ESMO Handbook of Cancer Diagnosis and Treatment Evaluation (European Society for Medical Oncology Handbooks)

European Society for Medical Oncology

Handbook of Cancer Diagnosis and Treatment Evaluation Hans-Joachim Schmoll Laura Van’t Veer Jan Vermorken Dirk Schrijvers

European Society for Medical Oncology

Handbook of Cancer Diagnosis and Treatment Evaluation

CME test available online at www.esmo.org

European Society for Medical Oncology

Handbook of Cancer Diagnosis and Treatment Evaluation Edited by

Hans-Joachim Schmoll University Clinic Halle Halle, Germany

Laura Van’t Veer

Netherlands Cancer Institute Amsterdam, The Netherlands

Jan Vermorken

University Hospital Antwerp Antwerp, Belgium

Dirk Schrijvers

Ziekenhuisnetwerk Antwerpen-Middelheim Antwerp, Belgium

Informa Healthcare USA, Inc. 52 Vanderbilt Avenue New York, NY 10017 © 2009 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 ISBN-10: 0 415 39086 9 ISBN-13: 978 0 415 39086 6 This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequence of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data European Society for Medical Oncology handbook of cancer diagnosis and treatment evaluation / edited by Hans-Joachim Schmoll … [et al.]. p. ; cm. Includes bibliographical references and index. ISBN-13: 978-0-415-39086-6 (softcover : alk. paper) ISBN-10: 0-415-39086-9 (softcover : alk. paper) 1. Cancer–Handbooks, manuals, etc. 2. Tumors–Classification–Handbooks, manuals, etc. I. Schmoll, H.-J. (Hans-Joachim) II. European Society for Medical Oncology. III. Title: Handbook of cancer diagnosis and treatment evaluation. [DNLM: 1. Neoplasms–diagnosis. 2. Neoplasms–therapy. QZ 241 E8935 2009] RC262.5.E97 2009 616.99'4–dc22 2009001029 For Corporate Sales and Reprint Permissions call 212-520-2700 or write to: Sales Department, 52 Vanderbilt Avenue, 16th floor, New York, NY 10017. Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com Composition by Exeter Premedia Services Pvt Ltd, Chennai, India Printed and bound in Italy

Contents

Foreword Dr. Paolo G Casali

ix

1

Introduction

1

2

Pathology Introduction Aims in diagnosis and treatment Clinical implications and use

3 3 5 9

3

Biomarkers in oncology Introduction Clinically useful tumor markers “Omics” Conclusions

13 13 13 18 19

4

Radiological imaging Introduction Plain X rays Ultrasound Computed tomography Magnetic resonance imaging Newer techniques

21 21 21 22 23 25 25

5

Nuclear medicine imaging Introduction Positron emission tomography

29 29 29

6

Staging procedures Aim of staging procedures Relevant staging procedures in daily clinical practice

37 37 40

Head and neck tumors Small cell lung cancer Non–small cell lung cancer Esophageal cancer Gastric cancer Colorectal cancer Breast cancer Prostate cancer Bladder cancer Renal cell cancer Endometrial cancer Ovarian cancer Malignant melanoma Non-Hodgkin’s lymphoma Hodgkin’s disease

41 41 41 42 42 42 43 43 43 44 44 44 45 45 45

7 Prognostic criteria Introduction Patient-related prognostic factors Tumor-related prognostic factors Conclusion

49 49 50 51 55

8 Predictive tumor markers Introduction Tumor markers: definition and types Tumor markers: evaluation of their clinical utility Tumor markers: methodological, statistical, and reporting considerations Predictive tumor markers in routine use or in development Conclusion

57 57 57 57

9 Factors determining anticancer treatment Introduction Disease-related factors Patient-related factors Treatment-related factors Sociocultural factors Conclusion

65 65 65 66 69 69 72

vi

60 61 62

10

11

Treatment evaluation of activity: From global to personalized approach Introduction Evaluation of the treatment of solid tumors

75 75 75

Acute and subacute toxicities of medical anticancer treatment Introduction Tissue necrosis and phlebitis Nausea and vomiting Hypersensitivity reactions Tumor lysis syndrome Flu-like syndrome Hematologic toxicity Mucositis (stomatitis, diarrhea) Hair loss Skin toxicity Pancreatitis Liver toxicity Constipation and ileus Early-onset pulmonary toxicity Metabolic complications

79 79 79 80 82 85 86 87 91 93 94 95 96 96 97 98

12

Late toxicity Introduction Methodological aspects Second cancer Cardiovascular disease Endocrine effects Other long-term effects Conclusion

101 101 101 102 103 104 106 107

13

Acute and late effects in radiation oncology and surgery Introduction Radiotherapy Surgery

109 109 109 112

14

Psychosocial effects of cancer and treatment Introduction Psychosocial consequences

119 119 120 vii

Long-term survivorship Vulnerable cancer patients The role of the psychologist in oncology The role of the oncologist Psychological screening Conclusion

120 121 122 123 124 125

15 Incapacity due to cancer and cancer therapy Introduction General weakness and fatigue Cognitive and emotional impairment Neuropathy Gastrointestinal impairment Bladder disorders Sexual dysfunction Conclusion

127 127 127 129 130 131 131 132 132

16 Reintegration into the workplace Introduction Guidelines for integration Barriers for reintegration into the workplace Requalification and job applications Retirement Conclusion

135 135 136 137 137 138 138

17 Quality of life issues Introduction HRQOL in clinical trials: design and its impact on clinical results Using HRQOL measures in daily clinical practice: clinical impact Conclusion

141 141

18 Conclusion

147

Index

149

viii

142 144 146

Foreword Dr. Paolo G Casali

Since the 1940s, when Denoix conceived the TNM (Tumor, node, metastasis) system, Karnofsky codified the concept of tumor response and patient performance status, and Papanicolau introduced the vaginal smear, clinical oncology has developed a “clinical method”. At least in part, it has specificities, within the broader domain of the clinical method that every physician learns during training years. Unfortunately, though, little attention has been paid over the decades to teaching this method, and even less to further elaborating on it. This is in striking contrast with the formidable progress made, since the very same years, by the medical therapy of tumors, i.e., by medical oncology. Medical therapies of tumors have become more and more powerful, but medical oncology has found it difficult to focus on the clinical method with which they were used. The shortcomings of this can be found, I would say, in our routine practice. They are well perceivable as long as our treatment tools improve. Suffice it to recall the recent difficulties with assessing tumor response to molecularly targeted agents. It would be wrong to see these difficulties as exclusively radiological, thus technological. They are much more cultural, having to do with a concept—tumor response—which has always failed to find solid ground in biology as well as in the clinic. The notion of tumor response has been confined, theoretically, to Phase II studies, but it has been widely resorted to, actually, in the clinic, thus highlighting an obvious need. This Handbook is a rare attempt to make an appraisal of where we are in this field, by focusing on some key issues of the clinical method of medical oncologists. Authors should be praised for this, even before thanking them for the product of their work. I hope, as well, that ESMO might be

ix

acknowledged by kind readers to have tried to fill an educational gap at the heart of the discipline it wants to promote. The hope is that medical oncologists may recognize these issues as worth learning, of course, but also as a subject of research themselves, exactly as new drugs, or treatments, obviously are.

x

Introduction J Vermorken Department Medical Oncology University Hospital Antwerp Antwerp, Belgium

1

D Schrijvers Department Hemato-oncologie Ziekenhuisnetwerk Antwerpen-Middelheim Antwerp, Belgium

Cancer is one of the major health hazards in the world. In contrast to the situation a few decades ago, the majority of the global cancer burden now occurs in medium- and low-income countries. Assuming an annual increase in cancer incidence and mortality of 1%, by 2030 there could be 26.4 million new patients with cancer, 17.1 million annual cancer deaths, and 80 million persons alive with cancer within five years of diagnosis. The estimated costs of cancer diagnosis and treatment are important; they were 209.9 billion US$ in the U.S.A. in 2005 and 14.2 billion US$ or 9% of all disease costs in Canada in 1998; and cancer hospitalizations accounted for 6.2 billion US$ in France in 1999. The World Bank estimates that tobacco-related health care, of which cancer is an important proportion, accounts for between 6% and 15% of all annual health care costs and up to 1.1% of gross domestic product in high-income countries. Also, the costs of health care are increasing rapidly due to the introduction of new diagnostic techniques and treatments, limiting the resources for cancer diagnosis and treatment even more. Therefore, it is important that the available funding is used in an optimal way to ensure the continuity of adequate cancer diagnosis and treatment. Diagnosis should identify the presence of cancer, mostly by pathological or cytological examination, and the extent of the disease by staging. Several staging examinations are available, but only those that are relevant should be employed. Also, new techniques should be evaluated in randomized clinical trials before they enter daily clinical practice. 1

Results from pathology and staging examinations, together with patientrelated factors, can determine the prognosis. Combined with society-related factors, these examination results play an important role in determining optimal treatment. Several predictive factors that can indicate response to a specific treatment have been determined and can be used to direct treatment choices. When opting for a specific treatment, adequate treatment evaluation and prevention of acute and late toxicity should be taken into account to preserve the quality of life of cancer survivors. Revalidation and reintegration in society should be envisaged after diagnosis and treatment of cancer. This handbook describes and discusses cancer diagnosis and treatment evaluation.

Further reading http://www.who.int/cancer/en. World Health Organization. Cancer. 2006 World Cancer Declaration. Call to Action. UICC World Cancer Congress, July 8–12, 2006, Washington, D.C., U.S.A.

2

Pathology WAM Blokx, JHJM van Krieken Department of Pathology Radboud University Nijmegen Medical Centre Nijmegen, The Netherlands

2

Introduction What is pathology? Pathology is the study of structural and functional abnormalities that are expressed as diseases of cells, organs, or organ systems. Clinical pathology applies the knowledge of such studies for the diagnosis of disease in an individual patient. A pathological diagnosis is generally based on the integration of clinical, macroscopic, (sub)microscopic, and in some cases genetic findings. Histopathology is the study of tissues from patients, whereas cytopathology is the study of cells that are retrieved by either fineneedle aspiration (FNA) or by brushing or scraping of cells. Furthermore, spontaneously shed cells in body fluids like urine can be examined.

Histopathology The histopathological examination of tissue biopsies or resection specimens from patients forms the cornerstone of cancer diagnosis. There are national guidelines and standardized protocols for the pathological analysis of the most frequent tumor types. There are a large number of histochemical stainings that can be performed in addition to a routinely performed hematoxylin-eosin (H&E) staining. An important current development in histology is rapid tissue processing, enabling fast, one-day or one-hour diagnosis. For cancer diagnosis, immunohistochemistry and molecular pathology are commonly used for detailed classification of tumors.

Cytopathology The important advantage of cytology is that it is less invasive than a biopsy. The widest application of cytopathology is in early detection in the 3

context of cancer of the uterine cervix. Cytopathology is also useful in detection of early cancer in the bladder, lung, and endometrium. In addition cytopathology is, in some tumor types, the most feasible technique in detection of tumor recurrence, for instance in the urinary tract. With FNA virtually every organ is accessible. Under negative pressure, cells can be aspirated from a target organ or lesion. FNA can be performed under radiographic or ultrasound guidance. Most cytological specimens are stained by either Giemsa or by the Papanicolaou technique. Smears and possibly cell blocks are prepared from the aspirated cells. The latter has the advantage in that immunostaining can be performed. Advantages of cytopathology are that it produces less tissue damage, a larger sampling surface is available, and tissues difficult to be reached for biopsy can be evaluated. In addition a rapid diagnosis is possible, there is less discomfort for the patient, and it increases the detection rate of malignancy when combined with biopsies (for instance in lung cancer). Disadvantageous, in comparison to histology, is the limited possibility for detailed classification and the inability to differentiate in situ cancer from invasive cancer in, for instance, the breast and urinary bladder.

Immunohistochemistry Immunohistochemistry (IHC) aims to detect tissue or cell-specific antigens by applying labeled antibodies that can be visualized by light or fluorescence microscopy. In the past 20 years this field has developed rapidly and has become of great importance in daily practice, especially when this method became widely available for formalin-fixed paraffin embedded tissue. IHC has an important application in diagnosis of tumors by establishing the line of differentiation in poorly differentiated tumors. Most pathologists use a stepwise approach, with a first panel of generic markers containing cytokeratins (for epithelial differentiation), melanocytic markers, CD45 (leukocyte common antigen for hematopoietic differentiation), and vimentin (for mesenchymal differentiation). In a second step, more specific antibodies can be chosen based on the initial findings. It is important to pay careful attention to positive and negative controls in each immunostaining. In this respect, internal controls within the specimen 4

of interest are more reliable than external controls even if placed on the same glass slide because immunostaining is largely dependent on the fixation. If a metastasis from an unknown primary cancer is found, immunohistochemistry can indicate the site of origin. For instance, the transcription factor TTF1 is expressed in normal cells of the lung and thyroid, but also in tumors derived from these organs. IHC is, in addition to tumor diagnosis and classification, also important for prognostication and predicting therapy response. With the availability of targeted therapies, determination of the presence of a protein by IHC in the patient’s tumor can determine the subsequent treatment. Examples are the well-known estrogen receptor status, and more recently Her2-neu expression, in breast cancer.

Molecular pathology Assessing DNA and/or RNA (changes) in tumor tissue, generally referred to as diagnostic molecular pathology, is rapidly becoming indispensable. Several methods are available, which can be divided into those that use tissue slides (in situ hybridization) and those that use extracted nucleic acids. In situ hybridization is nowadays commonly used to detect specific gene amplifications, like Her2-neu in breast cancer, or chromosomal translocations, like the t(8;14) in Burkitt lymphoma. Extracted nucleic acids can be used to detect specific, known genetic alterations, like the H-RAS mutation in Spitzoid melanocytic tumors, or for a general overview of the genomic alterations in a tumor (comparative genomic hybridization array) or the RNA expression profile (expression array). The latter techniques are currently mainly used for research purposes but may soon become available for individual patients.

Aims in diagnosis and treatment Clinical pathology aims to diagnose and classify the disease of a patient based on the analysis of cells or tissues. When assessing a biopsy from a tumor, the first aim for a pathologist is to assess whether a tumor is reactive (inflammatory) or neoplastic. If neoplastic, the distinction between benign and malignant needs to be made. 5

Next, the line of differentiation must be established with accurate subtyping, in order to guide treatment. In many cases standard H&E stained tissue slides suffice (as in the case of “standard” squamous cell carcinoma or adenocarcinoma). However, about 20% of cases require additional techniques (Fig. 2.1). In specific tumor types additional molecular testing or protein expression can be performed when relevant for diagnosis or targeted treatment (for instance, mutational analysis in gastrointestinal stroma cell tumors).

DNA & RNA analysis Immunohistochemistry Enzyme histochemistry Electron microscopy

Molecular diagnosis

Histopathological diagnosis

Histopathology and cytopathology Tissue

Processing

Sectioning staining

DNA/RNA extraction Amplification analysis

Figure 2.1 The pyramid illustrates that most histopathological diagnoses can be made on standard H&E-stained histological tissue slides or by either Giemsa or Papanicolaou staining of a cytological specimen. However, about 20% of cases require additional techniques, mostly immunohistochemistry, and occasionally electron microscopy. In specific tumor types additional molecular testing or protein expression can be performed when relevant for diagnosis or targeted treatment. The lower panel illustrates the processing of tissues in a pathology lab from the macroscopic to the microscopic level, and sometimes sub-microscopic level with molecular analysis.

6

Screening and prevention The role of pathology herein is mainly to define and diagnose precursor lesions that can be treated before they evolve into cancer. Examples are the early detection of cervical cancer (by cytopathology) and regular histopathological evaluation of endoscopic biopsies in patients with longstanding Barrett esophagus or inflammatory bowel disease for development of dysplasia or cancer.

Establishment of the nature of a tumor Most pathologists use the following stepwise approach in diagnosing a malignant tumor. 1. Histology or cytology. A tumor can be diagnosed based on these alone because of characteristic morphology and architecture in 80–90% of all tumors. 2. Immunohistochemistry. In 10–20% of tumors additional immunohistochemistry is required to establish or confirm the line of differentiation, for establishing the primary site in case of a metastasis from an unknown primary, or for prognostication. 3. Molecular pathology. ■ Clonality assays. Clonality testing is performed in selected cases that are suspected for malignant lymphoma using the gene rearrangement pattern of antigen receptors. ■ Molecular cytogenetics. Techniques such as polymerase chain reaction (PCR), reverse transcriptase (RT)-PCR, Southern blot, and fluorescence in situ hybridization (FISH) can be used to detect chromosomal translocations, deletions, inversions, and numerical chromosomal abnormalities. For instance, the fusion gene BCRABL/(t(9;22)(q34:q11.2) in chronic myeloid leukemia patients can be detected and quantified in blood of affected patients by real-time PCR. It helps to establish the diagnosis, but it can also be used to monitor effect of targeted therapy with imatinib. The translocation can also be detected with FISH. ■ An example of diagnostic application of mutation detection is the demonstration of a clonal relation between two tumors in one patient, for instance by comparison of TP53 and CDKN2A mutations, in synchronous or metachronous melanoma or squamous 7

cell carcinoma. Because tumors are of clonal origin and mutations in these genes are frequently unique in each tumor, this type of mutation detection is helpful in discriminating a second primary from a metastatic tumor.

Grading and staging Tumors are graded and staged according to schemes and protocols to predict prognosis and serve as guidance to treatment choice. Grading is rather subjective and variably related to outcome. Grading is based upon histological resemblance of a tumor to the tissue of origin, and it takes into account the amount of anaplasia and proliferation rate. Most tumor types are divided into three grades of increasing malignancy. Welldifferentiated tumors resemble their benign counterparts, whereas poorly differentiated tumors bear little resemblance to them. Moderately differentiated tumors are all those in between. Staging is much more objective and is aimed to assess the extent of local and possible regional or distant tumor spread. Staging is independent of grading. Most used criteria for staging are tumor size, local tumor extension, regional/lymph node metastases, and distant lymph node or hematogenous metastases. These are codified in an international TNM (tumor, node, metastases) cancer staging system.

Recognition and establishment of etiology, like detection and testing in hereditary cancer syndromes In hereditary cancer syndromes mutations in disease-causing genes are transmitted in the germ-line of the family pedigree. In many familial cancer syndromes only one gene is responsible for one hereditary cancer, as in the case with the APC gene in familial adenomatous polyposis. However, sometimes multiple genes cause one hereditary syndrome such as mismatch repair genes in Lynch syndrome. In addition to responsible genes, in some cases a variety of polymorphisms may contribute to cancer predisposition. Pathologists have an important role in detection and testing of these cancer syndromes. Because pathologists often have access to automated patient data bases containing each patient’s previous medical history they are able to signal presence of risk of a cancer syndrome—for instance, in a patient 8

Table 2.1 Cancer syndromes and associated genes Familial adenomatous polyposis

APC

Multiple endocrine neoplasia 2a, 2b

RET

Retinoblastoma

RB1

Von Hippel-Lindau syndrome

VHL

Lynch syndrome (hereditary

hMSH2, hMLH1,

nonpolyposis colorectal cancer)

hPMS1, hPMS2

Hereditary breast ovarian syndrome

BRCA1, BRCA2

Li-Fraumeni syndrome

p53

Familial malignant melanoma

p16, CDK4

Ataxia telangiectasia

ATM

Source: Tomita N, Oto M. Molecular genetic diagnosis of familial tumors. Int J Clin Oncol. 2004; 9: 246–56. Review.

with colorectal cancer who also has a history of a Lynch syndrome–related tumor. Subsequently, analysis in cancer tissue of the patient by microsatellite instability (MSI) enables the pathologist to screen for defects in the mismatch repair system. In MSI-high patients genetic testing can be offered to the patient. The molecular techniques and applications currently available for diagnosing different categories of familial tumors are described by Tomita et al. (Table 2.1).

Clinical implications and use Pathologists have become important sparring partners of clinicians in multidisciplinary meetings, and their findings are of great importance in determining patients’ treatment and outcome. In some fields of pathology, like dermatopathology and soft tissue and bone tumors, clinicopathological correlation is of utmost importance for reaching the right diagnosis. Pathologists must keep up with all rapid developments in their field by adequate postgraduate training and panel meetings.

Review Pathologists are in the unique position that their diagnosis is based on tissue slides that are stored and thus can be reviewed later and that their 9

diagnosis can be shared with colleagues. For several areas in pathology it is common to discuss cases in a panel of expert pathologists. Pathology is increasingly becoming a field with sub-specialization, and therefore in unusual or difficult cases, expert consultation is a relatively cheap and easy method for quality improvement.

Future perspectives: pathology in the “omics” era and the era of targeted therapy At present the enormous amount of information that is generated by novel proteonomic and genomic applications is too large to be meaningfully analyzed. There is an important task for pathologists to translate this plethora of information into clinical useful applications. The development of information technology, with digitization of slides, archivation, optimalization, and possible quantification of high-throughput testing methods are expected to be of great benefit to patients, clinicians, and pathologists. Meanwhile, the development of targeted therapies now already places the pathologist in a situation in which expression of specific proteins or the presence of specific gene alterations is requested by the clinician in order to install specific therapy.

Further reading Blokx WA, Lesterhuis WJ, Andriessen MP, Verdijk MA, Punt CJ, Ligtenberg MJ. CDKN2A (INK4A-ARF) mutation analysis to distinguish cutaneous melanoma metastasis from a second primary melanoma. Am J Surg Pathol 2007; 31: 637–41. van Dijk MC, Aben KK, van Hees F, Klaasen A, Blokx WA, Kiemeney LA, Ruiter DJ. Expert review remains important in the histopathological diagnosis of cutaneous melanocytic lesions. Histopathology 2008; 52: 139–46. Finn WG. Diagnostic pathology and laboratory medicine in the age of “omics”: a paper from the 2006 William Beaumont Hospital Symposium on Molecular Pathology. J Mol Diagn 2007; 9: 431–6. Kievit W, de Bruin JH, Adang EM, et al. Cost effectiveness of a new strategy to identify HNPCC patients. Gut 2005; 54: 97–102. Netto GJ, Saad RD. Diagnostic molecular pathology: an increasingly indispensable tool for the practicing pathologist. Arch Pathol Lab Med 2006; 130: 1339–48.

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Tomita N, Oto M. Molecular genetic diagnosis of familial tumors. Int J Clin Oncol 2004; 9: 246–56. Van Krieken JH, Langerak AW, Macintyre EA, et al. Improved reliability of lymphoma diagnostics via PCR-based clonality testing: report of the BIOMED-2 Concerted Action BHM4-CT98-3936. Leukemia 2007; 21: 201–6.

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Biomarkers in oncology MJ Duffy Department of Pathology and Laboratory Medicine St Vincent’s University Hospital Dublin 4, Ireland

3

A Demir Department of Clinical Chemistry Meander Medical Center Amersfoort, The Netherlands

JMG Bonfrer General Clinical Laboratory The Netherlands Cancer Institute Amsterdam, The Netherlands On behalf of the European Group on Tumour Markers (EGTM).

Introduction The optimum management of patients with several types of malignancy requires the use of tumor biomarkers. Table 3.1 lists some of the most useful markers currently available, and the clinical utility of these markers is described in detail in this chapter. In addition, the likely clinical value of certain new “omics,” especially transcriptomics, which is also known as gene expression profiling, is discussed.

Clinically useful tumor markers Carcinoembryonic antigen (CEA) in colorectal cancer CEA has three main uses in patients with colorectal cancer (CRC): 1. determining prognosis, 2. surveillance following curative resection, and 3. monitoring therapy in patients with advanced disease. 13

Table 3.1 Tumor markers that might be used in clinical practice Cancer type

Marker(s)

Main use(s)

Colorectal

CEA

Prognosis, postoperative surveillance, monitoring therapy

Germ cell

AFP, HCG,

Prognosis, postoperative surveillance,

LDH (prognosis only)

monitoring therapy

Trophoblastic

HCG

Prognosis, postoperative surveillance,

Ovarian

CA-125

monitoring therapy Monitoring therapy, differential diagnosis of benign and malignant masses in postmenopausal women Prostate

PSA

Screening,a prognosis, postoperative surveillance, monitoring therapy

Breast

ER, PR

Predicting response to hormone therapy, prognosis

HER-2

Predicting response to trastuzumab and lapatinib, prognosis

uPA, PAI-1

Prognosis in node-negative patients

CA 15-3, CEA

Postoperative surveillance,b monitoring therapyc

Hepatocellular

AFP

Diagnostic aid, prognosis, postoperative surveillance, monitoring therapy

Thyroid (differentiated)

Thyroglobulin

Postoperative surveillance, monitoring therapy

Most useful tumor markers currently available. a Not yet validated for population screening. b Guidelines differ on value of surveillance. c Should not be used alone in monitoring therapy. Abbreviations: CEA carcinoembryonic antigen, AFP, alpha-fetoprotein; HGC, human choriogonadotrophin; LDH, lactate dehydrogenase; PSA, prostate-specific antigen; ER, estrogen receptor; PR, progesterone receptor; uPA, urokinase plasminogen activator; PAI plasminogen activator inhibitor

14

Preoperative levels of CEA should be determined because they may provide independent prognostic information, help with surgical management, and provide a baseline level for subsequent determinations. Preoperative levels, if elevated, may also help identify high-risk node-negative patients that could benefit from adjuvant chemotherapy. Following curative surgery for CRC, it is common practice that patients undergo regular follow-up. Indeed, several meta-analyses have shown that the use of an intensive follow-up regime that included regular determinations of CEA resulted in a modest but statistically significant better survival rate than either no follow-up or minimal follow-up. Consequently, expert panels such as the European Group on Tumour Markers (EGTM), the European Society for Medical Oncology, and the American Society of Clinical Oncology (ASCO) recommend that serial postoperative CEA levels should be measured approximately every three months in patients with stage II or III disease for at least three years, if the patient is a potential candidate for surgery or chemotherapy of metastatic disease. Similarly, serial CEA measurements should be determined in patients with advanced CRC undergoing systemic therapy. A confirmed increase of >30% generally indicates progressive disease, provided the possibility of false-positive increases can be excluded.

