New Aspects in the Diagnosis and Treatment of Prostate Cancer: Oncology

New Aspects in the Diagnosis and Treatment of Prostate Cancer Guest Editors K. Miller, Berlin T. Wiegel, Berlin W. Hi...

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New Aspects in the Diagnosis and Treatment of Prostate Cancer

Guest Editors

K. Miller, Berlin T. Wiegel, Berlin W. Hinkelbein, Berlin

Basel 폷 Freiburg 폷 Paris 폷 London 폷 New York 폷 Bangalore 폷 Bangkok 폷 Singapore 폷 Tokyo 폷 Sydney

S. Karger Medical and Scientific Publishers Basel 폷 Freiburg 폷 Paris 폷 London New York 폷 Bangalore 폷 Bangkok Singapore 폷 Tokyo 폷 Sydney

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Drug Dosage The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.

All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center (see ‘General Information’). © Copyright 2003 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISBN 3–8055–7625–0

Vol. 65, Suppl. 1, 2003

Contents

1 Adjuvant Hormonal Treatment for Prostate Cancer: The Bicalutamide Early

Prostate Cancer Program Wirth, M.P.; Froehner, M. (Dresden) 5 Bisphosphonates in the Management of Metastatic Prostate Cancer Heidenreich, A. (Marburg) 12 Quantitative Real-Time RT-PCR for Detection of Circulating

Prostate-Specific Antigen mRNA Using Sequence-Specific Oligonucleotide Hybridization Probes in Prostate Cancer Patients Straub, B.; Müller, M.; Krause, H.; Schrader, M.; Miller, K. (Berlin) 18 Salvage Radiotherapy in Patients with Persisting Prostate-Specific Antigen

after Radical Prostatectomy for Prostate Cancer Bottke, D.; Wiegel, T.; Höcht, S.; Müller, M.; Schostak, M.; Hinkelbein, W. (Berlin) 24 Intermittent Androgen Deprivation for Locally Advanced Prostate Cancer.

Preliminary Experience from an Ongoing Randomized Controlled Study of the South European Urooncological Group Calais da Silva, F. (Lisbon); Bono, A. (Varese); Whelan, P. (Leeds); Brausi, M. (Modena); Queimadelos, M. (Santiago de Compostela); Portillo, J. (Santander); Kirkali, Z. (Izmir); Robertson, C. (Glasgow) 29 Neoadjuvant Hormonal Treatment and Radiotherapy for Prostate Cancer Wachter, S.; Wachter-Gerstner, N.; Pötter, R. (Vienna)

© 2003 S. Karger AG, Basel Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Access to full text and tables of contents, including tentative ones for forthcoming issues: www.karger.com/ocl_issues

Oncology 2003;65(suppl 1):1–4 DOI: 10.1159/000072484

Adjuvant Hormonal Treatment for Prostate Cancer: The Bicalutamide Early Prostate Cancer Program Manfred P. Wirth Michael Froehner Department of Urology, University Hospital ‘Carl Gustav Carus’, Technical University of Dresden, Dresden, Germany

Key Words Prostate cancer W Adjuvant W Hormonal treatment W Bicalutamide W Radical prostatectomy W Radiotherapy W Watchful waiting

Abstract Adjuvant hormonal therapy has been demonstrated to be able to delay disease progression in nonmetastatic prostate cancer. To date, however, a favorable impact on survival has only been demonstrated in lymph-nodepositive disease and in external-beam radiotherapy series with locally advanced and probably mainly micrometastatic tumors. The Bicalutamide Early Prostate Cancer Program is the largest study under way to define the role of adjuvant treatment in early prostate cancer and identify subgroups of patients likely to benefit from immediate hormonal therapy. At the time of the most recently published analysis, the risk of objective clinical progression was significantly reduced in the bicalutamide arm (hazards ratio 0.58, 95% confidence interval 0.51–0.66, p ! 0.0001). However, further maturation of data is needed to see whether this difference will lead to a survival advantage.

Adjuvant Treatment for Prostate Cancer

If prostate cancer is organ confined, radical prostatectomy achieves disease-specific 10-year survival rates of about 90% [1]. There are, however, subsets of patients with a markedly less favorable outcome. When disease has spread outside the prostate, survival is compromised. In a multicentric study with 298 stage cT3 patients treated by pelvic lymph node dissection with or without subsequent radical prostatectomy, the prostate cancerspecific 10-year survival rate was only 57% [2]. Radiotherapy alone for locally advanced prostate cancer produced unfavorable results as well [3]. Whereas the longterm outcome after radical prostatectomy is excellent in tumors with a Gleason score of 2–6, the disease-specific 15-year survival is clearly compromised when the Gleason score is 7–10 [4]. In the especially problematic subgroup of patients with Gleason score 8–10 disease, disease-specific 15-year survival after radical prostatectomy is less than 50% [4]. Several clinical trials investigated the effect of adjuvant hormonal therapy to improve these results. Generally, to date, a favorable impact of adjuvant hormonal treatment on survival has only been demonstrated in lymph-node-positive disease and in external-

Copyright © 2003 S. Karger AG, Basel

Professor Manfred P. Wirth is principal investigator of the ‘Bicalutamide Early Prostate Cancer Program’ which is supported by AstraZeneca.

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Accessible online at: www.karger.com/ocl

Manfred P. Wirth, Professor and Chairman Department of Urology, University Hospital ‘Carl Gustav Carus’ Technical University of Dresden Fetscherstrasse 74, DE–01307 Dresden (Germany) Tel. +49 351 4582447, Fax +49 351 4584333, E-Mail [email protected]

Table 1. Overview over selected studies on adjuvant hormonal treatment after curative therapy for prostate cancer Authors

Year

Setting

Inclusion criteria

Hormonal treatment

Progression

Survival

Pilepich et al. [5] Lawton et al. [6]

1997 2001

RT

stage C or D1

LHRH analogues

advantage for adjuvant treatment

advantage for adjuvant treatment in Gleason score 8–10 subgroup

Granfors et al. [7]

1998

RT

T1–4N0–1

orchiectomy


advantage for adjuvant treatment in N1 subgroup

Arcangeli et al. [8]

1998

RT

confined to the pelvis

multiple regimens

no advantage for adjuvant treatment

disadvantage for adjuvant treatment

Hanks et al. [9]

2000

RT

T2b–T4, PSA ! 150 ng/ml

LHRH analogues plus flutamide


advantage for adjuvant treatment in high risk subsets (cT3–4 or cT2 with Gleason score 8–10, all Gleason score 8–10 cancers)

Bolla et al. [10]

2002

RT

T1–T4N0–x

LHRH analogues



Zincke et al. [11]

1992

RPE

pN+

multiple regimens


advantage for adjuvant treatment in diploid subgroup

Seay et al. [12]

1998

RPE

pN+

orchiectomy or LHRH analogues


advantage for adjuvant treatment in diploid subgroup after 10 years

Messing et al. [13]

1999

RPE

pN+

orchiectomy or LHRH analogues



Prayer-Galetti et al. [14]

2000

RPE

stage C

LHRH analogues


not available

Zincke et al. [15]

2001

RPE

seminal vesicle involvement

orchiectomy or oral hormones



Wirth et al. [16] Wirth et al. [17]

1997 2003

RPE

stage C

flutamide


no detectable difference

RT = Radiotherapy; RPE = radical prostatectomy.

beam radiotherapy series with locally advanced and probably mainly micrometastatic tumors (table 1). Adjuvant treatment after the resection or destruction of all macroscopic tumor tissue is intended to prevent progression of suspected microscopic residual cancer. During the last decades, new means of hormonal deprivation (LHRH analogues, antiandrogens) have been developed which allow for reversible and time-limited treatment. Since even in incurable locally advanced or metastatic prostate cancer, immediate hormonal treatment offers only a small survival advantage over deferred treatment after 10 years – detectable only in a meta-analysis including more than 2,000 patients [18] – trials investigating the effect of adjuvant treatment in early prostate cancer require very large numbers of patients enrolled and a long follow-up. The optimal duration of adjuvant treatment and the question whether delayed onset of hormonal treatment (controlled by PSA monitoring) may be as effective as immediate treatment in risk patients [19] remain the subject of an ongoing debate.

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Oncology 2003;65(suppl 1):1–4

The Bicalutamide Early Prostate Cancer Program

In early breast cancer, adjuvant treatment with the antioestrogen tamoxifen resulted in a significant survival benefit over local therapy only [20]. Since prostate cancer is also a hormone-sensitive tumor, it has been hypothezised that early antiandrogenic therapy may be beneficial in this tumor entity as well [21, 22]. In the ‘Bicalutamide Early Prostate Cancer Program’ (for clinical stages T1b4N0-1M0), the nonsteroidal antiandrogen bicalutamide is being evaluated as primary or adjuvant therapy for early prostate cancer. The program consists of three doubleblind, parallel-group trials (one in North America (trial 23, n = 3,292), one in Mexico, South Africa, Australia and Europe (trial 24, n = 3,603), and one in Scandinavia (trial 25, n = 1,218) [22]. In trial 23, all patients underwent radical prostatectomy or radiotherapy prior to study entry. In trials 24 and 25, watchful waiting was possible as a primary management option besides both treatments with cura-

Wirth/Froehner

Fig. 1. Freedom from objective clinical progression at 5 years [22].

Fig. 2. Freedom from biochemical progression at 5 years [22].

tive intent [21, 22]. For an exact description of the inclusion and exclusion criteria, see See et al. [22]. With a total of 8,113 patients, this program is the largest currently ongoing study on prostate cancer [23]. The patients were randomized on a 1:1 basis to receive either bicalutamide 150 mg once daily (n = 4,052) or placebo (n = 4,061) [22]. In North America, more than 80% had undergone radical prostatectomy and 20% received radiotherapy prior to randomization, compared to 46 and 18% in the Mexico, South Africa, Australia and Europe trial and 13 and 5% in the Scandinavian trial [22]. In North America, more than 70% of patients entered had a tumor stage of less than T3, compared with approximately 60% in Europe and Scandinavia [22–24]. The patients received the adjuvant medication for 2 or more years [22]. Time to objective clinical progression (defined as tumor progression confirmed by either biopsy, bone scan, computerized tomography, ultrasound, or magnetic resonance imaging or death of any causes) and survival are the primary end points in the Bicalutamide Early Prostate Cancer Program [21, 22]. Time to treatment failure (withdrawal from treatment), PSA progression (defined as doubling of the PSA value measured immediately prior to the initiation of the application of the study medication) and tolerability are secondary end points [21, 22]. After a median follow-up of 3 years, 38.1% of patients in the bicalutamide group and 31.8% in the placebo group discontinued the treatment. Adverse events were the most common reason for withdrawal from treatment in the bicalutamide group versus disease progression in the placebo group [22]. Gynecomastia and/or breast pain were the most frequent adverse events in the bicalutamide arm with almost 3 of 4 patients being affected [22]. These symptoms improved or re-

solved after withdrawal of treatment in the majority of cases. Whereas breast pain disappeared in 84% of affected patients within 1 year after cessation of therapy, the resolution rate of gynecomastia depended on the duration of bicalutamide treatment with only 29% resolution in those patients who took the medication for more than 18 months [22]. At the time of the most recently published analysis [22], 363 patients in the bicalutamide arm and 559 patients in the placebo arm fulfilled the criteria of objective clinical progression (fig. 1). This reduction in the risk of clinical progression by 45% in the bicalutamide arm was highly significant (hazards ratio 0.58, 95% confidence interval 0.51–0.66, p ! 0.0001). This result needs to be qualified by emphasizing that in trial 23, with its much more favorable risk profile, there was no detectable difference concerning objective progression at this time (83 events in the bicalutamide arm and 87 events in the placebo arm). Overall, the reduction in the risk was observed in the whole study population regardless of the primary (curative or noncurative) treatment. Subgroup analyses revealed a hazards ratio of 0.63 (p ! 0.001) for patients who had radical prostatectomy or radiotherapy and of 0.53 (p ! 0.001) for those who did not undergo curative treatment [22]. As expected, the risk reduction was greater in patients with locally advanced disease and in those selected for watchful waiting [22]. Not unexpectedly, considering PSA progression, there was also a highly significant advantage in the bicalutamide arm (fig. 2). For a survival analysis, however, there were too few events observed up to the time of analysis, and a longer follow-up is needed to see whether the delayed clinical progression in the bicalutamide arm will translate into a survival advantage which is the most urgent question to be answered.

Bicalutamide Early Prostate Cancer Program


3

Conclusion

Adjuvant treatment for prostate cancer has been shown to provide a survival advantage in patients with histopathologically proven lymph node involvement or with a high risk of microscopic spread. It is, however, still controversial whether a slightly delayed treatment (onset at PSA relapse) may be equally effective. Except for the above-mentioned high-risk patients, randomized trials on

adjuvant treatment have so far revealed a delay of progression but no survival advantage in early prostate cancer. The maturation of data of large ongoing trials like the Bicalutamide Early Prostate Cancer Program will increase our knowledge base. However, further studies investigating the appropriate length of adjuvant hormonal therapy are also needed. Efforts are necessary to improve our understanding of factors influencing the survival of men with early prostate cancer.

References 1 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;152:1850–1857. 2 Gerber GS, Thisted RA, Chodak GW, Schröder FH, Frohmüller HG, Scardino PT, Paulson DF, Middleton AW, Rukstalis DB, Smith JA, Ohori M, Theiss M, Schellhammer PF: Results of radical prostatectomy in men with locally advanced prostate cancer: Multi-institutional pooled analysis. Eur Urol 1997;32:385–390. 3 Bolla M: Adjuvant hormonal treatment with radiotherapy for locally advanced prostate cancer. Eur Urol 1999;35(suppl 1):23–26. 4 Barry MJ, Albertsen PC, Bagshaw MA, Blute ML, Cox R, Middleton RG, Gleason DF, Zincke H, Bergstralh EJ, Jacobsen SJ: Outcomes for men with clinically nonmetastatic prostate carcinoma managed with radical prostactectomy, external beam radiotherapy, or expectant management: A retrospective analysis. Cancer 2001;91:2302–2314. 5 Pilepich MV, Caplan R, Byhardt RW, Lawton CA, Gallagher MJ, Mesic JB, Hanks GE, Coughlin CT, Porter A, Shipley WU, Grignon D: Phase III trial of androgen suppression using goserelin in unfavourable prognosis carcinoma of the prostate treated with definitive radiotherapy – report of RTOG protocol 85– 31. J Clin Oncol 1997;15:1013–1021. 6 Lawton CA, Winter K, Murray K, Machtay M, Mesic JB, Hanks GE, Coughlin CT, Pilepich MV: Updated results of the phase III radiation therapy oncology group (RTOG) trial 85–31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001;49: 937–946. 7 Granfors T, Modig H, Damber JE, Tomic R: Combined orchiectomy and external radiotherapy versus radiotherapy alone for nonmetastatic prostate cancer with or without pelvic lymph node involvement: A prospective randomized study. J Urol 1998;159:2030–2034. 8 Arcangeli G, Saracino B, Micheli A, D’Angelo L, Pansadoro V, Cruciani E, Marchetti P: Radiotherapy with or without androgen deprivation in the treatment of localized adenocarcino-

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11

12

13

14

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ma of the prostate. Am J Clin Oncol 1998;21: 1–5. Hanks GE, Lu J, Machtay M, Venkatesan V, Pinover W, Byhardt R, Rosenthal SA: RTOG Protocol 92–02:A phase III trial of the use of long-term androgen suppression following neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate (abstract). Proc ASCO 2000;19: 327a. 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;360:103–106. Zincke H, Bergstralh EJ, Larson-Keller JJ, Farrow GM, Myers RP, Lieber MM, Barrett DM, Rife CC, Gonchoroff NJ: Stage D1 prostate cancer treated by radical prostatectomy and adjuvant hormonal treatment. Cancer 1992; 70:311–323. Seay TM, Blute ML, Zincke H: Long-term outcome in patients with pTxN+ adenocarcinoma of prostate treated with radical prostatectomy and early androgen ablation. J Urol 1998;159: 357–364. Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D: Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 1999:341:1781–1788. Prayer-Galetti T, Zattoni F, Capizzi A, Dal Moro F, Pagano F on behalf of the study group: Disease free survival in patients with pathological ‘C stage’ prostate cancer at radical retropubic prostatectomy submitted to adjuvant hormonal treatment (abstract). Eur Urol 2000; 38(suppl 4):504. Zincke H, Lau W, Bergstralh, Blute ML: Role of early adjuvant hormonal therapy after radical prostatectomy for prostate cancer. J Urol 2001;166:2208–2215.

