz R, Caldamone A, Ehrlich R. Tubularized incised plate hypospadias repair: results of a multicenter experience. J Urol 1996;156(2 Pt 2):839-41. http://www.ncbi.nlm.nih.gov/pubmed/8683797 16. Meyer-Junghanel L, Petersen C, Mildenberger H. Experience with repair of 120 hypospadias using Mathieu’s procedure. Eur J Pediatr Surg 1995;5(6):355-7. http://www.ncbi.nlm.nih.gov/pubmed/8773227 17. Kocvara R, Dvoracek J. Inlay-onlay flap urethroplasty for hypospadias and urethral stricture repair. J Urol 1997;158(6):2142-5. http://www.ncbi.nlm.nih.gov/pubmed/9366331 18. Perovic S, Vukadinovic V. Onlay island flap urethroplasty for severe hypospadias: a variant of the technique. J Urol 1994;151(3):711-4. http://www.ncbi.nlm.nih.gov/pubmed/8308994 19. Bracka A. Hypospadias repair: the two-stage alternative. Br J Urol 1995;76 (Suppl 3):31-41. http://www.ncbi.nlm.nih.gov/pubmed/8535768

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20. Hayashi Y,Kojima Y, Mizuno K, Nakane A, Kurokawa S, Maruyama T, Kohri K. Neo-modified Koyanagi technique for the single-stage repair of proximal hypospadias. J Ped Urol 2007;3(3):239-42. http://www.ncbi.nlm.nih.gov/pubmed/18947743 21. Lam P.N., Greenfield S.P., Williot P. 2-stage repair in infancy for severe hypospadias with chordee: long-term results after puberty. J Urol 2005;174(4 Pt 2):1567-72. http://www.ncbi.nlm.nih.gov/pubmed/16148653 22. Ahmed S, Gough DC. Buccal mucosal graft for secondary hypospadias repair and urethral replacement. Br J Urol 1997;80(2):328-30. http://www.ncbi.nlm.nih.gov/pubmed/9284210 23. Amukele SA, Stock JA, Hanna MK. Management and outcome of complex hypospadias repairs. J Urol 2005;174(4 Pt 2):1540-2. http://www.ncbi.nlm.nih.gov/pubmed/16148648 24. Caldamone AA, Edstrom LE, Koyle MA, Rabinowitz R, Hulbert WC. Buccal mucosal grafts for urethral reconstruction. Urology 1998;51(5A Suppl):15-9. http://www.ncbi.nlm.nih.gov/pubmed/9610551 25. Mokhless IA, Kader MA, Fahmy N, Youssef M. The multistage use of buccal mucosa grafts for complex hypospadias: histological changes. J Urol 2007;177(4):1496-9;discussion 1499-500. http://www.ncbi.nlm.nih.gov/pubmed/17382762 26. Asanuma H, Satoh H, Shishido S. Dorsal inlay graft urethroplasty for primary hypospadiac repair. Int J Urol 2007;14(1):43-7. http://www.ncbi.nlm.nih.gov/pubmed/17199859 27. Schwentner C, Gozzi C, Lunacek A, Rehder P, Bartsch G, Oswald J, Radmayr C. Interim outcome of the single stage dorsal inlay skin graft for complex hypospadias reoperations. J Urol 2006;175(5):1872-1876; discussion 1876-7. http://www.ncbi.nlm.nih.gov/pubmed/16600785 28. Moriya K, Kakizaki H, Tanaka H, Furuno T, Higashiyama H, Sano H, Kitta T, Nonomura K. Long-term cosmetic and sexual outcome of hypospadias surgery: norm related study in adolescence. J Urol 2006;176(4 Pt 2):1889-92; discussion 1892-3. http://www.ncbi.nlm.nih.gov/pubmed/16945681

7. Congenital penile curvature 7.1

Background

Penile curvature may be ventral, dorsal or lateral. Most of ventral curvatures are associated with hypospadias due to chordee or ventral dysplasia of cavernous bodies (1). Similarly, the dorsal curvature is mostly associated with epispadias (2). Isolated penile curvature is not frequent with an incidence of 0.6 % (3) (Level of evidence: 2). The curvature is caused by asymmetry of the cavernous bodies (1, 4). Curvature over 30 degrees is considered clinically significant; curvature over 60 degrees may interfere with satisfactory sexual intercourse in adulthood (5) (Level of evidence: 4).

7.2

Diagnosis

Diagnosis is made during hypospadias or epispadias repair using an artificial erection (6). The isolated anomaly is usually not recognized until later in childhood because the appearance of the penis is normal. The curvature is only observed during erections.

7.3

Treatment

The treatment is surgical. An artificial erection is used to determine the degree of curvature and to check the symmetry after the repair (6). In hypospadias, chordee related to the tethering of the ventral skin and to the spongiosal pillars is first released. Only in a few cases the penile curvature is caused by a short urethral plate, which should be cut. To repair the corporeal angulation in the isolated curvature or curvature associated with hypospadias, different techniques of plication of corpora cavernosa (orthoplasty) are used (5). In epispadias, a combination of complete release of the urethral body from the corpora and a different kind of corporoplasty with or without corporotomy is usually necessary to achieve a straight penis (7, 8).

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7.4

REFERENCES

1.

Baskin LS, Duckett JW, Lue TF. Penile curvature. Urology 1996;48(3):347-56. http://www.ncbi.nlm.nih.gov/pubmed/8804484 2. Baka-Jakubiak M. Combined bladder neck, urethral and penile reconstruction in boys with the exstrophy-epispadias complex. BJU Int 2000;86(4):513-8. http://www.ncbi.nlm.nih.gov/pubmed/10971283 3. Yachia D, Beyar M, Aridogan IA, Dascalu S. The incidence of congenital penile curvature. J Uro 1993;150(5 Pt 1):1478-9. http://www.ncbi.nlm.nih.gov/pubmed/8411431 4. Cendron M. Disorders of the penis and scrotum. In: Gearhart JP, Rink RC, Mouriquand PDE, eds. Pediatric urology. Philadelphia: WB Saunders, Philadelphia, 2001, pp. 729-37 5. Ebbehoj J, Metz P. Congenital penile angulation. BJU Int 1987;60(3):264-6. http://www.ncbi.nlm.nih.gov/pubmed/3676675 6. Gittes RF, McLaughlin AP 3rd. Injection technique to induce penile erection. Urology 1974;4(4):473-4. http://www.ncbi.nlm.nih.gov/pubmed/4418594 7. Woodhouse CRJ. The genitalia in exstrophy and epispadias. In: Gearhart JP, Rink RC, Mouriquand PDE, eds. Pediatric urology. Philadelphia: WB Saunders 2001, pp. 557-64. 8. Zaontz MR, Steckler RE, Shortliffe LM, Kogan BA, Baskin L, Tekgul S. Multicenter experience with the Mitchell technique for epispadias repair. J Urol 1998;160(1):172-6. http://www.ncbi.nlm.nih.gov/pubmed/9628644

8. VARICOCELE IN CHILDREN AND ADOLESCENTS 8.1

Background

Varicocele is defined as an abnormal dilatation of testicular veins in the pampiniformis plexus caused by venous reflux. It is unusual in boys under 10 years of age and becomes more frequent at the beginning of puberty. It is found in 15-20% of adolescents, with a similar incidence during adulthood. It appears mostly on the left side (78-93% of cases). Right-sided varicoceles are least common; they are usually noted only when bilateral varicoceles are present and seldom occur as an isolated finding (1, 2). Varicocele develops during accelerated body growth by a mechanism that is not clearly understood. Varicocele can induce apoptotic pathways because of heat stress, androgen deprivation and accumulation of toxic materials. Severe damage is found in 20% of adolescents affected, with abnormal findings in 46% of affected adolescents. Histological findings are similar in children or adolescents and in infertile men. In 70% of patients with grade II and III varicocele, left testicular volume loss was found. However, studies correlating a hypoplastic testicle with poor sperm quality have reported controversial results (3, 4). Several authors reported on reversal of testicular growth after varicocelectomy in adolescents (level of evidence: 2) (5, 6). However, this may partly be attributable to testicular oedema associated with the division of lymphatic vessels (Level of evidence: 2) (7). In about 20% of adolescents with varicocele, fertility problems will arise (8). The adverse influence of varicocele increases with time. Improvement in sperm parameters has been demonstrated after adolescent varicocelectomy (Level of evidence: 1) (3, 9).

8.2

Diagnosis

Varicocele is mostly asymptomatic, rarely causing pain at this age. It may be noticed by the patient or parents, or discovered by the paediatrician at a routine visit. The diagnosis depends upon the clinical finding of a collection of dilated and tortuous veins in the upright posture; the veins are more pronounced when the patient performs the Valsalva manoeuvre. Varicocele is classified into 3 grades: Grade I - Valsalva positive (palpable at Valsalva manoeuvre only); Grade II - palpable (palpable without the Valsalva manoeuvre); Grade III - visible (visible at distance) (10). The size of both testicles should be evaluated during palpation to detect a smaller testis. Venous reflux into the plexus pampiniformis is diagnosed using Doppler colour flow mapping in the supine and upright position (11). Venous reflux detected on ultrasound only is classified as subclinical varicocele. The ultrasound examination includes assessment of the testicular volume to discriminate testicular hypoplasia. In adolescents, a testis that is smaller by more than 2 mL compared to the other testis is considered to be hypoplastic (Level of evidence: 4) (1).

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In order to assess testicular injury in adolescents with varicocele, supranormal follicle-stimulating hormone (FSH) and luteinizing hormone (LH) responses to the luteinizing hormone-releasing hormone (LHRH) stimulation test are considered reliable, as histopathological testicular changes have been found in these patients (9, 12).

8.3

Therapy

Surgical intervention is based on ligation or occlusion of the internal spermatic veins. Ligation is performed at different levels: • inguinal (or subinguinal) microsurgical ligation • suprainguinal ligation, using open or laparoscopic techniques (13-16). The advantage of the former is the lower invasiveness of the procedure, while the advantage of the latter is a considerably lower number of veins to be ligated and safety of the incidental division of the internal spermatic artery at the suprainguinal level. For surgical ligation, some form of optical magnification (microscopic or laparoscopic magnification) should be used because the internal spermatic artery is 0.5 mm in diameter at the level of the internal ring (13-15,17). The recurrence rate is usually less than 10%. Angiographic occlusion is based on retrograde or antegrade sclerotization of the internal spermatic veins (18, 19). Lymphatic-sparing varicocelectomy is preferred to prevent hydrocele formation and testicular hypertrophy development and to achieve a better testicular function according to the LHRH stimulation test (Level of evidence: 2; Grade of recommendation: A) (7, 13, 16, 17, 20). The methods of choice are subinguinal or inguinal microsurgical (microscopic) repairs, or suprainguinal open or laparoscopic lymphatic-sparing repairs. Angiographic occlusion of the internal spermatic veins also meets these requirements. However, although this method is less invasive, it appears to have a higher failure rate (Level of evidence: 2; Grade of recommendation: B) (1, 19). There is no evidence that treatment of varicocele at paediatric age will offer a better andrological outcome than an operation performed later. The recommended indication criteria for varicocelectomy in children and adolescents are (1, 21): • varicocele associated with a small testis • additional testicular condition affecting fertility • bilateral palpable varicocele • pathological sperm quality (in older adolescents) • varicocele associated with a supranormal response to LHRH stimulation test • symptomatic varicocele. Repair of a large varicocele physically or psychologically causing discomfort may be also considered. Other varicoceles should be followed-up until a reliable sperm analysis can be performed (Level of evidence: 4; Grade of recommendation: C).

8.4

REFERENCES

1.

Kogan SJ. The pediatric varicocele. In: Gearhart JP, Rink RC, Mouriquand PDE, eds. Pediatric urology. Philadelphia: WB Saunders, 2001, pp. 763-773. 2. Oster J. Varicocele in children and adolescents. An investigation of the incidence among Danish school children. Scand J Urol Nephrol;1971;5(1):27-32. http://www.ncbi.nlm.nih.gov/pubmed/5093090 3. Laven JS, Haans LC, Mali WP, te Velde ER, Wensing CJ, Eimers JM. Effects of varicocele treatment in adolescents: a randomized study. Fertil Steril 1992;58(4):756-62. http://www.ncbi.nlm.nih.gov/pubmed/1426322 4. Pinto KJ, Kroovand RL, Jarow JP. Varicocele related testicular atrophy and its predictive effect upon fertility. J Urol 1994;152(2 Pt 2):788-90. http://www.ncbi.nlm.nih.gov/pubmed/8022015 5. Kass EJ, Belman AB. Reversal of testicular growth failure by varicocele ligation. J Urol 1987;137(3): 475-6. http://www.ncbi.nlm.nih.gov/pubmed/3820376 6. Paduch DA, Niedzielski J. Repair versus observation in adolescent varicocele: a prospective study. J Urol 1997;158(3 Pt 2):1128-32. http://www.ncbi.nlm.nih.gov/pubmed/9258155 7. Kocvara R, Dolezal J, Hampl R, Povysil C, Dvoracek J, Hill M, Dite Z, Stanek Z, Novak K. Division of lymphatic vessels at varicocelectomy leads to testicular oedema and decline in testicular function according to the LH-RH analogue stimulation test. Eur Urol 2003;43(4):430-5. http://www.ncbi.nlm.nih.gov/pubmed/12667726

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8.

World Health Organization. The influence of varicocele on parameters of fertility in a large group of men presenting to infertility clinics. Fertil Steril 1992;57(6):1289-93. http://www.ncbi.nlm.nih.gov/pubmed/1601152 9. Okuyama A, Nakamura M, Namiki M, Takeyama M, Utsunomiya M, Fujioka H, Itatani H, Matsuda M, Matsumoto K, Sdonoda T. Surgical repair of varicocele at puberty: preventive treatment for fertility improvement. J Urol 1988;139(3):562-4. http://www.ncbi.nlm.nih.gov/pubmed/3343743 10. Dubin L, Amelar RD. Varicocele size and results of varicocelectomy in selected subfertile men with a varicocele. Fertil Steril 1970;21(8):606-9. http://www.ncbi.nlm.nih.gov/pubmed/5433164 11. Tasci AI, Resim S, Caskurlu T, Dincel C, Bayrakter Z, Gurbuz G. Color Doppler ultrasonography and spectral analysis of venous flow in diagnosis of varicocele. Eur Urol 2001;39(3):316-21. http://www.ncbi.nlm.nih.gov/pubmed/11275726 12. Aragona F, Ragazzi R, Pozzan GB, De Caro R, Munari PF, Milani C, Glazel GP. Correlation of testicula volume, histology and LHRH test in adolescents with idiopathic varicocele. Eur Urol 1994;26(1):61-6. http://www.ncbi.nlm.nih.gov/pubmed/7925532%2C7925635 13. Goldstein M, Gilbert BR, Dicker AP, Dwosh J, Gnecco C. Microsurgical inguinal varicocelectomy with delivery of the testis: an artery and lymphatic sparing technique. J Urol 1992;148(6):1808-11. http://www.ncbi.nlm.nih.gov/pubmed/1433614 14. Hopps CV, Lemer ML, Schlegel PN, Goldstein M. Intraoperative varicocele anatomy: a microscopic study of the inguinal versus subinguinal approach. J Urol 2003;170(6 Pt 1):2366-70. http://www.ncbi.nlm.nih.gov/pubmed/14634418 15. Kocvara R, Dvoracek J, Sedlacek J, Dite Z, Novak K. Lymphatic-sparing laparoscopic varicocelectomy: a microsurgical repair. J Urol 2005;173(5):1751-4. http://www.ncbi.nlm.nih.gov/pubmed/15821575 16. Riccabona M, Oswald J, Koen M, Lusuardi L, Radmayr C, Bartsch G. Optimizing the operative treatment of boys with varicocele: sequential comparison of 4 techniques. J Urol 2003;169(2):666-8. http://www.ncbi.nlm.nih.gov/pubmed/12544340 17. Marmar J, Benoff S. New scientific information related to varicoceles. (Editorial). J Urol 2003;170 (6 Pt 1):2371-3. http://www.ncbi.nlm.nih.gov/pubmed/14634419 18. Mazzoni G, Minucci S, Gentile V. Recurrent varicocele: role of antegrade sclerotherapy as first choice treatment. Eur Urol 2002;41(6):614-8; discussion 618. http://www.ncbi.nlm.nih.gov/pubmed/12074778 19. Thon WF, Gall H, Danz B, Bahren W, Sigmund G. Percutaneous sclerotherapy of idiopathic varicocele in childhood: a preliminary report. J Urol 1989;141(4):913-5. http://www.ncbi.nlm.nih.gov/pubmed/2926889 20. Minevich E, Wacksman J, Lewis AG, Sheldon CA. Inguinal microsurgical varicocelectomy in the adolescent: technique and preliminary results. J Urol 1998;159(3):1022-4. http://www.ncbi.nlm.nih.gov/pubmed/9474223 21. Kass EJ, Reitelman C. The adolescent with a varicocele: who needs repair? Probl Urol 1994;8: 507-17.

9. Micropenis 9.1

Background

Micropenis is a small but otherwise normally formed penis with a stretched length of less than 2.5 SD below the mean (1-3). Besides an idiopathic micropenis, two major causes of abnormal hormonal stimulation have been identified: • Hypogonadotropic hypogonadism (due to an inadequate secretion of GnRH) • Hypergonadotropic hypogonadism (due to failure of the testes to produce testosterone).

9.2

Diagnosis

The penis is measured on the dorsal aspect, while stretching the penis, from the pubic symphysis to the tip of the glans (1). The corpora cavernosa are palpated, the scrotum is often small, and the testes may be small and descended. Micropenis should be distinguished from buried and webbed penis, which is usually of normal size.

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The initial evaluation has to define whether the aetiology of the micropenis is central (hypothalamic/ pituitary) or testicular. A paediatric endocrinology work-up has to be carried out immediately. Karyotyping is mandatory in all patients with a micropenis. Endocrine testicular function is assessed (baseline and stimulated testosterone, LH and FSH serum levels). Stimulated hormone levels may also give an idea of the growth potential of the penis. In patients with non-palpable testes and hypogonadotropic hypogonadism, laparoscopy should be carried out to confirm vanishing testes syndrome or intra-abdominal undescended hypoplastic testes. This investigation can be delayed until the age of 1 year (2).

9.3

Treatment

Pituitary or testicular insufficiency are treated by the paediatric endocrinologist. In patients with testicular failure and proven androgen sensitivity, androgen therapy is recommended during childhood and at puberty to stimulate the growth of the penis (Level of evidence: 2; Grade of recommendation: B) (4-7). In the presence of androgen insensitivity, good outcome of sexual function is questioned and gender conversion can be considered (8-10).

9.4

REFERENCES

1.

Feldman KW, Smith DW. Fetal phallic growth and penile standards for newborn male infants. J Pediatr 1975;86(3):395-8. http://www.ncbi.nlm.nih.gov/pubmed/1113226 2. Aaronson IA. Micropenis; medical and surgical implications. J Urol 1994;152:4-14. http://www.ncbi.nlm.nih.gov/pubmed/8201683 3. Gonzales JR. Micropenis. AUA Update Series 1983;2:1. 4. Burstein S, Grumbach MM, Kaplan SL. Early determination of androgen-responsiveness is important in the management of microphallus. Lancet 1979;2(8150):983-6 http://www.ncbi.nlm.nih.gov/pubmed/91775 5. Choi SK, Han SW, Kim DH, de Lignieres B. Transdermal dihydrotestosterone therapy and its effects on patients with microphallus. J Urol 1993;150(2 Pt 2):657-60. http://www.ncbi.nlm.nih.gov/pubmed/8326617 6. Diamond M. Pediatric management of ambiguous and traumatized genitalia. J Urol 1999;162 (3 Pt 2):1021-8. http://www.ncbi.nlm.nih.gov/pubmed/10458424 7. Bin-Abbas B, Conte FA, Grumbach MM, Kaplan SL. Congenital hypogonadotrophic hypogonadism and micropenis: effect of testosterone treatment on adult penile size. Why sex reversal is not indicated. J Pediatr 1999;134(5):579-83. http://www.ncbi.nlm.nih.gov/pubmed/10228293 8. Calikoglu AS. Should boys with micropenis be reared as girls? J Pediatr 1999;134(5):537-8. http://www.ncbi.nlm.nih.gov/pubmed/10228285 9. Reilly JM, Woodhouse CR. Small penis and the male sexual role. J Urol 1989;142(2 Pt 2):569-71. http://www.ncbi.nlm.nih.gov/pubmed/2746779 10. Husmann DA. The androgen insensitive micropenis: long-term follow-up into adulthood. J Pediatr Endocrinol Metab 2004;17(8):1037-41. http://www.ncbi.nlm.nih.gov/pubmed/15379413

10. daytime lower urinary tract conditions 10.1

Background

Following the new terminology document by the ICCS, ‘daytime LUT conditions’ is the new term used to group together functional incontinence problems in children (1). After any possible underlying uropathy or neuropathy has been excluded, a problem of incontinence in children is grouped into the category of ‘daytime LUT conditions’. Night-time wetting is known as ‘enuresis’. Although exact data are unavailable, it is clear that the incidence of daytime LUT conditions is increasing. The changes in toilet training and toilet habits associated with a modern lifestyle have been blamed for the increase in incidence, but with little evidence. Rather, it is that modern life and higher hygiene standards have probably resulted in incontinence problems receiving more attention, so that an increase in prevalence

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could be probably be attributed to an increased awareness. There exists a wide variation in reported prevalence ranging from 2% to 20% (2-6). This wide variation might reflect the variation in definitions used.

10.2

Definition

Daytime LUT conditions are conditions that present with lower urinary tract symptoms (LUTS), including urge, incontinence, weak stream, hesitancy, frequency and urinary tract infections, but without overt uropathy or neuropathy. Normal bladder storage and voiding involves low pressure and adequate bladder volume filling. This is followed by a continuous detrusor contraction, which results in complete bladder emptying, associated with an adequate relaxation of the sphincter complex. Normal urine storage by the bladder and evacuation are controlled by a complex interaction between the spinal cord, brain stem, midbrain and higher cortical structures, associated with a complex integration of sympathetic, parasympathetic and somatic innervations (7). It is understandable that this complex control mechanism is likely to be susceptible to developing different types of dysfunction. Various functional disorders of the detrusor-sphincter complex may occur during the sophisticated early development of normal mechanisms of micturition control. Voiding dysfunction is therefore thought to be the expression of incomplete or delayed maturation of the bladder sphincter complex. Normal daytime control of bladder function matures between 2 and 3 years of age, while nighttime control is normally achieved between 3 and 7 years of age (8). There are two main groups of voiding dysfunction, namely, filling-phase dysfunctions and voiding-phase dysfunctions. 10.2.1 Filling-phase dysfunctions In filling-phase dysfunctions, the detrusor can be overactive, as in overactive bladder (OAB) and urge syndrome, or underactive, as in underactive or highly compliant bladder (formerly known as ‘lazy bladder’). Some children habitually postpone micturition leading to voiding postponement. 10.2.2 Voiding-phase (emptying) dysfunctions In voiding-phase (emptying) dysfunctions, interference with the sphincter and pelvic floor during detrusor contraction is the main dysfunction. The general term for this condition is dysfunctional voiding. Different degrees of dysfunction are described, depending on the strength of interference with the sphincter and pelvic floor. Weak interference results in staccato voiding, while stronger interference results in interrupted voiding and straining, due to an inability to relax during voiding. Bladder sphincter dysfunction is often associated with bowel dysfunction such as obstipation and soiling. Sometimes, secondary anatomical changes are observed, such as trabeculation, diverticulae and vesicoureteral reflux.