Alpha-fetoprotein, human choriogonadotrophin, and lactate dehydrogenase in germ cell cancer Alpha-fetoprotein (AFP), human choriogonadotrophin (HCG), and lactate dehydrogenase (LDH) are mandatory in determining prognosis in patients with germ cell cancer with all three markers included in the International Union Against Cancer/American Joint Committee on Cancer staging systems for this malignancy. AFP and HCG are also essential in surveillance and monitoring treatment in patients with germ cell tumors. Following curative treatment for non-seminomatous germ cell tumors of the testis, consistently rising AFP or HCG levels without radiological or clinical findings suggest active disease and should lead to the initiation of treatment, provided likely causes of false-positive marker levels are excluded.

CA-125 in ovarian cancer The main uses of CA-125 are in the differential diagnosis of benign and pelvic masses in postmenopausal women and in monitoring chemotherapy 15

in patients with ovarian cancer. According to EGTM guidelines, if a postmenopausal woman presents with a pelvic mass, CA-125 should be determined. If elevated, the woman should be promptly referred to a specialized gynecological oncology unit. CA-125 should also be used in monitoring chemotherapy in patients with ovarian cancer. However, the role of CA-125 in the follow-up of asymptomatic patients who have completed treatment for ovarian cancer is currently unclear but is being evaluated as part of a randomized prospective trial. CA-125 should not be used in screening for ovarian cancer outside the setting of a randomized clinical trial.

Prostate-specific antigen in prostate cancer Although widely used, the effect of prostate-specific antigen (PSA) screening on reducing mortality from prostate cancer remains to be established. Thus, guidelines from expert panels on PSA screening vary, with some recommending screening and others opposed to the practice. Most expert panels agree, however, that prior to screening, a discussion should take place between the doctor and patient regarding the potential benefits, limitations, and dangers associated with the procedure. PSA can provide prognostic information in patients with prostate cancer. For such purposes, PSA may be used in different ways. These include the use of absolute pretreatment levels (the higher the PSA level, the worse the outcome), a combination of pretreatment levels and established prognostic factors to generate nomograms, and the use of serial levels to calculate either PSA velocity or PSA doubling time. The wide variability in PSA levels, however, may limit its ability to determine velocity and doubling time. Finally, serial PSA levels may be used in post-therapy surveillance, in active surveillance, or in monitoring therapy in patients with diagnosed prostate cancer.

Biomarkers in breast cancer Estrogen and progesterone receptors as prognostic and predictive markers Measurement of both estrogen (ER) and progesterone receptors (PR) is used for predicting the response of invasive breast cancers to hormonal therapy. The role of hormone receptors in predicting sensitivity to endocrine therapy in patients with ductal carcinoma in situ of the breast is less clear. 16

Although primarily used in selecting for endocrine sensitivity, ER may also be used for determining prognosis in newly diagnosed breast cancer patients. As a prognostic factor for breast cancer, however, ER has two main limitations: (1) the beneficial effect of its presence only lasts for the first six to seven years after diagnosis and (2) it has only minor effectiveness as a prognosticator in patients with lymph node–negative breast cancer. Despite these limitations, the most recent St Gallen Consensus Group recommended that ER and PR be included in a new risk classification scheme for newly diagnosed breast cancer patients.

HER-2 as a predictive and prognostic marker The primary use of HER-2 in breast cancer is for predicting response to anti–HER-2 therapies such as trastuzumab and lapatinib. Like ER, HER-2 can be both predictive and prognostic in patients with breast cancer. HER-2–positive patients with lymph node–positive disease have a worse outcome compared with HER-2–negative patients in the absence of adjuvant anti–HER-2 treatment.

Urokinase plasminogen activator and PAI-1 as prognostic markers Urokinase plasminogen activator (uPA) and plasminogen activator inhibitor (PAI)-1 are among the best-validated prognostic markers in oncology. The prognostic impact for these two proteins in lymph node–negative breast cancer patients has been validated in both a multicenter prospective randomized trial and a pooled analysis of individual data from over 8,000 patients. The results from both these level I evidence studies showed that lymph node–negative breast cancer patients with low levels of uPA and PAI-1 have a minimal risk of disease relapse and thus may be able to avoid having to receive adjuvant chemotherapy. The requirement of fresh or freshly frozen tumor tissue, however, limits the availability of these assays.

CA 15-3 in postoperative surveillance and monitoring therapy The role of serial measurements of CA 15-3 and CEA in the postoperative monitoring of asymptomatic patients with a previous diagnosis of breast cancer is controversial. According to the EGTM, CEA and a MUC-1– related marker (e.g., CA 15-3 or BR 27.29) should be used in postoperative surveillance following a diagnosis of breast cancer. In contrast, the ASCO expert panel is opposed to the use of serum markers in follow-up of asymptomatic breast cancer patients. 17

However, CA 15-3 and CEA may be used in combination with radiology for monitoring therapy in patients with advanced breast cancer. These markers are particularly useful in monitoring therapy in patients that are difficult to evaluate using radiology.

“Omics” The “omics” technologies involve genomics (the study of an organism’s entire genome), transcriptomics (the study of an organism’s entire mRNA), and proteomics (the study of an organism’s entire protein). Of these three technologies, transcriptomics, or gene expression profiling, has emerged as being the most clinically useful. Gene expression profiling involves the simultaneous measurement of multiple mRNA species. This can be accomplished using either microarray (gene chips) or multiplex reverse transcriptase–polymerase chain reaction (RT-PCR). The main clinical application of gene expression profiling to date is in determining the prognosis in patients with newly diagnosed cancer. Although prognostic signatures have been reported for several types of cancer, it is in breast cancer where the most extensive investigations have been carried out. Two profiles, in particular, have undergone detailed studies in this malignancy: MammaPrint® and Oncotype DX®. ■

■

18

MammaPrint is a 70-gene profile that was originally shown to predict outcome in lymph node–negative breast cancer patients 55 years of age or younger. Subsequently, the prognostic signature was both internally and externally validated and shown to predict outcome independent of the classical prognostic factors for breast cancer. In 2007, MammaPrint was cleared by the U.S. Food and Drug Administration (FDA) for predicting outcome in lymph node–negative breast cancer patients younger than 61 years of age. Currently, MammaPrint is undergoing prospective validation as part of the Microarray in Node-Negative Disease May Avoid Chemotherapy (MINDACT) trial. The Oncotype DX test measures the expression of 21 genes (16 cancerrelated and 5 control genes) using multiplex RT-PCR in paraffinembedded and formalin-fixed tumor tissue. Based on the relative expression of the 16 cancer-related genes, a recurrence score is calculated. Currently, the main use of the test is for predicting the risk of

recurrence in newly diagnosed breast cancer patients with lymph node– negative ER-positive breast cancer treated with adjuvant tamoxifen. In contrast to gene expression profiling, the use of proteomics to provide clinically useful information has to date been disappointing. Although multiple preliminary reports have claimed that one form of proteomics known as surface-enhanced laser desorption and ionization can detect several cancer types with considerably enhanced sensitivity and specificity compared with existing markers, few of these findings have been confirmed using external validation studies. At present, therefore, proteomics has no role in either the detection or management of patients with cancer.

Conclusions Currently, the most frequent applicant of tumor biomarkers is in postoperative surveillance and monitoring therapy in patients with advanced disease. There are, however, a number of points that should be borne in mind when using markers in these settings. 1. With the possible exception of HCG in patients with trophoblastic disease, none of the available biomarkers is elevated in serum from all patients with a specific cancer, even in the presence of advanced disease. In certain situations, therefore, a second-line biomarker may be required. 2. Therapy should not be altered following a single increase or decrease in a biomarker level. All increases and decreases in marker levels should be confirmed with a second sample. 3. Transient increases in biomarker concentrations can occur following the start of specific therapies. The spurious increases or spikes are probably due to therapy-mediated apoptosis or necrosis of tumor cells and not due to tumor progression. 4. Benign diseases may give rise to elevated biomarker concentrations. These increases may be transient or persistent, depending on the specific abnormality. Increases found in benign disease, however, are rarely of the same magnitude as that seen in advanced cancer. 5. The impact of measuring serial levels of tumor biomarkers on patient outcome is unclear in many malignancies. The use of CEA as part of 19

a surveillance strategy in patients who have had curative surgery for CRC does, however, have a modest but significant impact on patient survival. 6. Finally, it is important to state that many of the tumor markers currently available do not satisfy evidence-based criteria for their clinical utility. These include CA 19-9 in pancreatic cancer; SCC in squamous cell carcinomas; NSE, chromogranin, and calcitonin in neuroendocrine tumors; and specific cytokeratins in several different types of carcinomas. Guidelines for the use of these markers are available at http://www. aacc.org/members/nacb/LMPG/OnlineGuide/DraftGuidelines/ TumorMarkers/Pages/default.aspx.

Further reading Cardoso F, Van’t Veer L, Rutgers E, et al. Clinical application of the 70-gene profile: The MINDACT Trial. J Clin Oncol 2008; 26: 729–35. Duffy MJ. Role of tumor markers in patients with solid cancers: a critical review. Eur J Int Med 2007; 18: 175–84. Duffy MJ, van Dalen A, Haglund C, et al. Tumor markers in colorectal cancer: European Group on Tumor Markers (EGTM) guidelines for clinical use. Eur J Cancer 2007; 43: 1348–60. Duffy MJ, Bonfrer JM, Kulpa J, et al. CA 125 in ovarian cancer: European Group on Tumor Markers (EGTM) guidelines for clinical use. Int J Gynecol Cancer 2005; 15: 679–91. Harris L, Fritsche H, Menel R, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 2007; 25: 5287–312. Jeffrey GM, Hickey BE. Follow-up strategies for patients treated for non-metastatic colorectal cancer (Cochrane Review). The Cochrane Library. Chichester, U.K.: Wiley, 2004. Lilja H, Ulmert D, Vickers AJ. Prostate-specific antigen and prostate cancer: prediction, detection and monitoring. Nature Rev Cancer 2008; 8: 268–78. Molina R, Barak V, van Dalen A, et al. Tumor markers in breast cancer: European Group of Tumor Markers (EGTM) recommendations. Tumor Biol 2005; 26: 281–93. Sparano JA, Paik S. Development of the 21-gene assay and its application in clinical practice and clinical trials. J Clin Oncol 2008; 26: 721–28. Sturgeon CM, Duffy MJ, Stenman UH, et al. National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem 2008; 54: e11–79.

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Radiological imaging SJ Gwyther, S Waas Department of Medical Imaging East Surrey Hospital Surrey, United Kingdom

4

Introduction Radiological imaging plays a crucial role in cancer disease. It can be used to confirm the histological diagnosis, which is often made by image-guided biopsy and in the detection of local and distant disease at diagnosis. The diagnosis and accurate staging of cancer is imperative in determining whether potentially curative or palliative therapy is instituted. Radiological techniques can also be used during therapy to evaluate response to treatment. This can be done by comparing the pre-treatment (baseline) examination with subsequent examinations, thereby determining if the disease has responded to treatment, is stable, or has progressed. This may influence further treatment approach. Response evaluation by radiology is accurate with the use of traditional “cytotoxic” agents that kill cells and decrease tumor size. However with the newer “cytostatic” agents (e.g., anti-angiogenesis agents) the radiological tumor size may not change. The main difference between clinical practice and clinical trials is that in many clinical trials measurable disease of a minimum size at baseline is required and that pre-determined examinations with set imaging protocols within specific time frames relating to the administration of therapy are undertaken. The following sections summarize the common imaging modalities used in clinical practice and clinical trials.

Plain X rays Plain films are cheap and convenient. However they are relatively insensitive. 21

Indications The most common examination is the chest radiograph (CXR) which can detect abnormal soft tissue masses projected over the lung fields.

Disadvantages ■

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It is difficult to see lesions less than 10 mm, though they may be seen retrospectively once they have enlarged. “Hidden” areas behind the heart and diaphragm make detection difficult. Lymph nodes are not demonstrated unless they are very bulky. The detection of lytic bone metastases is even less sensitive and requires 70% loss of bone before becoming detectable.

Ultrasound Ultrasound is readily available and cheap.

Indications ■

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Ultrasound offers real-time imaging and a noninvasive means of assessing the abdominal and pelvic viscera and other “solid” tissues such as the thyroid gland, lymph nodes, subcutaneous nodules, and breast lumps. It readily distinguishes between solid masses and cysts. Biopsies of suspicious tissue can be undertaken using fine needle aspiration or core biopsy.

Disadvantages ■

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22

Lesions greater than 7 mm are reliably detected but the examination is subjective and is both operator- and patient-dependent. In obese patients the examination may be limited because the ultrasound beam cannot penetrate large distances. Deep structures such as the para-aortic regions and pancreas may not be visualized. Structures may be obscured by gas in the overlying bowel because the ultrasound beam cannot penetrate gas. Though ultrasound is invaluable clinically, its subjective nature makes it unsuitable for clinical trials because lesions may not be measured accurately in the same plane on successive examinations and independent review is not possible.

Computed tomography Computed tomography (CT) represents true cross-sectional imaging.

Indications ■

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CT is the main imaging modality used to accurately stage diseases in the thorax, abdomen, and pelvis. In the thorax, the para-tracheal, anterior, and sub-carinal lymph nodes are visible, as are lesions behind the heart and at the apices, otherwise “hidden” on the CXR. Technological advances have led to the introduction of multi-slice CT (MSCT) scanners, which can produce 16, 64, and even 256 contiguous thin “slices”, enabling the entire thorax, abdomen, and pelvis to be scanned in under 8 seconds with the ability to “reconstruct” highdefinition images in any anatomical plane (Fig. 4.1). MSCT scans reliably demonstrate small intra-parenchymal lung lesions in the order of 2–3 mm. Viewing the images on a work station enables the radiologist to “scroll” through the thorax and distinguish nodules from small vessels. Intravenous (IV) contrast agents accentuate differences in normal viscera from those containing a tumor. Some tumors such as carcinoid, hepatocellular carcinoma, and some colorectal metastases are hypervascular and are best visualized during the arterial phase, typically about 20–30 seconds after injection of IV contrast rather than during the portal venous phase, which occurs about 70–80 seconds after injection, when most tumors are best demonstrated. CT is sensitive in detecting lytic bone metastases, particularly when a soft tissue component co-exists and also in cases of soft tissue and brain tumors. CT provides an objective imaging modality that is largely patient- and operator-independent. Computer software programs such as CT colonography and volumetric studies have enhanced tumor detection. The latter is used to follow small solitary lung nodules on serial CT scans, and although the axial imaging may suggest the nodule is unchanged in size the software accurately determines any volume change. CT is an anatomical imaging modality and relies on an anatomical abnormality or enlargement of normal structures. 23

(a)

(b)

Figure 4.1 (a) Axial IV contrast-enhanced MSCT scan of the pharynx in a 72-year-old woman with a history of localized papillary cell carcinoma of the left lobe of the thyroid gland diagnosed and treated 3 years earlier. A large asymptomatic enhancing mass is seen in the right parapharyngeal space (arrow). (b) Axial MSCT scan showing a percutaneous core biopsy needle within the mass. Because there was suspicion that the mass was a lymphoma, a core biopsy rather than a fine-needle aspirate was performed. This needle trajectory was chosen to ensure it did not pass close to the common carotid artery or internal jugular vein because inadvertent biopsy of these structures could lead to uncontrollable bleeding. The biopsy proved to be recurrent poorly differentiated papillary cell carcinoma of the thyroid.

Disadvantages ■

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24

Lymph nodes are not regarded as abnormal unless they measure greater than 10 mm in their short axis, but CT cannot determine if a node is malignant or reactive irrespective of the size of the node. Lung cancer studies have shown that up to 21% of mediastinal lymph nodes under 10 mm sampled at diagnosis contain a tumor and up to 40% of nodes greater than 10 mm do not contain a tumor. This has serious implications in lung cancer staging and treatment paradigms if anatomical imaging alone is undertaken.

Magnetic resonance imaging Magnetic resonance imaging (MRI) is another true cross-sectional imaging modality.

Indications MRI is of particular benefit in diagnosing and staging central nervous system tumors. Imaging sequences highlighting the bone marrow are extremely sensitive in detecting marrow infiltration by metastatic tumor, much more so than conventional isotope bone scans and often before the manifestation of clinical symptoms. MRI identifies the anatomical site for biopsy and subsequent histological confirmation. MRI is also sensitive in the detection of invasion beyond the serosal wall in prostate, bladder, and rectal tumors and many gynecological tumors such as those in the cervix and endometrium. Abnormal local lymph nodes are also demonstrated. Single breath–hold contrast-enhanced sequences allow the liver to be imaged, and liver-specific contrast agents such as superparamagnetic iron oxide particles and manganese-based agents further increase the sensitivity of detection of liver metastases.

Newer techniques The above all require an anatomical abnormality to be detected. Either a mass in an abnormal site or a change in the normal appearance of a lymph node must occur before detection is possible. Newer techniques aim to demonstrate early changes in the pathophysiology of tumor metabolism and angiogenesis. These changes represent “functional” parameters. ■

Dynamic scanning primarily uses MRI, though CT and ultrasound also show changes in tumor blood flow, blood volume, and permeability. Dynamic MRI scanning of a breast mass can determine whether it is malignant at diagnosis with the characteristic type-3 curve. Changes in blood flow, blood volume, and permeability during therapy act as surrogates, predicting response to treatment. Diffusion and perfusion 25

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(a)

MRI studies are still largely experimental, but data suggest that they demonstrate early changes in tumor metabolism and angiogenesis and in the effects of anti-angiogenesis agents and changes in tumor metabolism and function. Positron emission tomography (PET) scanning plays an increasing role in staging disease at the time of diagnosis and is a useful surrogate in determining response to therapy. It has poor spatial resolution (10 mm), so it is of limited use alone. When PET is combined with CT to form a PET-CT scan, the anatomical site is accurately demonstrated.  PET-CT is more sensitive than PET or CT alone in assessing the primary tumor, mediastinal nodes, and distant metastases in lung cancer and leads to a change in treatment in 25–30% of patients compared with CT alone. Usually this precludes futile curative surgery (Fig. 4.2), though for patients with bulky reactive mediastinal lymph nodes surgery is indicated.

(b)

Figure 4.2 (a) Non-contrast-enhanced axial CT component of PET-CT scan in a patient with non-small cell lung cancer of the thorax at the sub-carinal level with potentially operable disease by CT criteria. The primary tumor is seen in the posterior segment of the right lower lobe. There is no other convincing evidence of disease. (b) Fused PET-CT scan at the same level showing increased abnormal uptake in the primary tumor, at the right hilus, in the sub-carinal lymph nodes, in the left rib anterior, and in the posterior elements of the vertebra, indicating inoperable metastatic stage 4 disease.

26



PET-CT is more sensitive in detecting hepatic and extrahepatic metastases from colorectal cancer than CT alone. In patients with metastatic colorectal disease confined to the liver and potentially resectable by CT alone, the addition of PET-CT demonstrates extensive disease in 25% of patients, thus precluding surgery. However, for those for whom surgery is indicated based on PET-CT, longterm survival is enhanced.

Further reading Antoch G, Stattaus, Nemat T, et al. Non-small cell lung cancer: Dual-modality PET/CT in preoperative staging. Radiology 2003; 229: 526–33. Kuhl CK, Mielcareck P, Klaschik S, et al. Dynamic breast MR imaging: Are signal intensity time course data useful for differential diagnosis of enhancing lesions? Radiology 1999; 211: 101–10. Seddon BM, Workman P. The role of functional and molecular imaging in cancer drug discovery and development. Brit J Radiol 2003; 76: S128–38.

27

Nuclear medicine imaging G Jerusalem Medical Oncology Division of Medical Oncology and Hematology CHU Sart Tilman Liege, Belgium

5

N Withofs Nuclear Medicine Division of Nuclear Medicine CHU Sart Tilman Liege, Belgium

Introduction Nuclear medicine imaging has contributed significantly to diagnosis, treatment planning, and response evaluation in patients with cancer for many years (Table 5.1). It has also been used to monitor side effects (e.g., radionuclide ventriculography for the cardiac toxicity of anticancer drugs). More recently, positron emission tomography (PET) has become the imaging technique of choice in many clinical situations in oncology (Table 5.2).

Positron emission tomography PET has the ability to detect cancer based on molecular and biochemical processes within the tumor tissues. The most widely used radiotracer at this time is the glucose analog 18F-fluorodeoxyglucose (18F-FDG). The expression of cell surface glucose transporters is up-regulated in many malignant cells and after its transport 18F-FDG is trapped and accumulates within the cell. 18

F-FDG PET should be used as an imaging tool in addition to conventional radiologic methods.

29

Table 5.1 Current indications for nuclear medicine in oncology (excluding PET) ■

Bone scan (99mTc-methylenediphosphonate) Staging for bony disease in prostate, breast, lung, and other cancers (initial staging and suspected relapse)

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Sestamibi scan (99mTc-sestamibi) Localization of active disease

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Metaiodobenzylguanadine scan (131I or

123

I labeled MIBG)

Localization of neuroendocrine tumors that take up norepinephrine (e.g., pheochromocytoma, paraganglioma, neuroblastoma) ■

Octreotide scan (111In-octreotide) Detection, staging, and follow-up of tumors with somatostatin receptors (e.g., neuroendocrine and carcinoid tumors, gastroenteropancreatic tumors, medullary thyroid cancer, neuroblastoma)

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Iodine-scan (131I) Localization of metastases from differentiated papillary and follicular thyroid cancer

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Sentinel node lymphoscintigraphy (99mTc-sulphur colloids) Identification of the lymphatic drainage pathways in breast cancer and melanoma

False-positive and false-negative studies 18

F-FDG PET can result in false-negative or false-positive studies.

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30

Any positive finding that could lead to a clinically significant change in patient management should be confirmed by subsequent histopathological examination. Uptake of 18F-FDG in infectious and inflammatory processes (including inflammatory changes after radiotherapy) is the most common explanation for false-positive uptake. Physiologic uptake in the ureter, bowel, lymphatic tissue, thymus, brown fat, and muscle can be misinterpreted. Hyperplasia of thyroid or adrenal adenoma can also explain increased 18F-FDG uptake. False-negative PET studies can be due to the partial volume effect related to the limited spatial resolution of the technique (uptake in tumors

Table 5.2 Clinical indications for 18F-FDG PET Diagnosis: Solitary pulmonary nodule Unknown primary Pancreatic cancer (inconclusive CT) Staging: Hodgkin’s disease and aggressive and potentially curable non-Hodgkin’s lymphoma Esophageal cancer (especially to detect distant metastases) Non–small cell lung cancer Head and neck cancer Colorectal cancer (liver metastases staging) Suspected relapse: Lymphoma Breast cancer Colorectal cancer Head and neck cancer Thyroid cancer (131I whole body findings negative with high thyroglobulin levels) Primary brain tumors Ovarian cancer End of treatment evaluation: Hodgkin’s and non-Hodgkin’s lymphoma Testicular cancer (pure seminoma)

≤10 mm can be underestimated). Tumor glucose metabolic activity can be poor or moderate in some low-grade tumors (e.g., lymphocytic or mucosa-associated lymphoid tissue lymphoma, broncheo-alveolar carcinoma, and mucinous adenocarcinoma) and well-differentiated lesions (e.g., prostate and hepatocellular carcinomas, neuroendocrine tumors). Routine whole-body 18F-FDG PET is not useful for the detection of brain metastases because of the high physiological 18F-FDG uptake in the cerebral cortex. 31

PET or PET/CT? Only a few well-performed studies addressing this issue have been published. Concurrent use of PET and computed tomography (CT) in dualmodality systems provides a diagnostic advantage over either PET or CT alone.