16 Wirth M, Frohmüller H, Marx F, for the study group: Adjuvant antiandrogenic treatment after radical prostatectomy in stage C prostate cancer – preliminary results of a randomized controlled multicenter trial (abstract). J Urol 1997;157(suppl):1308. 17 Wirth MP, Weissbach L, Marx FJ, Heckl W, Jellinghaus W, Riedmiller H, Noack B, Froehner M: Prospective randomised trial comparing flutamide as adjuvant treatment versus observation after radical prostatectomy for stage pT3pN0 prostate cancer (abstract). J Urol 2003;169:343. 18 Nair B, Wilt T, MacDonald R, Rutks I: Early versus deferred androgen suppression in the treatment of advanced prostatic cancer. Cochrane Database Syst Rev 2002;(1):CD003506. 19 Wirth MP, Froehner M: The value of endocrine therapy for early and locally advanced prostate cancer. Drugs Aging 2003;20:115– 124. 20 Early Breast Cancer Trialists’ Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomized trials. Lancet 1998;251:1451–1467. 21 Wirth M, Tyrrell C, Wallace M, Delaere KP, Sanchez-Chapado M, Ramon J, Hetherington J, Pina F, Heynes CF, Borchers TM, Morris T, Stone A: Bicalutamide (Casodex) 150 mg as immediate therapy in patients with localized or locally advanced prostate cancer significantly reduces the risk of disease progression. Urology 2001;58:146–151. 22 See WA, Wirth MP, McLeod DG, Iversen P, Klimberg I, Gleason D, Chodak G, Montie J, Tyrrell C, Wallace DM, Delaere KP, Vaage S, Tammela TL, Lukkarinen O, Persson BE, Carroll K, Kolvenbag GJ; Casodex Early Prostate Cancer Trialist Group: Bicalutamide as immediate therapy either alone or as adjuvant to standard care of patients with localized or locally advanced prostate cancer: First analysis of the early prostate cancer program. J Urol 2002;168:429–435. 23 See WA, McLeod D, Iversen P, Wirth M: The Bicalutamide Early Prostate Cancer Program. Demography. Urol Oncol 2001;6:43–47. 24 Wirth MP, Froehner M: Perspectives in adjuvant treatment of prostate cancer. Urol Int 2002;85:1–5.

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Bisphosphonates in the Management of Metastatic Prostate Cancer Axel Heidenreich Department of Urology, Philipp University Marburg, Marburg, Germany

Key Words Prostate cancer W Zoledronate W Ibandronate W Androgen deprivation W Osteoporosis W Palliation W Pain management

domized trials will have to explore the clinical role of BPs in the prevention of bone metastases following local therapy with curative intent in men at high risk for PCA recurrences. Copyright © 2003 S. Karger AG, Basel

Abstract Prostate cancer (PCA) frequently metastasizes to the bones, and skeletal metastases represent the most common cause of morbidity in advanced PCA. Besides the development of skeletal events due to metastases, patients with PCA are at higher risk for benign osseous complications, such as osteoporosis and fractures. Bisphosphonates (BPs) have emerged as an integral part of the management of skeletal disease related to PCA. Currently available data support their routine use to prevent androgen-deprivation-induced osteoporosis and its secondary complications. Dosing at 3-month intervals is appropriate; further studies will have to demonstrate the efficacy of annual dosing. In men with already established bone metastases, BPs might be helpful in preventing skeletal-related events in patients who do not respond to alternative therapies and are at high risk for bone fractures or spinal cord compression. In patients with hormone-refractory prostate cancer, BPs might be administered for analgesic purposes. Prospective ran-

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Introduction

Prostate cancer (PCA) frequently metastasizes to the skeleton, most commonly to the vertebral column, pelvic bones and the lower extremities. Together with carcinomas of the breast, thyroid, kidney and lung, PCA accounts for more than 80% of metastatic bone disease in human malignancies [1]. Bone metastases represent the most frequent cause of morbidity in advanced PCA due to bone pain, pathologic fractures, spinal cord compression, anemia. Despite extensive screening programs, 10–20% of patients with newly diagnosed PCA develop bone metastases, another 30% of the patients will develop bone metastases following local therapy with curative intent due to locally advanced PCA [2]. Common complications due to skeletal metastases include bone pain in up to 80%, vertebral collapse or deformity in 18%, pathologic fractures in 9%, spinal cord compression in 6% [3]. Extensive bone lesions, extensive bone

Priv. Doz. Dr.med. Axel Heidenreich, Associate Professor of Urology Department of Urology and Pediatric Urology, Philipps University Marburg Baldingerstrasse, DE–35043 Marburg (Germany) Tel. +49 6421 286 2514, Fax +49 6421 286 5590 E-Mail [email protected]

pain, poor performance status and high serum concentrations of alkaline phosphatase represent common predictors of skeletal morbidity. Bone metastases in PCA are dominated by osteoblastic lesions on radiographic images; however, histomorphometric studies have demonstrated both, osteoblastic and osteolytic lesions in PCA [4–6]. After entering the widechanelled sinusoids of the bone marrow cavity, cancer cells might invade the marrow stroma and travel to the endosteal bone surface where they might stimulate the activity of osteoclasts and/or osteoblasts [5, 6]. The mechanisms by which cancer cells cause osteoblastic metastasis are not fully understood. However, there are accumulating data that circulating endothelin-1 [7], TGF-ß2 [8], and bone morphogenetic proteins [9, 10] might cause osteoblast proliferation and development of osteoblastic metastases. Overexpression of the serine protease urokinase (uPA) and its amino-terminal fragment has been shown to exert mitogenic activity for osteoblasts associated with the formation of metastases [11]. On the other hand, PSA itself might activate osteoblast-stimulating factors such as IGF-1, TGF-ß, PTHrH fragments [12, 13]. The extensive mobilization of calcium results in stimulation of osteoclasts with generalized bone resorption and secondary hyperparathyroidism (bone hunger syndrome). Besides the development of skeletal events due to metastases, patients with PCA are at higher risk for benign osseous complications, such as osteoporosis and osteopenia, due androgen deprivation therapy [14–23]. The incidence, rate, and severity of benign skeletal complications are associated with the duration of hormonal therapy. According to recent studies, the risk to suffer from osteoporotic hip fractures is as high as 5 and 20% 5 and 10 years after initiation of androgen deprivation. Androgen deprivation interferes with bone metabolism and results in increased bone resorption due to stimulation and activation of osteoclasts. Since the indication for androgen deprivation has been extended to high-risk patients and patients with nodal metastases, the group of patients at risk for treatment-induced osteoporosis has increased so that the prevention of benign skeletal complications might become even more important in the future. Bisphosphonates (BPs) inhibit osteoclast-mediated bone resorption, activity of osteoclast precursors and osteoblast-induced activiation of osteoclasts and might thus be beneficial in preventing skeletal morbidity in patients with advanced PCA. Currently, there are 4 indications for the application of BPs in the management of advanced PCA: (1) prevention of osteoporosis and benign skeletal complications due to

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androgen deprivation; (2) prevention of skeletal complications due to osseous metastases; (3) palliative pain management in hormone-refractory PCA (HRPCA) with painful osseous metastases, and (4) prevention of the formation of visceral and bone metastases in patients at high risk for systemic recurrence following local therapy with curative intent. It is the purpose of this review to highlight the current role of BPs in the prevention and management of benign and malignant skeletal complications due to PCA.

Efficacy and Side Effects

BPs are pyrophosphates in which the central oxygen in the phosphorus – oxygen – phosphorus has been replaced by carbon. Variation in the attached side chains determines the affinity for the bone mineral surface and the relative potency. Dependent on the side chain, 4 major groups of BPs can be distinguished: (1) BPS without nitrogen: etidronate, clodronate, tiludronate; (2) Amino-BPs: pamidronate, alendronate, neridronate; (3) Amino-BPs with substitutions at the nitrogen: olpadronate, ibandronate, and (4) BPs with basic, nitrogen-containing heterocycles: risedronate, zoledronate. Depending on the presence or absence of a nitrogen molecule, BPs act either by direct cellular toxicity or by interference with specific intracellular pathways in osteoclasts. Non-nitrogen-containing BPs are metabolized intracellularly to substances toxic to the cells. Nitrogen-containing BPs on the other hand interfere with specific enzymes of the mevalonate biosynthetic pathway and inhibit the production of small GTP-binding proteins essential for the integrity of the cytoskeleton and intracellular signaling. Due to these molecular events, osteoclasts become inactive or undergo apoptosis. Furthermore, BPs stimulate the secretion of the osteoclast resorption inhibitor (ORI) by osteoblasts thereby reducing the number of osteoclast precursors and osteoclasts. BPs appear to be of potential relevance in the management of PCA since they have been shown to inhibit the adhesion of PCA cells to artificial bone matrices or bone slices under in vitro conditions.

Prevention of Osteoporosis

About 5% of men 150 years of age have osteoporosis and 30–50% have osteopenia. In American men older than 65 years, the incidence of hip fractures as indicator

Heidenreich

for clinically relevant osteoporosis is 5 in 1,000. In patients with PCA treated with androgen suppression, the risk for androgen-deprivation-associated fractures is 5fold increased [14–19]. At 5 and 10 years, the incidence of skeletal fractures is 96 and 80%, respectively [15]. Duration of androgen deprivation, race and body mass index are the strongest predictors of skeletal fractures with white slender males being at the greatest risk. BPs have been proven to be effective in the reversal of androgen-suppression-induced osteoporosis. In a recent prospective randomized double-blind trial, the daily intake of alendronate at 10 mg for 2 years resulted in a significantly reduced risk of vertebragenic fractures and led to a significant increase in the bone mineral density of the lumbar spine and the femoral neck [20]. In a recent randomized, double-blind, placebo-controlled trial conducted in 106 men receiving initial androgen deprivation therapy for PCA, zoledronic acid has been shown to significantly increase the bone mineral density (BMD) in the lumbar spine, femoral neck, trochanter and total hip compared to the placebo group [21]. All patients received 4 mg zoledronic acid as a 15-min infusion every 3 months for 1 year. In another double-blind, randomized, placebo-controlled cross-over study, 21 men with metastatic PCA treated with combined androgen blockade received a single infusion of pamidronate (90 mg) or normal saline with a cross-over at 6 months [22]. The data of the study group were compared with those from 10 men with localized PCA who were managed by radiotherapy. There was a significant reduction in bone mineral density in 70% of patients in the placebo and the control group whereas the single infusion of pamidronate resulted in a significant increase in BMD. Smith et al. [23] demonstrated that the application of pamidronate every 3 months for 1 year resulted in a significant increase in the BMD of the femoral neck and the lumbar spine whereas the BMD in the control group decreased significantly. Based on the current data in the literature, the routine use of BPs for prevention of androgen-deprivation-induced osteoporosis and its secondary complications can be recommended. However, further prospective randomized trials still have to resolve the issue whether similar benefits can be achieved with complementary but less expensive therapies, such as vitamin D and calcium, ipriflavone [24].

Bisphosphonates and Prostate Cancer

Use of BPs in the Prevention of Skeletal Complications due to Osseous Metastases from HRPCA

Skeletal complications associated with bone metastases such as bone pain, pathologic fractures, spinal cord compression, need for palliative radiation therapy or orthopedic surgery represent the most common causes for cancer-associated morbidity in patients with HRPCA. Two prospective randomized, placebo-controlled trials have been conducted to investigate the clinical utility of BPs to prevent skeletal-related events in metastatic PCA [25, 26]. In a study performed by the Medical Research Council 311 patients with HRPCA where randomized to receive either oral clodronate or placebo [25]; median time to symptomatic progression was significantly prolonged in the clodronate group (26 vs. 20 months); median survival was in favor of the clodronate group with 34 months versus 27 months. However, updated results have to be awaited before significant conclusions can be drawn from the study. In the largest single phase III trial 643 men with HRPCA metastatic to the bone were randomized to receive zoledronate at 4 or 8 mg every 3 weeks for 15 consecutive months or placebo [26]. In addition, all patients received 500 mg calcium and 400–500 IU vitamin D daily. The primary endpoint of the study was the reduction in skeletal related events; secondary endpoints included time to first skeletal-related event, skeletal morbidity rate, time to disease progression, objective bone lesion response, and quality of life. Renal insufficiency represented the most significant side effect of the group receiving 8 mg, which resulted in termination of this arm and inclusion of the patients in the 4-mg group. Approximately 38, 28 and 31% of the patients who received zoledronic acid at 4 mg, 8 mg or placebo, respectively, completed the study. There was a significant reduction in skeletal-related events between the 4-mg group and the placebo group (33 vs. 44%, p = 0.021); however, there was no significant difference between the 8-mg group and the placebo group. The frequency of pathologic fractures was significantly lower in the 4-mg group compared to the placebo group (13.1 vs. 22.1%, p = 0.015). However, the statistically significant difference only holds true for the sum of all pathologic fractures whereas there was no statistically significant difference for the frequency of vertebral and nonvertebral fractures between the 4-mg group and the placebo group. The time to first skeletal-related event was significantly prolonged in the 4-mg group; furthermore, only 43 and 55% (p = 0.011) of the 4-mg group and the


7

placebo group were without any skeletal-related event 450 days after initiation of therapy. There were no significant differences between the groups with regard to the mean time to disease progression, objective bone response, and the median time to radiographic progression of bone lesions. Although the study demonstrated a positive effect of BPs in the prevention of secondary skeletal complications of osseous metastasis due to metastatic HRPCA, there are some limitations that should caution the treating physician against introducing zoledronic acid as standard practice for the treatment of metastatic PCA to the bone [27]. It is unknown whether the effects of zoledronic acid are the result of an antiosteoporotic effect on the general skeleton rather than specifically on bone metastases. Since there were no significant differences between the groups with regard to the incidence of spinal cord compression, radiation therapy to the bone, and surgery to the bone, prevention of osteoporosis and its secondary complications might have significantly contributed to the positive treatment results. Although the authors state that zoledronic acid was well tolerated by patients and that there was no significant difference with regard to quality of life, the incidence of specific parameters such as fatigue, anemia, myalgia, fever, lower limb edema and dizziness were all higher by 5–9% in the treatment group. These differences are in the same order as those in the primary endpoint and might explain why quality of life did not improve with therapy. Last but not least the cost-effectiveness of using zoledronic acid has to be determined since such analyses, for instance for pamidronate, have shown that its use is associated with high incremental costs per adverse event avoided. Currently, zoledronic acid might be a reasonable option for patients who do not respond to alternative therapies and who are at high risk for bone fractures or spinal cord compression; predictors of skeletal fractures have been recently defined and include extensive bone lesions, extensive bone pain, poor performance status and high serum concentrations of alkaline phosphatase [14].