10.3

Diagnosis

A non-invasive screening, consisting of history-taking, clinical examination, uroflow, ultrasound and voiding diary, is essential to reach a diagnosis. In the paediatric age group, where the history is taken from both the parents and child together, a structured approach is recommended using a questionnaire. Many signs and symptoms related to voiding and wetting will be unknown to the parents and should be specifically requested, using the questionnaire as a checklist. A voiding diary is mandatory to determine the child’s voiding frequency and voided volumes as well as the child’s drinking habits. History-taking should also include assessment of bowel function. Some dysfunctional voiding scores have recently been developed and validated (9, 10). Upon clinical examination, genital inspection and observation of the lumbosacral spine and the lower extremities is necessary to exclude obvious uropathy and neuropathy. Uroflow with post-void residual evaluates the emptying ability, while an upper urinary tract ultrasound screens for secondary anatomical changes. A voiding diary provides information about storage function and incontinence frequency, while a pad test can help to quantify the urine loss. In the case of resistance to initial treatment, or in the case of former failed treatment, re-evaluation is warranted and further video-urodynamic studies may be considered. Sometimes, there are minor, underlying, urological or neurological problems, which can only be suspected using video-urodynamics. In the case of anatomical problems, such as urethral valve problems, syringocoeles, congenital obstructive posterior urethral membrane (COPUM) or Moormann’s ring, it may be necessary to perform further cystoscopy with treatment. If neuropathic disease is suspected, MRI of the lumbosacral spine and medulla can help to exclude tethered cord, lipoma or other rare conditions. Psychological screening may be useful for children or families with major psychological problems associated with the voiding dysfunction.

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10.4

Treatment

Treatment of voiding dysfunction consists of lower urinary tract rehabilitation, mostly referred to as urotherapy. Urotherapy means non-surgical, non-pharmacological, treatment of lower urinary tract (LUT) function. It is a very broad therapy field, incorporating many treatments used by urotherapists and other healthcare professionals (11). Urotherapy can be divided into standard therapy and specific interventions. 10.4.1 Standard therapy Standard urotherapy is defined as non-surgical, non-pharmacological, treatment for LUT malfunction. It includes the following components: • Information and demystification, which includes explanation about normal LUT function and how a particular child deviates from normal function. • Instruction about what to do about the problem, i.e. regular voiding habits, sound voiding posture, avoiding holding manoeuvres, etc. • Lifestyle advice, regarding fluid intake, prevention of constipation, etc • Registration of symptoms and voiding habits using bladder diaries or frequency-volume charts • Support and encouragement via regular follow-up by the caregiver. A success rate of 80% has been described for urotherapy programmes, independent of the components of the programme. However, the evidence level is low as most studies of urotherapy programmes are retrospective and non-controlled. 10.4.2 Specific interventions As well as urotherapy, there are some specific interventions, including physiotherapy (e.g. pelvic floor exercises), biofeedback, alarm therapy and neurostimulation. Although good results with these treatment modalities have been reported, there have been no randomised controlled treatment trials (RCTs), so that the level of evidence is low (11-15). In some cases, pharmacotherapy may be added. Antispasmodics and anticholinergics have been shown to be effective, though the level of evidence was low. More recently, a few RCTs have been published. One trial on tolterodine showed safety but not efficacy (16), while another RCT on propiverine showed both safety and efficacy (17) (level of evidence: 1) (17). The difference in results is probably due to study design. Despite the low level of evidence for the use of anticholinergics and antimuscarinics, their use is recommended (grade of recommendation: B) because of the large number of studies reporting a positive effect on OAB symptoms. Although alpha-blocking agents are used occasionally, an RCT showed no benefit (18). Botulinum toxin injection seems promising, but can only be used off-label (19).

10.5

REFERENCES

1. Neveus T, von Gontard A, Hoebeke P, Hjälmås K, Bauer S, Bower W, Jørgensen TM, Rittig S, Walle JV, Yeung CK, Djurhuus JC. The standardization of terminology of lower urinary tract function in children and adolescents: report from the Standardisation Committee of the International Children’s Continence Society. J Urol 2006;176(1):314-24. http://www.ncbi.nlm.nih.gov/pubmed/16753432 2. Hellström AL, Hanson E, Hansson S, Hjälmås K, Jodal U. Micturition habits and incontinence in 7-year-old Swedish school entrants. Eur J Pediatr1990;149(6):434-7. http://www.ncbi.nlm.nih.gov/pubmed/2332015 3. Bakker E, van Sprundel M, van der Auwera JC, van Gool JD, Wyndaele JJ. Voiding habits and wetting in a population of 4,332 Belgian schoolchildren aged between 10 and 14 years. Scand J Urol Nephrol 2002;36(5):354-62. http://www.ncbi.nlm.nih.gov/pubmed/12487740 4. Söderstrom U, Hoelcke M, Alenius L, Söderling AC, Hjern A. Urinary and faecal incontinence: a population-based study. Acta Paediatr 2004;93(3):386-9. http://www.ncbi.nlm.nih.gov/pubmed/15124844 5. Sureshkumar P, Jones M, Cumming R, Craig J. A population based study of 2,856 school-age children with urinary incontinence. J Urol 2009;181(2):808-15; discussion 815-6. http://www.ncbi.nlm.nih.gov/pubmed/19110268 6. Sureshkumar P, Craig JC, Roy LP, Knight JF. Daytime urinary incontinence in primary school children: a population-based survey. J Pediatr 2000;137(6):814-8. http://www.ncbi.nlm.nih.gov/pubmed/11113838 7. Franco I. Overactive bladder in children. Part 1: Pathophysiology. J Urol 2007;178(3 Pt 1):761-8; discussion 768. http://www.ncbi.nlm.nih.gov/pubmed/17631323

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8. Hellstrom AL, Hanson E, Hansson S, Hjälmås K, Jodal U. Micturition habits and incontinence in 7-year-old Swedish school entrants. Eur J Pediatr 1990;149(6):434-7. http://www.ncbi.nlm.nih.gov/pubmed/2332015 9. Akbal C, Genc Y, Burgu B, Ozden E, Tekgul S. Dysfunctional voiding and incontinence scoring system: quantitative evaluation of incontinence symptoms in pediatric population. J Urol 2005;173(3):969-73. http://www.ncbi.nlm.nih.gov/pubmed/15711352 10. Farhat W, Bägli DJ, Capolicchio G, O’Reilly S, Merguerian PA, Khoury A, McLorie GA. The dysfunctional voiding scoring system: quantitative standardization of dysfunctional voiding symptoms in children. J Urol 2000;164(3 Pt 2):1011-5. http://www.ncbi.nlm.nih.gov/pubmed/10958730 11. Hellstrom AL. Urotherapy in children with dysfunctional bladder. Scand J Urol Nephrol Suppl 1992;141:106-7. http://www.ncbi.nlm.nih.gov/pubmed/1609245 12. Vijverberg MA, Elzinga-Plomp A, Messer AP, van Gool JD, de Jong TP. Bladder rehabilitation, the effect of a cognitive training programme on urge incontinence. Eur Urol 1997;31(1):68-72. http://www.ncbi.nlm.nih.gov/pubmed/9032538 13. De Paepe H, Hoebeke P, Renson C, Van Laecke E, Raes A, Van Hoecke E, Van Daele J, Vande Walle J. Pelvic-floor therapy in girls with recurrent urinary tract infections and dysfunctional voiding. Br J Urol 1998;81(Suppl 3):109-13. http://www.ncbi.nlm.nih.gov/pubmed/9634033 14. De Paepe H, Renson C, Van Laecke E, Raes A, Vande Walle J, Hoebeke P. Pelvic-floor therapy and toilet training in young children with dysfunctional voiding and obstipation. BJU Int 2000;85(7):889-93. http://www.ncbi.nlm.nih.gov/pubmed/10792172 15. Bower WF, Yeung CK. A review of non-invasive electro neuromodulation as an intervention for nonneurogenic bladder dysfunction in children. Neurourol Urodyn 2004;23(1):63-7. http://www.ncbi.nlm.nih.gov/pubmed/14694460 16. Nijman RJ, Borgstein NG, Ellsworth P, Djurhuus JC. Tolterodine treatment for children with symptoms of urinary urge incontinence suggestive of detrusor overactivity: results from 2 randomized, placebo controlled trials. J Urol 2005;173(4):1334-9. http://www.ncbi.nlm.nih.gov/pubmed/15758796 17. Marschall-Kehrel D, Feustel C, Persson de Geeter C, Stehr M, Radmayr C, Sillén U, Strugala G. Treatment with propiverine in children suffering from nonneurogenic overactive bladder and urinary incontinence: results of a randomized placebo-controlled phase 3 clinical trial. Eur Urol 2008 May 7. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/18502028 18. Kramer SA, Rathbun SR, Elkins D, Karnes RJ, Husmann DA. Double-blind placebo controlled study of alpha-adrenergic receptor antagonists (doxazosin) for treatment of voiding dysfunction in the pediatric population. J Urol 2005;173(6):2121-4; discussion 2124. http://www.ncbi.nlm.nih.gov/pubmed/15879863 19. Hoebeke P, De Caestecker K, Vande Walle J, Dehoorne J, Raes A, Verleyen P, Van Laecke E. The effect of botulinum-A toxin in incontinent children with therapy resistant overactive detrusor. J Urol 2006;176(1):328-30; discussion 330-1. http://www.ncbi.nlm.nih.gov/pubmed/16753434

11. MONOSYMPTOMATIC ENURESIS 11.1

Background

Enuresis is synonymous to intermittent nocturnal incontinence. It is a frequent symptom in children. With a prevalence of 5-10% at 7 years of age, it is one of the most prevalent conditions in childhood. With a spontaneous yearly cure rate of 15%, it is considered relatively benign (1, 2). However, 7 out of 100 children wetting the bed at age 7 will take this condition into adulthood. As it is a stressful condition, which puts a high psychological burden on children resulting in low self-esteem, treatment is advised from the age of 6-7 years onwards. Treatment is unnecessary in younger children in whom spontaneous cure is likely. The child’s mental status, family expectations, social issues and cultural background need to be considered before treatment can be started.

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11.2

Definition

Enuresis is the condition describing the symptom of incontinence during night. Any wetting during sleep above the age of 5 years is enuresis. However, most importantly, there is a single symptom only. Children with other LUT symptoms and enuresis are said to have non-monosymptomatic enuresis. Thorough history-taking, excluding any other daytime symptoms, is mandatory before diagnosing monosymptomatic enuresis. Any associated urinary tract symptoms make the condition a ‘daytime LUT condition’ (3). The condition is described as ‘primary’ when the symptom has always existed and the patient has not been dry for a period longer than 6 months. The condition is described as ‘secondary’, when there has been a symptom-free interval of 6 months. Genetically, enuresis is a complex and heterogeneous disorder. Loci have been described on chromosomes 12, 13 and 22 (3). Three factors play an important pathophysiological role: • high night-time urine output • night-time low bladder capacity or increased detrusor activity • arousal disorder. Due to an imbalance between night-time urine output and night-time bladder capacity, the bladder can become easily full at night and the child will either wake up to empty the bladder or will void during sleep if there is a lack of arousal from sleep (1-3).

11.3

Diagnosis

The diagnosis is obtained by history-taking. In a patient with monosymptomatic enuresis, no further investigations are needed. A voiding diary, which records daytime bladder function and night-time urine output, will help to guide the treatment. An estimate of night-time urine production can be obtained by weighing diapers (nappies) in the morning and adding the volume of the morning void. Measuring the daytime bladder capacity gives an estimate of bladder capacity compared to normal values for age (4). In most children, bedwetting is a familial problem, with most affected children found to have a history of bedwetting within the family.

11.4

Treatment

Before using alarm treatment or medication, simple therapeutic interventions should be considered. 11.4.1 Supportive treatment measures Explaining the condition to the child and his parents helps to demystify the problem. Eating and drinking habits should be reviewed, stressing normal fluid intake during day and reducing fluid intake in the hours before sleep. Keeping a chart depicting wet and dry nights has been shown to be successful. Counselling, provision of information, positive reinforcement and increasing (and supporting) motivation of the child should be introduced first. There is a high level of evidence showing that supportive treatment is more successful than doing nothing, though the cure rate is not significantly high. However, supportive therapy as an initial management carries a high grade of recommendation (4). If supportive measures have no success, further treatment modalities must be considered, of which pharmacological treatment and alarm treatment are the two most important. 11.4.2 Alarm treatment Alarm treatment is the best form of treatment for arousal disorder (level of evidence: 1) (grade of recommendation: A). Initial success rates of 80% with low relapse rates are realistic, especially when nighttime diuresis is not too high and bladder capacity is not too low (5). 11.4.3 Medication In the case of high night-time diuresis, success rates of 70% can be obtained with desmopressin (DDAVP), either as tablets, 200-400 μg or as sublingual desmopressin oral lyophilisate, 120-240 µg. A nasal spray is no longer recommended due to an increased risk of overdosing (6) (level of evidence: 1) (grade of recommendation: A) (7). However, relapse rates are high after DDAVP discontinuation (4). In the case of a small bladder capacity, treatments with antispasmodics or anticholinergics are possible (4). However, when these medications are necessary, the condition is no longer considered to be monosymptomatic. Imipramine, which has been popular in the treatment of enuresis, achieves only a moderate response rate of 50% and has a high relapse rate. Furthermore, cardiotoxicity and death with overdose are described. Its use should therefore be discouraged (level of evidence: 1) (grade of recommendation: C) (8).

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11.5

REFERENCES

1. Lackgren G, Hjalmas K, van Gool J, von Gontard A, de Gennaro M, Lottmann H, Terho P. Nocturnal enuresis: a suggestion for a European treatment strategy. Acta Paediatr 1999;88(6):679-90. http://www.ncbi.nlm.nih.gov/pubmed/10419258 2. Neveus T, von Gontard A, Hoebeke P, Hjälmås K, Bauer S, Bower W, Jørgensen TM, Rittig S, Walle JV, Yeung CK, Djurhuus JC. The standardization of terminology of lower urinary tract function in children and adolescents: report from the Standardisation Committee of the International Children’s Continence Society. J Urol 2006;176(1):314-24. http://www.ncbi.nlm.nih.gov/pubmed/16753432 3. Neveus T, Lackgren G, Tuvemo T, Hetta J, Hjalmas K, Stenberg A. Enuresis–background and treatment. Scand J Urol Nephrol Suppl 2000;206:1-44. http://www.ncbi.nlm.nih.gov/pubmed/11196246 4. Hjalmas K, Arnold T, Bower W, Caione P, Chiozza LM, von Gontard A, Han SW, Husman DA, Kawauchi A, Lackgren G, Lottmann H, Mark S, Rittig S, Robson L, Walle JV, Yeung CK. Nocturnal enuresis: an international evidence based management strategy. J Urol 2004;171(6 Pt 2):2545-61. http://www.ncbi.nlm.nih.gov/pubmed/15118418 5. Glazener CM, Evans JH, Peto RE. Alarm interventions for nocturnal enuresis in children. Cochrane Database Syst Rev 2005;(2):CD002911. http://www.ncbi.nlm.nih.gov/pubmed/15846643 6. Dehoorne JL, Raes AM, van Laecke E, Hoebeke P, Vande Walle JG. Desmopressin toxicity due to prolonged half-life in 18 patients with nocturnal enuresis. J Urol 2006;176(2):754-7; discussion 757-8. http://www.ncbi.nlm.nih.gov/pubmed/16813936 7. Glazener CMA, Evans JH. Desmopressin for nocturnal enuresis. Cochrane Database Syst Rev 2002;(3):CD002112. http://www.ncbi.nlm.nih.gov/pubmed/12137645 8. Glazener CMA, Evans JHC, Peto R.Tricyclic and related drugs for nocturnal enuresis in children. Cochrane Database Syst Rev 2000;(2):CD002117. http://www.ncbi.nlm.nih.gov/pubmed/12917922

12. MANAGEMENT OF NEUROGENIC BLADDER IN CHILDREN 12.1

Background

Neurogenic detrusor-sphincter dysfunction (NDSD) can develop as a result of a lesion at any level in the nervous system. This condition contributes to various forms of lower urinary tract dysfunction, which may lead to incontinence, urinary tract infections (UTIs), vesicoureteral reflux (VUR), and renal scarring. Surgery may be required to establish adequate bladder drainage. If not managed properly, NDSD can potentially cause renal failure, requiring dialysis or transplantation. The management of neurogenic bladder sphincter dysfunction in children has undergone major changes over the years. Although nappies (diapers), permanent catheters, external appliances, Crede’s manoeuvre and various forms of urinary diversion have been acceptable treatment methods, these are now reserved for only a small number of resistant patients. The introduction of clean intermittent catheterisation (IC) has revolutionised the management of children with neurogenic bladder. Not only has it made conservative management a very successful treatment option, but it has also made surgical creation of continent reservoirs a very effective treatment alternative, with a good outcome for quality of life and kidney protection (1-3). Neurogenic bladder in children with myelodysplasia presents with various patterns of detrusor-sphincter dysfunction within a wide range of severity. About 15% of neonates with myelodysplasia have no signs of neurourological dysfunction at birth. However, there is a high chance of progressive changes in the dynamics of neurological lesions with time. Even babies with normal neurourological function at birth have a one in three risk of developing either detrusor sphincter dyssynergia or denervation by the time they reach puberty. At birth, the majority of patients have normal upper urinary tracts, but nearly 60% of them develop upper tract deterioration due to infections, bladder changes and reflux (4-7). As our understanding of urodynamic studies has evolved, it has allowed us to understand the nature and

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severity of problems and manage these patients in a more rational and individualised manner. Despite the remarkable changes of the last quarter of the 20th century, the main goals of treatment have remained the same, i.e. prevention of urinary tract deterioration and achievement of continence at an appropriate age.

12.2

Definition

The most common presentation is at birth with myelodysplasia. The term myelodysplasia includes a group of developmental anomalies that result from defects in neural tube closure. Lesions may include spina bifida occulta, meningocele, lipomyelomeningocele, or myelomeningocele. Myelomeningocele is by far the most common defect seen and the most detrimental. Traumatic and neoplastic spinal lesions of the cord are less frequent in children. Additionally, different growth rates between the vertebral bodies and the elongating spinal cord can introduce a dynamic factor to the lesion. Scar tissue surrounding the cord at the site of meningocele closure can tether the cord during growth. In occult myelodysplasia, the lesions are not overt and often occur with no obvious signs of neurological lesion. In nearly 90% of patients, however, a cutaneous abnormality overlies the lower spine, and this condition can easily be detected by simple inspection of the lower back (8). Total or partial sacral agenesis is a rare congenital anomaly that involves absence of part or all of one or more sacral vertebrae. This anomaly can be part of the caudal regression syndrome, and must be considered in any child presenting with anorectal malformation (ARM). Patients with cerebral palsy may also present with varying degrees of voiding dysfunction, usually in the form of uninhibited bladder contractions (often due to spasticity of the pelvic floor and sphincter complex) and wetting. Bladder sphincter dysfunction is poorly correlated with the type and spinal level of the neurological lesion.

12.3

Classification

The purpose of any classification system is to facilitate the understanding and management of the underlying pathology. There are various systems of classification of neurogenic bladder. Most systems of classification were formulated primarily to describe those types of dysfunction secondary to neurological disease or injury. Such systems are based on the localisation of the neurological lesion and the findings of the neurourological examination. These classifications have been of more value in adults, in whom neurogenic lesions are usually due to trauma and are more readily identifiable. In children, the spinal level and extent of congenital lesion are poorly correlated with the clinical outcome. Urodynamic and functional classifications have therefore been more practical for defining the extent of the pathology and planning treatment in children. The bladder and sphincter are two units working in harmony to make a single functional unit. The initial approach should be to evaluate the state of each unit and define the pattern of bladder dysfunction. According to the nature of the neurological deficit, the bladder and sphincter may be in either an overactive or inactive state: • the bladder may be overactive with increased contractions, and low capacity and compliance, or inactive with no effective contractions • the outlet (urethra and sphincter) may be independently overactive causing functional obstruction, or paralysed with no resistance to urinary flow • these conditions may present in different combinations. This is mainly a classification based on urodynamic findings. The understanding of the pathophysiology of disorders is essential to plan a rational treatment plan for each individual patient. In meningomyelocele, most patients will present with hyper-reflexive detrusor and dyssynergic sphincter, which is a dangerous combination as pressure is built up and the upper tract is threatened.

12.4

Urodynamic studies

Urodynamic studies enable the clinician to observe lower urinary tract function and its deviations from normal. Since the treatment plan mainly depends upon a good understanding of the underlying problem in the lower urinary tract, a well-performed urodynamic study is mandatory in the evaluation of each child with neurogenic bladder. As the bony level often does not correspond with the neurological defect present, and as the effect of the lesion on bladder function cannot be entirely determined by radiographic studies or physical examination,

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the information gained from a urodynamic study is priceless. A urodynamic study also provides the clinician with information about the response of the vesicourethral unit to therapy, as demonstrated by improvement or deterioration in follow-up. It is important to determine several urodynamic parameters, including: • the bladder capacity • the intravesical filling pressure • the intravesical pressure at the moment of urethral leakage • the presence or absence of reflex detrusor activity • the competence of the internal and external sphincteric mechanisms • the degree of coordination of the detrusor and sphincteric mechanisms • the voiding pattern • the post-voiding residual urine volume. 12.4.1 Method of urodynamic study There is very little comparative data evaluating the complexity and invasiveness of urodynamic testing for neurogenic bladders in children. 12.4.2 Uroflowmetry As uroflowmetry is the least invasive of all urodynamic tests, it can be used as an initial screening tool. It provides an objective way of assessing the efficiency of voiding, and, together with an ultrasonographic examination, the residual urine volume can also be determined. Unlike in children with non-neurogenic voiding dysfunction, uroflowmetry will rarely be used as a single investigational tool in children with neurogenic bladders, as it does not provide information for bladder storage, yet it may be very practical to monitor emptying in the follow-up. The main limitation of a urodynamic study is the need for the child to be old enough to follow instructions and void on request. The recording of pelvic floor or abdominal skeletal muscle activity by electromyography (EMG) during uroflowmetry can be used to evaluate coordination between detrusor and the sphincter. As it is a non-invasive test, combined uroflowmetry and EMG may be very useful in evaluating sphincter activity during voiding (9-12) (level of evidence: 3) (grade of recommendation: C). 12.4.3 Cystometry Although moderately invasive and dependent on a cooperative child, cystometry in children provides valuable information regarding detrusor contractility and compliance. The amount of information obtained from each study is related to the degree of interest and care given to the test. It is important to be aware of the alterations in filling and emptying detrusor pressures as the infusion rates change during cystometry. Slow fill cystometry (filling rate < 10 mL/min) is recommended by the International Children’s Continence Society (ICCS) for use in children (13). However, it has been suggested that the infusion rate should be set according to the child’s predicted capacity, based on age and divided by 10 (14). Several clinical studies using conventional artificial fill cystometry to evaluate neurogenic bladder in children have reported that conventional cystometry provides useful information for diagnosis and follow-up of children with neurogenic bladder (15-20). All the studies were retrospective clinical series and lacked comparison with natural fill cystometry, so that the grade of recommendation for an artificial cystometry in children with neurogenic bladder is not high (level of evidence: 4). Additionally, there is evidence suggesting that natural bladder behaviour is altered during regular artificial filling cystometry (21, 22). However, conventional cystometry in infants is useful for predicting future deterioration. Urodynamic parameters, such as low capacity and compliance and high leak-point pressures, are poor prognostic factors for future deterioration. Resolution of reflux is less likely to happen in such bladders (15, 20, 22) (level of evidence: 4). During natural fill cystometry, the bladder is allowed to fill naturally and the bladder and abdominal pressures are recorded using microtransducer catheters. Theoretically, this allows investigation of bladder function in near-physiological conditions. Studies on natural fill cystometry in children report similar results to those of studies done in adults. Natural fill cystometry gives a lower detrusor pressure rise during filling, and lower voided volumes with higher voiding pressures. The incidence of bladder overactivity is higher with natural filling cystometry when compared with conventional artificial filling cystometry (21, 23, 24).