Clinical application of 18F-FDG PET Screening 18

F-FDG PET scan is not indicated for screening because of the substantial cost and its lack of specificity.

Differential diagnosis: benign versus malignant 18

F-FDG PET can be used as a diagnostic aid for indeterminate pulmonary nodules. However, its use is limited in lesions smaller than 1 cm in diameter. 18 F-FDG PET is mostly beneficial by avoiding futile surgeries in low-risk patients. Negative 18F-FDG PET findings can be followed up with observation alone. However, a histopathological investigation is indicated in any high-risk patient.

Cancer of unknown origin: detection of the primary site PET is able to identify the primary tumor in some patients. Unfortunately, the impact of the PET result on therapeutic management has not been sufficiently investigated.

Staging and restaging The impact of PET on the quality of staging has been shown for various tumors. It allows a better selection of patients who are candidates for a surgical intervention with a curative intent. It is important to point out that its sensitivity is lower than a sentinel lymph node biopsy (e.g., melanoma, breast cancer).

Routine follow-up of asymptomatic patients Intensive follow-up evaluation for diseases such as breast cancer, melanoma, or non–small cell lung cancer is of questionable value because these tumors are generally incurable once metastases develop and early detection 32

of relapse is unlikely to result in increased survival. In contrast, salvage therapy for recurrent Hodgkin’s or non-Hodgkin’s lymphoma is effective in many patients, justifying closer follow-up. Nevertheless, routine follow-up by 18F-FDG PET is not recommended.

Monitoring response to treatment The purpose of PET for monitoring is to provide an early yet accurate assessment of the response monitoring to multicourse treatment with the ultimate goal of tailoring therapy according to the information provided (Fig. 5.1). Responses seen by PET often precede CT changes. This may justify the use of subclinical response as a criterion for the evaluation of anticancer drugs in early clinical trials and may provide some improvement in routine patient management. However, methodological developments in this area are still required. The optimal timing of post-therapy 18 F-FDG scans has yet to be determined in order to reduce overestimation (related to host inflammatory cells) and underestimation (related to transient metabolic activity early after chemotherapy) of 18F-FDG uptake in tumor cells. In 1999 the European Organization for Research and Treatment of Cancer published guidelines for tumor metabolic response assessment. Their criteria were based on the measurement of the standardized uptake value (SUV) in the tumor volume. The SUV is a simple semi-quantitative index obtained by dividing the tumor radiotracer concentration (MBq/l) by the injected activity (MBq) and multiplying it by the body weight (kg). This value may be useful but it is not to be followed blindly, as it greatly varies according to several parameters such as the time of image acquisition after 18 F-FDG injection and the blood glucose level. Further validation and standardization of PET procedures are needed before using this parameter in clinical practice.

End-of-treatment evaluation 18

F-FDG PET is able to distinguish between viable tumors and necrosis or fibrosis in residual masses that may be present after treatment. This feature appears most relevant in patients with lymphoma or testicular cancer but could also be important in other cancers, such as those of the head and neck region. The decision to administer salvage therapy should only be made after the positive PET finding has been confirmed by biopsy. 33

(a)

(b)

(c)

(d)

Figure 5.1 58-year old woman with a diffuse large B cell lymphoma who underwent 18F-FDG PET/CT (low dose) for initial staging. Pretreatment coronal PET image (a) showed 18F-FDG-avid bone marrow (green arrow), hepatic (blue arrow), and splenic (red arrow) lesions. The metabolic response, after two cycles of chemotherapy, was complete (b). Axial fused PET/CT images demonstrated a small left axillar lymphadenopathy (green arrows) at initial staging (c), which responded well to treatment (d).

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(e)

(f)

Figure 5.1 (Continued) Sagital fused PET/CT images showed areas of high 18F-FDG uptake (e) within the spine and sternum, completely resolved after chemotherapy (f).

New tracers Research is ongoing to develop new tracers that target specific biological properties of cancer cells. Oncologic research aims at more specific tumor targeting and improvements in the delivery and scheduling of anticancer therapies. Molecular imaging could provide information on in vivo distribution of biological markers in response to targeted therapy and could improve the selection of patients before therapies. A careful evaluation of all these new radiotracers is warranted.

Further reading Eary JF. Nuclear medicine in cancer diagnosis. Lancet 1999; 354: 853–7. Fletcher JW, Djulbegovic B, Soares HP, et al. Recommendations on the use of 18F-FDG PET in oncology. J Nucl Med 2008; 49: 480–508.

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Jerusalem G, Hustinx R, Beguin Y, et al. PET scan imaging in oncology. Eur J Cancer 2003; 39: 1525–34. Juweid ME, Cheson BD. Positron-emission tomography and assessment of cancer therapy. N Engl J Med 2006; 354: 496–507. Pantaleo MA, Nannini M, Maleddu A, et al. Conventional and novel PET tracers for imaging in oncology in the era of molecular therapy. Cancer Treat Rev 2008; 34: 103–21.

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Staging procedures B Zakotnik Institute of Oncology Ljubljana Department of Medical Oncology Ljubljana, Slovenia

6

H van Halteren Oosterschelde Hospital Department of Internal Medicine Goes, The Netherlands

Aim of staging procedures Introduction A single mutated cancer cell starts to grow locally to form a tumor composed of malignant and stromal cells, which spreads to adjacent and distant organs via lymphatic and blood vessels. The cancer growth pattern depends on the cell of origin and type of mutation(s); it can therefore progress slowly or in a very short time. Staging procedures are examinations and tests performed to define the extent of cancer within the body. Staging procedures focus on the size of the tumor, lymph node involvement, and distant metastases. The stage as the measure of the tumor burden in the body strongly influences disease outcome. This is illustrated by Figure 6.1, which shows cancer survival according to stage. In the majority of malignancies, treatment is tailored to tumor stage in order to obtain best outcome in terms of survival and treatment-related toxicity. The aim of staging is therefore to avoid under- and overtreatment.

Clinical staging Over time different staging systems and staging classifications have evolved and even today they are being fine-tuned with new outcome data. The most commonly used staging system is the TNM system (Table 6.1). The TNM system is based on 3 variables: tumor size (T0-T4), extent of

37

100

Stage TxN0M0 (n=10764)

80 60

Stage TxN+M0 (n=7488)

40

Stage unknown (n=1203)

20

Stage TxN+M1 (n=6116) Tx = T0 –T4; N+ = N1-N3

0 0

1

2

3

4

5

years

Figure 6.1 Relative 5-year survival of all cancers in men in Slovenia (2001–2005). Source: Cancer Registry of Slovenia.

lymph node involvement (N0–N3), and presence of distant metastases (M0, M1). In most types of cancer TNM staging is used. Different staging systems are used for central nervous system cancers, lymphomas (Ann Arbor staging classification), leukemias, multiple myeloma, and gynecological cancer (International Federation of Gynecology and Obstetrics/FIGO stage).

Pathological staging The pathological classification (postsurgical histopathological classification) (pTNM) is based on the evidence acquired before treatment, supplemented, or modified by the additional evidence acquired from surgery and from pathological examination. The pathological classification can be determined in the primary tumor (pTX, primary tumor cannot be assessed; pT0, no histological evidence of primary tumor; pTis, carcinoma in situ; pT1–pT4, according to size and/or local extension of primary tumor), regional lymph nodes (pNX, regional lymph nodes cannot be assessed histologically; pN0, no regional lymph node metastases; pN1–pN3, increasing involvement of 38

Table 6.1 Principles of TNM staging Primary tumor (T) TX

Primary tumor cannot be evaluated

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1, T2, T3, T4

Size and/or extent of the primary tumor

Regional lymph nodes (N) NX

Regional lymph nodes cannot be evaluated

N0

No regional lymph node involvement

N1, N2, N3

Involvement of regional lymph nodes (number and/or extent of spread)

Distant metastasis (M) MX

Distant metastasis cannot be evaluated

M0

No distant metastasis

M1

Distant metastasis

regional lymph nodes), and distant metastasis (pMX, distant metastasis cannot be assessed histologically; pM0, no distant metastasis; pM, distant metastases). The evaluation of lymph nodes has been adapted with the venue of the sentinel node procedure and the determination of isolated tumor cells.

Molecular staging Until the late 1990s, the staging systems mentioned above were informative enough to develop a tailored treatment plan, which consisted of local treatment (surgery, irradiation) and/or systemic treatment (chemotherapy). The advent of molecular tumor biology has recently enabled us to design targeted drugs and to identify molecular factors (e.g., oncogenes, enzymes) related to outcome or treatment-related toxicity. This is illustrated by Figure 6.2. In the future, molecular and clinical staging may together tailor cancer treatment (omitting treatment in low-risk patients, using the right drug 39

1

Probability

0.8

p < 0.01

0.6 0.4 0.2 0 0

24

48

72

96

Survival months censored

Lum A Basal

Lum C NonB-like ERBB2+ and Lum B

Figure 6.2 Overall survival according to gene expression pattern in 49 breast cancer patients.

for the right patient depending on the molecular profile of the tumor and pharmacogenetic profile of the patient).

Relevant staging procedures in daily clinical practice Physical examination, imaging procedures, laboratory tests, pathology reports, and surgical reports provide information to determine cancer stage. ■

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Physical examination may provide information on tumor location and size, as well as possible spread to lymph nodes and/or to other organs. Imaging studies such as X rays, ultrasound, computed tomography (CT) scans, magnetic resonance imaging (MRI) scans, and positron emission tomography (PET) or PET/CT scans can show the location of the cancer, the size of the tumor, and where the cancer has spread. Pathology reports should include information about the size of the tumor, the growth of the tumor into other tissues and organs, the histological type and grade of the tumor, and resection margins of the surgical specimen (free, distance of the tumor from nearest margin, invaded).

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Surgical reports should describe the size of the tumor, observations about lymph nodes and nearby organs, as well as the surgeons’ opinion regarding the radicality of the operation (if tumor left in place, size of remaining tumor).

Head and neck tumors Head and neck cancer encompasses a variety of cancers, mostly squamous cell cancers. Physical examination underestimates the presence of locoregional lymph node metastases in up to 30% of patients. A contrastenhanced CT scan can provide information on local tumor infiltration. In comparison with CT, MRI provides a more superior definition of soft tissue but is less accurate at detecting lymph node metastases. A PET scan has the highest yield for lymph node metastases, with a sensitivity of at least 90%. Due to its limited spatial resolution, PET scanning cannot accurately localize the disease. When available, a PET/CT offers the best staging results.

Small cell lung cancer The main goal of staging is to identify patients with disease limited to the ipsilateral hemi-thorax, as such patients are usually treated with combined radiotherapy and chemotherapy (i.e., limited disease). Patients with extensive disease are treated with chemotherapy only. Because of its high metastasizing tendency, small cell lung cancer staging requires an extensive work-up, which includes a CT scan of thorax and abdomen, a cranial CT or MRI, and a bone scan. There are no large-scale studies, which have evaluated the additional value of PET scanning in the staging process.

Non–small cell lung cancer A posteroanterior and lateral chest X ray should be obtained as an initial estimate of the extent of disease. An abdominal/thoracic CT scan and bone scan should be made to estimate the depth of local tumor invasion and to exclude distant metastases. If surgery is being considered, a PET or PET/ CT scan should be made. If the PET scan reveals occult mediastinal metastases, tissue sampling should provide further clarity. Depending on available equipment and localization of the hot spots, tissue sampling could be performed by means of cervical mediastinoscopy, endobronchial 41

ultrasound, transesophageal endoscopic ultrasound (EUS), or blind transbronchial needle aspiration.

Esophageal cancer A CT scan of the thorax and upper abdomen can identify patients with gross locoregional or distant spread, but it lacks sensitivity. It cannot reliably predict the extent of locoregional disease and EUS is the staging modality of choice. A CT scan also often fails to identify nodal metastases in the region of the celiac axis and peritoneal metastases. A PET scan is a more expensive procedure, but its sensitivity for distant metastases is higher. The combination of PET and EUS has been shown to be more costeffective than the combination of CT and EUS. The routine use of staging laparoscopy remains a controversial issue.

Gastric cancer A chest X ray is generally recommended in spite of its limited sensitivity for metastases. In patients with a suspicious chest X ray or a negative image and pulmonary complaints, a CT scan of the thorax should be performed. In more than 30% of patients an abdominal CT scan does not accurately predict the T-stage of the primary tumor and lymph node metastases are missed in up to 35% of patients. EUS provides a more accurate prediction of T-stage. Furthermore, it offers the possibility of lymph node examination by means of fine needle aspiration. Nevertheless, even patients with locoregionally advanced tumors might still be candidates for surgery. This may explain why EUS does not appear to affect the treatment plan, in spite of its higher staging accuracy. EUS is therefore not recommended for routine use.

Colorectal cancer It is customary to perform a chest X ray prior to surgery to rule out pulmonary metastases. An abdominal CT scan can provide information on the presence of hepatic metastases. The sensitivity of a CT scan for detecting nodal metastases and assessing the depth of transmural invasion—which is especially important in patients with rectal cancer—is low. For patients 42

with rectal cancer endosonography and contrast-enhanced MRI is mandatory in order to predict the status of the circumferential resection margins. A PET scan may provide additive information, if resection of isolated pulmonary/hepatic metastases is being anticipated.

Breast cancer Thorough clinical examination, mammography, and ultrasound usually suffice for locoregional staging. The role of MRI is limited, because it lacks specificity. For women with stage III breast cancer, the risk of metastasis is high enough to warrant a radionuclide bone scan, a chest X ray, and ultrasound (or CT) of the liver. In women with an earlier stage, such procedures should be confined to those with a suspicious anamnesis. Estrogen and progesterone receptors, as well as Her2, should be determined in the tumor tissue.

Prostate cancer A CT scan of the abdomen and pelvis cannot accurately predict extraprostatic extension, seminal vesicle invasion, and nodal spread. It merely serves to determine the treatment field in case of external beam radiotherapy. If prostatectomy is being anticipated, an endorectal coil MRI may provide more accurate information on extraprostatic extension and seminal vesicle invasion, whereas fine needle aspiration may provide further information on enlarged lymph nodes. In patients with a T1 or T2 tumor, a combined Gleason score of 6 or less and a serum PSA lower than 10 ng/mL, the risk of bone metastases is sufficiently low to refrain from performing a bone scan. In the instance of a positive bone scan, plain radiographs of the hot spots should be made. In case of doubt, a CT or MRI scan may provide further clarity.

Bladder cancer Cystoscopy allows the urologist to estimate the intravesical extent of the tumor or tumors and to obtain histology. Intravenous pyelography is gradually being replaced by CT scanning. In the majority of patients, an abdominal CT scan or MRI can provide reliable information on the extent of extravesical tumor spread. It is customary to perform a chest X ray prior 43

to operation. In patients with a suspicious chest X ray or a negative image and pulmonary complaints, a CT scan of the thorax should be performed. In patients with invasive bladder cancer and bone pain or an elevated alkaline phophatase concentration, a radionuclide bone scan should be performed.

Renal cell cancer The extent of local and regional involvement can be determined by means of an abdominal CT scan. It is customary to perform a chest X ray prior to surgery. In patients with bone pain an X ray of the affected bones (or a CT in case of a negative X ray) is recommended.

Endometrial cancer A chest X ray should be performed to exclude pulmonary metastases. An abdominal CT scan appears to be a poor predictor of depth of disease, presence of nodal metastases, and cervical involvement. In a few cases, it may reveal hepatic metastases and prevent an unnecessary staging laparotomy. The extent of locoregional disease is being determined by means of surgical staging, which comprises a total extrafascial hysterectomy and bilateral salpingo-oophorectomy. Suspicious intraperitoneal and retroperitoneal lesions should be biopsied and peritoneal fluid should be sent for cytologic examination. During operation the hysterectomy specimen should be opened to evaluate the depth of tumor infiltration. In stage I endometrial cancer, pelvic and para-aortic lymph node dissection is only indicated in case of enlarged lymph nodes. If the tumor invades the cervix or the uterine serosa, lymph node dissection is mandatory.

Ovarian cancer In case of complaints suggestive for a primary tumor in the gastrointestinal tract, the breast, or the uterus, such tumors should be excluded, because they can spread to the ovaries. Preoperative staging usually includes a thorough physical examination, an abdominal CT scan, and a chest X ray. During surgical staging all intra-abdominal organs and surfaces should be palpated and biopsied, when indicated. The omentum should be resected. In the absence of suspicious nodes, pelvic and para-aortic nodes should be sampled to exclude the possibility of microscopic stage III disease. 44

Malignant melanoma In asymptomatic patients with stage I/II melanoma the risk of metastasis is low. A chest X ray and serum lactic dehydrogenase concentration may serve as baseline for the future. More extensive radiologic studies are not recommended. In patients with a melanoma thicker than 1 mm locoregional sentinel lymph node biopsy is indicated. If the indicator node reveals metastasis, a complete regional lymphadenectomy should be performed. In patients with stage III disease the risk of metastasis is sufficiently high to warrant CT scans of the thorax and abdomen.

Non-Hodgkin’s lymphoma In patients with non-Hodgkin’s lymphoma, histopathology is more important than other factors such as age, performance status, and stage. The staging procedure should include a thorough physical examination directed at all potentially involved and reachable sites, i.e., the tonsils, base of the tongue; nasopharynx; occipital, preauricular, epitrochlear, cervical, supraclavicular, axillar, femoral, and popliteal lymph nodes; liver; spleen; skin; and testicles. Furthermore, a CT scan of the neck, thorax, abdomen, and pelvis, as well as a bone marrow biopsy, should be performed. In case of nasopharyngeal localization, an MRI should be performed to rule out spread to the cerebrospinal circulation.

Hodgkin’s disease The staging procedure should include a thorough physical examination of all possibly affected and reachable sites. Furthermore, a CT scan of the neck, thorax, abdomen, and pelvis (or, if available, a PET-CT), as well as a bone marrow biopsy, should be performed.

Further reading A predictive model for aggressive non Hodgkin’s lymphoma: the international non Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 1993; 329: 987–94. Ardizzoni A, Grimaldi A, Repetto L, et al. Stage I-II melanoma: The value of metastatic work up. Oncology 1987; 44: 87–9.

45

Berg WA, Gutierrez L, Nessaiver MS, et al. Diagnostic accuracy of mammography, clinical examination, US, and MR imaging in preoperative assessment of breast cancer. Radiology 2004; 233: 830–49. Branstetter BF, Blodgett TM, Zimmer LA, et al. Head and neck malignancy: is PET/CT more accurate than PET or CT alone? Radiology 2005; 235: 580–586 Buchsbaum HJ, Lifshitz AS. Staging and surgical evaluation of ovarian cancer. Semin Oncol 1984; 11: 227–37. Byrne MF, Jowell PS. Gastrointestinal imaging: endoscopic ultrasound. Gastroenterology 2002; 122: 1631–48. Cancer Registry of Slovenia. Cancer Incidence in Slovenia 2005. Institute of Oncology, Ljubljana, Slovenia, 2008. Fanning J, Tsukada Y, Piver MS. Intraoperative frozen section diagnosis of depth of myometrial invasion in endometrial adenocarcinoma. Gynecol Oncol 1990; 137: 47–50. Gerber B, Seitz E, Muller H, et al. Perioperative screening for metastatic disease is not indicated in patients with primary breast cancer and no clinical signs of tumor spread. Breast Cancer Treat 2003; 82: 29–37. Giede KC, Kieser K, Dodge J, Rosen B. Who should operate on patients with ovarian cancer? An evidence-based review. Gynecol Oncol 2005; 99: 447–61. Gold JS, Jaques DP, Busam KJ, Brady MS, Coit DG. Yield and predictors of radiologic studies for identifying distant metastases in melanoma patients with a positive sentinel lymph node biopsy. Am J Surg Oncol 2007; 14: 2133–40. Herth F, Becker HD, Ernst A. Conventional vs endobronchial ultrasound guided transbronchial needle aspiration: a randomized trial. Chest 2004; 125: 322–5. Johnson CD, Dunnick NR, Cohan RH, Illescas FF. Renal adenocarcinoma: CT staging of 100 tumors. Am J Roentgenol 1987; 148: 59–63. Kim B, Semelka RC, Ascher SM, et al. Bladder tumor staging: comparison of contrast-enhanced CT, T1, and T2 weighted MR imaging, dynamic gaudolineumenhanced imaging, and late gaudolineum-enhanced imaging. Radiology 1994; 193: 239–45. Mentzer SJ, Swanson SJ, DeCamp MM, Bueno R, Sugarbaker DJ. Mediastinoscopy, thoracoscopy, and video-assisted thoracic surgery in the diagnosis and staging of lung cancer. Chest 1997; 112: 239S–241S. Mercury Study Group. Diagnostic accuracy of preoperative magnetic resonance imaging in predicting curative resection of rectal cancer: prospective observational study. BMJ 2006; 333: 779. Mi A, Webb MJ, Keeney GL, Aletti G, Podrata KC. Endometrial cancer: predictors of peritoneal failure. Gynecol Oncol 2003; 89: 236–42. Rosenberg SA. Validity of the Ann Arbor staging classification for the non Hodgkin’s lymphomas. Cancer Treat Rep 1977; 61: 1023–7.

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Sørlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001 Sep 11; 98(19): 10869–74. Taylor AJ, Youker JE. Imaging in colorectal carcinoma. Semin Oncol 1991; 18: 99–110. Van Poppel H, Ameye F, Oyen R, van de Voorde W, Baert L. Accuracy of combined computerized tomography and fine needle aspiration in lymph node staging of localized prostatic carcinoma. J Urol 1994; 151: 1310–4. Wallace MB, Nietert PJ, Earle C, et al. An analysis of multiple staging management strategies for carcinoma of the esophagus: computed tomography, endoscopic ultrasound, positron emission tomography, and thoracoscopy/laparoscopy. Ann Thorac Surg 2002; 74: 1026–32. Wang L, Hricak H, Kattan MW, et al. Prediction of organ-confined prostate cancer: incremental value of MR imaging and MR spectroscopic imaging to staging nomograms. Radiology 2006; 238: 597–603. Wieder HA, Rosenberg R, Lordick F, et al. Rectal cancer: MR imaging before neoadjuvant chemotherapy and radiation therapy for prediction of tumor-free circumferential resection margins and longterm survival. Radiology 2007; 243: 744–51. Yoshida S, Tanaka S, Kunihiro K, et al. Diagnostic ability of high frequency ultrasound probe sonography in staging of early gastric cancer, especially for submucosal invasion. Abdom Imaging 2005; 30: 518–23.

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Prognostic factors D Schrijvers Department Hemato-Oncology Ziekenhuisnetwerk Antwerpen-Middelheim Antwerp, Belgium

7

Introduction A prognostic factor or test is any measurement available at the time of diagnosis that correlates with disease-free or overall survival in absence of therapy and correlates with the natural history of the disease. It serves as a variable that can explain some of the heterogeneity associated with the expected course and outcome of a disease. This is in contrast to a predictive factor, i.e., any measurement predicting treatment outcome to a given therapy. A prognostic marker should be readily accessible and tested with a uniformly available technology, have a standardized methodology, and be reproducible and independent from other known prognostic markers. It should predict a wide range of clinical outcomes and be validated prospectively in an independent patient population treated with the current standard of care. Prognostic factors may be linked to patient- or tumor-related characteristics. They vary among different patient populations and tumor types and whereas some factors are prognostic for most cancer patients (e.g., performance status, TNM classification), specific prognostic factors may be present. For several tumor types, prognostic indices or nomograms have been developed that may predict the prognosis of patients and be used for patient stratification in studies or treatment selection. Treatment strategies are dependent on prognostic factors that involve the patient, the tumor, and the environment as it relates to the opportunities for early treatment and follow-up care. Newer and more specific prognostic factors dealing with molecular diagnostic studies are being introduced into

49

evaluation and treatment strategies in daily clinical practice, but they should be validated by standard evidence-based methods.