Pain Palliation and BPs

The first randomized, placebo-controlled trial using etidronate was reported by Smith et al. [29] in 57 patients with metastatic HRPCA. The authors could not demonstrate any benefit in the etidronate group compared to the placebo group. However, one has to take into consideration that etidronate has a very low antiresorbing poten-

8


cy, i.e. only one tenth and one hundredth of clodronate and pamidronate activity, respectively. The first clodronate-based human study in patients with PCA metastatic to bones has been performed by Adami et al. [30]. The authors treated 17 patients with multiple osteoblastic bone metastases; the patients received clodronate intravenously (300 mg/daily) for 14 days and orally (3,200 mg/day) or intramuscularly (100 mg) for another 4–11 weeks. A significant improvement in pain and Karnofsky index was observed in 16/17 patients over 4–8 weeks; 2 patients were painfree for 18 months. Analgesic status could be restored by renewed intravenous administration of clodronate. In a second study [31], 41 patients with HRPCA and painful osseous metastases were given clodronate 300 mg i.v. for 8 days followed by an oral treatment with 1,600 mg. 20 (71%) patients had a significant reduction in pain, with 9 patients being completely painfree; mean duration of response was 7 weeks, with 2 patients remaining pain free for 5 months. Considering their short survival, patients experienced a significant pain reduction for at least 60% of their remaining time. Furthermore, pain relapse could be effectively abolished by another 3-day infusion of clodronate. In another 2 studies, 27 [32] and 16 patients [33] were treated with intravenous clodronate at 300 mg/day over 10 and 6 days, respectively, followed by oral clodronate at 3,200 mg. Significant pain relief was noted in 10/27 (37%) and 9/16 (56.2%) patients. The latest study [34], comprising the largest patient cohort with HRPCA with painful osseous metastases treated with clodronate, reported a significant reduction in pain in 75% of the patients and thus confirmed the results of the two prior trials. These results are even more remarkable when considering the patients’ poor general state (mean Karnofsky index 45%) and the extensive tumor disease at the time of referral and initiation of therapy. However, not all clinical trials achieved such positive results. In a recent double-blind placebo-controlled study, a decrease in pain scores and a significantly lower increase in the requirement of analgesics was achieved by the clodronate group [35]. In another study, clodronate was only beneficial to patients with a very high pain baseline [36]. Parenteral therapy is the major prerequisite to achieve rapid onset of pain control in most patients. Following an initial parenteral saturation phase, oral administration of 1,600mg/day clodronate most likely results in bone saturation and persistent pain relief for several weeks. Pamidronate also has been shown to be effective in the management of painful osseous metastases [37, 38]. Us-

Heidenreich

ing doses in the range of 30–60 mg weekly to 90–120 mg every 3–4 weeks, pain reduction was achieved in about 50% of the patients. Ibandronate has also been assessed in the palliation of bone pain in a recent prospective open single-arm pilot study including 25 patients. Pain palliation was achieved in 92% of the patients associated with a parallel increase in the Karnofsky index [39]. The clinical efficacy of 186Re-etidronate was recently evaluated in a double-blind, placebo-controlled, randomized clinical trial including 111 patients with painful osseous metastases due to HRPCA [40]. There was a significant higher pain response (27 vs. 13%, p ! 0.05) and a lower frequency of additional palliative radiation therapy (44 vs. 67%) in the etidronate group compared to the placebo group. In conclusion and in concordance with recent evidence-based guidelines for palliative care [41], BPs appear to have a role in the management of pain from bone metastases due to PCA refractory to conventional analgesic measures and where oncological and orthopedic intervention is not appropriate.

BPs as Adjuvant Therapy in the Prevention of Bone Metastases

The development of bone metastases requires primary cancer cells to enter the systemic circulation and the sinusoids of the bone marrow cavity, migrate across the sinusoidal wall, invade the marrow stroma, generate their own blood supply and travel to the endosteal bone surface [5, 6]. Although the exact molecular mechanisms stimulating bone formation which is associated with metastatic tumors are not known, accumulating data identify growth factors involved in the development of bone metastases, as indicated in the introduction [5–13]. Based on in vitro and in vivo data, BPs have an antitumor, apoptotic and antiproliferative potential [42–50]. It has been demonstrated in in vitro studies that pamidronate and clodronate induce cell death in prostate cancer cell lines, whereas zoledronic acid results in a significantly decreased cell proliferation rate. In addition, BPs inhibit tumor invasion and adhesion of PCA cells to mineralized and unmineralized bone matrices; inhibition is proportional to the potency of the BP with the following ranking: zoledronic acid 1 ibandronate 1 risedronate 1 clodronate. BPs can inhibit local invasiveness of PCA cells by downregulation of the membrane type I matrix metalloproteinase protein and mRNA.


Preclinical data using bone invasion models of prostate and breast cancer indicate that BPs might prevent the formation of osteolytic and osteoblastic bone metastases if given prior to the inoculation of tumor cells in the bone [47–50]. Using an SCID mouse model, Lee et al. [47] investigated the efficacy of zoledronic acid in limiting the formation or progression of osteolytic and osteoblastic lesions produced by the intratibial injection of PCA cell lines PC-3 and LAPC-9. The mice were treated with either 30 Ìg or 150 Ìg of zoledronic acid prior to tumor implantation (pretreatment group), at weekly intervals after tumor implantation or starting 1 month after tumor implantation (delayed treatment group). Whereas the control groups developed osteolytic (PC-3) or osteoblastic (LAPC-9) metastases, zoledronic acid effectively limited the formation of osteolytic lesions in the pretreatment group. However, in tibias implanted with the LAPC-9 cells zoledronic acid was not effective in halting the formation of osteoblastic lesions. In another study, ibandronic acid was shown to prevent and inhibit or revert growth of established osteolysis in a nude rat model of breast cancer. Using an in vivo model in which intracardiac inoculation of MCF-7 breast cancer cells overexpressing Neu causes osteoblastic bone metastases in nude mice, Yi et al. [50] demonstrated that pre-treatment with ibandronate (4 mg/day, 5 days/week, s.c.) markedly decreased the development of osteoblastic bone metastases and tumor burden compared to the control group. Preclinical data also indicate that BPs have no effect on soft-tissue metastases if they are administered after the metastases are already established. Whereas phase III trials have investigated the role of adjuvant administration of BPs to prevent the formation of bone metastases in breast cancer, none of these studies have been performed in men with PCA [53, 54]. In breast cancer, BPs significantly reduced skeletal morbidity and decreased the incidence of bone metastases by 50%; furthermore, there was a reduction in death rate in the clodronate arm at both 36 and 55 months following initiation of therapy [52]. Currently, phase III trials are under way to explore the clinical efficacy of BPs in men at high risk for PSA recurrences following radical prostatectomy. The primary endpoint of these trials was metastasis-free survival. Based on the findings that the combination of BPs with taxanes has some additive effects on antiproliferative activity [55, 56], some protocols combine androgen deprivation and BPs with taxotere in the adjuvant setting.


9

Conclusion

BPs have emerged as an integral part of the management of skeletal disease related to prostate cancer. Currently available data support their routine use to prevent androgen deprivation induced osteoporosis and its secondary complications. Dosing at 3-month intervals is appropriate; further studies will have to demonstrate the efficacy of annual dosing. In men with already established

bone metastases, BPs might be helpful in preventing skeletal-related events in patients who do not respond to alternative therapies and are at high risk for bone fractures or spinal cord compression. In patients with HRPCA, BPs might be administered for analgesic purposes. Prospective randomized trials will have to explore the clinical role of BPs in the prevention of bone metastases following local therapy with curative intent in men at high risk for PSA recurrences.

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21 Smith MR, Shasha D, Mansour R, Zinner N: Zometa increases bone mineral density in men undergoing androgen deprivation therapy for prostate cancer. Skeletal Complications of malignancy (abstract C8). Proc Third North American Symposium, Bethesda, 2002, pp 25– 27. 22 Diamond TH, Winters J, Smith A, de Souza P, Kersley JH, Lynch WJ, Bryant C: The antiosteoporotic efficacy of intravenous pamidronate in men with prostate carcinoma receiving combined androgen blockade. Cancer 2001;92: 1444–1450. 23 Smith MR, McGovern FJ, Zietman AL, Fallon MA, Hayden DL, Schoenfeld DA, Kanthoff PW, Finkelstein JS: Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 2001;345: 989–991. 24 Moyad MA: Complementary therapies for reducing the risk of osteoporosis in patients receiving luteinizing hormone-releasing hormone treatment/orchiectomy for prostate cancer: A review and assessment of the need for more research. Urology 2002;59(suppl 4A):34– 40. Prevention of Skeletal Complications 25 Dearnaley DP, Sydes MR, on behalf of the MRC PRO5 collaboration: Preliminary evidence that oral clodronate delays symptomatic progression of bone metastases from prostate cancer: First results of the MRC pro5 trial. Proc Am Soc Clin Oncol 2001;20:174a. 26 Saad F, Gleason DM; Murray R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goas JA, Chen B: A randomised, placebo-controlled trial of zoledronic acid in patients with hormone refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94: 1458–1468. 27 Canil CH, Tannock IF: Should bisphosphonates be used routinely in patients with prostate cancer metastatic to the bone. J Natl Cancer Inst 2002;94:1422–1423. 28 Hillner BE, Weeks JC, Desch CE, Smith TJ: Pamidronate in prevention of bone complications in metastatic breast cancer: A cost-effectiveness analysis. J Clin Oncol 2000;18:72–79.

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38 Lipton A, Glover D, Harvey H, Grabelsky S, Zelenakas K, Macerata K, Seaman J: Pamidronate in the treatment of bone metastases: Results of 2 dose ranging trials in patients with breast and prostate cancer. Ann Oncol 1994; 5(suppl):S31–S35. 39 Heidenreich A, Elert A, Hofmann R: Ibandronate in the treatment of prostate cancer associated painful osseous metastases. Prostate Cancer Prostatic Dis 2002;5:231–235. 40 Han SH, de Klerk JM, van het Schip AD, Derksen BH, van de Kruitwagen CL, Blijham GH, van Rijk PP, Zonnenberg BA: The PLACOHREN study: A double-blind, placebo-controlled randomized radionuclide study with 186Re-etidronate in hormone-resistant prostate cancer patients with painful bone $metastases. Placebo Controlled Rhenium Study. J Nucl Med 2002;43:1150–1156. 41 Mannix K, Ahmedzai SH, Anderson H, Bennett M, Lloyd-Williams, Wilcock A: Using bisphosphonates to control pain of bone metastases: Evidence-based guidelines for palliative care. Palliat Med 2000;14:455–461. Adjuvant Therapy 42 Lee MV, Fong EM, Singer FR, Guenette RS: Bisphosphonate treatment inhibits the growth of prostate cancer cells. Cancer Res 2001;61: 2602–2608. 43 Boissier S, Magnetto S, Frappart L, Cuzin B, Ebetino FH, Delmas PD, Clezardin P: Bisphosphonates inhibit prostate and breast carcinoma cell adhesion to unmineralised and mineralised bone extracellular matrices. Cancer Res 1997; 57:3890–3894. 44 Stearns ME, Wang M: Alendronate blocks metalloproteinase secretion and bone collagen I release by PC-3 ML cells in SCID mice. Clin Exp Metastasis 1998;16:693–702. 45 Stearns ME: Alendronate blocks TGF-beta 1 stimulated collagen 1 degradation by human prostate PC-3 ML cells. Clin Exp Metastasis 1998;16:332–339. 46 Boissier S, Ferreras M, Peyruchaud O, Magnetto S, Ebetino FH, Colombel M, Delmas P, Delaisse JM, Clezardin P: Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res 2000;60:2949–2954.

47 Yu-Cheng S, Geldorf AA, Newling DWW, Rao BR: Progression delay of prostate tumor skeletal metastasis effects by bisphosphonates. J Urol 1992;148:1270–1273. 48 Lee YP, Schwarz EM, Davies M, Jo M, Gates J, Zhang X, Wu J, Lieberman JR: Use of zoledronate to treat osteoblastic versus osteolytic lesions in a severe-combined-immunodeficient mouse model. Cancer Res 2002;62:5564– 5570. 49 Fischer C, Neudert M, Krempien B, Bauss F, Seibel MJ: Ibandronic acid prevents the development and induces remission of bone metastasis in a nude rat model of human breast cancer. Proc ASCO 2001;20:84a. 50 Yi B, Williams PJ, Niewolna M, Story B, Mundy GR, Yoneda T: Reduction of osteoblastic bone metastases by the bisphosphonate ibandronate. J Bone Min Res 1999;14(suppl 1): SA055. 51 Paterson AHG: The potential role of bisphosphonates as adjuvant therapy in the prevention of bone metastases. Cancer 2000;88:3038– 3046. 52 Diehl I, Solomeyer EP, Costa S, Gollan C, Goerner R, Wallwiener D: Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 1998;339: 357–363. 53 Saarto T, Blomqvist C, Virkkunen P, Elomaa I: Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in nodepositive breast cancer: 5-year results of a randomized controlled trial. J Clin Oncol 2001;19: 10–17. 54 Diehl IJ: Bisphosphonates in the prevention of bone metastases: Current evidence. Semin Oncol 2001;28(suppl 6):75–80. 55 Stearns ME, Wang M: Effects of alendronate and taxol on PC3 ML cell bone metastases in SCID mice. Invasion Metastasis 1996;16:116– 131. 56 Magnetto S, Boissier S, Delmas PD, Clezardin P: Additive antitumor activities of taxoids in combination with the bisphosphonate ibandronate against invasion and adhesion of human breast carcinoma cells to bone. Int J Cancer 1999;83:263–269.


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Quantitative Real-Time RT-PCR for Detection of Circulating Prostate-Specific Antigen mRNA Using Sequence-Specific Oligonucleotide Hybridization Probes in Prostate Cancer Patients Bernd Straub Markus Müller Hans Krause Mark Schrader Kurt Miller Department of Urology, Universitätsklinikum Benjamin-Franklin, Freie Universität Berlin, Berlin, Germany

Key Words Polymerase chain reaction W Prostate-specific antigen W Prostatectomy W Prostate cancer

Abstract Objective: A great number of studies have failed thus far to demonstrate that the presence of PSA-expressing tumor cells in the blood of prostate cancer (PC) patients is a highly sensitive prognostic marker, particularly after radical prostatectomy (RPX). These studies have only relied on qualitative or semiquantitative detection techniques, however. We report our initial experience in testing real-time RT-PCR for the detection of PSA mRNA using a quantitative online PCR system, the LightCyclerTM, and sequence-specific oligonucleotide hybridization probes. Methods: Blood samples were obtained before and after surgery from 129 patients undergoing RPX for localized PC and from 19 patients undergoing transurethral resection of the prostate for benign prostatic hyperplasia (BPH). Quantitative RT-PCR for the detection PSA mRNA was performed using the LightCycler system with RNA Amplification Kit Hybridization Probes and sequence-specific oligonucleotide hybridization probes. Results: PSA mRNA was detected by the LightCycler in 28 patients (39%) with pT2 tumors, in 22 pa-

ABC

© 2003 S. Karger AG, Basel 0030–2414/03/0655–0012$19.50/0



tients (38%) with 1pT2 tumors, but in only 3 patients (16%) with BPH. The mean values of the LNCaP cell equivalents were higher in 1pT2 patients than in pT2 patients (37 ! 103 and 104 ! 103) or BPH patients (7.1 ! 103 and 4.8 ! 103) both preoperatively (333 ! 103/ml blood) and postoperatively (545 ! 103). Conclusion: Real-time RT-PCR with the LightCycler appears to be a promising method for the preoperative detection of circulating LNCaP tumor cells in PC as reflected by PSA mRNA. Considering the low detection rates in BPH patients, the method may also be suitable for patient monitoring after RPX and could thus play an important role in deciding on early radiotherapy or even hormone ablation therapy. Additional long-term follow-up will have to show whether patients with high expression of PSA mRNA actually have an increased risk or recurrence and whether the method is suitable as well to detect progression. Copyright © 2003 S. Karger AG, Basel

Introduction

Adenocarcinoma of the prostate is the second most frequent cause of death among male cancer patients in Western industrialized countries [1]. About 70% of all initially

B. Straub, MD Department of Urology, Universitätsklinikum Benjamin Franklin Freie Universität Berlin, Hindenburgdamm 30 DE–12200 Berlin (Germany) Tel. +49 30 8445 2577, Fax +49 30 8445 4620, E-Mail [email protected]

diagnosed prostate carcinomas are primarily local tumors and are thus amenable to local therapy [2]. It is particularly important for the further course in these cases to establish how far the tumor has already progressed. Though the spread of PC can be assessed approximately by first diagnostic measures such as needle prostate biopsies, digital rectal examination, prostate-specific antigen (PSA) values or even imaging techniques, organ-confined or locally advanced tumor growth is often difficult to assess accurately [3]. High-sensitivity reverse-transcription polymerase chain reaction (RT-PCR) amplification techniques to detect circulating tumor cells have already been mentioned as techniques with potentially high sensitivity for early subclinical recognition of metastatic tumor disease [4]. The possibility of detecting circulating tumor cells in prostate cancer patients by RT-PCR was demonstrated several years ago. However, its suitability to monitor the clinical course of the disease or as a screening tool has been discussed for some time [5, 6]. A great number of studies have thus far failed to demonstrate that PSAexpressing tumor cells in the blood of prostate cancer patients are a highly sensitive prognostic marker, particularly after radical retropubic prostatectomy (RPX) [7–12]. One reason for this may be that these studies have only relied on qualitative detection of PSA-expressing cells [13], or on semiquantitative techniques, even if measures were taken to increase their sensitivity by using nested PCR techniques or radioactive detection methods [14, 15]. So far, only a relatively small number of studies have used various semiquantitative approaches [12, 13, 16– 18]. However, these approaches do not show linearity to the amount of PSA mRNA found. We feel that qualitative or semiquantitative detection is inadequate for assessing the suitability of RT-PCR for detection of PSA mRNA as a staging, prognostic marker, particularly since PSA mRNA is also found in BPH. The potential benefits of the quantitative online RT-PCR system LightCyclerTM (Roche Diagnostics GmbH, Mannheim, Germany) have been demonstrated in other clinical specialties [19, 20]. The LightCycler is a rapid thermal cycler combined with a microvolume fluorimeter. There are two different methods for online detection and evaluation of fluorimetric PCR in glass capillaries. The PCR products formed may be detected either via fluorophores that bind to all doublestranded DNA molecules regardless of the sequence, as for example the double-stranded DNA binding dye SYBR Green I, or via fluorophores such as LightCycler-Red 640 and fluorescein coupled to sequence-specific oligonucleotide hybridization proves that only detect certain PCR products. First results with real-time RT-PCR for detec-

Quantitative Real-Time RT-PCR for Detection of PSA mRNA in Prostate Cancer

tion of PSA mRNA using the SYBR Green I method, though not sequence specific, have already demonstrated the basic suitability of the procedure [21]. However, the major criticism is still that even non-sequence-specific PCR products, like primer dimers, can fluoresce and could thus also be quantified. We have therefore used a PCR method with fluorescent sequence-specific oligonucleotide hybridization probes that only detect certain PCR products. We gained initial experience in establishing real-time RT-PCR detection of PSA-expressing cells by using the LightCycler in combination with sequence-specific oligonucleotide hybridization probes before and after RPX and transurethral resection of the prostate (TUR-P).