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Although there are only a few studies on natural fill cystometry in children with neurogenic bladder, the results suggest that natural fill cystometry detects new findings compared with diagnoses delivered by conventional cystometry (21) (level of evidence: 3). However, the comparison between natural fill and artificial fill cystometry has not been performed against a gold standard, making it difficult to conclude which study is a true reflection of natural bladder behaviour. Findings in the non-neurogenic adult population have questioned the reliability of natural fill cystometry, as natural fill cystometry has shown a high incidence of bladder overactivity in totally normal asymptomatic volunteers (25). The main disadvantage of natural fill cystometry is that it is labour-intensive and time-consuming. Moreover, because of the transurethral catheter used during this study, false-positive findings caused by the catheter are possible. Especially in children, the recording of events is difficult and there is an increased risk of artefacts, which makes interpretation of the huge amount of data even more difficult. Natural fill cystometry remains a new technique in the paediatric population. More data need to be gathered in a standard way before it can be widely accepted (11).

12.5

Management

The medical care of children with myelodysplasia with a neurogenic bladder requires constant observation and adaptation to new problems. In the first years of life, the kidneys are highly susceptible to back-pressure and infection. During this period, the emphasis is on documenting the pattern of NDSD, and assessing the potential for functional obstruction and VUR. 12.5.1 Investigations An abdominal ultrasound obtained as soon as possible after birth will detect hydronephrosis or other upper genitourinary tract pathology. Following ultrasound, a voiding cystourethrogram should be obtained to evaluate the lower urinary tract. Measurement of residual urine during both ultrasound and cystography should also be done. These studies provide a baseline for the appearance of the upper and lower urinary tracts, can facilitate the diagnosis of hydronephrosis or VUR, and can help identify children at risk for upper genitourinary tract deterioration and impairment of renal function. A urodynamic evaluation can be done after some weeks, and needs to be repeated at regular intervals, in combination with evaluation of the upper tracts (26-28) (level of evidence: 3) (grade of recommendation: B). 12.5.2 Early management with intermittent catheterisation Overwhelming experience gained over the years with early management of neurogenic bladder in infants has led to a consensus that children do not have upper tract deterioration when managed early with IC and anticholinergic medication. IC should be started soon after birth in all babies, especially in those with signs of possible outlet obstruction (26, 29-37) (level of evidence: 2) (grade of recommendation: B). The early initiation of IC in the newborn period makes it easier for parents to master the procedure and for children to accept it as they grow older (38, 39). Early management results in fewer upper tract changes, but also better bladder protection and lower incontinence rates. It has been suggested that increased bladder pressures due to detrusor sphincter dyssynergia cause secondary changes of the bladder wall. These fibroproliferative changes in the bladder wall may cause further loss of elasticity and compliance, resulting in a small non-compliant bladder with progressively elevated pressures. Early institution of IC and anticholinergic drugs may prevent this in some patients (2, 37, 40) (level of evidence: 3). The retrospective evaluation of patients has also shown that significantly fewer augmentations were required in patients with an early start of IC (33, 34) (level of evidence: 4). 12.5.3 Medical therapy At present, oxybutynin, tolterodine, trospium and propiverine are the most frequently used drugs, with oxybutynin being the most studied. Two different forms of tolterodine have been investigated in children with neurogenic bladder. The extended release formulation of tolterodine has been found to be as efficient as the instant release form, with the advantages of being single dosage and less expensive. Although the clinical outcome is encouraging, the level of evidence is low for anticholinergic medication because there are no controlled studies (40, 41-47) (level of

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evidence: 3) (grade of recommendation: B). The use of medication to facilitate emptying in children with neurogenic bladder has not been well studied in the literature. A few studies investigating the use of α-adrenergic blockade in children with neurogenic bladder have reported a good response rate, but the studies lacked controls, and long-term follow-up is warranted (48) (level of evidence: 4) (grade of recommendation: C). 12.5.3.1 Botulinum toxin injections In neurogenic bladders that are refractory to anticholinergics and remain in a small-capacity, high-pressure state, a novel treatment alternative is the injection of botulinum toxin into the detrusor. Initial promising results in adults have initiated its use in children. So far, studies of the clinical effect of botulinum toxin in children have been open trials, and there is a lack of prospective controlled trials. However, the injection of botulinum toxin in therapy-resistant bladders appears to be an effective and safe treatment alternative. This treatment seems to be more effective in bladders with evidenced detrusor overactivity, while noncompliant bladders without obvious detrusor contractions are unlikely to respond to this treatment (49-52). The dosage in children should be determined by body weight and minimum age, with caution with regard to total dose if it is also being used to treat spasticity. Currently, it is unclear how many times this treatment can be repeated, although repetitive treatment has been found to be safe in adults (53-55) (level of evidence: 3) (grade of recommendation: C). In a single study, urethral sphincter botulinum-A toxin injection has been shown to be effective in decreasing urethral resistance and improve voiding. The evidence is still too low to recommend its routine use in decreasing outlet resistance, but it could be considered as an alternative in refractory cases (56). 12.5.4 Management of bowel incontinence Children with neurogenic bladder have disturbances of bowel function as well as urinary function. Bowel incontinence in these children is frequently unpredictable. It is related to the turnover rate of faecal material in the anal area after evacuation, the degree of intactness of sacral cord sensation and motor function, and reflex reactivity of the external anal sphincter (57). Bowel incontinence is managed most commonly with mild laxatives, such as mineral oil, combined with enemas to facilitate removal of bowel contents. A regular and efficient bowel emptying regimen is often necessary to maintain faecal continence, and may have to be started at a very young age. With antegrade or retrograde enemas, most of these children will have decreased constipation problems and may attain some degree of faecal continence (58-62) (level of evidence: 3). Biofeedback training programmes to strengthen the external anal sphincter have not been shown to be more effective than a conventional bowel management programme in achieving faecal continence (63). Electrostimulation of the bowel may also offer a variable improvement in some patients (64) (level of evidence: 3) (grade of recommendation: C). 12.5.5 Urinary tract infection UTIs are common in children with neurogenic bladders. In the absence of reflux, UTIs should be treated symptomatically. There is strong evidence for not prescribing antibiotics to patients who have bacteriuria but no clinical symptoms. Although bacteriuria is seen in more than half of children on clean IC, patients who are asymptomatic do not need treatment (65-67) (level of evidence: 3). Patients with VUR should usually be placed on prophylactic antibiotics to reduce the incidence of pyelonephritis, which can potentially lead to renal damage (68, 69). 12.5.6 Sexuality Sexuality, while not an issue in childhood, becomes progressively more important as the patient gets older. This issue has historically been overlooked in individuals with myelodysplasia. However, patients with myelodysplasia do have sexual encounters. Studies indicate that at least 15-20% of males are capable of fathering children and 70% of females can conceive and carry a pregnancy to term. It is therefore important to counsel patients about sexual development in early adolescence. 12.5.7 Bladder augmentation Children with a good response to anticholinergic treatment and an overactive sphincter may be continent

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between catheterisations. Bladder pressure and development of the upper urinary tract will determine whether additional treatment is necessary. Therapy-resistant overactivity of the detrusor, or small capacity and poor compliance, will usually need to be treated by bladder augmentation. A simple bladder augmentation using intestine may be carried out if there is any bladder tissue, a competent sphincter and/or bladder neck, and a urethra that can be catheterised. Stomach is rarely used as an augmenting patch because of the associated complications (70). Ileal or colonic patches are frequently used for augmenting the bladder, with either intestinal segment appearing to be equally useful. Despite some advantages (e.g. avoiding mucus, decreased malignancy rate and fewer complications), alternative urothelium-preserving techniques, such as autoaugmentation and seromuscular cystoplasty, have not proven to be as successful as standard augmentation with intestine (71, 72). A range of applications of engineered bladder tissues are at different stages of development. There have been a few in pre-clinical trials; recent progress suggests that engineered bladder tissues may have an expanded clinical application in the future (73). 12.5.8 Bladder outlet procedures Children with detrusor overactivity, but with underactive sphincters, will be better for protecting their upper tracts, although they will be severely incontinent. Initial treatment is IC (as it might reduce the degree of incontinence and offers much better control over UTIs) with anticholinergic drugs. At a later age, the outlet resistance will be increased in order to render them continent. No medical treatment available has been validated to increase bladder outlet resistance. Alpha-receptor stimulation of the bladder neck has not been very effective (74-79). When conservative measures fail, surgical procedures need to be considered for maintaining continence. Although a simple augmentation is sufficient for most low-capacity, high-pressure bladders, augmentation with additional bladder outlet procedures is required when both the bladder and outlet are deficient. Bladder outlet procedures include bladder neck reconstruction or other forms of urethral reconstruction. Various procedures can be used on the bladder neck to increase resistance, but all of them may complicate transurethral catheterisation. Augmentation with surgical closure of the bladder neck may be required primarily, or as a secondary procedure in certain rare clinical situations. In this situation, a continent stoma will be required. However, most surgeons prefer to leave the bladder neck and urethra patent as a safety precaution. 12.5.9 Continent stoma Augmentation with an additional continent stoma is utilised primarily after failure of previous bladder outlet surgery. It is also advisable when an inability to catheterise transurethrally is likely. An abdominal wall continent stoma may be particularly beneficial to wheelchair-bound spina bifida patients, who often have difficulty with urethral catheterisation or are dependent on others to catheterise the bladder. For continence with augmentation and an abdominal wall stoma, an adequate bladder outlet mechanism is essential to maintain continence. 12.5.10 Total bladder replacement Total bladder replacement in anticipation of normal voiding in children is very rare, as there are infrequent indications for a total cystectomy, with preservation of the bladder outlet and a competent urethral sphincter. This type of bladder replacement is much more common in adult urological reconstruction. Any type of major bladder and bladder outlet construction should be performed in centres with sufficient experience of the surgical technique, and with experienced healthcare personnel to carry out post-operative follow-up (80-82). 12.5.11 Lifelong follow-up of neurogenic bladder patients Neurogenic bladder patients require lifelong supervision, and the monitoring of renal function is extremely important. Periodic investigation of upper tract changes, renal function and bladder status is mandatory. Repeat urodynamic tests are therefore needed more frequently (every year) in younger children and less frequently in older children. From the urological viewpoint, a repeat urodynamic study is warranted when the patient has a change in symptoms or undergoes any neurosurgical procedure. In the case of any apparent changes in the upper and lower urinary tract, or changes in neurological symptoms, a more detailed examination including urodynamics and spinal magnetic resonance imaging is indicated. Renal failure can progress slowly or occur with startling speed in these children. Patients who have undergone reconstructive procedures using intestine should be regularly followed-up for complications such as infection,

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stone formation, reservoir rupture, metabolic changes, and malignancy (83).

12.6

REFERENCES

1.

Bauer SB. The management of the myelodysplastic child: a paradigm shift. BJU Int 2003;92(Suppl 1):23-8. http://www.ncbi.nlm.nih.gov/pubmed/12969005 2. Retik AB, Perlmutter AD, Gross RE. Cutaneous ureteroileostomy in children. N Eng J Med 1967;277(5):217-22. http://www.ncbi.nlm.nih.gov/pubmed/4226464 3. Lapides J, Diokno AC, Silber SJ, Lowe BS. Clean, intermittent self-catheterization in the treatment of urinary tract disease. 1972. J Urol 2002;167(2 Pt 2):1131-3; discussion 1134. http://www.ncbi.nlm.nih.gov/pubmed/11905887 4. Bauer SB. The management of spina bifida from birth onwards. In: Whitaker RH, Woodard JR, eds. Paediatric urology. London: Butterworths, 1985, pp. 87-112. 5. Bauer SB. Early evaluation and management of children with spina bifida. In: King LR (ed). Urologic surgery in neonates and young infants. Philadelphia: WB Saunders, 1988, pp. 252-264. 6. Wilcock AR, Emery JL. Deformities of the renal tract in children with meningomyelocele and hydrocephalus, compared with those of children showing no such deformities. Br J Urol 1970;42(2):152-7. http://www.ncbi.nlm.nih.gov/pubmed/5420153 7. Hunt GM, Whitaker RH. The pattern of congenital renal anomalies associated with neural-tube defects. Dev Med Child Neurol 1987;29(1):91-5. http://www.ncbi.nlm.nih.gov/pubmed/3556803 8. Pierre-Kahn A, Zerah M, Renier D, Cinalli G, Sainte-Rose C, Lellouch-Tubiana A, Brunelle F, Le Merrer M, Giudicelli Y, Pichon J, Kleinknecht B, Nataf F. Congenital lumbosacral lipomas. Childs Nerv Syst. 1997;13(6):298-334; discussion 335. http://www.ncbi.nlm.nih.gov/pubmed/9272285 9. Aoki H, Adachi M, Banya Y, Sakuma Y, Seo K, Kubo T, Ohori T, Takagane H, Suzuki Y. [Evaluation of neurogenic bladder in patients with spinal cord injury using a CMG.EMG study and CMG.UFM.EMG study.] Hinyokika Kiyo 1985;31(6):937-48. [article in Japanese] http://www.ncbi.nlm.nih.gov/pubmed/4061211 10. Casado JS, Virseda Chamorro M, Leva Vallejo M, Fernandez Lucas C, Aristizabal Agudelo JM, de la Fuente Trabado M. [Urodynamic assessment of the voiding phase in childhood.] Arch Esp Urol 2002;55(2):177-89. [article in Spanish] http://www.ncbi.nlm.nih.gov/pubmed/12014050 11. Wen JG, Yeung CK, Djurhuus JC. Cystometry techniques in female infants and children. Int Urogynecol J Pelvic Floor Dysfunct 2000;11(2):103-12. http://www.ncbi.nlm.nih.gov/pubmed/10805268 12. Bradley CS, Smith KE, Kreder KJ . Urodynamic evaluation of the bladder and pelvic floor. Gastroenterol Clin North Am 2008;37(3):539-52. http://www.ncbi.nlm.nih.gov/pubmed/18793995 13. Norgaard JP, van Gool JD, Hjalmas K, Djurhuus JC, Hellstrom AL. Standardization and definitions in lower urinary tract dysfunction in children. International Children’s Continence Society. Br J Urol 1998;81(Suppl 3):1-16. http://www.ncbi.nlm.nih.gov/pubmed/9634012 14. Bauer SB. Pediatric urodynamics: lower tract. In: O’Donnell B, Koff SA, eds. Pediatric urology. Oxford: Butterworth-Heinemann, 1998, pp. 125-151. 15. Tanikaze S, Sugita Y. [Cystometric examination for neurogenic bladder of neonates and infants.] Hinyokika Kiyo 1991;37(11):1403-5. [article in Japanese] http://www.ncbi.nlm.nih.gov/pubmed/1767767 16. Zoller G, Schoner W, Ringert RH. Pre-and postoperative urodynamic findings in children with tethered spinal cord syndrome. Eur Urol 1991;19(2):139-41. http://www.ncbi.nlm.nih.gov/pubmed/2022217 17. Ghoniem GM, Roach MB, Lewis VH, Harmon EP. The value of leak pressure and bladder compliance in the urodynamic evaluation of meningomyelocele patients. J Urol 1990;144(6):1440-2. http://www.ncbi.nlm.nih.gov/pubmed/2231938 18. Ghoniem GM, Shoukry MS, Hassouna ME. Detrusor properties in myelomeningocele patients: in vitro study. J Urol 1998;159(6):2193-6. http://www.ncbi.nlm.nih.gov/pubmed/9598568

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planning

19.

Palmer LS, Richards I, Kaplan WE. Age related bladder capacity and bladder capacity growth in children with myelomeningocele. J Urol 1997;158:1261-4. http://www.ncbi.nlm.nih.gov/pubmed/9258190 20. Agarwal SK, McLorie GA, Grewal D, Joyner BD, Bagli DJ, Khoury AE. Urodynamic correlates of resolution of reflux in meningomyelocele patients. J Urol 1997;158 (3 Pt 2):580-2. http://www.ncbi.nlm.nih.gov/pubmed/9224367 21. Zermann DH, Lindner H, Huschke T, Schubert J. Diagnostic value of natural fill cystometry in neurogenic bladder in children. Eur Urol 1997;32(2):223-8. http://www.ncbi.nlm.nih.gov/pubmed/9286658 22. Webb RJ, Griffiths CJ, Ramsden PD, Neal DE. Measurement of voiding pressures on ambulatory monitoring: comparison with conventional cystometry. Br J Urol 1990;65(2):152-4. http://www.ncbi.nlm.nih.gov/pubmed/2317646 23. McInerney PD, Vanner TF, Harris SA, Stephenson TP. Ambulatory urodynamics. Br J Urol 1991;67(3):272-4. http://www.ncbi.nlm.nih.gov/pubmed/2021814 24. Yeung CK, Godley ML, Duffy PG, Ransley PG. Natural filling cystometry in infants and children. Br J Urol 1995;75(4):531-7. http://www.ncbi.nlm.nih.gov/pubmed/7788266 25. Swithinbank LV, James M, Shepherd A, Abrams P. Role of ambulatory urodynamic monitoring in clinical urological practice. Neurourol Urodyn 1999;18(3):215-22. http://www.ncbi.nlm.nih.gov/pubmed/10338442 26. McGuire EJ, Woodside JR, Borden TA, Weiss RM. Prognostic value of urodynamic testing in myelodysplastic patients. 1981. J Urol 2002;167(2 Pt 2):1049-53. http://www.ncbi.nlm.nih.gov/pubmed/11905876 27. Sillen U, Hansson E, Hermansson G, Hjalmas, Jacobsson B, Jodal U. Development of the urodynamic pattern in infants with myelomeningocele. Br J Urol 1996;78(4):596-601. http://www.ncbi.nlm.nih.gov/pubmed/8944517 28. Tarcan T, Bauer S, Olmedo E, Khoshbin S, Kelly M, Darbey M. Long-term follow-up of newborns with myelodysplasia and normal urodynamic findings: is follow-up necessary? J Urol 2001;165(2):564-7. http://www.ncbi.nlm.nih.gov/pubmed/11176436 29. Kasabian NG, Bauer SB, Dyro FM, Colodny AH, Mandell J, Retik AB. The prophylactic value of clean intermittent catheterization and anticholinergic medication in newborns and infants with myelodysplasia at risk of developing urinary tract deterioration. Am J Dis Child 1992;146(7):840-3. http://www.ncbi.nlm.nih.gov/pubmed/1496955 30. Wang SC, McGuire EJ, Bloom DA. Urethral dilatation in the management of urological complications of myelodysplasia. J Urol 1989;142(4):1054-5. http://www.ncbi.nlm.nih.gov/pubmed/2795730 31. Lin-Dyken DC, Wolraich ML, Hawtrey CE, Doja MS. Follow-up of clean intermittent catheterization for children with neurogenic bladders. Urology 1992;40(6):525-9. http://www.ncbi.nlm.nih.gov/pubmed/1466106 32. Kaufman AM, Ritchey ML, Roberts AC, Rudy DC, McGuire EJ. Decreased bladder compliance in patients with myelomeningocele treated with radiological observation. J Urol 1996;156(6):2031-3. http://www.ncbi.nlm.nih.gov/pubmed/8965337 33. Wu HY, Baskin LS, Kogan BA. Neurogenic bladder dysfunction due to myelomeningocele: neonatal versus childhood treatment. J Urol 1997;157(6):2295-7. http://www.ncbi.nlm.nih.gov/pubmed/9146656 34. Kaefer M, Pabby A, Kelly M, Darbey M, Bauer SB. Improved bladder function after prophylactic treatment of the high risk neurogenic bladder in newborns with myelomeningocele. J Urol 1999;162 (3 Pt 2):1068-71. http://www.ncbi.nlm.nih.gov/pubmed/10458433 35. van Gool JD, Dik P, de Jong TP. Bladder-sphincter dysfunction in myelomeningocele. Eur J Pediatr 2001;160(7):414-20. http://www.ncbi.nlm.nih.gov/pubmed/11475578 36. Bauer SB. The argument for early assessment and treatment of infants with spina bifida. Dialogues in Pediatric Urology 2000;23:2-3. 37. Park JM. Early reduction of mechanical load of the bladder improves compliance: experimental and clinical observations. Dialogues in Pediatric Urology 2000;23:6-7. 38. Lindehall B, Moller A, Hjalmas K, Jodal U. Long-term intermittent catheterization: the experience of teenagers and young adults with myelomeningocele. J Urol 1994;152(1):187-9. http://www.ncbi.nlm.nih.gov/pubmed/8201663

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39. Joseph DB, Bauer SB, Colodny AH, Mandell J, Retik AB. Clean intermittent catheterization in infants with neurogenic bladder. Pediatrics 1989;84(1):72-82. http://www.ncbi.nlm.nih.gov/pubmed/2740179 40. Baskin LS, Kogan BA, Benard F. Treatment of infants with neurogenic bladder dysfunction using anticholinergic drugs and intermittent catheterization. Br J Urol 1990;66(5):532-4. http://www.ncbi.nlm.nih.gov/pubmed/2249125 41. Connor JP, Betrus G, Fleming P, Perlmutter AD, Reitelman C. Early cystometrograms can predict the response to intravesical instillation of oxybutynin chloride in myelomeningocele patients. J Urol 1994;151(4):1045-7. http://www.ncbi.nlm.nih.gov/pubmed/8126787 42. Goessl C, Knispel HH, Fiedler U, Harle B, Steffen-Wilke K, Miller K. Urodynamic effects of oral oxybutynin chloride in children with myelomeningocele and detrusor hyperreflexia. Urology 1998;51(1):94-8. http://www.ncbi.nlm.nih.gov/pubmed/9457296 43. Haferkamp A, Staehler G, Gerner HJ, Dorsam J. Dosage escalation of intravesical oxybutynin in the treatment of neurogenic bladder patients. Spinal Cord 2000;38(4):250-4. http://www.ncbi.nlm.nih.gov/pubmed/10822396 44. Ferrara P, D’Aleo CM, Tarquini E, Salvatore S, Salvaggio E. Side-effects of oral or intravesical oxybutynin chloride in children with spina bifida. BJU Int 2001;87(7):674-8. http://www.ncbi.nlm.nih.gov/pubmed/11350411 45. Ellsworth PI, Borgstein NG, Nijman RJ, Reddy PP. Use of tolterodine in children with neurogenic detrusor overactivity: relationship between dose and urodynamic response. J Urol. 2005 Oct;174(4Pt2):1647-51. http://www.ncbi.nlm.nih.gov/pubmed/16148673 46. Mahanta K, Medhi B, Kaur B, Narasimhan KL. Comparative efficacy and safety of extended-release and instant-release tolterodine in children with neural tube defects having cystometric abnormalities. J Pediatr Urol 2008;4(2):118-23. http://www.ncbi.nlm.nih.gov/pubmed/18631906 47. Franco I. Overactive bladder in children. Part 2: Management. J Urol 2007;178(3Pt1):769-74; discussion 774. http://www.ncbi.nlm.nih.gov/pubmed/17631332 48. Austin PF, Homsy YL, Masel JL, Cain MP, Casale AJ, Rink RC. Alpha-adrenergic blockade in children with neuropathic and nonneuropathic voiding dysfunction. J Urol 1999;162(3 Pt 2):1064-7. http://www.ncbi.nlm.nih.gov/pubmed/10458432 49. Smith CP, Somogyi GT, Chancellor MB. Emerging role of botulinum toxin in the treatment of neurogenic and non-neurogenic voiding dysfunction. Curr Urol Rep 2002;3(5):382-7. http://www.ncbi.nlm.nih.gov/pubmed/12354347 50. Leippold T, Reitz A, Schurch B. Botulinum toxin as a new therapy option for voiding disorders: current state of the art. Eur Urol 2003;44(2):165-74. http://www.ncbi.nlm.nih.gov/pubmed/12875934 51. Schulte-Baukloh H, Knispel HH, Michael T. Botulinum-A toxin in the treatment of neurogenic bladder in children. Paediatrics 2002;110(2 Pt 1):420-1. http://www.ncbi.nlm.nih.gov/pubmed/12165609 52. Lusuardi L, Nader A, Koen M, Schrey A, Schindler M, Riccabona M. [Minimally invasive, safe treatment of the neurogenic bladder with botulinum-A-toxin in children with myelomeningocele.] Aktuelle Urol 2004;35(1):49-53. [article in German] http://www.ncbi.nlm.nih.gov/pubmed/14997415 53. Hoebeke P, De Caestecker K, Vande Walle J, Dehoorne J, Raes A, Verleyen P,Van Laecke E. The effect of botulinum-A toxin in incontinent children with therapy resistant overactive detrusor. J Urol 2006;176(1):328-30. http://www.ncbi.nlm.nih.gov/pubmed/16753434 54. Kajbafzadeh AM, Moosavi S, Tajik P, Arshadi H, Payabvash S, Salmasi AH, Akbari HR, Nejat F. Intravesical injection of botulinum toxin type A: management of neuropathic bladder and bowel dysfunction in children with myelomeningocele. Urology 2006;68(5):1091-6. http://www.ncbi.nlm.nih.gov/pubmed/17113899 55. Akbar M, Abel R, Seyler TM, Bedke J, Haferkamp A, Gerner HJ, Möhring K. Repeated botulinum-A toxin injections in the treatment of myelodysplastic children and patients with spinal cord injuries with neurogenic bladder dysfunction. BJU Int 2007;100(3):639-45. Erratum in: BJU Int 2007;100(3):719. http://www.ncbi.nlm.nih.gov/pubmed/17532858

