Oncology: An Evidence-Based Approach (Chang, Oncology)

Oncology

Oncology An Evidence-Based Approach With 346 Figures in 501 Parts

Edited by Alfred E. Chang, MD Hugh Cabot Professor of Surgery; Chief, Division of Surgery Oncology; Department of Surgery, University of Michigan, Ann Arbor, Michigan

Patricia A. Ganz, MD American Cancer Society Clinical Research Professor, Director, Division of Cancer Prevention and Control Research, Jonsson Comprehensive Cancer Center at UCLA, Professor, Schools of Public Health and Medicine, University of California, Los Angeles, Los Angeles, California

Daniel F. Hayes, MD Clinical Director, Breast Oncology Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan

Timothy J. Kinsella, MD Vincent K. Smith Professor and Chairman, Department of Radiation Oncology, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio

Harvey I. Pass, MD Professor and Chief of Thoracic Surgery, Department of Cardiothoracic Surgery, Head, Thoracic Oncology, New York University School of Medicine and Comprehensive Cancer Center, New York, New York

Joan H. Schiller, MD Melanie Heald Professor of Medical Oncology, Department of Medicine, University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin

Richard M. Stone, MD Associate Professor, Department of Medicine, Harvard Medical School, Clinical Director, Adult Leukemia Program, Dana-Farber Cancer Institute, Boston, Massachusetts

Victor J. Strecher, PhD, MPH Professor and Director, Health Media Research Laboratory, Department of Health Behavior and Health Education, University of Michigan School of Public Health, Associate Director, Cancer Prevention and Control, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan

Foreword by Gabriel N. Hortobagyi, MD, FACP

Alfred E. Chang, MD Hugh Cabot Professor of Surgery Chief, Division of Surgery Oncology Department of Surgery University of Michigan Ann Arbor, MI, USA Daniel F. Hayes, MD Clinical Director, Breast Oncology Program University of Michigan Comprehensive Cancer Center Ann Arbor, MI, USA Harvey I. Pass, MD Professor and Chief of Thoracic Surgery Department of Cardiothoracic Surgery Head, Thoracic Oncology New York University School of Medicine and Comprehensive Cancer Center New York, NY, USA Richard M. Stone, MD Associate Professor, Department of Medicine Harvard Medical School Clinical Director, Adult Leukemia Program Dana-Farber Cancer Institute Boston, MA, USA

Patricia A. Ganz, MD American Cancer Society Clinical Research Professor Director, Division of Cancer Prevention and Control Research Jonsson Comprehensive Cancer Center at UCLA Professor, Schools of Public Health and Medicine University of California, Los Angeles Los Angeles, CA, USA Timothy J. Kinsella, MD Vincent K. Smith Professor and Chairman Department of Radiation Oncology University Hospitals of Cleveland Case Western Reserve University Cleveland, OH, USA Joan H. Schiller, MD Melanie Heald Professor of Medical Oncology Department of Medicine University of Wisconsin Comprehensive Cancer Center Madison, WI, USA Victor J. Strecher, PhD, MPH Professor and Director, Health Media Research Laboratory Department of Health Behavior and Health Education University of Michigan School of Public Health Associate Director, Cancer Prevention and Control University of Michigan Comprehensive Cancer Center Ann Arbor, MI, USA

Library of Congress Control Number: 2005926820 ISBN 10: 0-387-24291-0 ISBN 13: 978-0387-24291-0 Printed on acid-free paper. © 2006 Springer Science+Business Media, Inc. All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, Inc., 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed in the United States of America. (BS/MVY) 9 8 7 6 5 4 3 2 1 springeronline.com

I would like to dedicate this book to all of our cancer patients. They are the ones who have taught us about living, coping, and how to be better physicians. AEC Producing a new textbook is a little like designing a clinical protocol by committee: we had specific aims, with some proposed methods, and we got a pretty good result. I appreciate the team work of my co-editors, and especially the contributions of my colleagues who helped to launch survivorship as a recognized component of an oncology text. PAG To I. Craig Henderson, M.D., who first taught me the importance of scientifically-based clinical evidence for decision-making, and to my wife, Jane, who has provided so much so that I can pursue my whim: academic medicine. DFH Dedicated to my wife Susan and children for their unending support; also dedicated to my oncology mentors Sam Hellman, George Canellos and Eli Glatstein. TJK To my family, Helen, Ally, and Eric, who always put up with my tendency to get overextended, but always have time to make me feel loved HIP To my parents, my husband George, and my children Quintin, Craig, and Lindsey, all of whom have been incredibly supportive over the years JHS To my wife Jane and my children Ben, Rebecca, Sarah, and Harry RMS For Jeri, Rachael, and Julia VJS

Foreword

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ompared to more traditional subspecialties, oncology is a young, vibrant, and progressive branch of medicine that has relatively few ties to a dogmatic past. Perhaps for this reason many innovations in oncology have occurred as a consequence of rapid cultural changes within the specialty, and continued change remains an accepted and integral part of our field. While most other practitioners of medicine learned a “standard of practice” and some dedicate their practice to clinical and/or basic research, research has been an integral and inseparable part of oncology since its inception. Consequently, virtually all oncologists consider clinical trials and experimental therapeutics as bread and butter and as necessary components of an ongoing progress. The broad acceptance of the necessity of prospective clinical trials and the continued testing of new drugs, strategies, and concepts highlights the need for differentiating hypothesis from fact, experience from experimental results, and opinion from fact. Such separation is the basis of evidence-based medicine, and oncology is one of the specialties with perhaps the richest tradition of practicing it. Considering that medicine has relied almost exclusively on clinical observation, anecdotal series, and uncontrolled personal experience for the past many centuries, such rapid adoption of evidence-based medicine is somewhat surprising and attests to the scientific orientation of our discipline. For the past three decades several excellent textbooks on oncology were developed. The leading examples are multiauthored volumes that summarize the results of clinical trials placed in clinical context by experts on the field. These are encyclopedic textbooks in the best tradition of medicine, and several have progressed through multiple editions. In that context, what will the current textbook contribute to the field and how is it different from other volumes in the crowded field of oncology? Multiple answers to this question emerge from a careful review of this textbook. First, this book reflects a mature field of oncology; in addition to descriptions of natural history, clinical course, and the value of commonly used therapeutic strategies, much emphasis is placed on the cost, in terms of unwanted effects or toxicities associated with treatments. In addition to detailed presentations of acute side effects and their management, there is careful presentation of long-term effects, most of which are irreversible and some, potentially lethal. Only such careful assessment and tabulation of quantifiable therapeutic affects placed on the balance along with acute and long-term toxicities can provide a true picture of the therapeutic ratio of an intervention, which can then be translated in the context of each patient’s clinical situation, risk of progression, recurrence, or death. Second, the book presents a systematic approach to issues of survivorship. Physicians with a major interest in survivorship describe some of these, while survivors themselves describe others, providing a poignant perspective not found in books entirely authored by medical specialists. This aspect is the logical consequence of the increasing integration of users in breast cancer research and allocation of resources. Patient perspectives have contributed in a major way to identification of research fund over the past decade, and their participation in the activities of multiple research groups have contributed to identification of important questions to be addressed and the prioritization of research activities in cancer centers, SPOREs, and other multi-investigator activities. Such contributions are irreplaceable and of great importance to reaching the ultimate goals of cancer research: improvements in quality and duration of life. The third, and perhaps most important contribution of this volume, is the emphasis on determining the quality of evidence in the integration of research results into guidelines or recommendations for patient care or design of subsequent research. The first chapter is dedicated to the definitions of research quality, systematic approaches to quantify levels of evidence, and providing examples of such systematic approach to grading quality of cancer investigation. It is no accident that the editor in chief of the Journal of the National Cancer Institute, dedicated for many years to the assessment of the quality of research publications is the senior author of this chapter. In

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earlier decades, assessment of the quality of research was an intuitive process, and most seasoned oncologists based their enthusiasm for specific reports or research results on their subjective assessment of the research in question. Such subjective assessments were based, in part, on the name recognition of the reporting investigator(s), the reputation of the center or group behind the research, the sample size, and often the biases of those engaged in the assessment. The systematic approach to assigning specific levels of evidence to research reports goes a long way toward removing subjectivity from these assessments, focusing more on the methodology and the inherent strengths and weaknesses of any particular research approach than on the concordance of the results with preconceived biases or favored hypothesis. Identifying reports with the highest levels of evidence often clarifies seemingly confusing collections of data and often points out the glaring weaknesses or deficiencies of specific fields of interest. Sometimes it becomes apparent that despite decades of accepted treatment approaches, no evidence exists on which to base such approaches. It is apparent from such application of evidence-based scrutiny that modern medicine is still a hybrid filed, where evidence-based approaches coexist and often comingle with old observations, qualitative personal experiences, opinions, and anecdotes. It is amply clear that the generation of high-quality evidence requires time and resources, including the willing participation of users, in this case, research subjects and patients. It is also clear that in many situations, physicians will have to continue using clinical judgment, extrapolate from related evidence and utilize common sense in the day-to-day management of clinical problems, because only a relatively small proportion of oncological treatments have been subjected to strict, controlled, prospective clinical trials, and not every question will be the subject of high-quality clinical trials in the future. Limitations in time and resources and the ongoing supply of high-priority biological questions will always displace questions of lower priority. Let us examine then other features of this remarkable book. The first few chapters review the basic approaches to treat cancer. Surgery, radiotherapy, and chemotherapy are carefully presented, with a clear description of mechanisms of action and in the context of modern biological understanding of the malignant process. The chapter about radiation therapy is an example of the enormous progress made in our understanding of this highly technological branch of cancer treatment and the major progress that has occurred in this specialty over the past few years. Targeted therapy is the latest addition to our armamentarium, but it is one of the most exciting aspects of systemic treatments because it is based on clear understanding of the molecular underpinnings of the biological advantage of certain malignant cells over their normal components, biological characteristics that drive the proliferation, invasion, metastasis, and survival of such cells. The recent success of specific forms of targeted therapies (imatinib, trastuzumab, bevacizumab, and the endocrine agents) emphasize the enormous potential of this approach in the development of more specific treatments with fewer expected consequences on nonmalignant tissue. This chapter also highlights the many challenges encountered in the development of targeted agents, such as the need to validate molecular targets, to demonstrate in vivo that the agent accomplishes its desired effect on the target and, in consequence, can be expected to produce a specific clinical effect. These challenges have proved to be major obstacles in the case of certain targets, yielding easily in the case of others. Tumor markers are an inherently attractive concept. Would it not be desirable to have a marker of disease extent, activity or malignant potential that one can identify and quantify in a minimally invasive or noninvasive manner? Would it not be helpful to relay on such markers to determine the efficacy of therapy early in a therapeutic intervention? The author of Chapter 7 is a recognized expert in this field and has contributed to our conceptual systematization of the tumor marker field with the development of clear criteria for validating markers and guidelines for their utilization, as well as recommendations to avoid obvious pitfalls in this area. Much of the high-level evidence we have today was derived from prospective clinical trials. The chapter describing these master tools is authored by enormously experienced clinical trials who have contributed both conceptually and practically to the definition, implementation and analysis of randomized clinical trials. This chapter provides an excellent roadmap for current and future investigators. The ethics of human experimentation are a critical subject for all investigators and patients. Decades of controversy have refined our approach to randomized trials,

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no treatment or placebo controls, and defined optimal approaches for analysis and release of trial results. High-quality evidence can only be generated in the context of a highly ethical trial design. Screening and early diagnosis present particular challenges, largely because they relate to asymptomatic subjects, most of whom will not need nor benefit from these interventions. Therefore, these approaches benefit a few, while exposing many to potential risks. Trial design, ethics, and economics meet and often collide in this field. As increasing emphasis has been placed on patient autonomy and as the population at large has gained increasing access to medical information, issues related to alternative and complementary therapies have also become prominent. This field includes IT, where assessment of levels of evidence can provide enormous benefits to our patients and also to healthcare providers, who often have only a passing knowledge of such popular, but often untested approaches, to the treatment of cancer or its symptoms. The lead author is clearly one of the most knowledgeable experts on this field and provides a broad overview of the issues. Outstanding contributions cover the potential etiologies of cancer, as well as the basic biological principles of malignant transformation, invasion, and metastases. The role of the immune system is receiving increasing attention, as greater effort is being expended on the development of vaccines and other immunological approaches to cancer control. One of the outstanding examples of the application of evidence-based medicine is Chapter 23. The authors describe the complexity of research that brings together epidemiology, basic sciences, and chemoprevention trials, in a field where isolated causes of cancer are seldom identified and where control of all variables is an unrealistic expectation. These issues are highlighted in examples of dietary intervention or the use of specific components of the human diet, such as vitamins, minerals, and other micronutrients. The identification of genes involved in cancer predisposition has dramatically changed our approach to familial cancer syndromes. Our ability to precisely identify subjects at risk for certain malignant tumors has also placed in evidence complex social, psychological, financial, and ethical issues that need to be addressed with subjects potentially eligible for genetic screening or preventive interventions. Such advances have also uncovered potential leads for identifying other genes that influence the development of more common, apparently sporadic cancers in the population, and eventually point to future therapeutic strategies. The chapters dedicated to specific malignant tumors bring together updated information about epidemiology, carcinogenesis, natural history, diagnostic procedures, and therapeutic interventions. The book highlights, in general, that optimal care requires close interdisciplinary collaboration, both in the diagnostic process and therapeutic strategies. There is much emphasis on the results of randomized trials, as the major theme of the book would indicate. It is painfully clear, however, that for common adult malignancies there is much evidence generated from prospective randomized trials that allows the development of evidence-based treatment guidelines; however, this is often not the case for less common tumors, especially those most resistant to systemic treatments. For these, treatment strategies are often based on observational or single-arm prospective trials. The recent identification of molecular targets for some of these tumors (renal cell or pancreatic cancers) has led to renewed interest and some notable successes in recent clinical trials. Chapter 63 is an excellent example of how the editors envision the presentation of systematic knowledge about a specific disease condition. The authors synthesized an enormous body of information derived from clinical trials if patients with acute leukemia or myelodysplastic syndromes. The highest quality evidence, based on multiple phase III trials, is presented first, followed in descending order of quality by other types of evidence. The stepwise development of therapeutic interventions, comparing the best “standard” to an investigational approach, is a logical candidate for evaluation in prospective randomized trials. Patient selection can be predetermined, and, in general, treatments can be compared on relatively homogeneous groups of patients. That is clearly not the case for complications of malignancy or treatment; such events occur at different times of the clinical course of the disease, and of course, patients cannot be selected a priori. Rather, the development of the complication selects the patients and treatments must be adjusted to the patients’ circumstances.

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For these reasons it is all the more satisfying to review Chapter 71 about acute CNS complications. Such complications are almost always dramatic and require prompt intervention. It is, therefore, all the more admirable to find level I evidence and Grade A recommendations for the management of an oncological emergency. The secondary message of these results is that appropriate controlled trials can be ethically developed in almost every circumstance in the oncological patient, and high level evidence can be generated for optimal management of subsequent patients. Another excellent chapter, Chapter 76, summarizes current knowledge and therapeutic approaches to infectious complications of malignant disease and their treatments. While not presented with detailed assessment of levels of evidence, this chapter highlights current approaches to common and uncommon infections, the appropriate use of antibiotics and hematopoietic growth factors, and introduces methods to prevent or reduce the risk of infectious complications. It is gratifying how, from the number one cause of treatment-related mortality a few decades ago, infectious complications have become a much more manageable, and in fact, almost completely preventable complications of cancer treatment, especially in patients with solid tumors. Chapter 83 focuses on a difficult field of research, the assessment, management, and prevention of nausea and emesis. While a common side effect of cancer treatment, especially chemotherapy and radiotherapy, nausea and emesis are difficult research subjects because of the major subjective component, interindividual variability, and the lack of external, validated, hard endpoints, short of counting the numbers of emetic episodes. Despite these obstacles, multiple prospective randomized have been conducted, comparing antiemetics with placebo or no treatment, or two antiemetics, or single antiemetics with combination therapy. The tables not only describe the results of such research, but list them in the order of higher to lower level of evidence. Such ranking facilitate the assessment of relative value of information derived from different clinical trials and also identifies opportunities to conduct additional research to clarify or complement existing evidence. Other fields of research, especially those in the psychosocial and behavioral disciplines, have made less progress in the implementation of levels of evidence to research results. This observation is largely based on the predominantly “soft” endpoints utilized in many of these disciplines—endpoints that lend themselves less to easy quantification. As validated instruments are developed and employed in prospective research, this is also likely to change, and we can expect an increasing emphasis on evidence-based recommendations and guidelines in these fields too. Much progress has been made since the War on Cancer was declared in 1971. Some of it was the result of the outstanding laboratory based research conducted with the support of the National Institutes of Health, National Cancer Institute, American Cancer Society, and multiple foundations, and resulted in marked improvement in our understanding of the basic biological underpinnings of malignant disease and the processes that give it its life-threatening characteristics. Some progress was derived from the technological progress in developing new diagnostic methods, refining our ability for early diagnosis, staging, and focusing of therapeutic interventions. Some progress was the result of successful drug development resulting in more effective therapeutic interventions that reduced markedly the probability of recurrence and mortality for patients diagnosed with several common human solid tumors and hematological malignancies. However, progress has been costly in financial terms, infrastructure building, and human resources. With more than 1800 new oncological drugs in the pipeline, and almost half of them at some stage of clinical development, resources are becoming even scarcer and more precious. It behooves us, as a community, to find or develop more effective and more cost-effective methods to assess the efficacy of drugs and procedures, to identify patients more and less likely to benefit from a specific intervention, and to minimize waste in the utilization of the multiple diagnostic and therapeutic approaches we have available to us today. Such urgent need for cost-effective approaches is even more dramatically highlighted by the plight of the majority of countries with limited resources around the globe. Squandering precious resources in poorly designed healthcare strategies limits access to life saving procedures. Our best hope is the increasingly stringent application of high-level evidence to decision making at the level of public health officials but also at the level of each individual physician. To enhance our probability of success, we need to speak in the language of evidence, think of levels of evi-

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dence in the design of research projects and clinical trials, and increasingly limit our recommendations to those interventions supported by the highest levels of evidence. Anything less will limit access to high-quality care and dilute our efforts to serve our patients. We hope that this textbook and subsequent editions of it will lead the way towards the implementation of evidence-based oncology and set the tone for future textbooks in other medical fields. Gabriel N. Hortobagyi, MD, FACP Professor and Chair Department of Breast Medical Oncology Director of the Multidisciplinary Breast Cancer Research Program The University of Texas M. D. Anderson Cancer Center

Preface

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new textbook in oncology?! What is different about this book compared to other established texts that have already been published? Why do we need a new book? For anyone in the market for a textbook, the main reason is to keep pace with the knowledge base that is growing ever so rapidly in oncology, a field that is evolving faster than all other medical fields. This book does not attempt to be an encyclopedic summary of that information. Rather, this textbook strives to organize that knowledge into a unified approach that categorizes and summarizes the evidence that is currently available. We realize that clinicians are too busy to keep up with the literature that is published in the many available journals. Therefore, a key feature of this book is the evidence-based tables that collate the best available evidence from the literature, enabling the reader to make decisions on the basis of data. We have chosen current experts to create evidence-based chapters on topics that span the field from basic and translational science to prevention to clinical practice, and ultimately to survivorship, totaling 113 chapters written by more than 250 contributors. The tone of this book is established in the first chapter, “EvidenceBased Approach to Oncology,” which reviews the history of evidence-based medicine and describes the different levels of evidence. This book will be informative to residents, fellows, practicing clinicians, and allied health professionals. This book has several unique features. Section One, “Principles of Oncology,” contains several chapters that discuss areas that have only recently matured. The topics include the biologic principles of hematopoietic stem cell therapies; informatics infrastructure; economics of cancer care; and, patient decision making. The section on “Translational Basic Science,” includes chapters that review the basic concepts of cancer biology; these are written from the perspective of clinical translational science and how it is relevant to the physician. The chapter entitled “Technologies in Molecular Biology: Diagnostic Applications” is both timely and concise, while exploring the application of genomics to daily clinical practice. In the section on “Cancer Prevention and Control,” the chapter, “Behavioral Modification” is unique in the literature. Similarly, the section on “Cancer Imaging” has a chapter on the “Imaging of Gastrointestinal Stromal Tumor,” which is not found in current oncology textbooks. The chapter on PET imaging investigates the promise of that modality. In the “Practice of Oncology” section, several chapters discuss the care of subpopulations of patients who pose different challenges to the clinician: immunosuppressed patients; elderly patients; patients with organ dysfunction; and pregnant women. Foremost, an entire section of 13 chapters is devoted to “Cancer Survivorship.” These innovative chapters represent a broad and in-depth review of the longterm consequences of cancer treatment with respect to specific malignancies. A chapter on “Cancer Advocacy” from the perspectives of cancer survivors is in this section. Most of the chapters fall into sections on Solid Tumors, Hematologic Malignancies, and the Practice of Oncology. These sections cover site-specific malignances, treatment toxicities, oncologic emergencies, and supportive care. They focus on the latest multimodality approach to the patient, with an emphasis on the best-available evidence from the literature. Where available, we have asked authors to include Level 1 clinical, treatment, and management data for each site-specific chapter. In those instances where Level 1 evidence may not be available, the best clinical practices based on published clinical experience are summarized. As opposed to review articles or standard textbook chapters, the evidence-based chapters presented in this book strive to present the reader with a thorough search of the evidence, judgment of the scientific quality of the evidence, and lastly a bias-free conclusion of the evidence. This new book offers readers a user-friendly approach to the vast amount of information in the oncology literature. It is our intention that this book will become a useful tool for the improvement of readers’ clinical practices. The Editorial Board

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would like to acknowledge the outstanding effort of the Springer staff for pulling this project together. In particular, we would like to thank Laura Gillan who initiated this book project, and Paula Callaghan who brought it to its completion. Alfred E. Chang, MD Patricia A. Ganz, MD Daniel F. Hayes, MD Timothy J. Kinsella, MD Harvey I. Pass, MD Joan H. Schiller, MD Richard M. Stone, MD Victor J. Strecher, PhD, MPH

Contents Foreword by Gabriel N. Hortobagyi . . . . . . . . . . . . . . . . vii Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii Section One Principles of Oncology 1 Evidence-Based Approach to Oncology . . . . . . . . . . . . . . . . . . . Emily DeVoto and Barnett S. Kramer

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2 Principles of Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . Grace K. Dy and Alex A. Adjei

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3 Principles of Radiation Oncology . . . . . . . . . . . . . . . . . . . . . . . Timothy J. Kinsella, Jason Sohn, and Barry Wessels

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4 Principles of Surgical Therapy in Oncology . . . . . . . . . . . . . . . Michael S. Sabel, Kathleen M. Diehl, and Alfred E. Chang

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5 Principles of Targeted and Biological Therapies . . . . . . . . . . . . Stephen R.D. Johnston, Sue Chua, and Charles Swanton

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6 Biologic Principles of Hematopoietic Stem Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Robert J. Soiffer

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7 Evaluation of Tumor Markers: An Evidence-Based Guide for Determination of Clinical Utility . . . . . . . . . . . . . . . . . . . . . . Daniel F. Hayes

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8 Design and Analysis of Oncology Clinical Trials . . . . . . . . . . . James J. Dignam, Theodore G. Karrison, and John Bryant

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9 Ethics of Clinical Oncology Research . . . . . . . . . . . . . . . . . . . 127 Manish Agrawal, Lindsay A. Hampson, and Ezekiel J. Emanuel 10 Informatics Infrastructure for Evidence-Based Cancer Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jeffrey P. Bond and Scott D. Luria

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11 Economics of Cancer Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . James Khatcheressian and Thomas J. Smith

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12 Principles of Screening for Cancer . . . . . . . . . . . . . . . . . . . . . . Russell Harris and Linda S. Kinsinger

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13 Patient Decision Making . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Peter A. Ubel

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14 Establishing an Interdisciplinary Oncology Team . . . . . . . . . . . Nathan Levitan, Meri Armour, and Afshin Dowlati

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15 Principles of Complementary and Alternative Medicine for Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Andrew J. Vickers and Barrie Cassileth

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Section Two Translational Basic Science 16 Fundamental Aspects of the Cell Cycle and Signal Transduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jeffrey R. Skaar and James A. DeCaprio

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17 Viral Carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Michele Carbone and Giuseppe Barbanti-Brodano

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18 Environmental Carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . T. Sabo-Attwood, M. Ramos-Nino, and Brooke T. Mossman

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19 Cancer Metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kevin McDonnell and Anton Wellstein

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20 Tumor Immunology and Immunotherapy . . . . . . . . . . . . . . . . Jeffrey Weber, Sophie Dessureault, and Scott Antonia

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21 Technologies in Molecular Biology: Diagnostic Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Timothy J. Triche

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Section Three Cancer Prevention and Control 22 Cancer Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Melissa L. Bondy and Shine Chang 23 Evidence-Based Cancer Prevention Research: A Multidisciplinary Perspective on Cancer Prevention Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stephen D. Hursting, Michele R. Forman, Asad Umar, Nomeli P. Nunez, and J. Carl Barrett 24 Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stephen H. Taplin, Sarah Dash, Paula Zeller, and Jane Zapka 25 Genetic Screening and Counseling for High-Risk Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mary B. Daly 26 Behavior Modification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Christopher N. Sciamanna

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Section Four Cancer Imaging 27 Central Nervous System Imaging . . . . . . . . . . . . . . . . . . . . . . Dima A. Hammoud and Martin G. Pomper

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28 Breast Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Wendie A. Berg

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29 Imaging of Thoracic Malignancies . . . . . . . . . . . . . . . . . . . . . . Caroline Chiles and Suzanne L. Aquino

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30 Imaging of Gastrointestinal Stromal Tumor . . . . . . . . . . . . . . . Ihab R. Kamel and Elliot K. Fishman

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31 Genitourinary Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Satomi Kawamoto, Harpreet K. Pannu, David A. Bluemke, and Elliot K. Fishman

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32 Musculoskeletal Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Leanne L. Seeger and Kambiz Motamedi

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33 Positron Emission Tomography and Cancer . . . . . . . . . . . . . . . Daniel N. Chatzifotiadis, Julia W. Buchanan, and Richard L. Wahl

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Section Five Solid Tumors 34 Central Nervous System Tumors . . . . . . . . . . . . . . . . . . . . . . . Ravi D. Rao, Paul D. Brown, Caterina Giannini, Cormac O. Maher, Fredric B. Meyer, Evanthia Galanis, Brad J. Erickson, and Jan C. Buckner

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35 Eye, Orbit, and Adnexal Structures . . . . . . . . . . . . . . . . . . . . . Daniel M. Albert, Marni Feldmann, Heather Potter, and Amit Kumar

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36 Head and Neck Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ezra E.W. Cohen, Kerstin M. Stenson, Michael Milano, and Everett E. Vokes

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37 Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hak Choy, Harvey I. Pass, Rafael Rosell, and Anne Traynor

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38 Therapy for Malignant Pleural Mesothelioma . . . . . . . . . . . . . Harvey I. Pass, Nicholas Vogelzang, Steven Hahn, and Michele Carbone

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39 Mediastinum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alexander S. Krupnick and Joseph B. Shrager

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40 Esophageal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . John D. Urschel

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41 Stomach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Scott A. Hundahl, John S. Macdonald, and Stephen R. Smalley

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42 Colon, Rectal, and Anal Cancer Management . . . . . . . . . . . . . John M. Skibber and Cathy Eng

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43 Adenocarcinoma and Other Small Intestinal Malignancies . . . John H. Donohue

733

44 Cancer of the Liver and Bile Ducts . . . . . . . . . . . . . . . . . . . . . Michael L. Kendrick, Annette Grambihler, Gregory J. Gores, Steven Alberts, and David M. Nagorney

745

45 An Evidence-Based Approach to the Management of Pancreatic Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dan Laheru

764

46 Renal Cell Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Joseph I. Clark, Craig Hofmeister, Vicki Keedy, and Jeffrey A. Sosman

782

47 Ureter, Bladder, Penis, and Urethra . . . . . . . . . . . . . . . . . . . . . Cheryl T. Lee, Brent Hollenbeck, and David P. Wood, Jr.

806

48 Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Richard Whittington and David J. Vaughn

826

49 Testis Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Timothy Gilligan and Phillip W. Kantoff

844

50 Cervix, Vulva, and Vagina . . . . . . . . . . . . . . . . . . . . . . . . . . . . Julian C. Schink

874

51 Gestational Trophoblastic Neoplasia . . . . . . . . . . . . . . . . . . . . John R. Lurain

892

52 Ovarian Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Yukio Sonoda and David Spriggs

903

53 Uterine Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gini F. Fleming, Anthony C. Montag, Arno J. Mundt, and S.D. Yamada

928

54 Evidence-Based Management of Breast Cancer . . . . . . . . . . . . . Lisa A. Newman and Daniel F. Hayes

951

55 Thyroid and Parathyroid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gerard M. Doherty

983

56 Tumors of the Endocrine System . . . . . . . . . . . . . . . . . . . . . . . 1005 Jeffrey A. Norton 57 Sarcomas of Bone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1025 Randy N. Rosier and Susan V. Bukata 58 Soft Tissue Sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1039 T. Christopher Windham and Vernon K. Sondak 59 Cutaneous Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1073 Mark R. Albertini, B. Jack Longley, Paul M. Harari, and Douglas Reintgen 60 Nonmelanoma Cutaneous Malignancies . . . . . . . . . . . . . . . . . 1093 Montgomery Gillard, Timothy S. Wang, and Timothy M. Johnson

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61 Cancer of Unknown Primary Site . . . . . . . . . . . . . . . . . . . . . . 1110 F. Anthony Greco and John D. Hainsworth 62 Solid Tumors of Childhood . . . . . . . . . . . . . . . . . . . . . . . . . . . 1124 Crawford J. Strunk and Sarah W. Alexander

Section Six Hematologic Malignancies 63 Acute Myeloid Leukemia and the Myelodysplastic Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . 1151 Jonathan E. Kolitz 64 Acute Lymphoblastic Leukemia . . . . . . . . . . . . . . . . . . . . . . . . 1173 Olatoyosi M. Odenike, Laura C. Michaelis, and Wendy Stock 65 Chronic Lymphocytic Leukemia and Related Chronic Leukemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1201 Thomas S. Lin and John C. Byrd 66 Chronic Myeloid Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . 1220 Meir Wetzler 67 An Evidence-Based Approach to the Management of Hodgkin’s Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1231 Craig H. Moskowitz 68 The Non-Hodgkin’s Lymphomas . . . . . . . . . . . . . . . . . . . . . . . 1247 Andrew D. Zelenetz and Steven Horwitz 69 Multiple Myeloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1276 Robert L. Schlossman

Section Seven Practice of Oncology 70 Superior Vena Cava Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . 1291 Michael S. Kent and Jeffrey L. Port 71 Central Nervous System Emergencies . . . . . . . . . . . . . . . . . . . 1299 Kevin P. McMullen, Edward G. Shaw, and Volker W. Stieber 72 Metabolic Emergencies in Oncology . . . . . . . . . . . . . . . . . . . . 1312 Daniel J. De Angelo 73 Surgical Emergencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1323 David A. August, Thomas Kearney, and Roderich E. Schwarz 74 Oral Complications of Cancer Therapy . . . . . . . . . . . . . . . . . . 1340 Mark S. Chambers and Adam S. Garden 75 Alopecia and Cutaneous Complications of Chemotherapy . . . . 1354 Faith M. Durden and Paradi Mirmirani

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contents

76 Infectious Complications of Cancer Therapy . . . . . . . . . . . . . . 1363 Safdar Nasia, Christopher J. Crnich, and Dennis G. Maki 77 Acute Toxicities of Therapy: Pulmonary Complications . . . . . 1401 Scott E. Evans and Andrew H. Limper 78 Cardiac Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1411 Maged I. Gharib and Alan K. Burnett 79 Neurologic Complications of Therapy . . . . . . . . . . . . . . . . . . . 1418 Kristin Bradley and H. Ian Robins 80 Acute Toxicities of Therapy: Urologic Complications . . . . . . . 1426 Sandy Srinivas 81 Issues in Vascular Access with Special Emphasis on the Cancer Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1434 Paul F. Mansfield and David L. Smith 82 Management of Cancer Pain . . . . . . . . . . . . . . . . . . . . . . . . . . 1446 Donald P. Lawrence, Leonidas C. Goudas, Andrew J. Lipman, Joseph Lau, Rina M. Bloch, and Daniel B. Carr 83 Nausea and Vomiting in the Cancer Patient . . . . . . . . . . . . . . 1473 Paula Gill, Axel Grothey, and Charles Loprinzi 84 Nutritional Support for the Cancer Patient . . . . . . . . . . . . . . . 1488 Lawrence E. Harrison 85 Paraneoplastic Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1506 Shirish M. Gadgeel and Antoinette J. Wozniak 86 Malignant Effusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1518 Shamus R. Carr and Joseph S. Friedberg 87 Evidence-Based Use of Hematopoietic Growth Factors for Optimal Supportive Care of Patients with Cancer . . . . . . . 1526 George D. Demetri 88 Management of the Bone Marrow Transplant Patient . . . . . . . 1536 Daniel J. Weisdorf and Marcie Tomblyn 89 Management of Anxiety and Depression in Adult Cancer Patients: Toward an Evidence-Based Approach . . . . . . . . . . . . . 1552 Paul B. Jacobsen, Kristine A. Donovan, Zoë N. Swaine, and Iryna S. Watson 90 Reproductive Complications and Sexual Dysfunction in the Cancer Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1580 Leslie R. Schover 91 The Care of the Terminal Patient . . . . . . . . . . . . . . . . . . . . . . 1601 Andrew Putnam

contents

xxi

92 Metastatic Cancer to the Central Nervous System . . . . . . . . . 1612 Douglas B. Einstein 93 Metastatic Cancer to Lung . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1626 Jessica S. Donington 94 Surgical and Regional Therapy for Liver Metastases . . . . . . . . . 1636 Kenneth K. Tanabe and Sam S. Yoon 95 Metastatic Cancer to Bone . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1655 Patrick J. Getty, Jeffrey L. Nielsen, Thomas Huff, Mark R. Robbin, and Beth A. Overmoyer 96 Cancer in the Immunosuppressed Patient . . . . . . . . . . . . . . . . 1680 Patrick Whelan and David T. Scadden 97 Cancer in the Older Population . . . . . . . . . . . . . . . . . . . . . . . . 1708 Karim S. Malek and Rebecca A. Silliman 98 Chemotherapy in Patients with Organ Dysfunction . . . . . . . . 1721 John L. Marshall, Jimmy Hwang, Shakun Malik, and Asim Amin 99 Management of the Pregnant Cancer Patient . . . . . . . . . . . . . . 1738 Deepjot Singh and Paula Silverman

Section Eight Cancer Survivorship 100 Survivorship Research: Past, Present, and Future . . . . . . . . . . . 1753 Julia H. Rowland 101 Late Effects of Cancer Treatments . . . . . . . . . . . . . . . . . . . . . . 1768 Noreen M. Aziz 102 Medical and Psychosocial Issues in Childhood Cancer Survivors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1791 Smita Bhatia, Wendy Landier, Jacqueline Casillas, and Lonnie Zeltzer 103 Medical and Psychosocial Issues in Hodgkin’s Disease Survivors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1804 Jon H. Loge and Stein Kaasa 104 Medical and Psychosocial Issues in Testicular Cancer Survivors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1815 Sophie D. Fosså, Lois B. Travis, and Alvin A. Dahl 105 Medical and Psychosocial Issues in Gynecologic Cancer Survivors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1828 Karen Basen-Engquist and Diane C. Bodurka 106 Medical, Psychosocial, and Health-Related Quality of Life Issues in Breast Cancer Survivors . . . . . . . . . . . . . . . . . . . . . . . 1836 Julie Lemieux, Louise J. Bordeleau, and Pamela J. Goodwin

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107 Medical and Psychosocial Issues in Prostate Cancer Survivors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1859 Tracey L. Krupski and Mark S. Litwin 108 Physical and Psychosocial Issues in Lung Cancer Survivors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1871 Linda Sarna, Frederic W. Grannis, Jr., and Anne Coscarelli 109 Cancer Survivorship Issues in Colorectal Cancer . . . . . . . . . . . 1891 Clifford Y. Ko and Patricia A. Ganz 110 Medical and Psychosocial Issues in Transplant Survivors . . . . 1902 Karen L. Syrjala, Paul Martin, Joachim Deeg, and Michael Boeckh 111 Second Malignancies After Radiation Treatment and Chemotherapy for Primary Cancers . . . . . . . . . . . . . . . . . . . . . 1929 Lydia B. Zablotska, Matthew J. Matasar, and Alfred I. Neugut 112 Psychosocial Rehabilitation in Cancer Care . . . . . . . . . . . . . . . 1942 Richard P. McQuellon and Suzanne C. Danhauer 113 Cancer Advocacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1955 Ellen L. Stovall Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1959

Contributors Alex A. Adjei, MD, PhD Professor, Department of Oncology, Mayo Clinic Foundation, Rochester, MN, USA. Manish Agrawal, MD Staff Scientist, Department of Clinical Bioethics, Warren G. Magnuson Clinical Center and Medical Oncology Research Unit, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Daniel M. Albert, MD, MS Chair Emeritus, F.A. David Professor, and Lorenz E. Zimmerman Professor, Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI, USA. Mark R. Albertini, MD Associate Professor, Department of Medicine, University of WisconsinMadison; Chief of Oncology, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA. Steven Alberts, MD, MPH Associate Professor, Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA. Sarah W. Alexander, MD Assistant Professor, Department of Pediatrics, Case Western University, Division of Pediatric Hematology and Oncology, Rainbow Babies and Children’s Hospital, Cleveland, OH, USA. Asim Amin, MD, PhD Immunotherapy Co-Director, Blumenthol Cancer Center, Carolinas Medical Center, Charlotte, NC, USA. Scott Antonia, MD, PhD Medical Director, Cellular Therapies Core, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, Tampa, FL, USA. Suzanne L. Aquino, MD Assistant Professor, Department of Radiology, Harvard Medical School/ Massachusetts General Hospital, Boston, MA, USA. Meri Armour, RN, MSN Senior Vice President, Ireland Cancer Center/University Hospitals of Cleveland, Cleveland, OH, USA. David A. August, MD Associate Professor, Department of Surgery; Chief, Division of Surgical Oncology, UMDNJ/Robert Wood Johnson Medical School and the Cancer Institute of New Jersey, New Brunswick, NJ, USA. Noreen M. Aziz, MD, PhD, MPH Senior Program Director, Office of Cancer Survivorship, Division of Cancer Control and Population Sciences, National Cancer Institute, Rockville, MD, USA. xxiii

xxiv

contributors

Giuseppe Barbanti-Brodano, MD Professor, Department of Experimental and Diagnostic Medicine, Section of Microbiology, University of Ferrara, Ferrara, Italy. J. Carl Barrett, PhD Director, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. Karen Basen-Engquist, PhD, MPH Associate Professor, Department of Behavioral Science, The University of Texas at M. D. Anderson Cancer Center, Houston, TX, USA. Wendie A. Berg, MD, PhD Breast Imaging Consultant, Study Chair, American College of Radiology Imaging Network, Lutherville, MD, USA. Smita Bhatia, MD, MPH Director, Epidemiology and Outcomes Research, Department of Pediatric Oncology, City of Hope Cancer Center, Duarte, CA, USA. Rina M. Bloch, MD Assistant Professor, Department of Rehabilitation Medicine, Tufts-New England Medical Center, Boston, MA, USA. David A. Bluemke, MD, PhD Associate Professor, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins Hospital, Baltimore, MD, USA. Diane C. Bodurka, MD Associate Professor, Department of Gynecological Oncology, The University of Texas at M. D. Anderson Cancer Center, Houston, TX, USA. Michael Boeckh, MD Assistant Member, Program in Infectious Diseases, Fred Hutchinson Cancer Research Center; Assistant Professor of Medicine, University of Washington School of Medicine, Seattle, WA, USA. Jeffrey P. Bond, PhD Research Associate Professor, Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT, USA. Melissa L. Bondy, PhD Professor, Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. Louise J. Bordeleau, MD, FRCP(C), MSc Attending, Department of Medical Oncology, Mount Sinai Hospital, Toronto, Ontario, Canada. Kristin Bradley, MD Assistant Professor of Human Oncology, University of Wisconsin, Madison, WI, USA. Paul D. Brown, MD Assistant Professor, Division of Radiation Oncology, Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA. John Bryant, PhD Professor, Associate Director, Departments of Biostatistics, National Surgical Adjuvant Breast and Bowel Project Biostatistical Center, Pittsburgh, PA, USA.

contributors

xxv

Julia W. Buchanan, BS Associate in Research, Russell H. Morgan Department of Radiology and Radiological Science, Division of Nuclear Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Jan C. Buckner, MD Chair, Division of Medical Oncology, Professor of Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA. Susan V. Bukata, MD Assistant Professor, Department of Orthopedics, University of Rochester Medical Center/Strong Memorial Hospital, Rochester, NY, USA. Alan K. Burnett, MD, FRCPath, FRCP(Glasgow), FRCP(Edinburgh), FRCP(London), FMSci Professor, Department of Haematology, University of Wales College of Medicine, Cardiff, Wales, UK. John C. Byrd, MD Associate Professor, Department of Internal Medicine, Division of Hematology and Oncology, The Ohio State University, The Arthur James Comprehensive Cancer Center, Columbus, OH, USA. Michele Carbone, MD, PhD Associate Professor, Department of Pathology, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL, USA. Daniel B. Carr, MD, DABPM, FFPMANZCA(Hon) Saltonstall Professor of Pain Research, Department of Anesthesia; Medical Director, Pain Management Program, Tufts-New England Medical Center, Boston, MA, USA. Shamus R. Carr, MD Surgical Resident, Department of Surgery, Thomas Jefferson University, Philadelphia, PA, USA. Jacqueline Casillas, MD, MSHS Assistant Professor, Department of Pediatrics, Division of Hematology/ Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Barrie Cassileth, PhD Chief, Integrative Medicine Service; Laurance S. Rockefeller Chair in Integrative Medicine, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Mark S. Chambers, DMD Associate Professor, Head & Neck Surgery; Deputy Chief, Section of Oncologic Dentistry and Prosthodontics, M. D. Anderson Cancer Center, Houston, TX, USA. Alfred E. Chang, MD Hugh Cabot Professor of Surgery; Chief, Division of Surgery Oncology; Department of Surgery, University of Michigan, Ann Arbor, MI, USA. Shine Chang, PhD Associate Director, Office of Preventive Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

xxvi

contributors

Daniel N. Chatzifotiadis, MD Post Doctoral Research Fellow, Department of Radiology, Division of Nuclear Medicine, The Johns Hopkins Medical Institute, Baltimore, MD, USA. Caroline Chiles, MD Professor, Department of Radiology, Wake Forest University School of Medicine, Winston-Salem, NC, USA. Hak Choy, MD Nancy B. and Jake L. Hamon Distinguished Chair in Therapeutic Oncology Research, Professor and Chairman, Department of Radiation Oncology, Moncrief Radiation Oncology Center, University of Texas, Southwestern Medical Branch, Dallas, TX, USA. Sue Chua, MBBS, FRACP Senior Clinical Research Fellow, Breast Unit, Department of Medicine, Royal Marsden Hospital, Chelsea, London, UK. Joseph I. Clark, MD Associate Professor, Department of Medicine, Loyola University Chicago, Maywood, IL, USA. Ezra E.W. Cohen, MD Assistant Professor, Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA. Anne Coscarelli, PhD Research Psychologist, Department of Public Health; Director, Ted Mann Family Resource Center, UCLA/David Geffen School of Medicine, Los Angeles, CA, USA. Christopher J. Crnich, MD, MS Research Fellow, Section of Infectious Diseases, Department of Medicine, University of Wisconsin, Madison, WI, USA. Alvin A. Dahl, MD, PhD Professor, Department of Clinical Cancer Research, National HospitalRadium Hospital, Oslo, Norway. Mary B. Daly, MD, PhD Director, Cancer Prevention and Control Program, Department of Population Science, Fox Chase Cancer Center, Philadelphia, PA, USA. Suzanne C. Danhauer, PhD Assistant Professor and Associate Director, Psychosocial Oncology & Cancer Patient Support Programs, Department of Internal Medicine, Wake Forest University Baptist Medical Center, Winston-Salem, NC, USA. Sarah Dash, MPH Cancer Research Training Fellow, Applied Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA. Daniel J. De Angelo, MD, PhD Assistant Professor, Department of Medicine, Harvard Medical School; Adult Leukemia Program, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston, MA, USA.

contributors

xxvii

James A. DeCaprio, MD Associate Professor, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Joachim Deeg, MD Member, Clinical Research Division, Fred Hutchinson Cancer Research Center; Professor of Medicine, University of Washington School of Medicine, Seattle, WA, USA. George D. Demetri, MD Clinical Director, Sarcoma Program, Dana-Farber Cancer Institute; Associate Professor, Department of Medicine, Harvard Medical School, Boston, MA, USA. Sophie Dessureault, MD, PhD Staff, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, Tampa, FL, USA. Emily DeVoto, PhD, MSPH Health Science Policy Analyst, Office of Medical Applications of Research, National Institutes of Health, Bethesda, MD, USA. Kathleen M. Diehl, MD Assistant Professor, Division of Surgical Oncology, Department of Surgery, University of Michigan, Ann Arbor, MI, USA. James J. Dignam, PhD Assistant Professor, Department of Health Studies, University of Chicago and University of Chicago Cancer Research Center, Chicago, IL, USA. Gerard M. Doherty, MD Norman W. Thompson Professor; Section Head, General Surgery; Chief, Division of Endocrine Surgery; Director, Department of Surgery, University of Michigan Health System, Ann Arbor, MI, USA. Jessica S. Donington, MD Assistant Professor, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA. John H. Donohue, MD Consultant in Surgery, Department of General Surgery, Mayo Clinic; Professor of Surgery, Mayo Graduate School of Medicine, Rochester, MN, USA. Kristine A. Donovan, PhD, MBA Assistant Professor, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, FL, USA. Afshin Dowlati, MD Assistant Professor, Department of Medicine, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, OH, USA. Faith M. Durden, MD Assistant Professor, Department of Dermatology, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, OH, USA. Grace K. Dy, MD Fellow, Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA.

xxviii

contributors

Douglas B. Einstein, MD, PhD Assistant Professor, Department of Radiation Oncology, Case Western Reserve University, Cleveland, OH, USA. Ezekiel J. Emanuel, MD, PhD Chair, Department of Clinical Bioethics, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD, USA. Cathy Eng, MD Assistant Professor, Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. Brad J. Erickson, MD Associate Professor, Department of Radiology, Mayo Clinic Foundation, Rochester, MN, USA. Scott E. Evans, MD Instructor, Department of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Mayo Clinic Foundation, Rochester, MN, USA. Marni Feldmann, MD Resident, Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI, USA. Elliot K. Fishman, MD Professor, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Gini F. Fleming, MD Associate Professor, Department of Medicine, University of Chicago, Chicago, IL, USA. Michele R. Forman, PhD Senior Investigator, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA Sophie D. Fosså, PhD Professor, Department of Long-term Studies, National Hospital-Radium Hospital, University of Oslo, Oslo, Norway. Joseph S. Friedberg, MD Chief, Division of Thoracic Surgery, Department of Surgery, Thomas Jefferson University, Philadelphia, PA, USA. Shirish M. Gadgeel, MD Assistant Professor, Department of Internal Medicine, Division of Hematology & Oncology, Karmanos Cancer Institute/Wayne State University, Detroit, MI, USA. Evanthia Galanis, MD Associate Professor, Division of Medical Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA. Patricia A. Ganz, MD American Cancer Society Clinical Research Professor; Director, Division of Cancer Prevention and Control Research, Jonsson Comprehensive Cancer Center at UCLA, Professor, Schools of Public Health and Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

contributors

xxix

Adam S. Garden, MD Professor, Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. Patrick J. Getty, MD Assistant Professor, Department of Orthopaedic Surgery, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH, USA. Maged I. Gharib, MSc, MD, MRCP, MRCPath Attending, Department of Haematology, Royal Manchester Children’s Hospital, Manchester, UK. Caterina Giannini, MD Consultant, Department of Anatomic Pathology, Mayo Clinic Foundation, Rochester, MN, USA. Paula Gill, MD Fellow, Department of Oncology, Mayo Clinic Foundation, Rochester, MN, USA. Montgomery Gillard, MD Lecturer, Department of Dermatology, University of Michigan, Ann Arbor, MI, USA. Timothy Gilligan, MD Instructor in Medicine, Department of Medical Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA. Pamela J. Goodwin, MD, MSc, FBPC Professor, Department of Medicine, University of Toronto; Senior Scientist, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. Gregory J. Gores, MD Professor, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA. Leonidas C. Goudas, MD, PhD Assistant Professor, Department of Anesthesiology, Tufts-New England Medical Center, Boston, MA, USA. Annette Grambihler, MD Staff, First Department of Internal Medicine, University of Mainz, Mainz, Germany. Frederic W. Grannis, Jr., MD Assistant Professor, Department of Thoracic Surgery, City of Hope National Medical Center, Duarte, CA, USA. F. Anthony Greco, MD Medical Director, Sarah Cannon Cancer Center, Nashville, TN, USA. Axel Grothey, MD Mayo Foundation Scholar, Division of Medical Oncology, Mayo Clinic Foundation, Rochester, MN, USA.

xxx

contributors

Steven Hahn, MD Attending, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA. John D. Hainsworth, MD Director of Clinical Research, Sarah Cannon Cancer Center, Nashville, TN, USA. Dima A. Hammoud, MD Assistant Professor, Department of Diagnostic Radiology, Division of Neuroradiology, The Johns Hopkins University, Baltimore, MD, USA. Lindsay A. Hampson, BS Fellow, Department of Clinical Bioethics, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD, USA. Paul M. Harari, MD Associate Professor, Department of Human Oncology, University of Wisconsin Comprehensive Cancer Center, Madison, WI, USA. Russell Harris, MD, MPH Professor, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA. Lawrence E. Harrison, MD Associate Professor, Chief, Division of Surgical Oncology, UMDNJ-New Jersey Medical School, Newark, NJ, USA. Daniel F. Hayes, MD Clinical Director, Breast Oncology Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA. Craig Hofmeister, MD Fellow, Division of Hematology-Oncology, Loyola University Chicago, Cardinal Bernadin Cancer Center, Maywood, IL, USA. Brent Hollenbeck, MD Lecturer, Department of Urology, University of Michigan, Ann Arbor, MI, USA. Steven M. Horwitz, MD Clinical Assistant Physician, Lymphoma Services, Department of Hematology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Thomas Huff, MD Staff, Department of Orthopaedic Surgery, Case Western Reserve University, Cleveland, OH, USA. Scott A. Hundahl, MD, FACS, FSSO, FAHNS Professor, Department of Clinical Surgery, U.C. Davis; Chief of Surgery, VA Northern California Health Care System, Sacramento VA at Mather, Mather, CA, USA. Stephen D. Hursting, PhD, MPH Deputy Director, Office of Preventive Oncology, National Cancer Institute, Bethesda, MD, USA. Jimmy Hwang, MD Attending, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA. Paul B. Jacobsen, PhD Professor and Program Leader, Health Outcomes and Behavioral Program, Department of Psychosocial and Palliative Care Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

contributors

xxxi

Timothy M. Johnson, MD Professor, Departments of Dermatology, Otolaryngology, and Surgery, University of Michigan Medical School, University of Michigan, Ann Arbor, MI, USA. Stephen R.D. Johnston, MA, PhD, FRCP Consultant Medical Oncologist, Department of Medicine—Breast Unit, Royal Marsden Hospital, London, UK. Stein Kaasa, MD, PhD Professor, Department of Cancer Research and Molecular Medicine, Faculty of Medicine, The Norwegian University of Science and Technology and the Palliative Care Unit, St. Olavs Hospital, Trondheim, Norway. Ihab R. Kamel, MD, PhD Assistant Professor, The Russell H. Morgan Department of Radiology and Radiological Sciences, The Johns Hopkins Hospital, Baltimore, MD, USA. Phillip W. Kantoff, MD, PhD Professor, Department of Medicine; Chief, Division of Solid Tumor Oncology; Director, Lank Center for Genitourinary Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA. Theodore G. Karrison, PhD Research Associate, Associate Professor, Department of Health Studies, University of Chicago and University of Chicago Cancer Research Center, Chicago, IL, USA. Satomi Kawamoto, MD Assistant Professor, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins Hospital, Baltimore, MD, USA. Thomas Kearney, MD, FACS Associate Professor, Department of Surgery, UMDNJ/Robert Wood Johnson Medical School; The Cancer Institute of New Jersey, New Brunswick, NJ, USA. Vicki Keedy, MD Fellow, Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, USA. Michael L. Kendrick, MD Assistant Professor, Department of Surgery, Mayo Clinic College of Medicine, Rochester, MN, USA. Michael S. Kent, MD Staff, Department of Cardiothoracic Surgery, Weill-Cornell Medical Center, New York, NY, USA. James Khatcheressian, MD Assistant Professor, Department of Internal Medicine, Division of Hematology/Oncology, Virginia Commonwealth University Health System, Richmond, VA, USA. Timothy J. Kinsella, MD Vincent K. Smith Professor and Chairman, Department of Radiation Oncology, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH, USA.

xxxii

contributors

Linda S. Kinsinger, MD, MPH Assistant Director, VA National Center for Health Promotion and Disease Prevention, Durham, NC, USA. Clifford Y. Ko, MD Associate Professor, Department of Surgery, UCLA School of Medicine/West Los Angeles VA Medical Center, Los Angeles, CA, USA. Jonathan E. Kolitz, MD Director, Leukemia Service, Department of Medicine, North Shore University Hospital, New York University School of Medicine, Manhasset, NY, USA. Barnett S. Kramer, MD, MPH Associate Director for Disease Prevention, Office of Disease Prevention, National Institutes of Health, Bethesda, MD, USA. Alexander S. Krupnick, MD Fellow, Department of Surgery, Division of Cardiothoracic Surgery, Washington University, St Louis, MO, USA. Tracey L. Krupski, MD Resident, Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. Amit Kumar, MD Resident, Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI, USA. Dan Laheru, MD Assistant Professor, Department of Medical Oncology, The Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins, Baltimore, MD, USA. Wendy Landier, RN, MSN, CPNP Pediatric Nurse Practitioner, Division of Pediatrics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA. Joseph Lau, MD Professor, Department of Medicine, Institute for Clinical Research and Health Policy Studies, Tufts-New England Medical Center, Boston, MA, USA. Donald P. Lawrence, MD Assistant Professor, Division of Hematology-Oncology, Tufts-New England Medical Center, Boston, MA, USA. Cheryl T. Lee, MD Assistant Professor, Department of Urology, The University of Michigan, Ann Arbor, MI, USA. Julie Lemieux, MD Attending, Department of Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada. Nathan Levitan, MD, MBA Professor, Department of Medicine, Ireland Cancer Center/University Hospitals of Cleveland, Cleveland, OH, USA.

contributors

xxxiii

Andrew H. Limper, MD Professor of Medicine, Biochemistry, and Molecular Biology, Department of Pulmonary & Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA. Thomas S. Lin, MD, PhD Assistant Professor, Department of Internal Medicine, Division of Hematology and Oncology, The Ohio State University, Columbus, OH, USA. Andrew J. Lipman, MD Clinical and Research Fellow, Division of Hematology-Oncology, Tufts-New England Medical Center, Boston, MA, USA. Mark S. Litwin, MD, MPH Professor, Department of Urology and Health Services, David Geffen School of Medicine, School of Public Health, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA. Jon Håvard Loge, MD, PhD Professor, Department of Behavioural Sciences in Medicine, University of Oslo and the Centre for Palliative Medicine, Ulleval University Hospital, Oslo, Norway. B. Jack Longley, MD Professor, Department of Dermatology, University of Wisconsin-Hospital and Clinics, Madison, WI, USA. Charles Loprinzi MD Professor, Division of Medical Oncology, Mayo Clinic Foundation, Rochester, MN, USA. John R. Lurain, MD John & Ruth Brewer Professor of Gynecology and Cancer Research, Department of Obstetrics and Gynecology; Director, John I. Brewer Trophoblastic Disease Center; Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Scott D. Luria, MD Associate Professor, Department of Medicine, University of Vermont, Burlington, VT, USA. John S. Macdonald, MD Professor, Department of Medicine, New York Medical College; Medical Director, St. Vincent’s Comprehensive Cancer Center, New York, NY, USA. Cormac O. Maher, MD Chief Resident Associate, Department of Neurosurgery, Mayo Clinic College of Medicine, Rochester, MN, USA. Dennis G. Maki, MD Chief, Section of Infectious Diseases, Department of Medicine, University of Wisconsin Medical School, Madison, WI, USA. Karim S. Malek, MD Assistant Professor, Department of Medicine, Section of Hematology and Oncology, Boston University School of Medicine, Boston, MA, USA.

xxxiv

contributors

Shakun Malik, MD Chief, Center for Thoracic Medical Oncology, Director, Multidisciplinary Thoracic Oncology, Associate Professor, Division of Hematology/Oncology, Department of Medicine and Lombardi Cancer Center, Georgetown University Hospital, Washington, DC, USA. Paul F. Mansfield, MD, FACS Professor, Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. John L. Marshall, MD Associate Professor, Lombardi Cancer Center, Georgetown University, Washington, DC, USA. Paul Martin, MD Member, Clinical Research Division, Fred Hutchinson Cancer Research Center; Professor, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA. Matthew J. Matasar, MD Instructor, Department of Medicine, Columbia University Medical Center, New York, NY, USA. Kevin McDonnell, MD, PhD Fellow, Lombardi Cancer Center, Georgetown University, Washington, DC, USA. Kevin P. McMullen, MD Assistant Professor, Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA. Richard P. McQuellon, PhD Associate Professor and Director, Psychosocial Oncology & Cancer Patient Support Programs, Wake Forest University Health Sciences, Winston-Salem, NC, USA. Fredric B. Meyer, MD Professor, Department of Neurosurgery, Mayo Clinic College of Medicine, Rochester, MN, USA. Laura C. Michaelis, MD Fellow, Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA. Michael Milano, MD Chief Resident, Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA. Paradi Mirmirani, MD Assistant Professor, Department of Dermatology, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, OH, USA. Anthony C. Montag, MD Associate Professor, Department of Pathology, University of Chicago Hospital, Chicago, IL, USA. Craig H. Moskowitz, MD Associate Professor, Department of Medicine, Lymphoma Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

contributors

xxxv

Brooke T. Mossman Professor, Department of Pathology, College of Medicine, University of Vermont, Burlington, VT, USA. Kambiz Motamedi, MD Assistant Professor, Department of Radiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Arno J. Mundt, MD Associate Professor, Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA. David M. Nagorney, MD Professor, Department of Surgery, Mayo Clinic College of Medicine, Rochester, MN, USA. Alfred I. Neugut, MD, PhD Professor, Department of Epidemiology, Mailman School of Public Health; Department of Medicine, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA. Lisa A. Newman, MD, MPH Associate Professor, Division of Surgical Oncology; Director, Breast Care Center, University of Michigan, Ann Arbor, MI, USA. Jeffrey L. Nielsen, MD Chief Resident, Department of Radiology, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, OH, USA. Jeffrey A. Norton, MD Professor, Department of Surgery, Division of General Surgery, Stanford University Medical Center, Stanford, CA, USA. Nomeli P. Nunez, PhD, MPH Cancer Prevention Fellow, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. Olatoyosi M. Odenike, MD Assistant Professor, Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA. Beth A. Overmoyer, MD, FACP Assistant Professor, Department of Medicine, Case Western Reserve University, Cleveland, OH, USA. Harpreet K. Pannu, MD Consultant, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins Hospital, Baltimore, MD, USA. Harvey I. Pass, MD Professor and Chief of Thoracic Surgery, Department of Cardiothoracic Surgery; Head, Thoracic Oncology, New York University School of Medicine and Comprehensive Cancer Center, New York, NY, USA. Martin G. Pomper, MD, PhD Associate Professor, Department of Diagnostic Radiology, Division of Neuroradiology, The Johns Hopkins University, Baltimore, MD, USA.

xxxvi

contributors

Jeffrey L. Port, MD Assistant Professor, Department of Cardiothoracic Surgery, Weill-Cornell Medical Center/New York Presbyterian Hospital, New York, NY, USA. Heather Potter, MD Resident, Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI, USA. Andrew Putnam, MD Assistant Professor, Departments of Medicine and Oncology, Georgetown University, Washington, DC, USA. M. Ramos-Nino, PhD Research Assistant Professor, Department of Pathology, College of Medicine, University of Vermont, Burlington, VT, USA. Ravi D. Rao, MBBS Senior Associate Consultant, Division of Medical Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA. Douglas Reintgen, MD Director, Department of Surgery, Lakeland Regional Cancer Center, Lakeland, FL, USA. Mark R. Robbin, MD Chief, Musculoskeletal and Emergency Radiology; Assistant Professor of Radiology, Department of Radiology, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH, USA. H. Ian Robins, MD, PhD Professor, Department of Medicine, Human Oncology, and Neurology, University of Wisconsin, Madison, WI, USA. Rafael Rosell, MD Chief, Medical Oncology Service, Associate Professor, University of Barcelona; Scientific Director of Oncology Research, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Barcelona, Spain. Randy N. Rosier, MD, PhD Professor and Chairman, Department of Orthopaedics, The University of Rochester Medical Center/Strong Memorial Hospital, Rochester, NY, USA. Julia H. Rowland, PhD Director, Office of Cancer Survivorship, Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA. Michael S. Sabel, MD Assistant Professor, Division of Surgical Oncology, Department of Surgery, University of Michigan, Ann Arbor, MI, USA. T. Sabo-Attwood, PhD Fellow, Department of Pathology, College of Medicine, University of Vermont, Burlington, VT, USA. Nasia Safdar, MD, MS Clinical Instructor, Section of Infectious Diseases, Department of Medicine, University of Wisconsin Medical School, Madison, WI, USA.

contributors

xxxvii

Linda Sarna, RN, DNSc, FAAN Professor, School of Nursing, University of California, Los Angeles, Los Angeles, CA, USA. David T. Scadden, MD Professor, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Julian C. Schink, MD Chief, Division of Gynecologic Oncology; Professor of Obstetrics and Gynecology, Northwestern University Medical School, Chicago, IL, USA. Robert L. Schlossman Dana-Farber Cancer Institute, Boston, MA, USA. Leslie R. Schover, PhD Professor, Department of Behavioral Science, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. Roderich E. Schwarz, MD, PhD Director, Pancreatic Cancer Program, Department of Surgery, UMDNJRobert Wood Johnson Medical School; The Cancer Institute of New Jersey, New Brunswick, NJ, USA. Christopher N. Sciamanna, MD, MPH Assistant Professor, Department of Community Health/Psychiatry, Brown University, Providence, RI, USA. Leanne L. Seeger, MD, FACR Professor and Chief, Musculoskeletal Imaging, Department of Radiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Edward G. Shaw, MD Professor and Chair, Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA. Joseph B. Shrager, MD Associate Professor, Department of Surgery; Chief, Section of General Thoracic Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA. Rebecca A. Silliman, MD, PhD Professor, Department of Medicine and Public Health; Chief, Section of Geriatrics, Boston University School of Medicine, Boston Medical Center, Boston, MA, USA. Paula Silverman, MD Associate Professor, Clinical Program Director, Division of Hematology/ Oncology, University Hospitals of Cleveland, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.

xxxviii

contributors

Deepjot Singh, MD Assistant Professor, Division of Hematology/Oncology, University Hospitals of Cleveland, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA. Jeffrey R. Skaar Graduate Student, Department of Medical Oncology, Harvard University, Dana-Farber Cancer Institute, Boston, MA, USA. John M. Skibber, MD Professor, Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. Stephen R. Smalley, MD Director, Department of Radiation Oncology, Olathe Medical Center, Olathe, KS, USA. David L. Smith, MD Chief, Department of Surgery, Wilford Hall Medical Center, Lackland AFB, TX, USA. Thomas J. Smith, MD Professor and Chairman, Department of Internal Medicine, Division of Hematology/Oncology, Virginia Commonwealth University Health System, Richmond, VA, USA. Jason Sohn, PhD, DABR Associate Professor, Associate Director of Medical Physics and Dosimetry, Department of Radiation Oncology, Division of Medical Physics and Dosimetry, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH, USA. Robert J. Soiffer, MD Chief, Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Associate Professor of Medicine, Harvard Medical School, Boston, MA, USA. Vernon K. Sondak, MD Professor, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. Yukio Sonoda, MD Assistant Attending Surgeon, Department of Surgery, Gynecology/Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Jeffrey A. Sosman, MD Professor, Division of Hematology/Oncology, Vanderbilt University Medical Center; Medical Director; Clinical Trials Office; Co-Leader, Signal Transduction and Cell Proliferation Program, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. David Spriggs, MD Head, Division of Solid Tumor Oncology, Winthrop Rockefeller Chair of Medical Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Sandy Srinivas, MD Assistant Professor, Department of Medicine, Stanford University, PaloAlto, CA, USA.

contributors

xxxix

Kerstin M. Stenson, MD, FACS Associate Professor, Department of Surgery, Section of Otolaryngology-Head & Neck Surgery, Department of Surgery, University of Chicago, Chicago, IL, USA. Volker W. Stieber, MD Assistant Professor, Co-Director, Gamma Knife Unit, Department of Radiation Oncology, Comprehensive Cancer Center, Wake Forest University, Winston-Salem, NC, USA. Wendy Stock, MD Associate Professor, Department of Medicine, Section of Hematology/ Oncology; Director, Leukemia Program, University of Chicago, Chicago, IL, USA. Ellen L. Stovall President and CEO, National Coalition for Cancer Survivorship, Silver Spring, MD, USA. Crawford J. Strunk, MD Fellow, Department of Pediatric Hematology-Oncology, Case Western University, Division of Pediatric Hematology and Oncology, Rainbow Babies and Children’s Hospital, Cleveland, OH, USA. Zoë N. Swaine, Bsc (Hons) Graduate Student, Department of Clinical and Health Psychology, University of Florida, College of Public Health and Health Professions, Gainesville, FL, USA. Charles Swanton, MRCP, PhD CR-UK Clinician Scientist, Department of Medicine, Royal Marsden Hospital, London, UK. Karen L. Syrjala, PhD Associate Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Associate Professor of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA. Kenneth K. Tanabe, MD Associate Professor, Chief, Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. Stephen H. Taplin, MD, MPH Senior Scientist, Applied Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Rockville, MD, USA. Marcie Tomblyn, MD Assistant Professor, Department of Medicine/Hematology, Oncology, and Transplant, University of Minnesota, Minneapolis, MN, USA. Lois B. Travis Senior Investigator, National Institutes of Health, Department of Health and Human Services, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. Anne Traynor, MD Assistant Professor, Section of Medical Oncology, University of Wisconsin Comprehensive Cancer Center, University of Wisconsin Medical School, Madison, WI, USA.

xl

contributors

Timothy J. Triche, MD, PhD Professor, Department of Pathology & Pediatrics; Chair, Department of Pathology and Laboratory Medicine, Childrens’ Hospital Los Angeles; Vice Chair, Pathology, Keck School of Medicine at USC, Los Angeles, CA, USA. Peter A. Ubel, MD Director, Program for Improving Health Care Decisions, Department of General Medicine, University of Michigan, Ann Arbor, MI, USA. Asad Umar, DVM, PhD Program Director, Gastrointestinal and Other Cancers Research Group, National Cancer Institute, Rockville, MD, USA. John D. Urschel, MD, MA, FRCSC Lecturer, Department of Surgery, McMaster University, Hamilton, Ontario, Canada. David J. Vaughn, MD Associate Professor, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Andrew J. Vickers, PhD Staff, Integrative Medicine Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Nicholas Vogelzang, MD Professor, Department of Medicine, University of Nevada School of Medicine; Director, Nevada Cancer Institute, Las Vegas, NV, USA. Everett E. Vokes, MD Director, Section of Hematology/Oncology, John E. Ultmann Professor of Medicine and Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA. Richard L. Wahl, MD Director, Nuclear Medicine/PET, Russell H. Morgan Department of Radiology and Radiological Sciences, The Johns Hopkins School of Medicine, Baltimore, MD, USA. Timothy S. Wang, MD Assistant Professor, Department of Dermatology, University of Michigan, Ann Arbor, MI, USA. Iryna S. Watson, BA Research Study Coordinator, Department of Psychosocial and Palliative Care, H. Lee Moffitt Research Center, Tampa, FL, USA. Jeffrey Weber, MD, PhD Chief, Division of Medical Oncology, Department of Medicine, USC/Norris Cancer Center, Los Angeles, CA, USA. Daniel J. Weisdorf, MD Professor, Director, Adult Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN, USA. Anton Wellstein, MD, PhD Professor, Lombardi Cancer Center, Georgetown University, Washington, DC, USA.

contributors

xli

Barry Wessels, PhD Professor and Director, Department of Radiation Oncology, Division of Medical Physics and Dosimetry, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH, USA. Meir Wetzler, MD Associate Professor, Department of Medicine, Leukemia Section, Roswell Park Cancer Institute, Buffalo, NY, USA. Patrick Whelan, MD, PhD Instructor in Pediatrics, Harvard Medical School, Boston, MA, USA. Richard Whittington, MD Professor, Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA. T. Christopher Windham, MD Assistant Professor, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. David P. Wood, Jr., MD Professor and Chief of Urologic Oncology, Department of Urology, University of Michigan, Ann Arbor, MI, USA. Antoinette J. Wozniak, MD Professor, Department of Internal Medicine/Division of Hematology/ Oncology, Karmanos Cancer Institute/Wayne State University, Detroit, MI, USA. S.D. Yamada, MD Assistant Professor, Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, IL, USA. Sam S. Yoon, MD Assistant Professor, Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, MA, USA. Lydia B. Zablotska, MD, PhD Assistant Professor, Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA. Jane Zapka, ScD Professor, Department of Biometry and Epidemiology, Medical University of South Carolina, Charleston, SC, USA. Andrew D. Zelenetz, MD, PhD Chief, Lymphoma Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Paula Zeller, MA Communications Consultant, Olney, MD, USA. Lonnie Zeltzer, MD Professor, Departments of Pediatrics, Anesthesiology, Psychiatry and Biobehavioral Sciences; Director, Pediatric Pain Program, David Geffen School of Medicine at UCLA; Associate Director, Patients and Survivors Program, Division of Cancer Prevention and Control Research; UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.

SECTION ONE

Principles of Oncology

1

Evidence-Based Approach to Oncology Emily DeVoto and Barnett S. Kramer*

I

n the early years of the 21st century, clinicians and medical researchers often use the term evidence-based medicine. Cancer prevention, screening, diagnosis, and therapy, we hear, must be based on the best evidence to provide the best care. But is this approach new? And if it is, what have we been doing until now? In this chapter, we hope to provide perspectives on this question, by examining what evidence-based medicine (EBM)—oncology, in particular—is and is not, and by looking at the history of clinical inquiry, up to and including current research. We also hope to provide readers with a theoretical framework that will be useful in placing the results of new research into the context of existing knowledge, with the ultimate goal of improving clinical practice. The principles of EBM were delineated by a working group in Canada (led by Gordon Guyatt of McMaster University) and published in JAMA in 1992.1 According to Sackett and colleagues, some of the earliest promoters of the principles of the concept, EBM is “the integration of best research evidence with clinical expertise and patient values.”2 Thus, EBM is not cookbook practice performed by technicians without regard to experience, training, or independent clinical judgment. The practice of EBM has occurred with the recognition that upto-date, scientifically valid medical information is needed on a regular basis; that traditional sources of information (such as textbooks, expert opinion, and the flood of new research) are either unreliable or overwhelming; and that patient and other demands limit clinicians’ time available for keeping skills current and for identifying the most relevant information. In response, medicine has developed strategies and information systems for tracking down useful information quickly and mechanisms for stringent, systematic review and evaluation of clinical research.2 The purpose of textbooks such as this, and other forums for EBM, is to empower practicing clinicians with the skills to evaluate the literature, to identify relevant clinical guidelines and recommendations, and to understand the study design factors that affect the quality of medical evidence, in support of sound clinical decision making. Sackett and colleagues propose the following five steps for clinicians in making evidence-based decisions: “(1) Converting the need for information into an answerable question; (2) *The opinions expressed in this manuscript are those of the authors and do not represent official opinions or positions of the National Institutes of Health, the Department of Health and Human Services, or the federal government.