Material and Methods The investigations were conducted in agreement with the Helsinki Declaration. Institutional review board approval was obtained for this study. Each patient signed a consent form approved by the Committee on Human Rights in Research of our institution. Isolation of Mononuclear Cells Five-milliliter (EDTA) blood samples were obtained from 129 patients undergoing RPX for localized prostate cancer and 19 patients undergoing TUR-P for BPH. The blood samples were taken immediately before and after (within 10 min) RPX and TUR-P. Fifteen minutes after sampling, the blood was mixed 1:1 with phosphate-buffered saline (PBS) and applied on 4 ml LymphoprepTM (Nycomed, Oslo, Norway). Centrifugation and isolation of the mononuclear cells were done according to this protocol. The recovery rate of mononuclear cells was 45 B 3.1% (mean B SEM) and determined by a dilution series for 3H-thymidine-marked cells after centrifugation with Lymphoprep [21]. RNA Extraction RNA was prepared from tissue samples using RNACleanTM (Hybaid, Heidelberg, Germany) according to the manufacturer’s instructions. The quality of RNA was exclusively evaluated electrophoretically (presence of 28/18S RNA) and RT-PCR for ß-actin. All RNA probes could be used for further processing. LightCyclerTM Technique The LightCycler RNA Amplification Kit Hybridization Probes (Roche Diagnostics GmbH, Mannheim, Germany) is a specially adapted product for one-step RT-PCR in glass capillaries using the LightCycler and Hybridization Probes as detection format. Hybridization probes consist of two different oligonucleotides that hybridize to an internal sequence of the amplified fragment during the annealing phase of the PCR cycles. One probe is labeled at the 5)-end with a LightCycler-Red fluorophore (LC-Red 640), and modified with fluorescein at the 3)-end to avoid extension. During hybridization, the two probes are in close proximity, resulting in fluorescence resonance energy transfer (FRET) between the two fluorophores. During FRET, fluorescein, the donor fluorophore, is excited


13

Table 1. Patient characteristics

(means B SEM)

Patient characteristics

pT2 (n = 71)

1pT2 (n = 58)

p value (t test)

Age Patients after neoadjuvant hormone ablation Initial serum PSA, ng/ml Histopathological grading Gleason score

63.2B0.7 8 7.7B0.6 2.10B0.05 5.9B0.1

63.3B0.7 9 14.0B1.6 2.55B0.07 7.4B0.2

0.39

by the light source of the LightCycler, and part of the excitation energy is transferred to LightCycler-Red, the acceptor fluorophore. The emitted fluorescence of the LightCycler-Red fluorophore is measured. Using this hybridization protocol we were able to perform 35 PCR cycles in less than 60 min. Real-time one-step PCR for detection of PSA mRNA was performed using a LightCycler thermal cycler system according to the manufacturer’s instructions. Primers for PSA were: sense, 5)-CCT CCT GAA GAA TCG ATT CCT-3); antisense, 5)-CGT CCA GCA CAC AGC ATG AA-3). Hybridization probes primer were: ‘donor’ (5)-probe), 5)-GCC CAC CCA GGA GCC AGC ACT-3); ‘acceptor’ (3)-probe), LC Red 640 5)-ACC ACC TGC TAC GCC TCA GGC TGG-3). For one-step PCR, 0.5 Ìg of RNA were placed into 20 Ìl of reaction volume containing 1 Ìl of each primer (0.5 ÌM ), 0.8 Ìl of each probe (0.2 ÌM ), 2.4 Ìl (6 mM ) MgCl2, 4.0 Ìl LightCycler RTPCR Reaction Mix Hybridization Probes (10! conc.), and 0.4 Ìl LightCycler RT-PCR Enzyme Mix (Roche, Mannheim, Germany). Nucleotides, RNase H – reverse transcriptase, Taq DNA polymerase, and buffer were included in the LightCyclerTM RNA Amplification Kit Hybridization Probes. A typical protocol took approximately 60 min to complete and included a reverse transcription at 55 ° C for 600 s and a denaturation step at 95 ° C for 30 s followed by 45 cycles with a 95 ° C denaturation for 0 s, 50 ° C annealing for 15 s, and 72 ° C extension for 13 s. Extension periods varied with specific primers depending on the length of the product (F1 s/25 bp). Negative controls were run concomitantly to confirm that the samples were not cross-contaminated. A sample with 1 Ìl of diethylpyrocarbonatetreated water instead of RNA was concomitantly examined for each of the reaction units described above. The quantification data were analyzed with the LightCycler analysis software as described previously [19–21]. A positive control of RNA obtained from LNCaP cells was also performed with the LightCycler. A standard curve was plotted with LNCaP cells. The number of circulating LNCaP tumor cell equivalents in amplifications per microgram RNA per probe was estimated from the mean amplification value measured in a given number of LNCaP cells. Variables were examined for Gaussian distribution and by ANOVA or the unpaired Student t test; results are given as means B SEM. The significance of differences (p ^ 0.05) between the groups tested by ANOVA was assessed by the LSD test (least-squares differences), using the Statistical Package from StatisticaTM (StatSoftTM, Tulsa, Okla., USA).

14


!0.001 !0.001 !0.001

Results

Results of the Histopathological Examination Seventy-one of the 129 patients (55%) had an organconfined tumors (pT2; TNM, 5th ed.) and 58 (45%) had locally advanced tumor growth with penetration of the capsule B positive surgical margins (1pT2; TNM, 5th ed.). Thirty-eight of these patients (66%) had positive surgical margins on histopathological examination and 14 (24%) also had lymph node metastases. Patients in the pT2 group had a mean age of 63.2 years B 0.7, a serum PSA level at diagnosis of 7.7 B 0.6 ng/ml, a mean histopathological grading of 2.10 B 0.05 and a Gleason score of 5.9 B 0.1 versus a mean age of 63.3 B 0.7; p = 0.39), a PSA level of 14.0 B 1.6 ng/ml (p ! 0.001), a histopathological grading of 2.55 B 0.07 ( p ! 0.001), and a Gleason score of 7.4 B 0.2 (p ! 0.001) in the 1pT2 group (table 1). Eight patients from the pT2 group and 9 patients from the 1pT2 group underwent pretreatment by neoadjuvant hormone ablation. RT-PCR Results PSA mRNA was detected by LightCycler using sequence-specific oligonucleotide hybridization probes in 28 patients (39%) with pT2 tumors, 22 patients (38%) with 1pT2 tumors, but only 3 patients (16%) with BPH (ANOVA: p = 0.15, table 2). When considering the number of LNCaP cell-equivalent amplifications !103, the mean preoperative serum PSA mRNA level in pT2 tumors is considerably lower (104 B 53 ! 103/ml) in absolute value than in 1pT2 tumors (333 B 286 ! 103/ml) compared to 7.1 ! 103/ml in BPH (table 2). Only the positive probes were initially considered here. This difference is not significant because of the wide scatter (ANOVA: p = 0.51). The preoperative median number of cell copies in pT2 tumors is less markedly reduced (4.5 ! 103/ml) than in 1pT2 tumors (6.3 ! 103/ml) compared to the mean value (table 2).

Straub/Müller/Krause/Schrader/Miller

Table 2. Patients with positive RT-PCR and their assignment to the individual subgroups (means B SEM)

Patients expressing PSA by RT-PCR cells’a/ml

Circulating ‘tumor Preoperativelyb Postoperativelyb

serum !

pT2 (n = 71)

1pT2 (n = 58)

BPH (n = 19)

ANOVA p value

28 (39%)

22 (38%)

3 (16%)

0.15

333B286 545B479

7.1B7.0 4.8B4.6

0.51 0.56

103 37B16 104B53

Median value of circulating ‘tumor cells’a/ml serum ! 103 Preoperatively 4.5 Postoperativelyb 2.5 Circulating ‘tumor cells’a/ml serum ! 103 Preoperativelyc Postoperativelyc

a b c

7.9B3.9 14.7B8.9

6.3 4.9 76B66 143B127

n.d. 0.14 0.74B0.74 0.76B0.74

0.42 0.43

n.d. = Not detectable (only 2 patients). Number of circulating LNCaP tumor cell-equivalents in copies. Including only patients with a positive PCR. Including all patients.

The following values were obtained when including RT-PCR-negative patients in the evaluation of the preoperative number of LNCaP cell-equivalent amplifications: 7.9 B 3.9 ! 103 LNCaP cell equivalents for pT2 tumors compared to 76 B 66 ! 103 LNCaP cell equivalents for 1pT2 tumors (p = 0.42; table 2). The postoperative number of LNCaP cell equivalents in positive probes alone was 104 B 53 ! 103 for pT2, 545 B 479 ! 103 for 1pT2, and 7.1 B 7.0 ! 103 for BPH. All these values were higher than the preoperative values (table 2). Likewise, the mean values obtained on postoperative evaluation of the LNCaP cell equivalents in all patients (positive and negative probes) are higher than the preoperative values: 14.7 B 8.9 ! 103 for pT2, 143 B 129 ! 103 for 1pT2, and 0.76 B 0.74 ! 103 for BPH (table 2). There was no statistically significant correlation between clinical parameters such as age, PSA value at the time of diagnosis, pathological grading, and Gleason score and RT-PCR data like mRNA expression and the level of the LNCaP-equivalent cell number, where applicable.

Discussion

The idea of detecting circulating tumor cells in prostate carcinomas and using them as staging or prognostic parameters has been discussed in a number of studies [5–8].


In principle, the direct determination of PSA mRNA in blood to detect circulating tumor cells seems ingenious, and, considering tumor behavior and experience with other tumor types, the presence of tumor mRNA seems quite plausible. However the discrepancies between the results of individual study groups with respect to the clinical results and suitability of such a detection of PSA mRNA, which is in principle technically feasible, are sometimes considerable. These variations may be related to differences between the methods used, or, in other words, the sensitivity and specificity ranges of the various study groups with positive evaluations of RT-PCR for PSA mRNA in blood may have inadvertently fallen within the ‘quantitative’ ranges in which these results were found. A reliable quantification of RT-PCR could clarify many speculations about the value of this method for detection of PSA mRNA. Our study group has already reported positive results with real-time RT-PCR [21]. However, the method used at that time had the major basic disadvantage that the detected products were not necessarily specific for PSA mRNA but that basically all PCR products were quantified so that primer dimers, for example, were measured as well. The method we chose in this study works with sequence-specific oligonucleotide hybridization probes which only detect PSA mRNA-specific products, and is thus clearly superior.


15

The results of our study show markedly higher mean quantification values for LNCaP-equivalent cells in the 1pT2 group than in the pT2 group. The mean value is again considerably lower in the BPH group. However, the wide range of values suggests that the analysis of variance is not very significant. In a recent interesting study using a qualitative RT-PCR method, RT-PCR for detection of PSA mRNA was found to be an independent prognostic factor in prostate cancer [22]. Using this as a basis for discussion, 1pT2 patients and pT2 patients would not necessarily have to differ significantly in the level of detected LNCaP cell equivalents. The same applies to a correlation with the Gleason score, grading, and PSA value which likewise lacked statistical significance regarding the level of LNCaP tumor cell equivalents in our study. The quantitative online PCR system LightCycler we have used enables high standardization, is very fast, and the expenses do not exceed those for two-step qualitative RT-PCR. The LightCycler system with sequence-specific oligonucleotide hybridization probes has thus far not been applied for PSA-assisted detection of circulating LNCaP tumor cell equivalents in PC by RT-PCR. Our results show that the LightCycler with sequencespecific oligonucleotide hybridization probes for PSA mRNA-assisted detection of circulating LNCaP tumor cell equivalents in PC by RT-PCR is a promising technique. This has also been confirmed by the results ob-

tained by other groups. The low detection rate in BPH patients renders the method suitable as well for patient monitoring after RPX and could thus play an important role in deciding on early radiotherapy or even hormone ablation therapy. Additional long-term follow-up will have to show whether patients with a high expression of PSA mRNA actually have an increased risk of recurrence and whether the method is suitable as well to detect progressive disease.

Conclusions

We described the use of real-time one-step quantitative RT-PCR with the LightCycler sequence-specific oligonucleotide hybridization probes for PSA after RPX and TUR-P for BPH. Quantitative molecular diagnostics by RT-PCR for PSA with the LightCycler using sequencespecific oligonucleotide hybridization probes before and after RPX appear to be a promising tool for monitoring the course and establishing the prognosis of patients with prostate cancer. The long-term follow-up of such patients will demonstrate the clinical value of molecular diagnostics and laboratory examinations with the LightCycler system in accordance with the experience of other authors.

References 1 Landis SH, Murray T, Bolden S, Wingo PA: Cancer statistics. CA Cancer J Clin 1998;48:6. 2 Horninger W, Rogatsch H, Reissigl A, Volgger H, Klocker H, Hobisch A, Bartsch G: Prostate cancer screening in the Tyrol, Austria: Experience and results. Eur J Cancer 2000;36:1322. 3 Bai XZ, Masters JR, O’Donoghue N, Kirby R, Pan LX, Young M, et al: Prognostic markers in clinically localised prostate cancer. Int J Oncol 1999;14:785. 4 Pantel K, Cote RJ, Fodstad O: Detection and clinical importance of micrometastatic disease. J Natl Cancer Inst 1999;91:1113. 5 Okegawa T, Noda H, Kato M, Miyata A, Nutahara K, Higashihara E: Value of reverse transcription polymerase chain reaction assay in pathological stage T3N0 prostate cancer. Prostate 2000;44:210. 6 De la Taille A, Olsson CA, Katz AE: Molecular staging of prostate cancer: Dream or reality. Oncology 1999;13:187.

16

7 Oefelein MG, Ignatoff JM, Clemens JO, Watkin W, Kaul KL: Clinical and molecular followup after radical retropubic prostatectomy. J Urol 1999;162:307. 8 De la Taille A, Olsson CA, Buttyan R, Benson MC, Bagiella E, Cao Y, et al: Blood-based reverse transcriptase polymerase chain reaction assays for prostatic specific antigen: Longterm followup confirms the potential utility of this assay in identifying patients more likely to have biochemical recurrence (rising PSA) following radical prostatectomy. Int J Cancer 1999;84:360. 9 Gao CL, Maheshwari S, Dean RC, Tatum L, Mooneyhan R, Connelly RR, et al: Blinded evaluation of reverse transcriptase-polymerase chain reaction prostate-specific antigen peripheral blood assay for molecular staging of prostate cancer. Urology 1999;53:714. 10 Wood DP Jr, Beaman A, Banerjee M, Powell I, Pontes E, Cher ML: Effect of neoadjuvant androgen deprivation on circulating prostate cells in the bone marrow of men undergoing radical prostatectomy. Clin Cancer Res 1998;4:2119.