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56. Mokhless I, Gaafar S, Fouda K, Shafik M, Assem A. Botulinum A toxin urethral sphincter injection in children with nonneurogenic neurogenic bladder. J Urol. 2006 Oct;176(4Pt2):1767-70). http://www.ncbi.nlm.nih.gov/pubmed/16945643 57. Younoszai MK. Stooling problems in patients with myelomeningocele. South Med J 1992;85(7)8-24. http://www.ncbi.nlm.nih.gov/pubmed/1631686 58. Squire R, Kiely EM, Carr B, Ransley PG, Duffy PG. The clinical application of the Malone antegrade colonic enema. J Pediatr Surg 1993;28(8):1012-5. http://www.ncbi.nlm.nih.gov/pubmed/8229586 59. Whitehead WE, Wald A, Norton NJ. Treatment options for fecal incontinence. Dis Colon Rectum 2001;44(1):131-42 ; discussion 142-4. http://www.ncbi.nlm.nih.gov/pubmed/11805574 60. Krogh K, Kvitzau B, Jorgensen TM, Laurberg S. [Treatment of anal incontinence and constipation with transanal irrigation.] Ugeskr Laeger 1999;161(3):253-6. [article in Danish] http://www.ncbi.nlm.nih.gov/pubmed/10025223 61. Van Savage JG, Yohannes P. Laparoscopic antegrade continence enema in situ appendix procedure for refractory constipation and overflow fecal incontinence in children with spina bifida. J Urol 2000;164(3 Pt 2):1084-7. http://www.ncbi.nlm.nih.gov/pubmed/10958747 62. Aksnes G, Diseth TH, Helseth A, Edwin B, Stange M, Aafos G, Emblem R. Appendicostomy for antegrade enema: effects on somatic and psychosocial functioning in children with myelomeningocele. Pediatrics 2002;109(3):484-9. http://www.ncbi.nlm.nih.gov/pubmed/11875145 63. Loening-Baucke V, Desch L, Wolraich M. Biofeedback training for patients with myelomeningocele and fecal incontinence. Dev Med Child Neurol 1988;30(6):781-90. http://www.ncbi.nlm.nih.gov/pubmed/3234607 64. Marshall DF, Boston VE. Altered bladder and bowel function following cutaneous electrical field stimulation in children with spina bifida–interim results of a randomized double-blind placebocontrolled trial. Eur J Pediatr Surg 1997;7(Suppl 1):41-3. http://www.ncbi.nlm.nih.gov/pubmed/9497117 65. Hansson S, Caugant D, Jodal U, Svanborg-Eden C. Untreated asymptomatic bacteriuria in girls: I Stability of urinary isolates. BMJ 1989;298(6677):853-5. http://www.ncbi.nlm.nih.gov/pubmed/2497822 66. Hansson S, Jodal U, Lincoln K, Svanborg-Eden C. Untreated asymptomatic bacteriuria in girls: II - Effect of phenoxymethylpenicillin and erythromycin given for intercurrent infections. BMJ 1989;298(6677):856-9. http://www.ncbi.nlm.nih.gov/pubmed/2497823 67. Hansson S, Jodal U, Noren L, Bjure J. Untreated bacteriuria in asymptomatic girls with renal scarring. Pediatrics 1989;84(6):964-8. http://www.ncbi.nlm.nih.gov/pubmed/2587151 68. Johnson HW, Anderson JD, Chambers GK, Arnold WJ, Irwin WJ, Brinton JR. A short-term study of nitrofurantoin prophylaxis in children managed with clean intermittent catheterization. Pediatrics 1994;93(5):752-5. http://www.ncbi.nlm.nih.gov/pubmed/8165073 69. Schlager TA, Anderson S, Trudell J, Hendley JO. Nitrofurantoin prophylaxis for bacteriuria and urinary tract infection in children with neurogenic bladder on intermittent catheterization. J Pediatr 1998;132(4):704-8. http://www.ncbi.nlm.nih.gov/pubmed/9580774 70. Nguyen DH, Mitchell ME. Gastric bladder reconstruction. Urol Clin North Am 1991;18(4):649-57. http://www.ncbi.nlm.nih.gov/pubmed/1949398 71. Duel BP, Gonzalez R, Barthold JS. Alternative techniques for augmentation cystoplasty. J Urol 1998;159(3):998-1005. http://www.ncbi.nlm.nih.gov/pubmed/9474216 72. Bandi G, Al-Omar O, McLorie GA. Comparison of traditional enterocystoplasty and seromuscular colocystoplasty lined with urothelium. J Pediatr Urol 2007;3(6):484-9. http://www.ncbi.nlm.nih.gov/pubmed/18947800 73. Atala A, Bauer SB, Soker S, Yoo JJ, Retik AB. Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet 2006;367(9518):1241-6. http://www.ncbi.nlm.nih.gov/pubmed/16631879

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74. Naglo AS. Continence training of children with neurogenic bladder and detrusor hyperactivity: effect of atropine. Scan J Urol Nephrol 1982;16(3):211-5. http://www.ncbi.nlm.nih.gov/pubmed/7163785 75. Austin PF, Westney OL, Leng WW, McGuire EJ, Ritchey ML. Advantages of rectus fascial slings for urinary incontinence in children with neuropathic bladders. J Urol 2001;165(6 Pt 2):2369-71. http://www.ncbi.nlm.nih.gov/pubmed/11398778 76. Guys JM, Fakhro A, Louis-Borrione C, Prost J, Hautier A. Endoscopic treatment of urinary incontinence: long-term evaluation of the results. J Urol 2001;165(6 Pt 2):2389-91. http://www.ncbi.nlm.nih.gov/pubmed/11371983 77. Kassouf W, Capolicchio G, Bernardinucci G, Corcos J. Collagen injection for treatment of urinary incontinence in children. J Urol 2001;165(5):1666-8. http://www.ncbi.nlm.nih.gov/pubmed/11342951 78. Kryger JV, Leverson G, Gonzalez R. Long-term results of artificial urinary sphincters in children are independent of age at implantation. J Urol 2001;165( 6 Pt 2):2377-9. http://www.ncbi.nlm.nih.gov/pubmed/11371981 79. Holmes NM, Kogan BA, Baskin LS. Placement of artificial urinary sphincter in children and simultaneous gastrocystoplasty. J Urol 2001;165(6 Pt 2):2366-8. http://www.ncbi.nlm.nih.gov/pubmed/11371944 80. Mitchell ME, Piser JA. Intestinocystoplasty and total bladder replacement in children and young adults: follow up in 129 cases. J Urol 1987;138(3):579-84. http://www.ncbi.nlm.nih.gov/pubmed/3625861 81. Shekarriz B, Upadhyay J, Demirbilek S, Barthold JS, Gonzalez R. Surgical complications of bladder augmentation: comparison between various enterocystoplasties in 133 patients. Urology 2000;55(1):123-8. http://www.ncbi.nlm.nih.gov/pubmed/10654908 82. Medel R, Ruarte AC, Herrera M, Castera R, Podesta ML. Urinary continence outcome after augmentation ileocystoplasty as a single surgical procedure in patients with myelodysplasia. J Urol 2002;168(4 Pt 2):1849-52. http://www.ncbi.nlm.nih.gov/pubmed/12352374 83 . Metcalfe PD, Rink RC. Bladder augmentation: complications in the pediatric population. Curr Urol Rep. 2007 Mar;8(2):152-6. http://www.ncbi.nlm.nih.gov/pubmed/17303021

13. DILATATION OF THE UPPER URINARY TRACT (URETEROPELVIC JUNCTION AND URETEROVESICAL JUNCTION OBSTRUCTION) 13.1

Background

Dilatation of the upper urinary tract still presents a significant clinical challenge in determining which patient may gain benefit by therapy. Ureteropelvic junction (UPJ) obstruction is defined as impaired urine flow from the pelvis into the proximal ureter with subsequent dilatation of the collecting system and the potential to damage the kidney. It is the most common cause of neonatal hydronephrosis (1). It has an overall incidence of 1:1500 and a ratio of males to females of 2:1 in newborns. Ureterovesical junction (UVJ) obstruction is an obstructive condition of the distal ureter as it enters the bladder, commonly called a primary obstructive megaureter. Megaureters are ranked as second in the differential diagnosis of neonatal hydronephrosis. They occur more often in males and are more likely to occur on the left side (2). Much more difficult is the definition of obstruction. Creating a divide between ‘obstructed’ and ‘nonobstructed’ urinary tracts, as if entities could be as clearly differentiated as ‘black’ and ‘white’, is impossible. Currently, the most popular definition is that obstruction represents any restriction to urinary outflow that, if left untreated, will cause progressive renal deterioration (3).

13.2

Diagnosis

Due to the widespread use of ultrasonography during pregnancy, antenatal hydronephrosis is being detected

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with increasing frequency (4). The challenge in the management of dilated upper urinary tracts is to decide which child can be observed, which one should be managed medically, and which one requires surgical intervention. There is no single definitive test able to distinguish obstructive from non-obstructive cases (Figure 1). 13.2.1 Antenatal ultrasound Usually between the 16th and 18th weeks of pregnancy, the kidneys are visualised routinely, when almost all amniotic fluid consists of urine. The most sensitive time for fetal urinary tract evaluation is the 28th week. If dilatation is detected, ultrasound should focus on the laterality, severity of dilatation, and echogenicity of the kidneys, hydronephrosis or hydro-ureteronephrosis, bladder volume and bladder emptying, sex of the child, and amniotic fluid volume, respectively (5). 13.2.2 Postnatal ultrasound Since transitory neonatal dehydration lasts about 48 hours, imaging should be performed after this period of postnatal oliguria. In severe cases (bilateral dilatation, solitary kidney, oligohydramnios), immediate postnatal sonography is recommended (6). During ultrasound examination, the anteroposterior diameter of the renal pelvis, calyceal dilatation, kidney size, thickness of the parenchyma, cortical echogenicity, ureters, bladder wall and residual urine are assessed. 13.2.3 Voiding cystourethrogram (VCUG) In newborns with identified upper urinary tract dilatation, the presence of primary or important associated factors that must be detected include vesicoureteral reflux in up to 25% of affected children (15), urethral valves, ureteroceles, diverticula and neurogenic bladder. Conventional VCUG is the method of choice for primary diagnostic procedures (7). 13.2.4 Diuretic renography Diuretic renography is the most commonly used diagnostic tool to detect the severity and functional significance of urine transport problems. 99mTc-MAG3 is the radionuclide of choice. It is important to perform the study under standardised circumstances (hydration, transurethral catheter) between the fourth and sixth weeks of life (8). Oral fluid intake is encouraged prior to examination. Fifteen minutes before injection of the radionuclide, it is mandatory to give normal saline intravenous infusion at a rate of 15 ml/kg over 30 minutes and then at a maintenance rate of 4 ml/kg/hour throughout the whole time of the investigation (9). The recommended dose of furosemide is 1 mg/kg for infants during the first year of life, while 0.5 mg/kg should be given to children aged 1 to 16 years up to a maximum dose of 40 mg. Figure 2. Diagnostic algorithm for dilatation of the upper urinary tract

Postnatal ultrasound

Dilatation (uni- or bilateral)

No dilatation

Voiding cystourethrogram (VCUG)*

Repeat ultrasound after 4 weeks

Diuretic renography

* A diagnostic work-up including VCUG has to be discussed with the parents since a possibly detected reflux might have absolutely no clinical impact. On the other hand, a reflux rate of up to 25% in cases of prenatally detected and postnatally confirmed hydronephrosis is reported in the literature (15) and might therefore have some forensic impact as well.

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13.3

Treatment

13.3.1 Prenatal management Counselling the parents is one of the most important aspects of care. The prognosis for an hydronephrotic kidney, even if severely affected, is hopeful. An hydronephrotic kidney may still be capable of providing meaningful renal function, whereas a severely hypoplastic and dysplastic kidney has a hopeless outlook. It is important to explain to the parents the timing and accuracy of establishing the definitive diagnosis for their child. In some cases, there is an obvious indication of severity, including massive bilateral dilatation, bilateral evidence of hypoplastic dysplasia, progressive bilateral dilatation with oligohydramnios, and pulmonary hypoplasia. Intrauterine intervention is rarely indicated and should only be performed in well-experienced centres (10). 13.3.2 UPJ obstruction It is most important to make the decision on the basis of serial investigations, applying the same technique and performed by the same institution under standardised circumstances. Symptomatic obstruction (recurrent flank pain, urinary tract infection) requires surgical correction using a pyeloplasty, according to the standardised open technique of Hynes and Anderson (11). Recently, increasingly more data have become available supporting the use of a laparoscopic or retroperitoneoscopic approach to achieve a dismembered pyeloplasty. In addition, laparoscopic suturing has been improved by the use of robotics (16). However, these methods lack very long-term data and will require time to be fully proven. In asymptomatic cases, conservative follow-up can be the treatment of choice. Indications for surgical intervention are an impaired split renal function (< 40%), a decrease of split renal function of more than 10% in subsequent studies, increased anteroposterior diameter on the ultrasound, and grade III and IV dilatation as defined by the Society for Fetal Urology. 13.4 Megaureter Concerning the treatment options of secondary megaureters (see Chapter 14, reflux and valves). If a functional study reveals and confirms adequate ureteral drainage, conservative management is the best option. Initially, low-dose prophylactic antibiotics within the first year of life are recommended for prevention of urinary tract infections, although there are no prospective randomised trials to evaluate this regimen (12). With spontaneous remission rates of up to 85% in primary megaureter cases, surgical management is no longer recommended, except for megaureters with recurrent urinary tract infections, deterioration of split renal function and significant obstruction (13). The initial approach to the ureter can be either intravesical, extravesical, or combined. Straightening the ureter is necessary without devascularisation. Ureteral tapering should enhance urinary flow into the bladder. The ureter must be tapered to achieve a diameter for an antireflux repair. There are several tailoring techniques, e.g. ureteral imbrication or excisional tapering (14).

13.5

Conclusion

With the use of routine perinatal sonography, hydronephrosis caused by UPJ or UVJ obstruction is now increasingly recognised. Meticulous and repeat postnatal evaluation is mandatory to try to identify any obstructive cases at risk of renal deterioration and requiring surgical reconstruction. Surgical methods are fairly standardised and have a good clinical outcome.

13.6

REFERENCES

1. Lebowitz RL, Griscom NT. Neonatal hydronephrosis: 146 cases. Radiol Clin North Am 1977;15(1): 49-59. http://www.ncbi.nlm.nih.gov/pubmed/139634 2. Brown T, Mandell J, Lebowitz RL. Neonatal hydronephrosis in the era of sonography. Am J Roentgenol 1987;148(5):959-63. http://www.ncbi.nlm.nih.gov/pubmed/3034009 3. Koff SA. Problematic ureteropelvic junction obstruction. J Urol 1987;138(2):390. http://www.ncbi.nlm.nih.gov/pubmed/3599261 4. Gunn TR, Mora JD, Pease P. Antenatal diagnosis of urinary tract abnormalities by ultrasonography after 28 weeks’ gestation: incidence and outcome. Am J Obstet Gynecol 1995;172(2 Pt 1):479-86. http://www.ncbi.nlm.nih.gov/pubmed/7856673 5. Grignon A, Filiatrault D, Homsy Y, Robitaille P, Filion R, Boutin H, Leblond R. Ureteropelvic junction stenosis: antenatal ultrasonographic diagnosis, postnatal investigation, and follow-up. Radiology 1986;160:649-51. http://www.ncbi.nlm.nih.gov/pubmed/3526403

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Flashner SC, King LR. Ureteropelvic junction. In: Clinical Pediatric Urology. Philadelphia: WB Saunders, 1976, p. 693. 7. Ebel KD. Uroradiology in the fetus and newborn: diagnosis and follow-up of congenital obstruction of the urinary tract. Pediatr Radiol 1998;28(8):630-5. http://www.ncbi.nlm.nih.gov/pubmed/9716640 8. O’Reilly P, Aurell M, Britton K, Kletter K, Rosenthal L, Testa T. Consensus on diuresis renography for investigating the dilated upper urinary tract. Radionuclides in Nephrourology Group. Consensus Committee on Diuresis Renography. J Nucl Med 1996;37(11):1872-6. http://www.ncbi.nlm.nih.gov/pubmed/8917195 9. Choong KK, Gruenewald SM, Hodson EM, Antico VF, Farlow DC, Cohen RC. Volume expanded diuretic renography in the postnatal assessment of suspected uretero-pelvic junction obstruction. J Nucl Med 1992;33:2094-8. http://www.ncbi.nlm.nih.gov/pubmed/1460498 10. Reddy PP, Mandell J. Prenatal diagnosis. Therapeutic implications. Urol Clin North Am 1998;25(2):171-80. http://www.ncbi.nlm.nih.gov/pubmed/9633572 11. Novick AC, Streem AB. Surgery of the kidney. In: Walsh PC, Retik AB, Vaughan ED, Wein AJ (eds). Campbell’s Urology. Philadelphia: WB Saunders, 1998, p. 3044. 12. Arena F, Baldari S, Proietto F, Centorrino A, Scalfari G, Romeo G. Conservative treatment in primary neonatal megaureter. Eur J Pediatr Surg 1998;8(6):347-351. http://www.ncbi.nlm.nih.gov/pubmed/9926303 13. Peters CA, Mandell J, Lebowitz RL, Colodny AH, Bauer SB, Hendren WH, Retik AB. Congenital obstructed megaureters in early infancy: diagnosis and treatment. J Urol 1989;142(2 Pt 2):641-5. http://www.ncbi.nlm.nih.gov/pubmed/2746792 14. Sripathi V, King PA, Thomson MR, Bogle MS. Primary obstructive megaureter. J Pediatr Surg 1991;26(7):826-9. http://www.ncbi.nlm.nih.gov/pubmed/1895193 15. Thomas DF. Prenatally detected uropathy: epidemiological considerations. Br J Urol 1998;81(Suppl 2):8-12. http://www.ncbi.nlm.nih.gov/pubmed/9602790 16. Olsen LH, Rawashdeh YF, Jorgensen TM. Pediatric robot assisted retroperitoneoscopic pyeloplasty: a 5-year experience. J Urol 2007;178(5):2137-41. http://www.ncbi.nlm.nih.gov/pubmed/17870122 6.

14. Vesicoureteric reflux (VUR) 14.1

Background

Vesicoureteric reflux (VUR) is a very common urological anomaly in children and is probably one of the most controversial issues in paediatrics (1). Vesicoureteric reflux is defined as the non-physiological back-flow of urine from the urinary bladder into the ureter or the renal pelvis and the calyces. While primary VUR is a congenital anomaly of the ureterovesical junction with a genetic basis (2), secondary reflux is caused by an anatomical or functional bladder outflow obstruction and subsequently elevated pressures or inflammatory diseases. Primary VUR can be associated with other morphological and/or functional abnormalities of the lower urinary tract. About 1-2% of all children have VUR, while VUR occurs in 25-40% of children with acute pyelonephritis (1). In newborns, the incidence of reflux is higher in boys than in girls, but in later life, girls are approximately 4-6 times more frequently affected than boys. The incidence of prenatally diagnosed hydronephrosis caused by VUR ranges from 17-37% (3, 4). About 30-50% of children with symptomatic VUR have radiological evidence of renal scarring, resulting from congenital dysplasia and/or acquired postinfectious damage. Intrarenal reflux of infected urine appears to be primarily responsible for the renal damage. Reflux nephropathy (RN) may be the most common cause of childhood hypertension. Followup studies show that about 10-20% of children with RN develop hypertension or end-stage renal disease (5). Older studies have consistently attributed 15-30% of chronic renal failure in children and young adults to chronic pyelonephritis and RN (6). However, an awareness of VUR-related morbidity has led to more widespread diagnosis and treatment, which appears to have resulted in a decrease in the number of affected patients with RN. The diagnosis and treatment of VUR has therefore altered the epidemiology of hypertension and renal failure in children and young adults. In a recent series of renal transplant populations, approximately

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2-3% of cases were related to chronic pyelonephritis (7). Twin and family studies have revealed that VUR has a genetic basis (2). Siblings of patients with known reflux have an approximately 30% prevalence of reflux, with younger siblings being at greatest risk. Offspring of parents with reflux have an almost 70% risk of developing reflux. Since siblings and offspring of sufferers are mostly asymptomatic, it is advised that they should be routinely screened for reflux (8, 9). The management of affected children has been directed at preventing infection and permanent renal parenchymal damage and its late complications by antibiotic prophylaxis and/or surgical correction of reflux. However, controversy remains regarding the optimal strategies for management of children with primary VUR (10-12).

14.2

Classification

In 1985, the International Reflux Study Committee introduced a uniform system for the classification of VUR (13) (Table 1). The grading system combines two earlier classifications and is based upon the extent of retrograde filling and dilatation of the ureter, the renal pelvis and the calyces on a VCUG. The Committee also described a standardized technique of VCUG to allow comparability of results. Table 1: Grading system for vesicoureteric reflux, according to the International Reflux Study Committee (13) Grade I Reflux does not reach the renal pelvis; varying degrees of ureteral dilatation Grade II Reflux reaches the renal pelvis; no dilatation of the collecting system; normal fornices Grade III Mild or moderate dilatation of the ureter, with or without kinking; moderate dilatation of the collecting system; normal or minimally deformed fornices Grade IV Moderate dilatation of the ureter with or without kinking; moderate dilatation of the collecting system; blunt fornices, but impressions of the papillae still visible Grade V Gross dilatation and kinking of the ureter, marked dilatation of the collecting system; papillary impressions no longer visible; intraparenchymal reflux

14.3

Diagnostic work-up

A basic diagnostic work-up comprises a detailed medical history (including family history), physical examination, urinalysis, urine culture and, if renal function needs to be assessed, serum creatinine level. Diagnostic imaging for VUR encompasses both radiological and sonographic modalities (14). Radiological modalities comprise VCUG, the most widespread method for examination of reflux, and radionuclide cystography (RNC). In RNC, radiation exposure is significantly lower than in VCUG with continuous fluoroscopy, but the anatomical details depicted are much more inferior. With the introduction of pulsed fluoroscopy, the radiation exposure of VCUG could be markedly reduced. The use of VCUG allows the grade of reflux to be determined (in a single or duplicated kidney) and the assessment of bladder and ureteral configuration. Moreover, VCUG is the study of choice for imaging the urethra. The sonographic diagnosis of VUR with intravesical administration of an ultrasound (US) contrast agent (voiding urosonography [VUS]) is mostly used as the primary reflux examination modality in girls and during follow-up. In complex cases, magnetic resonance urography may be required for evaluation of the upper urinary tract. Dimercaptosuccinic acid (DMSA) is the best nuclear agent for visualizing cortical tissue, evaluating renal parenchyma, and documenting the presence of renal scars. Children with normal DMSA during an acute UTI have a low risk of renal damage. Children with normal follow-up DMSA and low-grade VUR have more frequent spontaneous resolution of VUR (15). In the case of incontinence or residual urine, urodynamic studies can be performed to reveal functional abnormalities of the lower urinary tract. Such testing is most important in patients in whom secondary reflux is suspected, such as patients with spina bifida or boys whose VCUG is suggestive of residual posterior urethral valves. Yet, in most cases of non-neurogenic voiding dysfunction, diagnosis and follow-up can be limited to non-invasive tests (voiding charts, US, uroflowmetry). In the few remaining children with inconclusive findings and who are refractory to treatment, urodynamic tests are necessary. Appropriate management of voiding dysfunction will often result in the resolution of reflux (16). In the past, cystoscopy was considered to be essential for the assessment of VUR. The position and shape of the ureteral orifices were thought to correlate with the grade and prognosis. Subsequent data have demonstrated that cystoscopic observations do not contribute significantly to the outcome of management (17). Cystoscopy may be performed at the time of open surgery to identify additional anatomical abnormalities, such as ureteral duplication and ureteral ectopia.