Tracking down the best evidence to answer the question; (3) Critically evaluating that evidence; (4) Integrating the critical evaluation with clinical expertise and knowledge of the patient; (5) Evaluating our effectiveness and efficiency in steps 1 to 4 and seeking ways to improve both for next time.”2 Later in this chapter, we elaborate on these steps to provide a practical framework for clinical decision making. First, however, we attempt to place the development of the concept of medical evidence in a historical context, focusing on aspects of research that point to quality of evidence.

The History of Evidence in Medicine Francois Joseph Victor Broussais (1772–1838) was a professor of General Pathology at Paris and one of the leading physicians in France. His central theoretical model of disease physiology was that vital processes depended on external stimuli, especially heat; these stimuli produced chemical changes, which modified normal tissue function. He conceived that if the stimuli are in balance, one is healthy, but if they are too weak or too strong, disease results. All disease is local, he held, but is transmitted to other organs by sympathy or via the gastrointestinal mucosa; he believed gastroenteritis was the basis of all pathology (Table 1.1). P.C.A. Louis (1787–1872), a French contemporary of Broussais, agreed with Broussais that objective observation is central to medicine, but in their methods of observation and the conclusions they drew, their views diverged greatly, and this is why Louis has the more-lasting legacy in the annals of medicine. Louis devoted himself to the observation of inflammatory diseases such as typhoid fever and pneumonia. Until his time, bloodletting (using leeches) was the unchallenged treatment for inflammatory disease. Louis and a few contemporaries were the first to question explicitly whether full-force application of leeches was appropriate under all circumstances, and Louis was the first to test the hypothesis. To address this question, Louis examined the medical records of 79 pneumonia patients in his practice and analyzed their disease duration and mortality experience with respect to the time of their first bleeding relative to the course of the disease. He also took into account the number of bleedings and the subjects’ ages. Of note, he started the investigation with a belief that bloodletting was effective. The finding of the study, that the beneficial effect of bloodletting was “much less than has been commonly believed,” probably contributed to the demise of bloodletting as a widespread practice.3

3

4

chapter

1

TABLE 1.1. Historical landmarks in the development of evidence-based medicine. 1747

• First use of comparison groups in a clinical experiment

1828

• First application of mathematical analysis to test a hypothesis • Introduction of concept of confounding (i.e., patients’ response may vary for reasons other than treatment) • First systematic use of statistics in medicine • Development of systematic data collection • Calculation of rates of morbidity and mortality, based on hospital intake and discharge data • Development of statistical methods: accounting for the role of chance in scientific studies • Development of experimental study design • First randomized clinical trial (RCT)

1853–1856

1920s–1930s

1948

1970s

1992

• U.S. 6th Circuit Court of Appeals grants RCTs status as a standard of evidence in the regulatory authority of the Food and Drug Administration • Principles of evidence-based medicine delineated and published

Louis was well ahead of his time in his use of standardized data collection and in his framing of research questions, but perhaps more importantly to the history of evidencebased medicine, Louis clearly recognized the limitations of his work. He wrote of the possibility that alternative, unmeasured factors (besides bloodletting) could explain his findings. He understood that his patients may have differed for reasons unrelated to treatment and that these differences might have had a more important influence on their outcomes than the treatment itself.3 That is, Louis questioned the cause-andeffect relationship between bloodletting and increased survival, whether or not he articulated it as such. The first historic example of the use of comparison control groups in clinical investigation comes from the wellknown story of James Lind, an 18th-century British physician (1716–1794) who addressed the issue of scurvy in the British Navy. The value of fresh fruit in treating and preventing scurvy had been suggested by an earlier scholar, but Lind was the first to apply an experimental design to the investigation of this hypothesis. In 1747, he selected 12 patients/seamen on board a navy vessel, as he said, “as similar as I could have them,” and then assigned 2 each to various treatments, one of which was to eat two oranges and one lemon per day (others were given cider or seawater). He found, of course, that the 2 who received the citrus fruits recovered the best, with those taking cider recovering next best. Although not a randomized design (he stated that “two of the worst” received the course of seawater), Lind at least attempted to start with a homogeneous group, reflecting his intent to reduce the

James Lind: experiments to treat scurvy in British sailors P.C.A. Louis: observations of the effect of timing of bloodletting on pneumonia outcomes

Florence Nightingale presented data on mortality in field hospitals during Crimean War, leading to fundamental changes in patient hygiene Ronald Fisher, as described in his book Design of Experiments (1935)

Sir Austin Bradford Hill assessed the use of streptomycin in treating tuberculosis

Working group led by Gordon Guyatt, McMaster University

effect of confounding. Although there was no formally declared untreated group, and each treatment group was quite small, the systematic, prospective construction of comparison groups was new to medical science.4 Florence Nightingale (1820–1910) collected data on the mortality experience of solders injured in the Crimean War (1853–1856). Her presentation of statistics on the vast improvement in patient outcomes following the introduction of hygienic practices into the field hospital led to widespread reforms in military medicine. Nightingale found, based on careful record keeping and comparisons to civilian populations, that infection among soldiers led to a doubling of expected mortality; this required development of new statistical methods. From this experience, Nightingale collaborated with other scientists to develop a systematic method for collecting data on disease and mortality in hospitals. The key data elements collected in this system were the counting of all patients entering and leaving the hospital, and the mean duration of stay, thus providing denominators for the reporting of true rates of morbidity and mortality.5 After scientists of the 19th century (such as Nightingale) developed their work in vital statistics, the growth of statistical theory, including ideas about randomization, flowered in the first half of the 20th century.6 Ronald Fisher, an agricultural scientist, pioneered the theory and use of randomization in experiments. Fisher asserted that a “properly designed” experiment is one about which one can say that “Chance would so rarely cause such a large difference in outcome that I shall attribute the observed difference to the treatments,”

e v i d e n c e - b a s e d a p p roac h t o o n c o l og y

and that the only two possible explanations are chance and the treatments, that is, not bias or confounding. Another key feature of the randomized design is to vary the essential conditions only one at a time. In summary, the two main principles of the experimental method are numerical balance (equal numbers of subjects in the test and control group) and randomization of all the factors that are not being tested.7 In the area of observational medical science, or epidemiology, Austin Bradford-Hill developed a set of criteria to evaluate cause-and-effect relationships in disease. Around the same time, Bradford-Hill launched the first randomized clinical trial, investigating the efficacy of streptomycin in treating tuberculosis, which introduced the only clinical study design able to assess the question of cause and effect directly (more on this design follows). The introduction of the randomized trial to clinical cancer research followed a few years thereafter. The design of clinical trials evolved in the 1950s and 1960s through the many trials that were initiated as a result of demand from the pharmaceutical industry, which wished to introduce to the market new drugs that met the standards of rigorous clinical testing. Despite struggles by research clinicians against rigorous randomized clinical trial designs (typically in the interest of providing all patients the opportunity of palliation or preventing disease progression), some important trials proceeded. In the 1970s, the U.S. 6th Circuit Court of Appeals granted randomized trials status as a standard of evidence toward the U.S. Food and Drug Administration’s regulatory authority over the pharmaceutical industry.8 Trials of chemotherapeutic agents and analgesics often gave disappointing results; however, a landmark randomized trial showing segmental mastectomy with axillary node dissection for breast cancer to be as effective as total mastectomy in demonstrating long-term survival was published by Bernard Fisher and colleagues in the National Surgical Adjuvant Breast and Bowel Program9 and produced a demonstrable breakthrough in breast cancer care. At the same time, the results overturned centuries-old assumptions about the biology of breast cancer and how it spreads.

5

set of central clinical issues to identify gaps in knowledge that need to be filled with additional clinical information, or by turning to the literature, or both. These issues are (1) clinical findings, (2) etiology, (3) clinical manifestations of disease, (4) differential diagnosis, (5) diagnostic tests, (6) prognosis, (7) therapy, (8) prevention, (9) patient experience and meaning, and (10) practitioner self-improvement.2 Then, the questions can be formulated, and the questions should comprise four components: description of the patient or target disorder of interest, intervention, comparison intervention (relevant for therapy questions), and outcome.10 Using the previous example, the clinician might ask, “For a 47-year-old woman with ductal carcinoma in situ, what is the likelihood that lumpectomy followed by radiation, compared to lumpectomy alone, will prevent recurrence?”

Research Design and Quality of Evidence Central to the idea of evidence-based medicine is the idea that there is a hierarchy of quality of evidence that is related to the design and conduct of the study or studies from which it arose. It should be kept in mind as well that different study designs on the same topic often answer rather different questions from one another. The hierarchy of study designs is illustrated in the pyramid in Figure 1.1, which also reflects the relative numbers of studies in each category. As described previously, P.C.A. Louis’ writings were centuries ahead of his time in terms of suggesting the possibility of alternative explanations for his findings, or the concept of confounding, defined as a factor that tends to co-occur with the predictive (presumed causal) factor under study and that also tends to co-occur with the outcome. Louis, for example, found that bloodletting later in the disease process was associated with longer survival. To our knowledge, Louis did not make note of his patients’ diet. It is possible that those who consumed more calories would have on the one hand received the bloodletting intervention later in their disease course, because they looked healthier to begin with, and on the other

Evidence-Based Medicine as a Tool for Clinical Decision Making Dr. A, a first-year oncology resident, sees patient X, a 47-yearold woman referred to the service with a 2-cm ductal carcinoma in situ found on a screening mammogram. How does Dr. A approach the management of patient X? The classic approach Dr. A. might take is to consult someone who has treated similar patients before. She can also call on her knowledge from coursework. Finally, she can consult the literature, which might well be a daunting task in itself. The primary literature consists of scores of thousands of original research articles; the secondary literature consists of thousands of review articles.

Asking Answerable Clinical Questions The first stage of evidence-based decision making is to look closely at the information available. When a clinical scenario is written down, the practitioner can scan it with regard to a

FIGURE 1.1. The pyramid of evidence represents levels of evidence as well as the relative numbers of studies at each level.

6 hand would have survived their disease better because in fact they were healthier. Diet would thus have been a confounder of the apparent association between timing of bloodletting and improved survival. Unmeasured confounding is a central reason for distortion of study results, although it arises in different ways, which we discuss as they appear throughout this chapter. One of those is selection bias: in the case of Louis’ work, patients may have been selected for late treatment as opposed to the early-treatment group for reasons other than random chance, thus leaving open the likelihood that factors (that is, the confounders) other than the treatment influenced the outcome.

Randomized Clinical Trials Random allocation to a treatment or control group is the basis of all experimental design, and it is the only way to isolate the effect of a single factor under study on a given outcome and thus avoid the distorting effects of confounding. Even though potential confounding variables still exist among study subjects, randomization is designed to distribute them evenly between the test and control groups, thus removing their effects. The power of the randomized design is that it should provide equal balance not only of known confounding factors but also of unknown potential confounders. We discuss a few refinements to the randomized study design in the remainder of this chapter, but an entire chapter of this book is dedicated to randomized trials in cancer as well (see Chapter 8). Another central (and related) tenet of scientific inquiry is the idea of a comparison or control group. In clinical research, in the absence of a control group similar in every way to the test group receiving an investigational intervention, it is impossible to discern how many subjects benefited from treatment as opposed to improving on their own. An important factor to consider when evaluating oncology research, particularly studies of cancer therapy, is the choice of endpoints. Endpoints include health outcomes (total mortality, cause-specific mortality, quality of life) or indirect surrogates for any of these. Examples of surrogate endpoints are disease-free survival, progression-free survival, or tumor response rate. Studies of surrogate endpoints represent weaker, more indirect, evidence; however, a clinician may weigh studies differently depending on patient values. The bulk of our understanding of risk factors and preventive factors for cancer comes from observational studies (that is, those described here). Recent research has moved toward testing hypotheses generated by observational studies in the context of clinical trials, sometimes with unexpected results, such as a study of prevention of cancer by beta-carotene in smokers that found that beta-carotene increased lung cancer incidence compared with placebo.11 This finding stood in contrast to results from nonrandomized observational studies, which had suggested a benefit.

Cohort Studies in Oncology A cohort study identifies a group of subjects on the basis of their naturally occurring exposure to an agent or agents of interest and follows them in time to observe their experience (incidence) of disease. Data can be collected from the present

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into the future (prospective cohort study) or use historic data, such as records of occupational exposure, to look from the present into the past (retrospective cohort study). For cancer, the cohort study design tends to be inefficient, because cancer is considered to be a relatively rarely occurring outcome requiring the following over time of rather large initial populations to observe statistically meaningful results. Most prospective cohorts that study cancer were constructed to study other diseases, such as heart disease (for example, the Framingham Heart Study), or a range of diseases (for example, the Nurses Health Study). The benefit of a prospective cohort design is that exposures are evaluated in individuals before their diagnosis of disease; thus, the disease cannot distort the measurement of exposure as in cross-sectional or retrospective study designs. Often cohort studies collect baseline exposure information in great detail that is highly useful (although imperfect) in controlling for confounding. A drawback of prospective cohort studies is the attrition of participation over time, or loss to follow-up. Cohort studies often involve the repeated filling out of lengthy, detailed questionnaires on diet and other lifestyle factors, clinical examinations, and/or telephone interviews. Subjects remaining in such studies tend to be healthy relative to those who drop out, or the most motivated by health concerns, and may differ from those who drop out in other respects that are difficult to measure, which can result in confounding. Other reasons for attrition are illness, changing residence, and other changes in life circumstances that may be associated with unmeasured characteristics which differ between those who remain in a cohort study and those lost to follow-up and that are associated with disease risk. Such differences can distort the results or make study results less representative of the original target population. In addition, cohort studies can be extremely expensive. Designing and implementing a cohort study that provides adequate richness of data and study outcomes and avoids issues of loss to follow-up is resource intensive, as are maintenance and analysis of the data, keeping track of the details of protocols, and many other administrative tasks.

Nested Case-Control Studies A nested case-control study selects, from subjects in a cohort study, subjects who have the disease of interest (called case subjects) and a sample of subjects who are disease free at the time of sampling as controls. Similar to a conventional casecontrol study, this study design is efficient for studying rare diseases. It is a useful design if it is too expensive to measure a risk factor for every subject within a cohort study. It also shares with cohort studies the advantage of having subjects selected at baseline from the same population, so that case and control subjects chosen later are likely to be more comparable than those in a conventional case-control study. It is possible, if the exposure of interest is not measured before subjects in the nested case-control study are selected, that such measurement will be essentially retrospective, for example, if a detailed dietary frequency questionnaire is administered, which results in the same limitations as a conventional case-control study. However, this design is useful for studying biologic markers of exposure that are measurable in blood or other tissue samples and that remain stable in

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storage, especially freezing. Often blood samples are taken from all subjects of a cohort at baseline and frozen for later analysis. As an example, the Kaiser Permanente Health Maintenance Organization collected and froze serum samples for all subjects on enrollment. Their record-keeping system provided longitudinal data on patients, including data on disease incidence. Researchers who wished to investigate the association between exposure to the pesticide DDT (dichlorodiphenyltrichloroethane) first selected, from the Kaiser cohort, breast cancer case subjects and a sample of control subjects who were disease free when the case was diagnosed. They then retrieved frozen serum samples that, for the case subjects, were taken at least several years before diagnosis with breast cancer, and measured the concentration of DDT in the samples to compare the concentrations in case and control subjects.12

Case-Control Studies Many life-threatening diseases studied by epidemiologists are relatively rare. Consider, for example, the likelihood of being diagnosed with breast cancer in a given year, compared with that of coming down with a cold. If you only had the resources to study 500 women aged 50, with average risk factors, over a 5-year period, only 5 or 10 of them would be expected to be diagnosed with breast cancer during that time, whereas a large majority of them are likely to come down with a cold at least once in 5 years. The number of breast cancer cases is simply not adequate to allow valid comparisons among different hypothesized risk factors between women who are diagnosed with breast cancer and those who are not. On the other hand, if you set out to identify 250 women newly diagnosed with breast cancer (case subjects) in a given population, and simultaneously identified a suitable comparison group of 250 women (control subjects), you could substantially improve the statistical power (also called efficiency) of the study. A study in which subjects are identified on the basis of their disease status has what is known as a case-control design. Once you identify the subjects, you can then interview them about hypothesized disease risk factors such as diet, pharmaceuticals, sun exposure, pregnancy history, and so on. This is the bread-and-butter design of the bulk of cancer epidemiology. However, it is particularly prone to sources of bias and confounding that randomized controlled trials and cohort studies are not. The most important downside of case-control studies is potential bias from errors in recalling and reporting risk factors. For example, many people tend to underestimate or underreport their alcohol consumption. If people with and without a disease under study underestimate their consumption to a similar degree, then a true association between alcohol consumption and the disease would be more difficult to observe. In contrast, if someone diagnosed with a disease believes that his or her past alcohol consumption may have played a role in the disease, that consumption could either be further underreported or overreported relative to the true exposure. In any case, it is quite possible that the recall is different from that of someone without the disease. Just as it is difficult to predict which way someone is likely to misreport exposure, it is by extension difficult to predict the effect

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of such misreporting on estimates of disease association or risk. Another drawback of case-control studies is the fact that exposures reported to occur at a given point in time might not represent the exposures that actually cause the disease. This consideration is important in diseases such as cancer that have a long latency period, that is, the time between a causal exposure and the diagnosis of disease. Conceivably, cancer itself could alter dietary or lifestyle patterns in the period before diagnosis, thus reversing the cause-and-effect sequence. In addition, if a marker of a hypothesized disease risk factor is measured in a body tissue, such as the concentration of a pesticide in blood, it is possible that the measurement could be affected by the disease, resulting in a spurious association or masking a true association. Selection of an appropriate control group is particularly important, but also particularly difficult, for case-control studies. Bias, used here to mean systematic error in an estimate, can arise if case subjects and control subjects arise from populations with different underlying baseline characteristics. The more the case and control populations differ from one another, the more difficult it is to ensure that observed differences in risk factors are not due to extraneous, unmeasured factors, or confounders, that are associated with the factors under study and with the disease. For example, a study might find that people with lung cancer are more likely to drink alcohol than a group of control subjects similar in age. Rather than assuming that this finding indicates that alcohol is a risk factor for lung cancer, it is prudent to consider whether alcohol consumption is related to smoking, an established cause of lung cancer. In summary, case-control studies are often more convenient to assemble than the preceding study designs when a rare disease or outcome is being studied, and they are less expensive than cohort (follow-up) or experimental studies. However, because exposure is assessed retrospectively, errors in recall are often a problem. In addition, it is sometimes difficult to generalize the results or to avoid bias from confounding because of the ways in which patient and control groups are selected. For these reasons, case-control studies tend to provide a lower level of evidence than cohort studies or experimental studies.

Cross-Sectional Studies A cross-sectional study estimates the prevalence of disease (the number of cases of a disease) and possible disease risk factors in a given population at one point in time. Such studies are most usefully conducted by random sampling, which helps ensure that their results are representative of the larger population of interest. A special case of the crosssectional design, which is, technically, a survey follow-up study because it is repeated on a regular basis, can be found in the Behavioral Risk Factor Surveillance System (http://www.cdc.gov/brfss/), an annual national survey that selects a representative sample of U.S. residents and interviews them about such behavioral factors as exercise, human immunodeficiency virus (HIV) awareness, drug use, and smoking. Statistics describing the prevalence of these factors can then be compared from year to year, and a new set of subjects is sampled each year.

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Similar to cohort studies, subjects in cross-sectional studies are not selected for study on the basis of their disease status. Similar to case-control studies, however, measurement of risk factors is either nondirectional or retrospective, and the presence of risk factors cannot be shown to precede disease; that is, the temporality requirement for declaration of cause and effect is lost. Therefore, although cross-sectional studies are sometimes used to evaluate associations between risk factors and disease and to generate hypotheses, their ability to support evidence of causation is more limited than that of other observational studies.

Case series based on medical records are also likely to lack adequate (if any) information on confounders. Finally, the decision as to which data to report may be selective, particularly if eligibility criteria are not established in advance. For example, striking results may lead to report of a case or a series of cases, distorting the sense of what would be expected in general. Unfortunately, for some exceedingly rare diseases, clinical knowledge rests on case series and case reports for lack of sufficient numbers to support more robust study designs (J. Lau, unpublished observation).

Ecologic Studies

Preclinical Studies

In studies of ecologic design, the number of people with an exposure is known, as is the number of people with a disease or outcome (mortality, for example), but the number of people with both the exposure and the disease is not known. In general, relevant information on individuals in the population is unknown. A study that is at least partly ecologic in design may be the only feasible option in the case of an environmental exposure experienced by an entire population. A wellknown example of an ecologic study stemmed from the observation that the number of deaths in London increased sharply relative to average death rates during a period of particularly heavy smog and was closely proportional to the ambient temperature during that period. Generally, however, the level of evidence provided by ecologic studies is considered quite weak, primarily because of the studies’ inability to correct for other variables, that is, confounders, at the individual or aggregate level that could explain the observed associations. Indeed, such confounding remains a possibility in the London smog example, in which the agent that caused the excess deaths cannot be known with certainty. A commonly encountered example of ecologic data is the observation that rates of certain kinds of cancer, especially breast cancer, are high in countries with high consumption of dietary fat and that cancer rates are low in those countries reporting low dietary fat consumption. Such observations are useful in generating hypotheses for further study; however, as in the example of dietary fat and breast cancer, epidemiologic studies based on individual-level data with the ability to adjust for confounding factors often show little or no association between dietary fat and breast cancer.

Laboratory studies using immortalized cell lines, whole tumors, or some other system below the level of the organism are important in basic oncology, but their purpose is to isolate small subsets of the complex tumor biology machinery to elucidate mechanisms (Table 1.2). Rarely should they be taken in isolation as evidence for or against a given treatment strategy. They do represent a level of control that may never be attainable or ethical in whole humans; on the other hand, it is their very lack of organismal context that makes them unreliable to extrapolate to humans. Despite a tendency of some researchers and the media to tout breakthroughs in biomedical research on the basis of laboratory studies, they should be seen by practicing clinicians for their intent: mechanistic, preliminary, and hypothesis generating in relation to medical practice. The toxic or beneficial effects of drugs, environmental agents, and foods are typically evaluated using laboratory rodents or other small mammals, according to stringent experimental and statistical analytic protocols. These protocols allow statistically efficient estimates of beneficial, safe, or toxic doses of chemicals in genetically homogeneous animals. Laboratory animals may also be used for mechanistic studies, for example, using gene knockout models. It is important to be able to test chemicals with uncertain safety on nonhumans. However, because mice and rats are not humans, assumptions must be made regarding the extrapolation of results to humans and again should not be used by the clinician in isolation for clinical decision making.

Case Series and Case Reports Reports of individual cases and case series represent the earliest known method of accumulating medical knowledge on most diseases. Although their importance is lower today given the availability of controlled studies, particularly clinical trials, they remain a popular mode of publication by clinicians of their investigations and observations. As evidence, however, case series and reports pose a number of problems and should be interpreted with substantial caution. Many case series are collected retrospectively from medical records, and recording of information may be selective and subject to incompleteness or other forms of error compared to information collected according to a predefined plan. Selection bias can occur when the series is not representative of the general population, in particular when subjects with similar prognosis are selectively lost to follow-up.

Expert Opinion Until modern times, ‘facts’ were deduced by arguments from premises approved by tradition and authority, without appeal to experimental validation. Even when observation ran counter to ‘facts,’ it was still believed that in some mysterious way authority must still be correct, particularly at a time in history when the fabric of society was such as to frown upon the challenge of authority. The modern therapeutic trial offers an alternative by relying upon impartial observance without regard for authoritarianism. Such an approach provides the foundation of scientific medicine.” —Bernard Fisher13

In other words, the evidence of expert opinion is only as strong as the empiric evidence from which it is derived. As Albert Einstein pointed out: “Propositions arrived at purely by logical means are completely empty as regards reality. Because Galileo saw this, and particularly because he drummed it into the scientific world, he is the father of modern physics—indeed of modern science altogether.” (From Ideas and Opinions, Modern Library, 1994)

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The Role of Meta-Analyses and Literature Reviews For many clinical questions, the practitioner will find that much of the work of reviewing and evaluating research has already been done, or at least addressed, and that summaries of literature exist. The end of this chapter offers a number of readily available sources of comprehensive literature reviews, along with other convenient sources of evidencebased medical knowledge. By way of definition, an overview or review of literature may be any type of summary, whereas the term meta-analysis describes a quantitative summary of results from different studies. Because a meta-analysis attempts to combine results from a number of studies into a summary statistic, it is important to be sure that the studies have a common outcome measure. Also, the underlying assumption is made that the studies are drawn from the same pool or universe of studies and can therefore be legitimately combined. Statistical tests for homogeneity are therefore often used to test this assumption. Also, the validity of a meta-analysis depends upon the assumption that there has not been substantial selective reporting of studies depending on their result (e.g., greater likelihood to report small positive studies than small negative studies). Funnel plots are used to assess this possibility graphically. In a funnel plot, the outcome variable for each study is graphed versus its variance. Literature reviews may be systematic or rely on the recall of the author. In a systematic review, a complete computer search is made of the relevant literature using specific search terms and prospective rules for inclusion or exclusion of studies found in the systematic search. To begin evaluating a review, the practitioner should ask two questions: does it ask a carefully focused clinical question, and is the method for including studies reasonable and appropriate? The latter question can be expanded as follows: are methodological standards articulated (for example, those laid out in this chapter), and do the studies chosen address the research question articulated by the reviewer? Stating inclusion criteria up front helps avoid any biases toward preconceived conclusions a reviewer might hold. Aspects of oncology studies to keep in mind when reviewing a review are outcomes (as described previously) and latency periods. Review writers should demonstrate that they exhaustively searched appropriate bibliographic databases (such as Medline), but also that they contacted experts in the area who might be aware not only of published studies not yet appearing in Medline, but of unpublished studies; this is important because studies with negative findings are less likely to reach publication. Practitioners reading reviews should consider whether results of reasonably comparable studies are similar. Metaanalyses study formally and quantitatively whether results of similar studies differ more than would be expected by chance alone. If so, it is likely that study designs differ enough to account for observed differences in results. A review should not simply compare the number of positive and negative studies of a given question to obtain an answer, as this fails to give different weight to large and small studies, large studies being more likely to show a positive result because of increased statistical power or efficiency. In addition, such a comparison ignores effects other than the

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primary outcome of interest, and says nothing about the magnitude of an effect, its clinical importance, or the relatively quality of individual studies.

Ranking the Evidence: The Role of Study Design and Study Quality Looking at evidence in the field of oncology is similar to analogous processes in other fields of medicine. An example evidence rating system for research on cancer screening and prevention is used by the Physician’s Data Query (PDQ) of the U.S. National Cancer Institute and can be found at http://cancer.gov. It rates evidence based on five domains of quality: • Study design (evidence from the best studies available, ranked in descending order of strength) • Internal validity (“quality” of execution within the study design) • Consistency (coherence)/volume of the evidence • Direction and magnitude of effects for health outcomes (both absolute and relative risks; as quantitative as possible; may vary for different populations) • External validity/generalizability to other populations When evaluating therapy studies, the strength of study endpoints (described under Randomized Clinical Trials) should be combined with the strength of the study design in ranking results (Table 1.3).

Illustration: Postmenopausal Hormone Therapy Recently, the administration of hormones to postmenopausal women was brought into the spotlight. For decades, doctors had prescribed various combinations of estrogen and progesterone not only to relieve menopausal symptoms but also to reduce women’s risk of osteoporosis, heart disease, and Alzheimer’s disease. Consistent evidence for the beneficial effect of these hormones for prevention of several chronic diseases came from a large number of prospective cohort studies (as well as observational studies of other designs) comprising hundreds of thousands of women. In 2002, the practice of prescribing hormones returned abruptly to attention when results from the Women’s Health Initiative, a large randomized controlled trial, showed that the drug PremPro (combined estrogen plus progestin) not only did not appear to protect women from heart disease and Alzheimer’s disease but actually produced a modest increase in cardiovascular outcomes and cognitive disorders as well as breast cancer.14 How is it possible that such a large, apparently authoritative body of evidence could give an answer at odds with that of a randomized trial, and the landscape of hormone therapy change so rapidly? In an observational cohort study, women are free to take postmenopausal hormones or not. Women who do choose hormone therapy tend to be more healthy and health conscious: they are more likely to see a physician on a regular basis, eat a healthful diet, and exercise. All these variables could affect the development and incidence of disease. Although an observational study can take such differences into account, there may remain other, unmeasured factors (confounding), or there may be systematic imprecision (bias) in the measurement of known factors, both of which

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TABLE 1.2. Summary of study designs. Study design

Description

+

-

Systematic reviews and meta-analyses

Summarize findings from a number of studies addressing a given clinical question; meta-analyses quantitatively estimate effects based on combining data from different studies.

Meta-analyses have greater statistical power than single studies to address questions. Convenient way to summarize findings from a range of studies.

Randomized clinical trial

Subjects randomly assigned to an intervention or control group. Randomization ensures that the intervention is the only factor to vary between the comparison groups.

Prospective cohort study (includes nested casecontrol study)

Exposures of subjects assessed at beginning of study; disease or other outcomes evaluated over time.

Represents true experiment. Randomization removes effects of confounding and bias. Considered gold standard among clinical studies. The most efficient method to test definitively for causal relationships between an intervention and health outcomes. More efficient for common diseases. Allows assumption that exposure precedes disease. Allows consideration of a wide range of confounders.

Must meet assumption that studies can legitimately be combined (based on population, study design, etc.). Literature searches must be performed systematically and studies included without bias. Expensive: requires extensive study infrastructure and training of staff. May be unethical or impracticable for some hypotheses.

Retrospective cohort study

Exposures of subjects assessed retrospectively, e.g., occupational exposures via historic job records.

Useful for assessing past exposures of large numbers of subjects over time.

Case-control study

Prior exposure and disease assessed at a point in time. Subjects selected on the basis of disease status (with or without); past exposures evaluated retrospectively.

More efficient for relatively rare diseases such as cancer. May allow consideration of a wide range of confounders.

can distort estimates of risk and benefit. Such unmeasured confounding is believed to have resulted from the crucial bias (selection bias) that rather impressively provided such consistency of results among observational studies of combined hormone therapy. The Women’s Health Initiative, in contrast, was able to eliminate whatever confounders were at play by virtue of its randomized placebo-controlled design.

Applying Research Evidence to the Individual After identifying relevant studies, the clinician must think about their applicability to the individual patient, because even the best studies report estimates of effect in terms of an average. Study participants and real-world patients are likely to differ by degree, rather than grossly, in their response to treatment.15 Individualizing treatment decisions involves estimation of the balance of risks and benefits, combined with a consideration of patient values. The number needed to treat (NNT) is the number of patients that need to be treated to prevent one additional adverse event, and it is the inverse

Often expensive: requires large study infrastructure. Time consuming (subjects often followed for years). Subject to confounding (measured or unmeasured). Attrition of study population can affect generalizability. Assumption that exposure precedes disease may be less strong than in prospective design. Confounders may have to be assessed at the present, and proxies for nonliving subjects may introduce bias. Disease itself may affect evaluation of exposure (changes to biochemical measurement, selective recall). Subject to various types of error in evaluation of past exposure. Subject to confounding (measured or unmeasured). Exposure does not necessarily precede disease.

of the absolute risk reduction, as described by McAlister et al.,16 who provide a detailed guide to individualizing evidence from research. The number needed to harm (NNH), in contrast, is the number of patients treated who would be expected to experience one adverse event. NNT and NNH illustrate the balance between benefits and risks of a given intervention; in oncology, this is particularly relevant with regard to screening, which may result in harms from followup of false positives, and treatment, which often produces dose-dependent toxicity. Clinicians should also consider the following levels of decision making when thinking about applying evidence to a particular patient, as conceptualized by Dr. Leon Gordis of Johns Hopkins University: Level 1: “Would you have this done for yourself or for someone else in your immediate family?” Influenced by one’s personal experience with the disease and capacity to deal with risk. Level 2: “Would you make this recommendation for your own patients?” Also influenced by prior experience, but

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e v i d e n c e - b a s e d a p p roac h t o o n c o l og y TABLE 1.2. (continued) Study design

Description

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Nested case-control study

Analysis similar to case-control study, but subjects sampled from within cohort study.

For prospective studies, combines efficiency of case-control design with ability to demonstrate that exposure precedes disease.

See prospective cohort study.

Cross-sectional study (also called prevalence study)

Exposure and disease assessed at one point in time. May be repeated with different population samples at set time intervals (e.g., annual surveys).

Useful for measuring prevalence of an exposure or disease. Useful for generation of hypotheses and evaluating associations (as opposed to cause and effect). Repeated sampling design allows evaluation of population trends.

Exposure cannot be shown to precede disease. Inefficient for studying rare diseases.

Ecologic studies

Population-wide disease incidence or prevalence is compared with population-wide exposure estimates.

Useful for generating hypotheses. Useful for exposures that cannot be estimated on an individual level (e.g., ambient pollution).

Does not allow consideration of interindividual differences, which obscures confounding effects.

Case series or case reports

Descriptions of disease manifestations or therapy outcomes in single or multiple individual subjects, without controls; data often collected retrospectively.

May be the only feasible design for extremely rare diseases.

Lack control group. Subject to selection bias. Tend to lack information on confounders.

Preclinical studies: animal studies

Experimental design using animals, typically genetically homogeneous.

Large studies of animals (especially rodents) are useful for screening drugs and other chemicals for toxic or therapeutic effects.

May be inappropriate to extrapolate from rodent and other species to humans. Doses of chemicals used in toxicity studies may not be extrapolatable to doses likely to be experienced by humans.

Preclinical studies: laboratory studies below the wholeorganism level

Experimental design utilizing controlled conditions, often involving effects of toxins or drugs on immortalized cancer cell lines or other cells.

Represent a level of control usually unattainable or unethical in humans. Generate hypotheses for human studies. Can elucidate biological mechanisms.

Lack organismal context, and therefore difficult to extrapolate to whole humans.

the strength of the scientific evidence may play a greater role. Level 3: “Would you make an across-the-board recommendation for a population?” Must be based even more on rigorous assessment of the scientific evidence.

Level 1 is the level at which we all operate when we are making our own personal decisions regarding a procedure; it rests heavily on our own personal value systems and tradeoffs. Nevertheless, it is important not to impose our own value systems on our patients. Level 2 is one in which clini-

cians engage in informed and shared decision making with patients. It is hoped that it involves reliance on strong evidence, although it is also heavily influenced by personal values of the patient if the decision is to be truly shared with the patient. Quick sound bites do not lend themselves to this format of informed decision making. By contrast, Level 3 involves an across-the-board recommendation for the entire population. Complexities are often sacrificed to strengthen the message. The messages are often sanitized of any mention of potential harms inherent in any test, procedure, or treatment. Here, therefore, recommendations should be based on particularly strong evidence.

TABLE 1.3. Levels of evidence. I II-1 II-2 II-3 III

Evidence obtained from at least one properly randomized controlled trial Evidence obtained from well-designed controlled trials without randomization Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group Evidence obtained from comparisons between times or places with or without the intervention; dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

From Canadian Task Force on the Periodic Health Examination. Can Med Assoc J 1979;121:1193–1254.

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Are We Practicing Evidence-Based Medicine? The goal of using evidence in medicine is to come closest to practice that represents best practice and to produce optimal health outcomes. Thus, it is desirable to evaluate the impact of medical knowledge on actual practice, in terms of both the practices themselves and, ultimately, their public health impact. On one level, the impact of evidence-based guidelines can be assessed by measuring practitioners’ beliefs and knowledge over a time period relevant to the introduction of new knowledge by means of surveys. However, such surveys may not fully reflect actual practice and are an indirect surrogate for health outcomes. The translation of knowledge into practice is often measured using administrative datasets such as Medicare claims data, which are assumed to reflect some robust proportion of procedures performed on enrollees, for example, screening mammography examinations. Such data are more objective than physician self-report, but may not capture all procedures of interest, as enrollees may undergo procedures outside the Medicare reimbursement system. For example, Medicare analyses are usually restricted to procedures in the age 65+ population for which the U.S. government is billed. Looking at effects of guidelines on health outcomes (such as cancer incidence and mortality) is of great interest. However, these endpoints are often the most difficult to evaluate with confidence in terms of their link to new knowledge, because so many other factors are likely to influence rates of disease. For the United States, the most comprehensive data on disease incidence and mortality are compiled by the SEER program (Surveillance, Epidemiology, and End Results). SEER is a national dataset that is designed to reflect the total cancer experience of the U.S. population. Despite these caveats, occasionally a breakthrough in cancer medicine results in clearly measurable improvements in outcomes. Feuer et al.17 reported on dramatic improvements in testicular cancer outcome statistics in SEER after the completion of a successful clinical trial of cisplatin, vinblastine, and bleomycin; improved survival rates then reached a plateau, apparently indicating the limits of diffusion of the results of the trial into medical practice. Questions of impact of knowledge may be addressed by looking at rates of disease and mortality over a time frame relevant to the introduction of a given guideline, or to media coverage of, for example, a diagnosis of cancer in or a cancer screening or treatment procedure undergone by a celebrity. This approach is essentially an ecologic study design and is subject to the limitations described earlier. In one notable case, rates of breast-conserving surgery, which had been increasing (relative to mastectomies) in the 1980s, appeared to decline abruptly, albeit briefly, after widespread publicity about a mastectomy undergone by then First Lady Nancy Reagan. Nattinger et al.18 carefully documented this change by analyzing news reports and the appropriate time period of subsequent SEER data. Despite this evidence, other unmeasured factors affecting these rates are undoubtedly still at play, and outside of the context of a controlled trial it is extremely difficult to establish a causal effect that an intervening factor may have had on population mortality rates. Progress in fighting cancer is often measured in terms of SEER-derived statistics; again, however, it is difficult to

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ascribe changes to a single factor. Recent reductions in deaths from breast cancer could be related to more widespread mammography screening, but improvements in breast cancer therapy are also likely to have an effect on mortality, and it is impossible to tease apart their effects on population-based mortality rates. Another example of the use of national data to assess the impact of evidence-based medicine is that of colorectal cancer. The U.S. Preventive Services Task Force recommends screening for colorectal cancer by any of four methods; however, the reported prevalence of screening is below 50% in many states. As for the rates of disease, long-term declines in colorectal cancer incidence have slowed. Although screening is thought to play a role in reducing incidence and mortality, risk factors for colorectal cancer—physical inactivity and obesity—have increased in the population.19 Although it is not possible to separate the effects of screening, improvements in therapy, and risk factors completely, they do act in different directions; the increase in physical obesity could conceivably explain the slowing of declines in incidence. A common error in interpreting population cancer statistics is in the use of 5-year survival as a gauge of progress against a disease. Five-year survival is an appropriate outcome in a trial of a therapy, where all subjects in the numerator and denominator of the survival rate have the disease and a comparison is made between two groups randomly assigned to treatment after their diagnosis. In the general population, however, 5-year survival is much more likely to be a function of the date of diagnosis relative to the course of the disease. As a result, 5-year survival is unrelated to mortality and is ultimately a misleading statistic in this context.20 For example, changes in screening patterns can advance the date of diagnosis without changing risk of death, thus artifactually lengthening survival time. Other relevant outcomes beyond physician practice but shy of hard health outcomes include smoking rates, which are known to be closely related to rates of lung and oral cancer as well as a number of other health outcomes and total mortality. The Behavioral Risk Factor Surveillance Survey and National Household Survey on Drug Abuse measure the prevalence of smoking in the United States and can be used to estimate the impact of smoking-cessation programs and tobacco-related policies.

Evidence-Based Medicine and Societal Issues Given finite resources, the medical system cannot provide every intervention no matter how small its potential benefit. From a societal perspective, it is therefore important for clinicians to judge interventions based on a balance between magnitude of benefit, quality of evidence, and resources. That is, one must keep in balance two questions: (1) Does it work? and (2) Should we do it? Otherwise, we could diminish the net health of the community by diverting resources from highly effective intervention to more marginally effective ones. The methods for such prioritization, however, are not yet well established. Cost-effectiveness analysis and costutility analysis are tools that can help, but many value judgments are necessary that go beyond quality of evidence. In the meantime, adhering to evidence-based principles of

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evaluating, for example, screening and diagnostic tools, may help eliminate ineffective redundancy and thus save costs while still achieving needed health outcomes.

Summary This introduction has attempted to put evidence-based decision making in a useful, practical framework with special attention to issues relevant to the study and practice of oncology. We hope we have made it clear that evidence-based medicine is neither theoretical nihilism nor cookbook practice, in that it incorporates clinicians’ knowledge and training with systematic methods for asking answerable questions, critically evaluating research, and taking into account patient values (thus marrying the tools of evidence-based medicine with the ethical concept of patient autonomy).

Resources The landscape of medical research changes constantly, and thus the best resources for practitioners of evidence-based medicine are those that adapt databases, recommendations, and guidelines regularly to take into account new findings. Key online resources relevant to oncology are the Physicians’ Data Query (PDQ) at http://cancer.gov, the public Website of the National Cancer Institute. The PDQ has several topical committees that meet regularly to develop and update Webbased resources and explicitly spell out their methodology for ranking evidence. The U.S. Agency for Healthcare Research and Quality (http://www.ahrq.gov) posts links to evidencebased guidelines, including their own U.S. Preventive Services Task Force, at the National Guidelines Clearinghouse (http://www.guideline.gov), and also offers access to comprehensive literature reviews on a wide variety of clinical questions. The Cochrane Library (http://www.cochrane.org) regularly updates its evidence-based databases on health care and publishes comprehensive literature reviews according to stringent rules of evidence. Two journals relevant to general medicine and oncology exist to help summarize the vast sea of new research into a manageable format and according to an evidence-based approach: ACP Journal Club (published by the American College of Physicians) and Cancer Treatment Reviews (from Elsevier; this journal now incorporates the former EvidenceBased Oncology). Further instruction in the general nuts and bolts of evidence-based medicine can be found in texts by the innovators of the field: David Sackett and colleagues (EvidenceBased Medicine: How to Practice and Teach EBM; Churchill Livingston, 2000) and the JAMA Users’ Guide to the Medical Literature: A Manual for Evidence-Based Clinical Practice. The JAMA guides are a compilation of a previously published series of articles in JAMA and can also be accessed online by subscription.

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References 1. Evidence-Based Medicine Working Group. Evidence-based medicine: a new approach to teaching the practice of medicine. JAMA 1992;268:2420–2425. 2. Sackett D, Straus SE, Richardson WS, et al. Evidence-Based Medicine: How to Practice and Teach Evidence-Based Medicine. Edinburgh: Churchill Livingston, 2000. 3. Morabia A. P.C.A. Louis and the birth of clinical epidemiology. J Clin Epidemiol 1996:49:1327–1333. 4. Dunn PM. James Lind (1716–94) of Edinburgh and the treatment of scurvy. Arch Dis Childhood 1997;76:F64–F65. 5. Keith JM. Florence Nightingale: statistician and consultant epidemiologist. Int Nurs Rev 1988;35:147–150. 6. Gehan E. The role of the biostatistician in cancer research. Biomed Pharmacother 2001;55:502–509. 7. Mainland D. The rise of experimental statistics and the problems of a medical statistician. Yale J Biol Med 1954;27:1–10. 8. Meldrum ML. A brief history of the randomized clinical trial: from oranges and lemons to the gold standard. In: Allegra CJ, Kramer BS (eds). Hematology/Oncology Clinics of North America: Understanding Clinical Trials. Philadelphia: Saunders, 2000. 9. Fisher B, Bauer M, Margolese R, et al. Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N Engl J Med 1985;312:665–673. 10. Centre for Evidence-Based Medicine, http://www.cebm. utoronto.ca/practise/formulate/. 11. Albanes D, Heinonen OP, Taylor PR et al. a-Tocopherol and bcarotene supplements and lung cancer incidence in the AlphaTocopherol, Beta-Carotene Cancer Prevention Study: effects of base-line characteristics and study compliance. J Natl Cancer Inst 1996;88:1560–1570. 12. Krieger N, Wolff MS, Hiatt RA, et al. Breast cancer and serum organochlorines: a prospective study among white, black, and Asian women. J Natl Cancer Inst 1994;86(8):589–599. 13. Fisher B. Clinical trials for the evaluation of cancer therapy. Cancer (Phila) 1984;54:2609–2617. 14. Roussouw JE, Anderson GL, Prentice RL et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized clinical trial. JAMA 2002;288:321–333. 15. Dans AL, Dans LF, Guyatt GH, et al. Users’ guides to the medical literature: XIV. How to decide on the applicability of clinical trial results to your patient. Evidence-Based Medicine Working Group. JAMA 1998;279:545–549. 16. McAlister FA, Straus SE, Guyatt GH et al. Users’ guides to the medical literature. XX. Integrating research evidence with the care of the individual patient. JAMA 2000;283:2829–2836. 17. Feuer EJ, Frey CM, Brawley OW, et al. After a treatment breakthrough: a comparison of trial and population-based data for advanced testicular cancer. J Clin Oncol 1994;12:368–377. 18. Nattinger AB, Hoffmann RG, Howell-Pelz A, et al.. Effect of Nancy Reagan’s mastectomy on choice of surgery for breast cancer by U.S. women. JAMA 1998;279:762–766. 19. Weir HK, Thun MJ, Hankey BF, et al. Annual report to the Nation on the status of cancer, 1975–2000, featuring the uses of surveillance data for cancer prevention and control. J Natl Cancer Inst 2003;95:1276–1299. 20. Welch HG, Schwartz SM, Woloshin S. Are increasing 5-year survival rates evidence of success against cancer? JAMA 2000; 283:2975–2978.

2

Principles of Chemotherapy Grace K. Dy and Alex A. Adjei

D

uring World War II, sailors who were accidentally exposed to nitrogen mustard following the explosion of a ship developed marrow and lymphoid hypoplasia.1 This serendipitous discovery led to the first clinical trial conducted in 1942 using nitrogen mustard in patients with malignant lymphomas at Yale University.2 This marked the beginning of a new era of research in the quest for effective and safe drugs used in cancer chemotherapy. The term chemotherapy has been loosely applied to the myriad systemic therapeutic options in cancer treatment exclusive of irradiation and surgical approaches. In this chapter, we confine our discussion of chemotherapy to refer to the use of conventional cytotoxic agents. Use of targeted and biologic agents such as hormone or signal transduction manipulation and gene therapy is explored in other chapters.

Cancer Cell Population Kinetics The discussion that follows briefly describes the various paradigms of tumor growth and response to cytotoxic agents to facilitate understanding of the rationale and basis for the approaches to cancer therapy with cytotoxic agents.

Skipper’s Exponential Tumor Growth/Log-Kill Hypothesis One of the pioneer investigations in tumor growth kinetics was made by Skipper and his colleagues,3 who described the first model of tumor growth kinetics. Despite its flaws and oversimplified nature, the empiric observations derived from this model underlie many of the tenets in cancer chemotherapy. A conclusion derived from his L1210 mouse leukemia model was the exponential (logarithmic) growth of tumor cells. Doubling time of cancer cells was proposed to be constant, yielding a straight line on a semilog plot (Figure 2.1). Another conclusion generated from their experiments was the log-kill hypothesis, which proposes that anticancer drugs act with first-order kinetics, and hence, assuming homogeneous sensitivity to the drug, they will eliminate a constant proportion rather than a constant number of tumor cells regardless of the initial size of the tumor; that is, magnitude of tumor cell kill is a logarithmic function.3 By this a posteriori reasoning, if sufficient drug is given, cure can be achieved when fewer than 1 tumor cell remains. Similarly, therapy against small-volume tumors or micrometastatic

14

disease should be easily successful in effecting cures. However, clinical experience in adjuvant chemotherapy has not borne out this deductive assumption as successfully as hoped.

Gompertzian Model of Tumor Growth With further studies, it became clear that Skipper’s model was oversimplified and applied only to the proliferating segment within the tumor. Some early-stage malignancies, such as testicular germ cell tumor, may behave in such a way when they are composed of proliferating cells highly responsive to chemotherapeutic agents. However, most human solid tumors do not respond to chemotherapy, contrary to what would have been expected if tumor growth was exponential. Rather, the experimental data in human solid tumors support the Gompertzian kinetics of tumor growth, akin to the sigmoid curve seen in microbial kinetics under a controlled environment, where the initial growth phase is steep at smaller volumes, eventually plateauing and decreasing with time once a critical mass is reached4 (Figure 2.2). As many anticancer agents are cell cycle specific and are usually most active against cells that are proliferating, a critical factor in drug responsiveness of tumors to cell-cycle-specific drugs depends on the particular phase the tumor is in its growth curve. This model also helps explain why, unless cure was effected, varying degrees of residual tumor volume result in similar relapse-free survival over time.

Norton–Simon Model In Skipper’s model, the exponential growth of tumors is presumed to be homogeneous. The Norton–Simon model takes into account the heterogeneity of a tumor cell population following the Gompertzian growth curve.5,6 The log kill would be greater for very small cancers than for larger tumors. However, smaller cancers also regrow faster. The greater fractional kill, such as against micrometastases in the adjuvant setting, is offset by fractional repopulation of tumor cells at the same fast rate. Thus, tumors are difficult to eradicate under this model. As already stated, this model predicts the observation that adjuvant chemotherapy does not have much impact on overall survival, as opposed to the improvement in disease-free survival. Survival can thus be improved only when tumor cell populations are eradicated or rendered

principles of chemotherapy 103

102

101

100 0

time

FIGURE 2.1. Skipper’s model of tumor growth (x-axis, time for tumor growth; y-axis, tumor volume).

dormant during the early growth phase. Another implication is that effective therapy should be delivered at reduced intervals to maximize the chances of tumor eradication and to minimize tumor regrowth in between cycles of therapy.

Goldie and Coldman Hypothesis An important corollary to tumor growth is the development of drug resistance resulting from spontaneous mutations that occur with cell proliferation, independent of the resistance inherent to the heterogeneity in cell kinetics described earlier. Goldie and Coldman had hypothesized that this occurs at a rate of 1 of 105 cells per gene.7 If 1 g tumor, the minimum size for detection, contains 109 cells, then such a tumor might contain 104 clones resistant to any given drug. However, resistance to two drugs would be seen in fewer than 1 cell in a 10-g (1010 cells) tumor. This idea is consistent with the known observation that combination chemotherapy is more effective than single-agent regimens. Nevertheless, single agents have remained successful in the treatment of

15

certain tumors, such as Burkitt’s lymphoma at sizes greater than 1 g.8 This hypothesis is one basis for the idea that chemotherapy should theoretically be started when tumor burden is smallest, to be effective; concomitant or alternating administration of noncross-resistant drugs is preferred to sequential chemotherapy. However, delaying therapy does not necessarily result in decreased responsiveness in many cases.9,10 Similarly, administration of chemotherapy preoperatively, although it may be predicted to be more beneficial based on this model, does not confer any significant improvement in the clinical outcomes in resectable early-stage breast cancer. This model also assumes a stepwise development of resistance to individual agents and thus does not account for multidrug resistance patterns. Tumor cell growth kinetics are complex and poorly understood. There are no available models that accurately describe all aspects of clinical behavior of solid tumors. The heterogeneous genetic abnormalities of different tumors underlie their behavior, making it impossible to make broad predictions.

Chemotherapy Approaches in the Management of Cancers Cancer chemotherapy has principally been used in the management of advanced or metastatic disease, following failed local therapies, or in disease for which no alternative therapy is effective. Chemotherapy is curative for several advanced human cancers, such as gestational trophoblastic disease, certain hematologic malignancies, or germ cell testicular cancer. However, most common solid tumors are not curable with current chemotherapeutic regimens when metastatic (Table 2.1). The roles of chemotherapy are manifold: induction chemotherapy denotes its use as primary therapy when there is no alternative treatment available or subsequently suitable even with tumor response, such as in hematologic malignancies, where disease is systemic. As an adjunct in combined modality therapy, chemotherapy is adjuvant when systemic treatment is applied after the tumor has been controlled by an alternative modality, such as surgery and/or radiotherapy, or neoadjuvant (primary) chemotherapy when localized cancer will otherwise not be optimally managed if systemic chemotherapy is not used before definitive local therapy.

Dose Intensity Versus Dose Density

0

200

400

600

800

1000 1200 1400

t [days] FIGURE 2.2. Gompertzian model of tumor growth (x-axis, time for tumor growth; y-axis, tumor volume).

Multiple laboratory experiments have established the proportionate dose–response curve, such that log kill is greater for the regimen with a higher dose intensity (i.e., by increasing the dose level delivered over a standard time interval). The slope of the curve is often steeper for tumors with a higher growth fraction. This observation underlies one of the principles in cancer chemotherapy—the administration of the highest possible dose of drugs in the shortest possible time intervals. The latter is typically limited by the recovery period of host organ function, such as the gastrointestinal tract and, in particular, the bone marrow, and thus explains the familiar 14- to 28-day intervals between cycles of therapy. Progress in understanding of tumor growth kinetics has led to the emergence of new concepts in the schedules and

16

chapter

2

TABLE 2.1. Responses of tumors to chemotherapy. Curable

Prolonged survival

Palliative/minimal

Hodgkin’s lymphoma Non-Hodgkin’s lymphoma (e.g., Burkitt’s, diffuse large cell)

Non-Hodgkin’s lymphoma (e.g., follicular) Bladder cancer Breast cancer Lung cancer Colorectal cancer Oligodendrogliomas

Multiple myeloma Chronic leukemias Malignant melanoma Renal cell carcinoma Glioblastoma multiforme Pancreatic carcinoma Hepatocellular carcinoma Head and neck cancers Esophageal carcinoma Gastric carcinoma Prostate carcinoma

Acute leukemias Testicular cancer Ovarian cancer Choriocarcinoma Childhood cancers (e.g., rhabdomyosarcoma, Wilm’s tumor, Ewing’s sarcoma)

dosing of cytotoxic agents. Dose intensity refers to the dose level or total amount of drug received over a fixed unit of time. It is a function of the magnitude of the dose level. Achieving a certain effective dose level is analogous to the concentration-dependent killing of some antibiotics, such as aminoglycosides, wherein increasing bactericidal activity is achieved with exposure to a higher dose until a threshold concentration of maximal efficacy is achieved. Dose intensity is an important concept derived from the well-observed steep dose–response effect of chemotherapy agents demonstrated in randomized trials such as in germ cell tumors.11 However, achieving a higher dose intensity by administration of higher dose levels of chemotherapy is hampered by concomitant increase in frequency and severity of toxicities. In addition, this concept may not be applicable in metastatic solid tumors, when tumor burden is largest. This restriction is illustrated by the negative results of myeloablative doses of chemotherapy compared to conventional chemotherapy in women with metastatic breast carcinoma.12 Moreover, it has been observed in vitro that one of the important determinants of cytotoxicity is the duration of drug exposure beyond a threshold drug concentration. Indeed, there may be a readily tolerable minimal dose level for tumors, as implied in a recent trial by the Cancer and Leukemia Group B (CALGB) trial. In that study, there was no survival benefit to the administration of a more dose-intense regimen of 5-fluorouracil, adriamycin, and cyclophosphamide (FAC) in the adjuvant setting among women whose tumors did not express the HER/2 neu oncoprotein.13 In contrast, dose density refers to the total amount of drug received over a variable given period of time. To illustrate, giving 2x amount of drug in cycles of y days (A) is twice more dose intense than x drug in y days (B), whereas B is less dose dense than x drug given in y/2 days (C). C is as dose intense

and dose dense as A. Simply, dose density is a function of frequency of dose administration within a treatment cycle. Dose density is analogous to the time-dependent killing activity of penicillins and cephalosporins wherein bactericidal activity is directly related to the time of exposure above the minimum inhibitory concentration (MIC), after which it becomes independent of drug concentration. A tumor thus relapses when subtotal eradication upon initial drug administration leads to tumor growth and development of drug resistance in between treatment cycles when the interval between therapy is prolonged. The dose-dense therapy may inhibit tumor regrowth between cycles and limit the emergence of malignant cell populations resistant to chemotherapy. Dose-dense strategy is the logical conclusion derived from the Norton–Simon model of tumor growth and drug response. Moreover, recent preclinical studies have shown that frequent administration in vivo of low doses of chemotherapeutic drugs, so-called “metronomic” dosing, may affect tumor endothelium and inhibit tumor angiogenesis, thus resulting in a better therapeutic index with reduced significant side effects (e.g., myelosuppression) involving other tissues. In solid tumors, this may be exemplified by the successful use of weekly paclitaxel in metastatic breast cancer.14

Chemotherapeutic Drugs Anticancer drugs may be subdivided into two large groups based on the dependence of their mechanism of action on the cell cycle (Table 2.2). Cell-cycle-nonspecific drugs, which include alkylating agents and most antitumor antibiotics, kill tumor cells in both the resting and cycling phases. On the other hand, it was previously mentioned that cell-cyclespecific drugs are most effective when tumor cells are

TABLE 2.2. Drugs according to cell-cycle effects. Cell cycle

Agents

Cell cycle nonspecific

Nitrogen mustards, aziridines, nitrosoureas, alkyl alkane sulfonates, nonclassic alkylating agents, anthracyclines, actinomycins, anthracenediones

Cell cycle specific S G2 M

Bleomycin, antimetabolites, camptothecins, epipodophyllotoxins Bleomycin, epipodophyllotoxins Vinca alkaloids, taxanes

principles of chemotherapy

17

transformation into active intermediates. Included in this latter group are procarbazine, dacarbazine, hexamethylmelamine, and temozolomide.

Nitrogen Mustards MECHLORETHAMINE Nitrogen mustards have been the most commonly used alkylating agents. The prototype is the vesicant mechlorethamine. It has an extremely short half-life of 15 to 20 minutes, as it undergoes rapid hydrolysis in the plasma to reactive metabolites. Its chief uses currently are in the treatment of lymphoma and mycosis fungoides (topical). Derivatives of mechlorethamine that have gained broader clinical use are the oxazaphosphorines cyclophosphamide and ifosfamide, chlorambucil, and melphalan. FIGURE 2.3. Cell-cycle-specific chemotherapeutic drugs and specific cell-cycle phase.

proliferating, that is, in cycles other than resting G0 phase (Figure 2.3). Moreover, these drugs are usually most active in a specific phase of the cell cycle. Cell-cycle-specific drugs include the antimetabolites, antitubulin agents, and drugs targeting topoisomerase. Tables 2.3 and 2.4 describe common toxicities for each drug that is discussed in more detail in the subsequent sections.

Classic Alkylating Agents Alkylating agents were the first class of agents to be clinically tested for cancer therapeutics. The alkylating agents form covalent bonds with nucleophilic cellular molecules, such as oxygen-, nitrogen-, phosphorus-, or sulfur-containing sites, through their alkyl groups. As a class, alkylating agents lack tumor selectivity but are generally active at very low doses. The bifunctional alkylating agents (two alkylating groups) not only alkylate but also crosslink DNA, leading to DNA template damage, subsequent cessation of DNA synthesis, and initiation of apoptosis upon recognition by cell-cycle checkpoint proteins such as p53. Alkylating agents thus are cytotoxic, teratogenic, and carcinogenic. Most secondary malignancies resulting from their use are acute leukemias. Dose-dependent myelosuppression is the usual toxicity common to alkylating agents. Dose-dependent nausea and vomiting are frequently encountered. Gonadal atrophy and alopecia are also common sequelae of alkylating agent treatment. Because of the steep dose–response curve, alkylating agents are standardly included in myeloablative high-dose chemotherapy regimens in various hematologic malignancies. In such cases, pulmonary toxicity, veno-occlusive disease of the liver (nitrosoureas, busulfan, thiotepa, cyclophosphamide, mitomycin C), and neurotoxicity (lipophilic agents such as ifosfamide, nitrosourea, thiotepa, busulfan, nitrosourea) may arise and are life threatening. The classic alkylating agents typically contain a chloroethyl group. They are classified as nitrogen mustards, aziridines, nitrosoureas, and alkyl alkane sulfonates. Nonclassic monofunctional alkylating agents, on the other hand, feature a common N-methyl group, do not produce DNA crosslinks, and are essentially prodrugs requiring metabolic

CYCLOPHOSPHAMIDE Both cyclophosphamide and ifosfamide require metabolic transformation by the cytochrome P-450 mixed-function oxidases in hepatic microsomes into their reactive intermediates.15 They are also capable of induction of the microsomal enzymes responsible for their metabolism. In the case of cyclophosphamide, the intermediates 4-hydroxycyclophosphamide and aldosphosphamide that escape oxidation by aldehyde dehydrogenase are converted by tumor cells into acrolein and phosphoramide mustard,16 the active alkylating agent that is responsible for the biologic effects of cyclophosphamide; this reaction is similar for ifosfamide. Because these metabolites are renally cleared, accumulation of acrolein in urine is responsible for hemorrhagic cystitis unique to these two agents,17 especially ifosfamide. Transitional cell carcinoma of the bladder developing as a late sequela has been described.18 Bladder toxicity may be reduced by hydration, frequent bladder emptying, and the use of thiol-containing agents such as N-acetyl cysteine (NAC) and mercaptoethane sulfonate (MESNA). These protectants are rich in sulfhydryl groups that bind and inactivate the charged toxic metabolites. Cyclophosphamide can be administered orally or intravenously. Nausea and vomiting are usually delayed, occurring hours after drug administration. Relative sparing of the platelet count at doses less than 30 mg/kg is very characteristic. Moreover, it exhibits a stem cell-sparing effect even at high doses, in contrast to busulfan and melphalan, because of the high levels of aldehyde dehydrogenase in the early bone marrow progenitor cells. Cyclophosphamide is the most immunosuppressive anticancer agent available. Cardiac toxicity is dose limiting in high-dose administration,19 although no cumulative toxicity of low to moderate doses is evident. A toxic tubular effect has also been described wherein water retention, and an SIADH-like (syndrome of inappropriate antidiuretic hormone) picture can occur with the use of 50 mg/kg or higher doses.20,21 Cyclophosphamide is used in various settings, such as in breast cancer, bone marrow transplant, and non-Hodgkin’s lymphoma (NHL), to name a few. IFOSFAMIDE Similar to cyclophosphamide, ifosfamide is well absorbed after oral administration. However, the oral metabolite chloracetaldehyde is highly neurotoxic and hence the oral form is not commercially available.22,23 It has a lower affinity for its activating enzymes, and thus its transformation to alkylating

Liver

Liver

Liver

Liver, renal Liver

Thiotepa

Carmustine (BCNU)

Lomustine (CCNU)

Streptozocin

Busulfan

Plasma decomposition, renal

Liver

Mitomycin C

Temozolomide

Plasma hydrolysis, renal

Melphalan

Liver, renal Liver, renal

Plasma hydrolysis

Mechlorethamine

Dacarbazine Altretamine

Liver

Ifosfamide

Liver

Liver

Cyclophosphamide

Procarbazine

Liver

Chlorambucil

Metabolism/ excretion

Myelosuppression; N&V, hemolysis (G6PD deficiency), MAOI crises, flu-like syndrome, disulfiram reactions with alcohol; neurotoxicity (paresthesias, neuropathies, ataxia, confusion, seizures), gonadal toxicity, secondary malignancy Myelosuppression, N&V, flu-like syndrome, photosensitivity N&V, myelosuppression, neurotoxicity (neuropathy, ataxia hallucinations), flu-like syndrome Myelosuppression, N&V, anorexia, headache, neurotoxicity (insomnia, somnolence, ataxia, hemiparesis, seizures), elevation of transaminases or cholestasis, peripheral edema

Myelosuppression, gonadal toxicity, secondary malignancy, mild N&V, skin hyperpigmentation (oral), hyperuricemia, cholestasis, hepatic VOD, seizures, bronchopulmonary dysplasia with pulmonary fibrosis, adrenal insufficiency

Myelosuppression, severe N&V, thrombophlebitis, seizures (wafers), hepatotoxicity, nephrotoxicity, pulmonary fibrosis, infusion-related hypotension and arrhythmias at high doses, gonadal toxicity, secondary malignancy Myelosuppression, severe N&V, gonadal toxicity, neurotoxicity (confusion, ataxia, dysarthria, lethargy), hepatotoxicity, nephrotoxicity, pulmonary fibrosis, secondary malignancy Nephrotoxicity, N&V, elevated transaminases and/or mild cholestasis, hypoglycemia, secondary malignancy

Myelosuppression, hyperuricemia, mild N&V, pulmonary fibrosis, seizures, gonadal toxicity, secondary malignancies Myelosuppression, hemorrhagic cystitis, N&V, alopecia, headache, nasal congestion with rapid infusion, SIADH, cardiomyopathy, immunosuppression, gonadal toxicity, pulmonary fibrosis (high-dose), secondary malignancy Myelosuppression, hemorrhagic cystitis, N&V, alopecia, metabolic acidosis, neurotoxicity (somnolence, hallucinations, ataxia, neuropathy), arrhythmias, CHF, SIADH, Fanconi syndrome, gonadal toxicity, azotemia, secondary malignancy Myelosuppression, severe N&V, dermatitis, thrombophlebitis, hyperuricemia, gonadal toxicity, secondary malignancy Myelosuppression, mild N&V, vasculitis, mucositis, diarrhea, SIADH hypersensitivity reactions, gonadal toxicity, secondary malignancy Myelosuppression, N&V, mucositis, HUS, DIC, microangiopathic hemolytic anemia, interstitial pneumonitis, thrombophlebitis, hepatic VOD, cardiomyopathy, bladder fibrosis (intravesical therapy) Myelosuppression, mild N&V, hyperuricemia, dermatitis, secondary malignancy, hemorrhagic cystitis (intravesical therapy)

Toxicity

Oral

IV infusion Oral

Oral

Oral or IV infusion

IV bolus or infusion

Oral

IV bolus or infusion, intrathecal, intravesical IV infusion, wafer implant (glioblastoma)

Slow injection IV bolus, infusion or oral Slow IV push or infusion, intravesical

Infusion or slow IV push

Infusion or oral

Oral

Administration

Consider dose reduction if bilirubin >3 mg/dl

Clcr 10–50 mL/min: 25% reduction Clcr < 10 mL/min: 50% reduction

Clcr 10–50 mL/min: 25% reduction Clcr < 10 mL/min: 50% reduction

Clcr 10–50 mL/min: 25% reduction Clcr < 10 mL/min: 50% reduction Clcr < 10 mL/min: 25% reduction

Scr 2.1–3.0 mg/dL: 25% to 50% reduction

Clcr < 10 mL/min: 25% reduction

Dose reduction in renal or liver dysfunction

chapter

Nonclassic alkylating agents

Classic alkylating agents

Chemotherapeutic agent

TABLE 2.3. Selected pharmacokinetic and toxicity features.

18 2

Antimetabolites

Antitumor antibiotics

Platinum compounds

Liver, renal

Liver

Liver

Kidney, renal

Epirubicin

Mitoxantrone

Dactinomycin

Bleomycin

Renal

Liver, renal

Idarubicin

Methotrexate

Liver, renal

Daunorubicin

Renal

Oxaliplatin

Liver

Renal

Carboplatin

Doxorubicin

Renal

Cisplatin

Myelosuppression, mucositis, renal failure, uric acid nephropathy, elevation in transaminases or cholestasis, hepatic fibrosis, pneumonitis, serositis, neurotoxicity (high-dose or intrathecal), gonadal toxicity, vasculitis, thromboembolic disease

Myelosuppression, mucositis, N&V, arrhythmias, cardiotoxicity(cumulative doses >140–160 mg/m2 cause CHF in ~10% of patients), elevated transaminases, urine discoloration, alopecia, secondary malignancy Myelosuppression, severe N&V, mucositis, cardiotoxicity, radiation recall, fatigue, hyperpigmentation, elevated transaminases, thrombophlebitis, hypocalcemia, hepatic VOD Skin reactions (erythema, peeling, etc.), pneumonitis, pulmonary fibrosis, anaphylactoid reactions, Raynaud’s phenomenon, arterial thrombosis, myocardial ischemia

Myelosuppression, mild N&V, mucositis, cardiotoxicity, radiation recall, alopecia, hyperpigmentation, urine discoloration, thrombophlebitis, gonadal toxicity

Myelosuppression, mild N&V, mucositis, alopecia, elevation of transaminases or cholestasis, GI hemorrhage, cardiotoxicity, radiation recall, hyperpigmentation, urine discoloration, thrombophlebitis

Myelosuppression, mild N&V, mucositis, alopecia, cardiotoxicity, elevation of transaminases, radiation recall, hyperpigmentation, urine discoloration

N&V, nephrotoxicity, electrolyte abnormalities, peripheral neuropathy, ototoxicity, myelosuppression, thromboembolic events, myocardial ischemia, ocular toxicity, thrombophlebitis, gonadal toxicity, mild elevation of transaminases or cholestasis, hypersensitivity reaction Myelosuppression, N&V, nephrotoxicity, neuropathy, electrolyte abnormalities, mild elevation of transaminases or cholestasis, delayed hypersensitivity reaction sensory > motor neuropathy, N&V, diarrhea, elevated liver transaminases, myelosuppression, nephrotoxicity, edema, hypersensitivity reaction Myelosuppression, mild N&V, mucositis, alopecia, cardiotoxicity, elevation of transaminases, radiation recall, hyperpigmentation, thrombophlebitis, urine discoloration

Oral, IV, IM, intrathecal

Slow IV bolus, IM, SC or intracavitary injection

Slow IV push

IV infusion, intraperitoneal

IV infusion

Oral, slow IV push or infusion

IV push or infusion

IV infusion, intraarterial, intravesical

IV infusion

IV infusion

IV infusion

Clcr 61–80 mL/min: 25% reduction Clcr 51–60 mL/min: 30% reduction Clcr 10–50 mL/min: 50–70% reduction Clcr 180 units: administer 75% of dose Bilirubin >5 mg/dL: do not use (continued)

Clcr 10–50 mL/min: 25% reduction Clcr 5 mg/dL or AST >180 IU: do not administer Serum creatinine >5 mg/dl: consider dose reduction Bilirubin 1.2–3 mg/dL or AST 2–4 times the upper limit of normal: 50% reduction Bilirubin >3 mg/dL or AST >4 times the upper limit of normal: 75% reduction Bilirubin 1.5–3 mg/dL: 50% reduction Bilirubin >3 mg/dl: 75% reduction

Bilirubin 1.5–3 mg/dL: 50% reduction Bilirubin 3.1–5 mg/dL: 75% reduction Bilirubin 2.1–3 mg/dL or AST 60–180 IU: 25% reduction Bilirubin 3.1–5 mg/dL or AST >180 IU: 50% reduction Bilirubin >5 mg/dL: omit use Serum creatinine ≥2 mg/dL: 25% reduction

Consider in renal dysfunction

Calvert’s formula

Clcr 10–50 mL/min: 25% reduction Clcr < 10 mL/min: 50% reduction

principles of chemotherapy

19

Renal Enzymatic catabolism

Enzymatic catabolism Enzymatic catabolism Enzymatic deamination Enzymatic deamination Enzymatic; renal (with high-dose therapy) Enzymatic; liver Renal

Renal Renal

Pemetrexed

5-Fluorouracil

5-FUDR

Capecitabine

Cytarabine

Gemcitabine

6-Mercaptopurine

Cladribine

Pentostatin

Fludarabine

Myelosuppression, N&V, mucositis, hepatotoxicity, hyperuricemia, crystalluria Myelosuppression, autoimmune hemolytic anemia, edema, immunosuppression, fever, elevated liver enzymes, neurotoxicity (somnolence, neuropathy, confusion, cortical blindness, coma), tumor lysis syndrome Myelosuppression, immunosuppression, edema, fever, headache, dizziness, tumor lysis syndrome Myelosuppression, immunosuppression, N&V, elevated liver enzymes, headache, lethargy, renal failure, acute pulmonary edema, ocular symptoms

Hepatotoxicity, hand-foot syndrome, myelosuppression, mucositis, neurotoxicity, edema, acute coronary syndrome, headache, ocular symptoms Diarrhea, hand-foot syndrome, myelosuppression, acute coronary syndrome, neurotoxicity, ocular symptoms; elevated transaminases or cholestasis Myelosuppression, N&V, GI ulcers, pancreatitis, cholestasis, hidradenitis, cerebellar dysfunction; with high-dose therapy: conjunctivitis, hand-foot syndrome, ARDS, elevated transaminases, hyperuricemia Myelosuppression, N&V, flu-like symptoms, asthenia, fever, hemolytic-uremic syndrome, pneumonitis, elevated liver enzymes, somnolence, paresthesias Myelosuppression, mild N&V, mucositis, hepatotoxicity, crystalluria, hyperuricemia, pancreatitis

Myelosuppression, fatigue, mucositis, hand-foot syndrome, edema, elevated liver transaminases or cholestasis Myelosuppression, mucositis, hand-foot syndrome, acute coronary syndrome, GI ulcers, neurotoxicity, ocular symptoms

Fatigue/asthenia, N&V, mucositis, severe diarrhea, myelosuppression, elevated liver transaminases or cholestasis, edema

Toxicity

IV infusion

IV infusion

IV infusion

Oral

Oral

IV infusion

IV infusion or bolus, IM, SC, intrathecal

Oral

Slow IV bolus or infusion, topical, intraarterial IV, intraarterial

IV infusion

IV infusion

Administration

Clcr 5.0 mg/dL or AST >180 units: omit dose bilirubin 1.5–3.0 mg/dL or AST 60–180 units: 50% reduction. bilirubin 3.0–5.0 mg/dL: 75% reduction Serum bilirubin >5.0 mg/dL or AST >180 units: omit dose Serum bilirubin 2.1–3 mg/dL: 50% reduction Serum bilirubin >3 mg/dL: 75% reduction Liver principles of chemotherapy

21

22

Procarbazine Dacarbazine Altretamine Temozolomide cisplatin carboplatin oxaliplatin Doxorubicin Daunorubicin Idarubicin Epirubicin Mitoxantrone Dactinomycin Bleomycin

Nonclassic alkylating agents

Antitumor antibiotics

Chlorambucil Cyclophosphamide Ifosfamide Mechlorethamine Melphalan Mitomycin C Thiotepa Carmustine (BCNU) Lomustine (CCNU) Streptozocin Busulfan

Classic alkylating agents

Chemotherapeutic agent

++++ ++++

+ ++++ ++++ ++++ +++ +++ ++++ +++ ++++ +++ +++ ++++ ++++ +++ +++ ±

++++

++++

++++ ++++ +++ ++++ ++ +++ +++ ++++ ++++ ++++ ++++ ++++ ++++ ±

+ ++ +++ ++++ + ++ + ++++

N&V

++++ ++++ ++++ ++++ ++++ ++++ ++++ ++++

M

TABLE 2.4. Frequency of adverse effects/toxicities.