Patient-related prognostic factors Several patient-related factors have been linked to prognosis. ■

■

■

■

■

■

■

50

Socioeconomic status. A lower socioeconomic status correlates with a worse prognosis. However, this might be due to the fact that low socioeconomic status is a determinant of delayed diagnosis and delayed access to treatment. Performance status. Performance status has been linked to the prognosis in most tumor types. Patients with a bad performance status have a worse outcome independent of cancer treatment. Age. In certain tumor types (e.g., breast cancer), younger age at diagnosis may translate into a worse prognosis. However, bias cannot be ruled out, because when standardized for other stronger prognostic indicators the correlation between age and prognosis may be less strong. Nutritional status. A high body mass has been linked to a worse prognosis in certain tumor types (e.g., breast cancer, colorectal cancer). Physical activity. Increased physical activity has been related to a better prognosis. Any moderately intense recreational physical activity, such as brisk walking, is associated with a lower risk of death. Encouraging patients to maintain or increase their physical activity after a diagnosis of cancer, especially breast cancer, may be beneficial to their overall health. Comorbidity. Comorbidity is an important prognostic factor. However, comorbidity affects both treatment and prognosis, making it difficult to separate the respective contributions of comorbidity, functional status, and treatment reduction to prognosis. Some studies have shown that diabetes mellitus, obesity, and hyperinsulinemia with insulin-resistance syndrome correlate with a worse prognosis in patients with specific tumor types. Smoking. In patients with lung cancer, smoking has a negative prognostic impact: patients with early-stage cancer who have never smoked have a significantly better survival rate than smokers, and a smoking history of ≥20 pack-years translates into a worse survival.

■

■

Immune status. In patients with an immune deficiency due to infection with a human immunodeficiency virus prognosis of Hodgkin’s lymphoma and lung, larynx, and prostate cancers is worse than in patients with an immune-competent system.  In patients treated with immunosuppressive medication for organ transplantation, it is not known at the moment if prognosis is impaired compared with immune-competent persons. Anemia. Anemia is a negative prognostic factor in a wide range of tumor types (e.g., cervical cancer, head and neck cancer), mainly due its central role in tumor hypoxia.

Tumor-related prognostic factors ■

Histology. Tumor histology has been linked with prognosis. Certain tumor types (e.g., small cell lung cancer, anaplastic thyroid cancer) have an inherently worse prognosis compared with other tumors (e.g., basal cell carcinoma).  Differentiation grade has an impact on prognosis: well-differentiated tumors have a better prognosis than undifferentiated tumors (e.g., prostate cancer). TNM classification. The TNM classification describes the anatomic extent of cancer and the prognosis of an individual tumor is related to the extent of the tumor at the primary site (T), the presence or absence of metastatic disease in regional lymph nodes (N), and the presence or absence of distant metastasis (M). A greater invasion of the primary tumor, a higher number of invaded lymph nodes, and the presence of distant metastatic disease translates into a worse prognosis. However, one of the difficulties in the current anatomic TNM system is that other known prognostic factors are not being included. Serum markers. Several serum markers have been linked to prognosis in hematological and solid tumors such as albumin, lactate dehydrogenase, soluble CD23, β2-microglobulin, thymidine kinase, interleukin-6 soluble receptor, transforming growth factor–β1, and tumor markers [e.g., carcinoembryonic antigen (CEA), β-human chorionic gonadotropin (βHCG), alpha fetoprotein (AFP)]. Some of these factors have been integrated in prognostic indices [e.g., International Prognostic Index (IPI) for non-Hodgkin’s lymphoma, follicular IPI for follicular lymphoma] or nomograms (e.g., prostate cancer, colon cancer). 

■

■

51

Table 7.1 Recommendations of the European Society for Medical Oncology and the American Society for Clinical Oncology in relation to serum and molecular markers in selected tumor types Breast cancer ■

Hormone receptors ER and PR are no longer considered as prognostic

■

Data are insufficient to recommend use of DNA content, S phase, or other

factors. flow cytometry–based markers of proliferation to assign patients to prognostic groups. ■

Data are insufficient to recommend measurement of Ki67, cyclin D, cyclin E, p27, p21, thymidine kinase, topoisomerase II, or other markers of proliferation to assign patients to prognostic groups.

■

The use of HER2 for determining prognosis is not recommended. However, HER2 expression and/or amplification should be evaluated in every primary invasive breast cancer either at the time of diagnosis or at the time of recurrence, principally to guide selection of trastuzumab in the adjuvant and/ or metastatic setting.

■

uPA/PAI-1 measured by ELISAs on a minimum of 300 mg of fresh or frozen breast cancer tissue may be used for the determination of prognosis in patients with newly diagnosed, node-negative breast cancer. Low levels of both markers are associated with a sufficiently low risk of recurrence, especially in hormone receptor–positive women who will receive adjuvant endocrine therapy, that chemotherapy will only contribute minimal additional benefit. Furthermore, CMF-based adjuvant chemotherapy provides substantial benefit, compared with observation alone, in patients with high risk of recurrence as determined by high levels of uPA and PAI-1.

Colorectal cancer ■

CEA may be determined preoperatively in patients with colorectal carcinoma. An elevated preoperative CEA (>5 mg/mL) may correlate with poorer prognosis. However, data are insufficient to support the use of CEA to determine whether to treat a patient with adjuvant therapy. (Continued )

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Table 7.1 (Continued) ■

Neither flow cytometrically derived DNA ploidy (DNA index) nor DNA flow cytometric proliferation analysis (% S phase) should be used to determine prognosis of early-stage colorectal cancer.

■

Present data are insufficient to recommend the use of p53 expression or mutation for screening, diagnosis, staging, surveillance, or monitoring treatment of patients with colorectal cancer.

■

Present data are insufficient to recommend the use of the ras oncogene for screening, diagnosis, staging, surveillance, or monitoring treatment of patients with colorectal cancer.

■

Thymidilate synthetase, thymidilate phosphorylase, and dihydropyrimidin dehydrogenase are not recommended for use in determining the prognosis of colorectal cancer.

■

Microsatellite instability ascertained by polymerase chain reaction (PCR) is recommended neither to determine the prognosis of operable colorectal cancer nor to predict the effectiveness of 5-fluorouracil adjuvant chemotherapy.

■

Assaying for loss of heterozygosity on the long arm of chromosome 18 (18q) or DCC protein determination by immunohistochemistry should not be used to determine the prognosis of operable colorectal cancer.

Testicular cancer ■

Seminoma testicular cancer 

Good prognosis. All of the following: normal AFP, any βHCG, any lactate dehydrogenase (LDH) and no nonpulmonary visceral metastases



Intermediate prognosis. Normal AFP, any βHCG, any LDH and nonpulmonary visceral metastases

■

Nonseminoma testicular cancer 

Good prognosis. All of the following: AFP 5.5 mg/L

Cytogenetics are major prognostic factors and should be obtained either by conventional karyotyping or fluorescent in situ hybridization analysis. The most relevant abnormalities are del(13), t(4;14) and del(17p), which are associated with a poorer outcome

■

Molecular markers. Several molecular markers have been identified that can predict prognosis in certain tumor types. These molecular markers can be components of different parts of the cell (cell membrane, cytoplasm, nucleus) and can be demonstrated by different techniques (immunohistochemistry, polymerase chain reaction, omics). At the moment, their use in clinical practice is relatively limited for the determination of prognosis, although they might be used in treatment decisions [e.g., estrogen receptor (ER), progesterone receptor (PR), Her2-neu overexpression].

The European Society for Medical Oncology and the American Society for Clinical Oncology formulated some recommendations in relation to serum and molecular markers in daily clinical practice (Table 7.1). 54

Conclusion Although many factors can be considered to be prognostic for the outcome of cancer, it is difficult to determine their impact in the individual cancer patient. Some of these prognostic factors have made their entrance into daily clinical practice, whereas others are only used in clinical study designs. The importance of prognostic factors is growing in relation to treatment decisions, and patients with a good prognosis can be spared of bothersome treatments after primary treatment.

Further reading Dal Maso L, Zucchetto A, Talamini R, et al. Prospective Analysis of Case-control studies on Environmental factors and health (PACE) study group. Effect of obesity and other lifestyle factors on mortality in women with breast cancer. Int J Cancer 2008; 123: 2188–94. Iasonos A, Schrag D, Raj GV, Panageas KS. How to build and interpret a nomogram for cancer prognosis. J Clin Oncol 2008; 26: 1364–70. Irwin ML, Smith AW, McTiernan A, et al. Influence of pre- and post-diagnosis physical activity on mortality in breast cancer survivors: the health, eating, activity, and lifestyle study. J Clin Oncol 2008; 26: 3958–64. McShane LM, Altman DG, Sauerbrei W, et al. Statistics Subcommittee of the NCIEORTC working group on cancer diagnostics. Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst 2005; 97: 1180–4. Soerjomataram I, Louwman MW, Ribot JG, Roukema JA, Coebergh JW. An overview of prognostic factors for long-term survivors of breast cancer. Breast Cancer Res Treat 2008; 107: 309–30. Spano JP, Costagliola D, Katlama C, et al. AIDS-related malignancies: state of the art and therapeutic challenges. J Clin Oncol 2008; 26: 4834–42. Woods LM, Rachet B, Coleman MP. Origins of socio-economic inequalities in cancer survival: a review. Ann Oncol 2006; 17: 5–19.

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Predictive tumor markers M Ignatiadis, C Sotiriou Medical Oncology Department Translational Research Unit Institut Jules Bordet Université Libre de Bruxelles Brussels, Belgium

8

Introduction Chemotherapy, endocrine treatment, and the newer targeted agents are used as systemic adjuvant treatment after curative surgery or as palliative treatment for metastatic disease in patients with various malignancies. However, these treatments do not benefit all patients and may cause serious toxicity. Therefore, factors that predict response/toxicity to systemic treatments are urgently needed.

Tumor markers: definition and types A tumor marker is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacological response to a therapeutic intervention in oncology. Tumor markers are characterized as prognostic (reflecting the metastatic potential and/or growth rate of the tumor) or predictive (reflecting the sensitivity or resistance of a tumor to a therapeutic agent). However, in most clinical cases tumor markers are both prognostic and predictive. Figure 8.1 shows purely prognostic and predictive tumor markers (Fig. 8.1a and b) as well as mixed tumor markers (Fig. 8.1c and d).

Tumor markers: evaluation of their clinical utility The three important questions that a medical oncologist needs to answer when using a predictive tumor marker in clinical practice are: ■

Can the new tumor marker be measured in a reliable and reproducible way? 57

Prognosis

Good Factor neg Factor neg

Factor 2 neg Factor 2 pos Factor 1 pos

Good

Factor 2 pos

Prognosis

Factor 1 neg

Factor 1 pos Factor 1 neg

Factor pos Poor

Factor pos No therapy

(a)

Poor Therapy

(b)

Factor pos

Factor 2 neg

Factor neg No therapy

Therapy

Factor pos Good Factor pos

Factor pos

Prognosis

Prognosis

Good

Factor neg

Poor

Factor pos

Factor neg

Factor neg Poor

(c)

Factor neg No therapy

Therapy

(d)

No therapy

Therapy

Figure 8.1 Schematic presentation of prognostic and predictive factors. (a) Pure prognostic factor. (b) Pure predictive factor. (c) Mixed factor associated with weakly favorable prognosis and strong response to specific therapy. (d) Mixed factor associated with unfavorable prognosis and strong response to specific therapy. Source: Modified from Hayes DF, Trock B, Harris AL. Assessing the clinical impact of prognosis factors: when is “statistically significant” clinically useful? Breast Cancer Res Treat 1998; 52: 305–19, with kind permission of Springer Science and Business Media. ■ ■

What are the specific clinical scenarios for using the new tumor marker? What is the magnitude of difference in outcome for those who are marker-positive and those who are marker-negative?

The Tumor Marker Utility Grading System was initially developed by members of the American Society of Clinical Oncology panel to grade the utility of tumor markers based on published information. Markers were characterized by level of evidence based on the relative quality of the published studies (Table 8.1). 58

Table 8.1 Level of evidence for determining utility of tumor markers Level

Type of evidence

I

Evidence from a single, high-powered, prospective controlled study that is specifically designed to test marker, or evidence from well-done meta-analysis and/or overview of level I studies. Ideally, the study is a prospective, randomized controlled trial in which diagnostic and/or therapeutic clinical decisions in one arm are determined at least in part on the basis of marker results, and diagnostic and/or therapeutic clinical decisions in the control arm are made independently of marker results, or Evidence from overview of level of evidence II studies addressing specific use.

II

Evidence from study in which marker data are determined in relationship to prospective therapeutic trial that is performed to test therapeutic hypothesis but not specifically designed to test marker utility. Specimen collection for marker study and statistical analysis are prospectively determined in protocol as secondary objectives.

III

Evidence from large but retrospective studies from which variable numbers of samples are available or selected. Statistical analysis for tumor marker was not dictated prospectively at time of therapeutic trial design.

IV

Evidence from small retrospective studies that do not have prospectively dictated therapy, follow-up, specimen selection, or statistical analysis.

V

Evidence from small pilot studies designed to determine or estimate distribution of marker levels in sample populations.

Source: Reprinted from Hayes DF, Bast RC, Desh CE et al. Tumor marker utility grading system: a framework to evaluate clinical utility of tumor makers. J Natl Cancer Inst 1996; 88(20): 1456–1466, permission of Oxford University Press.

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Tumor markers: methodological, statistical, and reporting considerations Published studies on tumor markers suffer both from methodological/ statistical as well as from reporting issues. In many cases, published tumor markers have been measured with assays that have been suboptimally standardized with low reproducibility, whereas the cut-off values chosen for positivity have not been adequately validated. Moreover, many studies on tumor markers often have had poor statistical designs, and have been conducted in archived samples from retrospective series. The three threats to validity that affect clinical tumor marker research are chance, bias, and generalizability. ■

■

60

Chance can undermine validity by two types of errors:  Type I error, when the investigators arrive at a false-positive conclusion that there is a difference in outcome between tumor marker-positive and -negative groups when no difference exists, and  Type II error, when the investigators arrive at a false-negative conclusion that there is no difference in outcome between tumor marker–positive and –negative groups when a difference exists. Increasing sample size will increase the power of a tumor marker study to detect a clinically meaningful difference. Bias is the systematically erroneous association of some characteristic with the marker-positive or -negative group in a way that distorts a comparison between the two groups. Bias is more difficult to assess both conceptually and logistically. An example of bias can be illustrated when a multigene predictor for response to chemotherapy is built by comparing gene expression profiles between patient groups that respond or not to neo-adjuvant chemotherapy and the two patient groups differ in the percentage of patients with estrogen receptor (ER)negative tumors. ER status is known to be associated with differential response to chemotherapy. In this case, the resulting multigene predictor will reflect differences between ER-positive and ER-negative tumors rather than the innate chemosensitivity of the tumor. Methods commonly used to address bias are randomization and blinding. However, neither randomization nor blinding can exclude the presence of unknown biases.

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Generalizability refers to the applicability of the comparison between tumor marker–positive and –negative patient groups to the broader patient population outside of the clinical study.

As the different “omics” (e.g., genomics, epigenomics, proteomics) are increasingly used to develop tumor markers, additional challenges in study design and interpretation are emerging, such as overfitting. This is a problem caused by chance when multivariable analysis is used to assess associations between large numbers of possible predictors and an outcome. In this case the association between the predictor and clinical outcome cannot be replicated outside the initial cohort of patients (training set). Therefore, validation of such predictors in an independent patient population (validation set) is needed. Many tumor marker studies have not been reported in a rigorous fashion to allow assessment of the quality of the study. In order to standardize reporting of tumor marker study results, the National Cancer Institute– European Organization for Research and Treatment of Cancer Working Group on Cancer Diagnostics developed Reporting recommendations for tumor MARKer prognostic studies (REMARK). These guidelines broadly outline items that should be addressed by researchers when reporting the results of tumor marker studies.

Predictive tumor markers in routine use or in development Although many potential predictive factors have been reported in the literature, only a few are routinely used in everyday clinical practice (Table 8.2). ■

■

CD20 is a tumor marker predictive for response to the monoclonal antibody rituximab in patients with B-cell lymphomas. ER, progesterone receptor (PR), and HER2 are predictive tumor markers routinely used in the treatment of breast cancer. According to the American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in oncology, ER and PR status should be used to identify patients most likely to benefit from endocrine forms of therapy in early and metastatic breast cancer. However, although patients with ER-negative tumors do not benefit from hormonal 61

therapy, not all patients with ER-positive tumors are sensitive to hormonal treatment and some of those who are initially responsive later become resistant to endocrine treatment. Therefore, extensive research is being conducted in order to understand the biology of sensitivity/ resistance to endocrine treatment in ER-positive disease and to identify new predictive biomarkers for endocrine sensitivity. According to the same panel, HER2 protein overexpression or HER2 gene amplification either at the primary tumor or at the site of relapse should be used to guide selection of trastuzumab in the adjuvant and metastatic setting. Most predictive tumor markers have high negative predictive value (a negative tumor marker predicts no response to treatment), whereas they have moderate positive predictive value (a positive tumor marker does not always predicts response to treatment). The sequencing of the human genome, the explosion of the “omics” technologies, and the advances in understanding the biology of malignant transformation and metastatic progression have provided insight into the pathways of response/resistance to various treatments and have led to numerous predictive tumor markers that are currently in different stages of development. The identification of several activating oncogenic mutations has provided predictive tumor markers for response of various solid tumors to targeted therapies (Table 8.2). During the last decade, powerful microarray technology has provided several new molecular classifications of different solid tumors but also new prognostic and predictive tools. For example, multigene signatures have demonstrated evidence for improving prognosis in breast cancer and are now being evaluated in international prospective clinical trials. Multigene predictors of response to chemotherapy, endocrine therapy, or targeted agents are in earlier stages of development in breast cancer. Similar multigene signatures are under development in other solid tumors.

Conclusion The development of predictive tumor markers offers the exciting possibility of individualizing treatment strategies in oncology and moving towards personalized medicine. However, reliable and reproducible assays for 62

Table 8.2 Simplified list of predictive tumor markers in breast and other solid tumors Type of cancer Tumor marker

Clinical scenario Impact/Use in (predicts response) clinical practice in Europe

Breast

ER/PR

Endocrine agents

Routine

HER2/neu

Anti-HER2 agents

Routine

uPA/PAI-1

Chemotherapy

Selected institutions

Multigene signatures Chemotherapy/

Selected institutions

endocrine agents Colorectal

K-ras mutations

Cetuximab

Selected institutions

Non–small cell

EGFR mutations

Gefitinib, erlotinib

Selected institutions

Gastrointestinal

C-kit or PDGFRA

Imatinib mesulate

Selected institutions

stromal tumors

mutations

lung cancer

measuring a new predictive tumor marker as well as a rigorous clinical validation procedure is needed before the new marker can be implemented in routine clinical practice.

Further reading Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 2007; 25: 5287–312. Henry NL, Hayes DF. Uses and abuses of tumor markers in the diagnosis, monitoring, and treatment of primary and metastatic breast cancer. Oncologist 2006; 11: 541–52. McShane LM, Altman DG, Sauerbrei W, et al. Reporting recommendations for tumor marker prognostic studies. J Clin Oncol 2005; 23: 9067–72. Ransohoff DF. Bias as a threat to the validity of cancer molecular-marker research. Nat Rev Cancer 2005; 5: 142–9. Sotiriou C, Piccart MJ. Taking gene-expression profiling to the clinic: when will molecular signatures become relevant to patient care? Nat Rev Cancer 2007; 7: 545–53.

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Factors determining anticancer treatment

9

D Schrijvers Department of Hemato-oncology Ziekenhuisnetwerk Antwerpen-Middelheim Antwerp, Belgium

Introduction Several factors should be taken into account before choosing and starting an anticancer treatment. They are related to the disease, the patient, and the impact of the treatment, but they are also related to society. When deciding on a treatment, all relevant tumor-related factors [e.g., histology, tumor characteristics (e.g., estrogen receptor, mutations)] and staging examinations should be available and discussed in a multidisciplinary staff meeting. All members of the multidisciplinary team should have their input in the treatment decision, which should be specific for the individual patient resulting from evidence-based or consensus-driven guidelines.

Disease-related factors Tumor-related factors Tumor type is one of the important factors in determining treatment. Based on tumor type, cancers can be divided into a cancer with indolent or aggressive behavior. Whereas surgery and radiotherapy may be effective in most tumor types (except for radio-resistant tumors such as renal cell carcinoma), medication is given specifically according to tumor histology, presence of specific markers (e.g., estrogen receptor, mutations), and primary tumor site. Some tumors (e.g., renal cell carcinoma, gastrointestinal stromal tumor, salivary gland tumors) are inherently resistant to chemotherapy. With the advent of new therapies, treatment of some but not all of these tumors has improved (e.g., renal cell carcinoma, gastrointestinal stromal tumor). 65

Stage-related factors The aim of anticancer treatment is partly determined by the stage of the disease. ■

■

Most patients with limited disease are candidates for curative treatment by a local treatment such as surgery or radiotherapy. These local treatments may be combined with neo-adjuvant or adjuvant therapy in case of locoregional spread. In patients with distant metastatic disease, palliative therapy with medication, in combination with radiotherapy and/or surgery, can be given. The aim of treatment in this patient population is to improve quality of life and, in some patients, to prolong life. In specific patients with metastatic disease (e.g., germ cell tumors, non-Hodgkin’s lymphoma) treatment may be given with curative intent.

Patient-related factors Before deciding on a specific anticancer treatment, several patient-related factors should be taken into account: ■ ■ ■ ■ ■

Will the treatment influence the course of the disease? Will the patient benefit from the treatment? Will the quality of life of the patient be positively influenced? Will the patient have predictable toxicities? Will the patient have unpredictable toxicities?

The benefit of an anticancer treatment is dependent on the life expectancy and the complaints of the patient.

Age Life expectancy depends on age and comorbidity (Table 9.1), and if treatment does not improve quality of life or extend life, one should not start such treatment.

Comorbidity It is important to consider comorbidities before starting anticancer treatment because the overall burden of comorbidity is associated with the behavior 66

Table 9.1 Life expectancy in relation to age and health status Age (years)

Life expectancy (years) (women/men) Healthy

Average

Sick

65

20.0/15.9

18.5/14.9

9.7/8.5

70

15.8/12.5

14.8/11.8

8.6/7.4

75

12.1/9.5

11.5/9.1

7.3/6.2

80

8.8/7.0

8.4/6.8

5.9/4.5

85

6.1/5.0

5.9/4.9

4.5/3.8

Source: Adapted from Extermann 2005.

of the tumor, the compliance or tolerance to treatment, and survival of the cancer patient. The impact of comorbidity on mortality can be measured by the Charlson Comorbidity Index, but prediction of toxicity from cancer therapy or risk of functional decline is more difficult to predict.

Impact of comorbidity on disease behavior ■

■

■

■

■

Diabetes mellitus decreases the 8-year disease-free survival of stage III colon cancer to an extent similar in magnitude to the beneficial effect of fluorouracil/levamisole adjuvant therapy. Hyperinsulinemia is associated with a worse disease-specific survival in prostate, colon, and breast cancer. Obesity is associated with a worse progression-free and overall survival in patients with ovarian cancer. Weight loss is a prognostic factor for survival in patients with cancer, and even a small weight loss (0–5% of body weight) can be clinically significant in patients with cancer. Depression is associated with an increased risk of cancer death, and untreated depressive disorders may be linked to faster disease progression. Psychological status seems to predict the length of survival and the baseline helpless/hopeless response exerts a significant effect on disease-free survival beyond 5 (and up to 10) years. However, there are few data regarding the unique role of mood on survival. Depression and depressive symptoms are prevalent in people with cancer, and prevalence 67

rates of depression from 20% to 50% have been reported and between 8% and 24% fulfill the criteria of a major depressive disorder.

Impact of comorbidity on patient outcome ■

A few integrated prognostic scores or indices have been developed that permit a rapid estimate of life expectancy.  The Palliative Prognostic Score includes the clinical prediction of survival, the performance status (PS), anorexia, dyspnea, total white cell count, and lymphocyte percentage. Based on this score, the 30-day survival can be predicted: – 0–5.5 probability >70%; – 6–11, probability 30–70% – 11.5–17.5 probability 1 g/m2 Carboplatin Ifosfamide Cyclophosphamide 1500 mg/m2 Dacarbazine

Epirubicin Daunorubicin Idarubicin Irinotecan Oral agents Cyclophosphamide Etoposide Temozolomide Vinorelbine Imatinib

Doxorubicin

Moderate risk (emesis 30–90%)

High risk (emesis >90%)

Etoposide Teniposide Pemetrexed Methotrexate Mitomycin Fluorouracil Cytarabine 20% marrow, human

Epoetin alpha in solid tumors, lymphoma, myeloma:

myeloma: 150 IU/kg s.c. TIW, increasing to

Neutropenia

Transfusions

Epoetin alpha in solid tumors, lymphoma,

Anemia

Treatment

Prevention

Hematological complication

Table 11.5 Guidelines for the use of hematological growth factors and/or transfusions

89

bleeding due to trauma or surgical procedures to a level of 50,000–100,000/µL

Prophylactic platelet transfusions to prevent

100,000/µL

50,000–100,000/µL; neurosurgical procedures

bleeding during surgical procedures or trauma:

Therapeutic platelet transfusions to control

Prophylactic platelet transfusion trigger =

Treatment

10,000/µL

total dose of 6 mg (general approach)

dose of either 100 µg/kg (individualized) or of a

recovery Pegfilgrastim injected s.c. as a single

day of chemotherapy until sufficient/stable ANC

G-CSF 5 µg/kg/day of s.c. 24–72 h after the last

cure rate, overall or disease-free survival

therapy, lack of protocol adherence if compromising

dose reduction below threshold, delay of chemo-

next treatment cycle considered life threatening,

Secondary prophylaxis if further infections in the

Prevention

Abbreviations: ANC, absolute neutrophil count; CHOP, cyclophosphamide, doxorubicine, vincristine and prednisone; IU, International unit; QW, weekly; s.c., subcutaneous; TIW, 3 times a week.