11 Zhang Y, Zippe CD, Van Lente F, Klein EA, Gupta MK: Combined nested reverse transcription-PCR assay for prostate-specific antigen and prostate-specific membrane antigen in detecting circulating prostatic cells. Clin Cancer Res 1997;3:1215. 12 Ylikoski A, Sjoroos M, Lundwall A, Karp M, Lovgren T, Lilja H, Iitia A: Quantitative reverse transcription-PCR assay with an internal standard for the detection of prostate-specific antigen mRNA. Clin Chem 1999;45:1397. 13 Verhaegen M, Ioannou PC, Christopoulos TK: Quantification of prostate-specific antigen mRNA by coamplification with a recombinant RNA internal standard and microtiter wellbased hybridization. Clin Chem 1998;44: 1170. 14 Smith MR, Biggar S, Hussain M: Prostate-specific antigen messenger RNA is expressed in non-prostate cells. Implications for detection of micrometastases. Cancer Res 1995;55:2640.

Straub/Müller/Krause/Schrader/Miller

15 Henke W, Jung M, Jung K, Lein M, Schlechte H, Berndt C, et al: Increased analytical sensitivity of RT-PCR of PSA mRNA decreases diagnostic specificity of detection of prostatic cells in blood. Int J Cancer 1997;70:52. 16 Sokoloff MH, Tso C, Kaboo R, Nelson S, Ko J, Dorey F, et al: Quantitative polymerase chain reaction does not improve preoperative prostate cancer staging: A clinicopathological molecular analysis of 121 patients. J Urol 1996; 156:1560. 17 O’Hara SM, Veltri RW, Skirpstunas P: Basal PSA mRNA levels detected by quantitative reverse transcriptase polymerase chain reaction (Q-RT-PCR-PSA) in blood from subjects without prostate cancer. J Urol 1996;155 (suppl):430A.


18 Corey E, Arfman EW, Liu AY, Vessella RL: Improved reverse transcriptase-polymerase chain reaction protocol with exogenous internal competitive control for prostate-specific antigen mRNA in blood and bone marrow. Clin Chem 1997;43:443. 19 Wittwer CT, Ririe KM, Andrew RV, David DA, Gundry DA, Balis UJ: The LightCycler: A microvolume multisample fluorimeter with rapid temperature control. Biotechniques 1997;22:176. 20 Nakanishi H, Kodera Y, Yamamura Y, Kuzuya K, Nakanishi T, Ezaki T, Tatematsu M: Molecular diagnostic detection of free cancer cells in the peritoneal cavity of patients with gastrointestinal and gynecologic malignancies. Cancer Chemother Pharmacol 1999;43(suppl): S32.

21 Straub B, Müller M, Krause H, Schrader M, Goessl C, Heicappell R, Miller K: Detection of prostate-specific antigen RNA before and after radical retropubic prostatectomy and transurethral resection of the prostate using ‘LightCycler’-based quantitative real-time polymerase chain reaction. Urology 2001;58:815. 22 Mejean A, Vona G, Nalpas B, Damotte D, Brousse N, Chrétien Y, et al: Detection of circulating prostate derived cells in patients with prostate adenocarcinoma is an independent risk factor for tumor recurrence. J Urol 2000; 163:2022.


17


Salvage Radiotherapy in Patients with Persisting Prostate-Specific Antigen after Radical Prostatectomy for Prostate Cancer Dirk Bottke a Thomas Wiegel a Stefan Höcht a Markus Müller b Martin Schostak b Wolfgang Hinkelbein a a Clinic

for Radiotherapy and Radiation Oncology and b Clinic for Urology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany

Key Words Prostate cancer W Prostate-specific antigen W Radical prostatectomy W Radiotherapy

Abstract Salvage radiotherapy in patients with persisting prostate-specific antigen (PSA) after radical prostatectomy for prostate cancer offers an approach to reduce local recurrence rates and to improve the rate of biochemical freedom from relapse. 30–70% of these patients experience a decrease in their PSA to an undetectable range; in about 40–50% of these patients, PSA remains stable after 5 years. Therefore, radiation therapy offers these patients an ultimate chance of cure. The pre-irradiation PSA value is of particular importance. The PSA level should not exceed 2 ng/ml because otherwise the rate of distant metastases increases significantly. Serious side effects are apparently low, thus confirming the suitability of this therapeutic approach. Copyright © 2003 S. Karger AG, Basel

ABC

© 2003 S. Karger AG, Basel 0030–2414/03/0655–0018$19.50/0



Introduction

Monitoring prostate-specific antigen (PSA) levels is a sensitive means of assessing the results of radical prostatectomy (RP) for prostate cancer. Following RP, PSA should become undetectable within 4–6 weeks, because the serum half-life of PSA is approximately 2–3 days [1]. Therefore, persistent serum PSA levels after RP indicate residual prostatic tissue, be it malignant disease or benign prostatic hyperplasia (BPH). In the former case, such levels predate clinically evident disease and correlate well with disease progression. However, the use of radiation therapy (RT) in this situation is problematic because it is not possible to primarily distinguish between locally persistent tumor and distant metastasis. On the other hand, only RT can offer the hope of cure to patients with truly localized malignant disease after RP. An increasing number of studies have been published on percutaneous RT for patients with PSA elevation out of the undetectable range or persisting PSA after RP, attesting to the importance of this clinical issue. The most critical questions are: In how many patients will it be possible to reduce an elevated PSA level after RP to the undetectable range by RT? And furthermore, in how many patients will the PSA level stay undetectable in follow-up? Probably only the latter patients have a chance of cure. Defining predictive criteria for the probability of cure remains an issue; as yet

Dr. med. Dirk Bottke Klinik für Radioonkologie und Strahlentherapie Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin Hindenburgdamm 30, DE–12200 Berlin (Germany) E-Mail [email protected]

no data from randomized prospective studies are available. Most studies published report data on patients with an increasing PSA and patients with persistent PSA – within the detectable range – after RP. However, it is unclear whether postoperatively persisting PSA values have to be interpreted in the same way as an increase out of the undetectable range or whether this is a sign of occult metastatic tumor spread [2]. Current data support both the latter and the former view, but all the relevant studies involve only small patient groups. Postprostatectomy examination of clinically staged T1/2a adenocarcinomas of the prostate reveals a pathologic stage T3/4 in up to 25% of cases; this probability increases to over 40% in clinical T2b tumors [3]. In central Europe, RP is frequently performed in patients with clinical stage T3 carcinomas. In these patients, the probability of postoperative tumor growth beyond the organ is 70–80% due to considerable preoperative staging uncertainties [4]. PSA examinations during follow-up have shown that in patients with pathologic stage pT3a–b (capsular penetration, infiltration of the periprostatic adipose tissue and/or seminal vesicles) or pT4 tumors (infiltration of adjacent organs) with or without positive margins, a persistently elevated PSA after RP or PSA elevation out of the undetectable range has to be expected in 15–60% of cases within 3–5 years [2–6]. Using punch biopsies from the urethrovesical anastomosis in 35–55% of all patients with PSA elevation after RP without clinical findings suggestive of recurrent tumor, vital tumor tissue was found by different examiners [7–9]. The huge gain in technology achieved over the past decade has led to significant improvements in radiation oncology (especially three-dimensional treatment planning, which by now is a generally accepted standard of care), which has made RT following RP increasingly attractive [10]. In phase III studies, conformal radiation treatment planning of prostate cancer has proven to reduce acute as well as late side effects [11].

Percutaneous RT for Persisting PSA after RP

The use of RT in cases of PSA elevation is problematic because it is impossible to distinguish between local tumor progression and distant metastases as the source of PSA production. This is particularly true if punch biopsies of the urethrovesical anastomosis are negative. Three studies have investigated the incidence of biopsy-proven tumors in patients exhibiting either PSA elevation or ‘per-

Salvage Radiotherapy in Patients with Persisting PSA after Radical Prostatectomy

sisting’ PSA levels after RP without radiologic evidence of local recurrence (including transrectal ultrasound). Tumor in the region of the anastomosis was revealed in about 35– 55% of the specimens. Thus, the proportion of patients with local tumor in the former prostate and seminal vesicle bed is probably even higher, as access to biopsy is limited to certain areas. These patients have a significantly higher risk of developing distant metastases [12, 13]. This is an argument of considerable strength for early onset of salvage treatment, when the probability of local tumor growth is 40–55% as soon as there is clear evidence of a continuous rise of PSA values [14]. On the other hand, there is a substantial risk of overtreating patients who either possibly do in fact have distant tumor recurrence or will not benefit because of reduced life expectancy due to comorbidities, as the time interval from PSA elevation to symptomatic tumor recurrence may be several years. Salvage radiation therapy therefore is justifiable only if rates of serious acute and long-term side effects are low. Still, one has to keep in mind that patients who underwent radical prostatectomy are a positively selected subgroup as they were fit for major surgery, and hence their life expectancy will generally not be dismal. Hormone therapy (HT), in contrast, in this situation has the advantage that the source of PSA elevation is irrelevant, therefore reducing the risk of futile therapy; still, although the effects of HT are frequently long-lasting, i.e. several years, it is a treatment of palliative nature, as progression due to hormone resistance will evolve over time and the impact of long-term HT on quality of life is not negligible. Percutaneous RT seems to offer the sole curative approach as long as there is isolated local tumor growth. An increasing number of papers are being published on RT for patients with PSA elevation out of the undetectable range or persisting PSA after RP. The major topics are: In how many patients can an elevated PSA level after RP be reduced to the undetectable range by RT? Moreover, in how many patients will the PSA level become and stay undetectable during follow-up? Probably only the latter group of patients will have a realistic chance of cure. Defining predictive criteria for the likelihood of response to salvage RT is another goal, as currently no data are available from randomized prospective studies.

Results of Salvage RT

In a significant number of patients it will be possible to reduce the increased or persistent PSA levels to the undetectable range by RT. Results vary between 10 and 73%,


19

Table 1. Patient series after RP with increase of PSA from the undetectable range or persistent PSA within the detectable range Reference

Patients

PSA progression-free

Median dose Gy

Median follow-up months

19% 48%

60

43

21

20/30 (67%) 3/15 (20%)

66–70

15

40 11

22

36% 18%

PSA after RP undetectable persistent

Catton et al. [15]

1131

Coetzee et al. [16]

45

Hudson and Catalona [17] Link et al. [18] Morris et al. [19] Wu et al. [20]

1062 25 48 533

22 30 44 13 12

10/13 5/12

30

12/18 (67%) 21/30 (70%)

56% 40%

16/53 (30%)

12/53 (23%) 10/38 (26%)

18 8 38

1 2 3

67

7/13 (53%) 1/12 (9%)

18 18 30 32 61.2

15

51 patients treated in an adjuvant group, 16 patients had a rising postoperative PSA with a palpable recurrence. 40 patients treated in an adjuvant group. PSA unknown in 7 cases.

with different patient selection criteria being the most probable explanation for that enormous divergence (table 1) [15–20]. Link et al. [18] reported on 12 patients who maintained detectable PSA following RP at a median postoperative level of 3 ng/ml (0.6–68 ng/ml). RT was initiated once they had regained continence at a median of 3 months postoperatively. Five patients (42%) had a subsequent decrease in PSA to less than 0.3 ng/ml, but only 1 (9%) has had a durable response to RT (median follow-up 30 months). In contrast, 7 of 13 patients (54%) whose PSA was undetectable after RP and who had a delayed increase in PSA achieved complete biochemical remission (median follow-up 18 months). Coetzee et al. [16] also reported a clear distinction in outcome between patients with undetectable versus detectable postoperative PSA values. 80% of 15 patients who retained a postoperatively elevated PSA failed treatment within 1 year (median 11 months) whereas 67% of 30 patients with a postoperative undetectable PSA remained disease-free with a median follow-up of 40 months. In the study by Wu et al. [20], 5 of 8 (63%) patients with a transiently undetectable postoperative PSA had no evidence of disease vs. 10 of 38 (26%) patients whose PSA level remained detectable after RP.

20

PSA undetectable after RT


Hudson et al. [17], from Washington University, reported on 106 patients who received RT after RP. Forty men who had pathologic stage T3 disease and undetectable PSA were given postoperative RT (the adjuvant group), and 22 men who had persistently detectable PSA after surgery were subsequently treated with RT and a third group of 44 men who initially had undetectable PSA levels after RP were given RT for a rising PSA level occurring at least 6 months after surgery. Patients who had a persistently detectable PSA level immediately after RP had an 82% biochemical failure rate with a median follow-up of 67 months, whereas patients with initially undetectable PSA after RP and a subsequent rise had a biochemical failure rate of 64% at the same point in time [17]. The experience from Massachusetts General Hospital with 55 men, all of whom had pathologic T3 tumors, and 76% positive margins, treated with doses of 60– 65 Gy using conventional fractionation, contrast sharply: among patients with a later rise from undetectable levels 67% (12 of 18) achieved an undetectable PSA after RT. Nearly the same rate was found among patients with persistent elevation of PSA postoperatively: 70% (21 of 30) achieved an undetectable nadir PSA value after RT. The fact that 48% remained biochemically free of disease 3 years after RT underlines the potential of cure for this group [19]. In the series of Forman et al. [21] from Wayne

Bottke/Wiegel/Höcht/Müller/Schostak/ Hinkelbein

Table 2. Influence of PSA before the start of RT as an indicator of treatment failure

Reference


PSA before RT, ng/ml


PSA before RT, ng/ml

PSA undetectable after RT, %

Median follow-up months

Forman et al. [21] Morris et al. [19] Schild et al. [37] Wu et al. [20]

24/29

!2 ! 1.7 ! 1.1 ! 2.5

6/18

12 1 1.7 1 1.1 1 2.5

83 vs. 33 66 vs. 29 78 vs. 18 52 vs. 8

36 32 25 15

14/27

State University, 41 patients had rising PSA values after achieving an undetectable PSA level postoperatively, and 41 patients had persistently detectable PSA levels following surgery. Median radiation dose was 66 Gy and median follow-up was 25 months. The most significant prognostic factor to discriminate favorable from unfavorable progression-free survival was the serum PSA level at the time of RT. The presence or absence of an undetectable PSA after surgery was one of the nonsignificant variables for biochemical progression-free survival [21]. In view of these conflicting data, we do not feel that it is justified to exclude patients from RT solely on the basis of a persisting PSA value after RP.

Technical Aspects of Percutaneous RT

Depending on initial tumor spread, the target volume of salvage RT is the prostatic bed with or without the area of the former seminal vesicles. Three-dimensional treatment planning is now the standard of care. To minimize toxicity, pelvic lymphatic drainage pathways are not irradiated [22]. The majority of authors used doses in the range of 60–70 Gy, with recommended single doses in the range of 1.8–2 Gy [23, 24]. Planning target volume (PTV) definition is a critical factor in adjuvant RT after RP. As there is considerable uncertainty in PTV definition, a preoperative computed tomogram may be of help [25].

2/26

2 ng/ml but only 6/18 (33%) with a level greater than 2 ng/ ml attained an undetectable PSA. Morris et al. [19], using 1.6 ng/ml as a cutoff value, reported similar results. The optimal PSA level before beginning irradiation treatment has not been definitely clarified (table 2). As mentioned above, these data are strong arguments against a wait-andsee strategy. The PSA level should not exceed 2 ng/ml because otherwise the rate of distant metastases increases significantly. RT should be commenced with PSA levels as low as possible. The time interval between RP and PSA elevation out of the undetectable range is another relevant factor for patient selection. When this period was less than 1 year, the rate of complete biochemical remission after RT was only 6% (1/16); it increased to 27% (12/44) and 44% if the interval was greater than 3 and 5 years, respectively [29]. Similar results were also reported by other authors [12, 26–28]. Other well-established prognostic factors in discerning patients prone to metastatic disease are involvement of seminal vesicles and lymph nodes, and Gleason scores of 8 and higher [12, 28]. To sum up, there are currently no clear-cut predictive criteria validated enough to justify withholding salvage RT, as even a high risk for metastatic spread does not exclude the possibility of a locally recurrent tumor only.