+ ++ + + +++ ++ + ++

++

+

+

+ ++

+

+

Constipation

+

+

+

++ + ± +

+ +

Mucositis

+ ++• + + ++ ++ ++ +

+ ± +++ +

+ +

++ +

+ ± + ++ ++ ++ +++ + ± ++

+ +

±

++++‡

+ +

± ± ± ± + +§

Liver

± + ± + ±

Diarrhea

± ± +

±

±

+

±

++§

+ +

± ± ±

Pulm

+

+ /+ ++ + +

+++ /±

+

±/+ +/± +/+ +§/±

+/+ ++/+++

Renal/ bladder

++

+ + + + + +

+

+

+§

+* +

+ +

CVS

+

+

++ + ++ +++ +++ + +++

± +

+

+ + +†

± + + +

Neuro

+ + ± + + + ± ++++ ++++ ++ ++++ ++ ++ ++

+

+

+++ ++++ + + + + +

Alopecia

+ + ± + ± + + + + + + + + +++

++

+

+ + + +++ + + +++ +

Skin

+ + ++

++

+ ±

+ +

+ +

+

±

Fever

++ ++ ++

+++

++

++

± +

+ +

Weakness /fatigue

± ± +

+ + + ±

+

+

±

HSR

23

Methotrexate Raltitrexed Pemetrexed 5-Fluorouracil 5-FUDR Capecitabine Cytarabine Gemcitabine 6-Mercaptopurine 6-Thioguanine Fludarabine Cladribine Pentostatin Vincristine Vinblastine Vinorelbine Paclitaxel Docetaxel Topotecan Irinotecan Etoposide Teniposide +++ +++ +++ ++++ ++ ++++ ++++ ++ +++ +++ +++ ++ +++ ± ++++ ++++ ++++ ++++ ++++ +++ ++++ ++++

+++ +++ ++ + ++ +++ ++ +++ + + ++ + +++ + + ++ + +++ ++++ ++++ ++ ++ + +++

+ + + ++ + ++ +

++ ++ + +++ ++ ++ + + + + +

++

+ + ++

+

++

+

+ +

++ ++ + ++ ++ +++ + ++ + + + + + + + + + ++ ++ ++++ + ++ ++ ± + + + + + ++ + +

++ ++ +++ ± ++++冕 ++ + +++ ++ + ±

± ±

+ ±

± + ++ /+ /+ /±

±

± ±

±/± ++ +

+

± ± ± ±

+ + ++

+

+ + +

+ + + + + ± ++ +++

++ + ++ + ± + + +

+

+ ++ + + + + ++ +++ ++ +

+ + + + +

++ +

+ + + +++ ++ ++ ++++ ++++ ++ +++ +++ +

+ + ± + + + + + ±

+ +

+ ++ +++ ++ + +++ + ++ + + + ++ ++ + + + + +++ ++

++ ++ ++

+++ +

+ + + ++ +

++

++ +++ +++ +++ +++

++ + + +

++

++

+++ +++

±, 1.5 mm thickness; clinical NO)

1998

240

Elective lymphadenectomy vs. therapeutic lymphadenectomy

11 years

F/U, follow-up. a

RT, radiation therapy to chest wall, internal mammary, axillary, and supraclavicular lymph nodes.

Results

No significant differences between groups in overall or disease-free survival No significant differences between groups in overall or disease-free survival No significant differences between groups in overall or disease-free survival No significant differences between groups in overall or disease-free survival No significant differences between groups in overall or disease-free survival No significant differences between groups in overall or disease-free survival

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clinical studies documenting the survival benefit of surgical resection of isolated metastases, there is a significant body of retrospective evidence indicating that this approach can result in significant long-term benefit in patients with either lung or liver metastases. Aside from the regional lymph nodes, both lung and liver represent the next most common sites to which solid tumors metastasize. The resection of metastases to the lung in patients with osteogenic or soft tissue sarcomas has been established from numerous retrospective reports. Both osteogenic and soft tissue sarcomas have a propensity to metastasize to the lung as the only site. Computed tomography studies of the lung are capable of identifying lesions that are a few millimeters in size. Multiple wedge excisions can be performed utilizing stapling devices without compromise of pulmonary function. Pulmonary metastasectomies for bone and soft tissue sarcoma can result in 5-year overall survival rates of approximately 35% if all disease is resected.26,27 The resection of metastases for adenocarcinomas is not so well documented. Primary adenocarcinomas often metastasize to multiple sites and do not result in isolated lung metastases. When they are confined to the lung, the metastases are often too numerous to consider wedge resections. There are retrospective reports indicating that, in select patients with metastatic adenocarcinomas to the lung (i.e., colorectal primaries), resection can result in long-term survival benefit.28,29 A large body of retrospective evidence documents the benefit of resecting isolated liver metastases; this is especially the case for colorectal primary cancers. These cancers appear to have a pattern of spread that involves the liver as the initial site of metastasis. Resection of solitary or multiple colorectal liver metastases has resulted in a 25% to 40% overall 5-year survival rate, depending on the extent of liver involvement. Factors that have been associated with better survival are node-negative primary cancers, prolonged disease-free interval from time of primary resection to diagnosis of liver metastases, negative margins of hepatic resection, and fewer numbers of hepatic metastases (see Chapter 95). Current trials are under way to determine if adjuvant therapies given after hepatic metastasectomies further improve survival in this patient group. Besides colorectal liver metastases, the resection of noncolorectal liver metastases also can be therapeutic or palliative for selected individuals. For example, the resection of functional neuroendocrine metastases to the liver can result in palliation and prolonged survival of patients.30 These tumors tend to be indolent in their growth rate; however, the symptoms associated with the metastatic lesion can often be detrimental to the quality of life of the patient. For other nonneuroendocrine, noncolorectal liver metastases, resection can result in survival benefit as well. Patients with isolated genitourinary or gynecologic primary malignancies with a prolonged disease-free interval have been reported to benefit from aggressive resection of hepatic metastases.31 Both liver and lung represent the majority of the evidence that resection of visceral metastases can result in long-term survival. These results have been observed usually in the absence of adjuvant systemic therapies. Our current concept that solid malignancies are systemic at their onset (i.e., breast cancer) would have us surmise that, with the presence of bulky visceral metastases, there must also be micrometastatic disease present at the time the bulky disease is resected.

63

Nevertheless, approximately 20% to 25% of individuals remain disease free for many years. This finding begs the notion that perhaps an immune mechanism is involved in preventing disease relapse in a subset of these patients. Besides liver and lung sites, there are clearly anecdotes and published series indicating that the resection of isolated metastases to skin, bowel, adrenal glands, pancreas, and other sites can result in survival benefit. One of the roles of the surgical oncologist is to know when it is appropriate to offer surgical resection of metastatic disease as a palliative or therapeutic option.

Diagnosis and Staging In addition to operating for curative purposes, the surgical oncologist will often operate for the purpose of obtaining tissue for diagnosis or staging or for monitoring response to therapy. Biopsies for diagnosis can be done with fine-needle aspiration, core-needle biopsy, or incisional or excisional biopsy.

Fine-Needle Aspiration Fine-needle aspirations obtain cell suspensions suitable for cytology or flow cytometry. This technique can be helpful in aspirating a thyroid nodule, sometimes a breast lump, or a lymph node whenever lymphoma is not primary in the differential diagnosis. The advantages to fine-needle aspiration include the lack of a scar, lack of need for anesthetic, good patient tolerance of the procedure, and the relatively fast turnover of cytology in obtaining a diagnosis. Cellsurface receptors cannot be evaluated, and cytology cannot distinguish between invasive and noninvasive cancers. A fine-needle aspiration should be done only when the determination of atypical or malignant cells will help in diagnosis or treatment, such as proceeding with a thyroid lobectomy or documenting whether a lesion is recurrent cancer in a patient with a known history of the disease. Although a determination of cell abnormality and malignancy can be done, it is usually not sufficient for determining the definitive diagnosis of a primary neoplasm, with the possible exception of abnormal cytology on brushings from an endoscopic examination in a patient with a pancreatic head mass or bile duct stricture. Because of the possibility of false-positive results, cytology is not considered sufficient for proceeding with a major surgical resection such as a mastectomy. In such instances, a method of biopsy that yields definitive histology should be obtained.

Core-Needle Biopsy Core-needle biopsies can be done percutaneously by palpating a mass or lymph node or by radiologic guidance. Core biopsy material yields tissue architecture, including the diagnosis of malignancy, the tissue of origin of the primary tumor, whether a tumor is noninvasive or invasive, and cell-surface receptors. Advantages include the ability to do the biopsy under local anesthesia, minimal scarring, and improved patient tolerance of the procedure. Care should be taken to keep the entry point for the needle in a location that can be incorporated in a definitive resection of the mass in the event the result shows a malignancy (Figure 4.2). A core-needle

64 biopsy when diagnostic can allow planning for either neoadjuvant or adjuvant therapies or for surgical resection. For example, a core-needle biopsy of a large breast mass can allow neoadjuvant chemotherapy of a breast malignancy and possibly downstage the patient to being a breast conservation candidate, particularly when an excisional biopsy would be cosmetically unacceptable and obligate a mastectomy. Thus, it is usually the procedure of choice for making a pathologic diagnosis in many areas of oncology. For large soft tissue tumors or bone lesions, core biopsies should be the first method to consider to obtain a diagnosis.32,33 However, core needle biopsies often do not yield sufficient tissue for making a diagnosis of primary lymphoma, which often requires incisional or excisional biopsies.

chapter

4

verse incision on the extremity can lead to an unnecessarily morbid procedure because the definitive resection must achieve negative margins around the area of previous dissection (Figure 4.4). Impeccable hemostasis should be obtained during incisional biopsy procedures because the complication of a postoperative hematoma can lead to the dissemination of tumor cells into tissue planes well beyond the area that would be resected for definitive surgical therapy. For large cutaneous lesions, a punch biopsy represents a form of incisional biopsy that will sample all layers of the skin including the subcutaneous fat (Figure 4.5A). This procedure can be performed under local anesthesia in the outpatient setting using disposable punch biopsy tools (Figure 4.5B).

Excisional Biopsy Incisional Biopsy Incisional biopsies are usually done when a needle biopsy is nondiagnostic or technically not feasible. Common examples include a pancreatic mass in which attempts at obtaining cytology by endoscopic brushings or fine-needle aspiration via endoscopic ultrasound have been nondiagnostic, or for a retroperitoneal mass that is potentially a lymphoma. For these intraabdominal tumors, the minimally invasive laparoscopic approach offers advantages of obtaining adequate tissue material as well as staging information that might not be appreciated by imaging modalities. For tumors outside the abdomen, care should be taken in planning an incisional biopsy to keep the biopsy within the area of the definitive operation. Biopsies of the extremity should be done along the line of the long axis of the extremity (Figure 4.3). An improperly placed trans-

Smaller tumors are often more amenable to excisional biopsy. Excisional biopsy implies the removal of the entire skin lesion or lump. Small, particularly superficial, mobile tumors can be difficult to obtain with an adequate needle biopsy. Small masses or skin lesions on the extremity or trunk that are potentially malignant are often best approached with an excisional biopsy, as it allows definitive diagnosis without risking violation of tissue planes. Disadvantages include the resultant scar, the need for anesthetic, and the potential need for reexcision for margins. It is important to orientate excisional biopsy specimens in three dimensions for the pathologist to determine margins if surgical reexcision is needed. The precautions regarding orientation of incisions, not violating tissue planes, and hemostasis are the same as mentioned in the previous section on incisional biopsies.

FIGURE 4.3. Placement of an incisional biopsy incision in a patient with an extremity soft tissue tumor. These incisions should be placed parallel to the long axis of the extremity. [By permission of Sondak VK. In: Greenfield LJ, et al. (eds). Surgery Scientific Principles and Practice. Philadelphia: Lippincott: Williams & Wilkins, 1993.]

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FIGURE 4.4. Improperly placed transverse incision of a large soft tissue tumor. The tumor proved to be a high-grade sarcoma, with the subsequent wide excision being compromised because of the initial procedure.

Care should be taken, when biopsying more then one lesion of the same patient, to use separate instrument setups between biopsies in the event that not all the lesions are malignant to avoid cross-contamination of malignant cells between surgical sites. In this setting, precise labeling of each biopsy specimen is needed in the event that only one of the biopsied lesions is malignant to correctly identify the area to be further treated. It is also important to ensure proper handling of specimens. For example, lymph node tissue obtained for the potential diagnosis of lymphoma should go to pathology fresh to procure part of the specimen for flow cytometry. In addition to obtaining biopsies to make a diagnosis, the surgical oncologist is increasingly called on to do a biopsy to assess response to adjuvant therapy because routine imaging studies do not always reflect what is happening at the tissue level. For example, necrotic tumor may still show as a mass on CT or mammography. In some protocols, serial biopsies are obtained to access response to therapy; this is most often done as a core-needle biopsy.

Sentinel Lymph Node Biopsy Increasingly, attempts at a more minimal approach to lymph node staging are being done with selective lymphadenectomy, also known as sentinel lymph node mapping or biopsy. The principle underlying this approach assumes that a cancer will

65

metastasize to one or more sentinel nodes in the regional lymph node basin(s) as defined by the anatomic distribution of lymphatic vessels present within and adjacent to the tumor (Figure 4.6).34 One can determine whether the lymph node basin is involved with tumor by removing the sentinel lymph nodes and performing careful histologic examination of the nodes. Negative sentinel nodes predict fairly accurately that the remaining nodes within that basin will also be uninvolved with tumor, thereby avoiding the need for a regional lymphadenectomy and its attendant complications. This method has become the standard of care for staging patients with invasive breast cancer or melanoma (greater than 1 mm thickness) and is increasingly being evaluated in other malignancies such as head and neck, lung, gynecologic (i.e., cervical cancer), and gastrointestinal malignancies (i.e., colorectal and gastric cancers). The sixth edition of the American Joint Commission on Cancer staging guidelines has been revised to reflect the identification of micrometastasis to lymph nodes in melanoma and breast cancer (see Chapters 55 and 60). Complete lymph node dissections of the affected lymph node basin should be performed for positive sentinel lymph nodes. Continued questions remain regarding the incorporation of sentinel lymph node biopsy into melanoma treatment, including whether this method of staging and treating lymph node basins affects overall or disease-free survival (as is being evaluated in the Multicenter Selective Lymphadenectomy Trial), the natural history of microscopic sentinel node metastasis, and whether survival is affected by lymphadenectomy or treatments with interferon alpha-2b in these patients (as is being evaluated in the Sunbelt Melanoma Trial).35 Sentinel lymph node biopsy has been accepted as accurately staging the clinically negative axilla in early-stage breast cancer patients with accuracy rates of 97% or greater. Currently, all patients with histologically proven metastasis to the sentinel node undergo completion axillary lymph node dissection.

Cancer Prevention With the exponential increase in our understanding of inherited genetic mutations and the identification of patients who are predisposed to malignant transformation, surgical therapy has expanded beyond the therapy of established tumors and into the prevention of cancer. Prophylaxis is not a new concept in surgical oncology. Patients with chronic inflammatory diseases are known to be at high risk of subsequent malignant transformation. This realization typically prompts close surveillance and surgical resection at the first identification of premalignant changes. However, with the ability to perform genetic screening for relevant mutations, cancer prevention can be implemented before the onset of symptoms or histologic changes. With the decoding of the entire human genome, it is likely that more genes responsible for specific cancers will be identified, and the potential role for prevention will expand. Although many interventions may ultimately be nonsurgical (such as tamoxifen for the chemoprevention of breast cancer), the role of surgical therapy remains a primary option in the prevention of cancer. It is for this reason that all surgical oncologists must be aware of those high-risk situations that require surgery to prevent subsequent malignant disease (Table 4.3).

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4

A

B FIGURE 4.5. Punch biopsy of large cutaneous lesions. (A) Schematic view demonstrating that all layers of the skin can be sampled using this technique. (B) Different size punch biopsy tools that can be used. (A: From Arca MJ, Biermann JS, Johnson TM, et al.,32 by permission of Surgical Oncology Clinics of North America.)

FIGURE 4.6. Schematic diagram illustrating the lymphatic drainage of the breast and sentinel lymph nodes.

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67

TABLE 4.3. Potential indications for prophylactic organ removal. Prophylactic surgery

Potential indications

Bilateral mastectomy (patients with no history of cancer)

BRCA1 or BRCA2 mutation Atypical hyperplasia or lobular carcinoma in situ (LCIS) Familial breast cancer BRCA1 or BRCA2 mutation Familial breast cancer or age of diagnosis less than 40 years History of atypical hyperplasia or LCIS followed by unilateral breast CA Difficult to evaluate contralateral breast BRCA1 mutation Familial ovarian cancer Hereditary nonpolyposis colorectal cancer Hysterectomy for endometrial cancer Colon resection for colon cancer

Bilateral mastectomy (patients with unilateral breast cancer)

Bilateral oophorectomy in patients with no history of cancer Bilateral oophorectomy in addition to other abdominal cancer surgeries (postmenopausal women) Thyroidectomy

Total proctocolectomy

RET proto-oncogene mutation Multiple endocrine neoplasia type 2A (MEN 2A) Multiple endocrine neoplasia type 2B (MEN 2B) Familial non-MEN medullary thyroid carcinoma (FMTC) Familial adenomatous polyposis (FAP) or APC mutation Ulcerative colitis Hereditary nonpolyposis colorectal carcinoma (HNPCC) germ-line mutation

Colorectal Cancer One of the earliest examples of surgical prophylaxis is the recommendation for total proctocolectomy for subsets of patients with chronic ulcerative colitis. Patients with pancolitis, onset of disease at a young age, and a long duration of colitis are at high risk of developing colorectal cancer.36 Other clinical diseases of the large intestine also illustrate the role of proctocolectomy in cancer prevention. Familial adenomatous polyposis coli (FAP) syndrome, defined by the diffuse involvement of the colon and rectum with adenomatous polyps often in the second or third decade of life, almost always predisposes to colorectal cancer if the large intestine is left in place. However, the role of screening and prophylactic proctocolectomy changed dramatically with the identification of the gene responsible for FAP, the adenomatous polyposis coli (APC) gene, located on the long arm of chromosome 5 (5q21).37 Now, children of families in which an APC mutation has been identified can have genetic testing before polyps become evident. Carriers can have screening and surgical resection once polyps appear, usually in the late teens or early twenties. Although not ideal, the palatability of proctocolectomy in this population was furthered with the description of the total abdominal colectomy, mucosal proctectomy, and ileoanal pouch anastomosis.38 As we identify additional syndromes and genes that carry an increased risk of colorectal cancer, the potential role of screening and prophylactic surgery also expands. Hereditary nonpolyposis colorectal carcinoma (HNPCC), or Lynch syndrome, is an autosomal dominant disorder that is estimated to be responsible for 5% to 10% of all colorectal cancers. Although the carcinomas arise from benign adenomas, HNPCC is not characterized by a large number of polyps. Two Lynch syndromes have been described. Lynch syndrome I features an early age onset of cancer, often metachronous. Lynch syndrome II involves cancers not only of the small and large intestine but also endometrial, ovarian, renal, gastric, and hepatobiliary. Although the genes responsible for HNPCC

have been identified, namely hMSH1, hMLH1, hPMS1, and hPMS2, these mutations do not have a 100% penetrance; thus, cancer will not develop in all carriers. Prophylactic surgery is recommended for some but not all carriers, but aggressive screening should be implemented and a subtotal colectomy should be performed if a cancer develops.39,40

Breast Cancer Another example of prophylactic surgery is the bilateral mastectomy for women at high risk of developing breast cancer. Before the identification of the BRCA genes, prophylactic mastectomies were typically reserved as an option for women with lobular carcinoma in situ (LCIS). However, with the identification of BRCA1 and BRCA2, the role of prophylactic mastectomies has been greatly expanded. For women with BRCA1 or BRCA2 mutations, the lifetime probability of breast cancer is between 40% and 85%.41–43 Because mastectomy cannot remove all breast tissue, women can expect a 90% to 94% risk reduction with prophylactic surgery.44 Schrag et al. calculated the estimated gain in life expectancy after prophylactic surgery versus no operation in women with either a BRCA1 or BRCA2 mutation and found a 30-year-old woman would be expected to gain 2.9 to 5.3 years of life, depending on her family history.45 However, potential benefits of prophylactic mastectomy must be weighed against quality of life issues and the morbidity of the surgery.46 In addition, other methods for prophylaxis, such as tamoxifen chemoprevention or bilateral oophorectomy, must be considered. Along with the increased risk of breast cancer with BRCA1/2 mutations, the risk of ovarian cancer is also increased. Bilateral oophorectomy after childbearing is complete not only reduces the risk of ovarian cancer47 but may also decrease the risk of breast cancer.48 A detailed discussion must be held with each patient considering bilateral mastectomies regarding the risks and benefits, the knowns and unknowns. It is becoming increasingly important that today’s surgical oncologist have a clear understanding of genetics and inherited risk.

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chapter

Medullary Thyroid Cancer Increased genetic knowledge has also changed our approach to thyroid cancer. Medullary thyroid cancer (MTC) is a wellestablished component of multiple endocrine neoplasia syndrome type 2a (MEN 2a) or type 2b (MEN 2b). Previously, family members at risk for MEN 2 underwent annual screening for elevated calcitonin levels; however, this only detected MTC after it developed. In 1993 it was identified that mutations in the RET proto-oncogene were present in almost all cases of MEN 2a and 2b. Now family members of MEN patients can be screened for the presence of a RET mutation. Those without the mutation need not undergo additional screening, whereas those with the mutation should undergo total thyroidectomy at a young age (6 years for MEN 2a, infancy for MEN 2b).49

Palliation Surgical intervention is sometimes required in the patient with unresectable advanced cancer for palliative indications. The common indications for palliation in this setting are pain, bleeding, obstruction, malnutrition, or infection. The surgeon needs to consider several factors regarding each situation as to whether the surgical intervention will add significantly to the quality of life of the patient. These factors include the expected survival of the individual, the potential morbidity of the procedure, the likelihood that the procedure will palliate the patient, and whether there are alternative nonsurgical methods of palliation. The acute onset of pain, bleeding, or obstruction represents a potential oncologic emergency. This topic is covered in more detail in Chapter 74 (Surgical Emergencies). Probably the most common oncologic emergency that the surgeon con-

4

fronts is the obstruction of a hollow viscus, which can give rise to an acute abdomen, perforation of the viscus, and possibly bleeding. The hollow viscus could be the bowel, biliary tree, endobronchial tree, ureters, or bladder. There are surgical interventions that can be employed to address these problems, and in certain instances, nonsurgical approaches with stents that are effective. Malnutrition is a common problem in the cancer patient, especially one with advanced, unresectable disease. Nutrition can be supplemented or replaced by intravenous hyperalimentation or enteral feedings via a gastrostomy or jejunostomy tube. Commonly, the surgeon is involved in placement of vascular access for hyperalimentation. If the gastrointestinal tract is functional, the surgeon may be called upon to place a feeding tube for enteral nutrition. The nutritional support of the cancer patient as well as aspects of vascular access are reviewed in more detail in Chapters 82 and 85. Occasionally, the surgeon is involved in palliating pain caused by a metastatic lesion compressing an organ or adjacent nerves. Examples include cutaneous or subcutaneous melanoma metastases, a large ulcerating breast cancer, or a recurrent intraabdominal sarcoma mass. As indicated previously, the surgeon needs to assess the relative risk-to-benefit ratio in resecting a symptomatic mass, knowing that it will not affect the overall survival of the patient. If the quality of life of the individual can be improved at an acceptable operative risk, then the surgical intervention is warranted.

Surgical Considerations in the Cancer Patient There are special considerations when planning operative procedures on cancer patients beyond the normal planning done for the same operation on a nononcologic patient (Table 4.4).

TABLE 4.4. Special considerations in the cancer patient. Oncologic factors

Tumor-specific factors: Gastrointestinal Head and neck/mediastinal Cerebral tumors/brain metastasis Paraneoplastic syndromes Cancer factors: Cachexia/malnutrion Hypercoagulability Bone metastasis Treatment-specific factors: Steroids Chemotherapy

Radiation therapy Tamoxifen

Potential associated problems

Obstruction and aspiration risk; gastrointestinal bleeding; bowel perforation Reduced oral intake; superior vena cava obstruction; airway compromise; difficulty with ventilation or intubation Decreased mental status; syndrome of inappropriate secretion of antidiuretic hormone; increased intracerebral pressures Syndrome of inappropriate secretion of antidiuretic hormone; hypercalcemia Increased infection; fluid and electrolyte management; wound healing Venous thrombosis; superior vena cava syndrome; pulmonary embolism Hypercalcemia; increased fracture risk; potential for cord compression; potential for difficulty with intubation Gastritis and gastrointestinal bleeding; diabetes; adrenal insufficiency; difficulties with wound healing Neutropenia and anemia; pulmonary fibrosis; cardiac dysfunction; stomatitis; alteration in mucosal integrity of the gastrointestinal tract; constipation; bowel perforation; nausea; vomiting; diarrhea; hypercoagulability Pulmonary fibrosis; difficulty with wound healing Hypercoagulability

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These considerations include cancer syndromes affecting nutrition, debilitated performance status, hypercoagulability, paraneoplastic syndromes, tumor-specific effects, and effects of chemotherapy or radiation therapy.

69

increased nutrient loss. An assessment of nutritional status can be done by assessing for a recent weight loss of 10% or more from prediagnosis weight, current caloric intake, or by measuring albumin, prealbumin serum transferrin, or cutaneous testing for anergy.

Tumor-Specific Effects Alteration of physiologic function or distortion of normal anatomy may occur due to specific tumor effects. For example, tumors of the mediastinum or neck may cause venous congestion, superior vena cava obstruction, airway compression, or tracheal deviation that may make establishment of an airway or ventilatory management difficult. Gastrointestinal tumors may cause obstruction, causing an aspiration risk. Cerebral tumors or brain metastases can cause changes in mental status, syndrome of inappropriate secretion of antidiuretic hormone making perioperative fluid management difficult, or may cause an increased intercerebral pressure that affects anesthesia management of the patient.

Paraneoplastic Syndromes Paraneoplastic syndromes such as hyponatremia due to inappropriate secretion of antidiuretic hormone such as seen in small cell lung cancers, prostate, pancreas, and other cancers, or hypercalcemia such as seen in squamous cell carcinomas of the lung, breast, or kidney, will alter nutritional and fluid and electrolyte management. Although mild hyponatremia can be associated with mild symptoms such as nausea and headaches, severe, acute hyponatremia can lead to more severe symptoms, even seizures or coma. Hypercalcemia is most often associated with bone metastasis, but it may be related to a paraneoplastic syndrome and can lead to neuromuscular symptoms such as weakness and fatigue and gastrointestinal symptoms such as nausea, ileus, and abdominal pain. Severe hypercalcemia can disturb cardiac conductivity. Given the tendency to malnutrition and low serum albumin in cancer patients, serum calcium levels are often best determined by measuring ionized calcium.

Malnutrition A hallmark warning sign of cancer is unexplained weight loss. Malnutrition has long been recognized in surgery as being related to an increased risk of infection, with difficulties in perioperative electrolyte and fluid management, and with difficulties in wound healing postoperatively. A large National Veterans Affairs Surgical Risk Study identified the preoperative serum albumin level as the single most important predictor of 30-day mortality.50 Cancer cachexia is a syndrome of malnutrition with muscle wasting, protein malnutrition with myopathy, incomplete nutrient utilization, glucose intolerance, and anemia with decreased nutrient absorption. Its causes are multifactorial. Cancer, or its treatment, can cause alterations in taste, stomatitis, dysphagia, anorexia, nausea and vomiting, alterations in intestinal tract absorptive surface area, gastroparesis, constipation, pancreatic insufficiency, or pain, fatigue, and depression, which in turn can lead to impaired oral intake. Gastrointestinal tumor with associated obstruction or head and neck tumors can interfere with, or prohibit, oral intake. In addition, tumor- or treatment-associated diarrhea, fistulas, or nephrotic syndrome can lead to

Hypercoagulability Cancer is associated with hypercoagulability and an increased risk of venous thrombosis or pulmonary embolism. This susceptibility can be compounded by decreased mobility resulting from fatigue and diminished functional status, or by pain related to the operative procedure. Operations particularly of risk include operations of the abdomen, pelvis, hip, or leg. Surgery that is of long duration, which uses laparoscopy, or has a degree of postoperative immobilization adds additional risk. Cancer patients have twice the risk of postoperative venous thrombosis, and three times the risk of fatal pulmonary embolism, as noncancer patients undergoing the same procedure.51 Patients at a higher risk are those with a history of previous myeloproliferative disorders such as polycythemia vera and primary thrombocytosis, or a history of obesity, varicose veins, cardiac dysfunction, indwelling central venous catheters, inflammatory bowel disease, nephrotic syndrome, pregnancy, or estrogen use, or treatment with tamoxifen or chemotherapy. Treatment with tamoxifen induces hypercoagulability with an associated two- to threefold greater risk of venous thrombosis. This risk is increased even more in women undergoing treatment with both chemotherapy and tamoxifen.52,53 Chemotherapy has been shown to increase the risk of thromboembolism up to 7% in early-stage breast cancer patients.52,54 A history of hypercoagulable abnormalities should be ascertained, such as activated protein C resistance (factor V, Leiden); prothrombin variant 20210A; antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibody); deficiency or dysfunction of antithrombin, protein C, protein S, or heparin cofactor II; dysfibrinogenemia; decreased levels of plasminogen and plasminogen activators; heparin-induced thrombocytopenia; or hyperhomocystinemia.55 Cancer patients older than 40 years undergoing major surgery without prophylaxis have a risk of deep venous thrombosis of 10% to 20% and a risk of fatal pulmonary embolism of 0.2% to 5.0%.10 Although most clinical trials show pneumatic compression devices to be similar in effectiveness to prophylactic doses of subcutaneous heparin, their effectiveness is directly dependent on compliance with their use, and most clinicians recognize that, in practice, pneumatic compression devices are only on the patient a portion of the time they are nonambulatory and therefore they are not as effective.56 The sixth American College of Chest Physicians consensus conference in 2000 recommended the following: (1) oncology patients more than 40 years old undergoing major surgery, or nonmajor surgery in patients more than 60 years old, with no other risk factors, receive pneumatic compression devices or low molecular weight heparin; (2) oncology patients more than 40 years old undergoing major surgery and additional risk factors receive pneumatic compression devices and prophylactic low molecular weight heparin; and (3) low-dose coumadin for patients with central venous catheters. They did not recommend routine continuation of anticoagulation after discharge for surgical patients;

70 however, many clinical studies are under way regarding the efficacy of continued prolonged anticoagulation after discharge from a surgical procedure.

Chemotherapy Considerations Agents such as adriamycin can affect cardiac function, and an assessment of functional status, a review of systems looking for decreased exercise tolerance, dyspnea, edema, orthopnea, etc., should be elicited. On physical examination, particular attention should be paid to signs of edema, tachycardia, or arrhythmias. At minimum, a 12-lead EKG should be done on any patient who has received adriamycin before undergoing a surgical procedure to look for conduction changes. An echocardiogram for an evaluation of function should be done for any symptomatic patients before any major surgical procedure in patients who have received an adriamycin-based chemotherapy. An evaluation of respiratory symptoms should be elicited in patients who have undergone radiation to the thorax or treatment with bleomycin-based chemotherapy to evaluate for pulmonary fibrosis. Treatment with corticosteroids can lead to diabetes or adrenal insufficiency requiring monitoring of glucose levels postoperatively and potential treatment with stress dose steroids and the implications for glucose control perioperatively. Treatment with steroids can also lead to gastritis and gastrointestinal bleeding or mask symptoms of peritonitis, making evaluation of abdominal pain difficult. Chemotherapy can also affect the gastrointestinal tract, with bowel perforation having been reported in patients undergoing treatment with cytosine arabinoside, taxol, and interleukin 2. In addition it should be remembered that oncology patients will still succumb to and need to be treated for the same illnesses as nononcologic patients such as cholecystitis and appendicitis; however, treatment with steroids, or immunosuppressive agents such as seen in patients after bone marrow transplantation, and the potential for neutropenic colitis in those undergoing chemotherapy can make evaluation of these more common diseases more difficult.57

Elderly Patient In addition, the readers are reminded that older or elderly patients will increasingly make up the population of patients with cancer. Currently 60% of all malignancies, and 70% of all cancer deaths, occur in people over the age of 65.58 In addition to the previously mentioned considerations, assessment of the older patient should include evaluation of activities of daily living, depression, cognitive function, current medications and potential medication interactions, and available social support.59–62

Clinical Trials: Role of the Surgical Oncologist At the very heart of evidence-based medicine, and nowhere is this truer than in oncology, are clinical trials. Although the early trials initiated by the National Cancer Institute (NCI) in the mid-1970s primarily considered nonsurgical issues (leukemia, lymphoma, stage IV disease), surgeons quickly became involved in significant roles in clinical oncology trials, such as the National Surgical Adjuvant Breast Project (NSABP), which has answered, and continues to

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answer, many important questions regarding the optimal surgical and adjuvant therapy of breast and colon cancer. Today, most cooperative groups include surgery committees to address ongoing questions regarding the surgical management of a variety of malignancies. The prominent role of surgery in the design and implementation of clinical oncology trials is best exemplified by the establishment of the American College of Surgeons Oncology Group (ACOSOG) to evaluate the surgical management of patients with malignant solid tumors. Created in May 1998 under the leadership of Dr. Samuel Wells, the ACOSOG is 1 of 10 cooperative groups funded by the NCI to develop and coordinate multiinstitutional clinical trials. As surgical oncologists, our obligation is not only to the patient who is sitting before us in the office, but to the progression of patients who will follow. The improved success and decreased morbidity of the treatments that we offer today are only possible because of the involvement of surgeons and their patients in clinical trials of the past. As the newest discoveries in all fields of oncology will have a direct impact on the surgical therapy, it is imperative that surgeons continue to play prominent roles as both leaders and participants in multidisciplinary cooperative group trials. All surgical oncologists should not only incorporate clinical trials into their practice but strongly encourage the participation of the general surgical community.

References 1. Lewison EF. Breast Cancer and Its Diagnosis and Treatment. Baltimore: Williams & Wilkins, 1955. 2. Rutledge RH. Theodore Billroth: a century later. Surgery (St. Louis) 1995;118:36–43. 3. Weir R. Resection of the large intestine for carcinoma. Ann Surg 1886;1886(3):469–489. 4. Halsted WS. The results of operations for the cure of cancer of the breast performed at the Johns Hopkins Hospital from June 1889 to January 1894. Ann Surg 1894;320(13):497–555. 5. Clark JG. A more radical method for performing hysterectomy for cancer of the cervix. Johns Hopkins Bull 1895;6:121. 6. Crile G. Excision of cancer of the head and neck. JAMA 1906; XLVII:1780. 7. Miles WE. A method for performing abdominoperineal excision for carcinoma of the rectum and terminal portion of the pelvic colon. Lancet 1908;2:1812–1813. 8. Krakoff IH. Progress and prospects in cancer treatment: the Karnofsky legacy. J Clin Oncol 1994;12:432–438. 9. Farber S, Diamond LK, Mercer RD, et al. Temporary regressions in acute leukemia in children produced by folic acid antagonist, aminopteroyl-glutamic acid. N Engl J Med 1948;238: 693. 10. Huggins CB, Hodges CV. Studies on prostatic cancer: the effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941;1:293–297. 11. Lawrence W Jr, Wilson RE, Shingleton WW, et al. Surgical oncology in university departments of surgery in the United States. Arch Surg 1986;121:1088–1093. 12. Fisher B, Remond C, Poisson R, et al. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1989;320:822–828. 13. Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy

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experience with ninety-six patients. Surgery (St. Louis) 1997; 121:625–632. Arca MJ, Biermann JS, Johnson TM, Chang AE. Biopsy techniques for skin, soft tissue, and bone neoplasms. Surg Oncol Clin N Am 1995;17:1–11. Barth RJ Jr, Merino MJ, Solomon D, Yang JC, Baker AR. A prospective study of the value of core needle biopsy and fine needle aspiration in the diagnosis of soft tissue masses. Surgery (St. Louis) 1992;112:536–543. Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992;127:392–399. Reintgen D, Pendas S, Jakub J, et al. National trials involving lymphatic mapping for melanoma: the Multicenter Selective Lymphadenectomy Trial, the Sunbelt Melanoma Trial, and the Florida Melanoma Trial. Semin Oncol 2004;31:363–373. Ekbom A, Helmick C, Zack M, et al. Ulcerative colitis and colorectal cancer: a population-based study. N Engl J Med 1990; 323:1228–1233. Miyoshi Y, Nagase H, Ando H, et al. Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum Mol Genet 1992;1:229–233. Ambroze W Jr, Dozois R, Pemberton J, et al. Familial adenomatous polyposis: results following ileal pouch-anal anastomosis and ileorectostomy. Dis Colon Rectum 1992;35:12–15. Rodriguez-Bigas MA, Boland CR, Hamilton SR, et al. A National Cancer Institute workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 1997;89:1758–1762. Lynch HT, Lynch J. Lynch syndrome: genetics, natural history, genetic counseling, and prevention. J Clin Oncol 2000;18(21a): 19s–31s. Mann GB, Borgen PI. Breast cancer genes and the surgeon. J Surg Oncol 1998;67:267–274. Eeles RA, Powles TJ. Chemoprevention options for BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2000;18:93s–99s. Anderson BO. Prophylactic surgery to reduce breast cancer risk: a brief literature review. Breast J 2001;7(5):321–330. Hartmann LC, Schaid DJ, Woods JE, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med 1999;340:77–84. Schrag D, Kuntz KM, Garber JE, Weeks JC. Decision analysis: effects of prophylactic mastectomy and oophorectomy on life expectancy among women with BRCA1 or BRCA2 mutations. N Engl J Med 1997;336:1465–1471. Newman LA, Keurer HM, Hunt KK, et al. Prophylactic mastectomy. J Am Cancer Soc 2000;191(3):322–330. Rebbeck TR. Prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2000;18(21s):100s–103s. Rebbeck TR, Levin AM, Eisen A, et al. Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst 1999;91:1475–1479. Phay JE, Moley JF, Lairmore TC. Multiple endocrine neoplasias. Semin Surg Oncol 2000;18:324–332. Daley J, Khuri SF, Henderson W, et al. Risk adjustment of the postoperative morbidity rate for the comparative assessment of the quality of surgical care: results of the National Veterans Affairs Surgical Risk Study. J Am Coll Surg 1997;185:328– 340. Kakkar AK, Williamson RC. Prevention of venous thromboembolism in cancer patients. Semin Thromb Hemost 1999; 25:239–243. Saphner T, Tormey DC, Gray R. Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer. J Clin Oncol 1991;9:286–294. Deitcher SR, Gomes MP. The risk of venous thromboembolic disease associated with adjuvant hormone therapy for breast carcinoma: a systematic review. Cancer (Phila) 2004;101:439–449.

72 54. Levine MN, Gent M, Hirsh J, et al. The thrombogenic effect of anticancer drug therapy in women with stage II breast cancer. N Engl J Med 1988;318:404–407. 55. Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001;119:132S–175S. 56. Maxwell GL, Synan I, Dodge R, Carroll B, Clarke-Pearson DL. Pneumatic compression versus low molecular weight heparin in gynecologic oncology surgery: a randomized trial. Obstet Gynecol 2001;98:989–995. 57. Diehl KM, Chang AE. Acute abdomen, bowel obstruction, and fistula. In: Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG (eds). Clinical Oncology. Philadelphia: Elsevier Churchill Livingstone, 2004:1025–1045.

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58. American Cancer Society: Cancer Facts and Figures 2003. Atlanta, GA: American Cancer Society, 2003. 59. Extermann M, Meyer J, McGinnis M, et al. A comprehensive geriatric intervention detects multiple problems in older breast cancer patients. Crit Rev Oncol Hematol 2004;49:69– 75. 60. Chen CC, Kenefick AL, Tang ST, McCorkle R. Utilization of comprehensive geriatric assessment in cancer patients. Crit Rev Oncol Hematol 2004;49:53–67. 61. Extermann M. Studies of comprehensive geriatric assessment in patients with cancer. Cancer Control 2003;10:463–468. 62. Balducci L. Geriatric oncology. Crit Rev Oncol Hematol 2003; 46:211–220.

5

Principles of Targeted and Biological Therapies Stephen R.D. Johnston, Sue Chua, and Charles Swanton

Development of Targeted Therapies

Target Identification

One of the characteristics of the malignant phenotype is the ability of cells to grow in an autonomous manner. Various components of the proliferative and/or survival signaling pathways can become constitutively activated or deregulated in human cancers.1 Many studies have attempted to show that a given molecular change is the key event involved in the pathogenesis of a specific cancer. Such information may not only provide a better understanding of cancer but may allow a novel target to be identified for therapeutic intervention. With our ever-increasing understanding of the pathogenesis of cancer, there are now a plethora of potential molecular targets in human cancer cells that are being utilized for the development of novel anticancer therapies (Table 5.1). Perhaps the oldest and most established targeted therapy is endocrine treatment for breast and prostate cancer, taking advantage of the estrogen receptor (ER) and androgen receptor (AR) that can readily be detected in many breast and prostate carcinomas, respectively. More recently, peptide growth factor receptors (EGFR and HER2) have become viable targets in human solid epithelial tumors such as lung, head and neck, breast, and colon cancer. The unraveling of the signal transduction cascade within cells has resulted in various small molecule signal transduction inhibitors (STIs) entering clinical development, whereas the complex protein interactions that regulate the cell cycle may allow various modulators to be developed to restore cell-cycle control in aberrantly behaving malignant cells. Likewise the ability to effectively trigger programmed cell death (apoptosis) in cancer cells adapted to prolonged survival is a promising new approach for the future. Finally, the capacity for malignant cells to acquire a blood supply is a key event in the growth of human tumors, and drugs are being developed that target either the endothelial cell or the vascular growth factor pathways. The principles and current status of targeted therapies in each of these six areas are reviewed in this chapter. However, a common theme to all these approaches is the need to confirm that a given molecular target is specifically involved in the pathogenesis of that cancer, to develop an assay to reliably detect the target in tumors, and to show that interrupting its function gives the desired anticancer effect.

Some of the problems of target identification in cancer are illustrated by considering kinases, regulatory enzymes that are integral to most signaling events inside cells. In cancer, these may be either pivotal or permissive for the pathogenesis of the malignant phenotype.2 Pivotal kinases are often critical to tumor growth and maintenance and may be subject to activation by mutation, gene amplification, or translocation (i.e., p210BCR-ABL in chronic myeloid leukemia), whereas permissive kinases are not mutated or amplified but still may have a role in signal transduction pathways important in neoplastic growth. One of the challenges has been to identify pivotal kinases for anticancer drug development and to select patients with aberrations in these critical signaling pathways for inclusion in early clinical trials. To do this, robust biologic assays are required that will readily identify potential targets in cancer cells. High-throughput screening using cDNA microarrays and techniques such as comparative genomic hybridization have been extensively employed to analyze gene expression in human tumors, thereby identifying novel targets for therapeutic drug development.3 Target identification and validation have been supported by tissue microarray profiling that allows the analysis of DNA, RNA, or protein levels in thousands of tumor specimens at a time to identify the frequency of molecular alterations in a population of patients with a given cancer type. In future, complex proteomic techniques using mass spectrometry will allow the identification of potential protein drug targets that are differentially expressed between tumor and normal tissue. Preclinical studies are important to determine what a gene product–protein target does in the cell, and moreover what the consequences are of inhibiting its expression or function, respectively. The technique of synthetic short interfering RNAs (siRNA) that lead to the degradation of complementary mRNA, thereby silencing gene expression, is a helpful new tool in analyzing the functional significance of certain gene products. Similarly, high-throughput screens using siRNAs in mammalian cells are in progress to identify molecular regulators that are involved in the acquisition of the malignant phenotype and also in the development of drug resistance.

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TABLE 5.1. Targets for the development of novel anticancer therapies. Molecular target

Steroid hormone receptor ER AR Growth factor receptor EGFR

Anticancer therapeutic strategy

Antiestrogen (tamoxifen, fulvestrant), Aromatase inhibitor, LHRH agonist Antiandrogen (flutamide), LHRH agonist

Approved breast Approved prostate

MoAb (cetuximab)

MoAb (trastuzumab) TKI (lapatinib, canertinib)

Approved colon; Phs III H&N, NSCLC. Approved NSCLC; Phs III breast Approved Breast Phs III breast, renal

TKI (imatinib)

Approved CML, GIST

FTIs (tipifarnib, lonafarnib)

Phs III MDS, CML, breast, NSCLC Phs II Melanoma Phs I Phs III breast, renal

TKI (gefitinib, erlotinib) HER2 Oncogenic kinase BCR-ABL Signal transduction pathway Ras Raf MEK m-TOR Cell cycle Cdk2 Proteosome Histone deacetylase Apoptosis regulators TRAIL Bcl-2 P53 Caspase XIAP, FLIP Angiogenesis Endothelial cell VEGF VEGF-R Integrins

Tumor type and stage of clinical development

B-RAF Kinase Inhib (BAY43-9006) MEK Kinase Inhib (PD0325901) mTOR Antag (temsirolimus, everolimus) CDKI (flavopiridol, UCN-01, E7070) Proteosome Inhib (bortezomib) HDACI (FR901228, MS-27-275)

Phs I Approved Myeloma Phs I

MoAb Antisense (G3139) P53 (ONXY-015, INGN201, Nutlin) Sphingosine kinase (phenoxodiol)

Phs Phs Phs Phs

Endo Inhib (thalidomide, TNP-740) Endostatin, angiostatin Antisense (angiozyme) MoAb (bevacizumab) TKI (SU11248, PTK787) MoAb (2C7) Integrin Inhib (cilengitide) MMPI (marimastat, BAY12-9566)

Phs II renal, H&N Phs I Phs I Approved Colon, phs II H&N Phs I Phs I Phs I Phs III NSCLC, gastric

Approach to Targeting Pharmacologic or biologic methods are usually employed in preclinical studies to establish the effect of altering the expression of the target gene or of interfering with the function of the target protein. Most approaches have utilized either small molecule inhibitors (often detected in screening assays) or monoclonal antibodies (MAbs) to interfere with the function of the target protein. In general, small molecule inhibitors have a short half-life and are orally delivered on a continuous long-term basis. However, side effects can be common and potentially troublesome, especially if there is a broader substrate for related cellular proteins/kinases. By contrast, MAbs have a longer half-life with a more acceptable toxicity profile, although they require regular intravenous administration. Monoclonal antibodies usually target surface receptors and may also lead to receptor downregulation, although there is the additional theoretical potential for direct tumor cell cytotoxicity via complement and antibody (antibody-mediated cellular cytotoxicity, ADCC). Side effects may relate to hypersensitivity reactions, with the potential

I II NHL II H&N, phs I II breast, prostate

also to develop human antimonoclonal antibodies (HAMAs) that may limit effectiveness. Other approaches to targeting include the use of antisense technology to inhibit target messenger RNA that is transcribed from a given gene, although a key limiting factor is appropriate delivery of nucleic acids to the tumor cell. The use of viral vectors in targeted therapy approaches to modify/replace or inhibit target genes has therefore attracted much attention, and this method has been used to replace or stabilize key tumor suppressor proteins that may regulate cell survival and apoptosis.

Targeted Therapies Hormone Receptor-Targeted Therapies Targeting hormonal growth pathways has been an effective strategy in the management of various tumors such as breast, prostate, and endometrial cancers. Early approaches were directed at surgical ablation of the glands supplying these

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hormonal stimuli (i.e., ovariectomy for breast cancer and orchiectomy for prostate cancer), but over the pst 30 years a large number of medical agents have become available based on an increasing understanding of molecular endocrinology.

Breast Cancer Medical endocrine strategies in breast cancer are designed to counteract the proliferative effects of estrogen in ER-positive breast cancer, either with drugs that compete with estrogen for ER and block its effect (i.e., antiestrogens), or strategies that induce estrogen deprivation and remove the proliferative signal [i.e., oophorectomy or gonadotropin-releasing hormone (GnRH) agonists in premenopausal women, and aromatase inhibitors in postmenopausal women]. Tamoxifen is a nonsteroidal estrogen receptor (ER) antagonist that inhibits breast cancer growth by competitive antagonism of ER, although its actions are complex as a result of partial estrogenic agonist effects, which in some tissues (i.e., bone) can be beneficial but which in others may be harmful, increasing the risk of uterine cancer and thromboembolism. Oral aromatase inhibitors prevent conversion of adrenal androgens (androstenedione and testosterone) into estradiol (E1) and estrone (E2) by the cytochrome P-450 enzyme aromatase. Alternative endocrine approaches are also being developed, including steroidal antiestrogens that selectively downregulate expression of ER.4

Prostate Cancer Normal prostate cells and tumor cells are sensitive to androgens, which are produced by two major sources: the testicles, which produce testosterone (95% of all androgens), and the adrenal glands, which produce dehydroandrosterone, dehydroandrosterone sulfate, and androstenedione. Both are under the influence of luteinizing hormone (LH), which in turn is controlled by GnRH produced by the hypothalamus. Testosterone levels have a negative feedback effect on GnRH release from the hypothalamus. Targeted endocrine medical treatment of prostate cancers aims to decrease the activity of androgens on the AR, either with antiandrogens (i.e., nonsteroidal agents such as flutamide, biclutamide) that competitively block dihydrotestosterone (DHT) binding to AR, and subsequent activation of AR-regulated genes, or by suppression of LH secretion (i.e., using specific LH agonists that ultimately inhibit LH secretion, thus reducing androgen production).

Growth Factor Receptor-Targeted Therapies In human cancer cells, aberrant signaling through the epidermal growth factor receptor (EGFR) has been associated with neoplastic cell proliferation, resistance to apoptosis, migration and stromal invasion, and enhanced angiogenesis. The EGFR (or ErbB-1) is part of a subfamily of four closely related receptors that include HER-2/neu (ErbB-2), HER-3 (ErbB-3), and HER-4 (ErbB-4).5 These receptors exist as inactive transmembrane monomers in cells, and dimerize after ligand activation either by homo- or heterodimerization between EGFR and another member of the ErbB receptor family. This dimerization results in activation of the intracellular tyrosine kinase domain through autophosphorylation, which in turn

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initiates a cascade of downstream signaling pathways that include Ras and mitogen-activated protein kinase (MAPK). In cancer cells, various mechanisms for activation of EGFR or related ErbB pathways include receptor overexpression (e.g., as a result of gene amplification in the case of HER-2), receptor mutation (e.g., truncated EGFR that lacks the extracellular domain but has a constitutively activated tyrosine kinase domain that functions independent of ligand), increased autocrine or paracrine expression of the various receptor ligands [e.g., transforming growth factor-alpha (TGF-a), amphiregulin, heparin-binding EGF], or decreased receptor turnover. Studies have shown that EGFR or HER-2 overexpression in cancer is often associated with a poorer prognosis and resistance to conventional therapies including hormonal therapy, cytotoxic drugs, and radiotherapy.6 Consequently, EGFR and related receptors represent an attractive target for the development of novel cancer therapeutics. The two most promising approaches have been MAbs against the extracellular ligand-binding domain of the receptor and small molecule inhibitors of the receptor intracellular tyrosine kinase enzymatic activity (TKIs).

Inhibition of Extracellular Domain Growth Factor Receptor: Monoclonal Antibodies Cetuximab (C225 or Erbitux) is a chimeric antibody that binds to EGFR, inhibiting downstream signaling and promoting receptor internalization, and significant growth inhibition has been observed in a variety of human cancer xenograft models.6 Additive effects were seen when cetuximab was combined with various cytotoxic agents and with ionizing radiation. The clinical development has focused on selecting patients with EGFR-overexpressing tumors, and Phase II/III trials have been conducted in head and neck cancer,7 colorectal cancer,8 and advanced non-small cell lung cancer9 (Table 5.2). These latter studies have investigated whether addition of cetuximab can enhance the activity of conventional therapies for these tumor types. Recent data demonstrate that cetuximab, in addition to irinotecan in patients with irinotecan-refractory metastatic colorectal cancer, improves median survival and time to progression.8 HER2 gene amplification occurs in 25% to 30% of breast tumors and contributes to cell growth and malignant transformation, rendering tumors more resistant to both endocrine and conventional chemotherapies.10 Trastuzumab (Herceptin) is a humanized MAb directed against HER2 and, when administered as a weekly intravenous infusion, gave clinical response rates of 35% as first-line therapy for patients with HER2+ve metastatic breast cancer.11 One of the central principles is the appropriate selection of patients with HER2+ve tumors, and validated assays have been developed to identify either HER2 overexpression by immunohistochemistry or HER2 gene amplification by fluorescence in situ hybridization (FISH). The addition of trastuzumab to taxane- or anthracycline-based chemotherapy enhanced both objective response and time to disease progression, which in turn significantly improved overall survival in advanced breast cancer (median, 25 versus 20 months, P < 0.046).12 As such, this represented one of the first examples of modern targeted therapies successfully modifying disease outcome.

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TABLE 5.2. Clinical trials with monoclonal antibodies against epidermal growth factor receptor (EGFR). Metastatic Colon Cancer Phase II Trial 329 EGFR-positive patients after irinotecan failure9

Cetuximab alone

Irinotecan + Cetuximab

Response rate Median time to progression Survival

10.8% 1.5 months 6.9 months (NS)

22.9% 4.1 months 8.6 months (NS)

Metastatic/Recurrent Head and Neck Cancer Phase III trial8

Cisplatin

Cisplatin + Cetuximab

Response rate Progression-free survival

9.3% 3.4 months

22.6% 3.4 months

Advanced Non-Small Cell Lung Cancer EGFR positive 1st line10

Vinorelbine + Cisplatin

Vinorelbine + Cisplatin + Cetuximab

32.2%

53.3%

Response rate

Inhibition of Intracellular Signaling: Tyrosine Kinase Inhibitors IMATINIB MESYLATE (STI-571 OR GLIVEC) When growth factor receptors are bound by their natural ligand, they undergo dimerization with subsequent activation of receptor tyrosine kinase activity, which in turn phosphorylates downstream signal transduction cascades. Small molecule tyrosine kinase inhibitors (TKIs) specifically target the receptor’s internal tyrosine kinase domain. The first to prove effective in the clinic was imatinib mesylate (STI-571 or Gleevec), which targets a small family of tyrosine kinases including ABL, Kit, and platelet-derived growth factor receptor (PDGF), as well as certain oncogenic mutants of these proteins such as the bcr-abl oncogene found in chronic myeloid leukemia.13 The success of this therapy relates to the dominant role that these pivotal kinases play in the pathogenesis of certain tumors; that is, 90% of gastrointestinal stromal tumors (GIST) exhibit aberrant signal transduction through KIT, primarily through activating point mutations in exon 11 that encodes the intracellular region of the protein, with evidence that KIT activation is an early tumorigenic event in most GIST tumors.14 KIT mutations were a strong predictor of response to imatinib in early clinical trials and produced significantly prolonged survival.15 The high level of efficacy appeared independent of tumor bulk and failure of prior chemotherapy, with objective responses in 54% of patients and stable disease in an additional 28% to 37%.16,17 This molecularly targeted therapy has transformed the management of this previously intractable disease. GEFITINIB (IRESSA) Several small molecule inhibitors of EGFR tyrosine kinase are in development, including the synthetic anilinoquinazoline gefitinib (Iressa), which is an orally active, potent, and selective inhibitor of EGFR-TK. In experimental models gefitinib induced dose-dependent antiproliferative effects that delayed tumor growth.18 The effects appeared mainly cytostatic, and additional studies suggested that, when given in combination with cytotoxic drugs, gefitinib could enhance their antitumor activity.19 This interaction did not always appear to be dependent on overexpression of EGFR, and the mechanism for any enhanced cytotoxic effect remains unclear.

Evidence of efficacy in Phase II non-small cell lung cancer (NSCLC) studies led to the accelerated approval for gefitinib by the U.S. Food and Drug Administration (FDA) for the treatment of NSCLC in patients previously treated with chemotherapy20,21 (Table 5.3). However, two Phase III randomized trials, INTACT-1 and INTACT-2 (Table 5.4), that compared platinum-based chemotherapy and gefitinib to chemotherapy alone in chemotherapy-naive NSCLC patients, failed to demonstrate a survival advantage for the addition of targeted therapy, despite the preclinical evidence for an additive benefit for gefitinib–chemotherapy combinations.22 Several theories have been proposed to explain the failure of these trials, including the possibility that cytostatic effects of targeted therapy may abrogate the cytotoxic effects of cycledependent chemotherapy. Unlike the trastuzumab studies, where patients were selected based on HER2 status, there were insufficient data at the time to predict which biologic markers may correlate with response to gefitinib. This failing may have severely reduced the chance of success in the Phase III setting, which contained patients with a heterogeneous selection of tumor phenotypes. Clinical trials have been undertaken with gefitinib in other tumor types, including breast cancer. There have been three Phase II monotherapy studies of gefitinib in patients with advanced breast cancer.23–25 Overall, the data are relatively disappointing with low clinical response rates. The only trial to report a significant number of responses included patients with ER+ve tamoxifen-resistant breast cancer,25 the setting in which preclinical models had shown evidence of

TABLE 5.3. Summary of Phase II studies in advanced platinumrefractory non-small cell lung cancer (NSCLC) with EGFR tyrosine kinase inhibitors (TKIs).

Response rate 1 year Survival Median survival

IDEAL 1 Gefitinib 250/500 mg25

IDEAL 2 Gefitinib 250/500 mg24

Erlotinib36

18/19% 35/30% 7.6/8.1 months

12/9% 29/24% 6.1/6.0 months

11% ? ?

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p r i n c i p l e s o f t a r g e t e d a n d b i o l og i c a l t h e r a p i e s TABLE 5.4. Phase III trials of gefitinib with chemotherapy as first-line treatment of NSCLC. INTACT 126

Gem/Cis alone

Chemo + Gefitinib 250 mg

Chemo + Gefitinib 500 mg

Response rate 1-year survival Median survival

44.8% 44% 10.9 months

50.3% 41% 9.9 months

49.7% 43% 9.9 months

Carbo/Paclitaxel alone

Chemo + Gefitinib 250 mg

Chemo + Gefitinib 500 mg

28.7% 42% 9.9 months

30.4% 41% 9.8 months

30% 37% 8.7 months

INTACT 2

Response rate 1-year survival Median survival

activity for gefitinib.26 More research is required to establish tumor phenotypes in responding versus nonresponding patients.27

disappointing.32 Important activity in previously treated glioblastoma multiforme was demonstrated in a Phase II study (with 8 of 49 patients achieving a partial response).

ERLOTINIB (TARCEVA) Erlotinib is an ErbB1 TKI that binds reversibly to the adenosine triphosphate (ATP) hydrophobic pocket. Table 5.3 summarizes data from recent Phase II trials in advanced NSCLC with erlotinib. A Phase II study in 56 patients with EGFRpositive NSCLC refractory to platinum-based therapy gave a response rate of 11% for erlotinib 150 mg/day.28 Results of Phase III combination studies of erlotinib with carboplatin and paclitaxel (TRIBUTE) or gemcitabine and cisplatin (TALENT) in NSCLC demonstrated no significant survival benefit or differences in time to progression.29,30 However, the NCI Canadian BR21 placebo-controlled Phase III trial of erlotinib in NSCLC patients failing one or two prior chemotherapy regimens demonstrated prolonged survival in the erlotinib arm (6.7 versus 4.7 months).31 Ongoing trials are investigating the activity for the combination of two targeted therapies in NSCLC, erlotinib and the VEGF antibody bevacizumab (avastin). Phase II data in other tumor types have revealed response rates in pretreated patients with ovary and head and neck tumors between 11% and 13%, although Phase II monotherapy trials in breast cancer have been relatively

CANERTINIB DIHYDROCHLORIDE (CI-1033); LAPATINIB (GW 572016) Canertinib dihydrochloride (CI-1033) is a selective and irreversible pan-erbB inhibitor. Activity has been demonstrated in Phase I studies with an acceptable side-effect profile, and Phase II studies are under way in breast and renal cancer.33 Lapatinib (GW 572016) is a dual inhibitor of EGFR and HER234 that has shown responses in trastuzumab-resistant breast cancer patients.35 Further studies of lapatinib in combination with either endocrine or cytotoxic therapy are ongoing in breast cancer.

FIGURE 5.1. The signal transduction inhibitors.

Signal Transduction-Targeted Therapies Elucidation of the signal transduction cascade downstream from growth factors and membrane receptor tyrosine kinases has revealed several key proteins involved in this malignant transformation, including the guanine nucleotide-binding proteins encoded by the ras proto-oncogene (Figure 5.1). Following posttranslational processing and addition of a hydrophobic 15-carbon farnesyl moiety, Ras is localized to the

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inner plasma membrane and acts as a molecular switch that plays a crucial role in linking tyrosine kinase activation at the cell membrane to downstream cytoplasmic and nuclear targets, ultimately resulting in cell differentiation, proliferation, and survival.36 Farnesylation has attracted attention because of its critical role for Ras signaling,37 and farnsesyl transferase inhibitors (FTIs) were initially developed as a novel therapy to target aberrant Ras function in cancer.

Farnesyltransferase Inhibitors As farnesyltransferase inhibitors (FTIs) have been developed and entered clinical trials, a fundamental research goal has been to understand their exact mechanism of action. Although FTIs clearly inhibit Ras farnesylation, it is unclear whether the antiproliferative effects of these compounds result exclusively from their effects on Ras alone. Other targets for FTIs include RhoB, a 21-kDa protein that regulates receptor trafficking and cell motility, and two centromereassociated proteins (CENP-E and CENP-F) that play a role in attaching centromeres to microtubules in early G2 phase.38 The FTI lonafarnib (SCH66336 or sarasar) is a tricyclic compound that inhibits the growth of several tumor cell lines as well as K-ras-transformed xenografts in vivo.39 In human xenograft studies a wide variety of tumors including colon, bladder, lung, prostate, and pancreas were growth inhibited in a dose-dependent manner, while prophylactic administration of SCH66336 delayed both tumor onset and growth.40 In patients with solid tumors, efficacy has been reported in early Phase I clinical studies in a variety of tumor types including lung and head and neck cancer,41 and confirmation of biologic efficacy has been demonstrated by inhibition of prenylation of prelamin A in buccal mucosa cells in treated patients42 (Table 5.5). Based on promising preclinical evidence that

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lonafarnib may synergize with taxane-based chemotherapy,43 randomized Phase II/III trials were initiated in NSCLC to investigate whether lonafarnib could further enhance the efficacy of standard taxane platinum-based chemotherapy. Tipifarnib (R115777 or zarnestra) is an imidazole-containing heterocyclic compound that is a potent and selective, orally active, nonpeptidomimetic inhibitor of the farnesyl protein transferase (FPTase) enzyme.44 There is considerable evidence that tipifarnib may have promising activity in hematologic malignancies, in particular, newly diagnosed acute myelogenous leukemia (AML) and myelodysplasia (MDS)45,46 (see Table 5.5). In view of the higher incidence of Ras mutations in gastrointestinal malignancies, two randomized double-blind placebo-controlled Phase III trials of tipifarnib were conducted in colorectal and pancreatic cancer. There was no significant improvement in overall survival versus best supportive care for tipifarnib as monotherapy in advanced refractory colorectal cancer,47 or for gemcitabine plus tipifarnib versus gemcitabine plus placebo in 688 patients with advanced pancreatic cancer.48 Although several Phase I studies have assessed combinations of FTIs with various cytotoxic agents, it remains unclear whether they will significantly enhance the efficacy of standard cytotoxic regimens. Several issues have arisen, including competing toxicities (i.e., myelosuppression) and uncertainty on the optimal sequence/schedule for FTI–chemotherapy combinations. There may be more promise for combining FTIs with noncytotoxic therapies. In breast cancer, preclinical data have shown additive or synergistic interactions of FTIs with endocrine therapy,49 and in view of this, randomized Phase II studies of both tipifarnib and lonafarnib with letrozole are in progress. Evidence has also emerged that FTIs may be radiosensitizers in selected cancer cell lines, and Phase I trials have investigated the feasibility of this combined modality in

TABLE 5.5. FTI Phase I/II clinical trials. Drug

SCH 66336 Lonafarnib

R115777 Tipifarnib

Author

No. patients (pts)

Dose-limiting toxicities

Dose range

Schedule

Adjei et al. Solid tumors

25–400 mg bid

7 days oral (q21)

20

Nausea, vomiting, diarrhea

Eskens et al.50 Head and neck cancer Lung cancer Johnston et al.56 Advanced breast cancer

25–300 mg bid

Continuous oral

24

Neutropenia, thrombocytopenia, vomiting, confusion Neutropenia, thrombocytopenia, neurotoxicity, and fatigue

51

Continuous dose (CD) of 300 or 400 mg bid n = 41) or intermittent dose (ID) of 300 mg bid for 21 days followed by 7 days rest (n = 35) 300 mg bid

Kurzrock et al.54 Myelodysplastic syndrome Karp et al.55 High-risk leukemias

100–1200 mg bid

76

21 days oral (q28)

21

Myelosuppression, fatigue and rash

21 days oral (q28)

34

Neurotoxicity

Clinical/biological activity

Inhibition of prelamin A farnesylation in buccal mucosal cells; PR in 1 pt with non-small cell lung Ca; 8 pts stable for 5–10 cycles Stable disease lasting >9 months in 2 pts (thyroid Ca, pseudoyxoma peritonei) CD: 4 partial responses (10%) lasting 4–12 months. 6 patients stable disease (15%) for at least 6 months ID: 5 partial responses (14%) and 3 patients with stable disease (9%) 1 complete remission 2 partial responses 3 pts with hematologic improvement 32% response rate in AML

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both lung and head and neck cancer. The true role for FTIs in cancer therapy thus remains to be determined.

m-TOR Inhibitors: Targeting the PI3K/AKT Pathway The mammalian target of rapamycin (mTOR) is a downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway that mediates cell survival, proliferation, and drug resistance (see Figure 5.1). The immunosuppressant rapamycin, together with the analogues CCI-779 (temsirolimus) and RAD-001 (everolimus), are specific inhibitors of mTOR that act by binding to the immunophilin FK506, thus blocking the action of p70S6 kinase and 4E-binding protein 1, which regulate transition through the G1 phase of the cell cycle. In preclinical experiments, cell lines from breast, prostate, small cell lung cancer, melanoma, T-cell leukemia, and glioblastoma were especially sensitive to CCI-779.50 In particular, breast cancer and prostate cell lines that had a constitutively activated PI3K/Akt pathway due to either upstream HER2 overexpression, loss of the PTEN suppressor gene, or Akt overexpression were markedly more sensitive to CCI-779 than resistant lines that lacked these features.51 CCI-779 has an acceptable toxicity profile in Phase I studies with reports of neutropenia, rash, fever, hypertriglyceridemia, mucositis, and fatigue as the main toxicities, with clinical activity seen in patients with NSCLC, breast, and renal cell carcinoma.52 Phase II studies in patients with advanced renal cell carcinoma demonstrated that CCI-779 was well tolerated with objective response rates of 7%, minor responses of 29%, and disease stabilized in 40% of patients.53 This trial precipitated a randomized Phase III study comparing CCI-779 with interferon-alpha or the combination in poor prognosis renal cell carcinoma. Single-agent activity has also been documented in locally advanced or metastatic breast cancer in patients who have failed prior anthracyclines or taxanes.54 Phase I studies of RAD-001 have demonstrated a similar toxicity profile to CCI-779.55

Raf Kinase Inhibitors: BAY 43-9006 RAF kinase is a critical signaling molecule downstream of RAS (see Figure 5.1). Activating mutations in BRAF (a RAF family member) occur in two-thirds of melanomas and at lower frequencies in other cancers.56 Promising Phase I data with the orally active RAF kinase inhibitor BAY 43-9006 in combination with chemotherapy have been reported, with stable disease for at least 12 weeks in 38 of 115 (33%) patients. Toxicities included skin rash, hand-foot syndrome, diarrhea, and fatigue. Phase II trials are in progress in melanoma with continuous monotherapy dosing of 400 mg bid,57 and in combination with carboplatin and paclitaxel.58

Intervention of the MAPK Pathway by Targeting MEK: CI-1040 and PD0325901 CI-1040 inhibits MEK allosterically at micromolar concentrations and is administered orally, thereby preventing activation of MAPK. The lack of sequence homology of the drug interaction site with other kinases increases the specificity of this small molecule inhibitor. CI-1040 is well tolerated in Phase I trials, with 98% of adverse events being only of grade 1 or 2 in severity (diarrhea, fatigue, rash, and vomiting).59 Dis-

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appointing Phase II results were seen in patients with breast, lung, colon, and pancreatic carcinoma.60 CI-1040 was limited by poor solubility, high metabolic clearance, and low bioavailability and was unable to consistently lead to more than 90% inhibition of the target in biopsied tumors. This result precipitated the development of PD0325901, a second-generation non-ATP-competitive allosteric MEK inhibitor. Preclinical studies have demonstrated promising activity with greater solubility, improved metabolic stability and bioavailability, and longer duration of MEK inhibition than its parent compound, and clinical trials are in progress.