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14.4

Treatment

Early diagnosis and vigilant monitoring are the cornerstones of treatment (Table 2). The ultimate objective of treatment is to allow normal renal growth and to prevent permanent renal parenchymal damage and its late complications (reflux nephropathy, see above). There is no single therapeutic strategy for all clinical settings of VUR. Therapeutic options comprise conservative (medical) management, including antibiotic prophylaxis, and interventional approaches (i.e. endoscopic subureteral injection, laparoscopic or open surgical correction of reflux), in isolation or combined. The individual choice of management is based on the presence of renal scars, the clinical course, grade of reflux, ipsilateral renal function, bilaterality, bladder capacity and function, associated anomalies of the urinary tract, age, compliance and parental preference. Surgical correction is warranted in recurrent febrile infections despite antibiotic prophylaxis (breakthrough infections), medical non-compliance, and new scars and in the presence of associated malformations (e.g. duplex systems, Hutch diverticulum, ectopic ureter). In secondary VUR, the objective of management is treatment of the underlying condition. If VUR persists after successful therapy of the underlying condition, further management depends on the individual clinical setting. Table 2: Treatment of reflux Patient’s age Grade of reflux/Gender Management < 1 year Conservative 1-5 year (s) Grade I-III Conservative Grade IV-V Surgical correction > 5 years Boys Indication for surgery is rare Girls Surgical correction

14.4.1 Conservative approach The rationale for conservative management is the observation that VUR can resolve spontaneously with time, mostly in young patients with low-grade reflux (81% and 48% in VUR grades I-II and III-V, respectively) (18,19). The objective of conservative therapy is prevention of febrile UTI. Education and consistent follow-up of the patient and parent, high fluid intake, regular and complete emptying of the bladder (if necessary with double micturition) and low-dose antibiotic prophylaxis are key aspects of conservative management. In boys with low-grade VUR, circumcision may be advised. Conservative management should be dismissed in favour of surgical intervention in all cases of febrile breakthrough infections, as well as in girls in whom VUR has persisted up to an age at which spontaneous resolution can no longer be expected. In boys 5 years and older antibiotic prophylaxis may be stopped, and indications for surgical reflux correction are rare. 14.4.2 Interventional therapy 14.4.2.1 Open surgery Various intra- and extra-vesical techniques have been described for the surgical correction of reflux. Although different methods have specific advantages and complications, they all share the basic principle of lengthening the intramural part of the ureter by submucosal embedding of the ureter. All techniques have been shown to be safe with a low rate of complications and excellent success rates (92-98%). Currently, the most popular procedures are the Lich-Gregoir, Politano-Leadbetter, Cohen and Psoas-Hitch ureteroneocystostomy (20, 21). Surgery in early infancy carries a high risk of severely damaging bladder function. If an extravesical procedure is planned, cystoscopy should be performed preoperatively to assess the bladder mucosa and position and configuration of the ureteric orifices. In bilateral reflux, intravesical antireflux procedures may be considered, as simultaneous bilateral extravesical reflux repair carries an increased risk of temporary postoperative urine retention (22). 14.4.2.2 Laparoscopic reflux correction In a small number of children, VUR has been corrected laparoscopically. Although success rates are similar to open surgery, laparoscopic reflux correction takes significantly longer and therefore has no obvious advantages (23). At present, a laparoscopic approach cannot be recommended as a routine procedure (24). 14.4.2.3 Endoscopic therapy Although still mainly experimental, endoscopic treatment of VUR offers the advantage of enabling treatment

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of the underlying anatomical defect while avoiding the morbidity of open surgery (25). With the availability of biodegradable substances, endoscopic subureteral injection of tissue-augmenting substances (bulking agents) have become an alternative to long-term antibiotic prophylaxis and surgical intervention in the treatment of VUR in children (26). Although there is not yet a prospective trial proving that endoscopic therapy is equally effective as the conservative management, endoscopic therapy is currently being used as the initial treatment of reflux in some centres. A sound clinical validation of its effectiveness is currently hampered by the lack of methodologically appropriate studies. In a recent meta-analysis (27), including 5,527 patients and 8,101 renal units, the reflux resolution rate (by ureter) following one treatment for grades I and II reflux was 78.5%, grade III 72%, grade IV 63% and grade V 51%. If the first injection was unsuccessful, the second treatment had a success rate of 68%, and the third treatment 34%. The aggregate success rate with one or more injections was 85%. The success rate was significantly lower for duplicated (50%) versus single systems (73%), and neuropathic (62%) versus normal bladders (74%).

14.5

Follow-up

Follow-up after surgical correction of VUR is a controversial issue. In a recent update of the International Reflux Study, the authors published the results of urography at 10 years after either medical or surgical treatment of VUR. They concluded that with careful management, only a small proportion of children with severe reflux developed new scars and then rarely after the first 5-year follow-up period, and that there was no difference between children treated medically or surgically (28). Routine radionuclide studies are therefore not recommended. As post-operative VCUG does not allow identification of children at risk of developing febrile UTI, this investigation is optional. Although VCUG may not be necessary in clinically asymptomatic cases after open surgery (29), it is mandatory following endoscopic treatment. Obstruction of the upper urinary tract is ruled out by sonography at discharge and 3 months postoperatively. The follow-up protocol should include blood pressure measurement and urinalysis.

14.6

REFERENCES

1.

Fanos V, Cataldi L. Antibiotics or surgery for vesicoureteric reflux in children. Lancet 2004;364(9446): 1720-2. http://www.ncbi.nlm.nih.gov/pubmed/15530633 2. Murawski IJ, Gupta IR. Vesicoureteric reflux and renal malformations: a developmental problem. Clin Genet 2006;69(2):105-17. http://www.ncbi.nlm.nih.gov/pubmed/16433689 3. Anderson NG, Wright S, Abbott GD, Wells JE, Mogridge N. Fetal renal pelvic dilatation - poor predictor of familial vesicoureteric reflux. Pediatr Nephrol 2003;18(9):902-5. http://www.ncbi.nlm.nih.gov/pubmed/12883970 4. Phan V, Traubici J, Hershenfield B, Stephens D, Rosenblum ND, Geary DF. Vesicoureteral reflux in infants with isolated antenatal hydronephrosis. Pediatr Nephrol 2003;18(12):1224-8. http://www.ncbi.nlm.nih.gov/pubmed/14586679 5. Blumenthal I. Vesicoureteric reflux and urinary tract infection in children. Postgrad Med J 2006;82(963):31-5. http://www.ncbi.nlm.nih.gov/pubmed/16397077 6. Ardissino G, Avolio L, Dacco V, Testa S, Marra G, Vigano S, Loi S, Caione P, De Castro R, De Pascale S, Marras E, Riccipetitoni G, Selvaggio G, Pedotti P, Claris-Appiani A, Ciofani A, Dello Strologo L, Lama G, Montini G, Verrina E; ItalKid Project. Long-term outcome of vesicoureteral reflux associated chronic renal failure in children. Data from the ItalKid Project. J Urol 2004;172(1):305-10. http://www.ncbi.nlm.nih.gov/pubmed/15201801 7. Vallee JP, Vallee MP, Greenfield SP, Wan J, Springate J. Contemporary incidence of morbidity related to vesicoureteral reflux. Urology 1999;53(4):812-5. http://www.ncbi.nlm.nih.gov/pubmed/10197863 8. Hollowell JG, Greenfield SP. Screening siblings for vesicoureteral reflux. J Urol 2002;168(5):2138-41. http://www.ncbi.nlm.nih.gov/pubmed/12394743 9. Giel DW, Noe HN, Williams MA. Ultrasound screening of asymptomatic siblings of children with vesicoureteral reflux: a long-term followup study. J Urol 2005;174(4 Pt 2):1602-4. http://www.ncbi.nlm.nih.gov/pubmed/16148662 10. Elder JS, Peters CA, Arant BS Jr, Ewalt DH, Hawtrey CE, Hurwitz RS, Parrott TS, Snyder HM 3rd, Weiss RA, Woolf SH, Hasselblad V. Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux in children. J Urol 1997;157(5):1846-51. http://www.ncbi.nlm.nih.gov/pubmed/9112544

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11. Smellie JM, Barratt TM, Chantler C, Gordon I, Prescod NP, Ransley PG, Woolf AS. Medical versus surgical treatment in children with severe bilateral vesicoureteric reflux and bilateral nephropathy: a randomised trial. Lancet 2001;357(9265):1329-33. http://www.ncbi.nlm.nih.gov/pubmed/11343739 12. Wheeler DM, Vimalachandra D, Hodson EM, Roy LP, Smith GH, Craig JC. Interventions for primary vesicoureteric reflux. Cochrane Database Syst Rev 2004; (3):CD001532. http://www.ncbi.nlm.nih.gov/pubmed/15266449 13. Lebowitz RL, Olbing H, Parkkulainen KV, Smellie JM, Tamminen-Mobius TE. International Reflux Study in Children: international system of radiographic grading of vesicoureteric reflux. Pediatr Radiol 1985;15(2):105-9. http://www.ncbi.nlm.nih.gov/pubmed/3975102 14. Darge K, Riedmiller H. Current status of vesicoureteral reflux diagnosis. World J Urol 2004;22:88-95. http://www.ncbi.nlm.nih.gov/pubmed/15173954 15. Camacho V, Estorch M, Fraga G, Mena E, Fuertes J, Hernandez MA, Flotats A, Carrio I. DMSA study performed during febrile urinary tract infection: a predictor of patient outcome? Eur J Nucl Med Mol Imaging 2004;31(6):862-6. http://www.ncbi.nlm.nih.gov/pubmed/14758509 16. Koff SA, Wagner TT, Jayanthi VR. The relationship among dysfunctional elimination syndromes, primary vesicoureteral reflux and urinary tract infections in children. J Urol 1998;160(3 Pt 2):1019-22. http://www.ncbi.nlm.nih.gov/pubmed/9719268 17. Elder JS. Guidelines for consideration for surgical repair of vesicoureteric reflux. Curr Opin Urol 2000;10(6):579-85. http://www.ncbi.nlm.nih.gov/pubmed/11148729 18. Arant BS Jr. Medical management of mild and moderate vesicoureteral reflux: followup studies of infants and young children. A preliminary report of the Southwest Pediatric Nephrology Study Group. J Urol 1992;148(5 Pt 2):1683-7. http://www.ncbi.nlm.nih.gov/pubmed/1433588 19. Smellie JM, Jodal U, Lax H, Mobius TT, Hirche H, Olbing H; Writing Committee, International Reflux Study in Children (European Branch). Outcome at 10 years of severe vesicoureteric reflux managed medically: report of the International Reflux Study in Children. J Pediatr 2001;139:656-63. http://www.ncbi.nlm.nih.gov/pubmed/11713442 20. Austin JC, Cooper CS. Vesicoureteral reflux: surgical approaches. Urol Clin North Am 2004;31(3): 543-57. http://www.ncbi.nlm.nih.gov/pubmed/15313064 21. Heidenreich A, Ozgur E, Becker T, Haupt G. Surgical management of vesicoureteral reflux in pediatric patients. World J Urol 2004;22(2):96-106. http://www.ncbi.nlm.nih.gov/pubmed/15221260 22. Lipski BA, Mitchell ME, Burns MW. Voiding dysfunction after bilateral extravesical ureteral reimplantation. J Urol 1998;159(3):1019-21. http://www.ncbi.nlm.nih.gov/pubmed/9474222 23. Janetschek G, Radmayr C, Bartsch G. Laparoscopic ureteral anti-reflux plasty reimplantation. First clinical experience. Ann Urol (Paris) 1995;29:101-5. http://www.ncbi.nlm.nih.gov/pubmed/7645993 24. El-Ghoneimi A. Paediatric laparoscopic surgery. Curr Opin Urol 2003;13(4):329-35. http://www.ncbi.nlm.nih.gov/pubmed/12811298 25. Chertin B, Puri P. Endoscopic management of vesicoureteral reflux: does it stand the test of time? Eur Urol 2002;42(6):598-606. http://www.ncbi.nlm.nih.gov/pubmed/12477657 26. Lightner DJ. Review of the available urethral bulking agents. Curr Opin Urol 2002;12:333-8. http://www.ncbi.nlm.nih.gov/pubmed/12072655 27. Elder JS, Diaz M, Caldamone AA, Cendron M, Greenfield S, Hurwitz R, Kirsch A,Koyle MA, Pope J, Shapiro E. Endoscopic therapy for vesicoureteral reflux: a meta-analysis. I. Reflux resolution and urinary tract infection. J Urol 2006;175(2):716-22. http://www.ncbi.nlm.nih.gov/pubmed/16407037 28. Olbing H, Smellie JM, Jodal U, Lax H. New renal scars in children with severe VUR: a 10-year study of randomized treatment. Pediatr Nephrol 2003(11);18:1128-31. http://www.ncbi.nlm.nih.gov/pubmed/14523634

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29.

Barrieras D, Lapointe S, Reddy PP, Williot P, McLorie GA, Bigli D, Khoury AE, Merguerian PA. Are postoperative studies justified after extravesical ureteral reimplantation? J Urol 2000;164(3 Pt 2): 1064-6. http://www.ncbi.nlm.nih.gov/pubmed/10958758

15. URINARY STONE DISEASE 15.1

Background

Paediatric stone disease is an important clinical problem in paediatric urology practice. Because of its recurrent nature, every effort should be made to discover the underlying metabolic abnormality so that it can be treated appropriately. Obtaining a stone-free state with interventional management and close follow-up are of utmost importance. Paediatric stone disease has its own unique features, which are different in both presentation and treatment compared to stone disease in adults. In contrast to adults with stone disease who are more likely to be male, boys and girls are affected almost equally. Most paediatric stones are located in the upper urinary tract. However, bladder stones are still common in underdeveloped areas of the world and are usually ammonium acid urate and uric acid stones, strongly implicating dietary factors (1). The incidence and characteristics of stones show a wide geographical variation in children. Although urinary stone disease is generally considered to be a relatively rare disease, it is quite common in some parts of the world. Paediatric stone disease is endemic in Turkey, Pakistan and in some South Asian, African and South American states. In the UK and other European countries, 75% of calculi in children are composed of organic matrix and struvite, with many coinciding with Proteus infection and urinary tract anomalies (2).

15.2

Stone formation mechanisms, diagnosis of causative factors and medical treatment for specific stone types

Urinary stone formation is the result of a complex process involving metabolic, anatomical factors and presence of infection. When supersaturated in urine calcium, oxalate, uric acid and cystine molecules may cause stone formation. A decreased concentration of crystallization inhibitors (citrate, magnesium, pyrophosphate, macromolecules and glycosaminoglycans) may sometimes be the sole factor playing a role in the formation of urinary stones. Urinary pH changes also affect stone formation. An impaired flow of urine due to abnormal morphology may facilitate stasis and increase the concentration of stone-forming substances. 15.2.1 Calcium stones Calcium stones are usually made from calcium oxalate or calcium phosphate. Either supersaturation of calcium (hypercalciuria) and oxalate (hyperoxaluria) or decreased concentration of inhibitors like citrate (hypocitraturia) play a major role in calcium oxalate stone formation. Hypercalciuria. This is defined by a 24-hour urinary calcium excretion of more than 4 mg/kg/day in a child weighing less than 60 kg. In infants younger than 3 months, 5 mg/kg/day is considered to be the upper limit of normal for calcium excretion (3). Hypercalciuria can be classified as either idiopathic or secondary. Idiopathic hypercalciuria is diagnosed when clinical, laboratory, and radiographic investigations fail to delineate an underlying cause. Secondary hypercalciuria occurs when a known process produces excessive urinary calcium. In secondary (hypercalcaemic) hypercalciuria, a high serum calcium level may be due to increased bone resorption (hyperparathyroidism, hyperthyroidism, immobilization, acidosis, metastatic disease) or gastrointestinal hyperabsorption (hypervitaminosis D) (4). A good screening test for hypercalciuria compares the ratio of urinary calcium to creatinine. The normal calcium-to-creatinine ratio in children is less than 0.2. If the calculated ratio is higher than 0.2, repeat testing is indicated. Neonates and infants have a higher calcium excretion and lower creatinine excretion than older children (3,4). If the follow-up ratios are normal, then no additional testing for hypercalciuria is needed. However, if the ratio remains elevated, a timed 24-hour urine collection should be obtained and the calcium excretion calculated. The 24-hour calcium excretion test is the criterion standard for the diagnosis of hypercalciuria. If calcium excretion is higher than 4 mg/kg/day (0.1 mmol/kg/day), the diagnosis of hypercalciuria is confirmed and further evaluation is warranted. Further evaluation includes levels of serum bicarbonate, creatinine, alkaline

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phosphatase, calcium, magnesium, pH, and parathyroid hormone. Freshly voided urine should be measured for pH (3-6). A 24-hour urine collection should also be collected for measurement of calcium, phosphorus, sodium, magnesium, citrate and oxalate. Meanwhile dietary manipulations should be tried to normalize urine calcium (6). Initial management is always to increase fluid intake and urinary flow. Dietary modification is a mandatory part of effective therapy. The child should be referred to a dietician to assess accurately the daily intake of calcium, animal protein, and sodium. Dietary sodium restriction is recommended as well as maintenance of calcium intake consistent with the daily needs of the child (7). A brief trial of a low-calcium diet can be carried out to determine if exogenous calcium intake is contributing to a high urinary calcium. However, great caution should be used when trying to restrict calcium intake for long periods (Level of evidence: 3; Grade of recommendation: B). Hydrochlorothiazide and other thiazide-type diuretics may be used to treat hypercalciuria at a dosage of 1-2 mg/kg/day (2, 8) (Level of evidence: 3; Grade of recommendation: C). Citrate therapy is also useful if citrate levels are low or if hypercalciuria persists, despite other therapies (2, 9) (Level of evidence: 4; Grade of recommendation: C). Hyperoxaluria. Oxalic acid is a metabolite excreted by the kidneys. Only 10-15% of oxalate comes from diet. Normal school children excrete less than 50 mg (0.57 mmol)/1.73m2/day (2, 10), while infants excrete four times as much. Hyperoxaluria may result from increased dietary intake, enteric hyperabsorption (as in short bowel syndrome) or an inborn error of metabolism. In primary hyperoxaluria, one of the two liver enzymes that play a role in the metabolism of oxalate may be deficient. In primary hyperoxaluria there is increased deposition of calcium oxalate in the kidney and in urine. With increased deposition of calcium oxalate in the kidneys, renal failure may ensue in resulting deposition of calcium oxalate in other tissues. The diagnosis is made upon laboratory findings of severe hyperoxaluria and clinical symptoms. The definitive diagnosis requires liver biopsy to assay the enzyme activity. Other forms of hyperoxaluria, as mentioned earlier, may be due to hyperabsorption of oxalate in inflammatory bowel syndrome, pancreatitis and short bowel syndrome. Yet, the majority of children who have high levels of oxalate excretion in urine may not have any documented metabolic problem or any dietary cause. This is known as idiopathic ‘mild’ hyperoxaluria, with urine oxalate levels elevated only mildly in these cases. The treatment of hyperoxaluria consists of the promotion of high urine flow, restriction of dietary oxalate and regular calcium intake. Pyridoxine may be useful in reducing urine levels, especially in primary hyperoxaluria (2, 10) (Level of evidence: 4; Grade of recommendation: C). Hypocitraturia. Citrate is a urinary stone inhibitor. Citrate acts by binding to calcium and by directly inhibiting the growth and aggregation of calcium oxalate as well as calcium phosphate crystals. Thus, low urine citrate may be a significant cause of calcium stone disease. In adults, hypocitraturia is the excretion of citrate in urine of less than 320 mg/day (1.5 mmol/day) for adults; this value must be adjusted for children depending on body size (11, 12). Hypocitraturia usually occurs in the absence of any concurrent symptoms or any known metabolic derangements. It may also occur in association with any metabolic acidosis, distal tubular acidosis or diarrhoeal syndromes. Environmental factors that lower urinary citrate include a high protein intake and excessive salt intake. Many reports emphasize the significance of hypocitraturia in paediatric calcium stone disease. The presence of hypocitraturia ranges from 30% to 60% in children with calcium stone disease. Due to the increased stone risk in hypocitraturia, the restoration of normal citrate levels is advocated to reduce stone formation. Although some studies have shown that citrate replacement therapy reduces the risk of stone formation in an adult population, there are few relevant studies in children. Hypocitraturia is treated by potassium citrate at a starting dose of 1 mEq/kg, given in two divided doses (12) (Level of evidence: 3; Grade of recommendation: B). 15.2.2 Uric acid stones Uric acid stones are responsible for urinary calculi in 4-8% of children. Uric acid is the end product of purine metabolism. Hyperuricosuria is the main cause of uric acid stone formation in children. A daily output of uric acid of more than 10 mg/kg/day is considered to be hyperuricosuria (2). The formation of uric acid stones is dependent, mainly on the presence of acidic urinary composition.

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Uric acid dissociation and solubility is strongly reduced at pH of less than 5.8. As the pH becomes more alkaline, uric acid crystals become more soluble and the risk of uric acid stone formation is reduced. In the familial or idiopathic form of hyperuricosuria, children usually have normal serum uric acid levels. In other children, it can be caused by uric acid overproduction secondary to inborn errors of metabolism, myeloproliferative disorders or other causes of cell breakdown. Hyperuricosuria is also caused by high purine and protein intake. Although hyperuricosuria is a risk factor for calcium oxalate stone formation in adults, this does not appear to be a significant risk factor in children. Uric acid stones are non-opaque stones. Plain X-rays are insufficient to show uric acid stones, and renal sonography and spiral CT are used for diagnosis. Alkalinization of urine is the mainstay of therapy and prevention for uric acid stones. Citrate preparations are useful as alkalinizing agents. Maintaining a urine pH of 6 to 6.5 is sufficient to prevent uric acid stones (2). 15.2.3 Cystine stones Cystinuria is the cause of cystine stone formation and accounts for 2-6% of all urinary stones in children. Cystinuria is an incompletely recessive autosomal disorder characterized by failure of renal tubules to reabsorb four basic amino acids, cystine, ornithine, lysine and arginine. Of these four amino acids, only cystine has poor solubility in urine, so that only cystine stones may form in the case of excessive excretion in urine. Cystine solubility is pH-dependent, with cystine precipitation beginning at pH levels < 7.0. Other metabolic conditions, such as hypercalciuria, hypocitraturia and hyperuricosuria, may accompany cystinuria, so leading to the formation of mixed-composition stones. Cystine stones are faintly radiolucent and may be difficult to show on regular radiograph studies. They are also hard in texture and more difficult to disintegrate by extracorporeal shock-wave lithotripsy (ESWL). The medical treatment for cystine stones aims to reduce cystine saturation in urine and increase its solubility. The initial treatment consists of maintaining a high urine flow and the use of alkalinizing agents, such as potassium citrate to maintain urine pH at above 7.0. If this treatment fails, the use of α-mercaptopropionil glycine or D-penicillamine may reduce cystine levels in urine and prevent stone formation. Use of these drugs can be associated with severe side effects, such as bone marrow depression and nephrotic syndrome (13) (Level of evidence: 4; Grade of recommendation: C). 15.2.4 Infection stones (struvite stones) Infection-related stones constitute nearly 5% of urinary stones in children. Bacteria capable of producing urease enzyme (Proteus, Klebsiella, Pseudomonas) are responsible for the formation of such stones. Urease converts urea into ammonia and bicarbonate, so alkalinizing the urine and further converting bicarbonate into carbonate. In the alkaline environment, triple phosphates form, eventually resulting in a supersaturated environment of magnesium ammonium phosphate and carbonate apatite, which in turn leads to stone formation. In addition to bacterial elimination, stone elimination is essential for treatment, as stones will harbour infection and antibiotic treatment will not be effective. Consideration should be given to investigating any congenital problem that causes stasis and infection. Genitourinary tract anomalies predispose to formation of such stones.