Thrombocytopenia

Hematological complication

Table 11.5 (Continued )

■

■

■

Secondary prophylaxis for standard therapy can be considered in case of  Further infections in the next cycle considered life-threatening,  Dose reduction below threshold,  Delay of chemotherapy, or  Lack of protocol adherence that may compromise overall cure rate or disease-free survival. hGFs are also recommended for the treatment of protracted FN (>7 days), hypotension, sepsis, pneumonia, or fungal infections. The use of granulopoietic colony stimulating factors (CSFs) is recommended in high-risk situations (autologous and allogeneic marrow transplant, graft failure).

Thrombocytopenia A decrease in platelet count is common in cancer patients, as a result of chemotherapy as well as direct tumor invasion in the bone marrow. Severe and prolonged thrombocytopenia is rare and, in general, is observed in hematologic malignancies and stem cell transplantation. Besides reducing the intensity of chemotherapy, there are limited options to prevent thrombocytopenia; it is therefore important to prevent complications from severe thrombocytopenia such as bleeding. Prophylactic platelet transfusions have substantially reduced mortality or morbidity due to bleeding. Because of the risk of transfusion reactions, infections, and platelet transfusion refractoriness, caution must be taken to administer platelet transfusions in patients without bleeding. The American Society for Clinical Oncology guidelines recommend the threshold of 10,000 platelets/µL for patients without active infections, bleeding, or need for surgery.

Anemia Anemia is one of the most common conditions associated with cancer, as a result of the disease as well as of anticancer treatments. Symptom severity depends on the rapidity of the onset of anemia, intensity of anticancer treatment, underlying malignancy, and patient’s cardiopulmonary function. Patients with anemia complain of fatigue, tiredness, and, as the severity of anemia increases, shortness of breath and lethargy. Red blood cell transfusion remains a rapid and reliable therapy, but it is not suitable for longterm treatment. The use of recombinant human erythropoietin should be 90

considered for patients with chemotherapy-associated anemia and hemoglobin levels of 9–11 g/dL.

Mucositis (stomatitis, diarrhea) Because of its high proliferation rate, the mucosal epithelium of the gastrointestinal tract is particularly sensitive to the damage induced by chemotherapy. The most common clinical manifestations of this injury are oral mucositis or stomatitis, and diarrhea.

Stomatitis Stomatitis is characterized by progressive alteration of the oral cavity and oropharyngeal tissues including erythema, edema, atrophy, and in the most severe cases, ulceration. The incidence of oral mucositis varies considerably among treatment regimens for different tumor types, and severe stomatitis is very frequent in the case of chemoradiation for head and neck cancers and in patients receiving high-dose conditioning regimens for hematopoietic stem cell transplantation. Nonkeratinzing mucosal areas, such as labial, buccal, soft palate mucosa, floor of the mouth, and ventral surface of the tongue, are the most affected. Clinical consequences are ■

■

■ ■

Very discomforting pain (requiring parenteral nutrition in the most severe situations), Increased risk of infection (in particular in the case of concomitant neutropenia), Need for or lengthened hospitalization, and Need for dose reductions or treatment interruptions.

Treatment of oral mucositis is usually conservative and symptomatic, including warm saline rinses, appropriate analgesia, and prophylactic antiviral and antifungal agents. Strategies to prevent oral complication include dental sanation (to avoid a potential source of infections and trauma) and education to perform meticulous oral hygiene. 91

Local cryotherapy is recommended in the case of bolus 5-fluorouracil and high-dose melphalan. Palifermin (keratinocyte growth factor-1) has been recently approved for the prevention of stomatitis in patients treated with high-dose chemotherapy and hematopoietic stem cell transplantation.

Diarrhea Diarrhea is a significant toxicity of cancer treatment. Drugs that commonly cause diarrhea are 5-fluorouracil, capecitabine, and irinotecan; moreover, almost all the small molecule–targeted agents (e.g., erlotinib, gefitinib, sorafenib, sunitinib, imatinib) cause diarrhea. Severe diarrhea is very debilitating and can be life-threatening. In fact, it can contribute to dehydration, electrolyte imbalances, decline in immune function, and malnutrition. Chemotherapy-induced diarrhea is a consequence of damage of the intestinal mucosa, including loss of integrity of epithelium, superficial necrosis, and bowel wall inflammation, which leads to an imbalance between absorption and secretion in the small bowel. Time to onset of diarrhea depends on the drug, dose, and schedule, but in general it ranges between 4 days and 14 days. Irinotecan can cause acute diarrhea, which appears immediately after chemotherapy and is caused by acute cholinergic effect. Neutropenic enterocolitis (also called typhlitis) is a life-threatening condition, generally observed with high-dose regimens but also with conventional dose regimens, in particular with taxanes. Mucosal injury and profound neutropenia favors microbial infections with necrosis of the bowel wall. Patients usually present with abdominal pain, diarrhea, fever, nausea, vomiting, and sepsis. General principles to manage diarrhea include ■

■ ■

92

Adequate hydration (either orally or by parenteral infusion in most severe situations), Electrolyte rebalance, Adequate diet, and

■

Medication.  Administer loperamide 4 mg followed by 2 mg every 2–4 hours.  In cases of severe persistent diarrhea, the somatostatine analogue octreotide 100–150 mcg sc three times a day is recommended.

Neutropenic enterocolitis should be managed initially with broad-spectrum antibiotics, granulocyte-colony stimulating factor (G-CSF), nasogastric decompression, and intravenous fluids. Antidiarrheals, anticholinergics, and opioids should be avoided. In nonresponding patients surgical removal of the necrotic tract of bowel should be considered.

Hair loss Temporary hair loss is a very common complication of cancer chemotherapy, and this side effect can cause a major psychological distress and affect the social life of patients. The extent of body hair loss is related to the type of drug used, its dose, and its schedule of administration. A list of agent with potential to induce reversible alopecia is provided in Table 11.6.

Table 11.6 Agents with potential to induce reversible alopecia Actinomycin D

Irinotecan

Amsacrine

Methotrexate

Bleomycin

Mitoxantrone

Cyclophosphamide

Mitomycin

Daunorubicin

Melphalan

Docetaxel

Paclitaxel

Doxorubicin

Topotecan

Epirubicin

Vinblastine

Etoposide

Vindesine

Hydroxyurea

Vincristine

Ifosfamide

93

Combination therapy with two or more agents generally produces higher incidences of and more severe alopecia compared to single-agent therapy. Hair loss often starts 2–3 weeks after chemotherapy; hair regeneration generally begins 1–2 months after chemotherapy is discontinued, and alteration in color and texture have been described. The effectiveness and safety of scalp cooling in preventing hair loss have been debated for several years, without conclusive results. To date these devices are not routinely recommended.

Skin toxicity A variety of cutaneous toxicities has been described with several anticancer agents. The recently developed anti-epidermal growth factor receptor (EGFR) agents and multikinase inhibitors cause several skin reactions. Dermatologic toxicities are the most common adverse reactions associated with EGFR inhibitors (e.g., cetuximab, panitumumab, erlotinib, gefitinib, lapatinib, and others), and they are likely to be a class effect of these drugs. Moreover, there is some evidence suggesting the appearance of skin rash as a surrogate marker of treatment activity. The most commonly reported skin reaction (reported on average in >50% of the patients) is a papulo-pustular eruption (also described as acne-like or acneiform rash) generally involving the seborrheic areas (scalp, face, neck, chest, shoulders, upper back) that usually develops in the first 7–10 days and stabilizes in the following weeks. The rash can be asymptomatic, or associated with itching. Other skin effect are xerosis (dry skin), regulatory abnormalities of hair growth (trichomegaly of the eyelashes/face, hypertrichosis), telangiectasia, and nail changes (paronychia and painful fissures of the nail fold). Preventive measures include appropriate moisturization of the dry areas of the body and minimization of sunlight exposure. No dose interruptions or reductions are recommended for mild to moderate toxicities. Topical treatment includes hydrocortisone, clindamycin, or pimecrolimus in association with either doxycycline or minocycline. ■

94

The multikinase inhibitor imatinib can cause rash (usually manifesting as exanthema), edema, puritus, and pigmentary abnormalities.

■

■

Dasatinib can induce dermatologic reactions in up to 35% of the patients (localized and generalized erythema, macular and popular eruptions, exfoliative rash). The antiangiogenic multikinase inhibitors sorafenib and sunitinib also have peculiar dermatologic reactions.  Sorafenib can frequently induce a facial eruption resembling seborrheic dermatitis that usually arises 1–2 weeks after starting therapy and can be aggravated by hot temperatures. Other skin reactions are hand-foot syndrome and dry skin.  Sunitinib can induce periorbital edema, dry skin, subungual splinter hemorrhages, transient yellow skin discoloration, hair depigmentation, and acral erythema generally appearing on the lateral sides of fingers or in periungual areas.

Cytotoxic agents can induce skin toxicities. Docetaxel, cytarabine, doxorubicin, liposomal doxorubicin, and capecitabine can commonly induce acral erythema, also called hand-foot syndrome. This condition is characterized by the development of discrete erythematous patches or edematous plaques on palms and soles, followed by desquamation. Plaques may be asymptomatic, painful, or itchy, and the majority of cases resolve within 3 weeks of desquamation. Management includes dose reduction, interval prolongation, and symptomatic treatment. Topical and oral steroids have been shown useful in small studies. Pyridoxine has been successfully used as treatment and prevention.

Pancreatitis Acute pancreatitis, which is characterized by elevation of serum amylase and lipase, often accompanied by abdominal pain, dyspepsia, nausea, and vomiting, is a rare but clinically relevant adverse effect of several frequently prescribed drugs, such as antihypertensive agents, cholesterol lowering agents, antidepressants, and proton-pump inhibitors. Cases of acute pancreatitis have been described also following the exposure of some antineoplastic agents, in particular asparaginase, mercaptopurin, cytarabine, and less frequently, platinum salts, methotrexate, vinorelbine, doxorubicin, trastuzumab, alemtuzumab, and gefitinib. 95

It is not established whether drugs causing acute pancreatitis can also cause chronic pancreatitis. However, recurrent episodes of acute or subacute pancreatitis could lead to chronic pancreatitis. Medical management of acute pancreatitis includes a regimen of no oral intake, narcotics for pain relief, and intravenous fluids.

Liver toxicity Alteration of hepatic enzymes is commonly observed in cancer patients, and several covariables may contribute to affected liver function, including but not limited to pre-existing liver disease, genetic variability, liver metastases, sepsis, exposure to blood products, and paraneoplastic cholestasis. Antineoplastic agents can cause hepatic function alterations by direct toxic effect on hepatocytes, or indirectly as a by-product of immune-mediated collateral damage. Cytotoxic agents most likely to cause enzymatic alterations are l-asparaginase, dactinomycin, doxorubicin, cytarabine, etoposide, high-dose methotrexate, vinca alkaloids (particularly vincristine), taxanes, gemcitabine, and interferons. Liver function test abnormalities, only rarely associated with clinical signs of hepatic failure, have also been described with novel thyrosine kinase inhibitors, such as gefitinib, imatinib, and lapatinib. Hepatocellular injury is generally reversible; however, a careful monitoring of liver function tests including alanine aminotransferase, alanine aminotransferase, bilirubin, alkaline phosphatase, and gamma-glutamyl transferase is recommended when using agents potentially causing hepatic toxicity. Abdominal ultrasound, computed tomography scan, and/or liver biopsy should be necessary for differential diagnosis. Guidelines for dose modifications according to hepatic profile are fundamentally empirical.

Constipation and ileus Constipation is the slow movement of feces through the large intestine with the consequence of infrequent bowel movements and the passage of dry, hard stools. The most common causes of constipation are inadequate fluid intake and medications, particularly opioids, serotonin antagonist antiemetics, and 96

chemotherapeutic agents that can cause autonomic neuropathy such as vinca alkaloids and thalidomide. In most severe cases the autonomic nerve dysfunction can result in a dynamic ileus, which is generally observed in patients receiving vincristine. Metabolic disorders, such as hypokalemia and hypercalcemia, can also cause constipation. Preventive measures of constipation include dietary recommendations, and judicious use of laxatives and stool softeners.

Early-onset pulmonary toxicity An increasing number of drugs are recognized as inducing pulmonary toxicity. In cancer patients, many coexisting factors including lung metastases, pulmonary embolism, cardiovascular disease, or infections may render difficult the diagnosis of drug-induced pulmonary toxicity. Moreover, symptoms, radiographic findings, and gas-exchange patterns are often nonspecific. Early onset–induced lung diseases include inflammatory interstitial pneumonitis, pulmonary edema, and pleural effusions. Clinical manifestations can occur at the first cycle or at subsequent drug administrations. Inflammatory interstitial pneumonitis is characterized by progressive dyspnea, nonproductive cough, and occasionally low-grade fever. Chest radiographic examination reveals either interstitial infiltrates or both interstitial and alveolar infiltrates. ■

■

■

■

Interstitial pneumonitis has been described with several chemotherapeutic agents, including methotrexate, gemcitabine, fludarabine, taxanes, cyclophosphamide, etoposide; with small-molecule thyrosine-kinase inhibitors, such as gefitinib and erlotinib; and with mTOR inhibitors (e.g., everolimus, temsirolimus). Bleomycin, which usually induces late-onset, dose-dependent, pulmonary fibrosis, can more rarely induce an early-onset interstitial pneumonitis, which is not dose-dependent. Noncardiac pulmonary edema can occur as a consequence of vascular permeability due to inflamed endothelium and has been reported in association with cytarabine, all-trans-retinoic acid, interleukin-2, and fludarabine. G-CSF and granulocyte-macrophage (GM)-CSF can induce a capillaryleak syndrome, with pulmonary edema and pleural effusions. 97

■

■

The Bcr-Abl tyrosine kinase inhibitor imatinib has been associated with acute pneumonitis and severe fluid retention, with pleuropericardial effusions, pulmonary edema, or ascites. The multikinase inhibitor dasatinib is associated with pleural effusions.

Treatment usually consists of discontinuation of the drug and supportive measures; in severe cases with acute respiratory failure, corticosteroids are recommended.

Metabolic complications Some new agents have been shown to induce metabolic complications. In particular: ■

■

mTor inhibitors can induce hyperglycemia and hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia). Dasatinib has been associated with grade 3-4 hypocalcemia.

Careful monitoring of blood tests is recommended.

Further reading Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 2008; 26: 2767–78. Floyd J, Mirza I, Sachs B, Perry MC. Hepatotoxicity of chemotherapy. Semin Oncol 2006; 33: 50–67. Greil R, Psenak O, Roila F, ESMO Guidelines Working Group. Hematopoietic growth factors: ESMO recommendations for the applications. Ann Oncol 2008; 19 (Suppl 2): ii116–ii118. Greil R, Thödtman R, Roila F, ESMO Guidelines Working Group. Erythropoietins in cancer patients: ESMO recommendations for use. Ann Oncol 2008; 19 (Suppl 2): ii113–ii115. Herrstedt J, Roila F, ESMO Guidelines Working Group. Chemotherapy-induced nausea and vomiting: ESMO clinical recommendations for prophylaxis. Ann Oncol 2008; 19 (Suppl 2): ii110–ii112. Heidary N, Naik H, Burgin S. Chemotherapeutic agents and the skin: an update. J Am Acad Dermatol 2008; 58: 545–70. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Medicine 2008; 358: 2482–94.

98

Lenz HJ. Management and preparedness for infusion and hypersensitivity reactions. Oncologist 2007; 12: 601–9. Meadors M, Floyd J, Perry MC. Pulmonary toxicity of chemotherapy. Semin Oncol 2006; 33: 98–105. Peterson DE, Bensadoun RJ, Roila F, ESMO Guidelines Working Group. Management of oral and gastrointestinal mucositis: ESMO clinical recommendations. Ann Oncol 2008; 19 (Suppl 2): ii122–ii125. Schrijvers DL. Extravasation: a dreaded complication of chemotherapy. Ann Oncol 2003; 14 (Suppl 3): iii26–iii30. Slichter SJ. Evidence-based platelet transfusion guidelines. Hematology Am Soc Hematol Educ Program 2007; 2007: 172–8.

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Late toxicity SD Fosså Department of Clinical Research Rikshospitalet University Hospital Oslo, Norway

12

University of Oslo Division of the Norwegian Radium Hospital Oslo, Norway

CE Kiserud Department of Clinical Research Rikshospitalet University Hospital Oslo, Norway

Introduction Cancer survivors are defined as tumor-free patients alive for at least 5 years after their first malignant diagnosis. Individuals observed for shorter periods are called “cancer patients”. Late toxicity comprises post-diagnosis morbidity occurring ≥1 year after diagnosis or persisting for at least 1 year. There is increasing evidence that 30–50% of cancer patients suffer from life-threatening or at least bothersome late morbidity related to their cancer and/or its treatment. This chapter deals with the most important late somatic effects diagnosed in cancer patients and cancer survivors.

Methodological aspects Epidemiological research on late toxicity of cancer is principally retrospective, evaluating treatment modalities that may no longer be used in today’s patients. Nonetheless, such studies increase our understanding of etiological aspects of late effects. Further, clinicians and general practitioners will meet these cancer survivors, treated with “outdated” therapies and surviving for 10–30 years. Population-based registries such 101

as the Nordic Cancer registries or the Surveillance, Epidemiology, and End Results program (U.S.A.) are an optimal source for studies on incidence and mortality, though they most often lack detailed information on treatment. However, except for second cancer, few large registries exist that document late morbidity in cancer patients. Most publications on morbidity are based on surveys performed by one or a few institutions, with compliance rates between 60% and 80%. Some surveys rely on self-report only, such as the Childhood Cancer Survivor Study in the United States. Other studies combine questionnaires with clinical examinations and have thus the possibility to detect subclinical medical problems, which at the time of the survey have not yet resulted in a patient’s experience of health problems. Most often patients record their experience of late effects on scales or as multiple choice options presented to them in questionnaires that have undergone rigorous psychometric testing. Alternatively, late effects are assessed by an external observer using internationally developed instruments for this purpose (Common Toxicity Criteria, National Cancer Institute, Radiation Therapy Oncology Group, Somalent). A frequent finding is that external observers underestimate the patient’s experience of bothersome symptoms that have an impact on the patient’s overall well-being. An important requirement, especially in studies collecting self-reports only, is the inclusion of an age- and gender-matched control group, preferably from the general population or from similar cancer patients with minimal treatment. Obesity, cardiovascular disease, and slight degrees of urinary problems are, for example, not unusual in aging individuals without cancer and must be considered when late effects after cancer or its treatment are evaluated. Further, the interpretation of results from epidemiological studies and/or surveys requires detailed knowledge about treatment strategies and eventual changes. Interviews of individual patients and discussions with focus groups are methods to assess the type of late morbidity among cancer survivors using qualitative research strategies.

Second cancer During their lifetime cancer patients display an increased risk of developing a second solid or hematological malignancy, either on the 102

background of shared etiology (known genetic syndrome, shared environmental factors, inherent genetic susceptibility) or due to genetic somatic mutations related to cytotoxic treatment (e.g., radiotherapy, cytotoxic drugs). Chronic immunosuppression is suspected to contribute to second cancer development. The incidence rate for a second cancer decreases with increasing age and ranges between 1% and 2.5%. It increases with a factor of 5–8 after childhood cancer.

Cardiovascular disease If the myocardium is irradiated by target doses of 30–40 Gray (as previously applied to patients with Hodgkin’s lymphoma), decreased left ventricle function and valvular insufficiency or stenosis is diagnosed in 20-40% of the patients after 10–15 years. This development is often without clinical symptoms for many years but is detectable by echocardiography. Young patients and probably females are at a particularly high risk. The recognition of this late cardiac toxicity has led to modification of radiotherapy techniques and radiation doses in patients with Hodgkin’s disease. But even very low radiation doses (due to scattered irradiation) may be responsible for premature cardiac deaths, as shown for example after treatment for testicular cancer, even without mediastinal radiotherapy, or in breast cancer patients. Anthracyclines, but also high-dose cyclophosphamide, directly reduce the myocardial function by interaction with mitochondrial function. In adults a cumulative dose of doxorubicin of 300 mg/m2 should not be exceeded. Again, young age of the patient increases this risk, as does the combination of cytotoxic drugs with radiotherapy. During recent years it has become clear that testicular cancer patients are at increased risk to develop endothelial damage after cisplatinbased chemotherapy. This may be clinically manifested as hypertension and display together with hyperlipidemia and overweight increased risk of metabolic syndrome. This may be one explanation for the increased risk of cardiovascular death after chemotherapy of testicular cancer patients. Though small-molecule targeted anticancer drugs such as trastuzumab, bevacizumab, and sunitinib may lead to cardiovascular problems during treatment, these drugs’ long-term effects are mostly unknown. 103

Endocrine effects Pituitary/hypothalamus It is well known that cranial irradiation at doses of ≥40 Gray may lead to hypofunction of the pituitary gland and of the hypothalamus and may thus secondarily lead to dysfunction of the thyroid, adrenals, and gonads. However, even smaller doses due to scattered irradiation—e.g., during treatment of head and neck cancer—may lead to pituitary insufficiency. The impact of chemotherapy on pituitary function and secondary endocrine dysfunction is more uncertain but should not be overlooked.

Hypogonadism/infertility During pre-cancer counseling of young patients post-treatment gonadal function has to be considered because abdominal surgery, radiotherapy, and/or chemotherapy may reduce gonadal function at least transiently and thus threaten fertility. The long-term consequences are different for males and females. ■

■

Depending on the intensity of cytotoxic treatment and the patient’s age (Fig. 12.1) even heavily impaired spermatogenesis may recover in young men, though this may take many years. Destructed primordial follicles by cancer treatment in women are not substituted. Young women are thus threatened by premature menopause (menopause before the age of 40 years), even though they may regain menstruation after their cytotoxic treatment. Female cancer survivors with post-treatment plans of motherhood should therefore be informed about the risk of premature infertility problems, enabling appropriate timing of family building.

The gender-related differences are even more obvious for the prevention of post-treatment infertility. ■ ■

Semen cryopreservation has become routine in oncologic practice. Cryopreservation of ovarian tissue is still regarded as experimental, with only a few post-cancer pregnancies.

The balance of sex hormones in cancer survivors should not be overlooked. 104

0.6 C: Age 0.5

Male ≤30 yrs

0.4 Female ≤30 yrs 0.3

0.2 male >30 yrs 0.1 Female >30 yrs 0.0

0

100

200 300 400 Months since diagnosis

500

600

Figure 12.1 Probability of first post-cancer parenthood in cancer patients aged 15–45 years at diagnosis related to age and gender. Source: Fosså, et al. JNCI Monograph 2005; 34: 77–82.

■

■

Low serum testosterone and/or elevated luteinising hormone in male survivors after malignant lymphoma or testicular cancer (Fig. 12.2) indicates the risk of treatment-induced Leydig cell insufficiency and, in the presence of clinical symptoms, the need to consider testosterone substitution. The risk of androgen insufficiency is related to treatment intensity and type of cytotoxic agent. Estrogen deficiency in young females needs to be treated, not least to prevent osteoporosis.

Hypothyroidism Cancer survivors may develop symptoms of hypothyroidism and need to be supplemented with thyroxin after irradiation of the neck. In addition to use on survivors of Hodgkin’s lymphoma this diagnosis has to be considered after radiotherapy of head and neck and breast cancer. 105

% 80 Normal gonadal hormones

70 60

Exocrine hypogonadism

50 40

Endocrine hypogonadism

30 20 10 0 No chemo / Med-NHL Low

Med-HL

High-NHL

High-HL

Figure 12.2 Proportions of male lymphoma survivors with normal gonadal hormones, exocrine hypogonadism, and endocrine hypogonadism. (Normal gonadal hormones: testosterone, SHBG, LH, and FSH within normal ranges. Exocrine hypogonadism: isolated elevated FSH; testosterone, SHBG, and LH within normal ranges. Endocrine hyogonadism: elevated LH and/or low testosterone.) Treatment groups: No chemo / low: radiotherapy only / low gonadotoxic chemotherapy; Med-HL: medium gonadotoxic chemotherapy for non-Hodgkin’s lymphoma (NHL); Med-HL: medium gonadotoxic chemotherapy for Hodgkin’s lymphoma (HL); High-NHL: highly gonadotoxic chemotherapy for NHL; High-HL: highly gonadotoxic chemotherapy for HL. Abbreviations: FSH, follicle-stimulating hormone; LH, luteinizing hormone; SHBG, sex-hormonebinding-globulin. Source: Kiserud, et al. Abstract 8594. ASCO, 2008.