Cell-Cycle-Targeted Therapies The cell cycle is regulated by a number of key proteins that appear to be frequently inactivated or aberrantly expressed in human cancer. The cyclin D and E family of proteins, together with their cyclin-dependent kinase (cdk) partners (cdk4 and -6) phosphorylate the retinoblastoma (Rb) tumor suppressor protein, which regulates G1/S transition and commitment to cell-cycle transition (Figure 5.2). Cyclin/cdk activity is restrained by cdk inhibitors (CKIs) of the p16ink4a and the p21cip1 family of proteins. The appropriate interaction of the cyclin/cdk families and the CKIs regulate the cell-cycle checkpoints at the G1/S and G2/M transitions, ensuring faithful chromosome replication and separation to preserve genetic stability. Failure of these checkpoints to arrest cells in response to certain stimuli is characteristic of cancer cells and is due to the frequent genetic aberration in expression and function of cell-cycle regulatory proteins in transformed cells. The greater understanding of the cell cycle has led to the development of a number of compounds that might restore the control of cell division in cancer cells. In particular, two strategies are now being explored in the clinic. First, compounds have been developed to mimic the action of CKIs by interfering with action of the cdk molecules.61 Second, pharmacologic agents have been developed to target the proteosome or histone deacetylases, thereby interfering with the degradation and expression of key molecules that regulate the cell-cycle checkpoint.

Cdk Inhibitors FLAVOPIRIDOL Flavopiridol targets the ATP-binding pocket of cdk2 and arrest cells at either the G1/S or G2/M checkpoints and may inhibit other cdks including cdk1, cdk7, and cdk9. The initial Phase I trial explored a 72-hour continuous infusion of flavopiridol, but dose-limiting toxicities included secretory diarrhea and symptomatic hypotension62 (Table 5.6). In three separate phase II studies with this schedule, objective tumor responses were rare, although disease stabilization was seen in a number of patients.63–65 Previous preclinical studies had shown synergy and induction of apoptosis when flavopiridol was combined with standard cytotoxic therapies,66 and clinical activity using combination therapy has been seen in patients previously resistant to the given cytotoxic drug alone.67,68 Preclinical evidence of synergism with paclitaxel therapy followed by flavopiridol in animal models further supported clinical studies of this combination,69 and Phase I combination studies have demonstrated promising activity in lung, esophagus, and prostate cancer.70 Thus, although cdk

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FIGURE 5.2. Cell-cycle-targeted therapies.

inhibitors alone may only have a cytostatic effect, combined therapy may prove more promising in enhancing their anticancer mode of action. UCN-01 UCN-01 is a cell-cycle modulator with a number of complex effects resulting in both G1/S arrest and aberrant entry into M phase. These cell-cycle kinetics are associated with an increased p27kip2–cdk2 interaction, Rb hypophosphorylation, and cdk1 activation due to chk1 inhibition. Phase I trials examined a 72-hour continuous infusion schedule, with doselimiting toxicities that included nausea, hypotension, hyper-

glycemia, and pulmonary toxicity, and evidence for activity was seen in two patients with melanoma and lymphoma. E7070 E7070 is a novel sulphonamide compound that inhibits the activation of cyclin E–cdk2 complexes and in vitro has demonstrated activity against both colon and lung cancer xenografts. A number of Phase I studies have investigated different schedules. The main dose-limiting toxicity has been myelosuppression; alopecia, stomatitis, and diarrhea have also been reported.71,72 Tumor stabilizations were seen in some of these studies, but documented tumor regressions

TABLE 5.6. Flavopiridol clinical trials. Author

Trial

Tumor type

Dose

Toxicity

Response

Senderowicz77

Phase I N = 76

Refractory neoplasms

72 h ivi q 2 wk MTD 50–78 mg/m2/24 h

1 partial response (PR) 3 minor responses

Schwartz86

Phase I Paclitaxel + FP

Advanced solid tumors

P Day 1 24 h or 3 h ivi FP Day 2 24 h ivi

Bible82

Phase I 5-FU and LV N = 24

Advanced solid tumors

FP 40–100 mg/m2/24 h Day 1 5-FU 350 mg/m2/day 1 h ivi Days 2–5 LV 20 mg/m2 Days 2–5

Stadler et al.78

Phase II N = 35

Advanced renal

50 mg/m2/d ivi over 72 h q 2 wk

Schwartz80

Phase II N = 16

Advanced gastric

50 mg/m2/d ivi over 72 h q 2 wk

Diarrhea (62.5 mg/m2/d ¥ 3) ADP 98 mg/m2/d ¥ 3 Hypotension Proinflammatory syndrome Neutropenia at P:FP doses of P 135 mg/m2/24 h: FP 10 mg/m2 & P 100 mg/m2/24 h FP 20 mg/m2 Diarrhea Headache Fatigue Hypotension Syncope Dehydration Asthenia Diarrhea G3/420% Thrombosis (26%) (MI, PE, DVT, TIA) Fatigue (93%) Diarrhea (73%) Venous thromboses (33%)

FP, flavopiridol; P, paclitaxel; 5-FU, 5-fluorouracil; LV, leucovorin; N, number of patients; ADP, antidiarrhea prophylaxis.

Activity in lung, esophagus, prostate cancer 1 PR (liver metastasis CRC) 13% SD

Ineffective in metastatic renal cell carcinoma

No major responses

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were rare in phase II monotherapy trials conducted in nonsmall cell lung cancer73 and in colorectal cancer74 with E7070.

Proteosome Inhibitors Protein concentrations within the cell may be altered by posttranslational modification leading to polyubiquitination followed by proteasome-mediated degradation. Prevention of ubiquitination and proteasome-mediated degradation of cellcycle proteins has been explored as a novel targeted anticancer therapy.75 Bortezomib (PS-341 or velcade) is a potent and selective proteasome inhibitor that prevents the degradation of the CKIs p21 and p27. In addition, key apoptosisrelated proteins are degraded by the proteasome such as IkappaB, an inhibitor of the transcription factor NFkappaB that regulates various apoptotic processes. In 2003, the FDA approved the use of bortezomib in patients with multiple myeloma who have received two previous lines of treatment, partly due to the results of a large multicenter phase II trial in 202 patients with relapsed refractory multiple myeloma that demonstrated a 35% response rate with a median survival of 17.8 months.76,77 A phase III trial comparing bortezomib with high-dose oral dexamethasone in relapsed or refractory multiple myeloma was terminated prematurely following the recommendation of an independent data monitoring committee to allow patients receiving high-dose dexamethasone to choose bortezomib therapy. Combination studies with cytotoxic agents are also under way, with promising activity already demonstrated.77

Histone Deacetylase (HDAC) Inhibitors Inside the nucleus of cells, histone acetylation–deacetylation modifies the chromatin structure and association between DNA and nucleosomes, thus modulating access for nuclear transcription factors such as E2F that are involved in initiating transcription of genes essential for S-phase entry.

FIGURE 5.3. Apoptosis-targeted therapies.

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Inhibitors of histone deacetylase result in G1 cell-cycle arrest and cell differentiation and appear to have anticancer effects including induction of apoptosis in transformed cells79 and enhanced expression of the cdk inhibitor p21.80 Two compounds have entered early clinical trials, depsipeptide (FR901228) and the synthetic benzamide derivative MS-27-275.

Apoptosis-Targeted Therapies Apoptosis, or programmed cell death, in normal human tissues has an essential role in controlling overall cell number. In many human tumors apoptosis is impaired, contributing to cellular transformation. Triggering of apoptosis is determined by the ratio of pro- and antiapoptotic proteins, in particular, members of the Bcl2 family, the intracellular antiapoptotic proteins (IAPs), tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), and the caspase family. Although cytotoxic chemotherapy drugs can induce apoptosis in malignant cells, resistance to chemotherapy may in some instances relate to alteration in the molecular pathways that regulate apoptosis. There are two major apoptotic pathways that can be triggered in cells: the extrinsic death-receptor-induced extrinsic pathway, and the intrinsic mitochondrial apoptosome-mediated pathway (Figure 5.3). The extrinsic pathway is regulated by members of the TNF superfamily, FASL (FAS ligand), TNF, and TRAIL. These “death receptors” signal through the “death-inducing signaling complex” (DISC), leading to caspase activation and apoptosis. The intrinsic mitochondria apoptosome pathway is controlled by members of the Bcl2 family. The proapoptotic members of this family (e.g., BAX, BAK, BIM, and BID) precipitate the release of cytochrome c from mitochondria, which promotes the formation of the apoptosome (cytochrome c/APAF1/caspase 9) complex. Members of the Bcl2 family that inhibit the pathway include

82 Bcl2 itself, Bclxl, and Bclw. P53 can regulate both the intrinsic pathway by promoting the transcription of BAX and the extrinsic pathway through upregulation of the death receptor. Apoptosis is also suppressed by the IAPs (inhibitors of apoptosis). Members of this family include XIAP, IAP1, IAP2, and survivin. These proteins interact with and inhibit selected effector caspases. IAP suppressors have also been identified and include Smac/DIABLO and XAF1. Many of the targeted therapies mentioned above act in part through the promotion of apoptosis; for example, the proteosome inhibitor bortezomib and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) precipitate apoptosis in tumor cells. Similarly, flavopiridol-mediated inhibition of the cell-cycle kinase, cdk1, enhances the cytotoxicity of doxorubicin in MCF7 human breast carcinoma xenografts through the suppression of survivin phosphorylation.81 However, some of the more direct therapies targeting components of the apoptosis pathway are discussed next.

Strategies to Modulate Apoptosis TRAILR1 Monoclonal Antibody This MAb targets TRAILR1 expressed on human cancer cells and induces apoptosis in human tumor cell lines. Although initial studies suggested that TRAIL activation preferentially leads to apoptosis of tumor cells over normal cells, recent data suggest that human hepatocytes may also be sensitive to TRAIL activity.82 Phase I studies are currently in progress.

Antisense Bcl2 Strategies: G3139 G3139 is an antisense phosphorothioate oligonucleotide that suppresses the expression of the antiapoptotic protein Bcl2. Results of a trial of 21 patients with non-Hodgkin’s lymphoma treated with subcutaneous G3139 demonstrated a response rate of 14% with a further 43% exhibiting stable disease.83 Phase III trials are in progress.

Strategies Targeting p53: ONYX-015, INGN 201, Nutlins ONYX-015 is a mutant adenovirus with a loss-of-function mutation of the adenoviral E1B gene product. The wild-type viral gene product E1B inactivates p53. ONYX-015 selectively replicates in p53-deficient tumor cells leading to cytolysis. The virus is unable to replicate in cells with wild-type p53.84 Promising results have been demonstrated in phase I and II trials, and also in combination with chemotherapy agents.85 Regional delivery of ONYX-015 has been attempted in different tumor types. A Phase II trial of intratumoral ONYX015 in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer demonstrated objective tumor responses with an acceptable toxicity profile.86 Furthermore, biopsies revealed selective adenoviral replication and necrosis within some tumor specimens. Intratumoral injection has also been attempted in patients with breast cancer chest wall recurrence. Hepatic artery infusion of ONYX-015 in a Phase I/II study of 35 patients with liver metastases secondary to colorectal carcinoma demonstrated antitumoral activity,87 while a Phase I trial of intraperitoneal regional delivery of ONYX-015 was conducted in refractory ovarian cancer.88

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INGN 201 is a replication incompetent adenovirus vector in which the E1 region has been replaced by wild-type p53 gene under the control of a cytomegalovirus promoter. Preclinical studies demonstrated anticancer properties in head and neck tumor cell lines and xenografts. A Phase I trial of stereotactic intratumoral injection of INGN 201 into recurrent glioma demonstrated minimal toxicity and the transfer of p53 to astrocytic tumor cells that led to transcriptionally active p53, with upregulation of target genes such as p21cip1 and apoptosis in subsets of cells. Phase II studies in patients with advanced recurrent squamous cell carcinoma of the head and neck treated with intralesional INGN 201 indicate that the virus is well tolerated.89 Disease stabilized in 6 of 17 patients with nonresectable disease, and 2 of 17 patients exhibited partial responses. Paradoxically, efficacy appeared independent of p53 status. Mdm2 inhibits p53 by promoting p53 nuclear export, impeding the interaction of transcription factors with the activation domain of p53 and triggering the degradation of p53 via the ubiquitin-proteosome pathway. Nutlins are a family of synthetic compounds that can successively displace Mdm2 from the N-terminus of p53, thereby promoting p53 activity.90 This is an exciting technical development for the manipulation of protein–protein interactions by small molecules. Furthermore, it raises the possibility of activating p53 in tumors that retain normal p53, thereby promoting apoptotic pathways.

Targeting Sphingosine Kinase Activity: Phenoxodiol Sphingosine kinase promotes the activity of the caspase inhibitory proteins XIAP and FLIP. The isoflavone phenoxodiol targets a regulator of sphingosine kinase thereby reducing XIAP and FLIP activity. Phase Ib/II data have recently been presented demonstrating promising activity of oral phenoxodiol in hormone refractory prostate cancer and late-stage ovarian cancer refractory to chemotherapy.90,92

Angiogenesis Folkman first postulated that angiogenesis (the formation of new blood vessels from the preexisting vascular bed) is required for tumor progression.93 Initially, malignant cells derive their nutrients from the normal host vessels by diffusion, but tumor growth is limited beyond 1 to 2 mm without new blood vessel growth.94 Neovascularization is initiated by increased permeability of preexisting vessels in response to vascular endothelial growth factor (VEGF) produced by the tumor; this allows for the extravasation of plasma proteins that lay down the matrix upon which activated growth factorsecreting endothelial cells migrate. Proteolytic degradation of the extracellular matrix and basement membrane then enables endothelial cells to form new capillaries. Normally, perivascular cells are attracted and form basal lumina around the vessels, thus limiting endothelial cell proliferation and decreasing their dependence on VEGF-A. However, in tumors, pericytes have a decreased association with new blood vessels, which as a consequence are leaky due to an imbalance of appropriate proangiogenic and antiantigenic controls that control the so-called angiogenic switch. Hypoxia stimulates the tumor cells to generate proangiogenic factors, including vascular endothelial growth factor (VEGF), fibro-

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blast growth factor (FGF), transforming growth factor-beta. (TGF-b), and tumor necrosis factor-alpha (TNF-a . ). VEGF and FGF are considered the most important factors for tumor angiogenesis. Tumor vascularization has been found to correlate with growth and metastatic potential in some tumor types, and microvessel density has been shown to be an adverse prognostic factor of distant disease and survival.95 Consequently, antiangiogenesis has been a new strategy for the development of anticancer treatment. The characterization of natural inhibitors and promoters of angiogenesis has led to the development of novel compounds that potentially interfere with various steps required for angiogenesis (Table 5.6, Figure 5.4). In principle, these approaches involve either targeting the endothelial cell, targeting activators of angiogenesis, or targeting the extracellular matrix.

Targeting the Endothelial Cell (Thalidomide, TNP-740, Endostatin, Angiostatin) Thalidomide has been found to have immunomodulating and antiangiogenic properties by impeding VEGF- and bFGFdependent angiogenesis through inhibition of TNF, interleukin (IL)-12, and IL-6 and stimulation of IL-2, interferon, and CD8+ T cells. Clinical activity has been seen in refractory multiple myeloma, myelodysplasia, Kaposi’s sarcoma, renal cell cancer, colorectal cancer, and recurrent glioblastomas. No benefit has been demonstrated in Phase III trials of metastatic breast and head and neck malignancies. The thalidomide analogue, CC-5013, has increased potency and efficacy with less sedation, constipation, and neuropathy and has demonstrated promising activity in Phase I trials of patients with advanced solid cancers.96 TNP-470 is a potent endothelial inhibitor in vitro, and animal models have demonstrated the broadest anticancer range of any known agent. In clinical trials, TNP-470 has shown evidence of antitumor effect both as monotherapy with responses observed in relapsed or refractory malignancies97 and in combination with chemotherapy.98

FIGURE 5.4. Inhibitors of angiogenesis.

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The clinical observation that the removal of the primary tumor can lead to the rapid growth of previously dormant micrometastases led to the discovery of angiostatin and endostatin, two potent endogenous antiangiogenic agents. Endostatin is a 20-kDa C-terminal fragment of collagen XVIII found in vessel walls and basement membranes. Recombinant human endostatin inhibited endothelial cell proliferation and tumor growth in preclinical studies, and in a subsequent Phase II trial there were 23 patients with stable disease and 2 with minor responses of the 37 evaluable patients.99 Angiostatin is a 38-kDa internal fragment of plasminogen, which has subsequently been shown to induce dormancy and regression of tumor models. Angiostatin binds to ATP synthase on the surface of human endothelial cells, induces apoptosis in endothelial cells and tumor cells, inhibits endothelial migration and tubule formation, and inhibits matrix-enhanced plasminogen activation. A Phase I trial in patients with advanced cancer demonstrated that it was well tolerated, with some patients (7 of 24) achieving long-term stable disease.100

Targeting Activators of Angiogenesis Vascular endothelial growth factor (VEGF-A), a critical regulator of physiologic angiogenesis during embryogenesis and skeletal growth, is also important in the pathologic angiogenesis of tumor growth. VEGF-A is a multifunctional cytokine expressed by many tumor cells, promoting microvascular permeability, endothelial cell migration, division, and survival, and inhibiting apoptosis. Oxygen tension/hypoxia, growth factors, oncogenes, inflammatory cytokines, and various hormones regulate the level of VEGFA. The effects of VEGF are mediated in part by two receptor tyrosine kinases (RTKs), VEGFR-1 (flt-1) and VEGFR-2 (flk-1), which are expressed on endothelial cells. The level of VEGFA expression in cancer cells has been found to correlate with tumor size, metastasis, poor disease free-survival (DFS), and overall survival (OS).101 Consequently, VEGF and its receptors

84 have been investigated for antiangiogenesis therapies in various malignancies. Different strategies have been designed to inhibit VEGF function, including inhibition of endogenous tumor VEGF secretion (antisense), neutralizing VEGF in the microcirculation, or preventing VEGF binding to its receptor (antibodies), and targeting subsequent signal transduction by VEGF (small molecule receptor tyrosine kinase inhibitors) (see Figure 5.4). Ribozymes are RNA molecules that can recognize RNA sequences and cleave specific sites on other RNA molecules. Angiozyme, a synthetic ribozyme that targets the VEGFR-1 mRNA, was well tolerated in a Phase I/II study of patients with refractory solid tumors,102 and further trials are in progress. Bevacizumab (avastin) is a recombinant anti-VEGF humanized MAb,103 which, in patients with untreated metastatic colorectal cancer given in combination with chemotherapy, showed a significant increase in response rate and time to progression compared with chemotherapy alone, with a 4.7-month prolongation of overall survival.104 This result represents the first clinical validation for antiangiogenesis therapy as an effective cancer treatment, and recent similar studies in untreated advanced non-small cell lung cancer have demonstrated improved response rates and time to progression with the addition of bevacizumab.105 Finally, several different small molecules targeting VEGF receptor tyrosine kinases have been developed, each with a different selectivity profile (Table 5.7); these include SU5416 (intravenously administered), SU6668, SU11248, and PTK 787.106,107

Targeting the Extracellular Matrix The matrix metalloproteinases (MMPs) are a family of zincdependent endopeptidases that mediate degradation of extracellular matrix expressed by tumor cells or stroma.108 They are synthesized as inactive zymogens (pro-MMP) and activated by proteinase cleavage. Their activity is regulated by endogenous inhibitors such as b2-macroglobulin, thrombospondin-2, tissue inhibitors of metalloproteinases (TIMPs), and small molecules with TIMP-like domains. MMPs can promote tumor progression by increasing cell growth, migration, invasion, metastasis, and angiogenesis. Several different approaches have been developed to inhibit the activity of MMPs, including antisense mRNA or ribozyme technology.109 Integrins are a group of heterodimeric transmembrane receptors that mediate cell–cell and cell–ECM interactions. Vitaxin, a humanized derivative of a mouse LM609 MAb, was developed to inhibit the MMP-2 interaction with integrin avb3, although its instability precluded further development.110 Cilengitide (EMD 121974) is a synthetic cyclic pentapeptide small molecule inhibitor of avb3 and avb5, which in a Phase I trial gave prolonged stable disease in 3 of 37 patients.111 Finally, MMP enzymatic inhibitors (MMPI) have been developed. Marimastat was the first orally available MMPI and has been tested in several phase III trials in glioblastoma, breast, ovarian, and small and non-small cell lung cancers. These trials were discontinued because marimastat failed to demonstrate superiority over placebo or standard chemotherapy. However, in a Phase III placebocontrolled trial in patients with advanced gastric cancer, marimastat showed significant improvement in OS (2-year survival, 5% versus 18%) and PFS over placebo-treated patients. These benefits remained significant even after

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longer follow-up.112 Other MMPIs in development are listed in Table 5.7.

Clinical Development of Targeted/Biologic Therapies Clinical Trial Design Clinical trials aim to identify effective drugs for further studies, while also allowing discontinuation of ineffective drugs in an ethical and efficient way. Traditional phase I/II/III clinical trials for cytotoxic agents assume that (1) the agent will reduce the size of the tumor in a dose-dependent manner; (2) the agent will have toxicities that are dose dependent; and (3) reduction in tumor size will lead to improved overall survival and/or improved quality of life. In contrast, newer targeted agents may not have an objective effect on tumor size other than tumor stabilization or metastasis prevention. There may not be a dose-dependent effect, and toxicities may only be modest.113 Consequently, there are limitations in testing target-based agents with conventional trials designed for cytotoxic drugs, and alternative endpoints/trial designs are required.

Phase I: Biologic Endpoints and Surrogate Markers Phase I trials are small studies aimed at finding the optimal dose of a drug using schedules determined from preclinical models. In conventional trials with cytotoxic agents, maximal tolerated dose (MTD) is often used to define the optimal dose rather than using the dose that has a quantifiable therapeutic effect. The dose of the agent is escalated in cohorts of three to six patients until there is unacceptable toxicity in two or more patients. The design of phase I trials is based on the assumption that the efficacy and toxicity of the drug increases as the dose increases and that the mechanism of toxicity and tumor effect are the same. Pharmacokinetic studies are included in Phase I trials but are not required to determine the optimal dose of a cytotoxic agent. Due to their selective effect, targeted agents have the potential to achieve maximum biologic effect with minimal side effects. Therefore, the optimal dose in Phase I trials may need to be defined by a biologic endpoint rather than toxicity. Their wider therapeutic ratio may in some cases make it difficult to determine the MTD. Furthermore, the mechanisms of toxicity and biologic effect may differ, and therefore, MTD cannot be used to define the optimal dose. Conversely, others contend that unless the MTD and intratumoral pharmacodynamics of the novel agent are determined in Phase I and II clinical trials, Phase III trials run the risk of inadequate dosing and suboptimal target inhibition.2 Consequently, biologic endpoints in tumor and surrogate tissue rather than dose-limiting toxicity are often used to define the optimal dose of targeted agents for subsequent clinical trials. This characterization requires a biologic understanding of the target, a specific and reproducible assay for target inhibition, knowledge of the distribution of the target in the tissues of interest, accessibility of the appropriate tissue, and demonstration that the tissue is a valid surrogate for the tissue of interest. Phase I trials with targeted agents aim to define the dose or concentration of a drug that

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p r i n c i p l e s o f t a r g e t e d a n d b i o l og i c a l t h e r a p i e s TABLE 5.7. Antiangiogenesis therapies. Agent

Mechanism of action

Trial

Major toxicity

TNP-740

Synthetic analogue of fumagillin; inhibition of Ets-1 Unknown

Phase II advanced cancer, lymphomas and acute leukemia

Cerebellar dysfunction

Phase I malignant glioma & melanoma Phase II non-small cell lung cancer; phase II in CRC, lymphoma, MDS, liver, CLL, NSCLC Phase III prostate, myeloma, RCC

Fatigue, somnolence, myelosuppression, peripheral neuropathy, thromboembolism (in combination with chemotherapy)

Thalidomide

Squalamine Combretastatin

Inhibition sodium-hydrogen exchanger, NHE3 Induction of apoptosis in proliferating endothelial cells

Endostatin Angiostatin Anti-VEGF antibody (bevacizumab) Anti-VEGFR-2 (IMC-2C7) Soluble VEGFR-1 (VEGF TRAP)

Ribozyme (angiozyme) SU11248

SU6668

PTK787/ZK22584 Cilengitide (EMD121974) Marimastat

Prinomastat (AG3340) Metastat (COL-3) Neovastat (AE941) BMS-275291

Humanized mAb to VEGF

Phase I solid tumors; phase II non-small cell lung cancer and solid tumors Phase I solid tumors; phase II to begin in mid2000 Phase I advanced neuroendocrine and melanoma Phase I advanced tumors Phase II metastatic RCC, advanced prostate, NSCLC, colorectal and other solid tumours

Antibody to VEGFR-2

Preclinical

Inhibition of VEGF signaling by sequestration of VEGF and possibly formation of inactive heterodimers with cellsurface VEGF receptors Cleavage of mRNA of VEGFR-1 Small molecule inhibitor of VEGFR-2, PDGFR, KIT and FLT-3

Phase I advanced tumors

Small molecule blocker of VEGF-receptor, FGF, and PDGF receptor signaling Inhibition of VEGFR-1,2,3 TKI Small molecule inhibitor of avb3 and avb5 Synthetic inhibitor that blocks TNF—a convertase; inhibitor of MMPs Synthetic MMP inhibitor MMP inhibitor and tetracycline derivative Natural MMP inhibitor; derivative of shark cartilage Synthetic MMP inhibitor

Rash Erythema Thrombosis, proteinuria, hypertension

Hypertension, fatigue, proteinuria

Phase I/II refractory solid tumors Phase I advanced solid tumors

Phase I in selected advanced tumors

Phase I/ II with chemotherapy in CRC

Asthenia, thrombocytopenia, neutropenia, skin discoloration, depigmentation Asthenia, thrombocytopenia, hypertension, diarrhea Fatigue, neuropathy, diarrhea

Phase I advanced tumors Phase I pancreatic cancer; phase III NSCLC, small cell lung cancer and breast cancer; phase I GBM Phase III NSCLC, hormone refractory prostate, pancreatic, and small cell lung cancer Phase I/II brain, Kaposi’s sarcoma

Musculoskeletal pain and joint swelling

Lupus, anemia

Phase II multiple myeloma, Phase III renal cell cancer, Phase III non-small cell lung cancer Phase I

provides maximal target inhibition.114 Because determining target inhibition within the tumor is technically demanding, the sampling of normal or surrogate tissues has been an alternative approach. Examples of surrogate tissue use include the measurement of p70S6 kinase activity in peripheral blood mononuclear cells after treatment with an mTOR inhibitor, the assessment of EGFR and ERK/MEK phosphorylation status in skin biopsies after treatment with EGFR tyrosine

kinase inhibitors, or assessment of prelamin A farnesylation in buccal mucosal cells following FTI treatment.42 However, reliance on surrogate endpoints to determine the efficacy of these targeted therapies has attracted criticism because the pharmacodynamics within normal tissue may not reflect target inhibition within the tumor mass. For example, clinical trials investigating the activities of the EGFR inhibitors have failed to adequately assess the intratumoral pharmaco-

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dynamics before and after drug exposure.2 Therefore, negative trial data may simply reflect inadequate drug dosage and tumor tissue concentrations of these agents rather than drug inactivity, which raises serious questions over the interpretation of negative clinical trial data unless proof of target inhibition is documented within tumor specimens rather than surrogate tissues. Noninvasive functional imaging techniques that can quantify the level of target function in vivo are under investigation and include dynamic contrast-enhanced MRI (DCE MRI) for measuring tumor vascularization and vascular permeability with angiogenesis inhibitors and positron emission tomography (PET) to monitor metabolic changes in uptake of 18F-fluoro-2-deoxy-d-glucose (18FDG) within the tumor mass. Other functional modalities include doppler ultrasound and dynamic infrared imaging of vascular perfusion patterns.115

Phase II The primary aim of a Phase II trial is to define the spectrum of antitumor activity for the new drug using the optimal dose and schedule determined from Phase I trials. With cytotoxic drugs, the traditional endpoint is response rate as measured by the percentage decrease in size of the tumor compared to the pretreatment size. However, objective response rate may not be an ideal endpoint for target-based agents because of their cytostatic properties. To overcome this difficulty, alternative endpoints have been used in Phase II clinical studies of targeted therapies. These include the following: • Pharmacodynamic endpoints: for example, quantifying posttranslational changes in biological markers in either tumor or surrogate tissues • Functional imaging studies to assess treatment response at the tumor site (FDG-PET or dynamic contrastenhanced MRI) • Assessment of time to disease progression and the proportion of patients with disease progression • Quality of life (regarded as a secondary endpoint for cytotoxic agents)113 116,117

None of these endpoints has been well validated. An alternative approach to clinical trials investigating the activity of targeted therapies is the use of the randomized discontinuation design. All patients are enrolled to receive the drug for an initial 2- to 4-month period. Patients with progressive disease, toxicity, or noncompliance during this period are removed from the study. The remaining patients are then randomized to continue the drug or a placebo. The endpoint is the percentage of patients that remain with stable disease in the randomized period. The advantages of this method are that it can overcome the slow accrual of trials that offer treatment or placebo upfront, eligibility criteria can be relatively broad, and enrichment of the randomized group may increase the efficiency of the trial.118 Other Phase II trial designs include utilizing the patient as the internal control, whereby a single cohort of patients with progressive disease is treated with a cytostatic agent to determine whether the agent slows the rate of disease progression with reference to the pretreatment rate of progression. Similarly, neoadjuvant treatment can provide a valuable system with tumor sampling for

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molecular analysis that can be performed at progressive time points during treatment.

Phase III The aim of Phase III trials is to determine efficacy or clinical benefit of a new regimen versus a standard therapy in a randomized study. Endpoints are usually progression-free survival or overall survival. With target-based agents, the traditional designs should remain relatively unchanged. It is important that the drug dose that optimally inhibits the target in question within patient tumor specimens be defined in advance of Phase III studies.

Patient Selection The target should be critical to the biology of tumor [e.g., bcrabl in chronic myeloid leukemia (CML)], and the targeted agent should be used in a biologically relevant population. Disease stage may also need to be considered in patient selection, as some agents may be less active in the advanced setting and more effective in patients with minimal disease. Many Phase III clinical trials conducted (with the exception of the trastuzumab and imatinib studies) have not selected patients based on target expression. It is noteworthy that had the Phase III study investigating the addition of trastuzumab to chemotherapy in patients with metastatic breast cancer not selected patients based on HER2 overexpression, the trial would have been negative. At the same time, our understanding of the molecular profile in a tumor that may predict response to targeted therapies remains naive. Little is known about resistance to targeted therapies to guide appropriate strategies of combining different inhibitors together to inhibit redundant or parallel signaling pathways, thus maximizing clinical benefit. Future trials of targeted therapies must incorporate a prospective analysis of tumor tissue during treatment so that response can be correlated with the molecular phenotype (either through microarray or proteomic techniques), thus identifying predictive markers for future studies.

Conclusion: Challenges for the Future Designing clinical trials to investigate the activity of these novel agents and optimize their use in a defined patient population are critical challenges to the success of targeted therapy. There remains much cause for optimism and enthusiasm, particularly following the notable successes in the past few years that have made it to the clinic, such as trastuzumab for breast cancer, bevacizumab for colorectal cancer, imatinib mesylate for CML and GIST, and gefitinib for lung cancer. The field is moving fast, with an exploding knowledge base of molecular abnormalities in cancer and an increasing array of molecules that can target abnormal or overexpressed onco-proteins. As reviewed here, targeted therapies include a wide spectrum of approaches that are applicable to many different cancers, and the principles which govern their development are evolving as we learn how to utilize these novel agents. Within the next decade we should find out whether we make a paradigm shift in the treatment and prevention of cancer by translating scientific progress into clinical practice. Many truly believe that we will.

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cell-cycle inhibitor, administered as a one-hour infusion every three weeks in patients with advanced cancer. J Clin Oncol 2002;20(16):3508–3521. Talbot D, Norbury C, Slade M, et al. A Phase II and pharmacodynamic study of E7070 in patients with non-small cell lung cancer (NSCLC) who have failed platinum-based chemotherapy. Proc Am Soc Clin Oncol 2002;21. Mainwaring PN, Van Cutsem E, Van Laethem J-L, et al. A multicentre randomised phase II study of E7070 in patients with colorectal cancer who have failed 5-fluorouracil-based chemotherapy. Proc Am Soc Clin Oncol 2002;21 (abstract). Adams J. The proteasome: a suitable antineoplastic target. Nat Rev Cancer 2004;4(5):349–360. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003;348(26):2609–2617. Berenson J, Jagannath S, Barlogie B, et al. Experience with longterm therapy using the proteosome inhibitor, bortezomib, in advanced multiple myelome (MM). Proc Am Soc Clin Oncol 2002;22 (abstract). Orlowski RZ. Phase I study of the proteosome inhibitor bortezomib and pegylated doxorubicin in patients with refractory haematological malignanacies. Blood 2003;102 (abstract). Marks PA, Richon VM, Rifkind RA. Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J Natl Cancer Inst 2000;92(15):1210–1216. Saito A, Yamashita T, Mariko Y, et al. A synthetic inhibitor of histone deacetylase, MS-27-275 with marked in vivo antitumour activity against human tumors. Proc Natl Acad Sci USA 1999; 96:4592–4597 (abstract). Wall NR, O’Connor DS, Plescia J, Pommier Y, Altieri DC. Suppression of survivin phosphorylation on Thr34 by flavopiridol enhances tumor cell apoptosis. Cancer Res 2003;63(1):230–235. Hu W, Kavanagh JJ. Anticancer therapy targeting the apoptotic pathway. Lancet Oncol 2003;4(12):721–729. Waters JS, Webb A, Cunningham D, et al. Phase I clinical and pharmacokinetic study of bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin’s lymphoma. J Clin Oncol 2000;18(9):1812–1823. Bischoff JR, Kirn DH, Williams A, et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 1996;274(5286):373–376. Hall AR, Dix BR, O’Carroll SJ, Braithwaite AW. p53-dependent cell death/apoptosis is required for a productive adenovirus infection. Nat Med 1998;4(9):1068–1072. Khuri FR, Nemunaitis J, Ganly I, et al. A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat Med 2000;6(8):879–885. Reid TR, Sze D, Galanis E, Abbruzzese JL, Kirn DH, Freeman S. Intra-arterial administration of a replication-selective adenovirus ONYX-015 in patients with colorectal carcinoma metastatic to the liver: safety, feasibility and biological activity. Proc Am Soc Clin Oncol 2003 (abstract). Vasey PA, Shulman LN, Campos S, et al. Phase I trial of intraperitoneal injection of the E1B-55-kd-gene-deleted adenovirus ONYX-015 (dl1520) given on days 1 through 5 every 3 weeks in patients with recurrent/refractory epithelial ovarian cancer. J Clin Oncol 2002;20(6):1562–1569. Clayman GL, el Naggar AK, Lippman SM, et al. Adenovirusmediated p53 gene transfer in patients with advanced recurrent head and neck squamous cell carcinoma. J Clin Oncol 1998; 16(6):2221–2232. Vassilev LT, Vu BT, Graves B, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004;303(5659):844–848. Davies R, Frydenberg M, Tulluch A, Kelly G. Interim results of a phase Ib/IIa study of a oral phenoxodiol in patients with

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late-stage, hormone-refractory prostate cancer. Proc Am Assoc Cancer Res 2004; LB-214 (abstract). Rutherford T, O’Malley D, Makkenchery A, et al. Phenoxodiol phase Ib/II study in patients with recurrent ovarian cancer that are resistant to > or = second line chemotherapy. Proc Am Assoc Cancer Res 2004;4457 (abstract). Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285(21):1182–1186. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995;1(1):27–31. Weidner N. Angiogenesis in breast cancer. Cancer Treat Res 1996;83:265–301. Sharma RA, Marriot JB, Clarke I, et al. Tolerability of the novel oral thalidomide analog CC-5013 demonstrating extensive immune activation and clinical response. Proc Am Soc Clin Oncol 2003 (abstract). Bhargava P, Marshall JL, Rizvi N, et al. A Phase I and pharmacokinetic study of TNP-470 administered weekly to patients with advanced cancer. Clin Cancer Res 1999;5(8):1989–1995. Herbst RS, Madden TL, Tran HT, et al. Safety and pharmacokinetic effects of TNP-470, an angiogenesis inhibitor, combined with paclitaxel in patients with solid tumors: evidence for activity in non-small-cell lung cancer. J Clin Oncol 2002; 20(22):4440–4447. Kulke M, Bergsland E, Ryan DP, et al. A phase II, open-label, safety, pharmacokinetic, and efficacy study of recombinant endostatin in patients with advanced neuroendocrine tumours. Proc Am Soc Clin Oncol 2003 (abstract). Voest EE, Beerepoot LV, Groenewegen G, et al. Phase I trial of recombinant human angiostatin by twice-daily subcutaneous injection in patients with advanced cancer. Proc Am Soc Clin Oncol 2002;21 (abstract). Eppenberger U, Kueng W, Schlaeppi JM, et al. Markers of tumor angiogenesis and proteolysis independently define high- and low-risk subsets of node-negative breast cancer patients. J Clin Oncol 1998;16(9):3129–3136. Weng DE, Weiss P, Kellackey C, et al. Angiozyme Pharmacokinetic and safety results: a phase I/II study in patients with refractory solid tumours. Proc Am Soc Clin Oncol 2001;20 (abstract). Kim KJ, Li B, Houck K, Winer J, Ferrara N. The vascular endothelial growth factor proteins: identification of biologically relevant regions by neutralizing monoclonal antibodies. Growth Factors 1992;7(1):53–64. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350(23):2335–2342. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2004;22(11):2184–2191. Raymond E, Faivre S, Vera C, et al. Final results of a phase I and pharmacokinetic study of SU11248, a novel multi-target tyrosine kinase, in patients with advanced cancers. Proc Am Soc Clin Oncol 2003;22 (abstract). Steward WP, Thomas AL, Morgan B, et al. Extended phase I study of the oral vascular endothelial growth factor (VEGF) receptor inhibitor PTK787/ZK 222584 in combination with oxaliplatin/5-fluorouracil (5-FU)/leucovorin as first line treatment for metastatic colorectal cancer. Proc Am Soc Clin Oncol 2003;22 (abstract). Stamenkovic I. Matrix metalloproteinases in tumor invasion and metastasis. Semin Cancer Biol 2000;10(6):415–433. Yonemura Y, Endo Y, Fujita H, et al. Inhibition of peritoneal dissemination in human gastric cancer by MMP-7-specific antisense oligonucleotide. J Exp Clin Cancer Res 2001;20(2): 205–212.

90 110. Silletti S, Kessler T, Goldberg J, Boger DL, Cheresh DA. Disruption of matrix metalloproteinase 2 binding to integrin alpha v beta 3 by an organic molecule inhibits angiogenesis and tumor growth in vivo. Proc Natl Acad Sci USA 2001;98(1):119– 124. 111. Eskens FA, Dumez H, Hoekstra R, et al. Phase I and pharmacokinetic study of continuous twice weekly intravenous administration of Cilengitide (EMD 121974), a novel inhibitor of the integrins alphavbeta3 and alphavbeta5 in patients with advanced solid tumours. Eur J Cancer 2003;39(7):917–926. 112. Bramhall SR, Hallissey MT, Whiting J, et al. Marimastat as maintenance therapy for patients with advanced gastric cancer: a randomised trial. Br J Cancer 2002;86(12):1864–1870. 113. Rowinsky EK. Challenges of developing therapeutics that target signal transduction in patients with gynecologic and other malignancies. J Clin Oncol 2003;21(suppl 10):175–186. 114. Gelmon KA, Eisenhauer EA, Harris AL, Ratain MJ, Workman P. Anticancer agents targeting signaling molecules and cancer cell

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Biologic Principles of Hematopoietic Stem Cell Transplantation Robert J. Soiffer

D

uring the past 25 years, hematopoietic stem cell transplantation (HSCT) has become accepted as routine treatment for many patients with hematologic malignancies. Traditionally, the primary biologic objectives of HSCT for malignant disease and marrow disorders include the following: • Delivery of chemotherapy/radiotherapy sufficient to destroy tumor cells • Infusion of a source of hematopoietic stem cells to replace damaged lymphoid or myeloid progenitors • Establishment of organ graft tolerance to prevent rejection of donor cells • Induction of graft-versus-tumor (GVT) activity by allogeneic immune effector cells Recent laboratory and clinical observations on the biology of transplantation have challenged many of the fundamental beliefs and practices established over the past quarter century. Insights into graft-versus-host disease (GVHD), graftversus-leukemia (GVL) activity, stem cell engraftment, donor selection, minimal residual disease (MRD), infectious complications, and treatment-related organ dysfunction all have contributed to revisions and refinements in the current approach to potential transplant recipients.

Indications for Transplantation For many diseases, the indications for transplantation were established in an era when standard treatment approaches had very little hope of producing cures or extended long-term survival. As both nontransplant therapeutic options and transplant-related methodologies have evolved, continued reassessment is needed to determine the place of transplantation in the design of treatment algorithms. It is a common misconception that research in transplantation is bereft of comparative clinical trials. It is true that many reported Phase 2 trials are difficult to interpret in the absence of rigorously defined control groups. Single institution case-control studies are only of limited value. However, the establishment of well-organized data repositories such as the International Bone Marrow Transplant Registry (IBMTR) and the European Bone Marrow Transplant (EBMT) registry have led to large retrospective observational

studies using standardized data collection tools across many centers. The reports emerging from these studies have proven useful in assessing the value of specific transplant strategies. However, these registry analyses do not take the place of rigorously conducted randomized trials. Indeed, there have been a number of randomized trials conducted in transplantation, although many have been underpowered to detect small, but significant, differences because of limited patient availability. Transplant indications can be divided into three groups based on the objective evidence that supports its use. The first group includes those diseases for which results from prospective randomized trials are available to guide treatment decisions. The most definitive randomized study supporting transplantation was the PARMA trial, conducted in patients undergoing autologous HSCT for non-Hodgkin’s lymphoma (Figure 6.1).1 Patients with relapsed NHL were treated with two cycles of salvage chemotherapy upon study entry. Those patients exhibiting a response were randomized to receive either high-dose chemotherapy and autologous bone marrow transplantation or four more cycles of chemotherapy. With extended follow-up in each arm, both disease-free survival and overall survival were far superior for patients undergoing transplantation. In another randomized trial conducted in Europe at the same time, a survival advantage was demonstrated for patients with recurrent multiple myeloma randomized to autologous transplantation compared to conventional therapy. This finding was recently confirmed in another large randomized study.2,3 The importance of randomized trials is not limited to positive studies. The highly publicized randomized trials in breast cancer patients with metastatic disease or with more than 10 positive nodes failed to demonstrate any survival advantage for autologous transplantation.4–6 Participation in these studies was critical in helping to determine that highdose chemotherapy and autologous HSCT, which had become standard treatment for many patients with advanced disease, offered no clear-cut advantage to conventional therapy. Still, proponents of transplant point to the lower relapse rates in the transplant arm and argue that if toxicity could be eliminated, high-dose therapy might still offer advantages. It is also important not to blindly extrapolate the results of positive studies to distinctly different clinical scenarios. For example, the encouraging results with autologous transplantation for intermediate-grade NHL in second remission

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92 prompted its use for patients thought to be at high risk for relapse in first remission. However, when a prospective randomized study was performed in these first remission patients, no clear benefit of transplantation could be demonstrated except perhaps in patients with very high international prognostic index (IPI) scores.7–9 There have also been circumstances in which different randomized studies have yielded conflicting results, as is most clearly the case for patients with acute myelogenous leukemia (AML) and acute lymphoblastic anemia (ALL) in first complete remission (CRI). Many of these trials were designed so that patients with HLA-identical donors were allocated (truly genetically selected) for allogeneic transplantation whereas those without donors were randomized to autologous transplantation or further chemotherapy. In some of these trials, allogeneic transplantation held a modest advantage when analyzed on an intention-to-treat basis. In other trials, no significant differences in disease-free survival (DFS) between the treatment arms could be found.10–13 More recent data on the prognostic implications of certain chromosome abnormalities associated with AML and ALL have influenced thinking on who should undergo transplantation in first remission. General agreement exists that patients with adverse cytogenetics (such as monosomy 7 or multiple complex abnormalities in AML or the Philadelphia chromosome in ALL) should undergo HSCT in CRI. Patients with favorable cytogenetics [such as t(8;21) or inv16] are usually not offered transplantation in first remission. Transplant decisions for patients with intermediate-risk cytogenetics in AML and ALL are more difficult and require careful deliberation with the patient and his/her family. The second group of transplant indications includes those diseases for which a cure rate has been established with HSCT that is superior to that obtained with conventional therapy but for which prospective randomized trials have not been conducted. This group includes patients with recurrent acute

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leukemia, recurrent Hodgkin’s disease, low-grade lymphoma, chronic lymphocytic leukemia (CLL), aplastic anemia, and chronic myelogenous leukemia (CML).14–24 CML deserves special consideration since the introduction of imatinib into practice in 2001.25–27 In the pre-imatinib era, cure rates were less than 5% and median survival was 5 to 6 years with either hydroxyurea or interferon, the mainstays of therapy. In contrast, for patients under 50 years of age with an HLAidentical sibling donor, HSCT performed in the first year after diagnosis of stable-phase CML cures more than 70% of patients.28,29 DFS for patients with unrelated donors appears to exceed 50% to 60% in identical circumstances.16 For these younger patients with CML, it could be safely argued that HSCT offered the only hope for cure. However, this conclusion did not necessarily mean that HSCT was an obvious choice for all these patients, because there was a very real possibility that transplantation would dramatically shorten the lifespan of a subset of patients as a result of transplant-related complications. In the current imatinib era, the transplant decisions faced by physicians and patients cannot necessarily be based on a reproducible median survival of 5 to 6 years without HSCT. It is not known what the median survival will be for newly diagnosed patients treated with imatinib. Despite the early data that indicate imatinib is superior to interferon in inducing hematologic and cytogenetic remissions, the duration of these responses is not known.30,31 Development of drug resistance has been identified in a number of patients.32,33 At this point, it is too early to know how imatinib should change the approach to transplantation for CML. The third group of transplant indications includes those diseases for which transplantation benefits some individuals but for which sufficient follow-up is not yet available in enough patients to determine the proper role of HSCT in disease management. Diseases that fall into this category include hemoglobinopathies, autoimmune disorders, and renal cell carcinoma.34–36 Transplantation for these indications should be considered investigational.

FIGURE 6.1. Randomized study of high-dose chemotherapy with autologous transplantation versus chemotherapy. Event-free survival in patients undergoing transplantation is superior to that in those receiving chemotherapy alone for recurrent chemotherapy-sensitive intermediategrade non-Hodgkin’s lymphoma. (Adapted from Philip et al.,1 by permission of New England Journal of Medicine.)

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Sources of Hematopoietic Stem Cells Hematopoietic stem cells for transplantation can be obtained from bone marrow (BM) or peripheral blood (PB). Bone marrow was the traditional source for stem cells until the 1980s. At that time, antibodies were developed that could recognize CD34+ hematopoietic progenitors, and it was recognized that these CD34+ cells circulate in PB. Moreover, the number of these CD34+ cells in the periphery increased during recovery from myelosuppressive chemotherapy and after administration of growth factors, particularly granulocyte colony-stimulating growth factor (G-CSF).37–39 Strategies to mobilize stem cells from the marrow out into PB with chemotherapy, growth factors, or a combination of the two were developed. Full lymphohematopoietic reconstitution was observed after ablation and infusion of these mobilized PB stem cells in the autologous transplant setting. Using mobilized PB containing a minimum of 2.0 ¥ 106 CD34+ cells/kg, engraftment of both neutrophils and platelets is considerably more rapid than when BM is used.40,41 For autologous transplantation, mobilized PB has replaced BM as the stem cell source in most centers. It is notable, however, that the use of peripheral blood stem cells (PBSCs) has not led to improved survival after autologous transplantation but has been associated with decreased duration of hospitalization. Physicians were initially reluctant to use PB for allogeneic transplantation as it was feared that the increased number of T lymphocytes infused with PB would increase the incidence and severity of graft-versus-host-disease (GHVD). The first trials published in the 1990s demonstrated rapid engraftment without apparent increases in GVHD.42,43 A number of randomized trials comparing allogeneic PBSC versus BM have been reported, as have a meta-analysis and registry data.44–49 As in the autologous setting, neutrophil and platelet engraftment were more rapid with PBSCs. There have been conflicting reports on the risk of acute GVHD posed by PBSCs. In a randomized trial involving 350 patients, both acute GVHD (grade II–IV) and severe acute GVHD (grade III–IV) were significantly increased in the PBSCT group (52% versus 39%, P = 0.014 and 28% versus 16%, P = 0.01, respectively).50 Other trials have found differences in acute GVHD that were not statistically significant. An IBMTR/EBMT retrospective review of 288 PBSC and 536 BM transplants revealed a borderline increase in grades II–IV acute GVHD [relative risk (RR), 1.19; 95% CI, 0.9–1.56].51 A meta-analysis of 15 studies (9 cohorts, 5 randomized trials, and 1 database review) suggested that use of PBSCs did increase risk of acute GVHD (RR, 1.16; 95% CI, 1.04–1.28).46 A number of studies have suggested a higher incidence of chronic GVHD with PB.44–46,51 An updated meta-analysis of the randomized trials demonstrated an overall relative risk of 1.57 (95% CI, 1.28–1.94) for chronic GVHD after PBSCT when compared with bone marrow transfer (BMT). The explanation for the increase in chronic GVHD may lie with the increase in the number of T cells infused, although there there may be an association between the development of chronic GVHD and the number of CD34 cells infused.52,53 It has been speculated that the larger number of T cells infused with mobilized peripheral blood might translate into improved immune reconstitution and a reduction in disease relapse posttransplant. In several studies, higher levels of B cells and T cells were noted after PBSCT compared to BMT,54

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with the increase in T-cell number associated with a lower incidence of confirmed infections (RR, 0.59; P < 0.001).55 With regard to relapse, several randomized studies have demonstrated a decrease in the rate of relapse after PBSCT compared to BMT.48,49 In the largest U.S. randomized trial, the hazard ratio for relapse was 0.49 (95% CI, 0.38–1.28) among patients transplanted with PBSCs.44 Unfortunately, despite these effects on lymphoid recovery and disease relapse, most randomized studies have yet to demonstrate a convincing improvement in overall survival for PBSCs. All the comparative studies of PBSCs and BM referenced previously have involved related donors. For unrelated donors, a single-arm cohort of PBSCT resulted in outcomes similar to that noted with BMT.56 Comparative rates of engraftment, acute and chronic GVHD, and survival in the unrelated setting await completion of large multiinstitutional randomized studies now under way. If there turns out to be no survival advantage to PBSCT compared with BMT in the allogeneic setting, policies regarding donor source may be determined by quality of life or economic issues. Donor preference for either PBSC or BM donation has been evaluated in one series of allogeneic donors with no differences in self-reported quality of life measures; however, patients randomized to donate autologous PBSC or BM have preferred PBSC collection.57,58 Because of the reduction in hospital stay associated with PBSCT, costs have been lower in comparative analyses although these studies did not factor in the potentially added economic burden of a higher incidence of chronic GVHD.59

Conditioning Regimens The conditioning regimen administered before stem cell infusion plays several potential roles in promoting the success of transplantation. Cytoreduction of the endogenous malignancy with high-dose chemo/radiotherapy has traditionally been central to transplantation and is the major mode by which autologous transplantation benefits patients. Typical conditioning regimens for autologous transplantation include cyclophosphamide/total-body irradiation (Cy/TBI), cyclophosphamide/busulfan (Bu/Cy), cyclophosphamide/ BCNU/VP-16 (CBV), BCNU/etoposide, ara-C, melphalan (BEAM), VP-16/busulfan, and cyclophosphamide/thiotepa/ carboplatin (CTCb). It is not clear if one particular regimen is superior in a particular clinical circumstance, although it is generally assumed that results with current standard regimens are reasonably equivalent. For allogeneic transplantation, the conditioning regimen not only reduces the disease burden but also suppresses the host to facilitate donor engraftment. The most common ablative combinations have been cyclophosphamide/total-body irradiation or cyclosphosphamide/busulfan. Several randomized studies of Cy/TBI and Bu/Cy have been conducted in patients with AML and CML.60–62 Socie et al. summarized the long-term results of four of these studies.63 With more than 7 years of follow-up in each study, no differences in long-term outcome were noted for patients with CML. They noted a nonsignificant 10% improvement for AML patients receiving Cy/TBI compared to Bu/Cy. The development of intravenous busulfan and strict pharmacokinetic monitoring to target

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TABLE 6.1. Comparison of autologous and allogeneic transplantation.

Advantages

Disadvantages

Autologous

Allogeneic

1. No HLA matching requirement 2. No graft-versus-host disease (GVHD) 3. No need for immunosuppression 1. ? Stem cell damage from prior therapy leading to delayed engraftment or myelodysplasia 2. ? Graft contamination with tumor 3. No graft-versus-tumor effect Lower risk of complications Higher risk of relapse

1. Stem cells have not been exposed to chemotherapy 2. Stem cells free of tumor 3. Graft-versus-tumor activity 1. Donor availability uncertain 2. GVHD 3. Infectious complications

plasma levels of the drug has helped optimize efficacy and limit toxicity of the Bu/Cy regimen.28,64 Attempts to escalate doses of the conditioning have been disappointing. In several studies in which TBI dose intensity was increased to more than 1,500 cGy, modest decreases in relapse rates were offset by increases in regimen-related morbidity and mortality.65–67 The introduction of monoclonal antibodies directed at marrow elements linked to radioisotopes in hopes of targeting only marrow and not vital organs may offer hope of providing truly selective myeloablation.68 The lack of benefit of conditioning regimen dose intensification and the recognition of the contribution of graftversus-tumor activity to disease eradication prompted the development of low-dose, nonmyeloablative regimens. These regimens are designed not to have direct antitumor activity but rather to provide sufficient host suppression to permit engraftment of donor hematopoietic and lymphoid effector cells. Many regimens ranging from nearly myeloablative to minimally myelosuppressive have been piloted. Most regimens have combined a purine analogue, such as fludarabine, with an alkylating agent or low-dose TBI with or without anti-T-cell antibodies such as thymoglobulin or altemuzumab.69–73 Studies indicate that these nonmyeloablative regimens can facilitate full donor engraftment with much decreased upfront toxicity, allowing transplantation to be performed in older patients or those with contraindications to high-dose therapy. Unfortunately, GVHD still is a problem. One-hundred-day transplant-related mortality is low in recipients of nonmyeloablative conditioning, but later morbidity and mortality, usually from GVHD, can be substantial.74 Several retrospective comparative studies have suggested similar overall outcomes in recipients of myeloablative and nonmyeloablative transplants, but prospective randomized studies are needed to determine the impact of these lessintensive regimens on toxicity and disease control.

Higher risk of complications Lower risk of relapse

Identification of a Suitable Donor Donor choice can have a profound influence on transplant outcome. Patients may receive either autologous or allogeneic stem cells. Pros and cons of each donor source are displayed in Table 6.1.

Autologous Transplantation A major issue facing investigators surrounding autologous transplantation is the potential of tumor cell contamination. The aim of purging in autologous transplantation is to eliminate any contaminating malignant cells and leave intact the hematopoietic stem cells that are necessary for engraftment. Most clinical studies in lymphoma and myeloma have demonstrated that purging can deplete malignant cells in vitro without significantly impairing hematologic reconstitution,75–77 but studies in AML using immunologic or chemical methods have been associated with delayed hematopoietic recovery (Figure 6.2).78,79 The rationale for removing tumor cells from hematopoietic cells might therefore appear compelling, yet the issue of purging remains highly controversial. Both positive (CD34+ columns) and negative (exposure ex vivo to antibodies directed at tumor cells) selection techniques for tumor cell purging are available. However, purging has not as Event Free Survival After ABMT 100

PCR neg (57 pts, 11 relapses)

80 60 p < 0.00005

40 20

Potential Obstacles to Successful Transplantation There are three major hurdles that must be overcome for HSCT to be successful: (1) identification of a suitable donor, (2) prevention and effective treatment of transplant-related complications, and (3) sustained eradication of underlying disease.

PCR pos (57 pts, 53 relapses)

2

4

6

8

10

12

14

16

18

20

Years FIGURE 6.2. Successful purging of tumor cells from autologous marrow is associated with improved survival after transplantation. Patients whose marrows had no detectable lymphoma cells by polymerase chain reaction studies after immunologic purging had superior survival compared to patients with persistent evidence of disease. (Courtesy of J. Gribben.)

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yet been universally adopted because there are no convincing data in Phase 2 trials that patients receiving purged marrow fare better than those receiving unpurged cells. A retrospective analysis of the European Blood and Marrow Transplant Lymphoma Registry compared the outcome of 270 patients whose BM had been purged and with the outcome of 270 casematched control patients.80 A variety of purging methodologies was used. Patients with low-grade lymphoma did not have a significantly improved progression-free survival if the BM was purged (P = 0.18), but they did have a significantly improved overall survival (P = 0.0018). In multiple myeloma, a Phase III randomized trial using purged versus unpurged autologous PBSC was performed using CD34 selection.81 After CD34 selection, tumor burden was reduced by a median of 3.1 log, with 54% of CD34-selected products having no detectable tumor. There was no improvement in disease-free or overall survival. Data indicate, however, that contamination of the stem cell inoculum with tumor cells contributes to posttransplant relapse. In studies at the Dana-Farber Cancer Institute, polymerase chain reaction (PCR) amplification of the t(14;18) was used to detect residual lymphoma cells in the BM before and after purging to assess whether efficient purging had any impact on disease-free survival.82 In this study, patients with B-cell non-Hodgkin lymphoma and the bcl-2 translocation were studied. Residual lymphoma cells were detected in all patients in the harvested autologous BM. Following three cycles of immunologic purging using the anti-B-cell mAbs and complement-mediated lysis, PCR amplification detected residual lymphoma cells in 50% of patients. Patients who were infused with a source of hematopoietic cells that was free of detectable lymphoma cells had improved outcome compared to those who had residual detectable lymphoma (see Figure 6.2). This finding was independent of degree of BM infiltration at the time of BM harvest or remission status at the time of autologous BMT. Further evidence supporting the contribution of contaminating tumor cells to posttransplant relapse comes from gene marking studies in AML and neuroblastoma.83–85

Allogeneic Donors When allogeneic transplantation is contemplated, an HLAidentical or closely matched donor must be found. The major HLA loci are located on chromosome 6 and are closely linked.86 Because every individual inherits one chromosome 6 from their mother and one from their father, the chance of any one sibling being a match is one in four. A complete match between donor and recipient was considered identity of both alleles at HLA-A, HLA-B, and HLA-DR loci. Other major loci, such as HLA-C and HLA-DQ, can influence outcome and must be checked when performing a search for an unrelated donor. Indeed, HLA-C identity is now considered as important as a match at HLA-A, -B, and -DR.87–90 Accurate HLA typing is essential. Serologic methods are no longer adequate. It is imperative that molecular techniques using site-specific oligonucleotide probes and direct sequencing be employed. The formation of the National Marrow Donor Registry (NMDR) has made possible thousands of unrelated transplants in the United States. More than 4 million people are registered as potential donors with the NMDP. The likelihood of finding an HLA-A, -B, and -DR

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match is 65% to 70%, although finding a donor is more difficult in minority populations. It can take weeks to many months between the time a search is initiated and a donor is identified, medically cleared, and ultimately donates. Even when a “complete” match is found, complications such as GVHD can still be substantial. The reason for this is that minor HLA antigens, which can influence graft rejection or GVHD, cannot be easily typed.91–93 Moreover, these minor antigens likely are not found on chromosome 6; therefore, a complete match of HLA major loci does not necessarily translate into a complete match of minor loci. Results of allogeneic transplantation using unrelated donors have been slightly worse than those of matched related transplants, but with improvements in typing, the gap has narrowed.94 Sometimes it is possible to identify more than one potential donor either within a family or through the NMDP. The most important characteristic in choosing a donor is HLA identity. The greater the HLA disparity, the greater the risk of GVHD, graft failure, and adverse outcome. Other factors that may increase GVHD include the use of female multiparous donors for male recipients (a minor HLA antigen located on the Y chromosome has recently been identified), older donor age, and prior cytomegalovirus (CMV) exposure.95,96 ABO compatibility is desirable but is not a prerequisite for transplantation. ABO incompatibility may lead to hemolysis and delayed red cell engraftment.97 Transplantation of hematopoietic stem cells from haploidentical family members has been associated with increased risks of GVHD and graft failure.98,99 Historically, outcome has been poor. Recent studies of infusion of large numbers of haploidentical peripheral blood stem cells exhaustively depleted of T cells through positive selection of CD34+ stem cells has been reported to result in high rates of engraftment and low rates of GVHD.100 Despite T-cell depletion, relapse rates have been low, particularly in patients with AML. It now appears that mismatching of KIR receptor on donor NK cells and KIR ligand on recipient cells may actually promote cell-mediated destruction of AML cells and recipient antigen-presenting cells, leading to lower relapse rates without GVHD.101,102 Recent studies have demonstrated that umbilical cord blood (UCB) is very rich in stem cells but low in alloreactive T cells. As a consequence, it was hypothesized that these cells might support engraftment with less GVHD. A series of studies have confirmed that engraftment can be obtained with unrelated UCB with a reduced risk of GVHD, even when partially HLA-mismatched unrelated transplants donor cells used.103–107 However, because the number of stem cells per kilogram recipient weight is relatively low in cord blood products, engraftment is slow. The number of cells available for transplantation from cord blood may make it difficult to utilize these products with large adult recipients. Strategies currently under investigation to address low cord blood cellularity include the use of multiple disparate products and expansion of stem cells ex vivo before infusion.108 UCB transplantation should be considered for patients for whom traditional related or unrelated products are not available.

Transplant-Related Complications When evaluating patients for potential complications of transplantation, it is critical to have a full understanding of

96 the entire treatment course to assemble a reasonable differential diagnosis. Factors that must be taken into account include donor source (allogeneic or autologous), interval posttransplant (early versus late), type of GVHD prophylaxis, infectious prophylaxis, current use of immunosuppressive medications, ablative regimen, and duration of granulocytopenia. The three major categories of transplant-related toxicities are (1) treatment-related organ damage, (2) infectious complications, and (3) graft-versus-host disease.

Organ Damage Damage can be manifested early or late after transplantation. Some of the more commonly recognized organ toxicities that are not clearly attributable to infection or GVHD are discussed next. IDIOPATHIC PNEUMONIA SYNDROME (IPS)/DIFFUSE ALVEOLAR HEMORRHAGE (DAH)/ENGRAFTMENT SYNDROME These processes usually occur during the transplant hospitalization around the time of neutrophil recovery, more commonly after allogeneic HSCT.109–111 These terms may represent slightly different manifestations of the same poorly understood entity. By definition, they have no clearly identified infectious etiology. Onset can be insidious, but decompensation can be sudden. Radiographic findings can be nonspecific. Mortality is extremely high in patients who require mechanical ventilation. Elevated circulating and bronchoalveolar lavage (BAL) levels of tumor necrosis factor (TNF) and other cytokines have been observed.112,113 Early intervention with high-dose steroids (1 g IV solumedrol) even before diagnostic studies are performed may be lifesaving.114 New agents, including TNF blockers such as etanercept (Enbrel), are being studied in clinical trials.115 INTERSTITIAL PNEUMONITIS (IP) Interstitial pneumonitis (IP) often occurs 2 to 6 months after transplant. IP may present as a delayed inflammatory response to a conditioning agent, such as BCNU. In these circumstances, complete responses can be obtained with a steroid dose of 1 mg/kg. IP can be steadily progressive and fatal, particularly after allo-HSCT. IP must be distinguished from infectious pneumonitis. HEPATIC VENO-OCCLUSIVE DISEASE (VOD) VOD is a clinical syndrome characterized by painful hepatomegaly, jaundice, ascites, fluid retention, and weight gain.116,117 The onset is usually before day + 35 after stem cell reinfusion, and other causes of these symptoms and signs are absent. VOD develops in 2% to 40% of patients after SCT and ranges in severity from mild, reversible disease to a severe syndrome associated with multiorgan failure and death, with established severe VOD shown to have a mortality rate approaching 100% by day + 100 post-SCT. VOD is believed to be caused by primary conditioning regimen-induced injury to sinusoidal endothelial cells and hepatocytes with subsequent damage to the central veins in zone 3 of the hepatic acinus.118 Early changes include deposition of fibrinogen, factor VIII, and fibrin within venular walls and sinusoids. As the process of venular microthrombosis, fibrin deposition, ischemia, and fibrogenesis advances, widespread zonal disruption leads to portal hypertension, hepatorenal syndrome, multiorgan failure, and death. Despite therapeutic interven-

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tions, including the use of antithrombotic and thrombolytic agents such as prostaglandin E1 and tissue-plasminogen activator (t-PA) with or without concurrent heparin, little success has been achieved in the treatment of severe VOD. Recently, the use of defibrotide (DF), a single-stranded polydeoxyribonucleotide that has specific aptameric-binding sites on vascular endothelium, has shown promise in the treatment of VOD.119,120 DF upregulates the release of prostacyclin (PGI2), prostaglandin E2, thrombomodulin (TM), and t-PA both in vitro and in vivo. Moreover, it has been shown to decrease thrombin generation, tissue factor expression, plasminogen activator inhibitor (PAI)-1 release, and endothelin activity. HEMOLYTIC-UREMIC SYNDROME (HUS)/ THROMBOTICTHROMBOCYTOPENIC PURPURA (TTP) Both HUS and, less commonly, TTP can occur after either allo- or autotransplant. HUS/TTP presents 2 to 12 months posttransplant. HUS is manifest by nonimmune-mediated hemolytic anemia characterized by schistocytes on smear, mild azotemia, and mild hypertension.121,122 It is likely precipitated by endothelial damage caused by the ablative regimen or by medications such as cyclosporine, tacrolimus, or siroloimus. HUS is usually self-limited, and treatment is supportive. Plasmapheresis is generally not indicated but isolated reports have indicated some benefit. CARDIOMYOPATHY Cardiac dysfunction can occasionally be observed after HSCT. It usually presents shortly after completion of conditioning and has been linked with cyclophosphamide.123 It can present as myopericarditis. If patients can be managed through the acute episodes, there may not be permanent dysfunction. Long-term cardiac complications are uncommon and usually can be related to previous anthracycline exposure. NEUROLOGIC DYSFUNCTION Neurologic dysfunction can be an unrecognized problem after HSCT. Potential issues include memory disturbance and learning disability secondary to irradiation, Guillain–Barre syndrome, limbic encephalitis, cyclosporine/tacrolimusassociated hypertensive encephalopathy and seizures, and peripheral neuropathies.124 CATARACTS Cataracts often develop in patients 1 to 5 years after transplant.125 The incidence is increased in patients who received TBI and those on prolonged steroid therapy for GVHD.

Infection Infection is a major cause of morbidity and mortality after transplantation. There are numerous predisposing factors that increase the risk of infection after HSCT, including the following: • Prolonged granulocytopenia • Disruption of mucosal barriers • Extensive use of antibiotics • Prolonged placement of indwelling venous access • Delayed recovery of cellular immunity • Impaired antibody production • Use of immunosuppressive medications to treat or prevent GVHD

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• Immune defects associated with underlying malignancy • Suppression of immune responses by GVHD itself It is important to have an understanding of the typical time course associated with risk of developing specific infections after HSCT.126 It is critical to anticipate the development of infection, and considerable attention has been paid to prophylaxis and preemptive therapy. Examples are detailed here: 1. Bacterial: During the transplant hospitalization, gut decontamination with oral nonabsorbable antibiotics is often employed along with systemic agents such as a quinalone. If patients become febrile while neutropenic, typical broad-spectrum coverage is employed. For outpatients with chronic GVHD on steroids, oral antibiotics targeting encapsulated organisms are frequently prescribed on a chronic basis for suppression. Although routine immunoglobulin (IgG) administration is not recommended after transplant, it is recommended that patients whose IgG levels are consistently very low should receive replacement therapy. 2. Fungal: There are data indicating that prophylactic fluconazole can prevent Candida infections and may improve long-term survival after transplant.127,128 Amphotericin B or a liposomal derivative has been routinely administered for fever and neutropenia unresponsive to antibacterial antibiotics. The newly available voriconazole may ultimately be substituted for amphotericin in this setting.129,130 Moreover, its oral administration and activity against Aspergillus may lead to it being more widely adopted as fungal prophylaxis after discharge for patients on steroids for GVHD. 3. Pneumocystis carinii: Pneumocystis carinii pneumonia (PCP) can develop as early as 1 month after transplant. Prophylaxis should be instituted no later than 30 days post-HSCT and be continued for approximately a year or longer if the patient remains on steroids for GVHD. Trimethoprim-sulfamethoxazole is the most efficacious agent. For patients with allergies or cytopenias, atovoquone or other agents (dapsone, pentamidine) may be substituted, but coverage should never be omitted. Practitioners should be aware of development of PCP in the months after discontinuation of prophylaxis.