Remaining BPH Tissue after RP Predictive Criteria for Response to Salvage RT

The PSA value before initiating RT is of particular importance: when it was less than 2.5 ng/ml, 52% (14/27) of patients attained an undetectable post-RT PSA, compared to only 8% (2/26) with levels greater than 2.5 ng/ml [20]. Comparable data were reported by Forman et al. [21]: 24/29 (83%) of patients with a PSA level less than


Fowler et al. [29] evaluated the results of transrectal ultrasound (TRUS)-guided anastomotic biopsies in the presence of PSA relapse after RP. In 10% (6 of 62) of the patients, biopsies only revealed BPH tissue [29]. Theoretically, residual benign tissue may result from unintentional disruption of the prostatic capsule during surgery and may account for a detectable postoperative PSA, although several observations indicate that undetected carcinoma


21

may coexist with benign tissue. In this series, the level of PSA ranged from 0.6 to 4.8 ng/ml when only BPH tissue was present in the biopsy. Considering that every gram of BPH tissue produces an average of 0.31 ng/ml PSA [30, 31], it seems rather unlikely that around 2–15 g of BPH tissue was left in place after surgery or was otherwise capable of such a fast regrowth. PSA doubling time in these cases ranged from 7.3 to 100 months and increased in an exponential manner. PSA elevation in men with progressive BPH is usually linear and around 0.09 ng/ml annually [32].

Side Effects

A low rate of side effects is of particular importance for a therapy without histologic confirmation. As literature data attest, doses up to 66.6 Gy given in the frame of three-dimensional RT treatment planning are rarely associated with serious long-term side effects (grade III/IV according to the RTOG-EORTC grading system) involving the rectum and bladder. Although in general side effects tend to be underreported in retrospective analyses, a proportion of !3% seems to be a realistic estimate. Fairly higher rates of 10% genitourinary grade III complications, namely anastomotic strictures and bladder neck contractures requiring dilatation, recently reported in a series of 115 patients from the Memorial Sloan-Kettering Cancer Center, need to be interpreted with caution [33]. It may be difficult to differentiate side effects of RT from preexisting disabilities and sequelae of RP. At least equivalent rates of severe genitourinary complications following RP alone have been reported in an SEER data base analysis of 11,522 patients published by the same institution [34]. When postoperative RT is performed in a threedimensionally planned, multiple-field technique with fields individually shaped to spare the bladder and rectum, RTOG grade I/II side effects occur in up to 25% of

patients, but they do not have a relevant negative impact on quality of life [23]. Formenti et al. [35] investigated the rate and degree of incontinence and impotence after nerve-sparing RP with or without adjuvant RT. Unfortunately, follow-up examinations only comprised a questionnaire with inherent weaknesses. No difference was found between 72 patients who underwent both RP and RT and 138 patients who underwent RP only when total doses of 45–54 Gy were applied [35]. In a randomized study comprising 100 patients, there was no difference in the number of fully continent patients after 24 months between the group receiving 60 Gy and the group under observation [36]. Similar results were obtained in a retrospective study of the Mayo Clinics [37]. However, with doses exceeding 70 Gy, the rates as well as the degree of side effects increased markedly [23, 39].

Conclusions

Salvage RT in patients with persisting PSA after RP for prostate cancer offers an approach to reduce local recurrence rates and to improve the rate of biochemical freedom from relapse, with low rates of acute and late morbidity. However, to date, there is no proven survival advantage. As a rule, salvage RT can be offered to patients with persisting PSA after RP provided distant metastases have adequately been ruled out. 30–70% of these patients will experience a decrease in their PSA to an undetectable range, and in about 40–50% of these patients, the PSA will remain stable after 5 years. This patient group, therefore, has a curative chance with RT that otherwise would not exist. Patients most likely to benefit from RT are those with PSA levels less than 2 ng/ml before RT. Serious side effects are apparently low, thus confirming the suitability of this therapeutic approach.

References 1 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;317:909–916. 2 Zeitman AL, Edelstein RA, Coen JJ, Babayan RK, Krane RJ: Radical prostatectomy for adenocarcinoma of the prostate: The influence of preoperative and pathologic findings on biochemical disease-free outcome. Urology 1994; 43:828–833.

22

3 Catalona WJ, Smith DS: 5-year tumour recurrence rates after anatomical radical retropubic prostatectomy for prostate cancer. J Urol 1994; 152:1837–1842. 4 Morgan WR, Bergstralh EJ, Zincke H: Longterm evaluation of radical prostatectomy as treatment for clinical stage C (T3) prostate cancer. Urology 1993;41:113–120.


5 Ohori M, Wheeler TM, Kattan MW, Goto Y, Scardino PT: Prognostic significance of positive surgical margins in radical prostatectomy specimens. J Urol 1995;154:1818–1824. 6 Partin AW, Pound CR, Clemens JQ, Epstein JI, Walsh PC: Serum PSA after anatomic radical prostatectomy: The Johns Hopkins experience after 10 years. Urol Clin North Am 1993; 20:713–725.

Bottke/Wiegel/Höcht/Müller/Schostak/ Hinkelbein

7 Lightner DJ, Lange PH, Reddy PK, Moore L: Prostate specific antigen and local recurrence after radical prostatectomy. J Urol 1990;144: 921–926. 8 van den Ouden D, Bentvelsen FM, Boeve ER, Schroder FH: Positive margins after radical prostatectomy: Correlation with local recurrence and distant progression. Br J Urol 1993; 72:489–494. 9 Shekarriz B, Upadhyay J, Wood DP, Hinman J, Raasch J, Cummings GD, Grignon D, Littrup PJ: Vesicourethral anastomosis biopsy after radical prostatectomy: Predictive value of prostate-specific antigen and pathologic stage. Urology 1999;54:1044–1048. 10 Zimmermann FB, Molls M: Three-dimensional treatment planning: Principles and practice. Onkologie 1998;21:474–484. 11 Dearnaley DP, Khoo VS, Norman AR, Meyer L, Nahum A, Tait D, Yarnold J, Horwich A: Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer: A randomized trial. Lancet 1999;353: 267–272. 12 Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC: Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999;281:1591– 1597. 13 Keisch ME, Perez CA, Grigsby PW, Bauer WC, Catalona W: Preliminary report on 10 patients treated with radiotherapy after radical prostatectomy for isolated elevation of serum PSA levels. Int J Radiat Oncol Biol Phys 1990;19: 1503–1506. 14 American Society for Therapeutic Radiology and Oncology Consensus Panel: 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. J Clin Oncol 1999;17:1155– 1163. 15 Catton C, Gospodarowicz M, Warde P, Panzarella T, Catton P, McLean M, Milosevic M: Adjuvant and salvage radiation therapy after radical prostatectomy for adenocarcinoma of the prostate. Radiother Oncol 2001;59:51–60. 16 Coetzee LJ, Hars V, Paulson DF: Postoperative prostate antigen as a prognostic indicator in patients with margin-positive prostate cancer, undergoing adjuvant radiotherapy after radical prostatectomy. Urology 1996;47:232– 235. 17 Hudson MA, Catalona WJ: Effect of adjuvant radiation therapy on prostate specific antigen following radical prostatectomy. J Urol 1990; 143:1174–1177.


18 Link P, Freiha FS, Stamey TA: Adjuvant radiation therapy in patients with detectable prostate specific antigen following radical prostatectomy. J Urol 1991;145:532–534. 19 Morris MM, Dallow KC, Zietman AL, Park J, Althausen A, Heney NM, Shipley WU: Adjuvant and salvage irradiation following radical prostatectomy for prostate cancer. Int J Radiat Oncol Biol Phys 1997;38:731–736. 20 Wu JJ, King SC, Montana GS, McKinstry CA, Anscher MS: The efficacy of postprostatectomy radio-therapy in patients with an isolated elevation of serum prostate-specific antigen. Int J Radiat Oncol Biol Phys 1995;32:317– 323. 21 Forman JD, Meetze K, Pontes E, Wood DP Jr, Shamsa F, Rana T, Porter AT: Therapeutic irradiation for patients with an elevated postprostatectomy prostate specific antigen level. J Urol 1997;158:1436–1440. 22 Wiegel T, Hinkelbein W: Locally advanced prostate carcinoma (T2b-T4 N0) without and with clinical evidence of local progression (Tx N+) with lymphatic metastasis. Is radiotherapy for pelvic lymphatic metastasis indicated or not? Strahlenther Onkol 1998;174:231–236. 23 Wiegel T, Steiner U, Hinkelbein W: Radiotherapy after radical prostatectomy: Indications, results and side effects. Strahlenther Onkol 1997;173:309–315. 24 Wiegel T, Bottke D, Bandlow P, Steiner U, Hinkelbein W: The value of PSA measurements at 30 Gy, 50 Gy and 60 Gy for dose limitation in patients with radiotherapy for PSA increase after radical prostatectomy. Strahlenther Onkol 2002;178:422–425. 25 Höcht S, Wiegel T, Bottke D, Jentsch H, Sternemann M, Rosenthal P, Hinkelbein W: Computed tomogram prior to prostatectomy. Advantage in defining planning target volumes for postoperative adjuvant radiotherapy in patients with stage C prostate cancer? Strahlenther Onkol 2002;178:134–138. 26 Anscher MS, Clough R, Dodge R: Radiotherapy for a rising prostate specific antigen after radical prostatectomy: The first 10 years. Int J Radiat Oncol Biol Phys 2000;48:369–375. 27 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;43:649–659. 28 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;24:395–406.

29 Fowler JE Jr, Brooks J, Pandey P, Seaver LE: Variable histology of anastomotic biopsies with detectable prostate specific antigen after radical prostatectomy. J Urol 1995;153:1011– 1014. 30 Patel A, Dorey F, Franklin J, deKernion JB: Recurrence patterns after radical retropubic prostatectomy: Clinical usefulness of prostate specific antigen doubling times and log slope prostate specific antigen. J Urol 1997;158: 1441–1445. 31 Richardson TD, Wojno KJ, Liang LW, Giacherio DA, England BG, Henricks WH, Schork A, Oesterling JE: Half-life determination of serum free prostate-specific antigen following radical retropubic prostatectomy. Urology 1996;48:40–44. 32 Carter HB, Pearson JD, Metter EJ, Brant LJ, Chan DW, Andres R, Fozard JL, Walsh PC: Longitudinal evaluation of prostate specific antigen levels in men with and without prostate disease. JAMA 1992;267:2215–2220. 33 Katz MS, Zelefsky MJ, Venkatraman ES, Fuks Z, Hummer A, Leibel S: Predictors of biochemical outcome with salvage conformal radiotherapy after radical prostatectomy for prostate cancer. J Clin Oncol 2003;21:483–489. 34 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;346:1138–1144. 35 Formenti SC, Lieskovsky G, Simoneau AR, Skinner D, Groshen S, Chen SC, Petrovich Z: Impact of moderate dose of postoperative radiation on urinary continence and potency in patients with prostate cancer treated with nerve sparing prostatectomy. J Urol 1996;155: 616–619. 36 Van Cangh PJ, Richard F, Lorge F, Castille Y, Moxhon A, Opsomer R, De Visscher L, Wese FX, Scaillet P: Adjuvant radiation therapy does not cause urinary incontinence after radical prostatectomy: Results of a prospective randomized study. J Urol 1998;159:164–166. 37 Schild SE, Wong WW, Grado GL, Halyard MY, Novicki DE, Swanson SK, Larson TR, Ferrigni RG: The results of radical retropubic prostatectomy and adjuvant therapy for pathological stage C prostate cancer. Int J Radiat Oncol Biol Phys 1996;34:535–541. 38 Syndikus I, Pickles T, Kostashuk E, Sullivan LD: Postoperative radiotherapy for stage pT3 carcinoma of the prostate: Improved local control. J Urol 1996;155:1983–1986. 39 Schild SE, Wong WW, Grado GL, Buskirk SJ, Robinow JS, Frick LM, Ferrigni RG: Radiotherapy for isolated increases in serum prostate-specific antigen levels after radical prostatectomy. Mayo Clin Proc 1994;69:613–619.


23


Intermittent Androgen Deprivation for Locally Advanced Prostate Cancer Preliminary Experience from an Ongoing Randomized Controlled Study of the South European Urooncological Group

F. Calais da Silva a A. Bono b P. Whelan c M. Brausi d M. Queimadelos e J. Portillo f Z. Kirkali g C. Robertson h a Hospital do Desterro, Lisbon, Portugal, b Ospedale di Circolo e Fond, Macchi, Varese, Italy, c St. James University Hospital, Leeds, UK, d Estensis Hospital, Modena, Italy, e Policlı´nico La Rosadela, Santiago de Compostela, Spain, f Hospital Marques de Valledecilla, Santander, Spain, g Dokus Eylul University, Izmir, Turkey, and h University of Strathclyde, Glasgow, UK

Approximately 80% of prostate cancer patients achieve symptomatic and objective responses following androgen suppression, and serum prostate specific antigen (PSA) levels decrease in almost all patients. Surgical or medical castration results in a median progression-free survival of 12–33 months and a median overall survival of 23–37 months in patients with stage M1 disease. However, for reasons that remain unknown, the cell death process induced by androgen ablation, by whatever means, fails to eliminate the entire malignant cell population [1]. Another limitation of conventional androgen ablation is that it increases the rate of progression of prostate cancer to an androgen-independent state [1], and, after a variable period of time averaging 24 months, the tumor inevitably recurs with increasing serum PSA levels and is characterized by androgen-independent growth. Over the past 20 years, most efforts have focused on maximizing the degree of androgen suppression therapy by combining agents that inhibit or block both testicular and adrenal androgens. However, maximal androgen ablation increases treatment-related side effects and expenses, while prolonging disease-free interval by 3–6 months in most patients [2].

ABC

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Experimental animal and early clinical experience with intermittent androgen suppression suggests that the quality of life is improved and progression to androgen independence may be delayed by using reversible androgen suppression and PSA level as the trigger point. Intermittent androgen suppression may offer a ‘way out’ of the immediate vs. delayed treatment controversy, by balancing the benefits of immediate androgen ablation against reduced treatment ablation with reduced treatment-related side effects and expense. Early attempts to minimize side effects of therapy with estramusine phosphate and diethylstilbestrol led to the administration of these estrogenic drugs on an intermittent basis with no apparent risk to the patient. Vahlensieck et al. [3] suggested that intermittent androgen administration of estramusine phosphate might produce a long-lasting reduction in serum testosterone without jeopardizing the results obtained with continuous treatment. Ninety-five patients with various stages of prostate cancer were randomly allocated to either a continuous treatment with estramusine phosphate for as long as a response was maintained or an intermittent treatment regimen. The rates of remission (28 and 13%, respective-

Dr. Fernando Calais da Silva Hospital do Desterro, Urologia PT–2700 Lisbon (Portugal) Tel. +351 213 136300, Fax +351 218 852153, E-Mail [email protected]

ly), stabilization (65 and 77%) and progression (6 and 10 months) were approximately the same in the two groups. Klotz et al. [4] investigated the intermittent regulation of testosterone with cyclic administration of estrogenic hormone. Nineteen patients with advanced prostate cancer received diethylstilbestrol until a clinical response was clearly demonstrated; treatment was then withheld until symptoms recurred. One additional patient was treated with flutamide, according to a similar schedule. The mean duration of the initial therapy was 30 months. Subjective improvement was noted in all patients when treatment was stopped. Twelve of 20 patients relapsed after a mean interval of 8 months of treatment, but all patients subsequently responded to re-administration of the drug. Therapy-induced impotence was reversed in 9 of 10 patients. An improved quality of life was achieved and no adverse effects on survival were apparent.