Other long-term effects Some cytotoxic drugs are associated with specific long-term effects in 10–30% of the patients, such as peripheral neuropathy (e.g., cisplatin, vinca alkaloids, taxanes), Raynaud’s phenomena (cisplatin), or ototoxicity (cisplatin). Though generally not life-threatening, these symptoms may reduce patients’ quality of life and/or lead to limitation of their social and professional activities. Pulmonary fibrosis may occur after radiotherapy to the lungs, but also some types of chemotherapy may lead to pulmonary dysfunction (e.g., bleomycin, alkylating agents). 106

Conclusion With increasing survival rates in cancer patients, the prevention, detection, and treatment of late toxicity has become an increasing area of clinical oncology. A particular challenge is the application of current knowledge within the general health care service and the provision of appropriate screening of high-risk groups.

Further reading Carver JR, Shapiro CL, Ng A, et al. American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects. J Clin Oncol 2007; 25: 3991–4008. Curtis RE, Freedman DM, Ron E, et al. New malignancies among cancer survivors: SEER Cancer Registries, 1973–2000. National Cancer Institute, NIH Publ. No. 05-5302. Bethesda, MD, 2006. Kiserud CE. Gonadal hormones after chemotherapy with or without radiotherapy in male lymphoma survivors. Abstract book ASCO 2008; abstract 8594. Lee SJ, Schover LR, Partridge AH, et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 2006; 24: 2917–31. Schwartz CL, Hobbie WL, Constine LS, Ruccione KS. Survivors of childhood and adolescent cancer: a multidisciplinary approach. Berlin: Springer, 2005. Ganz PA. Cancer Survivorship: today and tomorrow. Berlin: Springer, 2007.

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Acute and late effects in radiation oncology and surgery

13

P Meijnders Department of Radiotherapy Ziekenhuisnetwerk Antwerpen-Middelheim Antwerp, Belgium

P Willemsen Department of Surgery Ziekenhuisnetwerk Antwerpen-Middelheim Antwerp, Belgium

Introduction Both surgery and radiotherapy are essential components of anticancer treatment. They cause acute and late side effects that should be taken into account in the treatment choice. These side effects should be prevented, detected, and treated as soon as possible to preserve the quality of life of cancer patients.

Radiotherapy Although patients suffer most from the acute toxicity of radiation therapy, radiation oncologists fear the late effects. Acute effects appear during or within several weeks after therapy, are self-limiting, and heal within a few weeks after discontinuing treatment. Late effects can appear months to years after therapy, are progressive, and will never heal (Table 13.1). The side effects are usually limited to the treatment area and are dose dependent. The nature, severity, and longevity of side effects depend on the organs that are irradiated, the treatment itself (type of radiation, dose, treatment volume, fractionation, concurrent chemotherapy), and the patient. Most side effects are predictable and expected, although an individual 109

Table 13.1 Late effects of radiotherapy Organ system

Late effects

Bone, soft tissue

Abnormal growth; atrophy; fibrosis; osteonecrosis

Eye

Cataract; keratoconjunctivitis; retinopathy

Cardiovascular

Pericardial effusion; constrictive pericarditis; valvular disease; coronary artery disease

Pulmonary

Fibrosis; decreased lung volume

Central nervous system

Neuropsychological effects; spinal cord

Hematology

Myelodysplasia; cytopenia

Genitourinary

Hypertension; bladder fibrosis; contractures; atrophy; infertility

Gastrointestinal

Dental decay; xerostomia; malabsorption; enteritis; intestinal stricture; proctitis

Endocrine

Growth hormone deficiency; hypothyroidism; gonadal endocrine dysfunction

All tissues

Secondary malignancies

(hyper)sensitivity can be seen. A generalized effect of irradiation is fatigue, usually in the second half of the treatment period. The nature of this effect is poorly understood. One of the aims of modern radiotherapy is to reduce side effects to a minimum, and to help the patient to understand and to deal with those side effects that are unavoidable.

Acute complications Radiotherapy suppresses cell division. Cell loss in such rapidly dividing tissues as skin and mucosa leads to denudation within 2–3 weeks. After finishing treatment the organ can recover and supply new cells within 2–3 weeks. ■

Damage to the skin should be kept to a minimum. Patients are instructed to avoid scratchy clothing, and soap or lotions at the treatment site. The

110

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acute radiation dermatitis starts with inflammatory erythema and desquamation. This can best be treated with moisturizing, nonperfumed cream. Eventually this may lead to moist desquamation exposing the dermal layer. This can be rather painful. Treatment with hydrocolloid dressings or creams gives comfort and creates a moist environment at the wound site, which promotes cell generation. Denudation of mucosa leads to pain and dysphagia (mouth and esophagus), nausea (stomach) or diarrhea (bowel). Treatment is symptomatic (pain killers, antifungal medication, hydration, antiemetics, antidiarrheals). If necessary, soluble food is supplied or even a percutaneous gastrostomy is placed during the symptomatic period or prophylactically. Dysuria is due to irritation of the urethra. Treatment is symptomatic (extra fluid intake). Treatment of central nervous system sites can lead to symptomatic edema, which is usually treated with corticosteroids.

Late complications Most late effects are directly or indirectly caused by endothelial damage of the microvasculature, leading to vascular constrictions, particularly in the walls of arterioles. ■

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Tissues that have been irradiated tend to become less elastic over time due to a diffuse scarring process. This may lead to fibrosis in the treatment volume. Other changes are the formation of telangiectasia and pigment coloration changes. Hair follicles are damaged, causing alopecia (recovery is dependent of dose at the skin). One of the most unpleasant late effects is dryness of the mouth after irradiation of the head-and-neck region. This is caused by intolerance of the salivary glands to doses above 26–30 Gray. Periodontitis and caries is enhanced in these patients. Dental care should be given by experienced dentists in order to prevent osteoradionecrosis. Xerophthalmia can lead to chronic keratoconjunctivitis sicca. Thoracic irradiation can cause pneumonitis (usually within 6 weeks to 6 months), caused by an interstitial alveolitis. Patients experience a dry cough, some dyspnoe, and mild fever. 111

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Abdominal irradiation can cause (partial) kidney or liver failure. Damage to the intestines can lead to chronic enteritis or proctitis. Pelvic irradiation can cause vaginal dryness, which can cause discomfort during sexual intercourse.

Radiation therapy in children can cause growth disorders. Treatment of gonads usually leads to infertility. Late effects appear only in irradiated volumes above a certain threshold. For diagnosis and treatment of late effects the radiation oncologist should be contacted.

Cumulative side effects and complications If an irradiated area is re-treated, usually the threshold doses will be exceeded. This will increase the risk of late effects considerably. This kind of side effect should be separated from complications, which might be caused by errors in the treatment technique or due to an unexpected interaction (e.g., with chemotherapy or with new drugs). One of the most feared complications is spinal cord myelopathy leading to paralysis.

Surgery A surgical complication is any deviation from the expected recovery after surgery. Most surgical complications can be traced to the operating room and are related to the patient’s general health and the extent of the surgery. In surgical oncology one has to take into account that not only the disease, but also the other treatment modalities such as radio- and chemotherapy have an important impact on recovery after surgery. The prevention of complications starts preoperatively. ■

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The patient needs to be in the best possible health (e.g., smoking cessation, absence of cachexia). The extent of the disease and previous treatment must be known in order to choose the best surgical and anesthetic options. Thromboembolic prophylaxis is important in surgical oncology patients.

Intraoperatively meticulous surgical techniques and respect for the principles of surgical oncology will help to avoid early as well as late complications. 112

Postoperative monitoring is important to detect and accordingly correct any abnormalities early. Complications can be prevented through physiotherapy (respiration), early ambulation, and adequate nutritional support.

Early complications Early surgical complications are listed in Table 13.2. It is clear that the surgical oncology patient is more at risk for several of these early postoperative complications due to the nature of their disease. ■

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Surgery for malignancy can be extensive and this is sometimes associated with significant blood loss. A disturbed coagulation, due to hepatic impairment secondary to extensive liver metastasis, is an obvious risk of hemorrhage. The threshold for blood transfusion in surgical oncology patients might be higher because there is accumulating evidence that transfusion has an effect on host resistance to tumor progression and this affects longterm survival. Some tumors are associated with hypercoagulability (e.g., pancreatic cancer) or venous stasis due to tumor compression (pelvic malignancy) on the large veins, and this may cause venous thrombosis. Oncology patients are at risk of perioperative malnutrition due to the cancer cachexia state in advanced cancer or due to malfunction of the gastrointestinal system. Malnourishment impairs postoperative rehabilitation and more specifically causes suboptimal wound and anastomotic healing.

Surgery plays a role in all stages of oncologic diagnosis and treatment. ■

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In the diagnostic phase of a screen-detected breast lesion in a patient with extensive fibrocystic disease, sampling errors may have serious consequences. Image-guided wire location is required in these situations. Staging procedures such as lymph node dissection may cause complications. Upper extremity lymph edema after axillar node dissection in breast cancer can be quite refractory to treatment and the development of upper extremity angiosarcoma is a dreaded long-term consequence of chronic lymph edema. In minimally invasive sentinel node biopsy procedures the risk of allergic reactions to the blue dye must be 113

Table 13.2 Early surgical complications Shock

Immediately postoperatively (within 24 hr) due to bleeding (technical problem with hemostasis)

Surgical wound

Hematoma

complications

Seroma Wound dehiscence

Thromboembolic

Pulmonary embolism

events

Deep venous thrombosis

Respiratory

Atelectasis

complications

Pulmonary aspiration Pneumonia Postoperative pleural effusion Pneumothorax

Cardiac

Dysrhythmia

complications

Postoperative myocardial infarction Postoperative cardiac failure (fluid overload)

Gastrointestinal

Gastric dilatation

complications

Bowel obstruction Mechanical (adhesions) Paralytic Fecal impaction Pancreatitis

Hepatic dysfunction

Prehepatic jaundice due to hemolysis or reabsorption of hematoma Hepatocellular insufficiency (viral hepatitis, druginduced, ischemia, sepsis, extensive liver resection) Posthepatic obstruction

Postoperative

Often acalculous

cholecystitis

Chemical due to hepatic artery chemotherapy (Continued )

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Table 13.2 (Continued ) Urinary tract complications

Urinary retention Pelvic/perineal surgery Spinal anesthesia Urinary tract infection

Central nervous

Postoperative cerebrovascular accident

system

Convulsions (epilepsy/metabolic derangements/medication)

Psychiatric

Postoperative psychosis

complications

Delirium

Table 13.3 Tumor ablation syndrome: clinical signs Low-grade fever (rarely over 39°C) Fatigue Malaise Transient hyperbilirubinemia Elevated white cell count

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considered. Methylene blue appears to be less allergenic but there is a risk of skin necrosis from dermal injections of this agent. Radiofrequency ablation is a new technique that is increasingly used in surgical oncology in either a palliative or a curative setting. In the treatment of liver tumors it is used if a surgical resection is not possible. Thermal injury to adjacent viscera is a much feared complication because it might go undetected and cause peritonitis due to perforation of the gastrointestinal tract. Another complication is an intraparenchymal abscess and heat-related injuries to the biliary tract such as bilioma, biliary fistula, or biliary stenosis. The tumor ablation syndrome (Table 13.3) is a systemic inflammatory response after radiofrequency ablation due to inflammatory cytokines and other products of cellular destruction. Sometimes the clinical picture is indistinguishable from sepsis, but the syndrome usually resolves within 10 days. The severity of the syndrome is related to the amount of tissue ablated. 115

Serial culturing is necessary to differentiate this syndrome from a true infection and sepsis. Minimal access surgery has clear benefits regarding pain and shorter hospitalization and convalescence, and similar long-term survival results can be achieved as with open surgery. Initially port site metastases were reported, but in most cases this was due to poor surgical technique and improper handling of the tumor. The surgeon performing minimal-access oncologic surgery must be properly trained and experienced in these techniques.

Late complications Late surgical complications are given in Table 13.4. Stoma formation (ileostomy, colostomy, urostomy) is often necessary in achieving curative surgery. Careful stoma planning is important. Complications arise more frequently in unplanned stomas, in obese patients, and in the elderly. Early stoma complications are skin irritation due to poor adherence of the stoma device and exposure of the skin to stoma effluent; stoma necrosis; stoma retraction due to tension, improper construction, or leakage; and ischemia. Late stoma complications include stoma prolapse, parastomal hernia, stoma stenosis, and fistulization. The most dreaded late complications in surgical oncology are the local recurrences. Local recurrences are often difficult to treat. Salvage surgery often involves mutilating procedures. Meticulous surgical technique according to the principles of surgical oncology is the best way to avoid this complication. This is nicely illustrated by the introduction of total mesorectal excision (TME) in rectal cancer surgery. A multidisciplinary approach to the management of solitary tumors is beneficial. This, however, implies that proper planning of all the treatment modalities is of the utmost importance. Modern chemotherapy is associated with drug-specific histological changes in the normal liver and this may have an important effect on the outcome of liver resection. Therefore it is important to determine what the optimal interval is between the chemotherapy and liver resection in order to minimize postoperative chemotherapy-related complications. Whether the patient received neoadjuvant radio- and/or chemotherapy influences the timing and the extent of the surgery. It also has an impact on postoperative complications early 116

Table 13.4 Late effects of surgery Procedure

Late effects

Any procedure

Pain; cosmetic; psychosocial; wound healing

Surgery involving

Impairment of cognitition; motor sensory function;

neurologic structures

language; vision; swallowing; bowel/bladder control

Head and neck surgery

Communication; swallowing; breathing; cosmetic; impaired movement

Removal of lymph nodes

Lymph edema; retrograde ejaculation

Abdominal surgery

Intestinal obstruction; hernia; altered bowel function

Pelvic surgery

Sexual dysfunction; incontinence; hernia; intestinal obstruction

Splenectomy

Impaired immune function; risk of sepsis; hernia

Amputation

Functional changes; cosmetic deformity; psychosocial impact; accelerated arthritis; postsurgical phantom and/or neuropathic pain

Lung resection

Difficulty breathing; fatigue; generalized weakness

Prostatectomy

Urinary incontinence; sexual dysfunction; body image

Oophorectomy

Premature menopause; infertility

Orchiectomy

Infertility; testosterone deficiency

Ostomy

Bowel obstruction; constipation; nausea; vomiting; loss of appetite; fatigue; impaired body image

as well as late. This again is very well illustrated by the multidisciplinary management of rectal cancer. Neo-adjuvant radio-chemotherapy and TME resection spares the sphincter in more patients. Anastomotic leaks are more frequent in the low anastomosis in an irradiated area, and therefore more protective stomas are fashioned to avoid the potential lethal complications of an anastomotic leak. Fecal continence is not as good in these patients as in patients treated by TME surgery alone. As the multidisciplinary approach is quintessential for successful cancer treatment nowadays, it certainly is important in preventing and dealing with early and late complications of cancer treatment. 117

Further reading Bentzen SM. Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology. Nat Rev Cancer 2006; 6:702–13. Delanian S, Lefaix JL. Current management for late normal tissue injury: radiationinduced fibrosis and necrosis. Semin Radiat Oncol 2007; 17: 99–107. Ghafoori P, Marks LB, Vujaskovic Z, Kelsey CR. Radiation-induced lung injury: assessment, management, and prevention. Oncology 2008; 22: 37–47. Doherty GM, Mulvihill SJ, Pelligrini C. Postoperative complications. Current Surgical Diagnosis and Treatment, 11th edition, McGraw-Hill, 2003. Hakim NS, Papalois VE. Surgical complications, diagnosis, and treatment. London: Imperial College Press, 2007.

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Psychosocial effects of cancer and treatment

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MJ Schroevers University Medical Center Groningen Department of Health Sciences University of Groningen Groningen, The Netherlands

LM Gualthérie van Weezel The Netherlands Cancer Institute– Antoni van Leeuwenhoek Hospital Amsterdam, The Netherlands

R Sanderman University Medical Center Groningen Department of Health Sciences University of Groningen Groningen, The Netherlands

Introduction Psycho-oncology can be described as the discipline addressing the role of psychosocial factors in the development and course of cancer as well as the psychosocial consequences of a diagnosis of cancer on a patient’s quality of life. Moreover, psycho-oncology focuses on ways to improve the detection of psychological problems in cancer patients and to alleviate these problems by means of individual or group psychological interventions. Both the patient and significant others, such as a partner and children, are the focus of attention. This chapter describes the type and prevalence of psychosocial problems in cancer patients; several characteristics of the illness, the person, and the social context that make some cancer patients more vulnerable to psychosocial problems than others; and the important role that the psychologist 119

and the medical specialist may play in optimizing the psychosocial care of cancer patients.

Psychosocial consequences Despite increased survival rates for many types of cancer due to improvements in detection and cancer treatment, the life-threatening nature of a diagnosis of cancer still remains very stressful for most patients. Both the illness itself and its medical treatment with associated side effects (such as fatigue, pain, and functional limitations) may have consequences for the psychosocial well-being of patients. Research shows that the majority of cancer patients adapt relatively well to a diagnosis of cancer. Still, a significant minority experience psychosocial distress in the course of the illness, especially in the first year following diagnosis. About 25–30% of cancer patients experience depressive symptoms, such as crying spells, feelings of sadness, irritability, and sleeping problems, in the months following diagnosis. This is about twice as much as in the general population. Moreover, cancer patients report problems in their social functioning, mainly limitations in their work, social activities, and relationships with others.

Long-term survivorship Due to screening and improved multidisciplinary treatment, there is a large and growing group of patients who survive cancer. Research among these so-called cancer survivors (i.e., those who have survived cancer for at least 5 years) shows that, despite higher levels of physical complaints (such as fatigue), survivors report the same levels of psychosocial functioning as similar-aged individuals from the general population. Rather than an overall disturbed well-being, cancer survivors experience more specific problems, particularly feelings of uncertainty, thoughts about a possible recurrence of cancer, and greater attentiveness to physical symptoms. Remarkably, many survivors report that, in addition to late physical effects and long-term negative psychosocial consequences, they also experience positive consequences of having had cancer. About 30–50% of the cancer survivors report so-called benefits or post-traumatic growth, such as a more positive self-perception, better social relationships, and a greater appreciation of life, thereby taking life less for granted. 120

Vulnerable cancer patients Some patients may have a higher risk of experiencing psychosocial consequences. ■

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Medical factors such as the type of cancer, disease stage, and treatment (i.e., surgery, radiotherapy, and chemotherapy) and demographic factors such as gender, education, and marital status seem to have a relatively small impact on the report of psychosocial complaints. Some studies suggest that younger cancer patients are more at risk of depressive symptoms and social limitations than are older patients. Therefore, health practitioners should be alert to the increased risk of psychosocial distress among younger cancer patients. In the long term, younger cancer patients seem more likely than older cancer patients to report positive consequences of the cancer experience.  A possible explanation for these findings may be that, given that chronic illnesses including cancer are more common among the elderly, younger cancer patients may be less prepared for them. Furthermore, younger cancer patients may have a more profound sense of loss, as they may be especially challenged with disruptions of their daily routines and roles, uncertainty about the future and important life goals, concerns about their partner and children, feelings of disfigurement, sexual problems, and a sense of physical vulnerability experienced normally at a later stage. The confrontation with these issues may lead to a re-evaluation of personal goals, assumptions, and priorities and a search for positive meaning. As such, finding benefits in the cancer experience may be a way to manage the long-term negative consequences of the illness. Personal resources may have an impact on patients’ level of psychosocial functioning. Among cancer patients, a lower self-esteem, a more neurotic and less optimistic personality, lower perceptions of personal control, a negative problem-orientation (e.g., viewing stressful situations as a loss or severe threat rather than as a challenge), less use of active coping strategies (such as rational problem-solving, acceptance, and positive reappraisal), and more use of passive avoidance coping strategies (such as rumination) have been associated with more psychological distress. 121

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In addition, cancer patients who perceive and receive little emotional support (i.e., reassuring, comforting, and advice) from their family and friends, those who experienced recent stressful life events, and patients with comorbid chronic conditions seem to be at a greater risk of depressive symptoms and psychosocial maladjustment.

Some of these factors (such as low self-esteem) seem to primarily reflect a general vulnerability to depressive symptoms in the population, whereas others (such as little emotional support) reflect specific risk factors of poor psychosocial adaptation to cancer. Apparently, having someone to talk to about the illness and its consequences is of crucial importance for patients with cancer, with others being able to stimulate patients’ reinterpretation of the threatening situation and the use of active coping strategies.

The role of the psychologist in oncology Because a significant minority of cancer patients is bothered by psychosocial problems and report unmet informational and psychosocial care needs, there seems to be a necessity for psychological support for this group. Such support may assist patients in: ■ ■ ■

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Adaptive decision making regarding screening and treatment procedures, Management of aversive symptoms and side effects of treatment, Improvement of health-related behaviors (such as smoking, diet, or exercise), and Improvement of psychosocial well-being.

Most psychological interventions focus on improving patients’ well-being, by altering risk factors of maladaptation. ■

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Patients can be motivated to take a different perspective on stressful situations, thereby not only focusing and ruminating about the negative aspects but also paying attention to the things that are going well. In addition, rather than focusing on the uncontrollable aspects of the illness (such as course of the illness and the prognosis), patients can be stimulated to look for illness-related situations that are controllable (such as certain physical symptoms and lifestyle) or to shift attention to other domains in life (such as work or family life) that are more controllable.

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Moreover, the need for emotional support from others can be explored together with skills to ask for such support. Possible unhelpful thoughts that make it more difficult for patients to receive and accept support may be detected and challenged.

There is evidence that psychosocial interventions—both individual and group interventions—are effective in improving well-being. Most interventions are based on psychoeducation and a cognitive behavioral perspective, thereby focusing on current problems in terms of interacting thoughts, emotions, and behaviors and on changing irrational or unhelpful thoughts or behaviors. Such an approach seems to be most suitable for patients with mild to moderate problems. Other types of interventions, such as psychotherapy or psychiatric guidance, may be more appropriate for patients with more severe and complex problems. In these patients, problems resulting from cancer and its treatment often interact with existing non-cancerrelated problems (e.g., vulnerable personality traits, traumatic life events in the past, history of depression, comorbid somatic conditions). These factors need to be taken into account as well when trying to improve cancer patients’ psychosocial well-being.

The role of the oncologist In order to establish a basic level of psychosocial care in oncology, good communication and an attitude of empathic understanding towards the patient is of crucial importance. Research clearly shows that specialists who communicate in an honest, simple, supportive, and empathic way are highly valued by cancer patients, because it helps them to understand, accept, and adapt to the cancer. The busy clinical setting may pose difficulties herein for medical specialists, in terms of time constraints and multiple tasks (e.g., explaining test results, complex treatment procedures, and possible side effects). Personal fears of the medical specialist and lack of supervision may further hamper good communication. Therefore, courses have been developed to train medical specialists in communication skills. In order to increase the likelihood that these skills are transferred into practice and lead to improved patient outcomes, it is important that these courses focus on: ■

The provision of a clear rationale for the importance of psychosocial issues and good communication, 123

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Actual practice through role play, and The exploration of personal feelings that are evoked by communication.

Another important activity of medical specialists may be to correctly identify psychosocial problems in response to cancer (such as depressive symptoms, anxiety, and behavioral problems in terms of aggression or social isolation) and to refer patients with heightened levels of problems to a psychosocial service, inside or outside the hospital. One problem concerning the detection of psychological symptoms in medical patients including cancer patients is the difficulty in distinguishing between psychological symptoms related to mood disorders (e.g., depressive disorder or anxiety) and organic psychological symptoms directly due to cancer or its treatment (e.g., poor appetite, sleeping problems, cognitive problems). Factors that may further hamper the identification of psychosocial problems and needs are perceptions of the medical specialist that there is not enough time to ask patients about psychosocial issues or that it is not their task. Also, insufficient knowledge about psychological symptoms and possibilities for psychosocial care may play a role. Moreover, cancer patients may be reluctant to talk about psychosocial aspects of the illness, because they may be embarrassed or assume that it is normal to experience such problems. Due to these barriers, heightened psychosocial problems are often not recognized. Consequently, only cancer patients with clear psychological/ psychiatric problems and/or those with strong requests for support enroll in psychosocial services. Because psychosocial distress is common in a significant number of patients—associated with poorer outcomes, yet treatable by (non)pharmacological interventions—a growing number of organizations are now recommending the use of routine psychological screening procedures to detect psychosocial distress at an early stage.