4. Viral: Herpesviruses (HSV, VZV, EBV, HHV-6, and, most importantly, CMV) present the largest viral problem after transplant. HSV-induced mucositis can be completely prevented with acyclovir administration during the transplant hospital stay. Many centers will continue acyclovir for 1 year to prevent varicella-zoster virus (VZV) infections, which occur in 30% to 40% of patients not receiving prophylaxis.131 CMV usually occurs 2 to 6 months after transplant and is more common in allotransplant recipients. Patients at highest risk are those who are CMV seropositive and receive cells from a seronegative donor.132 In this circumstance, no anti-CMV immunity is transferred. CMVfiltered, or better still, CMV-negative blood products are essential to prevent nosocomial transmission. Data exist that demonstrate that treatment of patients preemptively with gancyclovir when CMV reactivation can be detected in blood or BAL fluid (before actual development of invasive infection) will reduce the risk of subsequent CMV pneumonitis and improve survival.133–136 Vaccinations are routinely administered to patients 1 and 2 years after HSCT. Diptheria tetanus, inactivated polio, MMR (measles-mumps-rubella), hepatitis B, pneumococcal, and Hemophilus influenzae vaccine are often given.137 The ability to make antibody is impaired post-HSCT and vaccinations are therefore usually delayed until the 1-year anniversary. Recent data suggest that vaccination of the donor before transplant may allow earlier transfer of immunity to the patient.138

Graft-Versus-Host Disease GVHD causes complications after allogeneic HSCT as a direct result of organ damage and as a consequence of infectious complications prompted by GVHD therapy. GVHD can be classified as acute or chronic based on timing of onset and clinical features. Acute GVHD usually develops within the first 2 months of BMT and affects mainly the skin, gastrointestinal (GI) tract, and liver.139 The current standard grading system for acute GVHD is based on the degree of involvement of these three organs (Table 6.2). When pharmacologic immunosup-

TABLE 6.2. Acute GVHD scoring. Extent of organ involvement

Skin

Liver

Gut

Stage 1

Rash on less than 25% of skin

Bilirubin 2–3 mg/dL

2

Rash on 25%–50% of skin

Bilirubin 3–6 mg/dL

3

Rash on more than 50% of skin

Bilirubin 6–15 mg/dL

4

Generalized erythroderma with bullous formation

Bilirubin more than 15 mg/dL

Diarrhea more than 500 mL/day or persistent nausea Diarrhea more than 1000 mL/day Diarrhea more than 1500 mL/day Severe abdominal pain with or without ileus

Stage 1–2 Stage 3 or 4 — Stage 4

None Stage 1 or 2 Stage 2–3 or Stage 4

Grade I II III IV

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None Stage 1 Stage 2–4 —

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FasL, TNF, IL-12, IFN-g, perforin/granzyme B H2O2, superoxide

Immunologic reactivity

MHC, Fas, GM-CSF, TNF, chemokines, IL-1, IL-6, IL-8, C¢ adhesion molecules

FasL, TNF, IL-12, IFN-g, perforin/granzyme B H2O2, superoxide

procoagulants, C¢, adhesion molecules, Fas, nitric oxide, IL-1, TNF, cytokines, chemokines

HSCT Hyper-reactive immune response

Conditioning

Hypo-reactive immune response

Time

pression is used as GVHD prophylaxis after myeloablative transplant, moderate to severe acute GVHD (grades II–IV) occurs in 25% to 60% of matched related donor transplant recipients and up to 45% to 70% in unrelated donor recipients. Development of grade II–IV acute GVHD is associated with decreased survival in patients after allogeneic BMT.140–143 Chronic GVHD has a later onset than acute GVHD and is often clinically distinct.144 Chronic GVHD may resemble an autoimmune collagen vascular disease. Patients can manifest sclerodermatous skin changes, keratoconjunctivitis, sicca syndrome, lichenoid oral mucosal lesions, esophageal and vaginal strictures, liver disease, and pulmonary insufficiency. Despite immunosuppresive agents, approximately 30% to 50% of patients develop chronic GVHD after conventional myeloablative HLA-identical sibling BMT. The incidence of chronic GVHD may be even higher after allogeneic transplantation using unmanipulated peripheral blood stem cells.45,46,51,52 Chronic GVHD may be classified as subclinical or clinical, limited or extensive. Although subclinical or clinically limited chronic GVHD often resolves spontaneously with minimal intervention, extensive chronic GVHD requires prolonged immunosuppressive treatment and is associated with significant morbidity and mortality. More than 50% of patients with extensive chronic GVHD will die, mostly secondary to infections resulting from severe immune dysfunction. Large single-institution and registry series have identified factors that place patients at higher risk for the development of GVHD. For acute GVHD, these include HLA incompatibility, use of an unrelated donor, prior donor allosensitization through pregnancy or blood transfusion, older patient or donor age, recipient CMV seropositivity, and increased intensity of the ablative regimen. For chronic GVHD, prior acute GVHD is the major risk factor, but also important are use of peripheral blood stem cells, histoincompatibility, and the prior use of corticosteroids.95,145–147

FIGURE 6.3. Pathophysiology of acute graft-versushost disease (GVHD). The cytokine theory of acute GVHD pathogenesis involves release of proinflammatory cytokines after conditioning regimen-induced injury, which then leads to stimulation of alloreactive effector cells, which then leads to the further release of cytokines and tissue injury. (Courtesy of J. Antin.)

GVHD Pathophysiology The pathophysiology of GVHD has received extensive attention. It is recognized that donor T cells are critical mediators in the graft-versus-host reaction. However, recent animal research suggests that the pathophysiology of acute GVHD is far more complex and that it involves intricate interactions between cellular and cytokine components of the immune system (Figure 6.3).148,149 Acute GVHD is now believed to occur in three phases: (1) tissue damage from conditioning regimen, (2) donor T-cell activation phase, and (3) inflammatory effector phase. In the earliest phase of GVHD, inflammatory cytokines are released from host tissue in response to damage by the pretransplant conditioning regimen. These cytokines, including interleukin 1 (IL-1) and tumor necrosis factor-alpha, upregulate the expression of adhesion molecules and host major histocompatibility complex (MHC) antigens and enhance recognition of the host tissue by mature donor T lymphocytes. During the second phase, donor T cells of the T-helper 1 (Th1) subset are activated upon recognition of alloantigens and secrete cytokines such as interleukin 2 and interferon-alpha. IL-2 plays a central role in the recruitment of other T cells, cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, monocytes, and macrophages.

GVHD Prophylaxis T cells remain the prime target for most current therapeutic strategies in GVHD prophylaxis in humans. Effective approaches for the prevention and treatment of GVHD involve direct blockade of T-cell function. These methods have included the downregulation of T lymphocytes by inhibiting cellular proliferation (methotrexate), inhibition of de novo purine synthesis (mycophenolate mofetil), suppression of IL-2 secretion by blocking calcineurin activity (cyclosporine, tacrolimus), interfering with downstream growth signaling pathways (rapamycin), reduction of T-cell

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responsiveness by blocking the IL-2 receptor (dacluzimab), and generation of immunosuppressive cytokines (extracorporeal photopheresis).150–156 Combination therapy with methotrexate and a calcineurin inhibitor, albeit flawed, remains the gold standard for GVHD prophylaxis.157–160 The recent combination of tacrolimus and sirilimus (rapamycin) has shown significant promise in recipients of HLA-matched unrelated and related transplants.161 The most effective means for GVHD prophylaxis has been ex vivo depletion of T cells from the donor inoculum.162 Donor T-cell depletion (TCD), when it was first introduced in the early 1980s, offered the potential for prevention of GVHD without the morbidity associated with immunosuppressive drugs such as methotrexate and cyclosporine. Numerous TCD methods have been utilized over the past two decades; these have included negative selection techniques using monoclonal antibody(ies) plus complement, immunotoxins, counterflow centrifugal elutriation, soybean lectin agglutination, and, more recently, positive selection through CD34+ columns.163–166 Most early trials documented that TCD could substantially limit acute and chronic GVHD. However, this reduction in GVHD did not translate into improved overall survival because of unexpected high rates of graft failure, Epstein–Barr virus (EBV)-associated lymphoproliferative disorders (EBV-LPD), and disease recurrence following TCD-BMT (Table 6.3).167–170 It is believed that certain sets of donor cells removed in the purging process are also important for graft maintenance, viral surveillance, and elimination of residual leukemia cells that have survived the high-dose ablative conditioning regimen. Despite the problems associated with Tcell depletion, there remains great interest in developing and improving this technology, particularly for recipients of mismatched or unrelated grafts. Reasonable applications for TCD may include those patients at high risk for GVHD (unrelated or mismatched grafts) or patients with comorbid medical conditions who might have a high risk of complications after conventional BMT. TCD may be ideal for patients with diseases where GVL activity is less critical, such as first remission acute leukemia. In the future, studies need to assess the potential role of T-cell depletion when mobilized PBSCs are used for allogeneic transplantation, particularly with respect to its effect on chronic GVHD. It would be ideal to be able to manipulate different lymphoid subgroups responsible for GVHD and GVL, but whether these processes can be effectively separated at a clinical level remains unknown.

GVHD Treatment Once established, administration of corticosteroids is the most effective approach to the treatment of both acute and

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chronic GVHD. Complete responses occur in 25% to 40% of patients. Addition of other agents to corticosteroids or increasing the steroid dose has not improved response rates or outcomes.171,172 A comparative trial of 2 and 10 mg/kg/day of methylprednisolone demonstrated no advantage of the higher dose in terms of response or survival.173 For acute GVHD, calcineurin inhibitors such as cyclosporine and tacrolimus are useful in patients who did not receive these agents initially as prophylaxis.174 Serotherapy with antithymocyte globulin (ATG) can produce responses, although subsequent infection rates are high and survival does not appear to be improved. Other anti-T-cell antibodies with distinct specficities have been studied. Responses have been reported, but these antibodies have not proven superior to steroids alone. Medications aimed at blocking T-cell proliferation (mycophenxlate mofetil) or activation (rapamycin) appear to induce responses in single-arm trials, but these agents have not yet been studied fully in randomized trials. Targeting cytokine receptors such as IL-2 (dacluzimab, denileukin difitox), IL-1 (IL-1RA), and tumor necrosis factor-alpha (TNFa) (infliximab) have yielded promising results in small uncontrolled trials but have not proven to add benefit in randomized trials.150–156,175,176 Treatment of extensive chronic GVHD with immunosuppressive therapy has been even less rewarding than that of acute GVHD. Although the combination of cyclosporine and prednisone is the treatment of choice in many centers, a recent randomized trial failed to show any survival advantage.177 Encouraging uncontrolled trials with thalidomide have been reported, but subsequent randomized studies did not demonstrate significant benefit.178,179 Both psoralen plus ultraviolet A (PUVA) therapy and extracorporeal photopheresis (ECP) have been reported to be effective in acute and particularly chronic GVHD.180,181 Randomized studies are currently under way to evaluate the value of ECP. The overall disappointing results of immunosuppressive therapy for chronic GVHD make other efforts, such as prevention of infection and physical therapy, even more critical to maintenance of patient well-being.

Sustained Eradication of Disease The goal of HSCT for malignant disease or marrow disorders is sustained eradication of disease. This result can be obtained in certain circumstances with high-dose chemotherapy. However, it is clear from preclinical models and clinical studies that immune-mediated allogeneic effects, termed graft-versus-tumor (GVT) or graft-versus-leukemia (GVL) effects, are central to the therapeutic effect of allogeneic

TABLE 6.3. Pros and cons of T-cell depletion. Advantages

Disadvantages

Decreased incidence of acute and chronic GVHD Reduced or no requirement for posttransplant immunosuppression as GVHD prophylaxis Decreased organ toxicity Lower early transplant-related mortality

Higher incidence of graft failure Loss of GVL activity (higher incidence of disease relapse, especially with CML) Delayed immune reconstitution Increased risk for posttransplant EBV-associated lymphoproliferative disorder

100 HSCT.182 Evidence to support the existence of GVL activity has come from several sources. First, a higher relapse rate has been noted in recipients of syngeneic transplants compared with allogeneic transplants from sibling donors, suggesting that the genetic/immunologic discrepancy between donor and host plays a role in disease control.140,183 Second, a reduced risk of relapse is observed in patients who develop GVHD after HSCT.184 Third, relapse rates are higher in recipients of T-cell-depleted grafts where alloreactive T cells are removed.167 Fourth, withdrawal of immunosuppression in some patients who have relapsed after transplant can induce a remission.185 All these lines of evidence still only provided indirect evidence of the existence of GVL activity. Direct evidence was finally obtained when donor lymphocyte infusions (DLI) were successfully used to treat patients with CML who had relapsed after BMT. Many reports confirmed the efficacy of DLI in inducing remissions in patients who have relapsed after transplant, particularly in patients with CML.186–188 DLI induces complete cytogenetic remissions in more than 70% in patients with CML when treated in either cytogenetic or hematologic relapse. Responses are noted in other diseases, including multiple myeloma, MDS, CLL, and low-grade lymphoma. Acute leukemia and advanced CML may be less sensitive to DLI. DLI can cause GVHD. However, it is exciting to note that DLI can induce remissions in the absence of GVHD, demonstrating that GVL and GVHD can be separable.189 The dramatic activity of DLI is what has led to the exploration of nonmyeloablative conditioning regimens in clinical situations that rely predominantly on GVL activity for therapeutic benefit. It is hoped that current efforts to identify targets of DLI will lead to generation of vaccines that can be tested in clinical trials.190,191

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147. Atkinson K, Horowitz MM, Gale RP, et al. Risk factors for chronic graft-versus-host disease after HLA-identical bone marrow transplantation. Blood 1990;75:2459–2464. 148. Ferrera JLM, Antin JH. Pathophysiology of graft-versus-host disease. In: Thomas ED, Blume KG, Forman SJ (eds). Hematopoietic Stem Cell Transplantation. Boston: Blackwell, 1999: 305–315. 149. Ferrara JL. Pathogenesis of acute graft-versus-host disease: cytokines and cellular effectors. J Hematother Stem Cell Res 2000;9:299–306. 150. Anasetti C, Hansen JA, Waldmann TA, et al. Treatment of acute graft-versus-host disease with humanized anti-Tac: an antibody that binds to the interleukin-2 receptor. Blood 1994;84:1320– 1327. 151. Przepiorka D, Kernan NA, Ippoliti C, et al. Daclizumab, a humanized anti-interleukin-2 receptor alpha chain antibody, for treatment of acute graft-versus-host disease. Blood 2000; 95:83–89. 152. Castagna L. Mycophenolate mofetil (MMF) for refractory chronic graft versus host disease (cGvHD). Haematologica 2003;88:ELT28; author reply ELT29. 153. Apisarnthanarax N, Donato M, Korbling M, et al. Extracorporeal photopheresis therapy in the management of steroidrefractory or steroid-dependent cutaneous chronic graftversus-host disease after allogeneic stem cell transplantation: feasibility and results. Bone Marrow Transplant 2003;31: 459–465. 154. Bisaccia E, Palangio M, Gonzalez J, Adler KR, Rowley SD, Goldberg SL. Treating refractory chronic graft-versus-host disease with extracorporeal photochemotherapy. Bone Marrow Transplant 2003;31:291–294. 155. Kiehl MG, Schafer-Eckart K, et al. Mycophenolate mofetil for the prophylaxis of acute graft-versus-host disease in stem cell transplant recipients. Transplant Proc 2002;34:2922– 2924. 156. Benito AI, Furlong T, Martin PJ, et al. Sirolimus (rapamycin) for the treatment of steroid-refractory acute graft-versus-host disease. Transplantation 2001;72:1924–1929. 157. Ruutu T, Volin L, Parkkali T, Juvonen E, Elonen E. Cyclosporine, methotrexate, and methylprednisolone compared with cyclosporine and methotrexate for the prevention of graftversus-host disease in bone marrow transplantation from HLAidentical sibling donor: a prospective randomized study. Blood 2000;96:2391–2398. 158. Chao NJ, Schmidt GM, Niland JC, et al. Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone for prophylaxis of acute graft-versus-host disease. N Engl J Med 1993;329:1225–1230. 159. Deeg HJ, Lin D, Leisenring W, et al. Cyclosporine or cyclosporine plus methylprednisolone for prophylaxis of graft-versus-host disease: a prospective, randomized trial. Blood 1997;89:3880– 3887. 160. Nash RA, Antin JH, Karanes C, et al. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors. Blood 2000; 96:2062–2068. 161. Antin JH, Kim HT, Cutler C, et al. Sirolimus, tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation. Blood 2003;102:1601–1605. 162. Ho VT, Soiffer RJ. The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation. Blood 2001;98:3192–3204. 163. Waldmann HG, Hale G, Cividalli G, et al. Elimination of graft-versus-host disease by in vitro depletion of alloreactive lymphocytes with a monoclonal rat anti-human lymphocyte antibody (Campath-1). Lancet 1984;2:483–486.

b i o l og i c p r i n c i p l e s o f h e m at o p o i e t i c s t e m c e l l t r a n s p l a n t at i o n 164. Filipovich AH, Vallera D, McGlave P, et al. T cell depletion with anti-CD5 immunotoxin in histocompatible bone marrow transplantation. Transplantation 1990;50:410–415. 165. Soiffer RJ, Murray C, Mauch P, et al. Prevention of graftversus-host disease by selective depletion of CD6-positive T lymphocytes from donor bone marrow. J Clin Oncol 1992;10: 1191–1200. 166. Reisner Y, Kapoor N, Kirkpatrick D, et al. Transplantation for acute leukemia with HLA-A and B nonidentical parental marrow cells fractionated with soybean agglutinin and sheep red blood cells. Lancet 1981;2:327. 167. Marmont A, Horowitz MM, Gale RP, et al. T-cell depletion of HLA-identical transplants in leukemia. Blood 1991;78: 2120–2130. 168. Kernan NA, Bordignon C, Heller G, et al. Graft failure after Tcell-depleted leukocyte antigen identical marrow transplants for leukemia: I. analysis of risk factors and results of secondary transplants. Blood 1989;74:2227–2236. 169. Goldman JM, Gale RP, Horowitz MM, et al. Bone marrow transplantation for chronic myelogenous leukemia in chronic phase. Increased risk for relapse associated with T-cell depletion. Ann Intern Med 1988;108:806–814. 170. Zutter MM, Martin PJ, Sale GE, et al. Epstein-Barr virus lymphoproliferation after bone marrow transplantation. Blood 1988;72:520. 171. Martin PJ, Schoch G, Fisher L, et al. A retrospective analysis of therapy for acute graft-versus-host disease: initial treatment. Blood 1990;76:1464–1472. 172. Martin PJ, Schoch G, Fisher L, et al. A retrospective analysis of therapy for acute graft-versus-host disease: secondary treatment. Blood 1991;77:1821–1828. 173. Van Lint MT, Uderzo C, Locasciulli A, et al. Early treatment of acute graft-versus-host disease with high- or low-dose 6-methylprednisolone: a multicenter randomized trial from the Italian Group for Bone Marrow Transplantation. Blood 1998;92: 2288–2293. 174. Ohashi Y, Minegishi M, Fujie H, Tsuchiya S, Konno T. Successful treatment of steroid-resistant severe acute GVHD with 24-h continuous infusion of FK506. Bone Marrow Transplant 1997; 19:625–627. 175. Antin JH, Weinstein HJ, Guinan EC, et al. Recombinant human interleukin-1 receptor antagonist in the treatment of steroid-resistant graft-versus-host disease. Blood 1994;84:1342– 1348. 176. Antin JH, Weisdorf D, Neuberg D, et al. Interleukin-1 blockade does not prevent acute graft-versus-host disease: results of a randomized, double-blind, placebo-controlled trial of interleukin-1 receptor antagonist in allogeneic bone marrow transplantation. Blood 2002;100:3479–3482. 177. Koc S, Leisenring W, Flowers ME, et al. Therapy for chronic graft-versus-host disease: a randomized trial comparing cyclosporine plus prednisone versus prednisone alone. Blood 2002;100:48–51.

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178. Koc S, Leisenring W, Flowers ME, et al. Thalidomide for treatment of patients with chronic graft-versus-host disease. Blood 2000;96:3995–3996. 179. Arora M, Wagner JE, Davies SM, et al. Randomized clinical trial of thalidomide, cyclosporine, and prednisone versus cyclosporine and prednisone as initial therapy for chronic graftversus-host disease. Biol Blood Marrow Transplant 2001;7: 265–273. 180. Dall’Amico R, Rossetti F, Zulian F, et al. Photopheresis in paediatric patients with drug-resistant chronic graft-versus-host disease. Br J Haematol 1997;97:848–854. 181. Besnier DP, Chabannes D, Mussini JM, Dupas B, Esnault VL. Extracorporeal photochemotherapy for secondary chronic progressive multiple sclerosis: a pilot study. Photodermatol Photoimmunol Photomed 2002;18:36–41. 182. Truitt RL, Johnson BD. Principles of graft-vs.-leukemia reactivity. Biol Blood Marrow Transplant 1995;1:61–68. 183. Gale RP, Horowitz MM, Ash RC, et al. Identical-twin bone marrow transplants for leukemia. Ann Intern Med 1994;120: 646–652. 184. Weiden PL, Flournoy N, Sanders JE, et al. Anti-leukemic effect of graft-versus-host disease contributes to improved survival after allogeneic marrow transplantation. Transplant Proc 1981; 13:248–251. 185. Collins RH, Rogers ZR, Bennett M, Kumar V, Nikein A, Fay JW. Hematologic relapse of chronic myelogenous leukemia following allogeneic bone marrow transplantation. Apparent graftversus-leukemia effect following abrupt discontinuation of immunosuppression. Bone Marrow Transplant 1992;10:391– 395. 186. Collins RH Jr, Shpilberg O, Drobyski WR, et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation [see comments]. J Clin Oncol 1997;15:433–444. 187. Kolb HJ, Schattenberg A, Goldman JM, et al., the European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 1995;86:2041–2050. 188. Porter DL, Antin JH. Adoptive immunotherapy for relapsed leukemia following allogeneic bone marrow transplantation. Leuk Lymphoma 1995;17:191–197. 189. Alyea EP, Soiffer RJ, Canning C, et al. Toxicity and efficacy of defined doses of CD4(+) donor lymphocytes for treatment of relapse after allogeneic bone marrow transplant. Blood 1998; 91:3671–3680. 190. Yang XF, Wu CJ, Chen L, et al. CML28 is a broadly immunogenic antigen, which is overexpressed in tumor cells. Cancer Res 2002;62:5517–5522. 191. Yang XF, Wu CJ, McLaughlin S, et al. CML66, a broadly immunogenic tumor antigen, elicits a humoral immune response associated with remission of chronic myelogenous leukemia. Proc Natl Acad Sci USA 2001;98:7492–7497.

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Evaluation of Tumor Markers: An EvidenceBased Guide for Determination of Clinical Utility Daniel F. Hayes

A

tumor marker is clinically useful if its results serve to separate a large heterogeneous population into smaller populations with more precisely predictable outcomes. In theory, if this separation is both reliable and disparate, one can apply therapy more efficiently to the population by exposing those most likely to need and benefit from the therapy while ensuring that the other group avoids needless toxicities. In essence, the term tumor marker has come to describe a variety of molecules or processes that differ from the norm in either malignant cells, tissues, or fluids in patients with malignancies. Assessing these alterations from normal can be used to place patients into categories that are distinguished by different outcomes, either in the absence of specific therapy or after various treatments are applied. Tumor markers can include changes at the genetic level (for example, mutations, deletions, or amplifications), at the transcriptional level (for example, over- or underexpression), at the translational or posttranslational level (for example, increased or decreased quantities of protein, or abnormal glycosylation of proteins), and/or at the functional level (for example, histologic description of cellular grade or presence of neovascularization). Each of these can be assessed by one or more assays, which can be performed using one or more methods with differing reagents. This enormous heterogeneity of approaches is the root of considerable confusion regarding the true value, in clinical terms, of a given tumor marker. The molecular revolution is now well into its fourth decade. Yet, in spite of impressive advances in our understanding of the biology of human malignancy and in the technology of investigating molecular processes, the number of clinically useful products from these advances is disappointing. For example, in 1995, the American Society of Clinical Oncology (ASCO) convened a panel of experts to establish guidelines for the use of tumor markers in colon and breast carcinoma. Although the Expert Panel reviewed many putative markers (including both tissue-based and circulating

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markers), their ultimate recommendations were surprisingly sparse (Table 7.1).1–3 Why are the ASCO guidelines so conservative? In reviewing the available literature, the Panel recognized that the science of clinical tumor marker investigation has been haphazard and relatively chaotic. Too often, studies of tumor markers are more inclined to be “fishing expeditions” with the hope that something interesting will be detected with statistical significance, rather than being prospective, hypothesis-driven investigations. In light of this confusion, several authors of the Guidelines separately developed a proposal for a framework in which previously published tumor marker studies might be critically evaluated in an evidence-based manner.4 The rest of this chapter reviews the generic concepts and policies related to tumor marker evaluation. Specific marker evaluation for a given disease are reviewed in the relevant chapter pertaining to that malignancy.

Critical Elements of a Clinically Useful Tumor Marker The first and most obvious element of evaluating a tumor marker is to determine its stated use. Tumor markers can be valuable for risk assessment, screening, diagnosis, prognosis, prediction of benefit from therapy, and monitoring disease course (Table 7.2). The most commonly accepted uses are for prognosis and prediction, as well as monitoring. The first two of these require more detailed understanding.

What Is the Question: Prognosis Versus Prediction? Estimating a patient’s prognosis requires a complicated set of evaluations, which includes the propensity of a malignancy to expand in volume (proliferative capacity), its ability to escape its natural site of origin and establish growth in a foreign tissue (metastatic potential), and its relative sensitiv-

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TABLE 7.1. American Society of Clinical Oncology clinical practice guidelines for use of tumor markers in breast and colon cancer (tissue factors only). Disease

Factor

Use

Guideline

Breast cancer

Estrogen and progesterone receptors

Predictive factors for endocrine therapy

DNA flow cytometrically derived parameters c-erbB-2 (HER-2/neu)

Prognosis or prediction

Measure on every primary breast cancer and on metastatic lesions if results influence treatment planning Data are insufficient to recommend obtaining results

Prognosis Prediction for: trastuzumab CMF-like regimens doxorubicin taxanes endocrine Rx

Colorectal cancer

P53 Cathepsin-D Circulating carcinoembryonic antigen

Prognosis or prediction Prognosis Screening Preoperative Postoperative

Lipid-associated sialic acid CA19-9 DNA ploidy and flow cytometry P53 Ras

Metastatic setting Monitoring Monitoring Prognosis Prognosis Prognosis

Data are insufficient to recommend obtaining results for this use c-erbB-2 should be evaluated on every primary breast cancer at time of diagnosis or at time of recurrence for use as predictive factor for trastuzumab; Committee could not make definitive recommendations regarding CMF-like regimens; c-erbB-2 may identify patients who particularly benefit from anthracyline-based therapy but should not be used to exclude anthracycline; treatment c-erbB-2 should not be used to prescribe taxane-based therapy or endocrine therapy Data are insufficient to recommend use of p53 Data are insufficient to recommend use of cathepsin-D Not recommended Recommended to guide surgical planning Recommended to monitor for early, asymptomatic, and resectable metastases Recommended to monitor benefit from therapy Not recommended for screening, diagnosis, staging, or monitoring Not recommended for screening, diagnosis, staging, or monitoring Data are insufficient to recommend use of DNA ploidy or flow cytometry Data are insufficient to recommend use of p53 Data are insufficient to recommend use of ras

Source: Adapted from Bast RC Jr, Ravdin P, Hayes DF, et al.,3 by permission of J of Clinical Oncology.

ity or resistance to therapy. Therapies for most solid tumors include surgery, radiation, and systemic therapies such as hormone therapies or chemotherapies. In this regard, the terms “prognostic” and “predictive” have taken on separate meanings.5,6 The prognostic factor designation is usually reserved for those markers that specifically provide an estimate of the odds of the recurrence of a given cancer after local therapy only. It is usually a measure of both proliferation and metastatic potential, and it usually implies the odds of systemic recurrence and/or death in a patient who does not receive systemic therapy. If the factor is associated with a poor prognosis, patients who are “positive” for the prognostic factor have a worse outcome than those who are “negative” in the absence of systemic therapy. Therapy may be

TABLE 7.2. Potential uses of tumor markers. Determination of risk Screening Differential diagnosis Benign vs. malignant Known malignant: tissue of origin Prognosis Prediction Monitoring disease course Detect recurrence in patient free of obvious disease Patient with established recurrence

effective, but it is equally so (in relative terms) for both factorpositive and factor-negative patients. The best examples of prognostic factors for most solid tumors are the TNM staging systems. A predictive factor helps select therapies most likely to work against that patient’s tumor. A predictive factor may be the precise target of the therapy, an associated molecule or pathway that modifies the effectiveness of the therapy, or simply an alteration that is an epiphenomenon linked to the target or pathway of the therapy (such as coamplification of a neighboring gene). If the factor is a pure predictive factor, prognosis in the absence of therapy is the same for factornegative and -positive patients (it has no prognostic effects). However, assuming it predicts for benefit from therapy, factor-positive patients have a much better prognosis than factor-negative patients in the presence of the therapy for which the factor is predictive. For example, it is now clearly established that the level of estrogen receptor (ER) content in breast cancer tissue is positively related to the odds of response and benefit from antiestrogen hormonal therapy, such as ovarian ablation, tamoxifen, or aromatase inhibitors, because the ER plays a fundamental role in estrogen-dependent tumor growth and biology.7 In contrast, p-glycoprotein content is a negative predictive factor for resistance to certain drugs, because this protein modulates multidrug resistance by increasing efflux of the antineoplastic agent from the cancer cell.8

108 Many, in fact most, factors may be both prognostic and predictive. For example, in addition to serving as a predictive factor, ER is also a favorable prognostic factor. Breast cancers with high ER content have generally slower growth potentials, and patients with ER-”positive” tumors have a better prognosis, even if they receive no treatment.9,10 To further complicate this discussion, some markers may be associated with a poor prognosis independent of therapy, but they may predict for an improved outcome related to specific treatment modalities. For example, in breast cancer, amplification and/or overexpression of HER-2 is a marker of poor prognosis in the absence of any systemic therapy.11–14 However, HER-2 serves as the target for a humanized monoclonal antibody, trastuzumab (herceptin), and response and benefit from trastuzumab are tightly linked to HER-2 amplification and/or overexpression.15,16 Thus, untreated HER-2positive patients have a worse prognosis than HER-2-negative patients if they do not receive trastuzumab, but they may actually have a more favorable prognosis if they do. These considerations are often ignored in many “prognostic factor” studies. Often, a population of patients is studied with a new, putative prognostic factor simply because the samples to be assayed happen to be available and the outcome for the patients is known. Indeed, a prognostic factor can only be evaluated in the absence of systemic therapy, or at least in the absence of any therapy with which it interacts. A predictive factor can only be evaluated in the context of an untreated control group, preferably one that is prospectively identified and followed, as in prospective randomized trials. It is not surprising that studies of a marker that might have both prognostic and predictive capabilities, especially if these effects are in opposition (as may be the case with HER-2), will provide relatively random and conflicting results if not carefully planned with appropriate consideration of treatment effects control groups and satisfactory control groups.

What Is the Strength of the Marker? A marker is only helpful if it separates an entire population into two different groups whose outcome is likely to be so different that one group might be treated differently from another. Again using breast cancer as an example, both ER and HER2 are good examples of strong predictive markers that are clinically useful. Patients with ER-negative tumors appear very unlikely to benefit from hormone therapy,17 and, likewise, it appears that patients with HER2-low or -negative cancers are very unlikely to benefit from trastuzumab.4,18 It is important to recognize that clinical utility of a marker is not justified simply because a tumor marker may separate two populations of patients whose outcomes differ with statistical significance. A P value less than 0.05 simply implies it is likely that those two populations are different (see following). Rather, for a marker to be clinically useful, it must not only separate the two populations with reliability, the separation must be of sufficient magnitude that one would treat the two groups differently. How large this magnitude needs to be for a tumor marker to be acceptable for clinical use is an arbitrary decision, and it depends on the perspectives of the patient, the caregiver, and the societal elements that pay for the care. Several studies

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have been performed in which patients are queried regarding how much benefit they would require to accept a given level of toxicity.19–21 Not surprisingly, results from these studies are heterogeneous, although in general a decreasing proportion of patients is willing to accept therapy as the absolute odds of benefit decrease. However, for a few patients, any benefit is worth the risk of toxicities, and for a few others therapy is never acceptable, even if the odds of benefit are enormous. Sophisticated tools are now available on paper and on the Internet to help patients understand and quantify the relative odds of benefit and toxicities of certain therapies in selected situations, such as for adjuvant therapy of primary breast cancer.22–24 These tools are based on clinical and pathologic prognostic and predictive factors, such as the T, N, and M status, and a few classic markers, such as ER. However, these tools are potentially flexible enough to be modified to permit incorporation of new prognostic factors if the estimate of magnitude between positive and negative subgroups is sufficiently reliable.

Is the Magnitude of Difference Between the Two Groups Reliable? The hallmark of any scientific observation is, of course, reproducibility. With few exceptions, tumor markers seem to pass through a “life cycle” in which the original report is extraordinarily positive with great acclaim, but subsequent studies fail to live up to the promise. There are several elements regarding both technical variability of the assay and clinical trial design that account for this phenomenon, and these may hinder acceptance of the assay for routine clinical use. There are fundamentally three reasons for this conundrum: (1) technical variability of the assay; (2) variations in the manner in which different assays for the same marker are performed; and (3) inadequate and variable study designs. The assay must be technically reliable and reproducible. Assay reproducibility is critical for any clinical test. Reproducibility hinges on several factors, all of which must be standardized and validated. Too often, an assay is developed in an individual investigator’s laboratory based on personal preferences and subjective techniques that are not easily transported to other investigators and laboratories. For an assay to be useful clinically, it must be shown to be accurate throughout a broad dynamic range of values and reproducible at each of these levels as well. Concern must be taken regarding fixatives and other processing of samples, because these can have an enormous impact on the results of an assay from one laboratory to the next, resulting in false positives or negatives.

Analysis and Quantitation of Results How the assay is “scored” or “read” is also critical for reproducibility. For example, when immunohistochemistry is performed, does the reader report the results as percent cells that stained, the intensity of staining, or a combination of both? Are the results reported as such, or in an index, such as 0–3+? Furthermore, selection of the cutoff that distinguishes positive from negative populations can give incredibly different results for the same assay. Several means of establishing a cutoff are employed, and there is no consensus regarding the optimal method.25 One method is to arbitrarily select a cutoff,

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based on some preconceived reason, such as the mean level of the assay in an affected population or the mean plus two standard deviations (2 SD) of the level in an unaffected population. A second method is to test several potential cutoffs in one population, selecting the one that appears most robust relative to separation of the outcomes of the two groups or to apparent statistical significance. Regardless of the method used, it is essential to validate the results in a separate group of patients.26 Thus, even if the same assay using the same reagents is applied in two different studies, use of different cutoffs will substantially affect the results.

Do Two Studies Use the Same Assay? Because of competition among scientists and commercial interests, different assays are often developed to evaluate the same marker. Thus, when reading what appears to be a confirmatory study of a given marker, one must be certain that the same assay was used in both studies. For example, HER2 status can be determined by examination of cancer tissue amplification of the erbB2 gene using a variety of techniques including Southern blotting, slot-blot quantification, or fluorescence in situ hybridization, and by evaluation of the protein using Western blotting, immunohistochemistry, immunofluorescence, or enzyme-linked immunosorbent assays (ELISA). Moreover, the circulating extracellular domain of HER2 can be quantified in human serum using ELISA.27 Although they are all correlated, each of these assays, which in one way or another provides an indication of overproduction of HER2, appears to differ from the other and to provide different results in regard to prediction of outcome. Furthermore, even if the assay format is the same, use of different reagents or conditions may affect results. For example, it has been clearly shown that different antibodies against HER-2 can provide very different results in immunohistochemical (IHC) assays.28 Thus, it is not surprising that results from study to study are not validated, if the assays that are being compared are not identical.

Was the Study Design Appropriate to Address the Hypothesis? The results of a tumor marker are most likely to be valid if they are studied in the context of a plausible hypothesis that is prospectively addressed; for example, a study of prognosis in the absence of the therapy being considered or prediction that the specific therapy will be beneficial. Many published studies report results related to hypotheses that are retrospectively derived from the observed data. Although such studies are valuable to generate hypotheses, these observations must be prospectively validated in subsequent, welldesigned studies.4,25 Unfortunately, most tumor marker studies are performed using archived specimens collected for reasons unrelated to the study under question. Therefore, it is difficult to validate exciting but preliminary observations, which requires time-consuming prospective studies. Nonetheless, failure to do so often leaves the reader unable to draw definitive conclusions and, in the long run, delays acceptance of the marker for clinical use.

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How Should Tumor Markers Be Selected for Clinical Use? To summarize the preceding paragraphs, a good tumor marker study should provide accurate estimate of the magnitude of difference in outcomes between subgroups of patients who are positive or negative for the marker, using a reliable, accurate, and reproducible assay. Do prognostic and predictive factors exist that permit such elegant selection of patients for treatment? Sadly, in most solid tumors, the answer is no. For patients with newly diagnosed solid malignancies, there is no example of a prognostic factor that predicts subsequent recurrence and death with absolute certainty. Therefore, when these markers are applied in the clinic, both physician and patient must accept some margin of error. These decisions involve both the tumor marker results, as already discussed, and also a careful assessment of the magnitude of effectiveness of therapy for the patient’s condition (proportional reduction in risk of events), the degree of toxicity of that therapy, and the patient’s willingness (as well as the caregiver’s and society’s) to either forgo potential benefit to avoid toxicity or to accept toxicity and cost to gain benefit. Therefore, part of the art, and science, of medicine is to determine which markers are most reliable in separating groups of patients into those that will do well from those that will not, and into those that will benefit from therapy from those that will not. If performed appropriately, tumor marker analysis should permit delivery of therapy as efficiently as possible, providing benefit to the greatest number of patients while avoiding exposure to toxicities as much as possible. Levels of Evidence (LOE) to evaluate tumor markers have been proposed, again by the American Society of Clinical Oncology Expert Panel on Tumor Markers (Table 7.3).4 LOE I data are generated from either a prospective, highly powered study that specifically addresses the issue of tumor marker utility or from an overview or meta-analysis of studies, each of which provides lower levels of evidence. LOE II data are derived from companion studies in which specimens are collected prospectively as part of a therapeutic clinical trial, with preestablished endpoints and statistical evaluation for the marker as well as for the therapeutic intervention. Ideally, the estimate of the relative strength of a marker for clinical utilities should be determined within the context of LOE I (or at worse II) studies. In these studies, the marker is the primary objective of a well-designed, highly powered, hypothesis-driven prospective clinical trial, or it is the objective of a statistically rigorous overview of LOE II and/or III studies. Furthermore, the strength of new prognostic or predictive factors can only be estimated by multivariate analytical methods, including preexisting accepted factors such as TNM staging and histopathology. It is possible that a marker may be quite prognostic or predictive when considered in a univariate fashion but that it is, in fact, only reflecting information already achieved through other, established methods. In this case, acceptance of the new marker would only occur if it can be performed more easily or reliably or less expensively.

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TABLE 7.3. Levels of evidence for grading clinical utility of tumor markers. Level

Type of Evidence

I

Evidence from a single high-powered prospective study that is specifically designed to test marker or evidence from meta-analysis and/or overview of Level II or III studies. In the former case, the study must be designed so that therapy and follow-up are dictated by protocol. Ideally, the study is a prospective randomized trial in which diagnostic and/or therapeutic clinical decisions in one arm are determined based at least in part on marker results, and diagnostic and/or therapeutic clinical decisions in control arm are made independently of marker results. However, may also include prospective but not randomized trials with marker data and clinical outcome as primary objective. 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 (i.e., marker study is secondary objective of protocol). However, specimen collection for marker study and statistical analysis are prospectively determined in protocol as secondary objectives. Evidence from large but retrospective studies from which variable numbers of samples are available or selected. Therapeutic aspects and follow-up of patient population may or may not have been prospectively dictated. Statistical analysis for tumor marker was not dictated prospectively at time of therapeutic trial design. Evidence from small retrospective studies which do not have prospectively dictated therapy, follow-up, specimen selection, or statistical analysis. May be matched case controls, etc. Evidence from small pilot studies designed to determine or estimate distribution of marker levels in sample population. May include “correlation” with other known or investigational markers of outcome, but not designed to determine clinical utility.

II

III

IV V

Source: From Hayes et al.,4 by permission of Journal of the National Cancer Institute.

Summary In summary, the field of tumor marker generation is evolving rapidly, with a convergence of molecular biology and technology and understanding of clinical trial design and analysis. Several of the large cooperative trialists’ groups have now established separate correlative/biologic committees that are charged with designing hypothesis-driven LOE I and II studies, based on results from pilot studies. The emergence of erbB-2 in breast cancer as a predictive factor, in a manner similar to ER, may serve as a model of directed studies that lead to determination of the relative strength of the marker and determination of whether it should be used clinically. One hopes that careful and thoughtful consideration of study design will considerably shorten the life cycle required to being a tumor marker from the laboratory to the clinic. Acknowledgment. Supported in part by NIH grant CA64057 and by the Fashion Footwear Association of New York (FFANY)/QVC Presents/Shoes on Sale.

References 1. ASCO Expert Panel. Clinical Practice Guidelines for the Use of Tumor Markers in Breast and Colorectal Cancer: Report of the American Society of Clinical Oncology Expert Panel. J Clin Oncol 1996;14:2843–2877. 2. ASCO Expert Panel. 1997 update of recommendations for the use of tumor markers in breast and colorectal cancer. J Clin Oncol 1998;16:793–795. 3. Bast RC Jr, Ravdin P, Hayes DF, et al. 2000 Update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001;19(6):1865–1878. 4. Hayes DF, Bast R, Desch CE, et al. A tumor marker utility grading system (TMUGS): a framework to evaluate clinical utility of tumor markers. J Natl Cancer Inst 1996;88:1456–1466. 5. McGuire WL, Clark GM. Prognostic factors and treatment decisions in axillary-node-negative breast cancer. N Engl J Med 1992;326(26):1756–1761.

6. Gasparini G, Pozza F, Harris AL. Evaluating the potential usefulness of new prognostic and predictive indicators in nodenegative breast cancer patients. J Natl Cancer Inst 1993; 85(15):1206–1219. 7. Osborne CK. Receptors. In: Harris J, Hellman S, Henderson I, Kinne D (eds). Breast Diseases, 2nd ed. Philadelphia: Lippincott; 1991:301–325. 8. Trock B, Leonessa F, Clarke R. Multidrug resistance in breast cancer: a meta-analysis of MDR1/gp170 expression and its possible functional significance. J Natl Cancer Inst 1997;89: 917–931. 9. Fisher B, Costantino J, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 1989;320:479–484. 10. Fisher B, Redmond C, Dimitrov N, et al. A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-negative tumors. N Engl J Med 1989;320: 473–478. 11. Ravdin PM. Should HER2 status be routinely measured for all breast cancer patients? Semin Oncol 1999;26(4 suppl 12): 117–123. 12. Press MF, Bernstein L, Thomas PA, et al. HER-2/neu gene amplification characterized by fluorescence in situ hybridization: poor prognosis in node-negative breast carcinomas. J Clin Oncol 1997; 15(8):2894–2904. 13. Hayes DF. Tumor markers for breast cancer. Ann Oncol 1993; 4:807–819. 14. Trock BJ, Yamauchi H, Brotzman M, Stearns V, Hayes DF. c-erbB-2 as a prognostic factor in breast cancer: a metaanalysis. Proc Am Soc Clin Oncol 2000;2000:97a. 15. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344(11):783–792. 16. Mass R. The role of HER-2 expression in predicting response to therapy in breast cancer. Semin Oncol 2000;27(6 suppl 11):46–52; discussion 92–100. 17. Early Breast Cancer Trialist’s Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351:1451–1467. 18. Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-

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19. 20.

21.

22.

23.

overexpressing metastatic breast cancer. J Clin Oncol 2002; 20(3):719–726. Coates AS, Simes RJ. Patient assessment of adjuvant treatment in operable breast cancer. New York: Wiley, 1992. Lindley C, Vasa S, Sawyer T, Winer E. Quality of life and preferences for treatment following systemic adjuvant therapy for early stage breast cancer. J Clin Oncol 1998;16:1380–1387. Siminoff LA, Ravdin P, Colabianchi N, Sturm CM. Doctorpatient communication patterns in breast cancer adjuvant therapy discussions. Health Expect 2000;3(1):26–36. Ravdin PM, Siminoff LA, Davis GJ, et al. Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol 2001;19(4):980–991. Loprinzi CL, Thome SD. Understanding the utility of adjuvant systemic therapy for primary breast cancer. J Clin Oncol 2001; 19(4):972–979.

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24. Whelan T, Levine M, Willan A, et al. Effect of a decision aid on knowledge and treatment decision making for breast cancer surgery: a randomized trial. JAMA 2004;292(4):435–441. 25. Simon R, Altman DG. Statistical aspects of prognostic factor studies in oncology. Br J Cancer 1994;69:979–985. 26. Clark GM. Prognostic and predictive factors. In: Harris J, Lippman M, Morrow M, Osborne CK (eds). Diseases of the Breast, 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2000:489–515. 27. Yamauchi H, Stearns V, Hayes DF. When is a tumor marker ready for prime time? A case study of c-erbB-2 as a predictive factor in breast cancer. J Clin Oncol 2001;19(9):2334–2356. 28. Press M. Sensitivity of HER-2/neu antibodies in archival tissue samples: potential source of error in immunohistochemical studies of oncogene expression. Cancer Res 1994;54(10): 2771–2777.

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Design and Analysis of Oncology Clinical Trials James J. Dignam, Theodore G. Karrison, and John Bryant

n this chapter, we discuss the design and analysis of oncology clinical trials. Because analysis follows naturally from design and is specified a priori in any well-planned trial, it is appropriate to discuss these topics together. We review clinical trial designs and associated analytical methods used in the different phases of therapy development. Along the way we identify areas in which the methodology is adapting to new approaches to therapeutic intervention. This chapter provides only a brief sketch of the main concepts and current research areas, and we refer the reader to primary sources and comprehensive texts on clinical trials in oncology for further details. Two excellent recent texts in particular, the Handbook of Statistics in Clinical Oncology1 and Clinical Trials in Oncology,2 provide the fundamentals of trial design, conduct, and analysis, as well as up-to-date discussion of new challenges and active research in statistical methods for oncology clinical trials.

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not find a new treatment to be superior is informative, and resources can then appropriately be directed into other more promising alternatives. In statistical hypothesis testing, type I or a error refers to the probability of incorrectly deciding in favor of a treatment difference when in fact none exists. Typically, the a probability is fixed at some small value, such as 0.05 or 0.01. When hypothesis tests are repeated, the probability increases that at least one test result will be erroneous. A particular complication arising in clinical trials is the need to periodically evaluate the primary hypothesis as information accumulates. These interim analyses are conducted to ensure that if definitive evidence of benefit or harm emerges before the anticipated end of the trial, then actions can be taken for the protection and benefit of trial participants. Appropriate statistical methodology to accommodate multiple serial analyses is discussed later.

Some General Statistical Concepts

Types of Trials and the Evolution of Treatment

Although we assume some familiarity with basic statistical concepts and space does not permit a detailed account, we review here some concepts vital to the design and analysis of clinical trials and associated studies. In the classical (e.g., frequentist) statistical hypothesis testing paradigm, a quantity referred to as type II or b error equals the probability that a statistical test fails to produce a decision in favor of a treatment effect when in fact the effect is manifest in the population. The complement of this probability (1 - b) is referred to as statistical power, and equals the probability of correctly detecting a treatment effect. Statistical power depends on the other principal parameters in hypothesis testing, specifically, the probability of incorrectly finding in favor of an effect when none exists (discussed in a following section), the sample size, and the size of the treatment effect. It is imperative that clinical trials be designed with adequate statistical power, typically 0.80 or greater for anticipated treatment effects that are both realistic and clinically material, so as not to obtain equivocal findings concerning the potential worth of a new treatment under consideration. Studies with low statistical power can cause delay in development or even abandonment of promising treatments and waste valuable resources, not least of which is the participation and goodwill of patients.3 In contrast, an adequately powered trial that does

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In this section we review design, conduct, and analysis of the three phases of therapy development. We also follow one clinical trial statistician’s recommendation that more descriptive names be used that reflect the goals of each study phase.4

Phase I or Dose Evaluation Trials Objectives The primary objective of a Phase I oncology trial is to determine the maximum tolerated dose (MTD) of a new experimental regimen. The general assumption is that as dose is increased, greater efficacy will be achieved; hence, the search for the highest dose level compatible with an acceptable toxicity profile. This assumption is certainly reasonable, particularly for cytotoxic drugs, although it need not always be the case. For example, the maximum beneficial effect of immunomodulating agents may occur at intermediate dosages, or the degree of efficacy may plateau so that little is gained by increasing the dose beyond a certain level. These situations create further design and analytical challenges that are probably best addressed in a randomized comparative

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setting. For the remainder of this section, we assume that the primary aim of a Phase I trial is to determine the MTD, under the assumption that the highest dose will produce the greatest beneficial effects. Secondary objectives may be to conduct pharmacokinetic studies in individual patients or detect evidence of antitumor activity. More recently, a better knowledge of drug metabolic pathways and pharmacogenomics is beginning to be incorporated into some trial designs, with the goal being to evaluate the relationship between toxicity and genotype.5

Clinical Issues Key clinical issues to be addressed when designing a Phase I trial include patient selection, the starting and subsequent dose levels to be evaluated, and the specification of doselimiting toxicities. The obvious ethical requirement when selecting patients for a Phase I trial is that no other effective treatment is available, although for a given patient there may be more than one experimental trial for which he/she is eligible. Most Phase I studies are conducted in adults with solid tumors; patients with leukemia and children are usually excluded or studied separately.6,7 Because assessment of activity is not the main objective of the trial, patients need not have measurable disease and multiple tumor types may be included. Life expectancy should be at least 3 months, the interval from any prior treatment should be sufficient to ensure that toxicities occurring over the course of the trial are due to the new agent and not prior therapy, and patients should generally have normal organ function and biochemical profiles. The manner in which a starting dose and subsequent dose levels are chosen, and the historical development behind the various recommendations for doing so, have been described.1–8 We simply note here that the starting dose is generally chosen to be low enough that there is a very small likelihood of severe toxicity. With regard to dose escalation, the increments are typically rapid initially, followed by smaller increases as one presumably approaches the toxic range. For example, the highly cited modified Fibonacci scheme begins by doubling the first dose, then increasing by factors of 1.67, 1.5, 1.4, and 1.33. The determination of the MTD is based on the toxicities (adverse events) observed in individual patients and is greatly facilitated by the U.S. National Cancer Institute’s Common Toxicity Criteria (CTC) system. In the CTC, adverse events (AEs) are grouped into various organ/symptom categories, with each AE graded as 0 (none), 1 (mild), 2 (moderate), 3 (serious/severe), 4 (life threatening), or 5 (fatal). Typically, any grade 3 or higher AE is deemed a “dose-limiting toxicity” (DLT) (although certain grade 3 AEs may be excluded). A second grading scale may be used to indicate whether, in the physician’s judgment, the AE is likely to have been related to the investigational treatment, and only those AEs scored to be at least “possibly” related to the agent are regarded as DLTs. Note that while common toxicities can be detected in Phase I trials, the sample sizes are far too small to detect lessfrequent adverse events. The criteria for a DLT should be clearly specified in the protocol, along with the time interval over which each patient will be observed for the occurrence of a DLT (typically one therapy cycle). With appropriately defined criteria, each

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patient’s outcome can be regarded as a binary random variable Y taking the value 0 if the patient did not have a DLT and 1 if the patient had a DLT within the specified time frame.

Trial Design Types The first issue to clarify is what, specifically, is meant by the MTD, for as Storer9 points out, “a strict quantitative definition of the MTD is rarely acknowledged in clinical protocols.” As discussed previously, a dose given to an individual patient is deemed “tolerable” in that patient if he/she does not experience a DLT, but in statistical terms the MTD must be defined with reference to the patient population. By virtue of the traditional and still frequently used “3 + 3” design, described below, the MTD is usually defined as the highest dose level for which the incidence of DLT is less than 33%. Thus, when employing this design, we are saying that we want to determine the dose that will be tolerable in at least 2/3 of the patients, and therefore are accepting that serious toxicity will be produced in up to 1/3 of the patients. Given that most cancers carry an appreciable risk of mortality, this seems an appropriate percentile to target, but it should not be used unthinkingly. There may be some patient populations, for example, in whom a lower percentile would be more appropriate; conversely, patients at a very high risk of mortality or morbidity may be willing to accept a greater chance of serious side effects for potential therapeutic benefits.

“3 + 3” In the traditional “3 + 3” design11 (Table 8.1), groups of three patients are treated. If none experiences a DLT, the dose is escalated, whereas if two or more experience a DLT, dose escalation is terminated and the previous dose level is provisionally defined as the MTD. If one of three has a DLT, three more patients are added at the same dose level, and if none of these has dose-limiting toxicity, dose escalation continues; otherwise, the previous dose level is considered the MTD. Once a presumed MTD is reached, however, if only three patients have been studied at that dose, three more are added and if two or more of these patients experience a DLT (yielding greater than one of six), further dose reduction occurs. Thus, it is intuitive that this design is targeting a dose that is close to but less than the 33rd percentile. Simulations conducted by Storer9 and others indicate that it is nearer to the 25th percentile.

Accelerated Titration One criticism of the traditional design, particularly when accompanied by a conservative starting dose, is that too many patients are treated at subtherapeutic levels. Simon et al.12 have therefore proposed a variant of the “3 + 3” algorithm, known as the accelerated titration design, to overcome this problem. Essentially, only one patient is treated at each dose level, and the dose is doubled for each subsequent patient until either a DLT is observed or two patients experience grade 2 or higher toxicity. At this point the design reverts to the traditional “3 + 3” with subsequent dose increments of 40%. Intrapatient dose escalation is also permitted if the patient had no worse than grade 1 toxicity at the previous

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TABLE 8.1. Design features for three “classic” statistical designs for Phase I trials. Design

Description

Pros

Cons

“3 + 3”

1) Begin at lowest dose, treating 3 patients. If DLT rate is — 0/3, escalate (to next pre-specified dose level) — 1/3, add 3 more: then if 1/6, escalate ≥2/6, go to step 2) — ≥2/3, go to step 2) 2) If 6 patients studied at the previous dose level (1/6 AEs), declare — that dose to be the MTD; otherwise, add 3 more: Then if — pT0 H A : pR > pR0 and pT £ pT0 where pR0 and pT0 are the response and toxicity rates associated with standard therapy. Thus, the null hypothesis is rejected only if the response rate is sufficiently high and the toxicity rate is not unacceptably high. One must model the association between response and toxicity by introducing another parameter, q, corresponding to the odds ratio for toxicity among responders relative to nonresponders. Fortunately, however, the design characteristics are fairly insensitive to the assumed value for q. Finally, as one might be willing to accept greater toxicity with higher response rates and vice versa, Conaway and Petroni36 propose a related design that incorporates such trade-offs.

Bayesian Trial Designs The previously mentioned designs are frequentist in nature, in that power and significance probabilities refer to the probability of events under given hypotheses about the parameters of interest. A Bayesian approach offers an alternative inferential framework, for which proponents argue is particularly suited to situations involving accumulating data.37 For example, Thall and Simon38 present a Bayesian design for Phase II trials in which a “moderately informative” prior distribution is assigned to pS, the response rate associated with standard therapy. A flat or “weakly informative” prior is assigned to pE, the response rate for the experimental treat-

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ment, to reflect the limited knowledge available for pE before the study is begun. A maximum sample size for the trial, nmax, is specified, patients are enrolled, and the trial is continued until the new drug is shown with high posterior probability to be either promising or not promising or until nmax is reached, in which case the study is deemed inconclusive. Thus, if Xn denotes the number of responders observed among the first n patients enrolled, n = 1,2, . . . nmax, the posterior probability that pE exceeds pS by some minimally interesting amount, d, is computed. If this probability is very high (say, greater than 0.95) or very low (say, less than 0.05), the trial is terminated and the drug is declared promising or not promising, respectively. Otherwise, the study is continued provided nmax has not been reached. Thall and Simon38 evaluate the frequentist operating characteristics of this design under continuous monitoring and a maximum sample size of nmax = 65. They also suggest setting a minimum sample size, nmin, of 10 patients so that, in effect, monitoring does not begin until the 10th patient is enrolled. Results show, for example, that under a fairly informative prior for pS centered, say, at 0.20, a weak prior for pE, and a minimally interesting difference of d = 0.15, that if pE = pS there is a 7.1% chance that the outcome would erroneously lead to a conclusion that the experimental drug is promising, an 83.5% chance that it will correctly be declared nonpromising, and a 9.4% chance that the results will be inclusive. If the true effect is positive (pE = 0.40), there is an 87.5% chance that the drug will be declared promising, a 7.7% chance that it will be declared nonpromising, and a 4.8% chance that the trial would be inconclusive. Subsequent work describes a Bayesian sequential design for more complicated situations involving multiple outcomes, such as response and toxicity.39 Another proponent of the Bayesian approach is Heitjan,40 who points out that in multistage, frequentist designs, the evidence required for terminating the trial is not the same at all analysis times, and that a drug can be rejected as inactive even though there is no strong evidence that the response rate is any less than that of the standard. He describes a Bayesian approach designed either to convince a skeptic that the drug is beneficial or to convince an enthusiast that it is not. This is accomplished by using different prior probabilities corresponding to these two states of belief and, after outcomes have been observed, calculating the posterior probability that

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(a) the new drug is better than the standard given the skeptic’s prior (the “persuade-the-pessimist probability”) and (b) the standard is better than the new drug given the enthusiast’s prior (the “persuade-the-optimist probability”). Thus, this method requires that the evidence be sufficient “to choose between hypotheses [favorable or unfavorable] to the satisfaction of all interested parties” and, if not, the results are regarded as inconclusive.40

Randomized Phase II Trial When there are multiple candidate agents to consider advancing to further development, randomized Phase II trials, sometimes called selection designs, provide a means to select agents for further study.41– 43 These trials, which allocate patients to different treatments under consideration by random assignment and compare outcomes between groups, have several advantages with respect to patient selection and other biases present in studies without parallel comparison groups (discussed in detail in the next section). However, as a means to determine efficacy in any absolute sense, these trials lack statistical power and a error control at the sample sizes typically envisaged for Phase II trials. Nonetheless, the initial intended use of randomized Phase II trials as “selection designs” has been broadened to encompass small-scale randomized trials with a standard therapy comparison group. Although this approach has some advantages, positive results emerging from these trials cannot be deemed sufficiently conclusive as to preclude Phase III investigation (see Liu in Reference 1 for discussion). Table 8.3 illustrates advantages and disadvantages of one-arm and randomized comparative Phase II trials.

Recent Design Concepts For cytostatic agents, where frank tumor shrinkage is not anticipated, there may be a need for alternative Phase II designs based on endpoints other than response rates. For trials enrolling patients who have failed prior therapy, Mick et al.44 propose a method that uses each patient as his/her own control, comparing the time to progression under the new agent with the time to progression under prior therapy. Rosner et al.45 propose a randomized discontinuation design, in which all patients are initially treated with the experimental agent. After a specified interval, responders remain on

TABLE 8.3. Advantages and disadvantages of single-arm versus randomized Phase II trials. Single-arm trial

Pilot randomized trial

Advantages

• Maximum adverse event information for new agent • Can offer new agent to all participants • Simple endpoint that is rapidly ascertained

Disadvantages

• Historical control group response rate must be used • Tumor response endpoint may be poor surrogate for survival extension • Time to event endpoints may be difficult to define and do not fit into multistage framework

• Concurrent control group • Randomization provides for rigorous ancillary studies of tumor response markers • Can use time to event endpoints more readily in this comparative setting • Low power, high a for feasible sample sizes • Necessity to randomize patients in terminal disease situation • Quantity of adverse event information for experimental agent is reduced • Positive findings may interfere with conduct of appropriately powered Phase III trial

Here, we are considering a randomized phase II trial as a relatively small (100 patients or fewer) study intended to serve as a pilot trial for potential efficacy. Note that the original proposal for use of randomized phase II trials was for selection of potentially superior candidates from among multiple new agents (see Simon et al.41 and Liu et al.42), and not to compare new therapies to existing standards. More recently, Bayesian designs for phase II randomized selection design trials have been proposed (see Esty and Thall43).

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treatment and those who progress discontinue, while those patients with stable disease are randomized to either continued treatment with the drug or placebo. The idea behind this design is that the randomized comparison allows one to assess whether the drug is truly slowing the rate of growth of the tumor, as opposed to having simply selected patients for study with slow-growing tumors. Because the patients with stable disease form a more homogeneous subgroup, this design also generally requires a smaller sample size than would a trial that randomized all patients at entry. It is important to bear in mind—and the authors also emphasize this point—that the purpose of this design is mainly to determine whether the drug is active in an explanatory sense. Obviously, it matters a great deal whether the initial percentage of patients exhibiting stable disease is high or low, as in the latter case the total sample size required may be quite large and a demonstration of activity in the randomized component would mean only that there is benefit in a small subset of the population. Korn et al.46 point out other caveats with this design. For example, patients may find it unattractive to potentially discontinue a treatment that appears to be working. They describe a number of other approaches, including single-arm trials with time to progression as an endpoint and trials with appropriately validated biologic response markers as surrogates for tumor response.

Phase III or Comparative Efficacy Trials General Description and Objectives The term Phase III trial is synonymous with a prospective comparison under randomized treatment assignment [alternately called a randomized controlled trial or randomized clinical trial (RCT)] of two or more treatment regimens, conducted for the purpose of establishing which is superior or, in some cases, to establish equivalence (in the sense that any difference in outcome is smaller than that considered clinically material) between different treatment regimens. Thus, two key features that distinguish RCTs are the inclusion of a concurrent control group and the use of randomization to assign treatment. The main purpose of concurrently evaluating individuals receiving the standard and test treatment(s) is to eliminate temporal trends in diagnosis, characterization of the disease, and ancillary care that would likely be present in any comparison with a historical control group. Concurrent evaluation also provides implicit control over the commonly seen phenomenon of research participation itself having a positive effect on outcomes, regardless of the type of intervention. Randomization, which disassociates treatment assignment from any and all extraneous factors on the part of the patient or the physician, is the fundamental means by which bias is removed from measures of treatment effect. The obvious alternative to randomization is a nonrandomized comparative trial, but this design is generally insufficient for definitive evaluation of treatments for the purpose of choosing one over another. While differences in characteristics between treatment groups can be addressed to various degrees in other ways, typically by comparing “like with like” through matching, stratification into homogeneous groups, or

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statistical modeling or adjustment, only randomization will reliably eliminate bias in treatment comparisons. Furthermore, it is often not the known potential confounding factors that we must concern ourselves with, but rather unknown or uncollected factors, where these methods are not relevant. Nonetheless, primarily due to ethical concerns, some advocate relying on observational studies with reference to historical experience, coupled with the use of statistical methods to account for potential confounding of treatment effects and other factors, to evaluate new treatments.47,48 Numerous problems with the validity of historically controlled comparative studies have been demonstrated specifically in cancer research, including temporal changes in disease definition,49,50 data quality issues,51 diagnostic bias in assessing treatment response,25 and out-of-date historical control comparisons that tend to inflate effects for new therapies.23 The RCT in and of itself represents a significant medical research advance, and, as the recognized gold standard evaluative tool in therapy development, is integral to the evidence-based medicine paradigm.

Trial Design Issues Endpoints and Sample Size Phase III trial design begins with specification of a primary endpoint, which is typically a simple binary event such as survived/died or recurred/remained recurrence free, but usually with one important difference relative to Phase II trials; for each patient the time from randomization until occurrence of this event will be recorded, rather than the event status at some fixed time landmark. These time-toevent endpoints are particularly suited for adjuvant therapy trials, where because the number of patients participating is appreciably larger than in Phase II trials, recruitment takes place over a lengthy interval and each patient will have a different follow-up duration at any given time from trial initiation. Use of follow-up time per patient is more efficient than waiting until all patients have reached some fixed time. The treatment effect measure is usually specified in terms of hazards, which can be thought of as failure probabilities or failure rates per unit of time, between two treatment groups. Hypotheses are thus usually formulated in terms of the hazard ratio (HR) as H0 : lA/lB = HR = 1.0 where lA and lB are the hazards for treatments A and B, versus alternative HA : HR < 1.0, for some value of the HR that represents a clinically material difference in outcomes. In the case of an equivalence trial, one might test a null hypothesis that the HR does not differ from 1.0 by more than some specified amount such that the two treatments would be considered equivalent (hence, this difference must be small) versus the alternative that a greater difference exists (see References 1, 2 for more on equivalence trials). Under the assumption that this ratio is relatively constant over time, a given HR can be converted to an absolute difference between groups in proportions remaining event free at a given follow-up time. For example, a new/standard HR equal to 0.75, or a 25% reduction in failure rate in the new relative to the standard group, may translate into an absolute difference in the proportion of patients remaining free of the event between groups of 4.6% at 5 years, given that the standard group 5-year survival percentage is 80% (Table 8.4).

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TABLE 8.4. Absolute difference in 5-year survival and number of events required for a two-arm Phase III trial. Reduction in hazard of failure for new treatment

20% 25% 33% 40% 50%

Standard group proportion event free at 5 years .50

.60

.70

.80

.90

.95

No. of events required

.074 .095 .130 .160 .207

.065 .082 .111 .136 .175

.052 .065 .088 .107 .137

.037 .046 .062 .075 .094

.019 .024 .032 .039 .049

.010 .012 .016 .020 .025

630 379 191 128 65

Table entries show the absolute difference (new - standard) in 5-year survival for the hazard reduction due to the new treatment on the left-hand column and the 5-year survival in the standard treatment group (middle columns, top), assuming exponential survival patterns. The right-most column shows the number of events required (Eq. 2) for 80% power at a two-sided a = 0.05. The number of patients required for the trial to obtain results in some specified time period will depend on the standard group failure rate and the rate at which patients can be accrued.

From the specification of difference of interest or effect size, the sample size in terms of number of events required to detect this difference with desired statistical power and significance level can be determined. Depending on the anticipated accrual rate and the prognosis (e.g., rapidity of failure events) in the control treatment group, the number of patients required can then be approximated. Typically, the required number of events is based on the normal theory approximation of the natural logarithm of the hazard ratio. For a two-arm trial, the total number of events is D=

(Z1-b + Za 2 )2 [log e (HR)]2 p A ◊ pB

of stratification factors needs to be limited to a few key factors, because the strata increase multiplicatively with the number of factors and factor levels. For example, the use of four factors [say, age groups (less than 50 years, 50–64 years, 65 years or older), lymph node status (positive, negative), performance status (0–1, more than 1), and surgical procedure (procedure A or B)] produces 3 ¥ 2 ¥ 2 ¥ 2 = 24 strata in which to balance treatment assignments. As the number of strata becomes large relative to the number of patients to be entered, the efficiency of stratification as a means to balance treatment arms diminishes.57

(2)

where Z1–b and Za/2 are the values from the standard normal distribution associated with the power and significance level desired, and pA and pB are the proportions of total patients to be allocated to the two arms, respectively (e.g., 0.5 for equal allocation). One can see from this equation that the number of events required depends strongly on the HR, becoming dramatically larger as the HR approaches 1.0 (see Table 8.4). The number of patients required and total duration of the trial depend on the rate of patient accrual and the failure rate in the control group, both of which contribute to the determination of how rapidly the requisite events will be observed. The accrual rate is typically estimated from previous experience and may also involve querying potential investigators to project the accrual rate per unit of time. Similarly, the failure rate for patients under standard therapy is derived from past observations and available literature estimates. The computations are straightforward but generally require computer programs (see Shuster in Reference 1, or commercial programs) or under certain assumptions, tabled values.52 Sample size methods have been extended to take into account other factors that will influence power, such as patients withdrawing from the study while it is ongoing (dropout), switching from the assigned treatment to the other group (cross-over), or deviating from protocol treatment (noncompliance).53–56 Another important design aspect concerns the desire to ensure that factors associated with outcomes, called prognostic factors, are balanced between treatment arms. Although random allocation to treatments naturally provides equal distribution of characteristics, using key prognostic variables as stratification factors, and incorporating these into the randomization process (by randomizing within strata or other means discussed in the next section), imbalances that can arise by chance can essentially be prevented. The number

Trial Conduct Randomization Because randomization is the signifying characteristic of Phase III trials, correct implementation and maintenance of this feature is vital. In the simplest case, a series of treatment assignments are generated from a random mechanism such as a random number table or computer program. Sequential assignments should only be revealed one at a time (to avoid compromising the randomness with respect to the next assignment), and thus it is preferable to have a secure centralized randomization procedure, via telephone or computer contact. To balance the number of patients in each arm, block randomization, in which an equal number of assignments on each treatment arm of the trial occurs after each block of patients is enrolled, can be used (for example, assigning ABABBA, AABABB, etc., for randomly ordered strings of assignments brings the number on each arm into balance after each set of six patients; note that the size of the block is not revealed and can also be varied to make the process unpredictable). To incorporate stratification factors to be balanced between treatment arms, blocked randomization can be used within each stratum. When the number of strata is large, and in particular in multicenter trials, this type of assignment scheme can become unwieldy and cannot necessarily assure balance. In this case, some type of dynamic allocation scheme can be used whereby the current assignment is generated based on previous assignments. This type of randomization must be centralized, as stratification factor data for all previously enrolled patients must be available when randomizing the current patient. Rather than deterministic assignments to balance the arms, often “biased-coin” randomization is used, in which the assignment probability is weighted toward the arm for which assignments are needed

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to achieve balance. The minimization algorithm is frequently used for dynamic balancing taking stratification factors into account.58 This allocation scheme balances treatment arms for each stratification factor singly, but not necessarily for every combination of factors, as in fully stratified randomization. However, it is much easier to manage over multicenter studies and performs well for multiple stratification factors.57 There are several ways in which the benefits of randomization can be eroded or nullified. Of course, any breach of the random assignment process has an irreparable effect on the validity of the trial. Second, a large number (or differential number per arm) of patients “canceled” or withdrawn from the trial calls into question the validity of the comparison for the remaining participants. Differential follow-up and ascertainment of status per arm can have a similar effect. Third, bias in assessment of outcomes can have a major impact on the estimated treatment effect, and thus, objective outcome measures and blinding of treatment assignment come into play. Treatment assignment blinding is not feasible for many oncology trials (e.g., radiotherapy and most chemotherapy regimens), but has been used with great success in others (e.g., tamoxifen). In either case, and in particular for studies that cannot be blinded (among patients or caregivers), unambiguous, objectively defined endpoints are essential. In cases where determination of the endpoint involves possible observer subjectivity, such as when reading a diagnostic scan to determine disease progression, keeping assessors unaware of treatment assignment may be necessary.

toward a significant difference in favor of the standard treatment would be continued until such a result was realized. Thus, an additional rule that allows for stopping early for “futility” with respect to the new treatment is usually also specified. Alternatively, asymmetric boundaries that more easily allow stopping early for evidence that the new treatment may actually be inferior to the standard (evidence de facto that the new treatment will not ultimately prevail) can be used. More comprehensive treatment of this topic can be found in clinical trials texts1,2 or books on group sequential monitoring.59 Regardless of the specific approach adopted, an interim analysis plan should be devised during trial design and adhered to throughout trial conduct because failure to account for multiplicity of analyses can result in spurious positive findings. Also, a specified plan may help to avoid diminished influence of a trial even when results are decidedly positive, which can occur if there is a perception by others that the trial had been terminated prematurely due to favorable results at a particular analysis time.60 The decision to discontinue the trial (accrual and/or treatment, depending on its current state) and release findings is typically vested in an independent Data and Safety Monitoring Committee (DSMC). However, in addition to evaluating according to the monitoring rule, the DSMC considers a broader body of information regarding the trial as well as external information that bears on treatment for the disease under study. Table 8.5 outlines the membership, aspects of trial conduct over which the DSMC has oversight, and recommendations that might arise from trial review and DSMC

As in earlier trials, Phase III trials include provisions for formal oversight of risks and benefits to ensure patient welfare and use resources efficiently. Interim monitoring consists of both continuous oversight of adverse events and periodic interim tests (a predetermined number) of primary study hypotheses. With respect to these interim tests, a large body of statistical developments has addressed how to conduct tests to determine if an early determination of treatment superiority is warranted while at the same time controlling for inflation of a error (e.g., false-positive findings) resulting from repeatedly performing statistical hypothesis tests. Caution is also warranted because early results from time-toevent data tend to be unstable and change as more information accumulates. In essence, these problems are addressed by simply requiring a stricter criterion than the typical P less than 0.05 “significance” for interim analyses, and early approaches to this problem used either a smaller constant significance criterion throughout interim and definitive analyses, chosen such that the significance level for the entire set of sequential tests does not exceed a, or a constant but much more stringent criterion early in interim analyses and a more conventional significance level after the trial has accumulated the requisite information for definitive analysis. Figure 8.1 shows these and some other examples of early stopping boundaries, which when exceeded at any of the interim analyses shown on the x-axis would prompt consideration of early stopping. These boundaries are symmetric with respect to superiority for either the new or standard treatment group, reflecting the fact that two-sided hypothesis tests remain the convention. In reality, it is unlikely that a trial tending

Z Statistic

Trial Monitoring 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 –0.5 –1.0 –1.5 –2.0 –2.5 –3.0 –3.5 –4.0 –4.5

O’Brien-Fleming Haybittle-Peto Pocock

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2

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4

Analysis Number FIGURE 8.1. Different types of stopping boundaries for monitoring a Phase III trial. The upper and lower boundaries represent statistical test values on the vertical axis (on a standard normal scale), which, if exceeded at a given analysis indicated on the horizontal axis, would prompt stopping of the trial (the fourth analysis is the definitive analysis at the predetermined requisite number of events). The horizontal lines at ±1.96 represent the standard P greater than 0.05 boundary. Note that the Pocock boundary uses a fixed, modestly more extreme value, but the final test result must then also be more extreme than the conventional 0.05 test to be considered significant. The Haybittle–Peto method uses a conventional final test value but is very conservative through the penultimate hypothesis test. The O’Brien–Fleming boundaries begin very conservatively, but change as more information accrues, and also allow that the final test be performed using the conventional significance level.