Recent Phase II Clinical Studies

More recently, several phase II clinical trials have been reported. Most studies have used maximal androgen blockade during the treatment intervals, which are typically 8 months in length. PSA has been used as a surrogate marker of disease reactivation during off-treatment intervals, generally with a threshold of 10 ng/ml for restarting treatment. However, the results are difficult to interpret because of the heterogeneity of the series as the studies concern small patient populations distributed in different stages (i.e. local, locoregional, metastatic). Furthermore, the types of hormone treatment differed considerably: diethylstilbestrol; antiandrogens – biclutamide, flutamide, cyproterone acetate (CPA); luteinizing hormone-releasing hormone (LHRH) agonists – LHRH-A goserelin, leuprolide. Theyer and Hamilton [5] recruited 60 patients into an intermittent androgen suppression trial. The duration of androgen suppression was 8 months, achieved by LHRHA and CPA. The PSA trigger point for restarting therapy was 20 ng/ml or greater. All patients showed a marked decline in serum testosterone level in response to suppression therapy, with low values registered during treatment and rapid recovery to pretreatment values upon cessation of the androgen blockade. 14% of localized and 40% of the metastatic prostate cancers progressed. A moderate reduction in tumor volume was observed by ultrasonography, indicating that the decline in PSA level could be attributed to both decreased synthesis of PSA and actual loss of tumor cells.

Intermittent Androgen Deprivation for Locally Advanced Prostate Cancer

Bruchovsky et al. [6] reported on 110 patients with localized prostate cancer, who had failed radiation therapy, as demonstrated by a progressive increase in serum PSA level. All patients received total androgen blockade and therapy was interrupted at 36 weeks. Median time off therapy was 36 weeks. Quality-of-life subscales reversibly affected by treatment are physical function, work limitation, hot flushes, sexual function, nocturia and overall quality of life. Preliminary results of intermittent androgen suppression in 47 patients using reversible medical castration and serum PSA as trigger points were reported by Goldenberg et al. [7] in 1995, and updated to include 60 patients of Gleave et al. [8] in 1997. Seventy patients with a minimum follow-up of 12 months (mean = 46 months) have now accrued, 41 with clinically localized and 29 with metastatic disease. Mean initial serum PSA was 110 ng/ml. Treatment was initiated with combined androgen blockade and continued for an average of 9 months. Because prognosis is poor in patients who do not achieve normal PSA levels after androgen ablation, only patients with PSA nadir levels below 4 ng/ml were eligible for the intermittent androgen suppression protocol. Medication was then withheld until serum PSA increased to mean values of 10–20 ng/ml. This cycle of treatment and no-treatment was repeated until the regulation of PSA became androgen independent. Thirty-two men are currently in their second cycle and 24 are in their third or higher cycle. The mean time to PSA nadir during the first three cycles was 5 months. The first two cycles averaged 18 months in length with 45% of the time off therapy, while the third cycle averaged 15.5 months. Serum testosterone returned to the normal range within a mean of 8 weeks of stopping treatment. The offtreatment period in all cycles was associated with an improvement in sense of well-being, and the recovery of libido and potency in the men who reported normal or near-normal sexual function before the start of therapy. Androgen-independent progression occurred in 10 out of 29 stage D patients and 7 out of 41 with localized disease after a mean follow-up of 43 months. Of 21 stage D2 patients, 12 remain on study with stable disease. Nine patients have died, 3 from non-cancer-related illness, with median time to progression and overall survival of 26 and 42 months, respectively. The European Organization for Research and Treatment of Cancer (EORTC) Genito-Urinary Group conducted a phase II feasibility trial on intermittent androgen suppression. A total of 114 patients with previously untreated metastatic prostate cancer, with PSA levels above


25

Table 1. Patient distribution by M and T categories and by WHO

performance score a Metastases

Intermittent Continuous

M0

M1

n.a.

Total

209 202

91 94

3 6

303 302

b T stage


T1

T2

T3

T4

n.a.

Total

1 2

16 16

240 231

41 46

5 7

303 302

c WHO score


0

1

2

n.a.

Total

184 187

105 94

9 15

5 6

303 302

At randomization, 76.3% had a PSA ! 4. In the remaining 23.7%, the PSA had fallen by more than 80%. In the intermittent arm, 50% of patients were off therapy for at least 45 weeks following the initial LHRH therapy, 40% were off therapy for over 18 months. Patients whose PSA was ! 4 at randomization were off therapy for a median of 55 weeks, compared with 18 weeks for those whose PSA was 1 4 at randomization (fig. 1). n.a. = Not available.

20 ng/ml, were recruited by 15 centers over an 18-month period. Treatment consisted of bicalutamide 50 mg/day and goserelin acetate 3.6 mg every 4 weeks. Treatment was stopped if the serum PSA level declined by at least 80% of baseline values within 9 months and was restarted when the PSA level rose by 50% or more with respect to its more recent nadir value. One to seven cycles of treatment were administered with a median of two cycles per patient. Of the patients 77% achieved a first nadir after a median period of 19 weeks of treatment and 71% of the patients who began a second cycle of treatment achieved a second nadir after a median of 13.6 weeks of treatment. The median durations of the first and second off-treatment periods were 14.3 and 16 weeks, respectively. Up to seven cycles of treatment were administered. Quality-oflife evaluation was included in the study design and was slightly better during the off-treatment periods, even though the limited number of patients precluded definitive conclusions.

26


The Portuguese Cooperative Group conducted the SEUG9401 study. A total of 765 patients with newly diagnosed clinical stage T3 and T4 prostate cancer, with serum PSA levels between 4 and 100 ng/ml, were enrolled, of whom 626 were randomized; 139 were ineligible. The induction period was 14 weeks, during which maximum androgen blockade, consisting of CPA and an LHRH agonist, was administered. Patients were randomized if, at the end of the induction period, the serum PSA level had fallen to normal levels (!4 ng/ml) or by at least 80% of the nadir level. 765 patients have been registered, 626 randomized and 139 were not eligible for randomization. The preliminary analysis relates to 605 randomized patients, 303 in the intermittent arm and 302 in the continuous arm. Twenty-one recently randomized patients with no follow-up are not included in this analysis. The average age was 72, ranging from 54 to 85; 67.9% of patients are M0 and 77.9% T3. The patients’ distribution regarding T stage and WHO score is equivalent (table 1). Follow-up: At the present time, overall 223 patients have gone off study and 91 patients have died. It is too early to draw any conclusions concerning treatment efficacy. Quality of life: It is still too early to make any statement about quality of life. Overall quality-of-life scores appeared to be similar in the two arms of the study at successive follow-ups. Nevertheless, concerning sexual activity, at registration 50% of men reported sexual activity in the last months. In the continuous arm, sexual activity was reported by 20%, at registration. Sexual activity is greater in the intermittent arm, and 40% of men report sexual activity at 15 months if off therapy. Among those who are sexually active, difficulty with erections is less and enjoyment of sex is greater among those on intermittent therapy, especially when off therapy. With a median follow-up of 36 months there have been a very limited number of events and it is far too early to assess progression and survival. So far, there is no difference in overall quality of life and subjective progression. Sexual activity is greater in the intermittent arm, and 40% of men report sexual activity at 15 months if off therapy. This trial shows that if a patient is given 3–4 months of treatment with MAB and his PSA falls to !4, he has an expectation of not needing further treatment for a period of approximately 1 year (95% confidence interval of 9–18 months). Another randomized trial (TULP study protocol) included 282 previously untreated patients with T2–T4 N0 M1 or T2 T4 N1 and M0 prostate cancer and PSA 110 ng/

Calais da Silva/Bono/Whelan/Brausi/ Queimadelos/Portillo/Kirkali/Robertson

1.0

PSA 0-4 mg/ml PSA >4 ng/ml

0.8

0.6

0.4

0.2

0 0

Fig. 1. Time to first return to therapy in the

20

40 60 Weeks off therapy

80

100

intermittent arm.

ml. Maximum androgen blockage consisted of nilutamide and buserelin. Patients whose PSA levels decreased to normal after 6 months of treatment were randomized to the intermittent or continuous treatment arm. The criteria for treatment restart differed according to disease status. Patients with distant metastases restarted treatment when the serum PSA level rose to 10 ng/ml or greater and those with only lymph node metastases were replaced on treatment when the PSA levels rose to 20 ng/ml or higher. Of the 282 patients entered into the study, 193 were randomized. Of the 97 patients who were assigned to the intermittent androgen suppression arm, 48 have had to restart treatment and 15 have been switched to continuous maximum androgen blockage due to failure to reach secondary PSA nadirs. The mean period off treatment was 14 months. Thirteen patients in the continuous arm and 8 in the intermittent androgen suppression arm had disease progression during follow-up.

Current Studies

One of the largest ongoing trials on intermittent androgen suppression is the cooperative SWOG-EORTC trial, which includes patients with stage D2 prostate cancer. Patients are evaluated after 7 months of maximum androgen blockage with bicalutamide and goserelin, and those with normalized PSA levels are randomized to receive either intermittent or continuous treatment. Patients on the intermittent arm restart treatment when the PSA level

Intermittent Androgen Deprivation for Locally Advanced Prostate Cancer

Table 2. Incidence of side effects

Hot flushes, % Gynecomastia, % Headaches, % Skin complaints, %

Intermittent

Continuous

18.6 9.3 5.5 1.7

27.6 17.6 7.5 6.8

rises to 20 ng/ml and may again stop treatment only after 7 months of maximum androgen blockage if serum PSA levels are normal at months 6 and 7. In this manner, intermittent patients may repeat treatment cycles until clinical progression or until failure to reach PSA normalization. The primary endpoint of this study is to determine whether patients on the intermittent androgen suppression arm have survival that is not substantially worse than those on the continuous treatment arm. The concept of intermittent treatment is also being tested in patients with biochemical relapse after radical prostatectomy. In the industry-funded ‘Relapse’ trial, patients with undetectable postoperative PSA levels whose PSA level then rises to 11 ng/ml are randomized to receive either a continuous or an intermittent LHRH agonist. The objectives of the study are to compare the incidence of subsequent androgen independence in the two groups and to compare side effects and toxicity.


27

The Portuguese Cooperative Group is running an international study to test a novel form of intermittent treatment. Patients with T3–T4, M0 and T1–T4, M1 disease receive maximum androgen blockade for 14 weeks, and those who achieve PSA normalization are randomized to receive either continuous maximum androgen blockade or intermittent antiandrogen alone (CPA 300 mg/day). The primary endpoints of this study are time to PSA failure, time to clinical progression, quality of life and survival (Study SEUG9901).

Conclusions

The urological community will be anxiously waiting for the long-term results of randomized trials to see what impact intermittent androgen suppression has on disease progression and survival. If patients receiving intermittent treatment fare at least as well as those on continuous treatment, while improving quality of life and reducing costs, intermittent androgen suppression may become a standard treatment modality.

References 1 Bruchovsky N, Rennie PS, Coldman AJ, Goldenberg SL, To M, Lowson D: Effects of androgen withdrawal on the stem cell composition of the Shionogi carcinoma. Cancer Res 1990;50: 2275–2282. 2 Louis D, Murphy GP: Overview of phase III trials on combined androgen treatment in patients with metastatic prostatic cancer. Cancer 1993;72(suppl):3888–3895. 3 Vahlensieck W, Wegner G, Lehmann HD, Frazen G, Steffens L, Wählby S: Comparison between continuous and intermittent administration of Estracyt in the treatment of carcinoma of the prostate. Urol Res 1985;13:209– 212.

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4 Klotz LH, Herr HW, Morse MJ, Whitmore WF Jr: Intermittent endocrine therapy for advanced prostate cancer. Cancer 1986;58:2546– 2550. 5 Theyer G, Hamilton G: Current status of intermittent androgen suppression in the intermittent treatment of prostate cancer. Urology 1998;52:353–359. 6 Bruchovsky N, Klotz LH, Crook JM, Armitage GR, Gleave ME: A phase II study of intermittent androgen suppression in men with a rising PSA after radiation for localized prostate cancer. J Urol 1998;159:A1287.


7 Goldenberg SL, et al: Intermittent androgen suppression in treatment of prostate cancer. A preliminary report. Urology 1995;45:839–845. 8 Gleave ME, Bruchovsky N, Goldenberg SL, Rennie P: Intermittent androgen suppression: Rationale and clinical experience; in Schroeder F (ed): Recent Advances in Prostate Cancer and BPH. London, Parthenon Publishing, 1997, pp 109–121.

Calais da Silva/Bono/Whelan/Brausi/ Queimadelos/Portillo/Kirkali/Robertson


Neoadjuvant Hormonal Treatment and Radiotherapy for Prostate Cancer Stefan Wachter Natascha Wachter-Gerstner Richard Pötter Department of Radiotherapy and Radiobiology, University Hospital of Vienna, Austria

Key Words Radiotherapy W Prostate cancer W Hormones

Abstract Adjuvant hormone treatment with radiotherapy has been demonstrated in two studies (Bolla and RTOG 8531) to be beneficial in patients with locally advanced prostate cancer. However, the vast majority of patients with early prostate cancer can be cured with radiotherapy alone. Subset analysis combining RTOG 8610 and RTOG 8531 has demonstrated a survival benefit only for patients with a biopsy Gleason score ^6 after short-term neoadjuvant hormonal therapy. The results of ongoing research will further clarify the use of hormone treatment with radiotherapy in patients with low and intermediate risk. Copyright © 2003 S. Karger AG, Basel

ABC

© 2003 S. Karger AG, Basel 0030–2414/03/0655–0029$19.50/0



Introduction

Radical radiotherapy has become one of the standards for the curative treatment of localized prostate cancer. The development of modern three-dimensional conformal radiotherapy has led to enormous improvement in curative radiotherapy. The use of computer-operated sectional-imaging-based radiotherapy enables dose escalation to the tumor without increasing the dose to the organs at risk [8, 11, 12, 22, 28, 35]. A number of studies have indicated that patient outcome defined as no biochemical evidence of disease may be improved by increasing the dose to more than 70 Gy using external beam radiotherapy [5, 13, 19, 25, 26, 34]. However, due to the close proximity of the prostate to the bladder and rectum, the dose remains the limiting factor in radical radiotherapy. Therefore attempts are now made to improve the control rates without further increasing the radiation dose. In prostate cancer, there are no effective chemotherapeutic agents, but there is however the possibility of androgen deprivation. Whereas androgen deprivation has been used in the management of advanced disease for many years, the curative potential of androgen deprivation and radiotherapy has only recently attracted increased attention.

Stefan Wachter Department of Radiotherapy and Radiobiology University Hospital of Vienna, Währinger Gürtel 18–20 AT–1090 Vienna (Austria) Tel. +43 1 40400 2665, Fax +43 1 40400 2666, E-Mail [email protected]

Rationale for Neoadjuvant Androgen Suppression Combined with Radiotherapy for Prostate Cancer

The concept of androgen deprivation therapy for prostate cancer dates back to the description of clinical responses of prostate cancer by Huggins and Hodges [18] in 1941. The histological changes have been well described and include nuclear pyknosis, inflammatory response, tumor gland shrinkage and empty glandular spaces [15]. Later on, programmed cell death (apoptosis) has been reported to be triggered by androgen deprivation [3, 10]. The combination of androgen deprivation and radiotherapy is based on the idea that both strategies may result in a common final pathway for tumor cell killing. Their potential action could be additive or superadditive. Lim Joon et al. [21] reported a fivefold increase in the apoptotic response when androgen deprivation preceded radiotherapy, thus demonstrating a sequence- and timedependent interaction. The clinical rationale for combining radiotherapy and androgen deprivation is first to debulk locally advanced cancer and second, to eradicate occult micrometastatic disease. Neoadjuvant androgen deprivation prior to radical prostatectomy resulted in a reduction in the proportion of positive margins [29], but this reduction did not translate into a improved rates of freedom from biochemical failure. One reason could be remaining extracapsular tumor foci beyond the resection margin. This hypothesis should be kept in mind when defining radiation targets after neoadjuvant hormonal treatment. Prostate volume reductions of 30–50% have been reported within 3 months of androgen deprivation [9, 30, 33]. Such volume reductions were shown to decrease the amount of normal tissue irradiated, which could decrease radiotherapyinduced side effects [30]. However, with a view to possibly remaining tumor foci, the pretreatment target volume should be kept in mind in case of advanced disease.