Psychological screening The idea underlying systematic screening is that cancer patients are screened at multiple times, for instance, during their first visit to the hospital, at the start of treatment, at the end of treatment, and at the follow-up visits in the hospital. In the ideal situation, the patient fills in a self-report questionnaire assessing distress or quality of life prior to the medical consult, 124

using paper-pencil or computer-based screening. After calculating a total score of psychosocial problems and comparison with norm scores, it can be decided whether the patient is experiencing psychosocial problems or is at risk for a psychological disorder. During the consult, the medical specialist can discuss the screening results with the patient and, if indicated and desirable, refer the patient to a psychosocial professional. Such a routine screening procedure may make it easier for the specialist and patient to address psychosocial issues. One worry could be that this requires extra time. However, research and clinical experience have proven that using such screening instruments may make the doctor-patient communication more efficient and effective, thus actually leading to a drop in consultation time. Nowadays, more and more institutions are making an attempt to set up regular psychological screening of cancer patients. But the progress in the implementation of screening programs is relatively slow. More use of computers to collect data in waiting areas may facilitate screening with minimal involvement of staff. Also, additional research is needed that demonstrates that early and regular screening works and leads to higher referral rates to a psychosocial professional, higher patient satisfaction, and better health outcomes.

Conclusion Cancer patients may face many psychosocial consequences, both negative and positive, as a result of the illness. Although the majority of cancer patients adapt remarkably well to the diagnosis and its treatment, a significant minority of patients experience psychosocial problems. These patients may benefit from psychosocial care. As psychological problems in many patients will reflect normal reactions to a life-threatening situation, rather than psychiatric morbidity, intensive psychotherapy will probably not be necessary for most cancer patients. Yet, for all cancer patients, good communication and an empathic attitude towards them may be of great value. Moreover, cancer patients with increased levels of distress or those with a need for psychosocial care may benefit from a supportive group or individual sessions with a psychologist. Such care should also be available for the partner or children of patients, because the illness may also impact their lives. 125

Further reading Fallowfield L, Jenkins V. Communicating sad, bad, and difficult news in medicine. Lancet 2004; 363: 312–19. Helgeson VS, Snyder P, Seltman H. Psychological and physical adjustment to breast cancer over 4 years: identifying distinct trajectories of change. Health Psychol 2004; 23: 3–15. Jacobsen PB. Screening for psychological distress in cancer patients: challenges and opportunities. J Clin Oncol 2007; 25: 4526–27. Kilbourn KM, Durning PE. Oncology and psycho-oncology. In Llewelyn S, Kennedy P, (eds.), Handbook of Clinical Health Psychology. Chichester: Wiley, 2003, pp. 103–30. Schroevers MJ, Ranchor AV, Sanderman R. Adjustment to cancer in the 8 years following diagnosis: a longitudinal study comparing cancer survivors with healthy individuals. Social Science & Medicine 2006; 63: 598–610.

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Incapacity due to cancer and cancer therapy

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K Strasser-Weippl, H Ludwig Department of Medicine I Center for Oncology and Hematology Wilhelminenhospital Vienna, Austria

Introduction Cancer and cancer therapy can lead to a plethora of incapacities in the daily life of cancer patients. This chapter gives an overview of the main impairments experienced by cancer patients, treatment strategies, if available, are discussed.

General weakness and fatigue The most prominent symptoms of cancer patients causing incapacities in daily life are fatigue and general weakness. The possible causes for these problems are manifold and the degree of weakness and fatigue is variable among different patients, tumor types, and settings. For example, patients with specific early-stage solid tumors such as stage I–III breast cancer and other cancers often do not experience any of these problems, whereas patients with hematological malignancies may report fatigue as one of the first symptoms at the time of diagnosis. ■

The tumor itself, depending on histology and setting, can cause fatigue via the production of inflammatory cytokines and possibly also via hitherto unidentified other factors. In some patients, the degree of weakness correlates with tumor burden. In these patients, successful treatment of their malignancy can effectively ameliorate their symptoms even if a short-term worsening of fatigue due to cancer therapy must be accepted. 127

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Infections and the corresponding inflammatory response may also result in fatigue and weakness. Often subclinical infections with concomitant inflammatory reactions do persist chronically, and they pose a frequent cause of chronic wasting. Therefore, infections need to be diagnosed and treated thoroughly. Particular attention should be paid to viral and fungal infections in patients undergoing immunosuppressive treatment. Another prominent cause of weakness is cachexia, a metabolic syndrome of weight loss, anorexia, and wasting of host lean body mass. Cachexia can be due to the side effects of treatment (anorexia of therapy), due to chronic malignant bowel obstruction or functional bowel impairment, or, most commonly, caused by the malignancy itself (anorexia of malignancy). It has been shown that weight loss and weakness are frequent causes of reduced physical activity in cancer patients, among other factors such as anemia and the presence of infections. Basic supportive measures include dietary counseling in order to enhance calorie intake, although evidence is lacking that currently available nutritional formulas can maintain or reverse malnutrition in a patient with advanced malignancy. In patients who are able to eat normally, high-caloric between-meal supplements should be offered. If oral food intake is impaired, enteral nutrition by gastrostomy or jejunostomy may be helpful. If enteral nutrition is not possible at all, e.g., because of chronic bowel obstruction, total parenteral nutrition can be an effective alternative, in particular when these measures are only needed for a limited period of time. Anemia caused by the disease itself (anemia of cancer) or by treatment, can intensify fatigue. Other causes of anemia, such as vitamin deficiencies or chronic blood loss, should be ruled out or treated appropriately. In patients with chemotherapy-associated anemia, erythropoietinstimulating agents should be offered. If they are ineffective or not indicated, red blood cell transfusions can be used to treat cases of severe, symptomatic anemia. Other causes of weakness and fatigue include hormonal and electrolyte imbalances, such as hypothyroidism or hyponatremia. They should be ruled out and, if indicated, substituted or treated when patients present with fatigue of an unknown cause. Also, dyspnea (e.g., caused by pleural effusions, metastases, pulmonary fibrosis, etc.) can lead to highly diminished physical capacity and fatigue.

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Finally, musculoskeletal impairments may lead to severe weakness and to other incapacities in the life of cancer patients. For example, pain, pathologic fractures, neuropathies, and myopathies (e.g., due to steroids or paraneoplastic dermatomyositis) may impair physical functioning. To prevent, or at least delay, physical impairment and increasing weakness, cancer patients who are only mildly impaired should be encouraged to maintain physical activity, because this will enhance their quality of life and improve their capacity to perform activities of daily life. For those with more severe functional deficits, physical therapy should be offered to achieve some degree of ambulation and reduce morbidity. In bed-bound patients, skin breakdown must be prevented by frequent repositioning, air-cushioned beds, and moisturizing creams. In addition, special care needs to be taken to prevent contractions.

Cognitive and emotional impairment Accumulating evidence indicates that cancer therapy may induce mild cognitive impairment. ■

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For cognitive symptoms occurring during chemotherapy, the term “chemobrain” has been coined, although definite proof is lacking whether the impairment is caused by chemotherapy itself, hormonal changes, or other, unknown factors. The symptoms reported by patients include difficulties in word finding, short-term memory lapses, and problems in multitasking and learning. Overall, 20–30% of patients undergoing chemotherapy report cognitive symptoms, the frequency and severity of which are increased by cofactors such as anemia, stress, pain medication causing drowsiness, or fatigue. For elderly patients, a correlation between cognitive impairment during chemotherapy and incapacities in activities of daily living has been reported. Whole-brain irradiation has also been shown to impair the neurocognitive function of cancer patients and thus their quality of life. In a study of patients undergoing brain irradiation, a decline in neurocognitive function preceded and predicted impairments in activities of daily living. In addition to chemotherapy and radiotherapy, the diagnosis of cancer itself may cause or aggravate symptoms of depression. Severe depression may cause emotional impairment, including symptoms of anxiety, 129

nervousness, inability to experience joy, and a severe reduction in quality of life. Presently, effective treatment that can reverse therapy-induced changes in cognitive functioning is not available. Symptoms of depression, however, should be identified because they can be treated effectively with antidepressants and psychological support.

Neuropathy Neuropathies seem to be an underestimated cause of moderate to severe impairments in cancer patients. Most neuropathies in cancer patients are induced by neurotoxic anticancer drugs such as cisplatin, oxaliplatin, paclitaxel, docetaxel, and vincristine, but also newer noncytotoxic agents such as thalidomide and bortezomib. In addition, some malignancies can directly lead to disease-associated (e.g., amyloidosis) or paraneoplastic neuropathies. Therapy-induced neuropathies are usually mixed sensorimotor neuropathies and they develop in a symmetrical, distal, progressive manner. Their severity correlates with the cumulative dose of the causative agent and therapy duration. The incapacities associated with upper-extremity neuropathy include important tasks of daily life, such as the inability to hold a glass, to button up a shirt, or to hold a pencil. In advanced cases of lower-extremity neuropathy, patients may be unable to climb stairs or walk without help. The severity of neuropathies can be graded with the use of a neurotoxicity assessment tool. Unfortunately the available medical treatment of therapyinduced neuropathies shows little effect, if any. For neuropathic pain, tricyclic antidepressants, amino acids, gabapentin, pregabalin, duloxetine, and lidocaine patches have been used with limited success. Useful interventions for motor impairments include physical modalities such as ultrasound and electric stimulation, as well as bracing and adaptive devices. In some cases, treatment-induced neuropathy resolves or improves over time, but in many cases it persists over years. 130

Gastrointestinal impairment Disorders of bowel movement are also frequent problems in cancer patients. ■

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The most common bowel disorder is constipation, which can be caused by carcinosis, opiates, neuropathy, or spinal cord or nerve root compression. Chronic constipation is best treated using dietary modifications, specific medication, and if possible, physical activity. If necessary, stool softeners (e.g., macrogol) or—in more severe cases—bowel stimulants (e.g., bisacodyl) should be used. In the case of delayed gastric emptying, metoclopramide should be administered. In the patient with neurogenic bowel dysfunction, stimulation from below may be necessary to initiate evacuation. Diarrhea is often the result of chemotherapy-induced mucosal toxicity. An additional cause can be short-bowel syndrome after surgery for gastrointestinal tumors. In the presence of antibiotics, pseudomembranous colitis from infection with Clostridium difficile must always be ruled out. Severe diarrhea can lead to extreme impairments in cancer patients, who may stop leaving their home for fear of incontinence, leading to social isolation and considerably reduced quality of life. Chronic diarrhea can be treated with loperamide, tinctura opii, the combination of diphenoxylate and atropine, and long-acting somatostatin analogues if necessary.

Bladder disorders Bladder disorders comprise urinary hesitancy due to nerve root compression or opiates, but also incontinence after pelvic surgery. ■

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Incontinence may be difficult to treat with medication and might require a permanent indwelling catheter or a condom in men to maintain quality of life and mobility. Urinary hesitancy can lead to reflux, hydronephrosis, and repeated urinary tract infections, which need to be treated appropriately. If medical treatment such as oxybutinine is ineffective, intermittent catheterization should be instituted in patients who are able to carry out the procedure on their own. Hemorrhagic cystitis, which may be caused by chemotherapy (e.g., ifosfamide, cyclophosphamide), pelvic irradiation, or bladder infections, should be treated with analgesics and antibiotics if necessary. 131

Sexual dysfunction Sexual dysfunction constitutes another large area of problems, which frequently diminish the quality of life of cancer patients. Chemotherapy, endocrine treatment, radiotherapy to the pelvis, pelvic surgery, and nerve compression can all lead to male or female sexual dysfunctions. In addition to these physical problems, the self-image of cancer patients may become impaired and patients simply might cease sexual activity. Furthermore, sexual desire is usually decreased during cancer treatment. One of the most important aspects in treating sexual dysfunction is its precise assessment by interview or by using a standardized questionnaire. Laboratory studies should include thyroid function tests and serum testosterone and prolactin levels in men. Treatment of sexual dysfunction should be based on sexual counseling, which can be very effective within a short period of time. ■

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In men erectile dysfunction can be improved by phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil, vardenafil) or, if contraindicated, by intrapenile prostaglandin injections or by erection devices or prostheses. Females can be offered lubricants or topical estrogens against dyspareunia and venlafaxine or transdermal testosterone for decreased libido.

Conclusion Cancer and its treatment can lead to a series of impairments and incapacities in daily living. In order to tackle these problems appropriately, more research is needed both in order to elucidate the exact pathological mechanisms of the ensuing symptoms and to improve our presently available therapeutic strategies.

Further reading Ardies CM. Exercise, cachexia, and cancer therapy: a molecular rationale. Nutr Cancer 2002; 42: 143–57. Creti L, Fichten CS, Brender W. Global sexual functioning: a single summary score for Nowinski and LoPiccolo’s Sexual History Form (SHF). In: Davis CM, Yarber WH, Bauserman R, Schreer G, Davis SL (eds). Sexuality-related measures: a compendium. 2nd ed. New York: Sage, 2008.

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Fouladiun M, Korner U, Gunnebo L, et al. Daily physical-rest activities in relation to nutritional state, metabolism, and quality of life in cancer patients with progressive cachexia. Clin Cancer Res 2007; 13: 6379–85. Li J, Bentzen SM, Li J, Renschler M, Mehta MP. Relationship between neurocognitive function and quality of life after whole-brain radiotherapy in patients with brain metastasis. Int J Radiat Oncol Biol Phys 2008; 71: 64–70. Minisini AM, De FS, Ermacora P, et al. Cognitive functions and elderly cancer patients receiving anticancer treatment: A prospective study. Crit Rev Oncol Hematol 2008; 67:71–9. Schover LRJSB. Sexuality and chronic illness: a comprehensive approach. New York: Guilford, 1988. Schover LR, Evans RB, von Eschenbach AC. Sexual rehabilitation in a cancer center: diagnosis and outcome in 384 consultations. Arch Sex Behav 1987; 16: 445–61. Tariman JD, Love G, McCullagh E, Sandifer S. Peripheral neuropathy associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs 2008; 12 (3 Suppl): 29–36.

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Reintegration into workplace I Belohorska Member, European Parliament Slovakia

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B Belohorska Comenius University, Faculty of Medicine St. Elisabeth Cancer Institute Slovakia

Introduction Cancer has a powerful personal impact and it depends on individual factors how a patient handles the moments of diagnosis, treatment, and follow-up. Emotional trauma consists of various negative feelings faced by patients after learning their diagnosis, and most patients experience anxiety caused by fear of loss of life and dignity. Other distress factors linked to cancer diagnosis are emotional trauma for the family members, mutilation, pain, financial impact, loss of productivity, and unemployment. Anticipating the rapid rise in cancer incidence, one should not only concentrate on actual cancer treatment, but also focus on socioeconomic effects of this disease. In the era of evidence-based medicine, it has been shown that environmental and socioeconomic factors have a major influence on cancer risk and treatment outcome. In spite of ongoing research, the majority of patients with advanced cancer do not achieve cure, but new anticancer therapies can prolong the lives of patients with active disease and quality of life should be one of the priorities. Preservation of quality of life depends not only on cancer and supportive treatment, but also on the patient’s well-being. Psychological and social functioning in family and employment therefore also play an important role. These factors contributed to the fact that more than 100 international leaders of government, patient advocacy, and cancer research organizations and 135

corporations signed “The Charter of Paris Against Cancer” at the World Summit Against Cancer in February 2000.

Guidelines for integration There are no universal guidelines for reintegration into the workplace of cancer patients. Many people need to take time to adjust to what has happened and rethink what they really want to achieve in their lives. Generally there are only a few reasonable obstacles that a doctor should think of and discuss with patients before advising them to continue or restart work. ■

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Patients can be divided into groups according to disease stage or treatment. It is mandatory to inform patients about their prognosis and the intention of the treatment, with a detailed treatment plan, possible side effects, and other risk factors linked to the treatment and cancer itself. Whenever possible, health care professionals should provide their patients with their long-term prospects. During cancer treatment, the patient is advised to comply with therapy and meet the exact dates of visits, which may interfere with work and employers’ objectives. Possible and frequent side effects during cancer treatment include fatigue, nausea, stomatitis, diarrhea, skin rash, neurological symptoms, and consequences of bone marrow suppression. These side effects together with psychological distress and disease complications such as pain can be objective obstacles in complying with daily work. Although patients should not be directed to stop work, detailed information should help them to find an appropriate and satisfactory working schedule. There are generally fewer limitations during the maintenance treatment and long-term follow-up, but patients should not be forced to work until they are fully recovered and psychologically prepared. There is a large variation in how quickly people return to their jobs.

The social reintegration plan as well as the treatment should be individualized and tailored: ■

For many people the return to work is a major milestone in their recovery. Some cannot wait to start working again, because it represents a major step on the road back to a normal life as part of

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social adaptation. It may be a sign that they have overcome cancer, and it brings structure and security back into their life. Some people have no choice but to start earning money again because of insufficient financial resources. Other patients manage to continue working throughout their treatment.

Possibilities of social help and funding depend on the local social systems. It is wise to inform patients about the actual status in their country and/or recommend they contact a financial and social advisor.

Barriers for reintegration into the workplace Several factors act as barriers for reintegration into the workplace, such as: ■

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Attitude of the society towards cancer and cancer patients. In the workplace, people with a serious health problem are often excluded, although antidiscrimination laws forbid discrimination based on health status. Cancer has a strong emotional connotation, resulting in different misbeliefs and misconceptions that cancer patients perform less well after treatment and cannot work anymore. Therefore, positive experiences should be highlighted to show employers and employees about the possibilities of reintegration into the workplace. Lack of knowledge and means. In most instances, different systems have been created to facilitate the reintegration of patients into the workplace, such as:  Part-time work with compensation by the health insurance companies,  Support by the controlling physician of the health insurance company or of the employer, and  Recertification programs during and after cancer treatment. Lack of coordination and cooperation. The cooperation of several actors (e.g., physicians, employer, employees, health insurance) can facilitate the reintegration of the cancer patient into the workplace.

Requalification and job applications People who feel worried and anxious about returning to their job can consider professional requalification, which can help them to find a new, 137

interesting, and different job. This job can, for example, be less stressful or less physically demanding, with adaptation of work times that can avoid rush hours; and patients can apply for part-time work in a first phase. Finding a new job can prevent patients from comparing how their work and relations with colleagues were before and after cancer diagnosis. In contrast, a familiar work environment and known coworkers can facilitate reintegration. Employers should ensure that employees with cancer are not disadvantaged compared with their colleagues and vice versa. If patients are asked about their health status and condition that may affect their ability to do a job when applying for a vacancy, they should answer honestly. If it is found out later that they did not disclose the fact that they had cancer, the employer could dismiss them for providing untruthful information. If a patient’s health has no direct impact on the planned job, if his abilities are not affected by cancer, and he or she feels fully capable to fulfill the employer’s demands, there is no legal obligation to disclose the diagnosis. Medical oncologists can only advise and inform patients and help them to find personalized solutions, often in cooperation with a psychologist, a social worker, and family members. Health care professionals have to avoid infraction of secrecy and only confirm the health status to the new employer if the patient demands this.

Retirement After an experience of cancer some people consider retiring from work, including taking early retirement. In this situation it is advisable for patients to discuss their financial circumstances with an independent financial advisor. If a patient works for a period and experiences that it is not fulfilling his expectations and that the work handicaps him physically or psychologically, he should be able to claim retirement benefits if needed.

Conclusion In the European Union, legal and health care systems differ from country to country. There are various disability discrimination acts that are 138

trying to simplify and control the rights of people including cancer patients. Discrimination of people and employees based on health status must be strictly avoided. If a patient encounters obstacles in finding an appropriate job solely because of cancer, this should lead to legal action without hesitation. There are ongoing efforts of members of the European parliament to improve and unify rights of cancer patients for adequate health care, treatment, access to innovative technologies, strategies, and social advantages. Reintegration into the workplace will surely be one of the major topics. Patients’ organizations such as the European Cancer Patient Coalition are trying to unify the efforts of patient advocacy groups and act as an umbrella organization for the rights and equality of cancer patients in society. The lack of help to reintegrate to a so-called normal life and social adaptation can make a complete cure or adequate quality of life unachievable.

Further reading http://www.cancerbackup.org.uk/Resourcessupport/Practicalissues/Lifeaftercancer/ Workaftercancer http://www.cancer.gov/cancertopics/life-after-treatment/page1 http://www.cancerworld.org/cancerworld/home.aspx?id_sito=9&id_stato=1DeVita, VT Jr, Hellman S, Rosenberg SA. Cancer: principles & practice of oncology, 7th ed. Philadelphia: Lippincott, 2005, pp. 2683–96. International Union Against Cancer (IUCC). Charter of Paris 2000. Available at http://www.uicc.org/index.php?Itemid=490&id=16261&option=com_ content&task=view Verbeek J, Spelten E, Kammeijer M, Sprangers M. Return to work of cancer survivors: a prospective cohort study into the quality of rehabilitation by occupational physicians. Occup Environ Med 2003; 60: 352–7.

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Quality of life issues A Bottomley Quality of Life Department European Organisation for Research and Treatment of Cancer Brussels, Belgium

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C Coens Quality of Life Department European Organisation for Research and Treatment of Cancer Brussels, Belgium

H Flechtner Clinic for Child and Adolescent Psychiatry and Psychotherapy Medical Faculty of the Otto-von-Guericke-University Magdeburg at City Hospital Magdeburg Magdeburg, Germany

G Velikova St James’s Institute of Oncology St James’s Hospital Leeds, U.K.

Introduction The World Health Organization defined health as a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity. In the same year, Karnofsky and Burchenal proposed a rating scale to help physicians assess the effects of treatment by comparing patient performance before and after therapeutic intervention. In 1960 the term quality of life (QOL) was used by the U.S. Presidential Commission on National Goals. In 1964 these goals were used to stimulate programs examining the QOL and needs of patients, and develop programs to improve QOL. 141

By 1977 QOL became a key word for the retrieval of journal articles in the U.S. National Library of Medicine. Since the mid-1980s hundreds of articles per year refer to quality of life and cancer; this number has risen to well over 2,500 papers annually. In 1989 the U.S. Congress passed the Outcomes Assessment Research Act to create the Agency for Health Care Policy and Research, with the task to measure functional status, well-being, and satisfaction with care along with other endpoints to evaluate policies that affect patient outcomes (Ware, 2003). Recently, patient-reported outcomes (PRO) became the widely accepted notion for any health status measurement occurring directly within the patient. The U.S. Food and Drug Administration draft “Guidance for Pharmaceutical Industry” regarding PRO measures states that “in clinical trials, a PRO instrument can be used to measure the impact of an intervention on one or more aspects of patient health status, hereafter referred to as PRO concepts, ranging from the purely symptomatic (response of a headache) to more complex concepts (e.g., ability to carry out activities of daily living), to extremely complex concepts such as QOL, which is widely understood to be a multi-domain concept with physical, psychological, and social components,” thereby placing QOL under the evolving umbrella of PRO. Today, health-related QOL (HRQOL) can be defined as the value assigned for the duration of life as modified by social opportunities, perceptions, functional states, and impairments that are influenced by disease or treatment. Patient qualitative perspective is a major component of QOL.

HRQOL in clinical trials: design and its impact on clinical results The implementation of HRQOL within randomized controlled clinical trials (RCTs) is decades old, and is similar to the classical clinical endpoints (e.g., survival, disease control). ■

The research objective of any sound HRQOL RCT is essential and should specify in detail the research question, the relevant clinical areas of HRQOL, the time period of interest, and the direction, magnitude, and duration of expected change. The trial objective should shape further design, analysis, and reporting.

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Once the objective has been established, an appropriate instrument (questionnaire) is selected. The choice of instrument determines the method of administration, the scope of the HRQOL domains to be assessed, the scoring of the data, and the interpretation of the results. When choosing instruments, it is imperative to consider the patient population, e.g.  In elderly patients, shorter questionnaires are preferred in order to reduce noncompliance (e.g., the EORTC Elderly questionnaire).  In an international study, it is important to verify whether validated translations exist.  The required domains should be included in the questionnaire, e.g., if pain is going to be a major issue, the instrument should have questions related to pain impact and, for example, may choose the brief pain inventory, a tool focused only on pain.  … The method of translating patient answers into numbers (scoring) needs to be clear, as should the interpretation of the results. Thousands of questionnaires exist to assess HRQOL. The most used tool, the EORTC QLQ-C30, has remained for over 16 years the best documented instrument, assessing both treatment symptoms and disease-related effects such as limitations in domains of physical, functional, emotional, and social well-being. A next design step is the RCT time schedule. Typically, patient HRQOL changes over time. Therefore, interest lies in evaluating whether such evolution differs between treatment arms. The choice of assessment times should coincide with the objective while minimizing patient burden. HRQOL data analysis is a logical extension of the objective. Although no HRQOL gold standard exists, many of the classical analysis techniques can be adapted. In order to deal with longitudinal data, either summary measures (which reduce multiple data points to one number) or modeling techniques (which preserve the ordering) are acceptable. However, two issues to consider are multiple testing and missing data. Multiple testing can be minimized at the design stage by limiting the planned number of analyses. Missing data is more difficult to avoid and is best countered by sensitivity analyses, i.e., applying a variety of analytical methods, each relying on different assumptions to investigate the reliability of the results. 143

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Finally, a good HRQOL study is not complete without careful interpretation of the results. The interpretation should reflect the original objective: does the data provide an answer to the research question? Statistical significance (p-values and confidence intervals) should be balanced with clinical significance. An overview of the limitations, with specific attention to the potential impact of missing data and a comparison with similar studies, place the conclusions in their final context. Be careful, though, in comparing data from different instruments.