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TABLE 8.5. Prototypical Phase III trial data and safety monitoring committee. Membership (voting members, external to trial)

Additional attendees

Physicians Statisticians Patient advocate Medical ethicist

Trial statistician Trial coordinator Trial chaira Sponsor representativesa

Review Scope: — Patient accrual, reporting delinquency and patient withdrawals, treatment compliance, data quality — Adverse events — Treatment efficacy endpoints — Other relevant materials, including confidential reports provided by other investigators Decision to stop/alter trial conduct and/or release findings may be based on: — Evidence of benefit or harm according to monitoring guidelines or adverse events (expected or otherwise) observed in the trial — Evidence of little likelihood that treatment difference will be realized — External information that raises concerns regarding the scientific, clinical, or ethical assumptions on which the current trial was based — Poor likelihood of trial yielding meaningful findings due to problems with accrual, compliance, or patient retention a Note that these individuals are typically excluded from discussions of interim efficacy data, although there is currently some debate regarding this issue.

deliberations. The policies and procedures for U.S. National Cancer Institute-sponsored Cooperative Group trials provide a good overview of DSMC structure and function for Phase III trials.61

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hazard ratio. The survival curve S(t) represents the probability of remaining event free until at least time t, or S(t) = Pr(T > t). This function is plotted from randomization (e.g., at t = 0, S(t) = 1.0) to some follow-up time that a remaining fraction of patients has reached. This points to an important feature of time-to-event data, that is, censoring, where it is known that a patient is event free as of some follow-up time, but the (potential) failure time is not yet observed. Censoring is a natural consequence of staggered enrollment into the trial, so that at any given time, some patients have less follow-up than others (administrative censoring), but also may occur because patients may withdraw from or be lost to follow-up before experiencing the event of interest. Administrative censoring can be reasonably assumed to be independent of failure risk except in cases where characteristics of participants enrolled changes over time (which is why well-defined entry criteria are necessary). Any censoring associated with propensity for failure (e.g., sicker patients more often withdrawing) that results in different rates of loss per treatment arm can bias treatment comparisons. In the case in which censoring is assumed independent of probability of failure, then estimating S(t) using available information per patient, including follow-up to censoring, is straightforward. For a set of ordered observed times where one or more patients had an event t1 < t2 < t3 < . . . < tJ, define dj as the number of events at time tj and Yj as the number of patients available to possibly fail (all those who have not yet failed and were not censored before tj; by convention, those censored exactly at tj are considered at risk to fail). The Kaplan–Meier (KM) estimator64 is the product of the quantities (1 - dj/Yj) over the J failure times

Analysis Definitive analysis commences when either the requisite number of events indicated in the trial design has been observed, or the DSMC has deemed that the trial results should be disclosed due to early stopping conditions being met. An important aspect of Phase III trial analysis is the definition of the analysis cohort. The concept of analysis by intention-to-treat is often discussed, but the definition of this term can sometimes be unclear, so it is best to explicitly describe which patients are included.62 In the strictest sense, the intention-to-treat cohort includes all patients randomized, irrespective of eligibility, acceptance of and adherence to assigned treatment, and any and all other postrandomization deviations from protocol. However, it is often the case that patients found ineligible for the trial after randomization due to having been incorrectly staged or for other reasons are excluded from the primary analysis, and this practice (used with caution) is sometimes advocated, as it allows for evaluation of the therapy in the population for which it was intended.2 A more controversial and rarely acceptable form of patient exclusion involves removal of patients who did not or could not comply with assigned therapy regimens or received nonprotocol therapy. Such exclusions can easily lead to biased comparisons, and in general, any post hoc analysis of treatment benefit in relation to dose received is fraught with interpretational difficulties and should be avoided in primary analysis.63 For time-to-event data, the principal summaries are the survival distribution (or survival curve) and the estimated

J dj ˆ Ê S(t) = ’ Á1 - ˜ Ë Y j¯ j =1

(3)

Although the KM curve is the typical graphical summary, the relative hazard of failure between groups is the principal measure of efficacy. The HR (and associated statistical tests) pertains to the entire span of follow-up, as opposed to a test of difference in the survival curves at a specific time point, in which case the result would depend on which time was chosen. The log-rank test, which frequently accompanies the KM curve, in fact compares underlying failure probabilities between groups over the J failure times.65 Issues related to this and other tests for comparing survival time distributions are discussed here. The HR can be estimated by computing the incidence density or average failure rate in each treatment group. For two treatment arms with nA and nB patients, respectively, the ¯A, where average failure rate for treatment arm A is IA = DA/T ¯A = Sni=1Ti, the sum of times to event or censoring for each T patient, and DA is the total number of events in arm A. For IB similarly computed, HR = IA/IB. More commonly, the HR is estimated via the Cox proportional hazards model,66 which relates the hazard of failure to covariates through the equation A

l (t, x ) = l0 (t) ◊ exp(b1 ◊ x1 + b2 ◊ x 2 + . . . b p ◊ x p )

(4)

where l0(t) is an unspecified “baseline hazard” and the x’s represent covariates, which may include indicators for treatment group and other factors. For example, for a single covariate, x1, representing treatment group with x1 = 0 for the standard

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A

propotion surviving

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logrank p < 0.0001 Wilcoxon p < 0.0001

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time 1.0

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propotion surviving

0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2

logrank p = 0.082 Wilcoxon p = 0.0003

0

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time 1.0

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propotion surviving

treatment and x1 = 1 for the new treatment, l0(t) exp(b1)/l0(t) = exp(b1) equals the HR. From this model, a significance test for HR = 1.0 and confidence interval for the HR are obtained. With additional prognostic factors included in the model, exp(b1) gives the HR adjusted or controlling for these factors. Prognostic factor analysis using this model or other techniques often follows primary analysis of Phase III trials. The modeling process, which entails deciding which factors to include, determining the correct way to represent a given factor (i.e., in categories, on a continuous scale, and so forth), consideration of interrelationships (e.g., interactions) among factors, and many other issues, can be complex, as can using model results for prediction of individual patient outcomes or classification into prognostic risk classes. A comprehensive review of current modeling methods applied to oncology data is provided by Schumacher et al. in Reference 1. One important issue concerning the HR and tests used to compare hazards pertains to how failure events occur over time in the groups being compared. The proportional hazards condition, whereby the HR is constant over time, is implicit in the previously described model (hence the name). Under this condition, the quantity loge (SA(t))/loge(SB(t)), where SA and SB are the KM estimates at time t in the two treatment groups, will be approximately the same at different time points on the survival curves. Note, however, that under this condition the absolute difference in proportions event free from the KM curve will not be constant, but in fact the curves will diverge over time. The log-rank test65 gives equal weight to failure events across the time span and is the optimal test under proportional hazards. For failure patterns that deviate from proportional hazards, there are a number of alternatives to the log-rank test that are more sensitive to differences between survival curves. The Wilcoxon67 test places more weight on failures occurring early, and so is more sensitive to the case where survival curves separate early but may later converge. Other tests also tend to weight earlier failures,68,69 and a generalized class of tests exists that encompass the standard logrank and Wilcoxon test as well as tests with other weighting schemes.70 Choice of test should be determined by whether there is specific interest in or expectation that differences will emerge under some pattern other than proportional hazards. In any case, when different tests differ, it is usually the case that the treatment effect is changing over time and thus a single HR may be an inadequate summary, and separate HR estimates for specific time intervals may be more appropriate. One of several formal tests for proportionality can be used when there is empirical evidence of nonproportionality from the KM curve plot. Heuristically, a single HR under strongly nonproportional hazards is akin to the mean of a highly skewed distribution, in that it may be computed but does not serve as a readily interpretable summary of the data. Figure 8.2 illustrates how statistical tests may differ under some different patterns of failure among survival cures being compared. Another issue with KM survival curve displays relates to the follow-up period shown. Often the curves are plotted until a time point for which very few patients are under observation. This practice can create the misleading illusion of a large expanse between the curves, when in fact variability on the estimated proportion event free when few patients remain is very large, and if a few patients or even one patient were to fail, the estimate would change substantially. It is more

0.8 0.7 0.6 0.5 0.4 0.3 0.2 0

logrank p = 0.033 Wilcoxon p = 0.084

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time FIGURE 8.2. Examples of survival curves exhibiting different failure patterns. Data are generated from hypothetical data with 500 subjects per group. In comparing curves, the Wilcoxon test gives greater weight to earlier failures, whereas the log-rank test weights failures equally throughout follow-up. (A) Curves follow the proportional hazards pattern. The hazard ratio is constant (HR = 2.0). (B) Curves show a violation of proportional hazards, converging over time as the hazard ratio becomes smaller. (C) These curves also are nonproportional, separating later in follow-up.

124 appropriate to plot the curves and cite proportions event free only at time landmarks that most of the patients who remain event free have reached.

Some Additional Topics Confirmatory Trials and Meta-Analyses Because of the planning, infrastructure, cost, and time required, Phase III trials are carefully designed to avoid equivocal findings, and thus provide definitive evidence for or against changes in therapy standards. Nonetheless, questions regarding the treatments under evaluation will invariably remain unanswered, and thus there is an important role for replicated (referred to as confirmatory) trials and the synthesis of similar trials into a coherent body of evidence. This is particularly important for clinical decision making, where evidence from trials must be weighed in relation to an individual patient’s utility for various treatment options. For the small to moderate benefits seen for most cancer treatment advances, these confirmatory trials may in fact be necessary to effect change.71,72 Although costly to obtain, such corroborating evidence can contribute greatly to practice changes, as the qualitative value of multiple trials with similar findings cannot be understated. It is also not uncommon that replicated trials fail to obtain similar results, providing an opportunity for closer scrutiny of differences between trials and their potential breadth of applicability. A more formal quantitative means of combining evidence from trials is by meta-analysis, a widely used analytic tool in many areas of social and medical science. Meta-analysis refers to a process whereby data from independent studies are combined to form a quantitative summary estimate of a given effect. Randomized trials are in fact more suited to metaanalysis than nearly all other research designs, as there is likely to be considerable similarity in disease definitions, study design features, classes of therapeutic agents or procedures, and endpoints, and this information is increasingly well documented in trial reports.73 Meta-analyses were initially carried out by extracting effect estimates from published literature and combining these into a single estimate using statistical techniques, but in medical meta-analysis studies, it is usually considered necessary to obtain patientlevel data from each trial, a laborious process that necessarily includes seeking data from unpublished trials to avoid the “publication bias” toward positive findings. Once these data are acquired and standardized for a common endpoint, the individual trial effect measures (i.e., hazard ratios) may be combined using an appropriate statistical model into a summary effect estimate. Results of each trial are also presented, as well as tests for evidence of significant heterogeneity among trials, in which case a single summary measure may be inappropriate and thus omitted. Often, a quality weight measure based on design features is assigned to each trial, providing a natural opportunity to evaluate trial quality. A principal advantage of meta-analyses is the ability to evaluate consistency among trial findings and possibly uncover small but clinically meaningful treatment effects that were not statistically significant in any one trial (although the meta-analysis is generally not considered the equivalent of an adequately powered RCT). One disadvantage

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is that combined trial estimates based on heterogeneous treatment regimens may be able to illustrate only a proof of principle (for example, “multidrug chemotherapy is effective”), which may be of limited use for specific clinical questions, such as which regimen to use. Furthermore, comparisons of different regimens from data aggregated across trials are subject to all attendant limitations and biases of observational studies. Despite these and other limitations and pitfalls,74,75 meta-analyses are a valuable complementary research strategy that has been influential in cancer treatment. An excellent example of the methods and data summaries used in meta-analysis in oncology can be found in the reports of the Early Breast Cancer Trialists’ Collaborative Group.76

Bayesian Approach As in the case of Phase I and II trials, Bayesian statistical methodology is increasingly being applied to various aspects of Phase III trials. In study design, a Bayesian approach to formulating the sample size in terms of the questions (1) “what treatment effect might realistically be realized with a new regimen?” and (2) “what magnitude of effect would prompt the current standard to be supplanted?” provides a useful framework that more closely resembles clinical practice.77,78 In trial monitoring, the use of “skeptical” and “optimistic” prior distributions introduced earlier, considered in conjunction with accumulating trial results, provides a rational means to determine whether current results are sufficiently convincing to justify early stopping.79

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38. Thall PF, Simon R. Practical Bayesian guidelines for phase IIB clinical trials. Biometrics 1994;50:337–349. 39. Thall PF, Simon R, Estey EH. Bayesian sequential monitoring designs for single-arm clinical trials with multiple outcomes. Stat Med 1995;14:357–379. 40. Heitjan DF. Bayesian interim analysis of phase II cancer clinical trials. Stat Med 1997;16:1791–1802. 41. Simon R, Wittes RE, Ellenberg SS. Randomized phase II clinical trials. Cancer Treat Rep 1985;69:1375–1381. 42. Liu PY, Dahlberg S, Crowley J. Selection designs for pilot studies based on survival. Biometrics 1993;49:391–398. 43. Estey EH, Thall PF. New designs for phase 2 clinical trials. Blood 2003;102:442–448. 44. Mick R, Crowley JJ, Carroll RJ. Phase II clinical trial design for noncytotoxic anticancer agents for which time to disease progression is the primary endpoint. Control Clin Trials 2000;21: 343–359. 45. Rosner GL, Stadler W, Ratain MJ. Randomized discontinuation design: application to cytostatic antineoplastic agents. J Clin Oncol 2002;20:4478–4484. 46. Korn EL, Arbuck SG, Pluda JM, et al. Clinical trial designs for cytostatic agents: are new approaches needed? J Clin Oncol 2001; 19:265–272. 47. Gehan E. The evaluation of therapies: historical control studies. Stat Med 1984;3:315–324. 48. Hellman S, Hellman DS. Of mice but not men. Problems of the randomized clinical trial. N Engl J Med 1991;324:1585–1589. 49. Dupont WD. Randomized vs. historical clinical trials: Are the benefits worth the costs? Am J Epidemiol 1985;122:940–947. 50. Micciolo R, Valagussa P, Marubini E. The use of historical controls in breast cancer. An assessment in three consecutive trials. Control Clin Trials 1985;6:259–270. 51. Byar DP. Why databases should not replace randomized clinical trials. Biometrics 1980;36:337–342. 52. Freedman LS. Tables of the number of patients required in clinical trials using the log-rank test. Stat Med 1982;1:121–129. 53. Lachin JM, Foulkes MA. Evaluation of sample size and power for analysis of survival with allowance for nonuniform patient entry, losses to follow-up, noncompliance, and stratification. Biometrics 1986;42:507–519. 54. Lagakos E. Sample size based on the log-rank statistic in complex clinical trials. Biometrics 1988;44:229–241. 55. Shih JH. Sample size calculation for complex clinical trials with survival endpoints. Control Clin Trials 1995;16:395–407. 56. Ahnn S, Anderson SJ. Sample size determination in complex clinical trials comparing more than two groups for survival endpoints. Stat Med 1998;17:2525–2534. 57. Therneau TM. How many stratification factors are “too many” to use in a randomization plan? Control Clin Trials 1993;14:98–108. 58. Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics 1975;31:103–115. 59. Jennison C, Turnbull J. Group Sequential Methods with Applications to Clinical Trials. London: Chapman & Hall/CRC, 2000. 60. George SL, Li C, Berry D, et al. Stopping a clinical trial early: frequentist and Bayesian approaches applied to a CALGB trial in non-small-cell lung cancer. Stat Med 1996;13:1313–1327. 61. Smith MA, Ungerleider RS, Korn EL, et al. Role of independent data-monitoring committees in randomized clinical trials sponsored by the National Cancer Institute. J Clin Oncol 1997;15: 2736–2743. 62. Gail MH. Eligibility exclusions, losses to follow-up, removal of randomized patients, and uncounted events in cancer clinical trials. Cancer Treat Rep 1985;69:1107–1113. 63. Redmond C, Fisher B, Wieand HS. The methodologic dilemma in retrospectively correlating the amount of chemotherapy received in adjuvant therapy protocols with disease-free survival. Cancer Treat Rep 1983;67:519–526.

126 64. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–481. 65. Mantel N. Evaluation of survival data and two rank order statistics in its consideration. Cancer Chemother Rep 1966;50: 163–170. 66. Cox DR. Regression models and life tables (with discussion). J R Stat Soc Ser B 1972;34:187–220. 67. Gehan EA. A generalized Wilcoxon test for comparing arbitrarily single-censored samples. Biometrika 1965;52:203–223. 68. Peto R, Peto J. Asymptotically efficient rank invariant test procedures. J R Stat Soc A 1972;135:189–198. 69. Prentice RL. Linear rank tests with right censored data. Biometrika 1978;65:167–179. 70. Harrington DP, Fleming TR. A class of rank test procedures for censored survival data. Biometrika 1982;69:553–566. 71. Parmar MK, Ungerleider RS, Simon R. Assessing whether to perform a confirmatory randomized clinical trial. J Natl Cancer Inst 1996;88:1645–1651. 72. Berry DA. When is a confirmatory randomized clinical trial needed? (editorial) J Natl Cancer Inst 1996;88:1606–1607.

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73. Moher D, Schulz KF, Altman D; CONSORT Group (Consolidated Standards of Reporting Trials). The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA 2001;285:1987–1991. 74. Rockette HE, Redmond CK. Limitations and advantages of meta-analysis in clinical trials. Recent Results Cancer Res 1988; 111:99–104. 75. Pignon JP, Hill C. Meta-analyses of randomized clinical trials in oncology. Lancet Oncol 2001;2:475–482. 76. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351:1451–1467. 77. Parmar MKB, Spiegelhalter DJ, Freedman LS, et al. The CHART trials: Bayesian design and monitoring in practice. Stat Med 1994;13:1297–1312. 78. Stenning SP, Parmar MKB. Designing randomized trials: both large and small trials are needed. Ann Oncol 2002;13:131–138. 79. Parmar MKB, Griffiths GO, Spiegelhalter DJ, et al. Monitoring of large randomized clinical trials: a new approach with Bayesian methods. Lancet 2001;358:375–381.

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Ethics of Clinical Oncology Research Manish Agrawal, Lindsay A. Hampson, and Ezekiel J. Emanuel

E

ver since the earliest days of cancer research, ethical issues have been integral. In 1891, a French physician, Victor Cornil, reported that to determine whether cancer was contagious, a small section of breast tumor removed from the breast of one woman was implanted in her contralateral noncancerous breast. The surgical resection and implant were conducted when the patient was anesthetized and without the patient’s consent. When this research study was initially reported it was condemned “as criminal.”1 In 1892, another cancer surgeon, William Coley, was conducting studies to determine whether “artificial erysipelas” (induced inflammation) would have antineoplastic effects. In describing one patient with a sarcoma, he noted that initially the patient was most reluctant to undergo the treatment. But “after some deliberation he consented, and on the 21st of April 1892 I began inoculations.” Since that time, there has been substantial thought about the ethical issues involved in clinical oncology research, producing both more systematic analyses and important empirical data relevant to these issues. We delineate a general framework for analyzing the ethics of clinical research studies and then examine ethical issues involved in individual topics: (1) randomization and clinical equipoise; (2) informed consent; (3) Phase I oncology research; (4) stored biologic samples; (5) genetic testing; and (6) conflict of interest.

General Framework Clinical oncology research must fulfill eight ethical requirements (Table 9.1).2,3 First, research must reflect a collaborative partnership between researchers and the community from which participants are drawn.4 Typically, a collaborative partnership is manifest in support from patient advocacy groups and the public for research funding, as well as inclusion of lay or patient representatives in research advisory and oversight boards such as institutional review boards (IRBs). Second, the research must be socially valuable, addressing meaningful gaps in therapy or scientific understanding.5 “Metoo” studies confirming well-known findings are unethical. Third, the study must be conducted to generate reliable and valid data so that there is a reasonable chance the data will be able to advance therapy or contribute knowledge. Trivial questions, invalid or biased methods, and poor statistical techniques are unethical because worthless science cannot

justify any risk or inconvenience to research participants. Consequently, there is no conflict between science and ethics. For research to be ethical, it must be good science. Fourth, subject selection must be fair.6,7 The eligibility requirements and recruitment strategies must be defined by the scientific objectives of the research study, not by social vulnerability or status. After scientific objectives, individuals likely to experience lower risks and greater benefits should be considered for recruitment and enrollment. It is not permissible to enroll privileged individuals preferentially in studies that are perceived to be especially promising. It is unreasonable to recruit individuals of a certain group into a study for convenience alone, when the conduct or results of that study would not benefit that group. Fortunately, unfair subject selection is rarely a problem in cancer research, where recruitment is necessarily tied to the disease under study. Fifth, the research must have a favorable risk-to-benefit ratio. Although risks can rarely be eliminated, they should be minimized. Similarly, the potential benefits to the participants and to future patients should be enhanced. When the benefits to individual participants are minimal, the risks are justified by the benefits of advancing knowledge for society. Sixth, research must also undergo independent review by a committee of peers and laypersons, such as an institutional review board (IRB). Such review is intended to provide unbiased evaluation of the scientific and ethical aspects of research as well as institutional and public accountability for that research. Seventh, subjects must offer their informed consent to participate in research.8,9 Informed consent has four requirements: (1) competence of the research participant to make decisions; (2) disclosure of relevant information by the researcher; (3) understanding of the information by the participant; and (4) voluntary consent by the participant to enroll. When participants lack competence, such as in pediatric research, permission from a surrogate is generally required. Finally, respect for persons does not end with informed consent. Researchers must respect the participants’ rights to privacy and to relevant new findings and recognize the continued voluntary nature of participation in the study. Most importantly, researchers must monitor the health and well-being of research participants and intervene when it is threatened. Each of these eight requirements must be satisfied; that is, all are necessary, although in particular circumstances,

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Nonexploitation and respect for community’s self-determination

Scarce resources and nonexploitation

Scarce resources and nonexploitation

Social or scientific value

Scientific validity

Underlying ethical values

Collaborative partnership

Requirement

TABLE 9.1. What makes oncology research ethical?

1) Specify the beneficiaries of the research. 2) Assess the importance of the health problems being investigated and the prospect of value of the research for each of the beneficiaries. 3) Enhance the value of the research for each of the beneficiaries through dissemination of knowledge, product development, long-term research collaboration, and/or health system improvements. 4) Prevent supplanting the extant health system infrastructure and services. 1) Ensure the scientific design of the research realizes social value for the primary beneficiaries of the research. 2) Ensure the scientific design realizes the scientific objectives while guaranteeing research participants the healthcare interventions they are entitled to. 3) Ensure the research study is feasible given the social, political, and cultural environment and with sustainable improvements in the local healthcare and physical infrastructure.

1) Ensure appropriate representation of researchers, health policymakers, and the community. 2) Involve researchers, health policymakers, and the community to share responsibilities for determining the importance of health problem, assessing the value of the research, planning, conducting, and overseeing the research, and integrating the research into the healthcare system. 3) Respect the community’s values, culture, traditions, and social practices. 4) Contribute to developing the capacity for researchers, health policymakers, and the community to become full and equal partners in the research enterprise. 5) Ensure recruited participants and communities receive benefits from the conduct and results of research. 6) Share fairly the financial and other rewards of the research.

Benchmarks for fulfillment

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Use of accepted scientific principles and methods, including statistical techniques, to produce reliable and valid data.

Evaluation of a treatment, intervention, or hypothesis with the aim of improving health and well-being or increasing knowledge.

Inclusion of the patients, representatives of advocacy groups, and other community members in determining research funding, research priorities, ethical oversight, and strategies for studies.

Explanation

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Distributive justice

Nonmaleficence, beneficence, and nonexploitation

Public accountability, minimizing influence of potential conflicts of interest

Respect for persons, autonomy

Respect for persons, autonomy, and welfare

Fair subject selection

Favorable risk–benefit ratio

Independent review

Informed consent

Respect for potential and enrolled subjects

1. Permitting withdrawal from the research 2. Protecting privacy through confidentiality 3. Informing of newly discovered risks or benefits 4. Informing about results of clinical research 5. Monitoring of the health and well-being of participants and providing treatments for adverse reactions from the research.

Provision of information to participants about purpose of the research, its procedures, potential risks, benefits, and alternatives so that the individual understands this information and can make a voluntary decision whether to enroll and continue to participate.

Review of the design of the research trial, its proposed subject population, and risk-tobenefit ratio by individuals unaffiliated with the research.

Selection of research participants so that stigmatized and vulnerable individuals are not targeted for risky research and favored or privileged individuals not preferentially enrolled in potentially beneficial research. Minimization of risks; enhancement of potential benefits. Risks to the individual participants are proportionate to the benefits to the individual participants and to society.

1) Involve the community in establishing recruitment procedures and incentives. 2) Disclose information in culturally and linguistically appropriate formats. 3) Implement supplementary community and familial consent procedures where culturally appropriate. 4) Obtain consent in culturally and linguistically appropriate formats. 5) Prevent penalization for withdrawal from the research. 1) Develop and implement procedures to protect the confidentiality of recruited and enrolled participants. 2) Ensure participants know they can withdraw without penalty. 3) Provide enrolled participants with information that arises in the course of the research study 4) Monitor and develop interventions for medical conditions, including research related injuries, of enrolled participants that are at least as good as existing local norms. 5) Inform participants and the study community of the results of the research.

1) Select the study population to ensure scientific validity of the research. 2) Select the study population to minimize the risks of the research and enhance other principles, especially collaborative partnership and social value. 3) Identify and protect vulnerable populations. 1) Assess the potential risks and benefits of the research to the study population in the context of its health risks. 2) Assess the risk–benefit ratio by comparing the net risks of the research project with the potential benefits derived from collaborative partnership, social value, and respect for study populations. 1) Ensure public accountability through reviews mandated by laws and regulations. 2) Ensure public accountability through transparency and reviews by other international and nongovernmental bodies. 3) Ensure independence and competence of the reviews.

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130 such as mental incompetence or emergency research, the consent of the individual research participant can be waived. Furthermore, these principles are universal; they apply to research in all countries, although precisely how they are fulfilled may vary depending on the particular economic, social, and cultural circumstances. For instance, in cultures in which signatures are not the common form of consenting, other mechanisms may be used.10 Finally, in designing any particular research study, tensions between the principles may arise. Different principles may have to be balanced against other principles; for some studies, lowering risk may have to be balanced against scientific validity or social value. Such balancing is inevitable. It means that there can be several different ethically acceptable ways to conduct a research study.

Randomization and Clinical Equipoise Randomized controlled trials (RCTs) permit the comparison of standard care with one or more new interventions. RCTs are the gold standard of clinical research. Controls and some form of randomization have been used for about 100 years,11 although the first modern randomized, placebo-controlled trial was conducted only in 1948 to evaluate streptomycin for pulmonary tuberculosis.12 There are many concerns about the ethics of randomization, including the need for researchers to suspend their suspicions about what treatment is superior and to follow a protocol rather than provide individualized care.13 In addition, randomization is probably the aspect of informed consent most commonly misunderstood by research participants. Controlling for factors that are unknown but might influence outcomes is the scientific justification for randomization. Clinical equipoise is the dominant ethical justification for randomization.14–16 Originally, the concept of theoretical equipoise was articulated as a justification for RCTs.17 Theoretical equipoise held that it was ethical to conduct a randomized research study when there was exactly balanced evidence for the various interventions being tested. Theoretical equipoise has many problems. Rarely is the evidence exactly balanced. It is “overwhelmingly fragile . . . balanced on a knife’s edge [because] it is disturbed by a slight accretion of evidence” for one intervention or the other.14 Furthermore, it relies on the personal views of individual physicians; it requires each physician who enrolls a patient to be in a state of uncertainty about which intervention is better—a situation that rarely occurs. In 1987, as an alternative, Freedman proposed clinical equipoise.14 It is based on the recognition that the purpose of a clinical trail is social, to change standards of medical practice within the community. Consequently, clinical equipoise exists when there is uncertainty or disagreement among the expert medical community about which intervention is better. An RCT is conducted to resolve this uncertainty within the medical community. Clinical equipoise is the ethical manifestation of the statistical dictum that an RCT must begin with an honest null hypothesis.14 More importantly, “clinical equipoise is consistent with a decided treatment preference on the part of the investigators. [Physicians] must simply recognize that their less-favored treatment is

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preferred by colleagues whom they consider to be responsible and competent.”14 Thus, it is the absence of consensus among the medical experts about the best intervention that ethically justifies the research study. One virtue of clinical equipoise is that it rejects special ethical significance for any individual physician’s hunch or intuitions about what is best. It relies on data, not on emotions. This approach can help convince patients that a trial is just as good an option as any alternative. Indeed, when there is clinical equipoise, then, at the start of the trial, whatever arm the patient is randomized to, should be as good as any other arm; all arms could be said to be in the patients’ best interest. The recent experience with the trial of bone marrow transplantation for breast cancer should emphasize to the oncology community the dangers—ethical, scientific, as well as for individual patients—of relying on feelings rather than data from RCTs to choose what treatment to receive. One important empirical question is whether clinical research does adhere to clinical equipoise. If it did, we should find that in many trials there is no difference between the new intervention and standard care, and that the numbers of trials demonstrating that the intervention arm is superior to standard care should be comparable with the number of trials demonstrating the superiority of standard care. The few metaanalyses that exist suggest that intervention arms are shown to be superior more frequently than standard care arms (Table 9.2).18,19 Indeed, at least some data suggest that there is an equal balance between studies that show superiority of the intervention arm and those showing superiority of standard therapy when research is sponsored by government agencies. However, when sponsored by commercial organizations, the innovative interventions were significantly more likely to be proven superior. These data suggest that at least when commercially sponsored, there may be too high a threshold for testing a new intervention in an RCT; that is, researchers initiate a new RCT when there is more than sufficient evidence favoring the new intervention’s effectiveness. This choice may be explained by the fact that launching an RCT is costly both in terms of effort and resources. Because of the costs, the research community may hesitate to initiate RCTs except when there is substantial evidence supporting the new intervention.20 Although clinical equipoise seems to solve many ethical problems with randomized control trials, some residual problems remain. For instance, why is a P value of 0.05 the level at which the community of medical experts is convinced that one intervention is better than another? Similarly, when the trial is nearing full accrual, clinical equipoise may not hold as data may suggest one arm is better than another. In such circumstances, there may be questions about the ethics of enrolling additional participants, even if the P value is not 0.05.

Informed Consent Informed consent is an important element of ethical clinical research and is the most extensively empirically studied aspect of research ethics.21–27 As noted earlier, to have valid informed consent requires fulfilling four elements: (1) competence, (2) disclosure, (3) understanding, and (4) voluntari-

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e t h i c s o f c l i n i c a l o n c o l og y r e s e a r c h TABLE 9.2. Data on adherence to clinical equipoise in randomized controlled trials. % favoring innovative therapy

% showing equality between innovation and standard therapy

% favoring standard therapy

Year published

Disease(s)

Studies

Djulbegovic et al.18

2000

Multiple Myeloma

136 reported between 1996 and 1998

29%

59%

12%

Joffe et al.19

2004

Adult cancers

103 from two U.S. cooperative cancer groups between 1981 and 1995

29%

68%

3%

Author

ness.2 The published studies have predominantly focused on understanding, by evaluating what research participants understand and what are their motivations (Table 9.3).26,28 Disclosure of information and voluntariness are less well studied.27,29–31

Limitations of the Empirical Data on Informed Consent Despite the emphasis placed on informed consent and the numerous empirical studies, the reliability of conclusions is limited by five serious methodologic problems. First, there are no standard instruments to measure the domains of informed consent. Thus, there are varying and inconsistent methods and outcome measures, and the questions asked vary considerably from study to study. Although there are some proposed measures, none are widely accepted, such as the SF-36 for measuring quality of life.32,33 This limits the comparability and generalizability of the available data. Second, there is confusion as to what should be measured. Studies claiming to assess understanding are often measuring motivations, recall, or voluntariness, none of which are understanding. For example, questions asking about the purpose of a study do not distinguish between the investigator’s purpose for conducting the study from the purpose a particular individual may have for participating in the study. Third, the studies tend to be small; they usually involve fewer than 100 participants and are from single institutions. Fourth, there is important variability in the timing of the assessment of understanding. Measuring understanding on the day a research participant decides to enroll in a study assesses understanding at the ethically key moment of decision making. Conversely, measurements made a week or more after signing consent assesses memory or recall rather than understanding. Such assessments may result in differences that could be completely due to the delay in assessment and have nothing to do with the quality of the informed consent process. Finally, insufficient attention has been given to the diversity of study contexts. Issues pertinent for informed consent in a randomized control trial for cancer differ from than those for a Phase I cancer trial, or an epidemiologic study, yet these differences are rarely addressed.28

Comments

Commercially sponsored trials were significantly more likely to favor new innovative therapy arms (74% vs. 26%; P = 0.004). Studies funded by nonprofit organizations showed no difference (53% vs. 47%; P = 0.61) Mean effect size = 1.19 (95% CI, 1.12–1.27), favoring innovative therapy arm.

For example, asking a person their understanding of the chances they might benefit by enrolling in a randomized control trial of adjuvant therapy for breast cancer is not comparable to asking a person enrolling in a Phase II study of a single agent for metastatic breast cancer. In the adjuvant situation, the goal is cure, whereas in the metastatic setting the goal is palliation. Thus, a single study attempting to evaluate understanding in patients in these different research contexts is difficult to interpret.

Data on Informed Consent Despite these limitations, three consistent results emerge from the published studies on informed consent. First, some problems exist with the informed consent process as it is currently practiced.23,34 In some cases, disclosure seems to be inadequate. Several studies have suggested that although regulations are being followed, informed consent documents have become increasingly unreadable, lengthy, and uninformative.22,35,36 These studies have found the forms written at the level of scientific journals rather than at an acceptable 8th-grade reading level.35,36 Another study evaluating disclosure by asking European investigators their practice of obtaining consent found that 12% failed to inform their patients about the trial before randomization, 38% reported not always telling patients that they had been assigned their treatment randomly, and 5% never sought consent.37 However, in the Phase I setting the available data suggest disclosure may be better. The only study evaluating the substantive content of Phase I oncology consent forms found that 99% of 272 forms explicitly stated the study was research and that in 86% this statement was prominent.38 Furthermore, 92% indicated safety testing was the research goal. Overall, the mean length of the risks section was 35 lines in contrast with 4 lines as the average length of the benefit section; and 67% of the forms mentioned death as a potential consequence of participation in the study, whereas only 5% mentioned cure as a possible benefit. Only 1 consent form indicated that any benefits were expected. In a different study, evaluating disclosure during the physician-patient discussion in the Phase I setting, Tomamichel et al. reported that the lack of known treatments and the investigational nature of the Phase I

1996

1997

1998

2000

1995

2001

2000

2001

2003

Itoh et al.41,65

Yoder et al.44

Hutchison et al.45

Daugherty et al.9

Tomamichel et al.39

Moore et al.75

Schutta et al.75a

Joffe et al.28

Meropol et al.48

Questionnaire after enrollment

Quantitative and qualitative analysis of taped interviews Pre- and posttreatment questionnaire and structured interviews Quantitative and qualitative analysis of taped focus group Mail survey 1–2 weeks after consent

Quantitative and qualitative interviews at entry and exit of study Interviews 2–4 weeks after consenting to participate Interviews within 1 week of receiving drug

Questionnaire after enrollment but before drug administration

Interview 1 week after treatment begun

60% expect to benefit

Three themes: 1) need to try everything 2) maintaining hope 3) help others Hope for therapeutic benefit

59% possibility of medical benefit

73% seeking anticancer response

Majority hope for benefit

70% to get best medical care; 85% decreased tumor size

19% treatment benefit; 63% no benefit but participate anyway

50% hope for improvement of their diseases; 30% pressure of family

75% knew trials done to improve treatment of future patients; 71% knew may be no medical benefit to themselves —

—

—

—

31% knew purpose

—

—

60%–80% recalled, “experimental,” “so far only animal studies,” “effect uncertain” 43% knew goal is to determine recommended dose

Awareness of study purpose and design

64% “unsure” or “maybe”

71% knew may not be direct medical benefit to them from participating

Described “living with the reality of incurable disease whilst still hoping for a miracle cure” —

—

“Most important reason . . . was hope it might help them” 73% thought there may be psychologic benefit

—

63% did not expect to benefit

—

—

90%

—

—

96%

96%

89%

—

81% said understood almost all information given to them

—

Satisfied with informed consent process

—

77%

—

—

—

—

100%

—

—

Would participate again

c

The initial publication by Cheng et al. of 30 patients, included in the 328 patients.

Survey of patients participating in phase I, II, and III studies. Total number of patients was 207 of which 50 were enrolled in phase I studies. Unfortunately, the analysis of the responses failed to stratify according to phase.

b

328c

50b

8

15

31

144a

28

37

32

10

Reasons for participating

The initial publication by Daugherty et al.19 of 27 patients is included in the 144 patients.

1984

Rodenhuis et al.40

Methods of evaluation

Confidence in benefit from enrolling in study

chapter

a

Year

Author

Sample size

TABLE 9.3. Studies evaluating the quality of informed consent in Phase I oncology trials.

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oncology study were verbally stated by physicians to cancer patients in more than 90% of consultations and the lack of sufficient knowledge of toxicity of the drug in more than 80%.39 Two other studies report similar findings.40,41 Several studies have focused on evaluating understanding by the research participant and found that the participants did not understand various aspects of the study.28,42 For example, a study by Penman et al. of 144 cancer patients participating in trials at academic cancer centers found that participants did not fully understand toxicity;42 participants recalled an average of 3 risks when the consent forms mentioned an average of 11 risks. More importantly, participants tended to recall the minor toxicities, such as hair loss, rather than major potential toxicities. Studies evaluating understanding have consistently found that participants most frequently fail to understand details of research design. In a study of 299 Finnish patients with breast cancer enrolled in a randomized control trial of hormonal treatment, 51% thought the doctor had chosen the therapy.43 More recently, Joffe et al. reported on 207 patients enrolled in Phase I, II, and III oncology studies surveyed 3 to 14 days after consent.19 Overall, 75% of participants knew that the main reason cancer trials are done is to improve the treatment of future cancer patients, while 71% reported that they may not experience direct medical benefit from participating in the clinical trial, yet 48% thought the treatments and procedures were standard for their type of cancer. The understanding aspect of informed consent in Phase I oncology trials has been the most extensively studied area of Phase I ethics research. Most participants in Phase I oncology studies are motivated to participate by hopes for stabilization, improvement, or even cure of their cancer (see Table 9.3).44–48 This observation has been widely interpreted to suggest patients have deficient understanding of the objectives, benefits, and risks of Phase I research. However, the data also show that patient decisions to participate may reflect a motivation to maintain hope in a difficult situation rather than misunderstanding of the information.44 For example, although Daugherty et al. found that 85% of patients were motivated to participate for possible therapeutic benefit, 78% were either unwilling or unable to state whether they believed they personally would receive benefit from participating in a Phase I trial.49 Similarly, Itoh et al. found 63% of the participants did not expect any benefit but wished to participate anyway.41 The largest study evaluating understanding by Meropol et al., which asked Phase I participants how confident they were being among those who would benefit, found only 27% thought they would definitely benefit from participating in research.48 Second, several intervention studies have been conducted in an attempt to improve the informed consent process. Three broad types of interventions have been tried: (1) modifying the consent form, (2) augmenting the discussion between research participants and investigators, and (3) using a multimedia or computer-based intervention.22,50 Regardless of the approach, the majority of the studies have not shown meaningful improvements in the understanding of research participants. The major exception is by Aaronson et al., finding that using a telephone-based nursing intervention could improve participants’ understanding.50 About 15% to 20% of participants in the intervention group showed improvements in the level of their understanding of side effects, trial objectives,

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and randomization. It should be noted that although studies using consent forms have failed to show a consistent and substantial improvement in understanding, they may still be important to research participants. Joffe et al. found that 84% read the consent carefully and 86% found it easy to understand.28 Finally, despite deficiencies, virtually all the studies report that research participants are generally satisfied with the informed consent process.23,42,51–53 Hietanen et al. reported that of 299 breast cancer patients, 68% thought they had enough time for decision making and 87% were happy with their decision to participate.43 Similarly, Verheggen et al. evaluated 198 research participants in 26 clinical trials, finding that the majority of participants were “quite satisfied with the oral and written information disclosure.”51 Daugherty et al., Tomamichel et al., and others report more than 95% satisfaction in the informed consent process by research participants of Phase I oncology trials.28,39,49

Future Directions in Research on Informed Consent That a discrepancy seems to exist between what patients understand and their satisfaction with the informed consent process poses several research issues. First, what individuals should understand when they decide to participate in research needs to be clearly delineated and justified. As there is not agreement of what constitutes good informed consent, it is difficult to judge the current informed consent process. Some argue understanding of purpose, methods, risks, benefits, and alternatives to the research are essential components of valid informed consent. Others lessen the importance of understanding and argue good faith effort at disclosure in nontechnical language is all that is required for valid informed consent even if patients ultimately do not fully understand. Furthermore, the standards of valid informed consent need to be defined in different research contexts, because what is required for patients to understand may be different depending on the context of the particular study. For example, in a natural history trial studying factors leading to health disparities, good disclosure may be all that is required. Conversely, in a study involving bone marrow transplant with high-dose chemotherapy, total-body irradiation, and a high chance for peritransplant mortality with a potential for prolonged and numerous hospital admissions, a more complete understanding may be more important. Second, what information matters to individuals when making decisions about participating in research needs to be further studied. One reason research participants may not understand certain aspects covered in informed consent is that the details are not that important to or salient for them. If research design is unimportant to research participants’ decision making, then it may be difficult, and even unnecessary, to improve their understanding of it. Besides those discussed previously, in the Phase I context, two issues are particularly important for further research. Studies that delineate between issues of understanding and those of motivation are needed. More importantly, research that evaluates the role hope plays in patients’ decisions to participate and whether this hope should be fostered or damped is needed.

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chapter

Phase I Oncology Studies Phase I oncology studies are critical to the development of drugs that fight cancer because they are the primary process by which basic research is translated into clinical applications that could potentially lead to larger clinical trials and effective cancer therapies. There are two fundamental ethical concerns about Phase I cancer research: the risk–benefit ratio and quality of informed consent.30,31,42,54–56 Data regarding the risk–benefit ratio are reviewed here, whereas the data on informed consent in Phase I studies were discussed earlier under the section on informed consent.

Risks and Benefits of Phase I Oncology Studies The risks and benefits of Phase I oncology studies have been primarily derived from meta-analyses looking at response rates and mortality.57,58 The two largest published meta-analyses of Phase I studies report on trials conducted between 1970 and 1987; they reveal response rates of approximately 5% and mortality of 0.5% (Table 9.4).57,58 Although there have been a few other meta-analyses, they are limited by including only single-institution studies, evaluating only a few trials, and not evaluating trials published in the past decade (Table 9.4).59–63 Consequently, neither the newer compounds currently being evaluated, such as antibodies, vaccines, immunotoxins, and antiangiogenesis factors, nor improved supportive care measures are reflected in the commonly cited response rate of 5%. More recent data suggest that the response rates may be higher. A recent meta-analysis of 477 Phase I studies sponsored by the Cancer Therapy Evaluation Program (CTEP) at the National Cancer Institute between 1991 and 2002, including 10,867 participants, reported a response rate of 4% for trials with one investigational agent but an overall response rate of 12.2% for all types of Phase I trials, including those escalating doses of proven therapies.64 In addition, another meta-analysis looking at all studies published in 2002, reports an overall response rate of 18%.65 With the exception of a few agents such as cis-platinum for testicular cancer and imatinib mesylate for chronic myeloid leukemia,

9

which produced a complete hematologic response rate of 98%, of which 96% lasted beyond 1 year, there are few data on the impact of Phase I oncology studies on other clinical parameters of benefit such as overall survival or symptom control.66–68 In regard to risks, the published meta-analyses report a mortality of 0.5% and the more recent meta-analyses report a slightly higher mortality of 0.7% to 1.3%.57,58,64,65 Besides traditional risks such as mortality, toxicity, and survival, nonmedical risks are raised as risks that should be factored in the risk–benefit ratio; these include frequent blood draws, radiologic evaluations, physician visits, and biopsies, all of which require a substantial commitment of time and resources from the patients and their families. However, it is unknown whether such factors adversely affect outcomes and quality of life of Phase I research participants. Similarly, there is a concern that nausea, vomiting, and other debilitating side effects are common; however, their overall frequency, severity, and impact on quality of life have been poorly documented. The few data that do exist on the quality of life effect suggest that despite the time commitment and side effects, participating in Phase I oncology studies may actually improve patients’ quality of life compared with the alternative of receiving supportive care.69–74 This result seems paradoxical. The improvement in quality of life of cancer patients in Phase I trials may be due to receiving psychologic benefit from participating in Phase I studies.49 For some participants, the routine and regular physician contacts reduce psychologic distress during a time of great uncertainty. For others, it may allow them to exercise their willpower in a situation they did not choose.45,75 In addition, some also receive comfort from knowing they are helping future patients with cancer.28,75,76 More clinical data besides response rates and mortality are needed to fully characterize the risks and benefits of participating in Phase I oncology studies. Besides obtaining a more complete picture of the risk–benefit ratio of Phase I oncology trials, there are several other research challenges. What criteria should we use to define a favorable risk–benefit ratio for Phase I oncology

TABLE 9.4. Response rates and death rates of Phase I oncology trials.

Trial years

Total no. of research agents evaluated

Total no. of trials evaluated

Decoster et al. Estey et al.58 Smith et al.58a

1972–1987 1974–1982 1984–1992

87 54 NR

211 187 23

6,639 6,447 610

4.5% 4.2% 3%

0.5%

Von Hoff et al.59 Itoh et al.60

1970–1983 1981–1991

113 38

228 56

7,960 2,200

6.3% 4%

NR NR

Sekine et al.63

1976–1993

399

12,076

4.1%

Bachelot et al.62 Han et al.61

1986–1993 1991–2000

9 16

154 420

6% 15%

0.6%

Horstman et al.64 Agrawal et al.56

1991–2002 2002

477 125

10,687 2,830

12.2% 18%

0.68% 1.3%

Author 57

16

No. of patients evaluated

Total response rate

Toxic death rate

1%

Other

No No Single institution No Japanese studies only Single-agent studies only UK studies only

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studies? Who should decide what criteria to use to define a favorable risk–benefit ratio? To determine when a risk–benefit ratio is favorable or unfavorable requires a standard of evaluation, and one appropriate for patients with advanced cancer whose health will most likely deteriorate and who will die, yet no standard has been explicitly articulated. Indeed, determining risk–benefit ratios is one of the most important, but least developed, areas of determining the ethics of research trials.2,77–79 One approach could be to elucidate a standard based on socially accepted determinations of risk–benefit ratios already used for cancer treatments, such as in FDA approval of cancer agents. For example, high-dose interleukin 2 (IL-2) is the only FDAapproved treatment for metastatic renal cell carcinoma. This IL-2 regimen has a response rate of 14% (5% complete responses, 9% partial responses), with a median response duration of 20 months.80 The possible toxicities of IL-2 are substantial, including a sepsis-like syndrome, requiring judicious use of fluids and vasopressor support to maintain blood pressure while avoiding pulmonary edema from capillary leak. Other chemotherapy treatments, such as gemcitabine, are the FDA-approved treatment of choice for metastatic pancreatic cancer, despite a 5.4% response rate, because of demonstrated quality of life benefits.81 Thus, an explicit standard, or at least a reasonable approach by which to judge a risk–benefit ratio of Phase I studies, is needed to meaningfully discuss whether a particular risk–benefit ratio is favorable or unfavorable.

Research with Stored Biologic Samples As information about activation of genes and expression of proteins in cancer tissues becomes more central to oncology, use of stored biologic samples has become an ever more important aspect of clinical oncology research. Over the past decade or so there has been great controversy about when and under what conditions it is ethical to conduct research with stored biologic samples. In 1995, the ELSI-DOE Working Group suggested that all research with stored biologic samples be reviewed by an IRB and that, to show respect for persons, consent should be obtained to use the sample even if not strictly required by the federal research regulations.82 Subsequently, other groups have advanced other positions. The American Society of Human Genetics argues recontact for consent is unnecessary for research using previously stored samples, provided the risks are minimal.83 In addition to the disagreements about whether consent should be obtained at all, there are disagreements about what individuals should have to consent to. The National Action Plan on Breast Cancer recommends asking individuals to consent to future research on the disease being studied and separately to consent to research on other diseases.84 The National Bioethics Advisory Commission (NBAC) argues that individuals should be offered six choices, including allowing individuals to authorize future research on the same disease, but requiring recontact for consent for research on other diseases.85 This disagreement has produced uncertainty about what the ethical requirements are and worries that research is being stymied. Regarding samples to be prospectively collected, the ethical principle of respect for persons suggests

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that consent should be obtained. However, there is a further question of what the person should consent to. Respect for persons alone does not determine how many or which choices individuals should be asked to consent to. For these issues, we need empirical data revealing which choices individuals find as expressions of respect. Similarly, for previously collected samples that lack consent, the question is, what procedures demonstrate respect for persons. Given these questions, empirical research is essential to determining when and how to obtain consent for research with stored samples. Although the available data are limited, they indicate that research participants are willing to have their biologic samples used for all kinds of research (Table 9.5).86–89 Indeed, these data suggest multiple questions on the consent form are unnecessary. Based on these data, it has been suggested that it is sufficient to prospectively ask research subjects to consent to any type of research with their stored biologic sample.86 It has also been suggested that previously collected clinical samples can be used in research when anonymized, based on presumed consent with an opt-out when feasible.

Genetic Testing Rapid advances in molecular biology resulting from new analytical techniques combined with detailed knowledge of the human genome, offer the opportunity of discovering the genetic basis of many cancers.90 As basic research into the genetic basis of cancer progresses, the clinical testing of cancer genes is becoming more common.91 Two ethical issues with genetics testing research are particularly relevant: confidentiality and informed consent. A fundamental aspect of respect for human persons is protecting confidentiality. The available research suggests that maintaining confidentiality is a real concern of potential research participants. For example, in a study in which Hadley et al. offered genetic testing to 111 eligible first-degree relatives of patients with hereditary nonpolyposis colon cancer (HNPCC), 51% chose to participate.92 Fears of discrimination and concerns about psychologic issues were major barriers to testing. A study by Armstrong et al. of BRCA1/2 testing found similar concerns about job and insurance discrimination.93 Worries about job and insurance discrimination are concerns for family members, and safeguards should be in place to protect confidentiality. Research on how valid these concerns are and how frequent breaches of confidentiality involving genetic tests in research occur would be helpful. If they are uncommon, dissemination of such information might increase enrollment into genetic testing research studies, and if they are common, it would help develop safeguards to protect confidentiality. A second important issue surrounds informed consent and genetics testing. In the context of genetics testing research, it is particularly important for research participants to understand the implications about genetic testing because of its potential psychologic impact on individuals.94 Indeed, the data suggest individuals with depressive symptoms are less likely to participate in genetic testing. A study by Lerman et al. of 208 members of four extended (HNPCC) families reported that those with symptoms of depression were four

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TABLE 9.5. Data on attitudes toward conducting research with stored biologic samples. Percent permitting research with their research-derived stored biologic samples

Author

Year

Population

Data source

Wendler and Emanuel86

2002

504 Americans; 246 enrolled in Alzheimer’s research and 258 Medicare beneficiaries

Survey of attitudes

Stegmayr and Asplund87

2002

Permission for genetic research

Malone et al.88

2002

1,311 people 11 years after blood sample collection in the MONICA project 5,411 individuals in ECOG cancer studies 2,154 individuals in ECOG cancer studies

Chen et al.89

2004

1,060 individuals enrolled in NIH studies

Permission as part of informed consent Permission as part of informed consent; more detailed form based on National Action Plan for Breast Cancer model requiring three questions Permission as part of informed consent

times less likely to obtain testing.95 Biesecker et al. reported similar findings in a study of psychosocial factors effecting genetics testing decisions among BRCA1/BRCA2 families.94 Furthermore, informed consent is also exceptionally important in genetics testing research because there is no real option of going back once the results of the test are known. Thus, individuals who do not really understand the potential impact of knowing they are carriers of a gene that predisposes them to cancer could potentially suffer long-term consequences. However, with the current emphasis on genetic counseling and the importance placed on it, valid informed consent may already be in place. Data on risks and benefits of genetic testing would be helpful in genetics testing research. For example, there is a perception of a potential tremendous psychologic burden from knowing the results of genetic tests, but there are few longterm data on how such knowledge affects quality of life, the impact of increased interaction with physicians, and potentially more testing and follow-up. Data on the effects on other family members and family dynamics would also be helpful.

Conflict of Interest After the Gelsinger case at the University of Pennsylvania and multiple cases at Fred Hutchinson Cancer Center, much attention has been focused on the financial conflicts of interest of clinical researchers in general and of oncology researchers in particular.96,97 This controversy raises five fundamental questions: What is a conflict of interest? How frequently do researchers have a financial interest in their own clinical research? Do financial interests distort the design, conduct, or dissemination of research data or compromise patient safety and well-being? How should they be regulated? How well do the safeguards work? What is a conflict of interest? All professionals have primary interests that define and orient their professional

87.9% (for anonymized samples collected as part of research) anonymized 93.0%

Comment

27.3% would require consent for research on clinically derived samples that are 22.3% wanted information about each use of their sample

89.4% 93.7% (cancer) 86.9% (other, noncancer kinds of research)

87.1%

6.7% refused future research with stored samples

activities. Teachers’ primary interest is to educate their students. Judges’ primary interest is to ensure justice is served for plaintiffs and defendants. Physicians’ primary interests are to promote patient well-being and to teach medical students. The primary interests of clinical researchers are to produce and disseminate generalizable knowledge that will improve health care for future patients and to ensure the health and well-being of their research participants. In addition to these primary interests, professionals also have secondary interests. For a researcher, these could include publishing, gaining recognition and fame, spending time with his or her family, and obtaining a good income. These secondary interests are not in themselves illegitimate or nefarious; in fact, secondary interests can often be praiseworthy. What makes them problematic is their ability to unduly influence decisions about an individual’s primary interest.98 A conflict of interest occurs when a secondary interest distorts or appears to distort a judgment related to a primary interest. In other words, a conflict of interest occurs when a reasonable person could “believe that professional judgment has been improperly influenced, whether or not it has.”98 Mere suspicion by a reasonable person that a professional judgment is biased or unduly influenced is sufficient reason for a conflict of interest to exist, regardless of whether an undue influence has actually occurred. Conflict of interest rules are meant both to ensure objectivity in professional judgments by minimizing the likelihood such judgments will be compromised and to minimize any harms that might result from the bias if it does exist. Thus, the aim of conflict of interest regulations is not to prevent secondary interests altogether, but to prevent the secondary interest from influencing or appearing to influence judgments concerning the primary interest.98 How frequently do researchers have financial interest in their own clinical research? With the passage of the Bayh–Dole Act in 1980, which granted universities and medical schools the exclusive licensing rights to intellectual

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property developed through federally funded research conducted at their institutions, industry support of research grew significantly.99 In 1986, 46% of all biotechnology firms supported research at universities; by 1996, the proportion had doubled to 92%. As a result, universities’ share of new gene patents increased from 53% to 73% between 1990 and 1999, and at least 2,900 companies have been formed around an innovation licensed from researchers at an academic institution since 1980.100,101 Consequently, from 1991 to 2000, the income to universities from licensing grew from $121 million to $997 million per year.99 Similarly, the fraction of clinical research supported by industry grew from 32% in 1980 to approximately 62% in 2000 while the federal government’s share fell.102 This expansion by industry has many positive effects for research and researchers, including providing access to industrial facilities and databases, increased financial support for research, and use of industrial expertise.103 However, this increase in industry support and involvement in research has also resulted in further opportunities for financial conflicts of interest in clinical research. Financial relationships between industry and researchers are common; studies suggest that between 23% and 28% of academic investigators in biomedical research receive funding from industry.104,105 Probably the most well documented rates of researcher-industry relations are those of the UCSF faculty, which consists of 900 PIs (principal investigators) in an institution with $374 million in National Institutes of Health (NIH) grants, placing it in the top five institutions receiving NIH funding.106 In 1999, 7.6% of the faculty reported having personal financial ties to their research sponsors.106 Of these, 34% had occasional speaking engagements, 33% had paid consultancy arrangements, 32% served on boards of directors or scientific advisory boards, and 14% had equity in a company, with the mean value of the equity being $100,000. Thus, although the prevalence of faculty with financial ties to industry was relatively low, those with financial interests often had multiple ties, some of which involved substantial sums. Do financial interests distort the design, conduct, or dissemination of research data or compromise patient safety and well-being? In one bone marrow protocol at the Fred Hutchinson Cancer Center, 80 of 82 enrolled research subjects died and the study investigators had $294 million of holdings in a drug company sponsoring part of the research.97 Importantly, this does not prove that the patients’ well-being was compromised by the potential conflict of interest, but it does raise questions. In fact, the researchers were cleared of conflict of interest allegations in a lawsuit that was brought against them and Fred Hutchinson Cancer Research Center by the patient’s families.107,108 Unfortunately, there are no data substantiating whether the financial interests of investigators compromise the safety of research subjects. This conjecture is difficult to establish, especially as there are no data on the overall safety of clinical research. Regarding the link between financial interests and research design, the data indicate that industry-sponsored research is certainly no worse methodologically than clinical research sponsored by nonprofit organizations, such as the NIH.109–112 Indeed, the data indicate that industry-sponsored research studies may well be more methodologically rigorous.18,113 In one study, industry-sponsored trials were more likely to be double blind than trials with other sources of

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funding.114 In another study that used a 100-point scale to evaluate five criteria for methodological rigor—randomization, outcome, inclusion/exclusion criteria, statistical analysis, and report of the interventions—industry-sponsored trials scored 73.1 while nonindustry-sponsored studies averaged 53.4 (P < 0.0001).115 Recently, Lexchin et al. comprehensively reviewed studies that assessed sponsorship, design, and conduct of research.116 They found that “none of the 13 [assessments in the literatures] reported that industry funded studies had poorer methodological quality . . . Of nine [out of 13 assessments] that provided statistical analyses, four found that drug company sponsored research had better quality scores.” Thus, it appears that financial interests do not compromise research design. Financial interests may, however, adversely affect data collection and interpretation. Many studies have reported that research funded by industry is more likely to be favorable to the industry’s experimental interventions than if the research was funded by a nonindustry source. Of 11 metaanalyses, 9 reported that industry-sponsored trials were significantly more likely to give pro-industry results.102 Indeed, when all studies were aggregated, having industry sponsorship was associated with an odds ratio of 3.60 (95% CI, 2.63–4.91) for having a pro-industry conclusion. For instance, Als-Nielsen et al. reported that among studies funded by forprofit entities, 51% reported results favorable to industry, whereas only 16% of studies funded by nonprofits generated results favorable to industry.117 Furthermore, one report summarizing a number of randomized studies conducted in multiple myeloma, found that 74% of industry-sponsored trials produced results favorable to the industry’s new treatment, whereas only 53% of trials funded by nonprofit entities generated results favorable to the experimental treatments.18 Specifically regarding oncology studies, Friedberg et al. reported that drug company-sponsored studies were much less likely to report unfavorable qualitative outcomes than studies funded by nonprofit sources (5% versus 38%).118 Importantly, such data do not necessarily demonstrate bias or compromised studies. The fact that industrysponsored studies generate pro-industry results may reflect a “pipeline” issue; that is, because conducting large research trials is very expensive, industry tends to only undertake drug trial studies when it is reasonably sure the results will be positive. Experimental interventions that are more uncertain or may not generate huge profits may be terminated before large randomized studies because of industry’s caution about expending resources. This decision may ultimately deprive society of important new interventions, but it does not constitute a financial conflict of interest that might compromise the integrity of the research design or the data collection and interpretation. However, none of the reported studies links industry funding to biased scientific judgments, which, in turn, produce too many study outcomes favorable to the funding industry. Just showing that industry-sponsored studies generate pro-industry conclusions is insufficient to demonstrate that financial conflicts of interest actually bias the conduct of studies. Nevertheless, there are data suggesting that industry financial support does distort the judgment of researchers. Stelfox and colleagues analyzed all published studies in 1995–1996 regarding the safety of calcium channel blockers

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TABLE 9.6. Support of calcium channel antagonists and financial interest.119

No. of respondents Financial interest in Ca blocker manufacturer Financial interest in any manufacturer Honorarium from any pharmaceutical manufacturer Research funding from any pharmaceutical manufacturer Employment or consultation for any pharmaceutical manufacturer

in postmyocardial infarction patients.119 They found 70 publications: 5 original research papers, 32 reviews, and 33 letters to the editor. As Table 9.6 shows, researchers with a financial interest in a manufacturer of calcium channel antagonist, or even those with a financial interest in any manufacturer, were significantly more likely to support the safety of calcium channel blockers than researchers without a financial interest. Indeed, this trend held true for researchers with any type of financial interest in any pharmaceutical manufacturer, including receiving honoraria and research funding. The only time there was no association between having a financial interest in any pharmaceutical manufacturer and supporting the safety of calcium channel blockers, was when the researchers’ financial interest was to have been employed by or served as a consultant to manufacturers. Finally, there are data showing that financial interests do alter dissemination of research results. A study of 42 placebocontrolled trials of selective serotonin reuptake inhibitors (SSRI) submitted to Swedish regulators found that, of the 21 studies showing positive effects of the drug over placebo, 19 were published, with the results frequently appearing in more than 1 article. Conversely, of the 21 studies that showed no difference between the experimental SSRI drug and placebo, only 6 were published.120 Whether this is a result of the publication bias against negative studies at major journals or the result of industry withholding negative data was not determined. However, a 1993 survey of 2,167 life science faculty from the 50 universities receiving the most NIH funding found that one-fifth of the faculty had delayed publication for more than 6 months during the past 3 years to allow for patent application or negotiation, to resolve intellectual property rights disputes, to protect their scientific lead over competitors, or to slow the distribution of undesired results. Delays in publication were associated with participation in a research relationship with industry [odds ratio (OR) = 1.34] and with commercialization of one’s own research results (OR = 3.15).104,121 More importantly, there have been a number of high-profile cases in which industry has actively and explicitly tried to prevent the dissemination of negative findings about drugs. In the Olivieri case in Toronto, Apotex, the company that funded Dr. Olivieri’s research on their drug, tried to prevent her from publishing findings suggesting that the drug was not only not beneficial for patients with iron overload, but may actually be harmful to them.122 Similarly, the manufacturers of Synthroid brand thyroid replacement, Boots Co., funded a study to compare Synthroid with generic thyroid replacement drugs.123 The results showed no difference in patient outcomes. Boots then tried to prevent the

Support Ca blockers

Neutral

Critical of Ca blockers

P value

24 (69%) 23 (96%) 24 (100%) 75% 87% 25%

15 (83%) 9 (60%) 10 (67%) 40% 40% 33%

30 (91%) 11 (37%) 13 (43%) 17% 20% 17%

0.02 50 years may find cancer, but not necessarily disease.

The ACS recommends offering PSA and DRE annually beginning at age 50 among men who have a life expectancy of at least 10 additional years, but only after appropriate discussion of risks and benefits.10

Screening for Other Cancers The USPSTF recommends against routine screening for bladder, thyroid, ovarian, and pancreatic cancers in the general population, even for individuals at higher risk for ovarian and thyroid cancers, because the available tests are either inadequate or have not been proven beneficial. For testicular, skin, and oral cancers, the USPSTF has determined that there is insufficient evidence to recommend for or against screening in the primary care setting, although discussions of screening options with selected patients at high risk for testicular cancer may be appropriate.14

Screening Is a Process While screening trials fund teams of specially trained individuals to ensure that recruitment, screening, and follow-up occur, these resources do not exist in daily clinical practice.12 In primary care practice, a number of organizations, institutions, and individuals must share responsibility for making sure that the entire screening process occurs. The number and complexity of steps in the screening process may lead to confusion or breakdowns in communication.12 These breakdowns may result in failure to follow up on a positive test or to treat diagnosed cancer.13,154,155 Factors outside the doctor–patient relationship, such as healthcare insurance and the clinical setting itself, influence individual propensity to seek screening and the likelihood that the screening process will be complete.12 This section summarizes some of what has been learned about the five major phases of the screening process: (1) identifying and understanding the population at risk; (2) identifying the method of recruitment; (3) clarifying the screening approach; (4) developing the follow-up approach; and (5) referring patients for treatment.

Recommendations

Identifying and Understanding the Population at Risk

The USPSTF report concludes that there is insufficient evidence to recommend either for or against screening with PSA.

The populations that should be screened for specific cancers are now easily identifiable from a strictly demographic

10 years before diagnosis in 1979–1985 10 years before diagnosis in 1976–1991

2–10 years before death in 1981–1990 1987–1990

Friedman220

RichertBoe222

Bartsch224

Lu-Yao223

1993 onward

1988–1996

Labrie151

Jacobsen221

Years of intervention

Study name

11 years

NA

NA

NA

8

Longest follow-up (years)

One state in Austria compared with surrounding states

Two separate geographic areas: Seattle-Puget Sound and Connecticut

HMO

Olmstead County, Minnesota

HMO

Quebec City

Site of study

45–75

65–80

Mean age at death 70.3 years

Mean age at death 79 years

Mean age 69.5 years

45–80 years

Age group

TABLE 24.8. Evidence for the efficacy of prostate cancer screening.

Ecologic study: cohort comparison

Case-control; cases were men with metastatic (stage D) prostate cancer dx Case-control; cases were men with prostate cancer listed on death certificate; age-matched controls Case-control: cases were men who died of prostate cancer Ecologic study: cohort comparison

RCT

Study design and screening comparison

Relative PSA rate, prostate Bx rate, radical prostatectomy rate, mortality rate PSA screening

DRE in 10 years prior

DRE in 10 years prior

DRE in 10 years prior

31,300 intervention (PSA & DRE), 15,432 control

Exposure (intervention)

N/A

N/A

N/A

N/A

Up to 7

Screening rounds

N/A

N/A

N/A

Annual

Screening interval (months)

32%

Seattle to Connecticut: relative PSA 5.4 (95% CI, 4.76–6.1), Bx 2.2 (95% CI, 1.8–2.7)

Screen DRE; 77% cases, 80% controls

2.45 exams among cases, 2.52 exams among controls 84% controls, 75% cases any DRE

23.00%

% Exposed to intervention (round) Measure of effect

Test of trend in deaths due to prostate cancer: 0.011e per year decrease in Tyrol compared with 0.0057 decrease in rest of Austria

OR of DRE in cases vs. controls, 0.84 (95% CI, 0.4–1.46) Mortality 1.03 (0.95–1.1)

OR of DRE in cases vs. controls, 0.51 (95% CI, 0.31–0.84)

OR of DRE in cases vs. controls, 0.9 (95% CI 0.5–1.7)

“Intention to treat” 4.6 vs. 4.8 deaths/1,000

Comment

Results unchanged when looked at exposure within 5 years. Radical prostatectomy was more common in Seattle: 2.7% vs. 0.5% of population.

No difference in timing of DRE exposure.

Control group had 6.5% screened. Reported benefit was not based on intention to treat.

333

screening

standpoint. For women, screening begins 3 years after onset of sexual activity or by age 21 to look for precursors to cervical cancer, by age 40 for breast cancer, and by age 50 for colorectal cancer. Screening for men begins at age 50 for colon cancer; a discussion of prostate cancer should also occur at that time so that men understand the strengths and weaknesses of current knowledge.10 However, identifying the population at risk involves more than specifying gender or age range. It is also important to understand the cultural characteristics of populations, their interest in screening, and their understanding of screening tests so that those at risk understand the recommendations and seek the appropriate tests.104,156,157 Those at highest risk of late-stage cancers after screening are those who have not been screened before.155 Figure 24.2 shows that screening rates in the United States vary from as low as 10% of women having had a recent endoscopic evaluation of colorectal cancer to as high as 81% having had a recent Pap smear.158 The figure shows that, as of the year 2000, less than 30% of men or women had undergone FOBT within the previous 2 years, and fewer had undergone endoscopy. Men are more likely to report having had a PSA test than either FOBT or endoscopic screening.159 Because the potential mortality reduction among individuals screened for colon cancer is promising, encouraging CRC screening is becoming a high priority.10,160 Although Figure 24.2 demonstrates rising rates of mammographic screening and sustained cervical cancer screening, women with lower incomes are less likely to have access to care and are less likely to be screened for these two cancers,

even though programs are in place to reach low-income women in all 50 states.161,162 Across the United States, an estimated 15% of individuals are without insurance coverage at any given time, and a much higher percentage is without coverage some time during the year.163 Lack of insurance and lack of a regular source of health care are highly correlated with lack of screening.158,164,165 For example, AfricanAmericans are less likely to have health insurance than Caucasians and are therefore less likely to undergo screening tests for CRC.162,166 It is estimated that cancer mortality is 19% higher in the lowest socioeconomic groups than in the highest.167 Recently, levels of cancer screening among racial minorities have improved to the point that they approach the levels of screening among Caucasians; people without health insurance or a regular source of health care continue to be underscreened.168 As a nation, we cannot achieve the maximum mortality reduction afforded by cancer screening if some populations go unscreened or untreated.

Identifying the Method of Recruitment Reaching individuals, however, is not only a function of income and access. Even when they have access to care, not all people seek recommended screening.155,169,170 Providers may work with their teams, practices, health plans, third-party payers, and community to develop recruitment methods for screening. There is evidence that changes in practice that affect multiple levels of health care, including reimbursement, records systems, and tailoring of recruitment messages, have the strongest impact.171,172

Men

90

45

80

40

70

35

60

30

50

25

Percent

Percent

Women

40

20

30

15

20

10

10

5

0 1987

1992

1996

2000

Year

0 1987

1992

1996

2000

Year

Pap Smear

FOBT

FOBT

Mammoram

CRE

CRE

PSA

FIGURE 24.2. United States screening rates (1987–2000). (Adapted from Swan et al.,158 by permission of Cancer.)