15.3

Clinical presentation

Presentation tends to be age-dependent, with symptoms such as flank pain and haematuria being more common in older children. Non-specific symptoms (e.g. irritability, vomiting) are common in very young children. Haematuria, usually gross, occurring with or without pain, is less common in children. However, microscopic haematuria may be the sole indicator and is more common in children. In some cases, urinary infection may be the only finding leading to radiological imaging in which a stone is identified (14,15).

15.4

Diagnosis

15.4.1 Imaging Generally, ultrasonography should be used as a first study. Renal ultrasonography is very effective for identifying stones in the kidney. Many radiolucent stones can be identified with a simple abdominal flat-plate examination. If no stone is found but symptoms persist, spiral CT scanning is indicated. The most sensitive test for identifying stones in the urinary system is non-contrast helical CT scanning. It is safe and rapid, with 97% sensitivity and 96% specificity (16-18) (Level of evidence: 2; Grade of recommendation: B). Intravenous pyelography is rarely used in children, but may be needed to delineate the caliceal anatomy prior to percutaneous or open surgery.

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15.4.2 Metabolic evaluation Due to the high incidence of predisposing factors for urolithiasis in children and high stone recurrence rates, every child with urinary stone should be given a complete metabolic evaluation (1, 19, 20). Metabolic evaluation includes: • Family and patient history of metabolic problems. • Analysis of stone composition (following stone analysis, metabolic evaluation can be modified according to the specific stone type). • Electrolytes, BUN, creatinine, calcium, phosphorus, alkaline phosphatase, uric acid, total protein, carbonate, albumin, and parathyroid hormone (if there is hypercalcaemia). • Spot urinalysis and culture, including ratio of calcium to creatinine. • Urine tests, including a 24-hour urine collection for calcium, phosphorus, magnesium, oxalate, uric acid citrate, cystine, protein, and creatinine clearance. Figure 3 provides an algorithm of how to perform metabolic investigations in urinary stone disease in children and to plan medical treatment accordingly.

15.5

Management

With the advance of technology stone management has changed from open surgical approach to endoscopic techniques that are less invasive. Deciding the form of treatment depends on the number, size, location, composition and anatomy of the urinary tract (19, 21, 22). Currently, most paediatric stones can easily be managed by ESWL. Endoscopic treatment can be applied easily for ureteric and bladder stones. Percutaneous removal of stones is also possible for kidney stones in children. Only a small portion of children will need an open surgical approach. 15.5.1 Extracorporeal shock-wave lithotripsy (ESWL) Many reports confirm that shock-wave lithotripsy (SWL) can be performed in children with no suspicion of long-term morbidity of the kidney (23-28). The mean number of shock waves for each treatment is about 1800 and 2000 (up to 4000 if needed) and the mean power set varies between 14kV and 21 kV. The use of ultrasonography and digital fluoroscopy has significantly decreased the radiation exposure and it has been shown that children are exposed to significantly lower doses of radiation compared to adults (21, 29, 30). Concerns about anaesthesia do not seem to be a problem any more because of advances in technique and medication, even in the infant period. The type of anaesthesia should be general or dissociative for children under 10 years of age, whereas conventional intravenous sedation or patient-controlled analgesia is an option for older children who are able to co-operate (31) (Level of evidence: 2b). Stone-free rates are significantly affected by various factors. Regardless of the location, as the stone size increases, the stone-free rates decrease and re-treatment rate increases. The stone-free rates for < 1 cm, 1-2 cm, > 2 cm and overall were reported as nearly 90%, 80%, 60% and 80%, respectively. As the stone size increases, the need for additional sessions increases (21, 29, 30, 32-36). Localization of the calculi has been described as a significant factor affecting the success rates in different studies. Stones in renal pelvis and upper ureter seem to respond better to SWL. In these mentioned sites, the stone clearance rates are nearly 90%. However, SWL was found to be less effective for caliceal stones particularly the lower caliceal stones. Several studies reported stone-free rates for isolated lower caliceal stones varying between 50% and 62% (37-40). ESWL treatment can also be used to treat ureteral calculi. However, this is a more specific issue and with controversies. The success rates with ESWL are less for distal ureteric stones. There may also be technical problems with localization and focusing of ureteric stones in children (37, 39, 40-42). The type of machine used has a strong effect on success rates and complications. First-generation machines can deliver more energy to a larger focal zone, resulting in higher fragmentation rates in a single therapy. However, general anaesthesia is usually required due to the intolerable discomfort associated with a first-generation machine. Later-generation machines have a smaller focal zone and deliver less energy, and have a lower risk of pulmonary trauma. However, additional treatments may be needed with later-generation machines. The success rate is higher in younger children (35). Although stenting does not affect stone clearance, overall complication rates are higher and hospital stay is longer in the unstented patient (34, 35). Stenting is essential in solitary kidneys undergoing ESWL treatment. Children with a large stone burden have a high risk of developing Steinstrasse and urinary obstruction and should be followed more closely for the risk of prolonged urinary tract obstruction after ESWL. Post-ESWL stent or nephrostomy tube placement may be needed in prolonged obstruction (20, 36).

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Paediatric stone patient Elimination of stones by spontaneous passage or active removal (ESWL, surgery)

Stone analysis

Mg Ammonium phosphate (struvite)

urine culture

Uric acid stone

Cystine

urine pH urine and serum uric acid levels

urine pH urine cystine level

Calcium stones CaOX -CaPO

cystinuria

possibly urease producing bacteria acidic urine hyperuricosuria hyperuricemia

total elimination of stone (surgery / ESWL) antibiotics

high fluid intake potassium citrate 3-4 mEq/kg/d mercaptopropiyonilglycine 10-50 mg/kg/d D-penicillamine 10-50 mg/kg/d

alkali replacement – K citrate Allopurinol (10 mg/kg) low purine diet

serum PTH

hypercalcaemia



urine - blood pH urine - blood Ca - uric acid levels, Mg, Phosphate urine Ca-Oxalate-Citrate-Mg-Uric A –Phosphate urine pH > 5.5

hyperparathyroidism

urine pH < 5.5

Further investigation for RTA

hypercalciuria

hyperoxaluria

hyperuricosuria

hypocitraturia

K-citrate diet (normal calcium low sodium intake) HCTZ (diuretic)

Diet low in ox. K-citrate pyridoxine

alkali replacement (K-citrate) allopurinol

citrate replacement K-citrate

ESWL = extracorporeal shockwave lithotripsy; HCTZ = hydrochlorothiazide; PTH = parathyroid hormone; RTA = renal tubular acidosis

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ESWL in children may have complications, but these are often self-limiting and transient. The most frequently observed complications are: • Renal colic • Transient hydronephrosis • Dermal ecchymosis • Urinary tract infection • Formation of Steinstrasse • Sepsis • Rarely, haemoptysis. In children with sterile pre-operative urine cultures, antibiotic prophylaxis to decrease the infectious complications is not recommended (43). However, every effort should be made to sterilize the urine before performing ESWL, ureteroscopy (URS), or percutaneous nephrolithotomy. 15.5.2 Percutaneous nephrolithotomy ESWL is the first choice for treating most renal paediatric stones. However, percutaneous renal surgery can be used for larger and complex stones. Pre-operative evaluation, indication and surgical technique are similar in children compared to adults. PCNL is used as monotherapy in most cases, but is also used as an adjunctive procedure to other therapies. The use of adult-sized instruments, in association with an increased number of tracts and sheath size, seems to increase the blood loss. However, small-calibre instruments have now been developed and there are some advantages for PCNL in children (particularly smaller children), such as smaller skin incision, single-step dilation and sheath placement, good working access for paediatric instruments, variable length, and lower cost (43, 44). Now that appropriate-size instruments are available, age is no longer a limiting factor for PCNL. As monotherapy, PCNL is considerably effective and safe. The reported stone-free rates in the recent literature are between 86.9% and 98.5% after a single session. These rates increase with adjunctive measures, such as second-look PCNL, ESWL and URS. Even in complete staghorn cases, a clearance rate of 89% has been achieved following a single session (45-48, 50, 51). The most frequently reported complications of PCNL in children are bleeding, post-operative fever or infection, and persistent urinary leakage. Bleeding requiring transfusion is reported in 0.4% to 23.9% and is closely associated with stone burden, operative time, sheath size and number of tracts. Post-operative fever and infection has been reported up to 29.3% and 5.5%, respectively; the origin of fever is not thought to be the infection (49-56). The mean post-operative hospital stay is similar to adults. It is reported as 3 to 4 days in all the previously mentioned studies and is much shorter than open surgery. The less invasive nature of this technique has made it a promising alternative to open surgery for treating renal stones in children (Level of evidence: 2; Grade of recommendation: B). 15.5.3 Ureterorenoscopy The increasing availability of smaller size endourological equipment has made it possible to manage paediatric ureteral stones using endoscopic techniques. The technique used in children is similar to the one used in adults. It is strongly recommended that guide wires are used and the procedure is performed using direct vision. Routine balloon dilation of ureterovesical junction and ureteral stenting are controversial. In general, ureteric dilatation is being done less and less and only in selected cases. The general tendency is to use hydrodilation more as it is shown to be as effective (57-60, 43, 61-63) (Level of evidence: 3; Grade of recommendation: B). Different lithotripsy techniques, including ultrasonic, pneumatic and laser lithotripsy, have all been shown to be safe and effective. Because of the smaller size of the probes, laser energy is easier to use in smaller instruments and is more useful for paediatric cases (50, 58, 60, 64-70). All studies reporting the use of endoscopy for ureteric stones in children have clearly demonstrated that there is no significant risk of ureteric strictures or reflux with this mode of therapy (Level of evidence: 1; grade of recommendation: A). 15.5.4 Open stone surgery Most stones in children can be managed by ESWL and endoscopic techniques. Yet in some situations, open surgery is inevitable. Good candidates for open stone surgery include very young children with large stones and/or a congenitally obstructed system which also requires surgical correction. Severe orthopaedic deformities may limit positioning for endoscopic procedures. Open surgery would also be a necessity for such children. Bladder stones in children can usually be managed by endoscopic techniques. Open surgery may also be used for very large bladder stones or for bladder stones caused by an anatomical problem.

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Recommendations for interventional management are given in Table 3. Table 3: Recommendations for interventional management in paediatric stones Stone size Primary LE Secondary and treatment treatment localization* option options Staghorn PCNL 2b Open/SWL Multiple sessions and accesses with PCNL may stones be needed Combination with SWL may be useful Pelvis < 10 mm SWL 1a RIRS/PCNL Pelvis 10-20 mm SWL 2b PCNL/Open Multiple sessions with SWL may be needed PCNL has similar recommendation grade Pelvis > 20 mm PCNL 2b SWL/Open Multiple sessions with SWL may be needed Lower pole SWL 2c RIRS/PCNL Anatomical variations are important for complete calix < 10 mm clearance after SWL Lower pole calix PCNL 2b SWL Anatomical variations are important for complete > 10 mm clearance after SWL Upper ureteric SWL 2b PCNL/URS/ stones Open Lower ureteric URS 1a SWL/Open Additional intervention need is high with SWL stones Bladder stones Endoscopic 2b Open Open is easier and with less operative time with large stones * Cystine and uric acid stones excluded. LE = level of evidence; PCNL = percutaneous nephrolithostomy; SWL = shock-wave lithotripsy; RIRS = retrograde intrarenal surgery; URS = ureteroscopy.

15.6

REFERENCES

1. Straub M, Strohmaier WL, Berg W, Beck B, Hoppe B, Laube N, Lahme S, Schmidt M, Hesse A, Koehrmann KU. Diagnosis and metaphylaxis of stone disease. Consensus concept of the National Working Committee on Stone Disease for the Upcoming German Urolithiasis Guideline. World J Urol 2005;23(5):309-23. http://www.ncbi.nlm.nih.gov/pubmed/16315051 2. Bartosh SM. Medical management of pediatric stone disease. Urol Clin North Am 2004;31(3):575-87, x-xi. http://www.ncbi.nlm.nih.gov/pubmed/15313066 3. Kruse K, Kracht U, Kruse U. Reference values for urinary calcium excretion and screening for hypercalciuria in children and adolescents. Eur J Pediatr 1984;143(1):23-31. http://www.ncbi.nlm.nih.gov/pubmed/6510426 4. Sargent JD, Stukel TA, Kresel J, Klein RZ. Normal values for random urinary calcium to creatinine ratios in infancy. J Pediatr 1993;123(3):393-7. http://www.ncbi.nlm.nih.gov/pubmed/8355114 5. Stapleton FB, Noe HN, Roy S 3rd, Jerkins GR. Hypercalciuria in children with urolithiasis. Am J Dis Child 1982;136(8):675-8. http://www.ncbi.nlm.nih.gov/pubmed/7102617 6. Stapleton FB, Noe HN, Roy S 3rd, Jerkins GR. Urinary excretion of calcium following an oral calcium loading test in healthy children. Pediatrics 1982;69(5):594-7. http://www.ncbi.nlm.nih.gov/pubmed/7079015 7. Borghi L, Schianchi T, Meschi T, Guerra A, Allegri F, Maggiore U, Novarini A. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med 2002;346(2):77-84. http://www.ncbi.nlm.nih.gov/pubmed/11784873 8. Preminger GM, Pak CY. Eventual attenuation of hypocalciuric response to hydrochlorothiazide in absorptive hypercalciuria. J Urol 1987;137(6):1104-8. http://www.ncbi.nlm.nih.gov/pubmed/3586136 9. Tekin A, Tekgul S, Atsu N, Bakkaloglu M, Kendi S. Oral potassium citrate treatment for idiopathic hypocitruria in children with calcium urolithiasis. J Urol 2002;168(6):2572-4. http://www.ncbi.nlm.nih.gov/pubmed/12441986

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10. Morgenstern BZ, Milliner DS, Murphy ME, Simmons PS, Moyer TP, Wilson DM, Smith LH. Urinary oxalate and glycolate excretion patterns in the first year of life: a longitudinal study. J Pediatr 1993;123(2):248-51. http://www.ncbi.nlm.nih.gov/pubmed/8345420 11. Defoor W, Asplin J, Jackson E, Jackson C, Reddy P, Sheldon C, Minevich E. Results of a prospective trial to compare normal urine supersaturation in children and adults. J Urol 2005;174(4 Pt 2):1708-10. http://www.ncbi.nlm.nih.gov/pubmed/16148687 12. Tekin A, Tekgul S, Atsu N, Sahin A, Ozen H, Bakkaloglu M. A study of the etiology of idiopathic calcium urolithiasis in children: hypocitruria is the most important risk factor. J Urol 2000;164(1):162-5. http://www.ncbi.nlm.nih.gov/pubmed/10840454 13. Tekin A, Tekgul S, Atsu N, Sahin A, Bakkaloglu M. Cystine calculi in children: the results of a metabolic evaluation and response to medical therapy. J Urol 2001;165(6 Pt 2):2328-30. http://www.ncbi.nlm.nih.gov/pubmed/11371943 14. Bove P, Kaplan D, Dalrymple N, Rosenfield AT, Verga M, Anderson K, Smith RC. Reexamining the value of hematuria testing in patients with acute flank pain. J Urol 1999;162(3 Pt 1):685-7. http://www.ncbi.nlm.nih.gov/pubmed/10458342 15. Sternberg K, Greenfield SP, Williot P, Wan J. Pediatric stone disease: an evolving experience. J Urol 2005;174(4 Pt 2):1711-4. http://www.ncbi.nlm.nih.gov/pubmed/16148688 16. Oner S, Oto A, Tekgul S, Koroglu M, Hascicek M, Sahin A, Akhan O. Comparison of spiral CT and US in the evaluation of paediatric urolithiasis. JBR-BTR 2004;87(5):219-23. http://www.ncbi.nlm.nih.gov/pubmed/15587558 17. Memarsadeghi M, Heinz-Peer G, Helbich TH, Schaefer-Prokop C, Kramer G, Scharitzer M, Prokop M. Unenhanced multi-detector row CT in patients suspected of having urinary stone disease: effect of section width on diagnosis. Radiology 2005;235(2):530-6. http://www.ncbi.nlm.nih.gov/pubmed/15758192 18. Strouse PJ, Bates DG, Bloom DA, Goodsitt MM. Non-contrast thin-section helical CT of urinary tract calculi in children. Pediatr Radiol 2002;32(5):326-32. http://www.ncbi.nlm.nih.gov/pubmed/11956719 19. Tiselius HG, Ackermann D, Alken P, Buck C, Conort P, Gallucci M; Working Party on Lithiasis, European Association of Urology. Guidelines on urolithiasis. Eur Urol 2001;40(4):362-71. http://www.ncbi.nlm.nih.gov/pubmed/11713390 20. Tekin A, Tekgul S, Atsu N, Ergen A, Kendi S. Ureteropelvic junction obstruction and coexisting renal calculi in children: role of metabolic abnormalities. Urology 2001;5(3)7:542-5. http://www.ncbi.nlm.nih.gov/pubmed/11248635 21. Raza A, Turna B, Smith G, Moussa S, Tolley DA. Paediatric urolithiasis: 15 years of local experience with minimally invasive endourological management of paediatric calculi. J Urol 2005;174(2):682-5. http://www.ncbi.nlm.nih.gov/pubmed/16006948 22. Rizvi SA, Naqvi SA, Hussain Z, Hashmi A, Hussain M, Zafar MN, Sultan S, Mehdi H. Paediatric urolithiasis: developing nation perspectives. J Urol 2002;168(4 Pt 1):1522-5. http://www.ncbi.nlm.nih.gov/pubmed/12352448 23. Willis LR, Evan AP, Connors BA, Blomgren P, Fineberg NS, Lingeman JE. Relationship between kidney size, renal injury, and renal impairment induced by shock wave lithotripsy. J Am Soc Nephrol 1999;10(8):1753-62. http://www.ncbi.nlm.nih.gov/pubmed/10446943 24. Villanyi KK, Szekely JG, Farkas LM, Javor E, Pusztai C. Short-term changes in renal function after extracorporeal shock wave lithotripsy in children. J Urol 2001;166(1):222-4. http://www.ncbi.nlm.nih.gov/pubmed/11435873 25. Aldridge RD, Aldridge RC, Aldridge LM. Anesthesia for pediatric lithotripsy. Paediatr Anaesth 2006;16(3):236-41. http://www.ncbi.nlm.nih.gov/pubmed/16490086 26. McLorie GA, Pugach J, Pode D, Denstedt J, Bagli D, Meretyk S, D’A Honey RJ, Merguerian PA, Shapiro A, Khoury AE, Landau EH. Safety and efficacy of extracorporeal shock wave lithotripsy in infants. Can J Urol 2003;10(6):2051-5. http://www.ncbi.nlm.nih.gov/pubmed/14704109 27. Aksoy Y, Ozbey I, Atmaca AF, Polat O. Extracorporeal shock wave lithotripsy in children: experience using a mpl-9000 lithotriptor. World J Urol 2004;22(2):115-9. http://www.ncbi.nlm.nih.gov/pubmed/14740160

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28. Vlajkovic M, Slavkovic A, Radovanovic M, Siric Z, Stefanovic V, Perovic S. Long-term functional outcome of kidneys in children with urolithiasis after ESWL treatment. Eur J Pediatr Surg 2002;12(2):118-23. http://www.ncbi.nlm.nih.gov/pubmed/12015657 29. Muslumanoglu AY, Tefekli A, Sarilar O, Binbay M, Altunrende F, Ozkuvanci U. Extracorporeal shock wave lithotripsy as first line treatment alternative for urinary tract stones in children: a large scale retrospective analysis. J Urol 2003;170(6 Pt 1):2405-8. http://www.ncbi.nlm.nih.gov/pubmed/14634438 30. Ather MH, Noor MA. Does size and site matter for renal stones up to 30-mm in size in children treated by extracorporeal lithotripsy? Urology 2003;61(1):212-5; discussion 215. http://www.ncbi.nlm.nih.gov/pubmed/12559298 31. Ugur G, Erhan E, Kocabas S, Ozyar B. Anaesthetic/analgesic management of extracorporeal shock wave lithotripsy in paediatric patients. Paediatr Anaesth 2003;13(1):85-7. http://www.ncbi.nlm.nih.gov/pubmed/12535048 32. Rodrigues Netto N Jr, Longo JA, Ikonomidis JA, Rodrigues Netto M. Extracorporeal shock wave lithotripsy in children. J Urol 2002;167(5):2164-6. http://www.ncbi.nlm.nih.gov/pubmed/11956471 33. Afshar K, McLorie G, Papanikolaou F, Malek R, Harvey E, Pippi-Salle JL, Bagli DJ, Khoury AE, Farhat W. Outcome of small residual stone fragments following shock wave lithotripsy in children. J Urol 2004;172(4 Pt 2):1600-3. http://www.ncbi.nlm.nih.gov/pubmed/15371769 34. Tan AH, Al-Omar M, Watterson JD, Nott L, Denstedt JD, Razvi H. Results of shockwave lithotripsy for pediatric urolithiasis. J Endourol 2004;18(6):527-30. http://www.ncbi.nlm.nih.gov/pubmed/15333214 35. Lottmann HB, Traxer O, Archambaud F, Mercier-Pageyral B. Monotherapy extracorporeal shock wave lithotripsy for the treatment of staghorn calculi in children. J Urol 2001;165(6 Pt 2):2324-7. http://www.ncbi.nlm.nih.gov/pubmed/11371942 36. Al-Busaidy SS, Prem AR, Medhat M. Pediatric staghorn calculi: the role of extracorporeal shock wave lithotripsy monotherapy with special reference to ureteral stenting. J Urol 2003;169(2):629-33. http://www.ncbi.nlm.nih.gov/pubmed/12544330 37. Ozgur Tan M, Karaoglan U, Sozen S, Bozkirli I. Extracorporeal shock-wave lithotripsy for treatment of ureteral calculi in paediatric patients. Pediatr Surg Int 2003;19(6):471-4. http://www.ncbi.nlm.nih.gov/pubmed/12736749 38. Demirkesen O, Onal B, Tansu N, Altinta , s R, Yalçin V, Oner A. Efficacy of extracorporeal shock wave lithotripsy for isolated lower caliceal stones in children compared with stones in other renal locations. Urology 2006;67(1):170-174; discussion 174-5. http://www.ncbi.nlm.nih.gov/pubmed/16413356 39. Ozgur Tan M, Karaoglan U, Sen I, Deniz N, Bozkirli I. The impact of radiological anatomy in clearance of lower calyceal stones after shock wave lithotripsy in paediatric patients. Eur Urol 2003;43(2):188-93. http://www.ncbi.nlm.nih.gov/pubmed/12565778 40. Onal B, Demirkesen O, Tansu N, Kalkan M, Altinta R, Yalçin V. The impact of caliceal pelvic anatomy on stone clearance after shock wave lithotripsy for pediatric lower pole stones. J Urol 2004;172(3):1082-6. http://www.ncbi.nlm.nih.gov/pubmed/15311043 41. Landau EH, Gofrit ON, Shapiro A, Meretyk S, Katz G, Shenfeld OZ, Golijanin D, Pode D. Extracorporeal shock wave lithotripsy is highly effective for ureteral calculi in children. J Urol 2001;165(6 Pt 2):2316-9. http://www.ncbi.nlm.nih.gov/pubmed/11371970 42. Hochreiter WW, Danuser H, Perrig M, Studer UE. Extracorporeal shock wave lithotripsy for distal ureteral calculi: what a powerful machine can achieve. J Urol 2003;169(3):878-80. http://www.ncbi.nlm.nih.gov/pubmed/12576804 43. Wu HY, Docimo SG. Surgical management of children with urolithiasis. Urol Clin North Am 2004;31(3):589-94. http://www.ncbi.nlm.nih.gov/pubmed/15313067 44. Jackman SV, Hedican SP, Peters CA, Docimo SG. Percutaneous nephrolithotomy in infants and preschool age children: experience with a new technique. Urology 1998;52(4):697-701. http://www.ncbi.nlm.nih.gov/pubmed/9763096 45. Sahin A, Tekgul S, Erdem E, Ekici S, Hascicek M, Kendi S. Percutaneous nephrolithotomy in older children. J Pediatr Surg 2000;35(9):1336-8. http://www.ncbi.nlm.nih.gov/pubmed/10999692