Retrospective Studies

1,586 men treated between January 1989 and August 1999 using three-dimensional conformal radiotherapy (median dose 70.4 Gy) were reported in a retrospective cohort study by D’Amico et al. [7] in 2000. Patients were treated with (n = 276) or without (n = 1,310) androgen deprivation for 6 months (2 months before, during and after radiotherapy). No significant difference in terms of freedom from biochemical failure (bNED) was observed

30


for low-risk patients: 5-year PSA outcome 92 versus 84%, p = 0.13. Intermediate-risk and high-risk patients had a 5and 2.5-fold reduction in risk of PSA failure when treated with androgen deprivation: 5-year PSA outcome 88 versus 62%, p = 0.003 and 68 versus 43%, p = 0.02. The ASTRO consensus definition was used, which may, however, overestimate PSA failure after androgen deprivation due to the PSA rebound effect after withdrawal of hormones. Furthermore retrospective studies confirm an improved bNED rate for the combined treatment in patients with adverse prognostic factors [1, 31]. Zelefsky et al. [32] and Crook et al. [4] reported a significant reduction in positive biopsy rates after neoadjuvant hormonal treatment. However, Zelefsky et al. found no statistically significant difference in terms of PSArelapse-free survival, incidence of distant metastases, disease-free survival and overall survival.

Randomized Trials

471 patients with bulky palpable tumour participated in the RTOG-8610 trial and were treated either with external beam radiotherapy alone or combined with neoadjuvant total androgen deprivation (goserelin and flutamide) 2 months before and 2 months during radiation therapy [27]. Patients treated with hormones showed statistically significant improvements in local control, survival with bNED, distant tumor control, disease-free survival and disease-specific mortality after a median followup of 6.7 years. Subset analysis showed a beneficial effect in patients with Gleason score ^6. For these patients, highly significant improvements in all endpoints including overall survival were observed. No statistically significant improvement was observed in locoregional tumor control or survival in patients with Gleason score 67. Combining RTOG 8610 and RTOG 8531, a subset analysis showed a statistically significant benefit in bNED, absence of distant metastases and disease-specific mortality in patients with Gleason score 67 when longterm versus short-term hormones were compared [17]. In a Canadian trial, patients undergoing complete androgen deprivation prior to and during radiotherapy showed significantly less positive biopsies at 12 and 24 months after radiotherapy. Median PSA levels at 12 and 24 months were also significantly lower following combined treatment [20]. Additional randomized trials comparing radiotherapy alone and some form of adjuvant hormonal treatment

Wachter/Wachter-Gerstner/Pötter

Table 1. Summary of completed and ongoing phase III trials examining the efficacy of combined neoadjuvant hormonal treatment with

external beam radiotherapy [modified from D’Amico, 6] Study

Hormones

Patient selection

Local control (p value)

Distant control PSA control (p value) (p value)

Overall survival (p value)

RTOG 8610

goserelin (4 mo vs. none)

cT 6 T2b, 1 25 cm3

0.016

0.04

! 0.0001

0.1

RTOG 9413

goserelin or leuprolide + flutamide (4 mo)

cT1b–4

NA

NA

NA

NA

RTOG 9408

goserelin flutamide (4 mo vs. none)

cT1b–cT2b and PSA ! 20

NA

NA

NA

NA

DFCI

goserelin flutamide (6 mo vs. none)

T1b–2b and PSA 1 10 or Gleason 6 7

NA

NA

NA

NA

NA = Not available.

have been published. In the EORTC 22863 trial, Bolla et al. [2] reported an improvement in the 5-year overall survival of patients who had received adjuvant hormones for 3 years (table 1).

Discussion

Despite differences in study design, combined hormonal treatment and external beam radiotherapy uniformly resulted in improvements in various measures of local and biochemical control of disease or disease-free survival. RTOG 92–02 addresses the impact on survival of longterm hormonal treatment compared to neoadjuvant hormonal treatment. For patients with biopsy Gleason scores ^6, 4 months of hormonal treatment seems adequate for a survival benefit in approximately 5% of patients; longer follow-up is needed to see whether there was a survival benefit in men with higher biopsy Gleason scores [14]. Considering the results of studies in locally advanced cancer, prospective randomized trials were initiated in the treatment of clinically localized prostate cancer. In the RTOG study, 9,408 patients were randomized to receive either neoadjuvant hormones (2 months before and 2 months during radiotherapy) or radiotherapy alone. Included are patients with PSA !20 ng/ml and T1–T2b. 1,700 men will be entered [6]. Another phase III randomized trial was initiated by D’Amico [6] that included patients with cT1b–cT2b and either PSA 110 ng/ml or Gleason score 67. Patients were randomized to receive either radiotherapy alone or

Neoadjuvant Hormonal Treatment and Radiotherapy for Prostate Cancer

6 months of leuprolide (2 months before during and after radiotherapy). These trials are nearly completed and should give more information on the optimal duration and timing of hormonal treatment in clinically localized prostate cancer. The data reported in the numerous clinical studies mentioned above are difficult to compare due to differences in many variables, such as prognostic factors, type of hormonal treatment, radiotherapy techniques and endpoints. As previously reported, statistically significant differences in outcome can be observed in outcome by changing the time points and the definition of end points [16]. Obviously, serum PSA level will rise a little after withdrawal of androgen deprivation. If using the ASTRO definition for biochemical failure with a sampling interval of 3 months, failure is estimated to be about 5–10%. Therefore D’Amico [6] suggested a sampling interval of 6 months to avoid overstimation of failure. However, since neoadjuvant androgen deprivation represents a hormonal intervention on asymptomatic patients, aspects of changes in quality of life changes during hormone therapy need to be considered. Relatively few studies have evaluated the impact of androgen deprivation on quality of life. Lubeck et al. [23] analyzed 67 patients who received quality-of-life questionnnaires immediately before androgen deprivation and a maximum of 6 months after the start of hormonal treatment. Only sexual functioning decreased at levels reaching statistical significance. After 8 months of hormonal treatment, 20% of men remain significantly hypogonadic but will return to baseline after 6 months, as discussed by D’Amico [6].


31

Besides the issue of optimal sequencing and timing, the optimal type of hormonal treatment is still unresolved. The use of total androgen deprivation with a luteinizing hormone-releasing-hormone (LHRH) agonist and an antiandrogen has become standard as some of the randomized trials have adopted this treatment [24]. However, the use of testicular androgen suppression alone, with antiandrogen only initially may be adequate.

In conclusion, nearly all available data demonstrate some benefit in intermediate-risk and high-risk patients when a combination of radiotherapy and hormonal treatment is instituted. However, the vast majority of patients with early prostate cancer can be cured with radiotherapy alone. Only for patients with a biopsy Gleason score ^6 does a 4-month hormonal treatment seem to be adequate for a survival benefit.

References 1 Anderson PR, Hanlon AL, Movsas B, Hanks GE: Prostate cancer patients subsets showing improved bNED control with adjuvant androgen deprivation. Int J Radiat Oncol Biol Phys 1997;39:1025–1030 2 Bolla M, Gonzalez D, Warde P, Dubois JB, Mirimanoff RO, Storme G, Bernier J, Kuten A, Sternberg C, Gil T, Collette L, Pierart M: Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997;337:295– 300. 3 Bostwick DG, Qian J: Current and proposed biologic markers in prostate cancer. J Cell Biochem 1994;19:197–210. 4 Crook JM, Perry GA, Robertson S, Esche BA: Routine prostate biopsies following radiotherapy for prostate cancer: Results for 226 patients. Urology 1995;45:624–632. 5 D’Amico AV, Whittington R, Kaplan I, Beard C, Jiroutek M, Malkowicz SB, Wein A, Coleman CN: Equivalent biochemical failure free survival after external beam radiation therapy or radical prostatectomy in patients with a pretreatment prostate specific antigen of 1 4–20 ng/ml. Int J Radiat Oncol Biol Phys 1997;37: 1053–1058. 6 D’Amico AV: Radiation and hormonal therapy for locally advanced and clinically localized prostate cancer. Urology 2001;58:78–82. 7 D’Amico AV, Schultz D, Loffredo M, et al: Biochemical outcome following external beam radiation therapy with or without androgen suppression therapy for men with clinically localized prostate cancer. JAMA 2000;284: 1280–1283. 8 Fieldname HJ: Vergleich der Spätnebenwirkungen bei konformaler gegenüber konventioneller Strahlentherapie des lokal begrenzten Prostatakarzinoms. Eine prospektiv randomisierte Studie. Strahlenther Onkol 1999;175: 350–351. 9 Forman JD, Kumar R, Haas G, Montie J, Porter AT, Mesina CF: Neo-adjuvant hormonal downsizing of localized carcinoma of the prostate: Effects on the volume of normal tissue irradiation. CA Invest 1995;13:132–133. 10 Gleave ME, Hsieh JT, Gao C, von Eschenbach AC, Chung LWK: Acceleration of human prostate cancer growth in vivo by factors produced by prostate and bone fibroblasts. Cancer Res 1991;51:3753–3761.

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11 Hanks GE, Schultheiss TE, Hunt M, Epstein BE: Factors influencing incidence of acute grade 2 morbidity in conformal and standard radiation treatment of prostate cancer. Int J Radiat Oncol Biol Phys 1995;31:25–29. 12 Hanks GE, Lee WR, Hanlon AL, Hunt M, Kaplan E, Epstein BE, Movsas B, Schultheiss TE: Conformal technique dose escalation for prostate cancer: Biochemical evidence of improved cancer control with higher doses in patients with pretreatment prostate-specific antigen 610 ng/ml. Int J Radiat Oncol Biol Phys 1996;35:861–868. 13 Hanks GE, Hanlon AL, Pinover WH, Horwitz EM, Price RA, Schultheiss T: Dose selection for prostate cancer patients based on dose comparison and dose-response studies. Int J Radiat Oncol Biol Phys 2000;46:823–832. 14 Hanks GE, Lu J, Machtay M, et al: RTOG Protocol 92–02: A phase III trial of the use of longterm androgen suppression following neoadjuvant hormonal cytoreduction and radiotherapy for locally advanced carcinoma of the prostate (abstract 1284). Proc Am Soc Clin Oncol 2000. J Clin Oncol 2000;19:327a. 15 Hellstrom M, Haggman M, Brandstedt S: Histopathological changes in androgen-deprived localized prostatic cancer. Eur Urol 1993;24: 461–465. 16 Horwitz EM, Vicini FA, Ziaja EL, Gonzalez J, Dmuchowski CF, Stromberg JS, Brabbins DS, Hallander J, Chen PY, Martinez AA: Assessing the variability of outcome for patients treated with localized prostate irradiation using different definitions of biochemical control. Int J Radiat Oncol Biol Phys 1996;36:565–571. 17 Horwitz EM, Winter K, Hanks GE, Lawton CA, Russel AH, Machtay M: Subset analysis of RTOG 85–31 and 86–10 indicates an advantage for long-term vs. short-term adjuvant hormones for patients with locally advanced nonmetastatic prostate cancer treated with radiation therapy. Int J Radiat Oncol Biol Phys Oncol 2001;49:947–956. 18 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. Cancer Res 1941;1:293–297.


19 Kupelian PA, Buchsbaum JC, Reddy AC, Klein EA: Radiation dose response in patients with favorable localized prostate cancer (stage T1-T2, biopsy Gleason ^6, and pretreatment prostate-specific antigen ^10). Int J Radiat Oncol Biol Phys 2001;50:621–625. 20 Lavardière J, Gomez JL, Cusan L, Suburu ER, Diamond P, Lemay M, Candas B, Fortin A, Labrie F: Beneficial effect of combination hormonal therapy administered prior and following external beam irradiation in localized prostate cancer. Int J Radiat Oncol Biol Phys 1997; 37:247–252. 21 Lim Joon D, Hasegawa M, Wu CS, et al: Supra-additive apoptotic response in predominantly quiescent prostate tumors, when treated with androgen-ablation and radiotherapy. Int J Radiat Oncol Biol Phys 1996;36:191. 22 Lee WR, Hanks GE, Hanlon AL, Schultheiss TE, Hunt MA: Lateral rectal shielding reduces late rectal morbidity following high dose threedimensional conformal radiation therapy for clinically localized prostate cancer: Further evidence for a significant dose effect. Int J Radiat Oncol Biol Phys 1996;35:251–257. 23 Lubeck DP, Grossfeld GD, Carroll PR: The effect of androgen deprivation therapy on health-related quality of life in men with prostate cancer. Urology 2001;58:94–99. 24 Pilepich MV, Krall JM, Al-Sarraf M, et al: Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostetic carcinoma: A randomized comparative trial of the Radiation Therapy Oncoloy Group. Urology 1995;45:616–623. 25 Pinover WH, Hanlon AL, Horwitz EM, Hanks GE: Defining the appropriate dose for prostate cancer patients with PSA ! 10 ng/ml. Int J Radiat Oncol Biol Phys 1998;42:142. 26 Pollack A, Smith LG, von Eschenbach AC: External beam radiotherapy dose response characteristics of 1,127 men with prostate cancer treated in the PSA era. Int J Radiat Oncol Biol Phys 2000;48:507–512. 27 Shipely WU: A phase III trial (RTOG 8610) comparing external beam irradiation plus short-term maximal androgen blockade with radiation therapy for locally advanced prostate cancer. Eur Urol 1994;26:3.

Wachter/Wachter-Gerstner/Pötter

28 Soffen EM, Hanks GE, Hunt MA, Epstein BE: Conformal static field radiation therapy treatment of early prostate cancer versus non-conformal techniques: A reduction in acute morbidity. Int J Radiat Oncol Biol Phys 1992;24: 485–488. 29 Soloway MS, Sharifi R, Wajsman Z, Mc Leod D, Wood DP, Puras-Baez A, for the Lupron depot neoadjuvant prostate study group: Randomized prospective study comparing radical prostatectomy alone vs. radical prostatectomy preceded by androgen blockade in clinical stage B2 (T2b Nx M0) prostate cancer. J Urol 1995; 154:424–428. 30 Yang FE, Chen GT, Ray P, et al: The potential for normal tissue dose reduction with neoadjuvant hormonal therapy in conformal treatment planning for stage C prostate cancer. Int J Radiat Oncol Biol Phys 1995;33:1009–1017.

Neoadjuvant Hormonal Treatment and Radiotherapy for Prostate Cancer

31 Zagars GK, Pollack A, von Eschenbach AC: Management of unfavorable locoregional prostate carcinoma with radiation and androgen ablation. Cancer 1997;80:764–765. 32 Zelefsky MJ, Leibel SA, Gaudin PB, Kutcher GJ, Fleshner NE, Venkatramen ES, Reuter VE, Fair WR, Ling CC, Fuks Z: Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer. Int J Radiat Oncol Biol Phys 1998;41:491– 500. 33 Zelefsky MJ, Leibel SA, Burman CM, Kutcher GJ, Harrison A, Happersett L, Fuks C: Neoadjuvant hormonal therapy improves the therapeutic ratio in patients with bulky prostatic cancer treated with three-dimensional conformal radiation therapy. Int J Radiat Oncol Biol Phys 1994;29:755–761.

34 Zelefsky MJ, Lyass O, Fuks Z, Wolfe T, Burman C, Ling CC, Liebel SA: Predictors of improved outcome for patients with localized prostate cancer treated with neoadjuvant androgen ablation therapy and three-dimensional conformal radiotherapy. J Clin Oncol 1998;16: 3380–3385. 35 Zierhut D, Flentje M, Sroka-Perez G, Rudat V, Engenhart-Cabillic R, Wannenmacher M: The conformal radiotherapy of localized prostatic carcinoma: Acute tolerance and early efficacy. Strahlenther Onkol 1997;173:98–105.


33

Author Index

Bono, A. 24 Bottke, D. 18 Brausi, M. 24 Calais da Silva, F. 24 Froehner, M. 1 Heidenreich, A. 5 Hinkelbein, W. 18 Höcht, S. 18 Kirkali, Z. 24 Krause, H. 12 Miller, K. 12 Müller, M. 12, 18

Portillo, J. 24 Pötter, R. 29 Queimadelos, M. 24 Robertson, C. 24 Schostak, M. 18 Schrader, M. 12 Straub, B. 12 Wachter, S. 29 Wachter-Gerstner, N. 29 Whelan, P. 24 Wiegel, T. 18 Wirth, M.P. 1

Subject Index

Adjuvant 1 Androgen deprivation 5 Bicalutamide 1 Hormonal treatment 1 Hormones 29 Ibandronate 5 Osteoporosis 5 Pain management 5 Palliation 5

ABC Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

© 2003 S. Karger AG, Basel


Polymerase chain reaction 12 Prostate cancer 1, 5, 12, 18, 29 Prostatectomy 12 Prostate-specific antigen 12, 18 Radical prostatectomy 1, 18 Radiotherapy 1, 18, 29 Watchful waiting 1 Zoledronate 5

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