334 Ultimately, practitioners must make choices about how to reach individuals with appropriate recommendations and encourage them to consider screening. This is a crucial step in the screening process; for example, a recommendation from a primary care physician is a primary predictor of whether women seek colorectal cancer screening.173 However, physicians’ recommendations are not always consistent with screening guidelines; for example, a nationwide survey of primary care physicians suggested the presence of knowledge gaps and suboptimal screening delivery for CRC screening.160 Primary care physicians also face substantial time limitations with regard to making all necessary and appropriate screening recommendations in light of their other prevention and treatment obligations174; therefore, systematic changes may have the largest impact on making the screening recommendation.172 One key systematic change is the implementation of clinical reminder systems, as there is strong evidence that issuing reminders leads to increased screening rates for film-screen mammography and cervical cancer.172,175–178 The two major types of reminders are inreach and outreach. Inreach reminders involve notifying a provider that a patient is due for a screening test while he or she is in the office. Systems to provide inreach reminders may be as simple as a chart review and paper alert or as sophisticated as an electronic note on an automated medical record. Overall, inreach reminders and physician feedback have been shown to result in the mammography screening of an additional 5% to 20% of the study population compared with “usual care” controls.179 Outreach reminders consist of contacting individuals outside of an office visit. Studies involving telephone calls from a cancer registry, mailed recommendations, and motivational telephone calls addressing specific barriers to screening have shown that such reminders result in the Pap and mammography screening of an additional 15% to 31% of the study population compared with usual care.175,177 Even after recommendations are made, ensuring that individuals seek screening may require adopting and adapting new strategies to encourage women to follow through on the recommendation. For example, McPhee and colleagues have shown that having female lay leaders discuss screening at gatherings in women’s homes promotes the use of film-screen mammography among Cambodians.180 Understanding factors that affect use of screening tests will help providers work with members of their organizations and communities to plan effective education and recruitment strategies for the populations they serve. The process of understanding and enabling individuals to manage their care has been called “self-management support” by some, and it may be critical to successful screening implementation.181

Clarifying the Screening Approach In addition to ordering the screening test, the primary care provider may be responsible for conduct the screening. Organizing the care within a practice is therefore critical to getting screening accomplished. How that screening occurs, however, differs by the organizational setting of healthcare delivery, the cancer site, the set of screening tests recommended, and which test or set of tests the patient prefers. For example, screening mammography and colonoscopy depend

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upon referrals whereas cervical cancer screening, FOBT, and sigmoidoscopy can be conducted by the primary care team. To incorporate cancer screening into a busy practice, primary care providers need to organize their approach and clarify who is talking with the patient, what is being said, and how tests are ordered. This is all part of organizing the approach to screening, and it has been shown to increase screening rates when implemented systematically in practice using the entire healthcare team.172,182–184

Developing the Follow-Up Approach When testing requires a referral, a tracking system to document the patient’s progress through the care continuum can be helpful. The proportion of positive screening tests varies with the type of test but, in general, is about 10% (see Tables 24.1, 24.3, 24.5, 24.7). Follow-up for these individuals is not automatic, and failure to ensure successful follow-up compromises the mortality reduction achievable.178 For example, follow-up for positive FOBT has been estimated to range between 49% and 79%,185 and follow-up after a mammogram was as low as 35% women in one HMO even though access to care was assured.186 In a review of published evaluations of follow-up after positive screening tests, Yabroff and colleagues found that two-thirds of reported studies had followup rates below 75%.13 Among the 45 observational studies in her review, only 1 showed follow-up greater than 90%.13 Factors that improved follow-up of abnormal tests included addressing the lack of health insurance for a patient, using peer counselors, making system-wide changes in a health plan or clinic, and more actively encouraging patients to manage their care.13,172 Because of apparent problems with follow-up of abnormal tests, a framework has been outlined for thinking through the issues and developing methods to ensure follow-up of positive tests.13 Healthcare team members can use the work of Yabroff and others to guide their design of a system to ensure follow-up. Studies indicate that several elements are necessary for a successful follow-up system. First, a mechanism to ensure communication between the person performing the screening and the providers responsible for follow-up is necessary. Even if the provider conducts the test, as is usually the case with cervical cancer screening, clinicians need some method of ensuring that they receive the test results. Second, the provider team needs to have a plan for dealing with a positive result once it is received, because not all positive results need to be acted upon and the primary care provider is not always the responsible party. For example, radiology facilities are obligated by the MQSA to report mammography results to all women screened. Yet even in this case, a woman notified by the radiologist may not respond. Communication with the patient about the follow-up plan is the next critical step in the implementation process. Such communication should clarify which tests are needed and what those tests involve for the patient. Research shows that communication from the provider to the patient about the importance of follow-up and the details about further workup will influence whether follow-up occurs.13,187 Women with fears of painful procedures or fatalistic views regarding cancer diagnosis are less likely to comply with follow-up recommendations.13 As shown in Tables 24.1, 24.3, 24.5, and

screening

24.7, evaluations needed after a positive test vary from repeating the test or ordering additional mammograms or colonoscopy to surgical consultation. Incorporating the patient into the care plan has become an important part of follow-up care and may increase adherence to the plan.13 For example, telephone contact addressing women’s perceptions of the cervical cancer screening test and educating them before or after the Pap test through interactive discussion improved follow-up by 24% to 26%.178 Ultimately, improving follow-up requires the coordinated effort of providers, staff working with them, and patients.

Referring for Treatment After developing the follow-up approach, the next critical step is ensuring that patients are referred to and receive appropriate specialty care. Referral to oncology specialists by primary care providers (PCPs) depends on some degree of coordinated care. Developing this coordination was highlighted in the National Cancer Policy Board’s 1999 analysis as a key step toward improving the quality of America’s health care. They concluded that optimal cancer care delivery should ensure, among other things, a “mechanism to coordinate services.”188 Also, a committee of the Institute of Medicine selected care coordination as one of 20 “priority areas” requiring concerted effort if the nation’s healthcare system is to be transformed.188 Literature is sparse regarding referral barriers relevant to screened cancers, but access and reimbursement for the uninsured are a clear challenge.162 However, difficulties are not confined to those traditionally considered underserved by the healthcare system. Access to quality cancer treatment in general is subject to numerous barriers, including patient characteristics such as old age, low SES,162 minority race or ethnicity,189 and lack of health insurance. Researchers studying older cancer patients concluded that patient preference is a “major determinant in the referral decisions of primary care providers.” Another potential issue is that PCPs might be unaware of cancer treatment options available to seniors.190 Recent work raises questions regarding referral patterns and points out that the majority of patients are not seen by an oncologist who might help them with decisions.191 Although treatment options and systems are not a focus of this chapter, clinicians need to be mindful of the institutional and insurance barriers that may limit access. Successful referrals in any cancer patient depend on factors such as physician characteristics (e.g., specialty, training, experience, age), quality of patient–provider communication, and complexity and constraints of the current healthcare environment.188 Steps are being taken to improve the coordination of cancer treatment after a positive screening. A pilot project that tested the effects of patient navigators (“proactive patient advocates”) on removing barriers to diagnosis and state-of-theart treatment found the concept promising.192 At the public policy level, Congress passed legislation in 2000 to fill the “treatment gap” in the National Breast and Cervical Cancer Early Detection Program by giving states the option to extend Medicaid benefits to uninsured women diagnosed through the program.193 To date, the U.S. Department of Health and Human Services has approved proposals from 48 states and the District of Columbia to implement the act (CDC).

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Summary and Conclusion This chapter has reviewed the evidence related to the epidemiology, natural history, and screening of four common cancers (breast, cervical, colorectal, and prostate). It presents this evidence within the context of the challenges of primary care practice and emphasizes the need to view cancer screening as a process of care. Ensuring access to screening and treatment for all is necessary to achieve the potential for mortality reduction afforded by current screening technologies. Regardless of healthcare coverage, organized systems are needed to ensure progress throughout the continuum of care. Implementation of the numerous steps and transitions in this continuum requires the interest, commitment, and collaborative action of patients, primary care providers, specialty care providers, administrators, and public health officials. Only through this collaboration can mortality reduction be maximized.171

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screening 146. Potosky AL, Feuer EJ, Levin DL. Impact of screening on incidence and mortality of prostate cancer in the United States. Epidemiol Rev 2001;23:181–186. 147. Perron L, Moore L, Bairati I, Bernard PM, Meyer F. PSA screening and prostate cancer mortality. C Med Assoc J 2002; 166:586–591. 148. Tornblom M, Eriksson H, Franzen S, et al. Lead time associated with screening for prostate cancer. Int J Cancer 2004;108: 122–129. 149. Partin AW, Brawer MK, Bartsch G, et al. Complexed prostate specific antigen improves specificity for prostate cancer detection: results of a prospective multicenter clinical trial. J Urol 2003; 170:1787–1791. 150. Caplan A, Kratz A. Prostate-specific antigen and the early diagnosis of prostate cancer. Am J Clin Pathol 2002;117:S104–S108. 151. Labrie F, Candas B, Dupont A, et al. Screening decreases prostate cancer death: first analysis of the 1988 Quebec prospective randomized controlled trial. Prostate 1999;38:83–91. 152. Potosky AL, Legler J, Albertsen PC, et al. Health outcomes after prostatectomy or radiotherapy for prostate cancer: results from the Prostate Cancer Outcomes Study. J Natl Cancer Inst 2000;92:1582–1592. 153. Schmid HP, Prikler L, Semjonow A. Problems with prostatespecific antigen screening: a critical review. Recent Results Cancer Res 2003;163:226–231. 154. McCarthy BD, Ulcickas-Yood M, Boohaker EA, et al. Inadequate follow-up of abnormal mammograms. Am J Prev Med 1996; 12:282–288. 155. Sung HY, Kearney KA, Miller M, et al. Papanicolaou smear history and diagnosis of invasive cervical carcinoma among members of a large prepaid health plan. Cancer (Phila) 2000;88:2283–2289. 156. Hiatt RA, Pasick RJ, Stewart S, et al. Community-based cancer screening for underserved women: design and baseline findings from the Breast and Cervical Cancer Intervention Study. Prev Med 2001;33:190–203. 157. Hiatt RA, Klabunde C, Breen N, Swan J, Ballard-Barbash R. Cancer screening practices from National Health Interview Surveys: past, present, and future. J Natl Cancer Inst 2002;94: 1837–1846. 158. Swan J, Breen N, Coates RJ, Rimer BK, Lee NC. Progress in cancer screening practices in the United States: results from the 2000 National Health Interview Survey. Cancer (Phila) 2003;97:1528–1540. 159. Sirovich BE, Schwartz LM, Woloshin S. Screening men for prostate and colorectal cancer in the United States: does practice reflect the evidence? JAMA 2003;289:1414–1420. 160. Klabunde CN, Frame PS, Meadow A, et al. A national survey of primary care physicians’ colorectal cancer screening recommendations and practices. Prev Med 2003;36:352–362. 161. Lawson HW, Henson R, Bobo JK, Kaeser MK. Implementing recommendations for the early detection of breast and cervical cancer among low-income women. MMWR Morbid Mortal Wkly Rep 2000;49(RR02):35–55. 162. Mandelblatt JS, Yabroff KR, Kerner JF. Equitable access to cancer services: a review of barriers to quality care. Cancer (Phila) 1999; 86:2378–2390. 163. Hidden costs, value lost: uninsurance in America. Washington, DC: Institute of Medicine, 2003. (Accessed February 2, 2004, at http://www.nap.edu/openbook/030908931X/html/2.html.) 164. Breen N, Wagener DK, Brown ML, Davis WW, Ballard-Barbash R. Progress in cancer screening over a decade: results of cancer screening from the 1987, 1991, and 1998 National Health Interview Surveys. J Natl Cancer Inst 2001;93:1704–1713. 165. Cokkinides V, Chao A, Smith RA, Vernon SW, Thun MJ. Correlates of underutilization of colorectal cancer screening among U.S. adults, age 50 years and older. Prev Med 2003;36: 85–91.

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166. Cooper GS, Koroukian SM. Racial disparities in the use of and indications for colorectal procedures in Medicare beneficiaries. Cancer (Phila) 2004;100:418–424. 167. Singh GK, Miller BA, Hankey BF, Feuer EJ, Pickle LW. Changing area socioeconomic patterns in U.S. cancer mortality, 1950–1998: Part I. All cancers among men. J Natl Cancer Inst 2002;94:904–915. 168. Sambamoorthi U, McAlpine DD. Racial, ethnic, socioeconomic, and access disparities in the use of preventive services among women. Prev Med 2003;37:475–484. 169. Jackson JC, Taylor VM, Chitnarong K, et al. Development of a cervical cancer control intervention program for Cambodian American women. J Community Health 2000;25:359–375. 170. Tu SP, Taplin SH, Barlow WE, Boyko EJ. Breast cancer screening by Asian-American women in a managed care environment. Am J Prev Med 1999;17:55–61. 171. Zapka JG. Interventions for patients, providers, and health care organizations. Cancer 2004;101(suppl 5):1165–1187. 172. Stone EG, Morton SC, Hulscher ME, et al. Interventions that increase use of adult immunization and cancer screening services: a meta-analysis. Ann Intern Med 2002;136:641–651. 173. Stockwell DH, Woo P, Jacobson BC, et al. Determinants of colorectal cancer screening in women undergoing mammography. Am J Gastroenterol 2003;98:1875–1880. 174. Yarnall KS, Pollak KI, Ostbye T, Krause KM, Michener JL. Primary care: is there enough time for prevention? Am J Public Health 2003;93:635–641. 175. Yabroff KR, Mandelblatt JS. Interventions targeted toward patients to increase mammography use. Cancer Epidemiol Biomarkers Prev 1999;8:749–757. 176. Mandelblatt JS, Yabroff KR. Effectiveness of interventions designed to increase mammography use: a meta-analysis of provider-targeted strategies. Cancer Epidemiol Biomarkers Prev 1999;8:759–767. 177. Wagner TH. The effectiveness of mailed patient reminders on mammography screening: a meta-analysis. Am J Prev Med 1998; 14:64–70. 178. Yabroff KR, Kerner JF, Mandelblatt JS. Effectiveness of interventions to improve follow-up after abnormal cervical cancer screening. Prev Med 2000;31:429–439. 179. Mandelblatt J, Kanetsky PA. Effectiveness of interventions to enhance physician screening for breast cancer. J Fam Pract 1995; 40:162–171. 180. Lam TK, McPhee SJ, Mock J, et al. Encouraging VietnameseAmerican women to obtain Pap tests through lay health worker outreach and media education. J Gen Intern Med 2003; 18:516–524. 181. Glasgow RE, Orleans CT, Wagner EH. Does the chronic care model serve also as a template for improving prevention? Milbank Q 2001;79:579–612. 182. Dietrich AJ, Carney PA, Winchell CW, Sox CH, Reed SC. An office systems approach to cancer prevention in primary care. Cancer Pract 1997;5:375–381. 183. Carney-Gersten P, Keller A, Landgraf J, Dietrich AJ. Tools, teamwork, and tenacity: an office system for cancer prevention. J Fam Pract 1992;35:388–394. 184. Taplin SH, Galvin MS, Payne T, Coole D, Wagner E. Putting population-based care into practice: real option or rhetoric? J Am Board Fam Pract 1998;11:116–126. 185. Myers RE, Turner B, Weinberg D, et al. Complete diagnostic evaluation in colorectal cancer screening: research design and baseline findings. Prev Med 2001;33:249–260. 186. Burack RC, Simon MS, Stano M, George J, Coombs J. Follow-up among women with an abnormal mammogram in an HMO: is it complete, timely, and efficient? Am J Manag Care 2000; 6:1102–1113. 187. Paskett E, Rimer B. Psychosocial effects of abnormal pap tests and mammograms: a review. J Womens Health 1995;4:73–82.

340 188. Institute of Medicine, Commission on Life Sciences National Research Council. Ensuring Quality Cancer Care. Washington, DC: National Academy Press, 1999. 189. Institute of Medicine. Unequal Treatment: Confronting Racial and Ethnic Disparities in Healthcare. Washington, DC: National Academies Press, 2003. 190. Townsley CA, Naidoo K, Pond GR, et al. Are older cancer patients being referred to oncologists? A mail questionnaire of Ontario primary care practitioners to evaluate their referral patterns. J Clin Oncol 2003;21:4627–4635. 191. Earle CC, Neumann PJ, Gelber RD, Weinstein MC, Weeks JC. Impact of referral patterns on the use of chemotherapy for lung cancer. J Clin Oncol 2002;20:1786–1792. 192. Freeman HP, Muth BJ, Kerner JF. Expanding access to cancer screening and clinical follow-up among the medically underserved. Cancer Pract 1995;3:19–30. 193. Lantz PM, Weisman CS, Itani Z. A disease-specific Medicaid expansion for women. The Breast and Cervical Cancer Prevention and Treatment Act of 2000. Womens Health Issues 2003; 13:79–92. 194. Bobo J, Lee N. Factors associated with accurate cancer detection during a clinical breast examination. Ann Epidemiol 2000; 10:463. 195. Oestreicher N, White E, Lehman CD, et al. Predictors of sensitivity of clinical breast examination (CBE). Breast Cancer Res Treat 2002;76:73–81. 196. Shapiro S, Benet W, Strax P, Venet L. Periodic Screening for Breast Cancer: The Health Insurance Plan Project and Its Sequelae, 1963–1986. Baltimore: Johns Hopkins University Press, 1988:55. 197. Miller AB, To T, Baines CJ, Wall C. The Canadian National Breast Screening Study. 1: Breast cancer mortality after 11 to 16 years of follow-up. Ann Intern Med 2002;137:E305–E315. 198. Alexander FE, Anderson TJ, Brown HK, et al. 14 years of followup from the Edinburgh randomised trial of breast-cancer screening. Lancet 1999;353:1903–1908. 199. Bjurstam N, Bjorneld L, Duffy SW, et al. The Gothenburg breast screening trial: first results on mortality, incidence, and mode of detection for women ages 39–49 years at randomization. Cancer (Phila) 1997;80:2091–2099. 200. Frisell J, Lidbrink E, Hellstrom L, Rutqvist LE. Follow-up after 11 years: update of mortality results in the Stockholm mammographic screening trial. Breast Cancer Res Treat 1997; 45:263–270. 201. Andersson I, Aspegren K, Janzon L, et al. Mammographic screening and mortality from breast cancer: the Malmo mammographic screening trial. Br Med J 1988;297:943–948. 202. Tabar L, Vitak B, Chen HH, et al. The Swedish Two-County Trial twenty years later. Updated mortality results and new insights from long-term follow-up. Radiol Clin N Am 2000;38:625– 651. 203. Wright TC Jr, Cox JT, Massd LS, Twiggs LB, Wilkinson EJ. 2001 Consensus guidelines for the management of women with cervical cytological abnormalities. JAMA 2002;278:2120–2129. 204. Nygard JF, Skare GB, Thoresen SO. The cervical cancer screening programme in Norway, 1992–2000: changes in Pap smear coverage and incidence of cervical cancer. J Med Screen 2002; 9:86–91. 205. Wright TC, Cox JT, Massad LS, et al. 2001 consensus guidelines for the management of women with cervical intraepithelial neoplasia. J Lower Genital Tract Dis 2003;7:154–167.

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206. Manos M, Kinney WK, Hurley LB, et al. Identifying women with cervical neoplasia: using human papillomavirus DNA testing for equivocal Papanicolaou results. JAMA 1999;281:1605– 1610. 207. Wright JC, Weinstein MC. Gains in life expectancy from medical interventions: standardizing data on outcomes [see comments]. N Engl J Med 1998;339:380–386. 208. Day NE. Effect of cervical cancer screening in Scandinavia. Obstet Gynecol 1984;63:714–718. 209. Lynge E. Effect of organized screening on incidence and mortality of cervical cancer in Denmark. Cancer Res 1989;49: 2157–2160. 210. Bigaard J. Cervical cancer screening in Denmark. Eur J Cancer 2000;36:2198–2204. 211. Greenberg PD, Bertario L, Gnauck R, et al. A prospective multicenter evaluation of new fecal occult blood tests in patients undergoing colonoscopy. Am J Gastroenterol 2000;95: 1331–1338. 212. Lieberman DA, Weiss DG. One-time screening for colorectal cancer with combined fecal occult-blood testing and examination of the distal colon. N Engl J Med 2001;345:555–560. 213. van den Akker-van Marle ME, van Ballegooijen M, van Oortmarssen GJ, Boer R, Habbema JD. Cost-effectiveness of cervical cancer screening: comparison of screening policies. J Natl Cancer Inst 2002;94:193–204. 214. Winawer SJ, Fletcher RH, Miller L, et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997;112:594–642. 215. Wherry DC, Thomas WM. The yield of flexible fiberoptic sigmoidoscopy in the detection of asymptomatic colorectal neoplasia. Surg Endosc 1994;8:393–395. 216. Rex DK. Current colorectal cancer screening strategies: overview and obstacles to implementation. Rev Gastroenterol Disord 2002;2:S2–S11. 217. Tagore KS, Lawson MJ, Yucaitis JA. Sensitivity and specificity of a stool DNA multitarget assay panel for the detection of advanced colorectal neoplasia. Clin Colorectal Cancer 2004; 3:47–53. 218. Mulhall BP. Recent findings on test performance. Washington, DC: Walter Reed Army Medical Center, 2003 (unpublished work). 219. U.S. Preventive Services Task Force. Screening for prostate cancer: recommendations and rationale. Am Fam Physician 2003;67:787–792. 220. Friedman GD, Hiatt RA, Quesenberry CP Jr, Selby JV. Casecontrol study of screening for prostatic cancer by digital rectal examinations. Lancet 1991;337:1526–1529. 221. Jacobsen SJ, Bergstralh EJ, Katusic SK, et al. Screening digital rectal examination and prostate cancer mortality: a populationbased case-control study. Urology 1998;52:173–179. 222. Richert-Boe KE, Humphrey LL, Glass AG, Weiss NS. Screening digital rectal examination and prostate cancer mortality: a casecontrol study. J Med Screen 1998;5:99–103. 223. Lu-Yao G, Albertsen PC, Stanford JL, et al. Natural experiment examining impact of aggressive screening and treatment on prostate cancer mortality in two fixed cohorts from Seattle area and Connecticut. BMJ 2002;325:740. 224. Bartsch G, Horninger W, Klocker H, et al. Prostate cancer mortality after introduction of prostate-specific antigen mass screening in the Federal State of Tyrol, Austria. Urology 2001;58:417–424.

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Genetic Screening and Counseling for High-Risk Populations Mary B. Daly

A

s we enter the 21st century, we are witnessing a historic transition in science that will reveal the genetic basis of common medical conditions and have an enormous impact on biology, medicine, health care, and society. The role of genetics in understanding and treating cancer has traditionally been limited to the observation of cytogenetic abnormalities in certain tumor types. With the recent stimulus of the Human Genome Project, new opportunities to define all cancer in genetic terms are emerging. Efforts to characterize the several classes of genes involved in the transformation and growth of cancer cells have not only advanced knowledge of the genetic basis of cancer but also stimulated the development of sophisticated high throughput technologies that open a new generation of opportunities for the next decade of clinical research and application. Molecular genetic analysis will permit the identification of cancer susceptibility patterns decades before the onset of symptoms or the appearance of disease. The impact of this genetic revolution will shape the practice of medicine, and in particular, the practice of oncology, in many ways. The growing appreciation of the molecular basis of carcinogenesis will have clinical applications in understanding cancer etiology and assigning more precise estimates of risk; in tailoring screening and prevention approaches to populations at defined levels of risk; in improving accuracy of diagnosis and prognosis based on molecular profiles; and in the rational design of therapeutic modalities based on molecular targets. Although the grouping of site-specific cancer clusters in some families has been recognized for decades, it was not until the past few decades, with the identification of genes such as BRCA1 and BRCA2, that hereditary patterns of cancer could be definitively linked to discrete germ-line mutations. Although hereditary cancers account for only 10% of all cancers, the identification of these genes and the attention devoted to these discoveries have heightened awareness of the genetic contribution to cancer in general among both the medical profession and the lay community and have provided a means to begin to recognize individuals and families with an increased genetic risk of cancer. Because deleterious mutations in genes associated with hereditary cancer syndromes diagnose a risk for cancer, not the disease itself, knowledge of germ-line cancer susceptibility genes has stimulated intense interest in preventive strategies that may be employed to alter an individual’s risk and

that of his or her family members. Studies are under way to understand the functions of cancer susceptibility genes and how their alteration contributes to carcinogenesis. Gene–gene and gene–environment interactions are being explored to understand the significant variation in penetrance of these genes. This work is likely to elucidate the causal mechanisms of the traditional epidemiologic factors associated with cancer that will have implications for the more common sporadic forms. This chapter explores the application of the rapidly expanding field of genetics to genetic screening and counseling for hereditary cancer syndromes in the clinical setting.

Kinds of Assays One component of the success of the Human Genome Project, in concert with the realization that all diseases have a genetic basis, is the advent of rapid and relatively inexpensive molecular genetic technologies that can be run at high throughput. There are different technologies for different types of mutations, and most are limited to specialized genetic laboratories or cancer research settings. The technologies for detecting mutations in the major cancer susceptibility genes are constantly evolving but can basically be divided into tests of gene function, such as protein truncation tests, gel shift assays, enzymatic mutations screens, and methods to directly sequence the genes. Because many of the genetic mutations associated with cancer syndromes result in premature truncation of the protein product, protein truncation tests have been widely used. This approach uses in vitro transcription and translation to produce a radiolabeled protein. Truncated forms can be detected when electrophoresed against normal controls on an agarose gel.1 Protein truncation tests are misleading when the gene length is normal, but its function is altered, or when the protein products produced by the mutated gene are too small for detection by this method.2 Gel shift assays compare the mobility through a gel matrix of a test DNA sample to that of a control sample. The motility of DNA in a gel matrix is determined by its length, base composition, single- and double-strand characteristics, and double-strand mobility in the presence of mismatched controls. Examples of gel shift assays are single-strand con-

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342 formation polymorphism (SSCP) analysis, denaturing gradient gel electrophoresis (DGGE), heteroduplex analysis (HA), and conformation-sensitive gel electrophoresis (CSGE). Although gel shift assays are relatively easy to perform and inexpensive, their sensitivity is lower than other types of assays, making them less appropriate for clinical genetic testing. Based on the principle that heteroduplexes form between wild-type and mutant genetic sequences, enzymatic mutation detection (EMD) methods use enzymes with high specificity for insertions, deletions, and base–substitution mismatches. Normal and mutant alleles of the target gene are amplified and labeled with fluorescent dyes. The enzyme scans the double-stranded DNA until it detects a structural distortion, where it cleaves the genetic material, forming two shorter, radiolabeled fragments. These products are analyzed on an automated DNA sequencer for relative mobility. EMD is easy to use and highly specific for all types of alterations and has the advantage of detecting multiple sequence variants in the same polymerase chain reaction (PCR) product.2 Direct sequencing of the gene is the gold standard for mutation scanning. All the coding regions, as well as the intron–exon boundaries of a gene, are amplified by PCR and sequenced, either manually or by automated techniques, in 250 to 400 base pairs. This approach is costly and labor intensive. Direct sequencing can miss certain types of mutations or large deletions or can detect mutations of unknown clinical significance. Many of these technical limitations will most likely be eliminated as the technology is improved and as clinical correlations are established for each mutation. Clinicians considering using a genetic testing facility for clinical purposes should consider the quality control circumstances of the testing facility being considered. All laboratories doing clinical genetic testing should be certified by the Clinical Laboratory Improvement Act (CLIA) and the College of American Pathology (CAP). Access to a medical geneticist is helpful to assist in test interpretation for difficult cases.

Hallmarks of Hereditary Cancers A list of known inherited cancer syndromes and their associated genes is shown in Table 25.1.3 This chapter discusses in more detail the hereditary patterns of breast/ovarian cancer, colorectal cancer, and multiple endocrine neoplasias, syndromes for which there are clinically available tests and which comprise a large portion of all hereditary cancer syndromes. The features of a pedigree that characterize hereditary patterns of cancer include early age of onset, high penetrance, bilaterality in paired organs, vertical transmission through either parent, and an association with other cancers.4 The actual prevalence of mutations leading to hereditary cancers varies considerably in the population and is sometimes related to ethnic ancestry. It is known that certain mutations, the “founder mutations,” are more common in families who are all traced to a certain ancestor believed to be the founder of the original mutation. In these cases, knowing the ethnicity of an individual may guide which mutations to explore. Penetrance refers to the proportion of individuals carrying the mutation who actually develop the associated disease(s). The observation that there are mutation carriers

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who never develop disease suggests that there are genetic, metabolic, and/or environmental events that can modify the effect of a mutation. A better understanding of these modifiers is likely to provide opportunities for prevention of the involved disease. There are also emerging data to suggest that the location of the mutation within the gene may influence the type and severity of the disease that is manifest.

Rationale for Genetic Screening Screening for cancer susceptibility genes has the potential to reduce the burden of cancer by providing opportunities for tailored early detection or primary prevention interventions to at-risk individuals. It can also spare those who receive truenegative results the burden of unnecessary screening and prevention procedures. The success of this approach is dependent upon the availability of surveillance measures and preventive strategies with documented efficacy and limited risk. The widespread clinical application of genetic testing, however, also poses specific challenges, including the implications for other family members who may not be involved or interested in the receipt of genetic risk information, the consequences of labeling healthy individuals with a disease predisposition, and the profound social and cultural significance awarded to genetic traits. Our understanding of the genetic basis of disease, and the rapid evolution in the science of human genetics, is moving at such a pace as to challenge the ability of both families and medical professionals to process and communicate the information becoming available. Several advisory bodies have issued guidelines for the application of genetic testing for cancer susceptibility to the clinical setting. In a statement adopted on March 1, 2003, the American Society of Clinical Oncology (ASCO) reaffirmed its commitment to the integration of cancer risk assessment and management into the practice of oncology. In this update of earlier guidelines, the society set forth a set of indications for clinical genetic testing, recommendations for counseling to accompany genetic testing, and a commitment to maintaining confidentiality of genetic information. At the same time, ASCO underscored the responsibility of the patient to communicate genetic test results to other family members. The ASCO statement supports the establishment of federal legislation to prevent discrimination on the basis of genetic status and urged public and private health insurance providers to cover genetic testing and counseling services. ASCO maintains its commitment to providing educational opportunities in genetics for healthcare providers.5 The American Society of Human Genetics (ASHG) also stated the importance of public and professional education to develop a responsible approach to genetic testing and supported the need for further research to determine optimal preventive strategies for individuals with a genetic predisposition to cancer.6 A position paper from the National Society of Genetic Counselors (NSGC) spells out in detail the components of the genetic testing process and stresses the need for a multidisciplinary approach, including genetic counselors, physicians, nurses, social workers, and behavioral scientists.7 As this field is moving so quickly, these recommendations continue to evolve, but constant is the need to protect the health and well-being of genetically susceptible individuals.

g e n e t i c s c r e e n i n g a n d c o u n s e l i n g f o r h i g h - r i s k p o p u l at i o n s

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TABLE 25.1. Inherited cancer syndromes for which clinical testing is available. Syndrome

Involved gene(s)

Associated cancers

Beckwith–Wiedemann syndrome

BWS critical region 11p15 Genes involved: KCNQ1OT1 IGF2 H19 CDKN2C BLM (RECQL3) at 15q26.1 BRCA1 at 17q21, BRCA2 at 13q12 PTEN at 10q23 APC at 5q21

Embryonal tumors, Wilms’ tumor, adrenocortical carcinoma, hepatoblastoma, rhabdomyosarcoma, neuroblastoma, gastric teratoma

Bloom syndrome Breast ovarian cancer (BOC) syndrome Cowden syndrome Familial adenomatous polyposis (FAP) Fanconi anemia

Hereditary nonpolyposis colon cancer Li–Fraumeni syndrome Familial melanoma Multiple colorectal adenomas Multiple endocrine neoplasia type 1 (MEN-1) Multiple endocrine neoplasia type 2 (MEN-2) Neurofibromatosis type 1 Neurofibromatosis type 2 Nevoid basal cell syndrome (Gorlin syndrome) Peutz–Jeghers syndrome Retinoblastoma syndrome Tuberous sclerosis Von Hippel–Lindau syndrome Down’s syndrome Klinefelter syndrome Turner syndrome

Leukemia, lymphoma, aerodigestive tract, skin, breast, cervix Breast, ovary, prostate, pancreas Breast, uterus, thyroid, kidney, melanoma, glioblastoma Colorectal, upper digestive tract, thyroid, hepatoblastoma

FANCA at 16q24.3 FANCC at 9q22.3 FANCD2 at 3p25.3 FANCF at 11p15 FANCG at 9p13 FANCE at 6p22 BRCA2 at 13q12.3 MSH2 at 2p22, MLH1 at 3p21, PMS1 at 2q31, PMS2 at 7p22, MSH6 at 2p16 TP53 at 17p13.1 CMM1 at 1p36, TP16 at 9p21, CDK4 at 12q14 MYH, 1p34

Multiple colorectal adenomas (15–100), autosomal recessive

MEN1 at 11q13

Parathyroid, pancreatic islet, and pituitary cancers

RET at 10q11.2

Medullary thyroid cancer, pheochromocytoma, benign parathyroid tumors Optic glioma, neurofibrosarcoma Meningioma, astrocytoma, acoustic neuroma, spinal schwannoma, ependymoma, neurofibroma Basal cell cancer, ovarian fibroma, medulloblastoma

NF1 at 17q11.2 NF2 at 22q12 PTC at 9q22.3 STK11 at 19p13.3 RB1 at 13q14.1

Leukemia, squamous cell cancers, hepatocellular, brain tumors

Colorectal cancer, endometrial, ovarian, gastric, small intestine, ureter and kidney cancers Sarcoma, breast cancer, leukemia, adrenocortical cancer, brain tumor Multiple melanomas

Colon, breast, pancreas, uterus, lung, testis, and ovarian cancer Retinoblastoma, osteosarcoma, Ewing sarcoma, leukemia, lymphoma, melanoma, lung and bladder cancer Childhood brain tumors, Wilms’ tumor, renal cell cancer

TSC1 at 9q34, TSC2 at 16p13.3 VHL at 3p25

Renal cell cancer, pheochromocytoma, hemangiomas

Trisomy 21 47XXY

Leukemia Male germ cell and breast cancer

45X

Wilms’ tumor, neurogenic tumors, uterine tumor, leukemia, and gonadal tumors

Source: Data from Schneider.3

Ethical, Legal, and Social Issues The exciting potential of the work emanating from the Human Genome Project has led to unbounded enthusiasm about our ability to affect the health of the population through population screening for genetic cancer predisposition, through a more sophisticated understanding of the molecular profile of the cancer phenotype, and through new gene-targeted drug development. However, the recent expan-

sion of technology into the field of medical genetics has outstripped our ability to conceptualize the ethical and moral dimensions of the application of molecular genetics to the clinical setting of oncology. There are outstanding ethical issues that concern patients and their families, the healthcare profession, and society at large. Most of the ethical debate for the public has centered on the ability to genetically characterize individuals for inherited cancer susceptibility syndromes. Limitations of test

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accuracy and the relative uncertainties about effective preventive strategies for those who test positive have led many to advise caution about the widespread adoption of genetic testing in the clinical setting. In fact, concern about the potential adverse consequences of genetic testing for cancer susceptibility has led to the view that genetic information is qualitatively different from other medical information because of its potential to be used in a discriminatory manner and its unique implications for family members. The public has expressed concern that the explosion of genetic information may result in an environment in which people will be labeled and disadvantaged in the workplace and in their ability to obtain insurance based on genetic information. In fact, the most common reason cited for not considering genetic testing for mutations in the BRCA1/2 genes is fear of insurance discrimination.8 Legislation for protection against discrimination based on genetic test results is incomplete and has not been thoroughly challenged in the court system. Responsibility to other family members is another concern voiced by individuals who undergo genetic testing. Privacy and confidentiality issues place the burden of communicating genetic test results with the proband, who may not have a sophisticated medical background and who may face difficult family dynamics in the communication process. The application of the new genetics to the diagnosis, characterization, and treatment of cancer has not generated as much concern and attention among cancer patients, who are often overwhelmed by their situation and the details of the treatments proposed to them. A good example of this is the increasing use of microsatellite instability (MSI) testing of colon tumors in the clinical setting without full disclosure to the patient that the testing may uncover a hereditary cancer syndrome in their family. The promise of the new genetic technologies is emerging at a time when healthcare resources are shrinking and when access to care is not shared by all members of society. Although advances in technology will most likely lead to more cost-effective assays, the costs will still put a significant strain on the healthcare budget. Disparities in cancer care will grow as more advanced technologies are introduced into the treatment setting. The role of insurance companies in providing coverage for these new costs is unclear. The magnitude of insurance and/or employment risks from discrimination on the basis of genetic risk information is also a major concern for state and federal government agencies and the insurance industry.

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There has been considerable debate about the issue of “genetic exceptionalism,” that is, whether genetic testing is sufficiently different from other types of medical tests to warrant special considerations. Because of some of the unique aspects of genetic information, the standard of care has evolved to obtain formal informed consent for the conduct of a specific genetic test, even when done strictly for clinical management and not in the context of research. Unique components of the consent process are the acknowledgment of potential social and family implications of the test results, including the potential for discrimination based on genetic risk status, the symbolic meaning of heritage in our culture, the probabilistic nature of the test results, and the potential for lifetime classification of an individual as “at risk.”9,10 Suggested components of the informed consent process are shown in Table 25.2. This process should take into account the participant’s prior experiences, beliefs, attitudes, concerns, expectations, and motivations concerning genetic risk and should be handled with attention to confidentiality and the needs of other family members. One special circumstance is the issue of genetic testing of children and adolescents. The ASHG and the American College of Medical Genetics, as well as ASCO, have suggested a series of points to consider in confronting this situation. The primary indication for genetic testing of a minor should be the provision of timely medical benefit. If the cancer occurs predominantly in childhood and risk reduction strategies and therapies are available, such as medullary thyroid cancer, there is justification for testing. Psychosocial benefits to competent adolescents, including reduction of uncertainty and anxiety, and contribution to life decisions may also be an indication. For those diseases, such as adult-onset cancers for which the medical and/or psychosocial benefits will not occur until adulthood, genetic testing should generally be deferred. The involvement and preparation of the family should be an integral part of this process. It is the responsibility of the provider to weigh the interests of the children and their families in their delivery of responsible genetic services.5,11 The ability to characterize individuals genetically facilitates the application of this technology on a global scale and, in addition to creating typologies of cancer susceptibility in the population, will permit the molecular definition of ancestry, ethnicity, intelligence, and other human features with the potential for misuse. All these issues call for public education about the issues the genetic revolution is raising and a general discourse on the use of genetics in the oncology setting.

TABLE 25.2. Components of informed consent for genetic testing. Purpose of the test Practical aspects of the test Interpretation of results Potential risks Potential benefits Privacy and confidentiality Alternatives

The purpose of the genetic test must be clearly described. Amount of blood to be drawn, length of time to receive results, other information to be collected, cost of testing, and a contact person should be included. The potential types of test results should be clarified, including true-positive, true-negative, indeterminant, and inconclusive results. Risks to be described are psychosocial, threats to family dynamics and health, and insurance discrimination. The use of genetic test information may provide both psychologic benefit as well as guidance in medical management interventions. Measures used to assure privacy and confidentiality of the test results should be described. A description of alternatives to genetic testing, including risk assessment based on clinical history, should be provided.

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Education of the Healthcare Providers As the genetic contribution to cancer continues to evolve, primary care providers will assume a more pivotal role in the provision of clinical genetic services, including providing education to patients and their families about genetic information in general, genetic testing in particular, and the use of genetic technologies in cancer risk reduction surveillance, diagnosis, and treatment. The involvement of the entire healthcare team will be critical to assess the outcomes of family decisions regarding genetic information and to guide individuals and their families through the complex world of cancer genetics. There are data to suggest, however, that among members of the healthcare profession, knowledge regarding the criteria for hereditary cancer syndromes, the indications for associated genetic testing, and the role that molecular genetics plays in the prevention, diagnosis, and treatment of cancer is limited. A nationally representative random sample of physicians in primary and tertiary care specialties found that fewer than one-third of physicians had recommended cancer genetic testing to a patient. Barriers to the use of genetic tests in their patient populations included lack of confidence in their ability to recommend testing and lack of access to counseling and testing services.12 Healthcare providers are often at a loss about how to understand and communicate genetic test results to individuals, about what is their responsibility to inform other at-risk relatives of their potential genetic risk, and about how to assure confidentiality and privacy of genetic information in the medical record system. Limited physician knowledge of genetics may pose a barrier to the referral of appropriate candidates for genetic testing and the standard utilization of genetic predictive testing in clinical practice for increased cancer surveillance, screening, and prevention. Based on the potential for identification, classification, prevention, and treatment for a wide variety of cancer types, physicians and other healthcare providers and their patients would greatly benefit from training in interpretation and use of genetic predisposition testing as part of their clinical practice.

Genetic Counseling The development of technology to locate and isolate cancer susceptibility genes has brought together the fields of oncology, cancer control, genetics, and genetic counseling to create a new specialty of cancer risk counseling whose goal is to communicate more accurate information about personal cancer risk profiles based on personal and family histories.13 The field of genetic counseling has evolved and plays a growing role in the evaluation and risk estimation of families with known or suspected genetic conditions. The traditional elements of genetic counseling have included (1) an accurate diagnosis of the genetic condition or predisposition; (2) an estimate of the probable cause of the disorder; (3) an estimation of risk of future occurrences of the condition within the family based on the pattern of inheritance of the disease; (4) communication of an understanding of the genetic and medical facts of the disorder; (5) an exploration of appropriate courses of action to manage the genetic risk and to alter the risk of occurrence; and (6) ways of coping with the disorder or risk of the disorder.14,15 Building on this tradition, cancer risk counseling is an interactive education and communica-

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TABLE 25.3. Basic elements of cancer genetic counseling. • Documentation of extended family medical history • Development of a family pedigree • Collection of medical records from proband and appropriate family members • Collection of information about other risk factors (biologic, environmental, lifestyle) • Careful assessment of risk • Education about cancer, genetics, and preventive options • Communication of risk estimate in clear and simple language • Development of individualized prevention and surveillance strategy • Attention to emotional and social needs and concerns of proband and family • Long-term follow-up and support

tion process whose purpose is to evaluate an individual’s potential risk of developing specific forms of cancer based on inherited susceptibilities, physiologic modulators, and lifestyle and environmental factors that contribute to cancer risk and to communicate this information in a comprehensible and sensitive way (Table 25.3). Familial cancer risk counseling uses a broad approach to place genetic risk in the context of other related risk factors, thereby customizing it to the experiences of the individual. In addition to addressing genetic risk and the clinical management of that risk, cancer risk counseling also considers the psychosocial needs of the individual and the family. Typically, the process involves the collection of pertinent medical, familial, and lifestyle information, the documentation of cancer diagnoses, the delivery of background information about cancer risks and cancer genetics, the identification of specific hereditary cancer syndromes, and the transmission of personalized risk estimates.16 The ultimate goal of the education and communication process is to help the individual and other family members make informed and appropriate decisions about genetic testing options and strategies for cancer prevention and/or early detection. Genetic counseling for genetic cancer risk represents a new direction in genetics and has raised some particularly interesting and difficult issues. Risk estimates for cancer may be either empirical or based on actual gene identification but are typically complex and sophisticated, challenging the communication skills of the counseling team. The nature of the counseling situation often requires the involvement of other family members to supply missing information or even for genetic screening, a situation that may compromise privacy and confidentiality within the family. The options offered by the counseling team, including genetic testing, may involve emotional and ethical dilemmas for which there are no clear answers. Despite these problematic issues, cancer risk counseling is a growing field that has tremendous potential to assist families in understanding their risk for cancer and in making informed choices for prevention.

Components of a Counseling Program Target Population Individuals who seek cancer risk counseling are often highly motivated by a personal experience with cancer in their family

346 and by concern for the risks faced by themselves and their offspring. Participants in cancer risk counseling are often selfreferred, but as physicians become more aware of the importance of family history in determining an individual’s risk for cancer, they are increasingly referring their patients for genetic evaluation. Although the general indication for participation in a cancer risk counseling program is a perception of increased risk for cancer based on family history and/or other recognized risk exposures, individual participants come to the process with a wide variety of experiences, health beliefs, expectations, and needs. An assessment of individual differences that can influence comprehension and compliance with appropriate health recommendations, therefore, is one of the primary goals of the counseling team.

The Counseling Team Traditionally, the medical genetics counseling team has included a medical geneticist, a genetic counselor, and often the referring primary care physician, usually an obstetrician or pediatrician. Genetic counselors typically earn a Master of Science degree at an accredited institution and are certified by the American Board of Genetic Counselors. Dedicated training in the field of cancer genetics has recently been added to the curricula of genetic counseling education programs. There is also a growing interest in genetics on the part of nurses, many of whom are beginning to seek specialized training in the field. As the field of genetic counseling has expanded to include adult diseases such as cancer, other disciplines, including oncology, molecular genetics, social work, and psychology have joined the team to provide the multidisciplinary approach needed. Originally, cancer risk counseling programs were mainly situated in cancer centers and academic institutions, but increasingly these services are expanding to community hospitals, worksites, and health centers where they are often one component of a more broadly based health promotion program.

Information Collection The very first step in evaluating an individual’s risk for cancer is to assess the individual’s concerns and reasons for seeking counseling to guarantee that personal needs and priorities will be met in the counseling process. The next step is to collect the pertinent medical, family, and personal information to assemble a risk profile and begin to explore options for dealing with the risk. A detailed family history is the cornerstone of effective genetic counseling. The counselor begins with the health of the proband and proceeds outward to include first-, second-, and third-degree relatives on both the maternal and paternal side. In addition to cancer diagnoses by primary site, age at onset, bilaterality when appropriate, and current age or age at death are recorded. Cancer diagnoses are validated by obtaining medical records, pathology reports, or death certificates when possible. Other medical and genetic conditions that may predispose individuals to cancer risk (e.g., Crohn’s disease and colon cancer, atypical ductal hyperplasia, and breast cancer) should also be noted. It is important to include information about family members unaffected with cancer to appreciate the penetrance of the disease and overall patterns of inheritance. Information about possible consanguinity is also valuable, particularly in the considera-

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FIGURE 25.1. Sample pedigree with standard nomenclature to illustrate family relationships and disease information.

tion of recessive disorders. Ancestry and ethnicity should be recorded, as some inherited conditions are more common in certain ethnic groups (founder effects). Family history data are graphically represented on a pedigree, which follows standard nomenclature to illustrate family relationships and disease information17 (Figure 25.1). Factors that limit the informativeness of the pedigree are small family size, early deaths in family members precluding the possibility of developing adult diseases, prophylactic surgeries that remove an organ from subsequent risk of cancer (e.g., total hysterectomy for uterine fibroids where the ovaries are also removed), and incomplete information about the health of family members. The degree of accuracy of reporting cancer diagnoses in relatives varies by how close the relatives are to the proband, with lack of information about specific cancer diagnoses in older second and/or third generations being a particularly common problem encountered in pedigree generation. The collection of a targeted medical history of the proband serves two purposes: (1) the identification of premalignant conditions associated with subsequent cancer progression and (2) the estimation of other risk factors that may interact with or modify familial cancer risk. A careful reproductive history is pertinent to a number of common cancers in women. Exogenous hormone use and other medication history is also of value. The knowledge of other medical conditions may affect the management recommendations for reducing cancer risk. Caution about the use of exogenous estrogens in women with a familial predisposition of breast cancer, for example, may be tempered by a strong personal or family history of osteoporosis. Environmental exposures and lifestyle factors, such as smoking, diet and alcohol use, and type of occupation may contribute to the overall estimation of risk, and their identification may offer opportunities for lifestyle changes to alter risk. Although occupational exposures to carcinogens such as benzene or asbestos account for a relatively small proportion of cancer, their recognition is very important in elucidating patterns of cancer and in eliminating other causes among exposed individuals. Environmental exposures and lifestyles are often shared by family members and must be recognized when assessing hereditary patterns of cancer. Finally, a record of past cancer screening practices establishes a history of health promotion behavior and will help guide the counselor in making reasonable and appropriate health recommendations.

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The Education Component

The Role of Genes in Cancer Development

Genetic risk information cannot be effectively communicated in the absence of general information about cancer risk, cancer genetics, and risk estimation. Individuals faced with a familial risk of cancer must assimilate complex and often highly technical information to make informed decisions about genetic testing, cancer screening, and preventive actions for themselves and to communicate that information to other family members. An integral part of the genetic counseling process is an educational preparation, provided either in a group or individual setting, to help the proband develop the understanding necessary to make informed decisions about his or her cancer risk. The basic educational components of cancer risk information include the following.

The counselor introduces the concepts and language of chromosomes, genes, DNA, and how genetic alterations can lead to cancer. It is particularly important for the proband to understand the difference between the acquisition of genetic alterations during his/her lifetime that may affect his/her risk for cancer, and the inheritance of cancer-related genetic alterations from a parent, which can also be passed on to his/her offspring. Within this context, the counselor can introduce information about the recently identified cancer susceptibility genes, such as BRCA1, BRCA2, APC, the hereditary nonpolyposis colorectal cancer (HNPCC) genes, etc., and the cancer syndromes associated with each, with an emphasis on those syndromes that appear to be most consistent with the proband’s family history. The educational component of cancer risk counseling is meant to be interactive with ample opportunity for the proband to ask questions and to tailor the information to the needs of the individual.

The Concepts of Cancer and Cancer Risk Factors The multifactorial nature of cancer is explored with an emphasis on the pathways of cancer formation and expression. Persons seeking counseling who are affected with cancer may be particularly interested in information about the presentation, diagnosis, and treatment of cancer. The basics of cancer epidemiology can be presented, and examples, such as the importance of hormonal regulation in breast cancer and the importance of diet in colon cancer, can be used to illustrate the role of both external factors and internal metabolism in changing normal cells to premalignant and malignant tissue.

The Role of Family History in Cancer Risk Assessment The interaction of shared environmental and genetic backgrounds among family members in determining risk is explored. Sample pedigrees can be used to illustrate the types of family cancer patterns (Table 25.4), and to demonstrate the concepts of vertical transmission through maternal or paternal lines, the significance of age at onset, and bilaterality of disease and penetrance issues. With this background, the counselor can then review the proband’s own pedigree for the patterns expressed and for the identification of pertinent risk factors.

TABLE 25.4. Family cancer patterns. Sporadic: A single occurrence of a cancer occurring on one side of the family. Familial: A pattern of cancers on one side of the family, seen in one or more generations, that does not fit an autosomal dominant pattern of inheritance of cancer. The cancers on that side of the family do not fit a known cancer family syndrome. The pattern seen may represent a clustering of incidental cancers or may be the result of shared environmental or lifestyle factors. Hereditary: A pattern of cancers on one side of the family, seen in two or more generations, in several members of the family, that fits an autosomal dominant pattern of cancers. The cancers on that side of the family may fit a known cancer family syndrome: OR Genetic testing performed on the proband or the proband’s family member has detected a mutation in a cancer predisposition gene (e.g., BRCA1) and inheritance of this mutation has been established.

The Assignment of Risk Cancer risk assessment is an attempt to quantify the probability of an individual’s risk for a particular cancer using empirical models that account for a variety of personal, familial, and environmental risk factors. It is a complex process, both because it is based on imperfect and often conflicting data and because it involves probabilistic statements about the chance of an event occurring, concepts that are difficult to convey and to understand. The concept of risk can be presented in a variety of ways, each of which has a different interpretation. Absolute risk refers to the rate of cancer occurrence in the population and often serves as the background risk to which individuals compare themselves. Relative risk is the comparison of risk in an individual with a particular set of risk factors at a particular point in time to that of an individual without those risk factors, thus implying some magnitude of vulnerability.18 Cumulative risk is the risk over a defined time period calculated by accumulating relative risks over time. Cancer risk counselors attempt to place the proband’s risk of cancer within the context of population risk, both in quantitative and qualitative terms, to provide a rationale for recommended health behaviors. The majority of families do not exhibit the features of hereditary cancer syndromes but rather represent the effect of a combination of multiple genetic and environmental factors that interact to increase cancer risk to a moderate degree. For these families, counselors often use empirical approaches based on epidemiologic data that provide age-specific risks of cancer in tabular formats which can incorporate several pertinent risk factors. For some cancers, these empirical data have actually been integrated into mathematical models that can predict cumulative risk estimates of developing a cancer over a defined time period in an individual’s lifetime. The Gail model, for example, predicts breast cancer risk from age 20 to 80 years, using a model that includes current age, age at menarche, age at first live birth, number of first-degree relatives with breast cancer, and number of breast biopsies.19 It has recently been validated by the Breast Cancer Prevention Trial20 and is most accurate in predicting breast cancer among women who are being screened with regular mammograms.21 This model is now available from the National Cancer Institute on a floppy

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disk, the “Risk Disc,” that can easily be used in the clinical setting. For families in whom a hereditary pattern of cancer is suspected, the recent cloning of rare but highly penetrant cancer susceptibility genes, such as BRCA1 and BRCA2, has made available the direct assessment of mutation status, thus obviating the need for empirical risk models. Other parameters, such as the Amsterdam Criteria and the Bethesda Guidelines for HNPCC,22,23 have been established to identify families who are candidates for genetic testing. In addition to these sets of criteria, mathematical models are appearing that, based on features of the family history, predict the likelihood of being a mutation carrier and help the counselor and clinician further refine genetic testing decisions.24,25 BRCAPRO is a statistical model based on published estimates of penetrance that uses information on personal and familial cancer status to calculate an individual’s probability of carrying a deleterious mutation on BRCA1 or BRCA and is used in the clinical setting to guide decisions about whether to undergo genetic testing.26

Genetic Testing: Interpretation of Test Results Genetic testing for cancer and its role, benefits, and limitations are discussed in the counseling session both in terms of the scientific merits of understanding the genetic basis of cancer and, when appropriate, as it may apply to further characterizing the cancer risk within the proband’s family. When possible, it is best to first consider testing an affected family member who meets the criteria for a hereditary cancer, as that individual is the one most likely to test positive. When a mutation is found, additional family members can be tested with an assay that specifically tests for that particular mutation. There are four possible interpretations of a genetic test result (Table 25.5). If a known risk-associated mutation is found within a family, those family members who test positive for the mutation are considered “true positives.” They are counseled that they are at increased risk for a spectrum of cancers, and options for risk management are discussed (see following). It must be emphasized that a positive mutation result is not a positive cancer test but rather a susceptibility estimate. A positive test result does, however, confirm a 50% chance of passing on the mutation to each biologic child of the carrier. A second outcome of a positive test result is the discovery of a variant of the gene of unknown clinical significance. These genes are truly altered but have not yet been clearly linked to disease risk and may represent neutral alter-

TABLE 25.5. Genetic test results. True positive True negative

Indeterminant

Inconclusive

The person is a carrier of an alteration in a known cancer-predisposing gene. A person is not a carrier of a known cancerpredisposing gene that has been positively identified in another family member. A person is not a carrier of a known cancerpredisposing gene and the carrier status of other family members is either also negative or is unknown. A person is a carrier of an alteration in a gene that currently has no known significance.

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ations in the gene structure that do not compromise its function. Over time, as more families are studied, most of these variants most likely can be separated into disease-related changes and benign changes, known as polymorphisms. Until then, families found to carry one of these variants must be counseled about the uncertain meaning of the result, and recommendations will be based on their family and personal history of disease. When a disease-related mutation has been identified in a family, subsequent family members who test negative for that mutation are thought to be “true negatives” whose risks for the relevant cancers are not increased over those of the general population. These family members may be spared the increased surveillance and/or consideration of prophylactic surgery offered to carriers. They can also be reassured that they will not pass on the deleterious mutation to their offspring. Finally, when no mutation is found in any family member (which is the most common situation), the meaning of a negative test result is ambiguous. It may mean that there truly is no mutation in the family and that the family history represents a clustering of sporadic cancers, it may mean a known disease-related mutation does exist in the family but no informative family members were available for testing, or it may mean that a mutation exists but cannot be detected by current technology. Again, counseling must emphasize the ambiguous nature of the test results. These families may still face a significantly increased risk of cancer and management should be based on other factors. A clear distinction is made between the probability of being a mutation carrier and the probability of developing cancer. Estimates of penetrance of the gene, that is, the chance that a mutation will actually result in cancer in a person, are also typically derived from small studies among narrowly defined families and are difficult to apply to any particular individual unless he or she matches the characteristics of the families studied. Information on other factors that may modify gene expression is rudimentary at this point for most of the genes identified.

Psychosocial Support Just as important as a careful risk factor analysis and interpretation of risk to family members is attention to the psychosocial issues raised by the enhanced risk and the emotional needs of those involved.27 This consideration is especially critical in the setting of counseling for cancer risk, which deals with the complexity of probabilities, which involves the entire family, and which may provide risk information that can become a source of discrimination. Cancer is one of the most feared diseases of modern times. Cultural beliefs about cancer, painful memories of relatives’ experiences with cancer, high levels of mental stress associated with cancer-related anxiety, unresolved grief, feelings of denial, guilt, and other family dynamics can all interfere with the receipt and understanding of risk information and with the formulation of strategies for risk reduction and can have a negative impact on quality of life. Both the information received during the process of genetic counseling and the information-seeking coping style of the individual may elicit further emotional reactions, especially if the counseling involves the receipt of genetic test results. The counselor takes an active role in helping the counselee identify his/her risk status, confront fears and anxieties about the meaning of

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that risk, develop coping strategies to deal with both the emotional and medical components of his/her unique situation and coping style, and facilitate decision making. The counselor can also assist the counselee in communicating cancer risk information to other family members, in dealing with their potential reactions, and in enrolling them in a counseling program. Follow-up genetic counseling sessions have been found to reinforce the information communicated in the original sessions, to solidify decisions made, to assess adjustment to risk status, and to make referrals for specialty consultations if needed.28

General Management Strategies One of the primary motivations for seeking cancer risk counseling is to identify ways to reduce or delay the risk of developing cancer or to enhance the possibility of detecting cancer at an early, curable stage. Individuals who seek these services clearly want recommendations for the medical management of their risk from their providers. By achieving a reliable estimate of cancer risk, either by considering personal and family history or by performing genetic testing, the cancer risk counselor, working with the medical team, can help to tailor primary and secondary prevention strategies to the individual. Although there are presently limited data on the longterm efficacy of prevention strategies directed at individuals with a familial or hereditary risk, clinical management decisions are being made based on the best available evidence. Recommendations fall into four general categories: increased screening, pharmacologic interventions (chemoprevention), surgical prophylaxis, and lifestyle changes. Screening recommendations are problematic for cancers, such as ovarian and pancreatic cancer, for which no early detection method has been found to be sufficiently sensitive and specific, and for situations such as the Li–Fraumeni syndrome, in which individuals are at risk for a wide spectrum of cancers during their lifetime. On the other hand, members of high-risk families are ideal candidates to participate in trials of newer imaging technologies and intermediate biomarkers to improve the early detection of cancer in younger individuals. There is intense interest on the part of high-risk individuals to learn about opportunities to reduce their cancer risk by changes in diet, exercise, or other lifestyle modifications that may minimize their exposure to carcinogens. Preliminary data suggest, for instance, that the use of exogenous estrogens, including oral contraceptives and estrogen replacement, may confer an increased risk for breast cancer among women with a hereditary predisposition29 and that limiting exposure to these agents may be beneficial. The exact role of diet and exercise remains elusive for most cancers, although recommendations can be made on the basis of general health and ideal weight maintenance. Dietary supplementation with micronutrients and other natural products to reduce cancer risk is so far unsupported by scientific data. Long-term studies are needed to assess the role of any of these strategies in the setting of familial risk for cancer. (See following for specific management options.) It is important that clinicians play an active role, in partnership with the genetic counselors, in the counseling of individuals predisposed to familial cancers to review current medical management strategies and to tailor recommendations to the unique needs of each individual.

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Effectiveness of Cancer Risk Counseling Several studies have attempted to assess the effectiveness and efficacy of genetic counseling and have identified a number of common predictors of response. Utilization of genetic counseling services is associated with higher socioeconomic status and educational level and, in the setting of prenatal genetic conditions, with intention to have children.30 Understanding and retention of the information received have been found to be higher among individuals who are self-referred, those with higher educational levels, and among those families at the higher risk levels. Multiple counseling sessions have been shown to boost understanding and information retention.31 Another consistent observation has been that, although it is important, the information obtained at a genetic counseling session is not the only factor contributing to risk-related decisions. Rather, perception of risk is a concept formed over a person’s lifetime and is a result of internalizing personal experiences and beliefs. Decisions made in the genetic counseling setting, therefore, reflect a complicated interplay of expectations, emotions, and value judgments. As a result, the genetic counselor is likely to be most successful when the information shared during genetic counseling is provided in the context of the counselee’s personal orientation and belief system.

Risk Management for Hereditary Cancer Syndromes Hereditary Breast/Ovarian Cancer Approximately 5% to 10% of all breast cancer demonstrates an autosomal dominant pattern of inheritance. Hereditary breast cancer is characterized by early age at onset (5 to 15 years earlier than sporadic cases), bilaterality, vertical transmission through both maternal and paternal lines, and association with tumors of other organs, particularly the ovary and prostate gland.4,32,33 Syndromes most often associated with hereditary breast cancer are the hereditary breast ovarian cancer (HBOC) syndrome associated with mutations in the BRCA1 and BRCA2 genes, the Li–Fraumeni syndrome associated with p53 mutations, and Cowden’s syndrome associated with mutations in PTEN. The clinical evidence of an autosomal dominant inherited predisposition to breast cancer was originally supported by segregation analysis, a quantitative method to determine if a particular trait is distributed in the population in a Mendelian manner of inheritance. Applied to the CASH data set, segregation analysis and goodness-offit tests of genetic models provided evidence for the existence of a rare autosomal dominant allele associated with increased susceptibility to breast cancer.34 In 1990, a susceptibility gene for breast cancer was mapped by genetic linkage to the long arm of chromosome 17, in the interval 17q12–21.35 The linkage between breast cancer and genetic markers on chromosome 17q was soon confirmed by others, and evidence for the coincident transmission of both breast and ovarian cancer susceptibility in linked families was observed.4 The BRCA1 gene was subsequently identified by positional cloning methods and has been found to encode a protein of 1,863 amino acids. This susceptibility gene appears to be responsible for disease in 45%

350 of families with multiple cases of breast cancer only and up to 90% of families with both breast and ovarian cancer.36 A second breast cancer susceptibility gene, BRCA2, was localized through linkage studies of 15 families with multiple cases of breast cancer to the long arm of chromosome 13. Germ-line mutations in BRCA2 are thought to account for approximately 35% of multiple case breast cancer families and are also associated with male breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer.37,38 The risk for breast cancer in female BRCA2 mutation carriers appears similar to that for BRCA1 carriers, but the age of onset is shifted to an older age distribution.39 Of the several hundred mutations described in these genes, most lead to a frame shift resulting in missing or nonfunctional proteins.40 In addition, tumors from individuals with BRCA1/2 mutations show deletion of the wild-type allele, supporting speculation that these genes play a role in tumor suppression. Both BRCA1 and BRCA2 also are involved in the control of meiotic and mitotic recombination and in the maintenance of genomic stability, suggesting an additional role in the DNA repair process.41–43 The growing body of data elucidating the functions of these genes suggests a gatekeeper role, characterized by interactions with other genes in the regulation of the cell cycle and DNA repair, which may provide novel opportunities to develop genotypebased therapeutic approaches to treatment and prevention. Although sporadic mutations of BRCA1/2 are rarely described, inactivation or decreased expression of these genes by epigenetic phenomena, such as hypermethylation, may account for some cases of breast and ovarian cancer in the population.44 The frequency of mutations in BRCA1 in the general population has been estimated to be 0.0006, which corresponds to a carrier frequency of 1 in 800. Carrier rates are not distributed evenly, however, and tend to concentrate in families with multiple cases of breast and/or breast/ovarian cancer. BRCA1 and BRCA2 also demonstrate differential prevalence rates in certain ethnic groups. Most notably, in the United States, three specific founder mutations, the 185delAG mutation and the 5382insC mutation on BRCA1 and the 6174delT mutation on BRCA2, have been found to be common in Ashkenazi Jews. The frequency of these three mutations approximates 1 in 40 in this population and accounts for up to 25% of early-onset breast cancer and up to 90% of families with both breast and ovarian cancer.45 Additional founder effects have been described in the Netherlands (BRCA1 2804 delAA and several large deletion mutations), in Iceland (BRCA2 995 del5), and Sweden (BRCA1 3171 ins5).46–49 The actual expression of disease in gene mutation carriers is estimated to range from 36% to 85% for breast cancer and from 16% to 60% for ovarian cancer. Male carriers of BRCA mutations are also at increased risk for breast cancer, with lifetime estimates of approximately 6%.50,51 Among female BRCA1 carriers who have already developed a primary breast cancer, estimates for a second contralateral breast cancer are as high as 64% by age 70 and for ovarian cancer as high as 44% by age 70.52 It is not generally known whether the specific location of mutations confer differential rates of penetrance, or what other genetic and/or environmental or lifestyle factors may interact with the presence of a mutation to determine expressivity. One region of BRCA2, however, the “ovarian cancer cluster region” in exon 11, appears to be

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associated with an increased risk of ovarian cancer and decreased risk of breast cancer.53 Ongoing studies are addressing the role of reproductive factors, endogenous and exogenous hormone exposure, diet, and lifestyle factors in the modulation of risk among carriers. The clinical presentation of BRCA1/2-associated breast cancer indicates distinctive pathologic features. Historically, medullary, tubular, and lobular histologic findings and improved survival have been associated with familial breast cancer.54 The Breast Cancer Linkage Consortium examined histopathologic features of breast cancer in women with BRCA1/2 mutations and, when compared to controls, they showed an excess of high-grade tumors in BRCA1 carriers and a relative lack of in situ component adjacent to invasive lesions.55 High mitotic and total grade, as well as higher rates of aneuploidy, estrogen receptor (ER) negativity, and high proliferative fractions were also reported for BRCA1 carriers in kindreds followed by Henry Lynch, who also noted higher rates of medullary histology.56 The phenotype for BRCA2related tumors appears to be more heterogeneous and may include an excess of lobular histology.57 Recently, differential gene expression profiles have been described for BRCA1, BRCA2, and sporadic breast cancers, suggesting functional differences in tumors depending on their genetic characterization.58 In accordance with the poor prognostic features noted histologically for BRCA1-related breast cancer, two European studies recently reported survival rates that were similar to or worse than sporadic cases, with a significantly increased risk of contralateral breast cancer.59,60 Breast cancer is also a component of the rare Li–Fraumeni syndrome in which germ-line mutations of the p53 gene on chromosome 17p have been documented.61 First reported by Bottomley et al.,62 this syndrome is characterized by premenopausal breast cancer in combination with childhood sarcoma, brain tumors, leukemia and lymphoma, and adrenocortical carcinoma. A germ-line mutation in the p53 gene has been identified in more than 50% of families exhibiting this syndrome, and inheritance is autosomal dominant with a penetrance of at least 50% by age 50. Although highly penetrant, the Li–Fraumeni gene is thought to account for less than 1% of breast cancer cases.63 One of the more than 50 cancer-related genodermatoses, Cowden’s syndrome is characterized by an excess of breast cancer, gastrointestinal and gynecologic malignancies, and thyroid disease, both benign and malignant.64 Skin manifestations include multiple trichilemmomas, oral fibromas and papillomas, and acral, palmar, and plantar keratoses. Germline mutations in PTEN, a protein tyrosine phosphatase with homology to tensin, located on chromosome 10q23, are responsible for this syndrome. Loss of heterozygosity observed in a high proportion of related cancers suggests that PTEN functions as a tumor suppressor gene. Its defined enzymatic function indicates a role in maintenance of the control of cell proliferation.65 Disruption of PTEN appears to occur late in tumorigenesis and may act as a regulatory molecule of cytoskeletal function. Although it accounts for a small fraction of hereditary breast cancer, the characterization of PTEN function will provide valuable insights into signal pathways and the maintenance of normal cell physiology.66 Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by neurologic deterioration, telangiectasias, immunodeficiency states, and hypersensitivity to

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ionizing radiation. It is estimated that approximately 1% of the general population may be heterozygous carriers of the mutated gene, ataxia telangiectasia-mutated (ATM), which has been localized to chromosome 11q22–23.67 The ATM gene encodes for a member of the phosphatidylinositol-3-kinaselike enzymes that are involved in cell-cycle control, meiotic recombination, telomere length monitoring, and DNA damage response pathways. AT cells are sensitive to ionizing radiation and radiomimetic drugs and lack cell-cycle regulatory properties after exposure to radiation.68 In vitro studies of AT carrier-derived lymphoblastoid cell lines have demonstrated defective control of apoptosis and mitotic spindle checkpoint control.69 Several epidemiologic studies have suggested a statistically increased risk of breast cancer among female heterozygote carriers, with estimated relative risks ranging from 3.9 to 5.1.70,71 ATM gene mutations associated with cancer in heterozygote carriers tend to be dominant negative missense mutations.72 Breast cancer among AT heterozygotes is characterized by early age at onset, bilateral disease, and prolonged survival.73 A comparative analysis of ATM transcripts in invasive breast cancers, benign lesions, and normal breast tissue found decreased expression of the ATM gene in the invasive tumors compared to the other tissues, suggesting a dominant negative effect of the mutation on breast carcinogenesis.74 Recently, two recurrent ATM mutations, T7271G and IVS10ÆG, were associated with an increased risk of breast cancer in multicase families in a population-based case-control study.75 Given the high heterozygote carrier rate in the population, this association could account for a significant proportion of hereditary breast cancer and poses a potential risk related to diagnostic radiation exposure in these individuals. Breast and/or ovarian cancer may also be a feature of Peutz–Jeghers syndrome, basal cell nevus (Gorlin) syndrome, multiple endocrine neoplasia type 1 (MEN1), and HNPCC. The identification and location of these and other breast/ ovarian cancer genes will permit further investigation of the precise role they play in cancer progression and allow us to determine the percentage of total breast cancer caused by the inheritance of mutant genes. This development, in turn, will ultimately enrich our understanding of all breast and ovarian cancer, sporadic as well as hereditary, and will facilitate the identification of high-risk individuals. Tailored management strategies for hereditary breast ovarian cancer (HBOC) are beginning to emerge. Individuals who appear to meet criteria for one of the BOC syndromes should be offered the opportunity to participate in clinical genetic counseling delivered by a team of trained healthcare professionals. Women who have tested positive for a BRCA1 or BRCA2 mutation are advised to start annual mammography between the ages of 25 and 35 years and to have clinical breast exams every 6 to 12 months.76 Because of the very early onset of breast cancer in women with germ-line p53 mutations, routine screening is recommended starting at age 20 to 25 for this group.77 There are preliminary data that magnetic resonance imaging (MRI) of the breast may be more sensitive in detecting early lesions in young women with dense breast tissue, although specificity is generally lower,78 and several trials are under way to determine the role of this imaging modality, especially in the setting of familial risk. Men testing positive for a BRCA1/2 mutation should also consider annual screening with mammography and clinical breast

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exam as well as annual prostate cancer screening with digital rectal exam and prostate-specific antigen (PSA) testing.76 Screening recommendations are problematic for ovarian cancer, for which no test or series of tests have been found to be sufficiently sensitive and specific. Despite the limitations, however, many practitioners have begun screening with the combination of pelvic exam, transvaginal ultrasound, and CA-125 in women with a family history of ovarian cancer. Although it is an important component of complete gynecologic care, the pelvic exam alone is clearly insufficient to detect most limited, early-stage epithelial ovarian tumors. Tumor markers, such as CA-125, lack the sensitivity and specificity to serve as the sole form of screening. Transvaginal ultrasound is currently being studied in a large screening trial nationwide and may prove to offer the best alternative to detect early-stage ovarian cancers. A recent report of the use of proteomics to identify early-stage ovarian cancer may represent a breakthrough for ovarian cancer screening. Proteomics is a new and emerging technology that can identify low molecular weight molecules in a high-throughput, nonbiased discovery approach using patient serum, plasma, urine, or tissue specimens. Petricoin et al.79 identified a small set of key protein values from patient serum that discriminated ovarian cancer cases from unaffected controls with a sensitivity of 100% and a specificity of 95%. Ultimately, a complementary series of markers may be combined for use in conjunction with ultrasonography to improve the predictive value of the screening process. Outcome data from chemoprevention trials are just beginning to emerge. The recently completed Breast Cancer Prevention Trial, which randomized more than 13,000 high-risk women to the antiestrogen tamoxifen or placebo found a 49% reduction in the incidence of breast cancer among women in the tamoxifen arm.80 The reduction in risk was limited to estrogen receptor-positive tumors. A very limited subset analysis of these data indicated that women with BRCA1 mutations (who are more likely to develop hormone receptor-negative breast tumors) did not benefit from tamoxifen whereas those with BRCA2 mutations did.81 A second large trial comparing tamoxifen to the selective estrogen receptor modulator raloxifene is under way. To date, there have been no Phase III randomized chemoprevention trials for ovarian cancer. However, because of the strong epidemiologic association between oral contraceptive (OC) use and a reduction in ovarian cancer rates,82 many gynecologists are recommending their use in women with an increased risk from either family history or nulliparity. Preliminary data from studies of women with BRCA1/2 mutations suggest that they enjoy the same degree of protection (approximately 40% reduction) from OCs as do women in the general population. Small pilot studies are now under way to determine the chemopreventive role of other agents, including members of the retinoid family as well as progestational agents. Prophylactic oophorectomy is being considered by women with a family history of ovarian cancer, particularly those who are BRCA1/2 mutation carriers, because of the uncertain nature of screening and the high case-fatality rate of advanced-stage cancer. Two large recent studies demonstrated an 85% to 96% reduction in ovarian cancer and a 50% reduction in breast cancer among women undergoing oophorectomy for prophylaxis.83,84 Prophylactic surgery does

352 not, however, eliminate the risk for primary peritoneal cancer, which is estimated to range from 1.9% to 10.7%.85 Furthermore, premenopausal women choosing this option must consider the long-term consequences of surgically induced menopause. Similarly, prophylactic mastectomy does not completely eliminate the risk of subsequent breast cancer, although a recent retrospective review of 2,029 women who had elected the procedure for a variety of reasons estimates a greater than 90% reduction in risk.86 This finding was supported by a prospective study of BRCA1/2 carriers in which no breast cancers were observed in the 76 women who underwent prophylactic mastectomy.87 This consideration occurs most commonly among women from high-risk families or those with known BRCA1/2 mutations who are making treatment choices for their first primary breast cancer, given the increased rate of second cancers in the same breast as well as the contralateral breast in that setting. Another indication for the procedure among high-risk women is extremely dense breast tissue, which renders both clinical breast examination and standard mammography less reliable. Studies are now under way to prospectively follow women who elect prophylactic oophorectomy or mastectomy to monitor long-term disease reduction as well as to document the variables influencing the decision to pursue prophylactic surgery and the medical and psychologic consequences of the surgery.