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46. Shokeir AA, El-Nahas AR, Shoma AM, Eraky I, El-Kenawy M, Mokhtar A, El-Kappany H. Percutaneous nephrolithotomy in treatment of large stones within horseshoe kidneys. Urology 2004;64(3):426-9. http://www.ncbi.nlm.nih.gov/pubmed/15351557 47. Boormans JL, Scheepe JR, Verkoelen CF, Verhagen PC. Percutaneous nephrolithotomy for treating renal calculi in children. BJU Int 2005;95(4):631-4. http://www.ncbi.nlm.nih.gov/pubmed/15705093 48. Dawaba MS, Shokeir AA, Hafez AT, Shoma AM, El-Sherbiny MT, Mokhtar A, Eraky I, El-Kenawy M, El-Kappany HA. Percutaneous nephrolithotomy in children: early and late anatomical and functional results. J Urol 2004;172(3):1078-81. http://www.ncbi.nlm.nih.gov/pubmed/15311042 49. Zeren S, Satar N, Bayazit Y, Bayazit AK, Payasli K, Ozkeceli R. Percutaneous nephrolithotomy in the management of pediatric renal calculi. J Endourol 2002;16(2):75-8. http://www.ncbi.nlm.nih.gov/pubmed/11962558 50. Desai MR, Kukreja RA, Patel SH, Bapat SD. Percutaneous nephrolithotomy for complex paediatric renal calculus disease. J Endourol 2004;18(1):23-7. http://www.ncbi.nlm.nih.gov/pubmed/15006048 51. Badawy H, Salama A, Eissa M, Kotb E, Moro H, Shoukri I. Percutaneous management of renal calculi: experience with percutaneous nephrolithotomy in 60 children. J Urol 1999;162(5):1710-3. http://www.ncbi.nlm.nih.gov/pubmed/10524919 52. Holman E, Khan AM, Flasko T, Toth C, Salah MA. Endoscopic management of pediatric urolithiasis in a developing country. Urology 2004;63(1):159-62; discussion 162. http://www.ncbi.nlm.nih.gov/pubmed/14751372 53. Aron M, Yadav R, Goel R, Hemal AK, Gupta NP. Percutaneous nephrolithotomy for complete staghorn calculi in preschool children. J Endourol 2005;19(8):968-72. http://www.ncbi.nlm.nih.gov/pubmed/16253060 54. Salah MA, Tallai B, Holman E, Khan MA, Toth G, Toth C. Simultaneous bilateral percutaneous nephrolithotomy in children. BJU Int 2005;95(1):137-9. http://www.ncbi.nlm.nih.gov/pubmed/15638911 55. Samad L, Aquil S, Zaidi Z. Paediatric percutaneous nephrolithotomy: setting new frontiers. BJU Int 2006;97(2):359-63. http://www.ncbi.nlm.nih.gov/pubmed/15638911 56. Salah MA, Toth C, Khan AM, Holman E. Percutaneous nephrolithotomy in children: experience with 138 cases in a developing country. World J Urol 2004;22(4):277-80. http://www.ncbi.nlm.nih.gov/pubmed/15448997 57. Hill DE, Segura JW, Patterson DE, Kramer SA. Ureteroscopy in children. J Urol 1990;144(2 Pt 2): 481-3; discussion 492-3. http://www.ncbi.nlm.nih.gov/pubmed/2374224 58. Caione P, De Gennaro M, Capozza N, Zaccara A, Appetito C, Lais A, Gallucci M, di Silverio F. Endoscopic manipulation of ureteral calculi in children by rigid operative ureterorenoscopy. J Urol 1990;144(2 Pt 2):484-5; discussion 492-3. http://www.ncbi.nlm.nih.gov/pubmed/2374225 59. Minevich E, Defoor W, Reddy P, Nishinaka K, Wacksman J, Sheldon C, Erhard M. Ureteroscopy is safe and effective in prepubertal children. J Urol 2005;174(1):276-9. http://www.ncbi.nlm.nih.gov/pubmed/15947666 60. Soygur T, Zumrutbas AE, Gulpinar O, Suer E, Arikan N. Hydrodilation of the ureteral orifice in children renders ureteroscopic access possible without any further active dilation. J Urol 2006 ;176(1):285-7; discussion 287. http://www.ncbi.nlm.nih.gov/pubmed/16753421 61. Al Busaidy SS, Prem AR, Medhat M. Paediatric ureteroscopy for ureteric calculi: a 4-year experience. Br J Urol 1997;80(5):797-801. http://www.ncbi.nlm.nih.gov/pubmed/9393306 62. Schuster TG, Russell KY, Bloom DA, Koo HP, Faerber GJ. Ureteroscopy for the treatment of urolithiasis in children. J Urol 2002;167(4):1813-5; discussion 1815-6. http://www.ncbi.nlm.nih.gov/pubmed/11912438 63. Richter S, Shalev M, Lobik L, Buchumensky V, Nissenkorn I. Early postoperative vesicoureteral refluxa temporary and infrequent complication: prospective study. J Endourol 1999;13(5):365-6. http://www.ncbi.nlm.nih.gov/pubmed/10446797

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64. Van Savage JG, Palanca LG, Andersen RD, Rao GS, Slaughenhoupt BL.Treatment of distal ureteral stones in children: similarities to the american urological association guidelines in adults. J Urol 2000;164 (3 Pt 2):1089-93. http://www.ncbi.nlm.nih.gov/pubmed/10958749 65. Bassiri A, Ahmadnia H, Darabi MR, Yonessi M. Transureteral lithotripsy in pediatric practice. J Endourol 2002;16(4):257-60. http://www.ncbi.nlm.nih.gov/pubmed/12042111 66. Raza A, Smith G, Moussa S, Tolley D. Ureteroscopy in the management of pediatric urinary tract calculi. J Endourol 2005 ;19(2):151-8. http://www.ncbi.nlm.nih.gov/pubmed/15798409 67. Satar N, Zeren S, Bayazit Y, Aridogan IA, Soyupak B, Tansug Z. Rigid ureteroscopy for the treatment of ureteral calculi in children. J Urol 2004;172(1):298-300. http://www.ncbi.nlm.nih.gov/pubmed/15201799 68. De Dominicis M, Matarazzo E, Capozza N, Collura G, Caione P. Retrograde ureteroscopy for distal ureteric stone removal in children. BJU Int 2005;95(7):1049-52. http://www.ncbi.nlm.nih.gov/pubmed/15839930 69. Dogan HS, Tekgul S, Akdogan B, Keskin MS, Sahin A. Use of the holmium:YAG laser for ureterolithotripsy in children. BJU Int 2004;94(1):131-3. http://www.ncbi.nlm.nih.gov/pubmed/15217447 70. Thomas JC, DeMarco RT, Donohoe JM, Adams MC, Brock JW 3rd, Pope JC 4th. Paediatric ureteroscopic stone management. J Urol 2005;174(3):1072-4. http://www.ncbi.nlm.nih.gov/pubmed/16094060

16. Obstructive pathology of renal duplication: ureterocele and ectopic ureter 16.1

Background

Ureterocele and ectopic ureter are the two main anomalies associated with a complete renal duplication. At present, antenatal ultrasonography detects both conditions in the majority of cases and diagnosis is confirmed after birth by further examination. Later on in life, these anomalies are revealed by clinical symptoms: UTI, pain, disturbances of micturition and urinary incontinence. 16.1.1 Ureterocele Ureterocele is a cystic dilatation developed on the intravesical part of the ureter corresponding to the upper pole of a renal duplication. It is more frequent in females than in males, the overall prevalence being 1 in 4,000 births. 16.1.2 Ectopic ureter Ectopic ureter is less frequent than ureterocele (1 in 40,000 births), but is again more common in females (male to female ratio, 1:5). Eighty per cent of ectopic ureters are associated with a complete renal duplication. In females, the ureteral orifice may be located: • in the urethra, from bladder neck to meatus (35%) • in the vaginal vestibule (30%) • in the vagina (25%) • in the uterus and Fallopian tube (rarely). In males, the ureteral orifice may be located: • in the posterior urethra above the verumontanum and never below the external sphincter (60%) • in the seminal tract (vas deferens, ejaculatory ducts, seminal vesicles) (40%).

16.2

Classification

Ureteroceles are usually obstructive for the upper pole moiety, but the degree of obstruction and functional impairment is variable according to the type of ureterocele and upper pole dysplasia. In the orthotopic

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form, there is often no, or only mild, obstruction and frequently the function of the moiety is normal or slightly impaired; the corresponding ureter may be dilated. In the ectopic form, the upper pole is altered, frequently dysplastic and hypofunctional or non-functional. The corresponding ureter is a megaureter. In the caecoureterocele (see definition below), the upper pole of the renal duplication is always dysplastic and nonfunctional. 16.2.1 Ectopic ureterocele Ectopic ureterocele is the most common form of ureterocele (> 80%) and occurs bilaterally in about 40% of cases. It is voluminous, dissociating the trigone and slipping into the urethra, and can rarely prolapse through the urethral meatus. The ureterocele orifice is tight, rarely large, and located near the bladder neck, either in the bladder itself or in the urethra below the bladder neck. The ureter corresponding to the lower pole moiety is raised by the ureterocele and is frequently refluxing or compressed by the ureterocele, leading to an obstructive megaureter. A contralateral renal duplication is associated in 50% of cases. Occasionally, very large ureteroceles are responsible for reflux or obstruction of the contralateral upper tract. 16.2.2 Orthotopic ureterocele Orthotopic ureterocele accounts for 15% of cases. It is exclusively observed in females, and is small and located strictly intravesically. Orthotopic ureteroceles are mostly combined with a single kidney system. 16.2.3 Caecoureterocele Caecoureterocele is very rare, occurring in less than 5% of cases. It is associated with an ectopic ureter and located in the urethra below the bladder neck.

16.3

Diagnosis

16.3.1 Ureterocele Prenatal ultrasound reveals easily voluminous obstructive ureteroceles. In cases of a very small upper pole or a slightly obstructive ureterocele, prenatal diagnosis will be difficult. If prenatal diagnosis has been impossible, the following clinical symptoms - beside incidental findings - can reveal the congenital anomaly at birth or later: • at birth, a prolapsed and sometimes strangulated ureterocele may be observed in front of the urethral orifice. In a newborn boy, it might cause acute urinary retention, simulating urethral valves • the early symptom of pyelonephritis in either sex may lead to the diagnosis • later symptoms can include dysuria, recurrent cystitis and urgency. In cases of prenatal diagnosis at birth, ultrasonography confirms the ureteral dilatation ending at the upper pole of a renal duplication. It also demonstrates the presence of an ureterocele in the bladder, with a dilated ureter behind the bladder. At this point, it is important to assess the function of the upper pole using nuclear renography in the region of interest. Magnetic resonance urography may visualize the morphological status of the upper pole and lower moieties and of the contralateral kidney. A VCUG is mandatory in identifying an ipsilateral or contralateral reflux and to assess the degree of intraurethral prolapse of the ureterocele. Urethrocystoscopy may reveal the pathology in cases where it is difficult to make the differential diagnosis between ureterocele and ectopic megaureter. 16.3.2 Ectopic ureter Most of the ectopic megaureters are diagnosed primarily by ultrasound. In some cases, clinical symptoms can lead to diagnosis: • in neonates: dribbling of urine, pyuria and acute pyelonephritis • an ectopic orifice may be found in the meatal region. Significant vaginal discharge may be the equivalent of incontinence in little girls • in pre-adolescent males: epididymitis is the usual clinical presentation and a palpable seminal vesicle may be found on digital rectal examination. Ultrasonography, nuclear studies, VCUG, MR urography and cystoscopy are the diagnostic tools to assess function, to detect reflux and to rule out ipsilateral compression of the lower pole and urethral obstruction. In the clarification of incontinence in girls, a methylene blue filling of the bladder can be helpful: in the case of loss of uncoloured urine, an ectopic ureter must be present.

16.4

Treatment

16.4.1 Ureterocele The management is controversial with the choice between endoscopic decompression, partial nephroureterectomy or complete primary reconstruction. The choice of a therapeutic modality depends on the

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following criteria: clinical status of the patient (e.g. urosepsis), age of the patient, renal function of the upper pole, presence or absence of reflux, obstruction of the ipsilateral ureter, pathology of the contralateral ureter, and parents’ and surgeon’s preferences. 16.4.1.1 Early diagnosis • in a clinically asymptomatic child with an ureterocele and non- or hypo-functional upper pole, without significant obstruction of the lower pole and without bladder outlet obstruction, prophylactic antibiotic treatment is given until follow-up procedures are instigated • in the presence of severe obstruction and infection, an immediate endoscopic incision or puncture is recommended. 16.4.1.2 Re-evaluation If decompression is effective and there is no reflux (approximately 25% of cases), the patient is followed-up conservatively. Secondary surgery is necessary if decompression is not effective, significant reflux is present or there is obstruction of the ipsi- or contra-lateral ureters and/or bladder neck obstruction. Surgery may vary from partial nephrectomy to complete unilateral reconstruction. 16.4.2 Ectopic ureter In the majority of cases, the upper pole is dysplastic and heminephro-ureterectomy should be considered. Ureteral reconstruction is a therapeutic option in cases in which the upper pole has function worth preserving.

16.5

REFERENCES

Ureterocele 1. Austin PF, Cain MP, Casale AJ, Hiett AK, Rink RC. Prenatal bladder outlet obstruction secondary to ureterocele. Urology 1998;52(6):1132-5. http://www.ncbi.nlm.nih.gov/pubmed/9836570 2. Borer JG, Cisek LJ, Atala A, Diamond DA, Retik AB, Peters CA. Pediatric retroperitoneoscopic nephrectomy using 2 mm instrumentation. J Urol 1999;162(5):1725-9; discussion 1730. http://www.ncbi.nlm.nih.gov/pubmed/10524923 3. Cain MP, Pope JC, Casale AJ, Adams MC, Keating MA, Rink RC. Natural history of refluxing distal ureteral stumps after nephrectomy and partial ureterectomy for vesicoureteral reflux. J Urol 1998;160(3 Pt 2):1026-7. http://www.ncbi.nlm.nih.gov/pubmed/9719270 4. Cendron J, Melin Y, Valayer J. [Simplified treatment of ureterocele with pyeloureteric duplication. A propos of 35 cases.] Chir Pediatr 1980;21(2):121-4. [article in French] http://www.ncbi.nlm.nih.gov/pubmed/7448978 5. Decter RM, Roth DR, Gonzales ET. Individualized treatment of ureteroceles. J Urol 1989;142 (2 Pt 2):535-7. http://www.ncbi.nlm.nih.gov/pubmed/2746775 6. Di Benedetto V, Montfort G. How prenatal utrasound can change the treatment of ectopic ureterocele in neonates? Eur J Pediatr Surg 1997;7(6):338-40. http://www.ncbi.nlm.nih.gov/pubmed/9493984 7. el Ghoneimi A, Lottmann H, Odet E, Bonnin F, Aigrain Y. [Ureteropyelostomy for obstructed duplicated ureter an easy and reliable operation in infants.] Ann Urol (Paris) 1998;32(4):241-6. [article in French] http://www.ncbi.nlm.nih.gov/pubmed/9791553 8. Husmann D, Strand B, Ewalt D, Clement M, Kramer S, Allen T. Management of ectopic ureterocele associated with renal duplication: a comparison of partial nephrectomy and endoscopic decompression. J Urol 1999;162(4):1406-9. http://www.ncbi.nlm.nih.gov/pubmed/10492225 9. Janetschek G, Seibold J, Radmayr C, Bartsch G. Laparoscopic heminephroureterectomy in pediatric patients. J Urol 1997;158(5):1928-30. http://www.ncbi.nlm.nih.gov/pubmed/9334640 10. Jayanthi VR, Koff SA. Long-term outcome of transurethral puncture of ectopic ureteroceles: initial success and late problems. J Urol 1999;162(3 Pt 2):1077-80. http://www.ncbi.nlm.nih.gov/pubmed/10458435 11. Moscovici J, Galinier P, Berrogain N, Juricic M. [Management of ureteroceles with pyelo-ureteral duplication in children. Report of 64 cases.] Ann Urol (Paris) 1999;33(5):369-76. [article in French] http://www.ncbi.nlm.nih.gov/pubmed/10544742

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12. Monfort G, Guys JM, Coquet M, Roth K, Louis C, Bocciardi A. Surgical management of duplex ureteroceles. J Ped Surg 1992;27(5):634-8. http://www.ncbi.nlm.nih.gov/pubmed/1625138 13. Pfister C, Ravasse P, Barret E, Petit T, Mitrofanoff P. The value of endoscopic treatment for ureteroceles during the neonatal period. J Urol 1998;159(3):1006-9. http://www.ncbi.nlm.nih.gov/pubmed/9474217 14. Rickwood AMK, Reiner I, Jones M, Pournaras C. Current management of duplex system ureteroceles: experience with 41 patients. Br J Urol 1992;70(2):196-200. http://www.ncbi.nlm.nih.gov/pubmed/1393443 15. Roy GT, Desai S, Cohen RC. Ureteroceles in children: an ongoing challenge. Pediatr Surg Int 1997; 12(1):448. http://www.ncbi.nlm.nih.gov/pubmed/9035209 16. Sherz HC, Kaplan GW, Packer MG, Brock WA. Ectopic ureteroceles: surgical management with preservation of continence - review of 60 cases. J Urol 1989;142(2 Pt 3):538-41. http://www.ncbi.nlm.nih.gov/pubmed/2746776 17. Stephens D. Caecoureterocele and concepts on the embryology and aetiology of ureteroceles. Aust N Z J Surg 1971;40(3):239-48. http://www.ncbi.nlm.nih.gov/pubmed/5279434 Ectopic ureter 1. Carrico C, Lebowitz RL. Incontinence due to an infrasphincteric ectopic ureter: why the delay in diagnosis and what the radiologist can do about it. Pediatr Radiol 1998;28(12):942-9. http://www.ncbi.nlm.nih.gov/pubmed/9880638 2. Cendron J, Schulman CC. [Ectopic ureter.] In: Paediatric urology. Paris: Flammarion Médecine Sciences, 1985, pp. 147-53. [article in French] 3. el Ghoneimi A, Miranda J, Truong T, Montfort G. Ectopic ureter with complete ureteric duplication: conservative surgical management. J Pediatr Surg 1996;31(4):467-72. http://www.ncbi.nlm.nih.gov/pubmed/8801293 4. Komatsu K, Niikura S, Maeda Y, Ishiura Y, Yokoyama O, Namiki M. Single ectopic vaginal ureter diagnosed by computed tomography. Urol Int 1999;63(2):147-50. http://www.ncbi.nlm.nih.gov/pubmed/10592508 5. Plaire JC, Pope JC 4th, Kropp BP, Adams MC, Keating MA, Rink RC, Casale AJ. Management of ectopic ureters: experience with the upper tract approach. J Urol 1997;158(3 Pt 2):1245-7. http://www.ncbi.nlm.nih.gov/pubmed/9258185 6. Robert M, Ennouchi JM, Chevallier P, Guiter J, Averous M. [Diagnosis of ectopic ureteral openings in the seminal tract. Value of modern imaging.] Progr Urol 1993;3(6):1028-33. [article in French] http://www.ncbi.nlm.nih.gov/pubmed/8305932 7. Smith FL, Ritchie EL, Maizels M, Zaontz MR, Hsueh W, Kaplan WE, Firlit CF. Surgery for duplex kidneys with ectopic ureters: ipsilateral ureteroureterectomy versus polar nephrectomy. J Urol 1989;142:532-4. http://www.ncbi.nlm.nih.gov/pubmed/2746774 8. Sumfest JM, Burns MW, Mitchell ME. Pseudoureterocele: potential for misdiagnosis of an ectopic ureter as a ureterocele. Br J Urol 1995;75:401-5. http://www.ncbi.nlm.nih.gov/pubmed/7735809

17. Disorders of sex development 17.1

Background

The formerly called ‘intersex disorders’ were recently the subject of a consensus document in which it was decided that the term ‘intersex’ should be changed to ‘disorders of sex development’ (DSD) (1, 2). The new classification has arisen because of advances in knowledge of the molecular genetic causes of abnormal sexual development, controversies inherent to clinical management and ethical issues. Controversial and pejorative terminology, e.g. ‘pseudohermaphroditism’ and ‘hermaphroditism’, have been renamed according to the new pathophysiological insights. Furthermore, some conditions presenting with severe male genital malformation, such as penile agenesis, cloacal exstrophy, which could not be categorized, have also been included. The term ‘disorders of sex development’ is proposed to indicate congenital conditions with atypical development of chromosomal, gonadal or anatomical sex. We refer to the consensus document as a general guideline, while this chapter will focus on what is

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relevant for the practising paediatric urologist. As the urologist is likely to be involved in both surgical and nonsurgical neonatal work, this chapter will discuss the neonatal emergency and the diagnostic and therapeutic role of the paediatric urologist. Overall, there is a low evidence base for the published literature on DSD. There are no randomized controlled trials and most studies are based on retrospective clinical descriptive studies (grade 4 level of evidence) or are expert opinion. An exception is the risk of gonadal cancer, for which the level of evidence is higher. Disorders of sex development require a multidisciplinary approach to diagnosis and treatment, which should include geneticists, neonatologists, paediatric and adult endocrinologists, gynaecologists, psychologists, ethicists and social workers. Each team member should be specialised in DSD and a team should have enough new patients to ensure experience.