Using HRQOL measures in daily clinical practice: clinical impact While HRQOL is now well established in RCTs, physicians vary in their interest in using HRQOL in clinical practice, in their ability to elicit psychosocial information from patients, and in their response to patients’ emotional and functional needs. Routine use of HRQOL measures in patient care can help oncologists to screen and detect symptoms, psychological, and functional problems; monitor disease symptoms over time, disease progression, and/or response to treatment; facilitate doctor-patient communication; and assess quality of care. The potential benefits from these approaches have not been fully realized. Practical barriers relate to the need to collect and rapidly process a large volume of HRQOL data and present results to oncologists in real time. These are now largely overcome by using touch-screen computers. Further work is ongoing to develop systems that store the HRQOL information as part of electronic patient records. Methodological and conceptual barriers exist with concerns that HRQOL instruments developed for group comparisons in clinical trials are not sensitive enough to be used in individual patients. There is uncertainty as to how to interpret the results: What is the clinical meaning of the scores and what difference is clinically significant? However, longitudinal assessment at multiple time points can establish a personal norm for each patient as an anchor for future change. It can also be expected that as HRQOL assessment becomes more common in clinical settings, intuitive familiarity will develop through both individual and collective experience. 144

Several recent oncology RCTs showed that when HRQOL is measured regularly by a standard questionnaire, information provided to physicians has positive effects on patient-doctor communication and on detection of psychological morbidity, and in one trial, improves patients’ well-being. ■

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In a randomized cross-over trial of 214 patients treated with palliative chemotherapy (Detmar et al. 2002) the impact of HRQOL information on patient-doctor communication and on physician awareness of patient physical and psychosocial problems was investigated. The findings suggest that patient social functioning, fatigue, and dyspnea were discussed more frequently in the intervention group, with discussion more often initiated by the clinicians. Physicians in the intervention group tended to identify more patients with moderate to severe problems. However, the identification of more problems did not play a role in the treatment decisions regarding palliative chemotherapy. The intervention had no effect on patient well-being. A randomized trial, involving 28 oncologists, randomized 286 cancer chemotherapy patients into an intervention group with regular completion of EORTC QLQ-C30 and the Hospital Anxieties and Depression Scale on touch-screen computers in clinics and with feedback of results to physicians; an attention-control group with completion of questionnaires, but no feedback; and a control group with no HRQOL measurement. Primary outcomes were patient HRQOL over time, measured by Functional Assessment of Cancer Therapy-General (FACT-G), doctorpatient communication, and clinical management, measured by content analysis of tape-recorded consultations. More frequent discussion of chronic nonspecific symptoms (such as insomnia, appetite) was found in the intervention group, without prolonged consultations. There was no detectable effect on patient management. Patients in the intervention and the attention-control group had better HRQOL than the control group, but intervention and attention-control groups were not significantly different. Positive effects were observed for physical, functional, and emotional well-being. In the intervention patients, HRQOL improvement was associated with explicit use of the data during the consultations and discussion of pain and role function (Velikova et al, 2004).

Clearly, HRQOL and patient-reported outcomes in oncology practice can have a positive impact on doctor-patient communication and patient well-being. 145

Conclusion HRQOL is now well established in oncology and is reported in thousands of RCTs. Though HRQOL data can present challenges to design and interpretation in trials, recent studies show it is feasible to monitor HRQOL of individual patients in clinical practice. Further work is needed to develop physician training in using and responding to the HRQOL data and to actively implement this approach in clinical practice.

Further reading Detmar SB, Muller MJ, Schornagel JH, Wever LD, Aaronson NK. Health-related quality-of-life assessments and patient-physician communication: a randomized controlled trial. JAMA 2002; 288: 3027–34. Fairclough DL. Patient reported outcomes as endpoints in medical research. Stat Methods Med Res 2004; 13: 115–38. U.S. Food and Drug Administration. Guidance for Industry Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients. www.fda.gov/cber/ gdlns/active.pdf. Velikova G, Booth L, Smith AB, et al. Measuring quality of life in routine oncology practice improves communication and patient well-being: a randomized controlled trial. J Clin Oncol 2004; 22: 714–24. Ware JE Jr. Conceptualization and measurement of health-related quality of life: comments on an evolving field. Arch Phys Med Rehabil 2003; 84 (4 Suppl 2): S43–S51.

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Conclusion D Schrijvers Department of Hemato-Oncology Ziekenhuisnetwerk Antwerpen-Middelheim Antwerp, Belgium

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Cancer remains a life-threatening disease. Its diagnosis, treatment, and care should be optimal for each individual patient. Therefore, it is important that every patient receives the best diagnostic approach and treatment to ensure an optimal chance of cure and/or quality of life in the case of incurable disease. Each cancer should be diagnosed by the most appropriate method, and for most cancers this is a biopsy. Cytology is also a valid method, but the information it provides in relation to the tumor-environment relationship is less extensive. Prognostic and predictive markers can be determined on tissues and are gaining in importance rapidly. After cancer diagnosis, staging is the second most important diagnostic procedure because it determines prognosis and treatment choices. Each tumor type has a specific diagnostic procedure that should provide all necessary information to classify the patient according to internationally accepted classification systems. After starting treatment, its effects in relation to activity and toxicity should be evaluated and registered in the patient file. For this, several systems have been developed, such as the RESIST criteria or the National Cancer Institute-Common Toxicity Criteria. Guidelines for follow-up have been developed by different scientific organizations but should be standardized in order to be cost-effective. Several new diagnostic techniques have been or are being developed. However, they should be tested according to strict criteria that also apply to the development of new treatments or medication before they are integrated into current clinical practice. Therefore, each new test should be evaluated

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according to strict guidelines such as thosedeveloped by the NCI-EORTC (e.g., REMARK) or if data are not available, by consensus of experts. In addition to the physical aspects of cancer, oncologists should also take psychosocial aspects into accounts. Each patient should receive psychosocial support by the multidisciplinary team in order to preserve personal integrity. Revalidation and reintegration into society and workplace should also be integrated into cancer care. Updated information on diagnosis and treatment evaluation can be found at http://www.esmo.org.

Further reading ESMO clinical recommendations. http://www.esmo.org/no_cache/research/esmoclinical-recommendations.html (9.11.2008). McShane LM, Altman DG, Sauerbrei W, et al. Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst. 2005; 97: 1180–4. National Cancer Institute. CTC v2.0 and Common Terminology Criteria for Adverse Events v3.0 (CTCAE). http://ctep.info.nih.gov/reporting/ctc.html (9.11.2008). Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205–16. Wolff AC, Hammond ME, Schwartz JN, et al. Pathologist guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007; 25: 118–45.

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Index

acute and subacute toxicities of anticancer treatment 79–98 alopecia 93 antiemetic prophylaxis 84 antineoplastic drugs, emetogenic potential of 83 bleomycin 97 constipation 96 early-onset pulmonary toxicity 97–8 emetic risk 84 extravasation, management 81 flu-like syndrome 86 granulocyte-macrophage (GM)-CSF 97 hair loss 93–4 hypersensitivity reactions 82–5 ileus 96 interstitial pneumonitis 97 irritant drugs 80 liver toxicity 96 metabolic complications 98 mucositis 91–3 nausea 80–2 noncardiac pulmonary edema 97 pancreatitis 95–6 phlebitis 79–80 skin toxicity 94–5 tissue necrosis 79–80 vagal abdominal afferents 81 vesicant drugs 79 vomiting 80–2 see also hematologic anticancer treatment toxicity; tumor lysis syndrome (TLS)

3 acute complications, of radiotherapy 110–11 denudation of mucosa 111 dysuria 111 skin damage 110 acute pancreatitis, anticancer treatment toxicity 95 age anticancer treatment affected by 66 patient-related prognostic factor 50 allopurinol 86 alopecia 93 alpha-fetoprotein (AFP) 15 American Society of Clinical Oncology (ASCO) 15 anemia 128 anticancer treatment toxicity 88, 90–1 patient-related prognostic factor 51 anthracyclines 81 anticancer treatment acute toxicities of 79–98 factors determining 65–72 age 66 comorbidity 66 disease-related 65–6 patient-related 66–8 sociocultural factors 69–72 stage-related 66 treatment-related factors 69 tumor-related 65 subacute toxicities of 79–98 see also acute and subacute toxicities

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antiemetic prophylaxis, anticancer treatment toxicity 84 antihistamines 85 antineoplastic drugs, emetogenic potential of 83 Bevacizumab 103 bias affecting tumor marker 60 biomarkers in treatment evaluation 76 categories 76 biomarkers in oncology 13–20 breast 14, 16–18 CA 15-3 as 17–18 CEA in colorectal cancer 13–15 clinically useful tumor markers 13 colorectal 14 estrogen as 16–17 germ cell 14–15 hepatocellular 14 HER-2 as 17 MammaPrint® 18 omics technologies 18–19 Oncotype DX® 18 ovarian 14–16 PAI-1 as 17 progesterone as 16–17 prostate 14–16 thyroid 14 trophoblastic 14 uPA as 17 bladder cancer, staging procedures 43–4 bladder disorders 131 bleomycin 97 bone scan (99mTcmethylenediphosphonate) 30 bowel disorder 131 breast cancer biomarkers in 16–18 serum and molecular markers in 52 staging procedures 43 tumor markers 14 CA 15-3 in postoperative surveillance and monitoring therapy 17–18

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CA-125 in ovarian cancer 15–16 cachexia 128 Carcinoembryonic antigen (CEA) in colorectal cancer 13–15 preoperative levels 15 cardiovascular disease 103 chance affecting tumor marker 60 clinical staging 37–8 clonality assays 7 cognitive dysfunction, impacting anticancer treatment 68 cognitive impairment, due to cancer and cancer therapy 129–30 colorectal cancer CEA in 13–15 serum and molecular markers in 52–3 staging procedures 42–3 tumor markers 14 comedication, impacting anticancer treatment 68 comorbidity affecting anticancer treatment 66 cognitive dysfunction 68 comedication 68 depression 67 diabetes mellitus 67 hyperinsulinemia 67 obesity 67 patient outcome impacted by 68 physiologic impairment 68 weight loss 67 patient-related prognostic factor 50 computed tomography (CT) 23–4 constipation 131 anticancer treatment toxicity 96 cost-benefit analysis 71 cost-effectiveness analysis (CEA) 71 cost-minimization analysis 71 costs of diagnosis 1 costs, affecting anticancer treatment 70 cost-utility analysis (CUA) 71 cultural factors, affecting anticancer treatment 70 cumulative side effects and complications 112 cytopathology 3–4

dasatinib 95 dexamethasone 85 diarrhea 131 as anticancer treatment toxicity 91–3 chemotherapy-induced 92 managing 92–3 medication 93 severe diarrhea 92 time to onset of 92 direct costs, affecting anticancer treatment 70 disease-related factors affecting anticancer treatment 65–6 distant metastasis (M) 39 dynamic scanning 25 dysuria 111

febrile neutropenia (FN) 87 fine needle aspiration (FNA) 3 flu-like syndrome 86 18 F-Fluorodeoxyglucose (18F-FDG) PET 29, 31 cancer of unknown origin detection 32 clinical application 32 diagnosis 31 differential diagnosis 32 end of treatment evaluation 31, 33 restaging 32 routine follow-up of asymptomatic patients 32 screening 32 staging 31 suspected relapse 31

early complications, of radiotherapy 113–16 early-onset pulmonary toxicity 97–98 economic factors, affecting anticancer treatment 70 emetic risk, anticancer treatment toxicity 84 emotional impairment, due to cancer and cancer therapy 129–30 endocrine effects 104–6 hypogonadism/infertility 104 pituitary/hypothalamus 104 endometrial cancer, staging procedures 44 endoscopic examination 7, 40 esophageal cancer, staging procedures 42 estrogen (ER) as biomarker 16–17 limitations 17 etiology 8–9 European Group on Tumour Markers (EGTM) 15 extracted nucleic acids, in molecular pathology 5 extravasation 79 management 81

gastric cancer, staging procedures 42 gastrointestinal impairment 131 gene expression profiling 18 generalizability affecting tumor marker 60 germ cell tumor markers 14 alpha-fetoprotein (AFP) 15 human choriogonadotrophin (HCG) 15 lactate dehydrogenase (LDH) 15 grading 8

false-positive and false-negative PET studies 30 fatigue due to cancer and cancer therapy 127–9

hair loss, anticancer treatment toxicity 93–4 temporary hair loss 93 head tumors, staging procedures 41 health-related QOL (HRQOL) 142 clinical results impacted by 142–4 design 142–4 in daily clinical practice 144–5 hematologic anticancer treatment toxicity 87–91 anemia 88, 90–1 neutropenia 87–90 thrombocytopenia 89, 90 hematopoietic growth factors (hGFs) 87 hemorrhagic cystitis 131 hepatocellular tumor markers 14 HER-2 as biomarker 17

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hereditary cancer syndromes detection and testing in 8–9 histology, tumor-related prognostic factor 7, 51 histopathology 3 Hodgkin’s disease, staging procedures 45 human choriogonadotrophin (HCG) 15 hypersensitivity reactions, anticancer treatment toxicity 82–5 oxaliplatin inducing 82 paclitaxel inducing 82 hyperuricemia, anticancer treatment toxicity 86 hypogonadism/infertility 104 hypothyroidism 105–6 ileus 96 imaging techniques 21–7 in treatment evaluation 75–6 see also nuclear medicine imaging; radiological imaging imatinib 94 immune status, patient-related prognostic factor 51 immunohistochemistry (IHC) 4–5, 7 in situ hybridization 5 incapacity due to cancer and cancer therapy 127–32 anemia 128 bladder disorders 131 cachexia 128 cognitive impairment 129–30 emotional impairment 129–30 fatigue 127–9 gastrointestinal impairment 131 hemorrhagic cystitis 131 infections 128 neuropathy 130 sexual dysfunction 132 urinary hesitancy 131 weakness 127–9 indirect costs, affecting anticancer treatment 70 infections due to cancer and cancer therapy 128

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integration, guidelines for 136–7 interstitial pneumonitis, anticancer treatment toxicity 97 intervention costs 71 intravenous (IV) contrast agents 23 iodine-scan (131I) 30 irritant drugs 80 lactate dehydrogenase (LDH) 15 late complications, of radiotherapy 111–12, 116–17 cumulative side effects and complications 112 growth disorders 112 liver failure 112 periodontitis 111 pneumonitis 111 stoma formation 116 vaginal dryness 112 xerophthalmia 111 late toxicity 101–6 cardiovascular disease 103 hypothyroidism 105–6 methodological aspects 101–2 post-treatment infertility 104 second cancer 102–3 see also endocrine effects liver toxicity 96 long-term survivorship 120 magnetic resonance imaging (MRI) 25 malignant melanoma, staging procedures 45 mammaPrint® 18 mechloretamine 81 metaiodobenzylguanadine scan (131I or 123I labeled MIBG) 30 microsatellite instability (MSI) 9 minimal access surgery 116 mitomycin 81 molecular cytogenetics 7 molecular markers 54 molecular pathology 5, 7 extracted nucleic acids 5 in situ hybridization 5

molecular staging 39 monitoring response to treatment 33 mucositis 91–3 oral mucositis 91 multiple myeloma, serum and molecular markers in 54 nature of tumor, establishment 7–8 clonality assays 7 grading 8 histology or cytology 7 immuunohistochemistry 7 molecular cytogenetics 7 molecular pathology 7 staging 8 nausea 80–2, 84 neck tumors, staging procedures 41 neuropathy 130 neutropenia 87–90 febrile neutropenia (FN) 87 hematopoietic growth factors (hGFs) preventing 87 neutropenic enterocolitis 92–3 noncardiac pulmonary edema 97 non-Hodgkin’s lymphoma, staging procedures 45 nonseminoma testicular cancer, serum and molecular markers in 53–4 non–small cell lung cancer, staging procedures 41–2 nuclear medicine imaging 29–35 see also positron emission tomography (PET) nutritional status, patient-related prognostic factor 50 octreotide scan (111In-octreotide) 30 omics technologies 18 oncology 13–20 see also biomarkers oncotype DX® 18 oral mucositis 91 ovarian cancer CA-125 in 15–16 staging procedures 44

tumor markers 14 oxaliplatin 82 paclitaxel 81–2 pancreatitis 95–6 acute pancreatitis 95 papanicolaou technique 4 papulo-pustular eruption 94 pathological staging 38–40 pathology 3–10 clinical implications 9–10 cytopathology 3–4 description 3 histopathology 3 immunohistochemistry (IHC) 4–5 molecular pathology 5 patient outcome impacting anticancer treatment 68 patient-related factors affecting anticancer treatment 66–8 prognostic factors 50–7 see also under prognostic factors patient-reported outcomes (PRO) 142 performance status, patient-related prognostic factor 50 periodontitis 111 phlebitis 79–80 physical activity, patient-related prognostic factor 50 physiologic impairment, impacting anticancer treatment 68 pituitary/hypothalamus 104 plain X rays imaging 21–2 plasminogen activator inhibitor (PAI)-1 17 polymerase chain reaction (PCR) 7 positron emission tomography (PET) 26, 29–35 bone scan (99mTcmethylenediphosphonate) 30 false-positive and false-negative studies 30 Iodine-scan (131I) 30 Metaiodobenzylguanadine scan (131I or 123I labeled MIBG) 30

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positron emission tomography (PET) (Continued ) Octreotide scan (111In-octreotide) 30 Sestamibi scan (99mTc-sestamibi) 30 solid tumors 76 see also 18F-Fluorodeoxyglucose post-treatment infertility 104 predictive tumor markers 57–63, 77 in breast and other solid tumors 63 estrogen as 16–17 in routine use or in development 61–2 CD20 61 ER 61 HER2 61 PR 61 prevention 7 primary tumor (T) 39 progesterone (PR) as biomarker 16–17 prognostic factors 49–55 molecular markers 54 patient-related 50–7 age 50 anemia 51 comorbidity 50 immune status 51 nutritional status 50 performance status 50 physical activity 50 smoking 50 socioeconomic status 50 tumor-related 51–54 histology 51 serum markers 51 TNM classification 51 prognostic markers, estrogen as 16–17 prostate cancer prostate-specific antigen in 16 staging procedures 43 tumor markers 14 prostate-specific antigen (PSA) in prostate cancer 16 psychosocial effects 119–25 long-term survivorship 120 oncologist role 123–4 psychological screening 124–5

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psychologist role in oncology 122–3 vulnerable cancer patients 121–2 quality of life (QOL) issues 141–5 health-related QOL (HRQOL) 142 patient-reported outcomes (PRO) 142 radiation oncology and surgery, acute and late effects in 109–17 see also acute complications; late complications; surgery complications radiofrequency ablation 115 radiological imaging 21–7 computed tomography (CT) 23–4 dynamic scanning 25 magnetic resonance imaging (MRI) 25 plain X rays 21–2 positron emission tomography (PET) scanning 26 ultrasound 22 radiotherapy acute complications 110–11 late complications 111–12 rasburicase 86 regional lymph nodes (N) 39 reintegration into workplace 135–78 barriers for 137 requalification and job applications 137–8 retirement 138 social reintegration plan 136 renal cell cancer, staging procedures 44 reverse transcriptase (RT)-PCR 7 screening 7 second cancer 102–3 seminoma testicular cancer, serum and molecular markers in 53 serum markers, tumor-related prognostic factor 51 breast cancer 52 colorectal cancer 52–3 multiple myeloma 54 testicular cancer 53–4

nonseminoma 53–4 seminoma 53 sestamibi scan (99mTc-sestamibi) 30 sexual dysfunction 132 skin anticancer treatment toxicity 94–5 cytotoxic agents inducing 95 dasatinib 95 imatinib inducing 94 papulo-pustular eruption 94 preventive measures 94 sorafenib 95 small cell lung cancer, staging procedures 41 smoking, patient-related prognostic factor 50 social reintegration plan 136 sociocultural factors, affecting anticancer treatment 69–72 economic evaluations 70 social factors 69 budget-impact analysis 70, 72 cost benefit 70–1 cost minimization 70–1 cost utility 70–1 cost-effectiveness 70–1 costs 70 cultural factors 70 direct costs 70 economic factors 70 indirect costs 70 individual social isolation 69 lack of access to health care 69 socioeconomic status, patient-related prognostic factor 50 solid tumors treatment evaluation 75–7 Positron emission tomography (PET) 76 RECIST guidelines 75 sorafenib 95 stage-related factors affecting anticancer treatment 66 staging procedures 8, 37–45 bladder cancer 43–4 breast cancer 43

clinical staging 37–8 colorectal cancer 42–3 in daily clinical practice 40–1 imaging studies 40 pathology reports 40 physical examination 40 surgical reports 41 endometrial cancer 44 esophageal cancer 42 gastric cancer 42 head and neck tumors 41 Hodgkin’s disease 45 malignant melanoma 45 molecular staging 39 non-Hodgkin’s lymphoma 45 non–small cell lung cancer 41–2 ovarian cancer 44 pathological staging 38–40 prostate cancer 43 renal cell cancer 44 small cell lung cancer 41 TNM staging 39 stoma formation complication 116 stomatitis 91–3 subacute toxicities see under acute and subacute toxicities sunitinib 103 surgery complications, of radiotherapy 112–117 early complications 113–16 minimal access surgery 116 tumor ablation syndrome 115 testicular cancer, serum and molecular markers in 53–4 thrombocytopenia 89, 90 thyroid tumor markers 14 tissue necrosis 79–80 TNM classification, tumor-related prognostic factor 51 TNM staging distant metastasis (M) 39 primary tumor (T) 39 principles 39 regional lymph nodes (N) 39

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trastuzumab 103 treatment evaluation of activity 75–7 biomarkers 76 solid tumors 75–7 imaging 75–6 treatment-related factors, affecting anticancer treatment 69 trophoblastic tumor markers 14 tumor ablation syndrome 115 tumor lysis syndrome (TLS) 85–6 aggressive hydration 86 Allopurinol 86 at-risk patients, preventive measures 86 hyperuricemia 86 intermediate-risk patients 86 Rasburicase 86 Uricozyme 86 tumor markers 57–63 bias affecting 60 chance affecting 60 clinical utility, evaluation 57–9 definition 57 generalizability affecting 60 methodological considerations 60–1 reporting considerations 60–1 statistical considerations 60–1 Tumor Marker Utility Grading System 58

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types 57 utility determination, level of evidence for 59 see also predictive tumor markers tumor-related factors affecting anticancer treatment 65 tumor-related prognostic factors 51–4 see also under prognostic factors typhlitis 92 ultrasound 22 uricozyme 86 urinary hesitancy 131 urokinase plasminogen activator (uPA) 17 vagal abdominal afferents 81 vesicant drugs 79 vinca alkaloids 81 vomiting, anticancer treatment toxicity 80–2, 84 vulnerable cancer patients 121–122 weakness due to cancer and cancer therapy 127–9 willingness-to-pay (WTP) approach 71 xerophthalmia 111

European Society for Medical Oncology

Handbook of Cancer Diagnosis and Treatment Evaluation Hans-Joachim Schmoll • Laura Van’t Veer Jan Vermorken • Dirk Schrijvers The diagnosis and evaluation of treatment for cancer is a crucial topic for medical oncologists, who need to judge the various diagnostic and therapeutic factors for each cancer, the relevance of staging, and the measurement of patient response. Written by a selection of international experts, this handbook is an ideal resource for medical oncologists and those involved in screening and chemotherapy programs. Also available: ESMO Handbook of Cancer Prevention (ISBN: 9780415390859) ESMO Handbook of Oncological Emergencies (ISBN: 9781841845234) ESMO Handbook of Advanced Cancer Care (ISBN: 9780415375306) ESMO Handbook of Principles of Translational Research (ISBN: 9780415410915)

DU0869 www.esmo.org