17.2

The neonatal emergency

The first step is to recognize the possibility of DSD (Table 4) and to refer the newborn baby immediately to a tertiary paediatric centre, fully equipped with neonatal, genetics, endocrinology and paediatric urology units. At the paediatric centre, the situation should be explained to the parents fully and kindly. Registering and naming the newborn should be delayed as long as necessary. 17.2.1 Family history and clinical examination A careful family history must be taken followed by a thorough clinical examination (Table 5). Table 4: Findings in a newborn suggesting the possibility of DSD (adapted from the American Academy of Pediatrics) • • •

Apparent male - Severe hypospadias associated with bifid scrotum - Undescended testis/testes with hypospadias - Bilateral non-palpable testes in a full-term apparently male infant Apparent female - Clitoral hypertrophy of any degree, non-palpable gonads - Vulva with single opening Indeterminate - Ambiguous genitalia

Table 5:

Diagnostic work-up of neonates with ambiguous genitalia

History (family, maternal, neonatal) • Parental consanguinity • Previous DSD or genital anomalies • Previous neonatal deaths • Primary amenorrhoea or infertility in other family members • Maternal exposure to androgens • Failure to thrive, vomiting, diarrhoea of the neonate Physical examination • Pigmentation of genital and areolar area • Hypospadias or urogenital sinus • Size of phallus • Palpable and/or symmetrical gonads • Blood pressure Investigations • Blood analysis: 17-hydroxyprogesterone, electrolytes, LH, FSH, TST, cortisol, ACTH • Urine: adrenal steroids • Karyotype • Ultrasound • Genitogram • hCG stimulation test • Androgen-binding studies • Endoscopy LH = luteinizing hormone; FSH = follicle stimulating hormone; TST = testosterone; ACTH = adrenocorticotropic hormone; hCG = human chorionic gonadotrophin.

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17.2.2 Choice of laboratory investigations The following laboratory investigations are mandatory: • Karyotype • Plasma 17-hydroxyprogesterone assay • Plasma electrolytes • Ultrasonography to evaluate the presence of Müllerian duct structures. These investigations will provide evidence of congential adrenal hyperplasia (CAH), which is the most frequently occurring DSD. If this evidence is found, no further investigation is needed. If not, then the laboratory work-up should proceed further. The hCG stimulation test is particularly helpful in differentiating the main syndromes of 46XYDSD by evaluating Leydig cell potential. When testosterone metabolism is evaluated, the presence or absence of metabolites will help to define the problem. An extended stimulation can help to define phallic growth potential and to induce testicular descent in some cases of associated cryptorchidism.

17.3 Gender assignment This is a very complicated task. It should take place after a definitive diagnosis has been made. The idea that an individual is sex-neutral at birth and that rearing determines gender development is no longer the standard approach. Instead, gender assignment decisions should be based upon: • Age at presentation • Fertility potential • Size of the penis • Presence of a functional vagina • Endocrine function • Malignancy potential • Antenatal testosterone exposure • General appearance • Psychosocial well-being and a stable gender identity. Each patient presenting with DSD should be assigned a gender as quickly as a thorough diagnostic evaluation permits.

17.4

Role of the paediatric urologist

The role of the paediatric urologist can be divided into a diagnostic role and a therapeutic role (Table 6). Each of these roles will be discussed briefly. Table 6: Role of the paediatric urologist Diagnostic role • Clinical examination • Ultrasound • Genitography • Cystoscopy • Diagnostic laparoscopy Therapeutic role • Masculinizing surgery • Feminizing surgery • Gonadectomy 17.4.1 Diagnosis 17.4.1.1 Clinical examination A good clinical examination in a neonate presenting with ambiguous genitalia is important. As well as a good description of the ambiguous genitalia, some detailed information should be given on palpability and localization of the gonads. Information gathered by the various examinations described below should help the team to come to a final diagnosis. Palpable gonad. It must be remembered that if it is possible to feel a gonad, it is almost certainly a testis; this clinical finding therefore virtually excludes 46XXDSD. Medical photography can be useful but requires sensitivity and consent (3). Phallus. The phallus should be measured. A cotton bud placed at the suprapubic base of the implant of the

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stretched phallus allows for a good measurement of phallic length. Urogenital sinus opening. The opening of the urogenital sinus must be well evaluated. Is there only one opening visible? Can a hymenal ring be seen? What does the fusion of the labioscrotal folds look like; do the folds show rugae or some discolouration? 17.4.1.2 Investigations Ultrasound can help to describe the palpated gonads or to detect non-palpated gonads. However, the sensitivity and specificity are not high. On ultrasound, the Mülllerian structures can be evaluated. Is there a vagina? Are there some abdominal gonads? Is there a vaginal or utriculur structure visible? (4,5). Genitography can provide some more information on the urogenital sinus. How low or how high is the confluence? Is there any duplication of the vagina? How does the urethra relate to the vagina? General anaesthesia. In some cases, further examinations under general anaesthesia can be helpful. On cystoscopy, the urogenital sinus can be evaluated and the level of confluence between the bladder neck and the bladder. Cystoscopy can also be used to evaluate the vagina or utriculus, e.g. the presence of a cervix at the top of the vagina can be important information. Laparoscopy is necessary to obtain a final diagnosis on the presence of impalpable gonads and on the presence of Müllerian structures. If indicated, a gonadal biopsy can be performed (6,7).

17.5

Management

Referring to the consensus document (1, 2), it is clear that the timing of surgery is much more controversial than it used to be. The rationale for early surgery includes: • Beneficial effects of oestrogen on infant tissue • Avoiding complications from anatomical anomalies • Minimizing family distress • Mitigating the risks of stigmatization and gender-identity confusion (8). However, adverse outcomes have led to recommendations to delay unnecessary surgery to an age when the patient can give informed consent. Surgery that alters appearance is not urgent. Early surgery should be reserved for those patients with high confluent urogenital tracts, girls with severely masculinized genitalia and boys with undervirilized genitals. Vaginoplasty should be delayed until puberty and milder forms of masculinization should not be treated surgically. 17.5.1 Feminizing surgery Clitororeduction. Reduction of an enlarged clitoris should be done with preservation of the neurovascular bundle. Clitoral surgery has been reported to have an adverse outcome on sexual function and clitoral surgery should therefore be limited to severely enlarged clitorises (9,10). Informed parental consent should be obtained. Although some techniques that conserve erectile tissue have been described, the long-term outcome is unknown (11). Separation of the vagina and the urethra is preserved for high confluence anomalies. Many techniques for urogenital sinus repair have been described, but their outcome has not been evaluated prospectively (12, 13). Vaginoplasty should be performed during the teenage years. Every technique (self dilatation, skin or bowel substitution) has its specific advantages and disadvantages (14). All carry a potential for scarring that would require further surgery before sexual function was possible. Aesthetic refinements. The goals of genital surgery are to maximize anatomy to allow sexual function and romantic partnering. Aesthetics are important in this perspective. The reconstruction of minor labiae from an enlarged clitoral hood is an example of aesthetic refinement. 17.5.2 Masculinizing surgery Hormone therapy early in life is advocated by many doctors. The level of evidence is low for restoration of normal penile size. Hypospadias surgery. See section on hypospadias (Chapter 6).

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Excision of Mullerian structures. In the DSD patient assigned a male gender, Müllerian structures should be excised. There is no evidence about whether utricular cysts need to be excised. Orchiopexy. See section on orchidopexy (Chapter 3). Phalloplasty. The increasing experience of phalloplasty in the treatment of female to male transsexual patients has led to reports about the reliability and feasibility of this technique. It has therefore become available to treat severe penile inadequacy in DSD patients. Aesthetic refinements. These include correction of penoscrotal transposition, scrotoplasty and insertion of testicular prostheses. Gonadectomy. Germ cell malignancy only occurs in patients with DSD who have Y-chromosomal material. The highest risk is seen in patients with gonadal dysgenesis and in patients with partial androgen insensitivity with intra-abdominal gonads (Level of evidence: 2). Intra-abdominal gonads of high-risk patients should be removed at the time of diagnosis (Grade of recommendation: A) (15).

17.6

REFERENCES

1. Lee PA, Houk CP, Ahmed SF, Hughes IA; International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Pediatrics 2006;118(2):e488-e500. http://www.ncbi.nlm.nih.gov/pubmed/16882788 2. Houk CP, Hughes IA, Ahmed SF, Lee PA; Writing Committee for the International Intersex Consensus Conference Participants. Summary of consensus statement on intersex disorders and their management. International Intersex Consensus Conference. Pediatrics 2006;118(2):753-7. http://www.ncbi.nlm.nih.gov/pubmed/16882833 3. Creighton S, Alderson J, Brown S, Minto CL. Medical photography: ethics, consent and the intersex patient. BJU Int 2002;89(1):67-1; discussion 71-2. http://www.ncbi.nlm.nih.gov/pubmed/11849163 4. Biswas K, Kapoor A, Karak AK, Kriplani A, Gupta DK, Kucheria K, Ammini A. Imaging in intersex disorders. J Pediatr Endocrinol Metab 2004;17(6):841-5. http://www.ncbi.nlm.nih.gov/pubmed/15270401 5. Wright NB, Smith C, Rickwood AM, Carty HM. Imaging children with ambiguous genitalia and intersex states. Clin Radiol 1995;50(12): 823-9. http://www.ncbi.nlm.nih.gov/pubmed/8536391 6. Chertin B, Koulikov D, Alberton J, Hadas-Halpern I, Reissman P, Farkas A. The use of laparoscopy in intersex patients. Pediatr Surg Int 2006;22(5):405-8. http://www.ncbi.nlm.nih.gov/pubmed/16521001 7. Denes FT, Mendonca BB, Arap S. Laparoscopic management of intersexual states. Urol Clin North Am 2001;28(1):31-42. http://www.ncbi.nlm.nih.gov/pubmed/11277066 8. [No authors listed] Timing of elective surgery on the genitalia of male children with particular reference to the risks, benefits, and psychological effects of surgery and anesthesia. American Academy of Pediatrics. Pediatrics 1996;97(4):590-4. http://www.ncbi.nlm.nih.gov/pubmed/8632952 9. Creighton SM. Adult female outcomes of feminising surgery for ambiguous genitalia. Pediatr Endocrinol Rev 2004;2(2):199-202. http://www.ncbi.nlm.nih.gov/pubmed/16429106 10. Minto CL, Liao LM, Woodhouse CR, Ransley PG, Creighton SM. The effect of clitoral surgery on sexual outcome in individuals who have intersex conditions with ambiguous genitalia: a crosssectional study. Lancet 2003;361(9365):1252-7. http://www.ncbi.nlm.nih.gov/pubmed/12699952 11. Crouch NS, Creighton SM. Minimal surgical intervention in the management of intersex conditions. J Pediatr Endocrinol Metab 2004;17(12):1591-6. http://www.ncbi.nlm.nih.gov/pubmed/15645692 12. Jenak R, Ludwikowski B, Gonzalez R. Total urogenital sinus mobilization: a modified perineal approach for feminizing genitoplasty and urogenital sinus repair. J Urol 2001;165(6 Pt 2):2347-9. http://www.ncbi.nlm.nih.gov/pubmed/11371975

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13. Leclair MD, Gundetti M, Kiely EM, Wilcox DT. The surgical outcome of total urogenital mobilization for cloacal repair. J Urol 2007;177(4):1492-5. http://www.ncbi.nlm.nih.gov/pubmed/17382761 14. Schober JM. Feminizing genitoplasty: a synopsis of issues relating to genital surgery in intersex individuals. J Pediatr Endocrinol Metab 2004;17(5):697-703. http://www.ncbi.nlm.nih.gov/pubmed/15237702 15. Cools M. Drop SL, Wolffenbuttel KP, Oosterhuis JW, Looijenga LH. Germ cell tumors in the intersex gonad: old paths, new directions, moving frontiers. Endocr Rev 2006;27(5):468-84. http://www.ncbi.nlm.nih.gov/pubmed/16735607

18. Posterior urethral valves 18.1

Background

Posterior urethral valves (PUV) are one of the few life-threatening congenital anomalies of the urinary tract found during the neonatal period. Despite optimal treatment, PUV in children may result in renal insufficiency in nearly 35% of cases. PUV are found in 1 in 1,250 in a population undergoing fetal ultrasound screening (1). An incidence of PUV of 1 in 5,000-12,500 live-births has been estimated (2, 3). In one report, up to 46% of fetuses with a PUV diagnosis were terminated (4), indicating a possible decrease in incidence.

18.2

Classification

18.2.1 Urethral valve Despite recent attempts to introduce new classification terms, such as ‘congenital obstructive posterior urethral membrane (COPUM)’ (5), the original classification by Hugh Hampton Young remains the most commonly used (6). Hampton Young described three categories: type I, type II and type III. However, today, only type I and type III are found to be obstructive. As type II seems to be more like a fold and not obstructive, it is no longer referred to as a valve. Hampton Young’s descriptions of type I and II are as follows: Type I (90-95%). ‘In the most common type there is a ridge lying on the floor of the urethra, continuous with the verumontanum, which takes an anterior course and divides into two fork-like processes in the region of the bulbo-membranous junction. These processes are continued as thin membranous sheets, direct upward and forward which may be attached to the urethra throughout its entire circumference. It is generally supposed that the valves have complete fusion anteriorly, leaving only an open channel at the posterior urethral wall. Yet the fusion of the valves anteriorly may not be complete in all cases, and this point a slight separation of the folds exist.’ (6) Type III. ‘There is a third type of which has been found at different levels of the posterior urethra and which apparently bears no such relation to the verumontanum. This obstruction was attached to the entire circumference of the urethra, with a small opening in the centre.’ (6). The transverse membrane described has been attributed to incomplete dissolution from the urogenital portion of the cloacal membrane (7). The embryology of the urethral valves is poorly understood. The membrane may be an abnormal insertion of the mesonephric ducts into the fetal cloaca (8).

18.3

Diagnosis

An obstruction above the level of the urethra affects the whole urinary tract in varying degrees. • The prostatic urethra is distended and the ejaculatory ducts may be dilated due to urinary reflux. The bladder neck is hypertrophied and rigid. • The hypertrophied bladder occasionally has multiple diverticula. • Nearly all valve patients have dilatation of both upper urinary tracts. This may be due to the valve itself and the high pressure in the bladder, or due to obstruction of the uretereovesical junction by the hypertrophied bladder. • If there is secondary reflux, the affected kidney functions poorly in most cases. During prenatal ultrasonography screening, bilateral hydroureteronephrosis and a distended bladder are suspicious signs of a urethral valve. If a dilated posterior urethra and a thick-walled bladder (‘keyhole’ sign) are seen, a PUV is likely. In the presence of increased echogenity of the kidney, dilatation of the urinary tract and oligohydramnion, the diagnosis of a PUV should strongly be considered.

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A voiding cysturethrography (VCUG) confirms a PUV diagnosis. This study is essential whenever there is a question of an infravesical obstruction, as the urethral anatomy is well outlined during voiding. A secondary reflux is observed in at least 50% of patients with PUV (9). Reflux is consistently associated with renal dysplasia in patients with PUV. It is generally accepted that reflux in the renal units acts as a ‘pressure pop-off valve’, which would protect the other kidney, leading to a better prognosis (10). Other types of pop-off mechanism include bladder diverticula and urinary extravasation, with or without urinary ascites (11). However, in the long-term, a supposed protective effect did not show a significant difference compared to other patients with PUV (12, 13). Nuclear renography with split renal function is important to assess kidney function. Creatinine, blood urea nitrogen and electrolytes should be monitored closely during the first few days. A nadir creatinine of 80 µmol/L is correlated with a better prognosis (14).

18.4

Treatment

18.4.1 Antenatal treatment About 40-60% of PUV are discovered before birth (15). The intrauterine obstruction leads to a decreased urine output, which could result in an oligohydramnios. Amnion fluid is necessary for normal development of the lung and its absence may lead to pulmonary hypoplasia, causing a life-threatening problem. Intrauterine attempts have been made to treat a fetus with PUV. As renal dysplasia is not reversible, it is important to identify those fetuses with good renal function. A sodium level below 100 mmol/L, a chloride value of < 90mmol/L and an osmolarity below 200 mOsm/L found in three fetal urine samples gained on three different days are associated with a better prognosis (16). The placing of a vesicoamniotic shunt has a complication rate of 21-59%, dislocation of the shunt occurs in up to 44%, mortality lies between 33% and 43%, and renal insufficiency is above 50% (16-18). Although shunting is effective in reversing oligohydramnios, it makes no difference to the outcome and longterm results of patients with PUV (17, 18). 18.4.2 Postnatal treatment Bladder drainage. If a boy is born with suspected PUV, drainage of the bladder and, if possible, an immediate VCUG is necessary. A neonate can be catheterized with a 3.5-5 F catheter. A VCUG is performed to see if the diagnosis is correct and whether the catheter is within the bladder and not in the posterior urethra. An alternative option is to place a suprapubic catheter, perform a VCUG and leave the tube until the neonate is stable enough to perform an endoscopic incision or resection of the valve. Valve ablation. When the medical situation of the neonate has stabilized and the creatinine level decreased, the next step is to remove the intravesical obstruction. Small paediatric cystoscopes and resectoscopes are now available either to incise or to resect the valve at the 4-5, 7-8 or 12 o’clock position, or at all three positions, depending on the surgeon’s preference. It is important to avoid extensive electrocoagulation as the most common complication of this procedure is stricture formation. Vesicostomy. If the child is too small and/or too ill to undergo endoscopic surgery, a vesicostomy is used to drain the bladder temporarily. If initially a suprapubic tube has been inserted, this can be left in place for 6-12 weeks. Otherwise, a cutaneous vesicostomy provides an improvement or stabilization of upper urinary tracts in over 90% of cases (19). Although there has been concern that a vesicostomy could decrease bladder compliance or capacity, so far there are no valid data to support these expectations (20-22). High diversion. If bladder drainage is insufficient to drain the upper urinary tract, high urinary diversion should be considered. Diversion may be suitable if there are recurrent infections of the upper tract, no improvement in renal function and/or an increase in upper tract dilatation, despite adequate bladder drainage. The choice of urinary diversion depends on the surgeon’s preference for high loop ureterostomy, ring ureterostomy, end ureterostomy or pyelostomy, with each technique having advantages and disadvantages (23-25). Reconstructive surgery should be delayed until the upper urinary tract has improved as much as can be expected. Reflux is very common in PUV patients (up to 72%) and it is described bilaterally in up to 32% (26). High-grade reflux is mostly associated with a poor functioning kidney. However, early removal of the renal unit seems to be unnecessary, as long as it causes no problems. It may be necessary to augment the bladder and in this case the ureter may be used (27). Life-long monitoring of these patients is mandatory, as bladder dysfunction is not uncommon and the delay in day- and night-time continence is a major problem (9, 14). Poor bladder sensation and compliance, detrusor instability and polyuria (especially at night) and their combination are responsible for bladder dysfunction. Between 10% and 47% of patients may develop end-stage renal failure (14, 28). Renal

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Figure 4. An algorithm providing information on assessment, treatment and follow up of newborns with possible PUV

Newborn with possible PUV, UUT dilatation and renal insufficiency • USG and VCUG • Assessment of renal function and electrolyte disorders Confirm diagnosis

Bladder drainage No stabilization

Nephrological care if needed

Valve ablation when baby is stable

Improvement in UT dilation and RF

• • • •

No improvement but stable

Consider diversion

Close follow-up Monitor urinary infection Monitor renal function Monitor bladder function and emptying • • •

Progressive loss of renal function Recurrent infections Poor emptying

Long term

No improvement and ill

Short term

• • • • •

Check residual PUV CIC if not emptying Consider overnight drainage Consider alpha-blockers Anticholinergics if OAB

Consider augmentation and Mitrofanoff PUV = posterior urethral valve; UUT = upper urinary tract; USG = urinary specific gravity; VCUG = voiding cystourethrogram; UT = urinary tract; RF = renal function; CIC = clean intermittent catheterization; OAB = overactive bladder.

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transplantation in these patients can be performed safely and effectively. Deterioration of the graft function is mainly related to lower urinary tract dysfunction (29, 30).

18.5

References

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Krahn CG, Johnson HW. Cutaneous vesicostomy in the young child: indications and results. Urology 1993;41(6):558-63. http://www.ncbi.nlm.nih.gov/pubmed/8516992 20. Kim YH, Horowitz M, Combs A, Nitti VW, Libretti D, Glassberg KI. Comparative urodynamic findings after primary valve ablation, vesicostomy or proximal diversion. J Urol 1996;156(2 Pt 2):673-6. http://www.ncbi.nlm.nih.gov/pubmed/8683757 21. Podesta M, Ruarte AC, Gargiulo C, Medel R, Castera R, Herrera M, Levitt SB, Weiser A. Bladder function associated with posterior urethral valves after primary valve ablation or proximal urinary diversion in children and adolescents. J Urol 2002;168(4 Pt 2):1830-5; discussion 1835. http://www.ncbi.nlm.nih.gov/pubmed/12352370 22. Jayanthi VR, McLorie GA, Khoury AE, Churchill BM. The effect of temporary cutaneous diversion on ultimate bladder function. J Urol 1995;154(2 Pt 2):889-92. http://www.ncbi.nlm.nih.gov/pubmed/7609206 23. Novak ME, Gonzales ET Jr. Single-stage reconstruction of urinary tract after loop cutaneous ureterostomy. Urology 1978;11(2):134-8. http://www.ncbi.nlm.nih.gov/pubmed/628990 24. Sober I. Pelvioureterostomy-en-Y. J Urol 1972;107(3):473-5. http://www.ncbi.nlm.nih.gov/pubmed/5010719 25. Williams DI, Cromie WJ. Ring ureterostomy. Br J Urol 1975;47(7):789-92. http://www.ncbi.nlm.nih.gov/pubmed/1222345 26. Scott JE. Management of congenital posterior urethral valves. Br J Urol 1985;57(1):71-7. http://www.ncbi.nlm.nih.gov/pubmed/3971107 27. Bellinger MF. Ureterocystoplasty: a unique method for vesical augmentation in children. J Uro 1993; 149(4):811-3. http://www.ncbi.nlm.nih.gov/pubmed/8455246 28. Reinberg Y, de Castano I, Gonzalez R. Influence of initial therapy on progression of renal failure and body growth in children with posterior urethral valves. J Urol 1992;148(2 Pt 2):532-3. http://www.ncbi.nlm.nih.gov/pubmed/1640516 29. DeFoor W, Tackett L, Minevich E, McEnery P, Kitchens D, Reeves D, Sheldon C. Successful renal transplantation in children with posterior urethral valves. J Urol 2003;170(6 Pt 1):2402-4. http://www.ncbi.nlm.nih.gov/pubmed/14634437 30. Salomon L, Fontaine E, Guest G, Gagnadoux MF, Broyer M, Beurton D. Role of the bladder in delayed failure of kidney transplants in boys with posterior urethral valves. J Urol 2000;163(4):1282-5. http://www.ncbi.nlm.nih.gov/pubmed/10737529

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19. ABBREVIATIONS USED IN THE TEXT

This list is not comprehensive for the most common abbreviations

AGS adrenogenital syndrome ACTH adrenocorticotropic hormone AMH anti-Müllerian hormone ARM anorectal malformation CAH congenital adrenal hyperplasia CIC clean self-intermittent catheterization CNS central nervous system COPUM congenital obstructive posterior urethral membrane CRP C-reactive protein DDAVP desmopressine CT computed tomography DHTST dihydrotestosterone DMSA dimercaptosuccinic acid EMG electromyography ESR erythrocyte sedimentation rate ESWL extracorporeal shockwave lithotripsy FSH follicle stimulating hormone GnRH gonadotrophin-releasing hormone hCG human chorionic gonadotrophin IC intermittent catheterisation ICCS International Children’s Continence Society IVU intravenous urogram LH luteinizing hormone LHRH luteinizing hormone releasing hormone LUT(S) lower urinary tract (symptoms) MRI magnetic resonance imaging NDSD neurogenic detrusor-sphincter dysfunction OAB overactive bladder PNL percutaneous litholapaxy RCT randomized controlled treatment trials RN reflux nephropathy RNC radionuclide cystography RTA renal tubular acidosis Tc-MAG3 (99m) technetium-99m mercaptoacetyltriglycine (MAG3) TIP tubularized incised urethral plate TST testosterone UPJ ureteropelvic junction URS ureterorenoscopy US ultrasound UTIs urinary tract infections VCUG voiding cystourethrography VRR vesicorenal reflux VUR vesicoureteral reflux VUS voiding urosonography

Conflict of interest All members of the Paediatric Urology Guidelines writing panel have provided disclosure statements on all relationships that they have and that might be perceived to be a potential source of conflict of interest. This information is kept on file in the European Association of Urology Central Office database. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

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