Hereditary Colorectal Cancer Syndromes (FAP, HNPCC) The adenomatous polyposis coli (APC) gene on chromosome 5q21 encodes a protein that is important in cell adhesion, signal transduction, and transcriptional activation. Germ-line mutations in APC are associated with familial adenomatous polyposis (FAP), a syndrome whose clinical phenotype includes hundreds to thousands of adenomatous polyps in the colon and rectum developing after the first decade of life and a 90% risk of developing colorectal cancer by the fourth decade of life.88 Additional features include extracolonic tumors including thyroid, periampullary, pancreatic, and gastric, hepatoblastoma in children, and congenital hypertrophy of retinal pigment epithelium (CHRPE). In some variants of FAP, the disease presentation may include fewer polyps and later onset of disease. One variant, called Gardner’s syndrome, includes osteomas, epidermoid cysts, fibromas, odontomas, and desmoid cysts.89 These attenuated forms of FAP are often associated with distinct locations of the mutation on the gene, supporting a genotype–phenotype correlation in this syndrome. For example, a FAP mutation at I1307K, prevalent in 6% of people of Ashkenazi Jewish descent, appears to effect a modest (twofold) increase in colon cancer in that population.90 Although highly penetrant, FAP accounts for less than 1% of all colon cancer. Genetic tests for FAP include protein truncation tests and full gene sequencing. The most common use of genetic testing for FAP is to determine if an unaffected relative of a patient with clinical manifestations of FAP has inherited the genetic mutation. Genetic testing is recommended at ages 10 to 12 years. Alternatively, at-risk individuals can pursue endoscopic screening for the phenotypic features of the syndrome. Annual endoscopic screening usually begins at puberty, with decreasing frequency with increasing decades of life. Some recommend screening for

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hepatoblastoma with alpha fetoprotein levels in children starting at age 5 years. For primary prevention of FAP, the recommended strategy is colectomy, usually in the second decade of life. Subtotal colectomy with ileorectal anastomosis, total protocolectomy with Brooke ileostomy, or protcolectomy and ileoanal pull-through are acceptable surgical options. Those who choose subtotal colectomy require frequent endoscopic evaluation of the rectum because of the persistent risk of rectal adenomas and carcinomas. The use of specific or nonspecific cyclooxygenase (COX)-2 inhibitors, such as celecoxib, has been recommended as an adjunct to endoscopic surveillance following subtotal colectomy.91 Upper endoscopic surveillance, as well as thyroid examination, are also recommended by some. HNPCC is an autosomal dominant condition caused by the germ-line mutation of one of several DNA mismatch repair genes, hMSH2 on chromosome 2p16, hMLH1 on chromosome 3p21, hPMS1 and hPMS2 on chromosomes 2q31 and 7q11, respectively, hMSH6 on chromosome 2p16, and hMSH3 on chromosome 5q11.2–q13.2.92 The function of these genes is to maintain the fidelity of DNA during replication. When mismatch repair is faulty, somatic mutations occur throughout the genome that can ultimately trigger the carcinogenic pathway.89 It is estimated that germ-line mutations in the HNPCC account for 3% to 5% of all colorectal cancers.93 Individuals with HNPCC have a lifetime risk of developing colorectal cancer of 70%, with a mean age at diagnosis of 44 years. Both synchronous and metachronous tumors are common, and both tumors and polyps are often right sided. Extracolonic cancers, including endometrial, ovarian, gastric, urinary tract, kidney, biliary tract, central nervous system, and small bowel, are also increased.89 Criteria for HNPCC, the Amsterdam criteria, were developed by the International Collaborative Group in 1990 and subsequently revised to include other HNPCC-associated cancers, such as endometrial cancer, small bowel cancers, and ureteral or renal pelvis cancers, whose relative risk ranges from 3 to 25 times that of the general population (Table 25.6).22,94 Because tumor DNA from individuals with HNPCC often have a distinct phenotype with changes in the length of nucleotide repeat sequences, termed MSI, the analysis of MSI in the tumor specimens is often recommended as the first step of evaluation before proceeding to full genetic sequencing for MLH1 or MSH2. Clinical indications for testing a

TABLE 25.6. The Amsterdam criteria for hereditary nonpolyposis colorectal cancer (HNPCC). The Amsterdam Criteria I: Histologically confirmed colorectal cancer in at least three relatives, one of whom is a first-degree relative of the other two. Occurrence of disease in at least two successive generations. Age at diagnosis below 50 years in at least one individual. Exclusion of familial adenomatous polyposis. Amsterdam Criteria II: Histologically confirmed HNPCC-related cancers (colorectal cancer, or cancer of the endometrium, small bowel, ureter, or renal pelvis) in at least three relatives, one of whom is a firstdegree relative of the other two. Occurrence of disease in at least two successive generations. Age at diagnosis below 50 years in at least one individual. Exclusion of familial adenomatous polyposis. Source: From Vasen et al.,94 by permission of Gastroenterology.

g e n e t i c s c r e e n i n g a n d c o u n s e l i n g f o r h i g h - r i s k p o p u l at i o n s TABLE 25.7. The revised Bethesda guidelines. Tumors from individuals should be tested for MSI in the following situations: Colorectal cancer diagnosed in a patient who is less than 50 years of age. Presence of synchronous, metachronous colorectal, or other HNPCC-associated tumors, regardless of age. Colorectal cancer with the MSI-H histology diagnosed in a patient who is less than 60 years of age. Colorectal cancer diagnosed in one or more first-degree relatives with an HNPCC-related tumor, with one of the cancers being diagnosed under age 50 years. Colorectal cancer diagnosed in two or more first- or second-degree relatives with HNPCC-related tumors, regardless of age. Source: By permission of A Umar, C Boland, J Terdiman, et al., Journal of the National Cancer Institute 96:261, 2004.

colonic tumor for MSI are outlined in the Bethesda criteria (Table 25.7) and include early age at onset (less than 50 years), an individual with multiple primary cancers, and a family history of colorectal and/or endometrial cancer.23,89 Of note, tumors that are positive for MSI (MSI high) are characterized by a better clinical outcome compared to tumors with low or no expression of MSI.95 Newer assays include immunohistochemistry staining of tumors using antibodies to the MLH1 and MSH2 protein products. Histopathologic features of HNPCC-related colorectal cancer include mucinous or signet-ring types, poor cellular differentiation, and peritumoral lymphocytic infiltration.96 The polyps that precede cancer are more often villous with areas of high-grade dysplasia than sporadic polyps.93 Other rare genetic syndromes associated with an increased risk for colon polyps and cancers are Turcot syndrome, Peutz–Jeghers sysndrome, and juvenile polyposis. Management strategies for HNPCC are based on the observed natural history of the diseases included in the syndrome. Because of the early age of onset of colorectal cancers, it is recommended that annual screening colonoscopy be initiated by age 25, or 5 years younger than the youngest affected individual in the family, and continued at frequent intervals for known mutation carriers. Those relatives who have a 50% chance of being a mutation carrier, but have not undergone genetic testing, are recommended to begin colonoscopy every 1 to 2 years, starting between 20 and 30 years, and annually after age 40. Because of the predominance of right-sided tumors in HNPCC, flexible sigmoidoscopy is not a sufficient screening tool. Because of the significantly increased risk for endometrial cancer in women with an HNPCC mutation, some form of screening of the uterus is recommended starting at age 25, although the optimal screening tool is not clear.93 Current options include annual transvaginal ultrasound or endometrial aspirates.97 Because of the high rate of metachronous tumors seen with HNPCC mutations (25%–40%), subtotal colectomy with ileorectal anastomosis rather than standard colectomy is recommended for individuals at the time of diagnosis of colon cancer.93 As in the case of BRCA1/2, oophorectomy (with hysterectomy) may be presented as an option for women with HNPCC.

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Multiple Endocrine Neoplasias (MEN) Types 1 and 2 The familial MEN syndromes are characterized by clustering of benign and malignant endocrine tumors and other systemic manifestations. MEN type 1 includes combinations of more than 20 different types of tumors, but the most characteristic are tumors of the parathyroid, pituitary, and pancreatic glands. The term multiple refers both to the occurrence of multiple tumors in the same gland and to multiple different kinds of tumors in the same individual and/or family. MEN1 is inherited as an autosomal dominant disease with variable penetrance and a prevalence of 1 in 30,000 to 1 in 50,000.98 The MEN1 gene has been localized to chromosome 11q13 and encodes a protein called menin. Menin is thought to interact with one or more transcription factors in the nucleus, and loss of its function is thought to be the mechanism of tumor formation in the syndrome.99 Much of the morbidity associated with this syndrome is attributable to the excess production of hormones. Hyperparathyroidism from parathyroid tumors is the most common (more than 90%) and earliest manifestation of the syndrome, occurring in the third decade of life and involving three or all four parathyroid glands. Enteropancreatic islet cell tumors occur in 30% to 75% of MEN1affected individuals and usually present with symptoms of hormone excess after age 40 years. Tumors occur both in the pancreas and in the duodenum and are commonly multicentric. Hormones secreted by pancreatic islet cell tumors can include chromogranin A and B, pancreatic polypeptide, glucagons, insulin, proinsulin, somatostatin, gastrin vasoactive intestinal polypeptide (VIP), serotonin, calcitonin, growth hormone (GH)-releasing factor, and neurotensin.99 The prevalence of pituitary adenomas in MEN1 ranges from 10% to 60%, and most are less than 1 cm in diameter. Other rare manifestations of MEN1 include carcinoid tumors, adrenal cortical hyperplasias, lipomas, and angiofibromas. MEN1 germ-line mutation testing is recommended for index cases with clinical MEN1 manifestations and their at-risk relatives. Periodic biochemical testing for hormone excess is a less efficient alternative. Management of MEN1 tumors includes surgery as well as medical management of hormone-secreting tumors. The treatment of choice for primary hyperparathyroidism is total parathyroidectomy, with immediate autotransplantation of parathyroid tissue to an accessible site, usually the forearm.100 Subtotal parathyroidectomy is associated with a high rate of subsequent recurrence. Insulinomas are often treated with surgical resection because of the difficulty in achieving medical management. Surgery for other islet cell tumors is controversial, as most are multicentric and can often be managed medically. Treatment of pituitary tumors depends on the type of adenoma but does not differ from that for sporadic pituitary tumors. Regular screening for hormone excess in known or suspected mutation carriers is controversial. If elected, annual biochemical screening should begin in early childhood and continue for life. Tumor imaging [e.g., magnetic resonance imaging (MRI) of the pancreas and pituitary] are recommended every 3 to 5 years.99 As in MEN1, the MEN2 syndromes represent several variants of benign and malignant tumors, all of which, however, show a high penetrance for medullary thyroid cancer (MTC), a rare calcitonin-producing tumor of the parafollicular cells of the thyroid gland.99 All MEN2 syndromes are caused by

354 germ-line mutations that activate the RET proto-oncogene, located on chromosome 10q11.2, which encodes the RET (rearranged during transfection) protein, a tyrosine kinase receptor expressed in tumors of neural crest origin.101 RET activates several downstream pathways involved in cell growth, survival, and differentiation.102 MEN2A, which accounts for 90% of all MEN2 cases, is characterized by MTC in 90% of mutation carriers, unilateral or bilateral pheochromocytomas, tumors of the adrenal chromaffin cells, in 50% of carriers, and multicentric parathyroid tumors in 20% to 30%. MEN2B accounts for 5% of MEN2 cases and is characterized by MTC, pheochromocytoma, and developmental abnormalities including mucosal and intestinal ganglioneuromatosis, marfanoid habitus, neurofibromas, and medullated corneal nerve fibers. MTC in MEN2b occurs at an earlier age and is thought to have a more aggressive course. MTC in multiple family members (four cases or more) is the only manifestation of familial MTC (FMTC) and is thought to have a more benign course. Other rare variants include MEN2A with cutaneous lichen amyloidosis and MEN2A or FMTC with Hirschsprung’s disease. DNA sequencing for RET mutations is clinically available and is indicated for all index cases and their at-risk relatives. Approximately 2.5% to 7% of mutations in RET are spontaneous new mutations, and therefore, genetic screening is recommended for all individuals with MTC, regardless of family history. RET mutations exhibit a characteristic genotype–phenotype correlation, with specific mutations associated with each variant of the syndrome. Because C cell hyperplasia is a precursor lesion to MTC, serum calcitonin levels provide an excellent tumor marker, particularly to monitor the tumor status of those diagnosed with MTC. Primary prevention is recommended in mutation carriers, however, with total thyroidectomy in childhood (before age 5 years in MEN2a and before 1 year in MEN2B). Pheochromocytomas usually present at a later age than MTC (between 30 and 40 years) with intractable hypertension and/or hypertensive crisis. Screening for pheochromocytoma is done by measurement of plasma metanephrines or 24-hour urinary catecholamines or metanephrines.99 Abdominal MRI is performed to confirm the diagnosis in suspected cases. Prophylactic adrenalectomy is not recommended because of the dangers of adrenal insufficiency. Hyperparathyroidism may present with hypercalciuria or renal calculi but is often asymptomatic. MEN2-associated hyperparathyroidism is managed in a manner similar to sporadic forms. There are several other rare genetic syndromes associated with cancer susceptibility, including basal cell nevus syndrome, von Hippel–Lindau syndrome, retinoblastoma, and neurofibromatosis (see Table 25.1), which are described in depth by Offit.1

Future Directions The rapidly evolving insights into the molecular genetic pathways of carcinogenesis will have broad application to the future of clinical oncology. The availability of predictive genetic testing to extend beyond the small number of highly penetrant genes will depend on the identification of an increased number of low penetrant genes that alter susceptibility to cancer in all individuals. Although the genes

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involved in complex carcinogenic pathways are likely to have a small individual effect on risk, their attributable risk can be high because they affect a large segment of the population. The relatively new field of molecular epidemiology is capitalizing on the existence of genetic polymorphisms to identify genetic clues of exposure to carcinogens or particular vulnerabilities to carcinogens. Genetic variation in the metabolism of carcinogens can alter response to environmental carcinogens by changing the rate of metabolism of procarcinogens or the catabolism of carcinogens. Genetic polymorphisms can also result in DNA damage or alterations in signal transduction pathways and represent an important component to cancer susceptibility.103 In addition to their role in carcinogenesis, genetic polymorphisms may also contribute to treatment toxicities and are likely to explain why some patients suffer severe adverse reactions to chemotherapy and/or radiation therapy. Furthermore, drug-metabolizing enzymes may also determine patterns of response in individual patients. A better understanding of the role of these polymorphisms and their complex interactions will ultimately permit individualized estimates of risk and lead to targeted prevention as well as therapeutic strategies. The application of a genetic approach to cancer diagnosis not only will lead to a better understanding of the pathophysiology of cancer, it will also provide tools for more accurate diagnosis and prognosis that will translate into more appropriate and targeted therapeutic approaches. Microarray technology is beginning to emerge as a powerful tool that allows both qualitative and quantitative screening for sequence variations in genomic DNA for thousands of genes in a biologic sample. Current tools for diagnosing cancer rely heavily on the histopathologic appearance of a tissue specimen, resulting in a limited classification scheme with inherent tumor heterogeneity. Microarray technology has the potential to create a taxonomy of tumors that will reflect their molecular diversity. Microarray technology is being applied in the area of cancer prognosis to better classify tumors and to predict outcome.104 The ability to create a genetic taxonomy for each cancer will greatly enhance our ability to match patients to appropriate treatment regimens.105 In breast cancer, for example, both the overexpression of HER2/neu and abnormal p53 expression are associated with decreased survival. In colon cancer, the presence of high-frequency microsatellite instability in the tumor is associated with early age of onset, a predominance of tumors in the proximal colon, increased sensitivity to chemotherapy, and improved survival. In addition to cancer prevention and early detection, genetic status will provide clinicians with the possibility of suitable, novel therapeutic options. Historically, cytotoxic therapies have been designed to capitalize on the increased cell proliferation rates generally manifested by cancer cells, a feature also shared by many benign cells, thus resulting in significant, dose-limiting toxicities. To improve the current state of cancer treatment, therapies specifically designed to reverse the specific genetic defect(s) expressed by a tumor are needed. The relatively new field of pharmacogenomics applies genome-based technologies to identify genetically determined targets for new drug development and to tailor drug regimens and schedules to individual genetic profiles.106 Cancer treatment resistance, a major barrier to effective therapy, is still poorly understood but is acknowledged to be

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largely attributable to gene expression variability. This is another area where microarray technology will be applied to stimulate progress in understanding cellular and subcellular resistance mechanisms. These and other targeted therapeutic advances likely represent the tip of the iceberg for rational drug design and will be followed by gene-based strategies using ribozymes, other growth factor receptor antibodies, immunotoxins, signal transduction inhibitors, and antiangiogenic molecules, to name a few. Finally, as we move from the setting of single gene identification, the possibility of whole-genome screening looms large on the horizon. The possibility of complete genomic sequencing as a routine clinical test on every individual to be used for predictive and preventive medicine will become feasible as the work of the Human Genome Project proceeds. However, its adoption as a part of routine medical practice must consider the criteria for the adoption of population screening on a public health basis. Widespread genetic screening for a disease should be restricted to those diseases that are relatively common and serious, for which the natural history is defined and consistent, and for which effective primary and/or secondary prevention interventions exist. The associated gene(s) must be well characterized and accurately identified through existing detection methods. Genetic testing must be relatively inexpensive, acceptable to the population, and associated with pre- and posttest counseling. Genetic screening for diseases that selectively affect a segment of the population should be targeted specifically to that group and not offered to the population as a whole. As we move into an era characterized by genetic identity, ethical and social concerns must be carefully considered.107

Conclusions As the importance of cancer prevention and control grows in recognition, cancer risk counseling services are becoming a standard component of primary health care. Individuals are becoming increasingly aware of the role of their family history in their own personal cancer risk. The growing sophistication in the process of risk identification, including the use of genetic tests for cancer susceptibility genes, is stimulating research to develop risk modification and cancer prevention strategies. Several registries of high-risk families are being assembled to provide prospective data on the epidemiology and natural history of familial cancers and the effectiveness of a variety of cancer control interventions. Optimal screening protocols for members of high-risk families are being developed and evaluated. Long-term follow-up of mutation carriers will help to define the spectrum of cancer risk, the clinical course of hereditary cancer, and response to treatment. Central to these research efforts are ongoing studies of the short- and long-term effects of cancer risk counseling on health behaviors and quality of life. Coincidental with this are the many new educational initiatives to prepare healthcare professionals to become part of the cancer risk counseling team.

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2. Andrulis IL, Anton-Culver H, Beck J, et al. Comparison of DNAand RNA-based methods for detection of truncating BRCA1 mutations. Hum Mutat 2002;20:65–73. 3. Schneider K. Counseling About Cancer. Strategies for Genetic Counseling, 2nd ed. New York: Wiley-Liss, 2002. 4. Narod S, Feunteun J, Lynch H, et al. Familial breast-ovarian locus on chromosome 17q12–23. Lancet 1991;338:82. 5. American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol 2003;21(12):2397–2406. 6. American Society of Human Genetics. Statement of the American Society of Human Genetics on genetic testing for breast and ovarian cancer predisposition. Am J Hum Genet 1994;55:i–iv. 7. National Society of Genetic Counselors. Predisposition genetic testing for late-onset disorders in adults: a position paper of the National Society of Genetic Counselors. JAMA 1997;278(15): 1217–1220. 8. Armstrong K, Calzone K, Stopfer J, et al. Factors associated with decisions about clinical BRCA1/2 testing. Cancer Epidemiol Biomarkers Prev 2000;9:1251–1254. 9. Burke W. Genetic testing. N Engl J Med 2002;347(23):1867–1875. 10. Geller G, Botkin JR, Green MJ, et al. Genetic testing for susceptibility to adult-onset cancer: the process and content of informed consent. JAMA 1997;277:1467–1474. 11. American Society of Human Genetics, American College of Medical Genetics. ASHG/ACMG report. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Am J Hum Genet 1995;57:1233– 1241. 12. Wideroff L, Freedman AN, Olson L, et al. Physician use of genetic testing for cancer susceptibility: results of a national survey. Cancer Epidemiol Biomarkers Prev 2003;12:295–303. 13. Baty B, Venne V, McDonald J, et al. BRCA1 testing: genetic counseling protocol development and counseling issues. J Genet Counsel 1997;6(2):223–244. 14. Peters J. Familial cancer risk. Part I: Impact on today’s oncology practice. J Oncol Manage 1994;3:18–30. 15. Muller H. Genetic counseling and cancer. In: Weber W, Laffer U, Durig M (eds). Hereditary Cancer and Preventive Surgery. Basel: Karger, 1990:12–18. 16. Peters J. Familial cancer risk. Part II: Breast cancer risk counseling and genetic susceptibility testing. J Oncol Manag 1994; 3:14–22. 17. Bennett R, Steinhaus K, Uhrich S, et al. Recommendations for standardized human pedigree nomenclature. Am J Human Genet 1995;56:745–752. 18. Mahon S, Casperson D. Hereditary cancer syndrome: part 1. Clinical and educational issues. Oncol Nurs Forum 1995; 22(5):763–771. 19. Gail MH, Brinton LA, Byar DP, et al. Projecting individual probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 1989;81(24):1879– 1886. 20. Costantino JP, Gail MH, Pee D, et al. Validation studies for models projecting the risk of invasive and total breast cancer incidence. J Natl Cancer Inst 1999;91:1541–1548. 21. Hoskins KF, Stopfer JE, Calzone KA, et al. Assessment and counseling for women with a family history of breast cancer. A guide for clinicians. JAMA 1995;273(7):577–585. 22. Vasen H, Mecklin J, Khan P, et al. The international collaborative group on hereditary non-polyposis colorectal cancer (ICGHNPCC). Dis Colon Rectum 1991;34:424–425. 23. Rodriguez-Bigas M, Boland C, et al. A National Cancer Institute workshop on hereditary nonpolyposis colorectal cancer syndrome: meeting highlights and Bethesda guidelines. JNCI 1997; 89(23):1758–1762. 24. Shattuck-Eidens D, Oliphant A, McClure M, et al. BRCA1 sequence analysis in women at high risk for susceptibility muta-

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tions, risk factor analysis and implications for genetic testing. JAMA 1997;278(15):1242–1250. Berry D, Parmigiani G, Sanchez J, et al. Probability of carrying a mutation of breast-ovarian cancer gene BRCA1 based on family history. JNCI 1997;89(3):227–238. Berry DA, Iversen ES, Gudbjartsson DF, et al. BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. J Clin Oncol 2002;20:2701–2712. Lynch H, Harris R, Organ C, et al. Management of familial breast cancer. Arch Surg 1978;113:1061–1067. Kessler S. The process of communication, decision making and coping in genetic counseling. In: Kessler S (ed). Genetic Counseling, Psychological Dimensions. New York: Academic Press, 1979. Ursin G, Henderson B, Halle R, et al. Does oral contraceptive use increase the risk of breast cancer in women with BRCA1/BRCA2 mutations more than in other women? Cancer Res 1997;57(17):3678–3681. Tambor E, Bernhardt B, Chase G, et al. Offering cystic fibrosis carrier screening to an HMO population: factors associated with utilization. Am J Hum Genet 1997;55:626–637. Evers-Kiebooms G, van den Berghe H. Impact of genetic counseling: a review of published follow-up studies. Clin Genet 1979; 15:465–474. Phipps RF, Perry PM: Familial breast cancer. Postgrad Med J 1988;64:847–849. Sellers TA, Potter JD, Rich SS, et al. Familial clustering of breast and prostate cancers and risk of postmenopausal breast cancer. J Natl Cancer Inst 1994;86:1860–1865. Claus EB, Risch N, Thompson WD. Genetic analysis of breast cancer in the cancer and steroid hormone study. Am J Hum Genet 1991;48:232–242. Hall J, Lee M, Newman B, et al. Linkage of early onset familial breast cancer to chromosome 17q21. Science 1990;250:1684– 1689. Easton DF, Bishop DT, Ford D, et al. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. Am J Hum Genet 1993;52:678–701. Wooster R, Neuhausen SL, Mangion J, et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12–13. Science 1994;265:2088–2090. Gayther SA, Mangion J, Russell P, et al. Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet 1997;15:103–105. Schubert EL, Lee MK, Mefford HC, et al. BRCA2 in American families with four or more cases of breast or ovarian cancer: recurrent and novel mutations, variable expression, penetrance, and the possibility of families whose cancer is not attributable to BRCA1 or BRCA2. Am J Hum Genet 1997;60:1031–1040. Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994;266:66–71. Scully R, Chen J, Plug A. Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 1997;88(2):265–275. Sharan SK, Morimatsu M, Albrecht U, et al. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking BRCA2. Nature (Lond) 1997;386:804–810. Blackwood A, Weber B. BRCA1 and BRCA2: from molecular genetics to clinical medicine. J Clin Oncol 1998;16(5):1969– 1977. Fraser JA, Reeves JR, Stanton PD, et al. A role for BRCA1 in sporadic breast cancer. Br J Cancer 2003;88:1263–1270. Neuhausen S, Gilewski T, Norton L, et al. Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer. Nat Genet 1998;13(1):126–128. Peelen T, van Vliet M, Petrij-Bosch A, et al. A high proportion of novel mutations in BRCA1 with strong founder effects among

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Dutch and Belgian hereditary breast and ovarian cancer families. Am J Hum Genet 1997;60(5):1041–1049. Thorlacius S, Olafsdottir G, Kryggvadottir L, et al. A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet 1996;13: 117–119. Arason A, Jonasdottir A, Barkardottir RB, et al. A population study of mutations and LOH at breast cancer gene loci in tumours from sister pairs: two recurrent mutations seem to account for all BRCA1/BTCA2 linked breast cancer in Iceland. J Med Genet 1998;35(6):446–449. Einbeigi Z, Bergman A, Kindblom LG, et al. A founder mutation of the BRCA1 gene in Western Sweden associated with a high incidence of breast and ovarian cancer. Eur J Cancer 2001; 37(15):1904–1909. Brose MS, Rebbeck TR, Calzone KA, et al. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst 2002;94:1365–1372. Easton DF, Steele L, Fields P, et al. Cancer risks in two large breast cancer families linked to BRCA2 on chromosome 13q12–13. Am J Hum Genet 1997;61:120–128. Greene MH. Genetics of breast cancer. Mayo Clin Proc 1997; 72:54–65. Ford D, Easton DF, Stratton M, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 1998;62:676–689. Malone KE, Daling JR, Weiss NS, et al. Family history and survival of young women with invasive breast carcinoma. Cancer (Phila) 1996;78:1417–1425. Breast Cancer Linkage Consortium. Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 and BRCA2 mutations and sporadic cases. Lancet 1997;349: 1505–1510. Marcus JN, Page DL, Watson P, et al. BRCA1 and BRCA2 hereditary breast carcinoma phenotypes. Cancer (Phila) 1997;80: 543–556. Marcus JN, Watson P, Page DL, et al. Hereditary breast cancer: pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage. Cancer (Phila) 1996;77:697–709. Hedenfalk I, Duggan D, Chen Y, et al. Gene-expression profiles in hereditary breast cancer. N Engl J Med 2001;344:539– 548. Verhoog LC, Brekelmans CTM, Seynaeve C, et al. Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet 1998;351:316–321. Johannsson OT, Ranstam J, Borg A, et al. Survival of BRCA1 breast and ovarian cancer patients: a population-based study from southern Sweden. J Clin Oncol 1998;16:397–404. Garber JE, Goldstein AM, Kantor AF, et al. Follow-up study of twenty-four families with Li-Fraumeni syndrome. Cancer Res 1991;51(22):6094–6097. Bottomley R, Condit P. Cancer families. Cancer Bull 1968;20:22. Ford D, Easton DF. The genetics of breast and ovarian cancer. Br J Cancer 1995;72:805–812. Tsou HC, Teng DHF, Ping XL, et al. The role of MMAC1 mutations in early-onset breast cancer: causative in association with Cowden syndrome and excluded in BRCA1-negative cases. Am J Hum Genet 1997;61:1036–1043. Lynch ED, Ostermeyer EA, Lee MK, et al. Inherited mutations in PTEN that are associated with breast cancer, Cowden disease, and juvenile polyposis. Am J Hum Genet 1997;61:1254– 1260. Myers MP, Tonks NK: Invited editorial: PTEN: sometimes taking it off can be better than putting it on. Am J Hum Genet 1997;61:1234–1238. Savitsky K, Bar-Shira A, Gilad S, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 1995;268:1749–1753.

g e n e t i c s c r e e n i n g a n d c o u n s e l i n g f o r h i g h - r i s k p o p u l at i o n s 68. Gilad S, Chessa L, Khosravi R, et al. Genotype–phenotype relationships in ataxia-telangiectasia and variants. Am J Hum Genet 1998;62:551–561. 69. Shigeta T, Takagi M, Delia D, et al. Defective control of apoptosis and mitotic spindle checkpoint in heterozygous carriers of ATM mutations. Cancer Res 1999;59:2602–2607. 70. Swift M, Morrell D, Massey RB, et al. Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med 1991;325:1831–1836. 71. Easton DF. Cancer risks in A-T heterozygotes. Int J Radiat Biol 1994;66(suppl 6):S177–S182. 72. Khanna KK. Cancer risk and the ATM gene: a continuing debate. J Natl Cancer Inst 2000;92:795–802. 73. Broeks A, Urbanus JH, Floore AN, et al. ATM-heterozygote germline mutations contribute to breast cancer susceptibility. Am J Hum Genet 2000;66:494–500. 74. Waha A, Sturne C, Kessler A, et al. Expression of the ATM gene is significantly reduced in sporadic breast carcinomas. Int J Cancer 1998;78:306–309. 75. Chenevix-Trench G, Spurdle AB, Gatei M, et al. Dominant negative ATM mutations in breast cancer families. J Natl Cancer Inst 2002;94:205–215. 76. Burke W, Daly M, Garber J, et al. Recommendations for followup care of individuals with an inherited predisposition to cancer II. BRCA1 and BRCA2. JAMA 1997;277(12):997–1003. 77. Daly M. NCCN practice guidelines: genetics/familial high-risk cancer screening. Oncology 1999;13(11A):161–183. 78. Warner E, Plewes DB, Shumak RS, et al. Comparison of breast magnetic resonance imaging, mammography, and ultrasound for surveillance of women at high risk for hereditary breast cancer. J Clin Oncol 2001;19(15):3524–3531. 79. Petricoin EF, Ardekani AM, Hitt, BA, et al. Use of proteomic patterns in serum to identify ovarian cancer. Lancet 2002;359: 572–577. 80. Fisher B, Costantino J, Wickerham L, et al. Tamoxifen for prevention of breast cancer: report of the national surgical adjuvant breast and bowel project P-1 study. J Natl Cancer Inst 1998; 90(18):1371–1388. 81. King MC, Wieand S, Hale K, et al. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA 2001;286(18):2251–2256. 82. Ness RB, Grisso JA, Klapper J, et al. Risk of ovarian cancer in relation to estrogen and progestin dose and use characteristics of oral contraceptives. Am J Epidemiol 2000;152:233–241. 83. Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 2002;346(21):1616–1622. 84. Kauf ND, Satagopan JM, Robson ME, et al. Risk-reducing salpingooophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2002;346(21):1609–1615. 85. Eisen A, Weber B. Primary peritoneal carcinoma can have multifocal origins: implications for prophylactic oophorectomy. J Natl Cancer Inst 1998;90(11):797–799. 86. Hartmann L, Jenkins R, Schaid D, et al. Prophylactic mastectomy: preliminary retrospective cohort analysis. Proc Am Assoc Cancer Res 1997;38:1123. 87. Meijers-Heijboer H, van Geel B, van Putten WL, et al. Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2001;345(3):159–164.

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88. Herrera L. Familial Adenomatous Polyposis. New York: Liss, 1990. 89. Solomon CH, Pho LN, Burt RW. Current status of genetic testing for colorectal cancer susceptibility. Oncology 2002;16(2): 161–171. 90. Laken SJ, Petersen GM, Gruber SB, et al. Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nat Genet 1997;17:70–83. 91. Higuchi T, Iwama T, Yoshinaga K, et al. A randomized, doubleblind, placebo-controlled trial of the effects of Rofecoxib, a selective cyclooxygenase-2 inhibitor, on rectal polyps in familial adenomatous polyposis patients. Clin Cancer Res 2003;9: 4756–4760. 92. Marra G, Boland CR. Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J Natl Cancer Inst 1995;87:1114–1125. 93. AGA technical review on hereditary colorectal cancer and genetic testing. Gastroenterology 2001;121:198–213. 94. Vasen HF, Watson P, Mecklin JP, et al. New criteria for hereditary non-polyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC (ICG HNPCC). Gastroenterology 1999;116:1453– 1456. 95. Gafà R, Maestri I, Matteuzzi M, et al. Sporadic colorectal adenocarcinomas with high-frequency microsatellite instability. Cancer (Phila) 2000;89:2025–2037. 96. Messerini L, Mori S, Zampi G. Pathologic features of hereditary non-polyposis colorectal cancer. Tumori 1996;82:114–116. 97. Burke W, Petersen G, Lynch P, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer I. Hereditary nonpolyposis colon cancer. JAMA 1997; 277(11):915–919. 98. Giruad S, Zhang CX, Serova-Sinilnikove O, et al. Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. Am J Hum Genet 1998; 63:455–467. 99. Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001;86(12):5658–5671. 100. Marx S, Spiegel AM, Skarulis MC, et al. Mulitple endocrine neoplasia type 1: clinical and genetic topics. Ann Intern Med 1998;129:484–494. 101. Eng C. RET proto-oncogene in the development of human cancer. J Clin Oncol 1999;17:380–393. 102. Bryant J, Farmer F, Kessler LJ, et al. Pheochromocytoma: the expanding genetic differential diagnosis. JNCI 2003;95:1196– 1204. 103. Nebert DW. Polymorphisms in drug-metabolizing enzymes: what is their clinical relevance and why do they exist? Am J Hum Genet 1997;60:265–271. 104. Ahr A, Holtrich U, Solbach C, et al. Molecular classification of breast cancer patients by gene expression profiling. J Pathol 2001;195:312–320. 105. Rosell R, Monzo M, O’Brate A, et al. Translational oncogenomics: toward rational therapeutic decision-making. Curr Opin Oncol 2002;14:171–179. 106. Herrmann J, Rastelli L, Burgess C, et al. Implications of oncogenomics for cancer research and clinical oncology. Cancer J 2001; 7:40–51. 107. Grody WW. Molecular genetic risk screening. Annu Rev Med 2001;54:473–490.

2 6

Behavior Modification Christopher N. Sciamanna

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here is no question at this point in our medical knowledge that health behaviors play a prominent role in morbidity and mortality from cancer and other diseases. The seminal paper by McGinnis and Foege “Actual causes of death in the United States” in 1993 did a great deal to put health behaviors on the map as significant public health problems. In their analysis, the authors concluded that approximately half of all deaths are due to health behaviors. The three most prominent behaviors in their analysis, tobacco (19%), diet and physical activity patterns (14%), and alcohol (5%), could be linked to more than one-third of all deaths in 1990.1 A reanalysis of the same question reached basically the same conclusions using data from the year 2000.2 This chapter takes a similar examination of the available evidence for the most common health behaviors that are implicated as contributing to cancer. We focus the analysis on tobacco use, diet, physical activity, being overweight, and sun exposure, as each is quite common and has been the subject of significant study. For each behavior, this chapter discusses one or more cancers with which the behavior is purported to be associated, yet the discussion focuses on behaviors, rather than cancers. For each behavior, this chapter examines (1) the evidence linking changes in the health behaviors to reducing cancer morbidity and mortality, (2) the effectiveness of physician counseling as a commonly used method of behavior modification, (3) the recommendations of professional groups regarding what individuals can do to improve these health behaviors, and (4) methods for improving the quality of physician counseling for behavior modification.

Efficacy of Risk Reduction The contributions of adverse health behaviors to cancer morbidity and mortality are substantial and well documented. A World Cancer Research Fund panel estimated that 30% to 40% of all cancers are attributable to inappropriate diet, physical activity, and high body weight.3 In this section, we review the evidence linking changes in several established cancer risk behaviors to changes in cancer morbidity and mortality. This review is not meant to be exhaustive, but intends to review the most common cancers, primarily those for which the most data exist.

Efficacy of Risk Reduction: Tobacco Use There is a large body of evidence from prospective cohort and case-control studies showing that many of the health risks of

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tobacco use can be reduced by smoking cessation. As compared with smokers, the excess risk of lung cancer decreases sharply in ex-smokers after approximately 5 years since quitting. Although an excess risk from smoking most likely persists through life, the excess risk approaches that of a never smoker after 15 to 20 years since quitting.4 After quitting, the risk of oral, pharyngeal, and laryngeal cancers decreases, approaching that of a never smoker in approximately 15 years.5,6 Also, within 2 years of quitting, the risk of pancreatic cancer decreases by approximately 50%.7–9

Efficacy of Risk Reduction: Diet Differences in dietary intake are thought to account for approximately 30% of cancers in Western countries, although less in developing countries.10 Although many studies have examined the association of different dietary components on cancer risk, very few have examined the likely effect of changing the diet on subsequent risk or survival from cancer. Early data showed that an increase in the polyunsaturated fatty acid concentration in membranes stimulated the oxidation of precarcinogens to reactive intermediates.11 The largest study to date, however, a pooled analysis on roughly 350,000 women, found no association between replacing monounsaturated, polyunsaturated fats with carbohydrates on the incidence of breast cancer.12 In this same study, a weak positive association was identified between replacing saturated fats with carbohydrates on breast cancer incidence. There is little evidence linking dietary fat to the incidence of colorectal cancer. A single large randomized trial, however, showed no effect of a diet low in fat and high in fiber, fruit, and vegetables on the recurrence of colorectal adenomas.13 Fruit and vegetable intake is negatively associated with incidence of many cancers, including those of the oral cavity, esophagus, pharynx,14 stomach,15 colorectal region,16–18 lung,19 cervix,14 and kidney.14 Intervention trials, however, in which fiber and fruit and vegetable intake have been augmented, have failed to slow the recurrence of colorectal adenomas.13,20,21 Similarly, a study of beta-carotene supplementation failed to decrease the incidence of lung cancer.22 Similar to other food groups, very little evidence exists to understand the effect of changes of fruit and vegetable intake on cancer incidence. The three studies that have examined increases in fruit and vegetable intake, including the Polyp Prevention Trial as mentioned previously, have not found decrease in the recurrence of colorectal adenomas.13,20,21 An ongoing randomized trial, the Women’s Healthy Eating and Living Study, will add

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to our understanding of the effect of a diet high in vegetables, fruits, and fiber and low in fat on breast cancer survival.23

Efficacy of Risk Reduction: Physical Inactivity In the United States, fewer than half of adults attain recommended levels of physical activity.24 There is conflicting evidence supporting a link between physical inactivity and cancers of the prostate, endometrium, and lung,25 and there have been no intervention trials showing a decrease in the incidence or recurrence of any cancer. Furthermore, little evidence exists examining the effect of changes in physical activity level on risk of cancer.

Efficacy of Risk Reduction: Alcohol Abuse Nearly one-third of U.S. adults drink an excessive amount of alcohol.26 Excessive alcohol use appears to be associated with cancers of the breast, oropharynx, pharynx, esophagus, and liver.27–31 Little evidence exists examining the effect on changes in alcohol consumption on the risk of breast or other cancers. Two studies from Italy observed that, although stopping smoking decreased the risk of laryngeal cancer within only a few years, stopping drinking led to a much smaller decline in laryngeal and esophageal cancer risk after more than a decade.32,33

Efficacy of Risk Reduction: Overweight and Obesity There is no end in sight for the epidemic of overweight and obesity in the United States. In 2001, a national survey observed more than 67% of adult men and 50% of adult women to be overweight [body mass index (BMI) greater than 25), and of those an equal number of men and women (21%) were classified as obese (BMI greater than 30).34 Although overweight and obesity are associated with breast cancer incidence, few studies have examined the effect of weight loss on the incidence of cancer, which precludes any firm conclusions.35,36 Although firm conclusions are not possible, some evidence can be found in the Nurses’ Health Study, in which women who gained more than 20 pounds from age 18 to midlife doubled their risk for breast cancer, compared to women who maintained a stable weight.37

Efficacy of Risk Reduction: Sun Exposure Exposure to the sunlight has been implicated in the high incidence of skin cancers, which most commonly include cutaneous melanoma, basal cell carcinoma, and squamous cell carcinoma.38–40 There is no direct evidence, however, that personal sun protection behaviors can reduce the incidence of melanoma, and evidence that sun protection behaviors modify the incidence of other skin cancers is mixed.41,42 For example, a randomized controlled trial of daily sunscreen use in a general population in Australia showed no effect on risk of basal cell carcinoma over 5 years of intervention and follow-up.43 Another randomized controlled trial, however, of sunscreen applied daily to the head, neck, hands, and arms reduced the number of new squamous cell carcinomas over a 5-year period.44 A third randomized trial observed that sunscreen use decreased the incidence of, and increased the regression rate of, solar keratoses.45,46

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Effectiveness of Physician Counseling This section highlights the evidence, and the strength of that evidence, regarding the efficacy of physicians in bringing about changes in health behaviors (intermediate outcomes) and in changing cancer incidence or survival (distal outcomes).

Effectiveness of Physician Counseling: Tobacco Use Of all the health behaviors, the most agreement exists regarding the efficacy of physician counseling. Several welldesigned randomized controlled trials have established that physician counseling helps smokers quit.47 Providing selfhelp brochures without clinical advice has limited efficacy, but physician advice alone can increase quit rates by as much as 10%.48,49 Cummings and colleagues observed that training internists for 3 hours and providing self-help books to smokers increased smoking cessation rates by approximately 2%.48 The 1996 and 2000 Clinical Practice Guidelines contain a summary of this evidence.47,50 The guidelines emphasized the role of (1) identification of smokers in practice, such as using smoking as a “vital sign,”51 (2) physician advice to quit, and (3) the use of medications to assist smokers in their quitting attempts. Several studies have also shown that feedback about smoking-specific risk factors such as pulmonary function and carbon monoxide testing by physicians can double smoking cessation rates.52–54

Effectiveness of Physician Counseling: Poor Diet There is inconclusive evidence that physician counseling can lead to dietary changes.55–59 In one such study, physicians gave patients a self-help booklet and a brief motivational message, which led to significant changes in the intake of fat and fiber, compared with a usual care comparison group.56 Most studies, however, have included several hours of physician education and training on diet counseling, as other studies have shown that physicians receive little training on diet and may often not be aware of the effect of dietary modifications.60–63 Similar studies have observed that brief training of physicians can lead to changes in blood cholesterol,64 saturated fat intake,65 and fruit and vegetable intake.55 Some studies, however, have found no effect of physician counseling, and many primary care-based studies have also employed office systems, computer-tailored print messages, and counseling by nutritionists and nurses, which make it difficult to understand the independent effects of physician counseling.55,57,65–67

Effectiveness of Physician Counseling: Physical Inactivity There is inconclusive evidence that physician intervention counseling can also lead to changes in physical activity, as studies have shown the effects to be mixed.57,68–72 A 2002 review by the United States Preventive Services Task Force identified only eight studies on which to base their conclusion.73 Most studies have tested low-intensity interventions such as 3 to 5 minutes of counseling in a routine outpatient visit and included several hours to several days of provider training. In some of the studies, the patients completed a self-

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report tool on physical activity levels or answered questions from a validated survey in the office waiting room or at home. In many of the studies, a research assistant or nurse conducted a baseline assessment and placed it in the chart for the physician to use during the clinical encounter. As such, it is difficult from many of the studies to understand the independent effects of physician counseling. In the six studies that compared an intervention condition, including physician counseling to a usual care control group, the effects on physical activity were mixed. Only one of the studies met all the methodological criteria for a quality rating of “good.”73 The U.S. Preventive Services Task Force (USPSTF) study found the available evidence to be inconclusive.73

patient’s use of sun protection behaviors or on subsequent development of skin cancer is not yet known.89 A randomized trial of a community-based, multiintervention program, including office-based counseling by physicians, showed that the intervention increased sun protection behaviors in the intervention towns.90 More parents recalled receiving advice to use sun protection behaviors in the intervention towns, giving some indirect evidence that the increased use of sun protection behaviors was due to more physician counseling. The United States Preventive Services Task Force concluded, in October 2003, that there was insufficient evidence to recommend for or against routine counseling by primary care clinicians to prevent skin cancer.91

Effectiveness of Physician Counseling: Alcohol Abuse

Recommendations of Professional Groups

There is a reasonable amount of evidence that physician counseling can decrease drinking in patients who abuse alcohol. At least three randomized trials have been conducted, all showing that counseling led to a decreased amount of drinking.74–76 In one such study, providers were trained to provide a brief (5 to 10 minutes) counseling intervention, and an office support system was used that screened patients and cued providers to intervene, in addition to making patient education materials available.76 The intervention led to a decrease of 5.8 drinks per week compared with a usual care condition.76,77 Two other large studies showed decreases in the range of 10 drinks per week in the intervention condition, compared to the control condition.74,75 Although not all studies have shown positive effects,78 two meta-analyses have shown that brief interventions, typically conducted by physicians, are effective at decreasing alcohol intake among heavy drinkers in outpatient settings.79,80

Effectiveness of Physician Counseling: Overweight and Obesity There is inconclusive evidence about the effects of physician counseling to help patients lose weight.65,81–85 In one such study, physicians counseled patients and incorporated meal replacements and nurse visits, which led to losses of approximately 4% of body weight, equal to the effects of two nutritionist-led intervention conditions.81 There have been few studies, however, and many studies that showed an effect on weight loss were actually designed to improve dietary patterns, such as decreasing saturated fat intake.64,65,86 A significant barrier to physician counseling for overweight and obesity is the apparent complexity of counting calories, which is the basis of all weight loss recommendations.87 Training programs have been developed and user-friendly reminder cards have been developed, but many barriers remain and conclusions based on the available evidence are difficult to make.87,88

Effectiveness of Physician Counseling: Sun Exposure Very little evidence exists to understand the effects of physician counseling on sun protection behaviors. At least one intervention has been shown to increase healthcare provider counseling, but the effects of physician counseling on

This section attempts to summarize the recommendations, including the similarities and differences, of recommendations from guidelines published by professional groups, such as the USPSTF, American Lung, American Heart, and health insurance companies, regarding the expected standards of care and reimbursement for behavioral counseling.

Recommendations of Professional Groups: Tobacco Use Professional groups are in broad agreement that tobacco use in any form and in any amount is not safe and should be discontinued. No safe level of smoking has ever been identified.10 Groups agree that tobacco use in the form of cigarette smoking, cigar smoking, snuff, and chewing are all carcinogenic and should be discontinued.47,50,92,93 Professional groups agree that physicians should advise their patients to discontinue tobacco use and to use pharmacotherapy as appropriate.47,50,92,93

Recommendations of Professional Groups: Poor Diet Professional groups differ on some of the specifics of diet, but generally recommend that patients limit the intake of highfat (especially saturated and trans-unsaturated fat) and high-sugar foods and eat a sufficient amount of fruits and vegetables (e.g., five or more servings) and whole grains. There are differences, however, in the specifics. For example, the United States Department of Agriculture’s 2000 “Dietary Guidelines for Americans” suggests eating no more than 30% of calories from fat, while the American Heart Association suggests eating between 25% and 35% of calories from fat.94,95 The American Cancer Society guidelines, released in 2002, are less specific but generally recommend the same above changes as other groups.96

Recommendations of Professional Groups: Physical Inactivity Professional groups generally agree that physical activity is an important part of staying healthy. The American College of Sports Medicine and the Centers for Disease Control released joint recommendations in 1995, suggesting that most Americans could benefit from regular physical activity,

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defined as at least 30 minutes of moderate or vigorous activity on most, or at least 5, days of the week.97 These recommendations have not changed in any significant manner since 1995. The 2002 American Cancer Society Guidelines are consistent with these recommendations.96 The USPSTF also recommends that lower amounts of vigorous activity, 20 minutes for 3 days each week, are acceptable levels of activity.73,98

effective in reducing skin cancer but that the evidence does not support physician counseling about SPBs with every patient.107 ACPM concluded that evidence does not support advising patients to use chemical sunscreens and that their use may actually increase the risk of malignant melanoma.108

Recommendations of Professional Groups: Alcohol Abuse

Although little direct evidence exists from randomized trials to inform us of the best ways to counsel patients to modify health behaviors, much can still be learned and applied from the available evidence. The way that a doctor communicates with a patient has a strong influence on patient satisfaction and patient adherence. There are several communication patterns in particular that appear to lead to positive outcomes. First, patients whose physicians encourage them to participate actively in their medical treatment decisions have improved health outcomes.109–112 Second, building rapport, through a discussion of psychosocial issues that help the physician understand the “whole person,” is associated with improved patient satisfaction and adherence to physicians’ recommendations.113,114 Third, providers who support motivations that are initiated by patients, also known as being “patient centered,” have patients who are more satisfied with their care and who take a more active role in their care and have better outcomes.110,114,115 Regardless of the interaction, these communication patterns are best to employ whenever possible. This is particularly true of health behavior counseling, which can be stressful for both the doctor and the patient, given patient resistance to change and the overall low likelihood of success of behavior change. A commonly used framework for organizing brief behavior counseling is the “5 A’s”116,117: “Address the Agenda,” “Assess,” “Advise,” “Assist,” and “Arrange.”47 We try to highlight these five activities and the previously mentioned communication patterns in a case study, adapted and reprinted with permission.63 This case study is related to diet, but the process (the 5 A’s) are the same for changing any health behavior.47,117–119

Recommendations for alcohol use differ in several ways between organizations, mainly based on the group toward which the recommendations are targeted. No safe level of alcohol intake has been identified, as the epidemiologic studies typically compared high versus low intake, rather than examining a possible threshold effect.27 Given the data supporting the cardiac benefits of moderate alcohol and the effects of alcohol on blood pressure, the American Heart Association recommends a limit of one drink per day for women and a limit of two drinks per day for men.99 The American Cancer Society is less specific, noting only “if you drink alcoholic beverages, limit consumption.”96

Recommendations of Professional Groups: Overweight and Obesity In the year 2000, the National Heart, Lung and Blood Institute, in partnership with the North American Association for the Study of Obesity, released “The Practical Guide: Identification, Evaluation and Treatment of Overweight and Obesity in Adults.”100 These guidelines defined a healthy body weight, based on the body mass index (BMI) [weight in kilograms/ (height in meters)2] between 18.5 and 25.0.100 According to these guidelines, individuals are considered to be overweight if the BMI is between 25 and 30 and obese if the BMI is greater than 30.100 The guidelines contain specific recommendations, including thresholds for considering various weight loss methods, such as caloric restriction, physical activity, medications, and surgery. These BMI recommendations are consistent with those of the American Heart Association,101 which also recommend that children and adolescents maintain a BMI less than the 85th percentile, according to ageappropriate growth charts. The American Cancer Society guidelines are less specific, suggesting to “maintain a healthful weight throughout life,” “balance caloric intake with physical activity,” and “lose weight if currently overweight or obese.”96

Recommendations of Professional Groups: Sun Exposure The American Cancer Society,102 the American Academy of Dermatology,103 the American Academy of Pediatrics,104 and the American College of Obstetricians and Gynecologists105 all recommend patient education about sun protection behaviors (SPBs), such as sun avoidance, clothing, hats, and sunscreens. The American Academy of Family Physicians recommends sun protection for all with increased sun exposure.106 The American College of Preventive Medicine (ACPM) concluded that sun-protective behaviors are probably

Improving the Quality of Physician Counseling for Behavior Modification

Case Mrs. R is a 55-year-old woman whom you have seen in your practice for the past 3 years. She has a history of previous cholecystectomy, and had a stage 2 infiltrating ductal carcinoma of the breast treated 2 years ago. She also has high blood cholesterol with the following profile 1 month ago: total cholesterol = 255, LDL = 176, HDL = 48, triglycerides = 155. She has no hypertension, no diabetes, no family history of myocardial infarction, and a BMI of 29. She is returning today to discuss the results of her lipid profile. 1. Address the Agenda: Express the desire to talk about the patient’s eating habits. For example, “I’d like to talk with you about how you are eating, because it can affect your blood cholesterol, your weight, and may affect the chance that your breast cancer returns.” Sometimes, behavior modification discussions can seem as if they come out of nowhere—this helps to get it on the table in a friendly way that makes no assumptions as to the quality of their diet.

362 2. Assess: a. Behavior level Before giving nutrition advice, you need to know the patient’s current eating pattern. Just because someone has high blood cholesterol or is overweight does not necessarily mean that they eat the wrong foods. It is difficult to accurately assess someone’s diet with a question or set of questions. One approach is to ask patients to describe their dietary pattern with a question such as “What do you eat in a typical day?” However, there are several formal written self-assessments that patients can complete in the waiting room that provide more detailed information to help you understand what changes, if any, are needed.88,120–124 One specific example is “Rate Your Plate,” developed by researchers at the Center for Primary Care and Prevention (CPCP) at Memorial Hospital of Rhode Island. This instrument assesses eating patterns by asking about 21 food habits (e.g., intake of meat, milk, sweets, etc.).88,124 This tool can be used for counseling and goal setting as well as assessment and has accompanying patient education materials. Based on your diet assessment, you learn that Mrs. R. eats a diet high in saturated fat (e.g., fatty cuts of red meat several times a week, cheese daily, high-fat snacks and desserts daily), and eats fewer than two servings of vegetables and fewer than two servings of fruits each day. Given the possible link between dietary fat and breast cancer, it seems prudent to counsel Mrs. R about decreasing her dietary fat to lower her risk of breast cancer recurrence. In addition, her cholesterol is high, so there may be more than one behavioral target for dietary counseling. It is important to discuss the results of the diet assessment with her as it will form the basis of much of the behavioral counseling to follow. b. Readiness to change • “Have you thought about changing your diet at all?” • “How much do you want to change your diet right now, on a scale of 1 to 10?” An open-ended question such as the first will often lead to an eye-opening discussion about the patient’s attitudes toward behavior change, their experience with past behavior change, and their plans for future behavior change. A closed-ended question such as the second can also be useful and can be later followed up by asking “What would make you more ready to change your diet right now?” c. History of change efforts • “Have you ever tried to cut down on the amount of fat you eat?” • “What was that like?” Behavior change is a process where repeated trial and error provides the learning necessary to change for good. If you find that, for example, the patient ate lower-fat snacks and desserts for 6 months, you should congratulate them (build their confidence), and ask how they did it and what led to them to change back to higher-fat choices. If, for example, the patient went back to eating more fatty snacks and sweets after the holiday season of eating out at parties and restaurants, this is a great chance to do problem solving and help them overcome a barrier that could impede their progress toward a healthy eating pattern.

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d. Knowledge of risks • “What do you know about the link between what you eat and breast cancer?” • “I see that your cholesterol is high. What do you know about how your eating habits can affect your cholesterol?” Nutrition knowledge varies widely. Data from 1994 showed that 60% of people knew about the dietary fat–heart disease link, although less than 10% knew about the saturated fat–heart disease link.125 The recent emphasis on dietary fat restriction has covered up the important differences between types of fat, and this is a chance to make those clear. In counseling, every opportunity to personalize the message to the patient should be taken, so including a discussion about cholesterol and weight, two issues specific to Mrs. R, is very useful. e. Reasons for changing or maintaining behavior. • “What are the positive (negative) things about the way you eat now?” • “What are the positive (negative) things about making a change in your eating habits?” Understanding the patient’s attitudes and motivations are important. Mrs. R may have had a brother who had been diagnosed with heart disease or another incentive for changing her diet that you could not have imagined but is critical to her. Many people are aware that they have unhealthy eating habits but are ambivalent about it. Allowing them to discuss both sides of the issue can help them to convince themselves to change, but it can also uncover barriers to changing (e.g., someone who eats many meals away from home) or opportunities to changing (e.g., has trouble affording cholesterol medications) that may not have been revealed otherwise. Letting the patient discover these issues is much more powerful than preaching them yourself. 3. Advise: • “As your doctor, I need you to know that reducing the fat, saturated fat, and calories you eat is important for your health because it will help you decrease your cholesterol, maintain a healthy weight, and may decrease the chance that your breast cancer returns.” Strong, clear, and personalized advice is best.47 Personalizing the message plays to the strengths of the clinician who knows the patient and his or her medical history well. Given the frequency of diseases related to diet, most patients in adult practice will have a specific reason for changing their diet. 4. Assist: a. Offer to correct misunderstandings and provide new information. • “Would you like to talk about food choices that would be better for your health?” The above quote may seem too passive for many physicians, but it helps to keep the focus of the counseling on the patient instead of on the physician. Although the word physician means teacher, you must first know whether you have a willing pupil in front of you. If the answer is “yes,” you may use it as a chance to explain the differences between saturated and unsaturated fats and how replacing high-fat snacks and sweets with lower-fat substitutes or using vegetable oils such as canola or olive

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oil, or liquid or tub margarine, would be better choices than butter or stick margarine. If they say “no,” then this may not be the right time for a detailed discussion. Keeping the door open for future discussions then becomes the goal. b. Express empathy • “It’s understandable that you might not want to take steps to change right now.” • “Changing your diet can be very difficult.” Empathy is one of the most critical skills toward building a strong doctor–patient relationship.110,114 Some people believe that empathy may give the patient an “easy way out”; that is, if you prepare them for the possibility of failure, they will fail. If Mrs. R tries to change her eating habits, and fails, she may feel uncomfortable the next time she comes to see you or might cancel her appointment altogether. This discomfort is a barrier to the therapeutic doctor–patient relationship. Empathy for the human condition and the difficulty of behavior change is a part of successful behavior counseling. c. Address barriers to change. • “What might make it difficult for you to eat less fat?” • “Can you think of ways to overcome your craving for sweets, or choose sweets that may be lower in fat?” Problem solving is a critical part of behavior change, either done at home or with the doctor in the office. Two important skills in problem solving are to identify two types of barriers to making the change: (1) attitudes that maintain the problem behavior (e.g., “I don’t like vegetables”) and (2) triggers, that is, situations or feelings that lead to the problem behavior (e.g., “When I go out to dinner, I always eat too much.”). After helping to identify the problems, discuss ways that the patient may overcome the barrier. It is not critical that you have all the answers: remember that the patient has many of them. In this capacity, the physician may serve as a “facilitator” rather than a “lecturer.” People who have more positive attitudes about dietary change or who feel more confident about dealing with their triggers are more likely to go on to change their behavior and, ultimately, to succeed in making behavior changes. d. Consider smaller steps toward the ultimate goal • “It is difficult to make big changes in how you eat all at once. Can you think of any small changes you can make now?” This is especially true for people who are not ready to change. For them, simply thinking about the reasons they have for changing would qualify as a step forward, as they are most likely still defending their habits. For someone like Mrs. R, with five separate behaviors to consider for diet counseling alone (meat, cheese, sweets, fruit and vegetable intake, and calorie intake), focusing on more than one behavior may be counterproductive. Encouraging more fruits and vegetables is often a good first step, as this is a positive change rather than a sacrifice. Increases in fruits and vegetables can lead to decreases in other higher-fat foods such as sweets and meats. Be as specific as possible: “How do you think you could eat more fruits and vegetables?” For example, eating a larger portion of vegetables at dinner, adding a fruit at breakfast and for a snack, etc.

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e. Make goal(s) clear • “Now I’d like us to set a goal for what you will do before you see me again. From what you have told me, you are going to add fruit to your breakfast, eat fruit for a snack, and eat a larger portion of vegetables at dinner. Does that sound like a reasonable goal?” Again, be as specific as possible, so the next time you see the patient, you’ll know exactly where to start and won’t have to go through a lengthy assessment a second time. You’ll be able to say: “When I last saw you, you agreed to work on adding a serving of fruit to your breakfast, eat fruit for a snack, and eat a larger portion of vegetables at dinner. How did that go?” In addition, when the goal is clear, you can give targeted patient information, instead of a generic guide to healthy eating. The patient will be more likely to listen, believing that it is more specific to their situation. f. Refer interested patients • “It seems that you’re eating too much saturated fat, which may be the reason why your cholesterol is high. First, I would like to help you try to improve your eating habits, before I consider giving you medications. Medications may have side effects and you may have to take them for the rest of your life. A nutritionist can really help you make changes in your eating habits. Do you think you would be interested in seeing a nutritionist?” For patients who have health problems that can be improved via a dietary change, strong consideration should be given to referral to a qualified dietitian. Given the fact that many patients will not follow through with referrals, asking about their interest in a nonjudgmental way allows you to save time and keep the patient feeling involved in the decision process. 5. Arrange follow-up: a. Keep the door open for further dialogue. • “Is this something you are willing to talk about again at your next visit?” Setting the stage for future discussions is critical to maintaining a therapeutic doctor–patient relationship. Repeated “doses” of behavioral counseling are often necessary over months or years and on a variety of topics aside from nutrition. Thus, neither the patient nor physician should view the counseling session as particularly stressful. This approach also reminds patients that they are an active member of their care team, thereby encouraging autonomy.115 b. Schedule follow-up appointment or phone call to further discussion. • “Would you be willing to schedule another appointment to talk about how your dietary changes are going and recheck your cholesterol?” Scheduling a return visit will help the patient to understand the importance of making dietary changes and, like a student held accountable for homework, will encourage the patient to follow through on the goals set above. Providing counseling or advice to your patients takes time, but it is worth the effort in helping your patient to achieve better health as well as improving the doctor–patient

364 relationship. Even if you cannot do everything this chapter suggests, physician advice alone has been shown to be more effective that no intervention at all,47 and these strategies are likely to improve patient adherence and satisfaction.

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107. Ferrini RL, Perlman M, Hill L. American College of Preventive Medicine practice policy statement: skin protection from ultraviolet light exposure. The American College of Preventive Medicine. Am J Prev Med 1998;14(1):83–86. 108. Ferrini RL, Perlman M, Hill L. Skin protection from ultraviolet light exposure: American College of Preventive Medicine Practice Policy Statement. Am J Prev Med 1998;14(1):83–86. 109. Greenfield S, Kaplan S, Ware JE Jr. Expanding patient involvement in care. Effects on patient outcomes. Ann Intern Med 1985;102(4):520–528. 110. Kaplan SH, Greenfield S, Ware JE Jr. Assessing the effects of physician-patient interactions on the outcomes of chronic disease. Med Care 1989;27(suppl 3):S110–S127. 111. Rost K, Flavin M, Cole K. Change in metabolic control and functional status after hospitalization: impact of patient activation intervention in diabetic patients. Diabetes Care 1991;14: 881. 112. Bertakis KD, et al. Physician practice styles and patient outcomes: differences between family practice and general internal medicine. Med Care 1998;36(6):879–891. 113. Safran DG, et al. Linking primary care performance to outcomes of care. J Fam Pract 1998;47(3):213–220. 114. Paasche-Orlow M, Roter D. The communication patterns of internal medicine and family practice physicians. J Am Board Fam Pract 2003;16(6):485–493. 115. Williams GC, Freedman ZR, Deci EL. Supporting autonomy to motivate patients with diabetes for glucose control. Diabetes Care 1998;21(10):1644–1651. 116. Glynn TJ, Manley MW. How to Help Your Patients Stop Smoking. Bethesda, MD: National Institutes of Health, National Cancer Institute, 1997. 117. Goldstein MG, et al. Models for provider-patient interaction: applications to health behavior change. In: Shumaker SA, et al (eds). The Handbook of Health Behavior Change. New York: Springer, 1998:85–113. 118. Pinto BM, Goldstein MG. Physician-delivered physical activity counseling. Med Health Rhode Island 1997;80(9): 303–304. 119. Sciamanna CN, et al. Nutrition counseling in the promoting cancer prevention in primary care study. Prev Med 2002; 35(5):437–446. 120. Retzlaff BM, et al. The Northwest Lipid Research Clinic Fat Intake Scale: validation and utility [see comments]. Am J Public Health 1997;87(2):181–185. 121. Kris-Etherton P, et al. Validation for MEDFICTS, a dietary assessment instrument for evaluating adherence to total and saturated fat recommendations of the National Cholesterol Education Program Step 1 and Step 2 diets. J Am Diet Assoc 2001;101(1):81–86. 122. Subar AF, et al. Fruit and vegetable intake in the United States: the baseline survey of the Five A Day for Better Health Program. Am J Health Promot 1995;9(5):352–360. 123. Thompson FE, et al. Evaluation of 2 brief instruments and a food-frequency questionnaire to estimate daily number of servings of fruit and vegetables. Am J Clin Nutr 2000;71(6): 1503–1510. 124. Gans KM, et al. Rate Your Plate: An eating pattern assessment and educational tool used at cholesterol screening and education programs. J Nutr Educ 1993;25:29–36. 125. Fogel RW. Continuing Survey of Food Intakes: Diet and Knowledge Health Survey Questionnaire. Rockville, MD: United States Department of Agriculture, 1996.

SECTION FOUR

Cancer Imaging

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Central Nervous System Imaging Dima A. Hammoud and Martin G. Pomper

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rain tumor imaging has four main goals, namely, evaluating lesion extent, estimating tumor grade, identifying associated complications, and defining a comprehensive differential diagnosis. It assesses the relationship of the lesion to various brain structures and identifies associated findings, such as increased intracranial pressure, impending herniation, hydrocephalus, hemorrhagic transformation, and mass effect. A comprehensive differential diagnosis is usually established based on the patient’s age, tumor location, and specific imaging findings. Cross-sectional imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is necessary for accurate brain tumor characterization. Plain film imaging has virtually no role. Before the advent of CT scan and MRI, imaging techniques, such as pneumoencephalography and plain film X-rays of the skull, were the only options for neurosurgeons in the preoperative evaluation of brain tumors. Crosssectional imaging has significantly facilitated the task of preoperative evaluation and planning of brain tumor surgery.

Computed Tomography Since its introduction in the 1970s, CT has enjoyed wide application within all the radiologic subspecialties. In fact, CT has effectively replaced conventional tomography and many other radiologic procedures (e.g., lymphangiography and pneumoencephalography). CT has undergone major changes in the past few years, with incremental improvements in hardware and software technologies, including refinement of spiral CT systems, overcoming limitations. In a typical modern spiral or “helical” CT scan, instead of obtaining data using sequential single exposures by moving the gantry, the patient is moved through a rotating, continuous fan-beam exposure, and a block of data in the form of a corkscrew or helix is obtained.1 Improvements, such as the introduction of higher heat capacity X-ray tubes, subsecond X-ray tube rotation times, detector technologies, and realtime image reconstruction computer hardware and software, transformed CT scan into a very fast, large-volume, multibeam acquisition technology. CT, however, currently plays a limited role in brain tumor imaging. Its availability in the emergency department makes it the first-line technique for evaluating patients presenting with signs and symptoms of increased intracranial pressure, seizures, and other neurologic symptoms that could be caused intracranial neoplasms. Inevitably, if a tumor is discovered on

CT, the patient will need further imaging, usually with contrast-enhanced MRI for adequate evaluation. Patients with contraindications to MRI, such as severe claustrophobia, a pacemaker, or severe obesity may have to undergo a contrast-enhanced CT scan instead of MRI. One of the advantages of CT is its ability to depict hemorrhagic and calcific findings, which could narrow the differential diagnosis of a detected lesion in certain cases (Figure 27.1). It also provides information about bony lesions, such as metastatic disease to the skull and hyperostotic changes associated with meningiomas. Detailed anatomy of the base of the skull, provided by CT imaging, can provide precious information in specific cases, such as intracranial extension of nasopharyngeal tumors and metastatic disease. Currently, CT is not routinely used in the evaluation of patients with brain tumors either pre- or postoperatively, with few exceptions.

Magnetic Resonance Imaging Magnetic resonance imaging has become the mainstay of diagnosis in the evaluation of primary and metastatic brain tumors. Unfortunately, MRI is very sensitive but not very specific. Although it provides excellent anatomic detail, MRI remains incapable of accurately grading tumors. Extension of T2 signal abnormalities, involvement of the corpus callosum, enhancement pattern, cortical involvement, intra- versus extraaxial localization, mass effect, and the age of the patient are some of the factors that allow the radiologist to narrow the differential diagnosis of a brain lesion. New techniques are constantly being developed to increase the specificity of MRI. Among the most promising of those new techniques are fast fluid-attenuated inversion recovery (FLAIR) imaging, diffusion-weighted imaging (DWI), perfusion imaging, and magnetic resonance spectroscopy (MRS). Functional MRI (fMRI), diffusion tensor imaging, magnetization transfer (MT) imaging, and perfusion imaging with arterial spin labeling are applied clinically only infrequently.

Fast Fluid-Attenuated Inversion Recovery (FLAIR) Imaging FLAIR is an MRI sequence that produces heavily T2-weighted images with cerebrospinal fluid (CSF) signal suppression by employing a specific inversion pulse placed at the CSF null point.2 Suppression of the CSF signal leads to better lesionto-CSF contrast, allowing better delineation of masses adja-

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FIGURE 27.1. (A) Oligodendroglioma: nonenhanced computed tomography (CT) scan showing left frontal hypodense mass with calcifications. (B) Intradiploic epidermoid cyst: nonenhanced CT scan showing bony erosion and expansion.

cent to ventricles and sulci (Figure 27.2); however, that is true only for relatively large lesions, as small tumors may be lost among the periventricular gliosis that appears bright on FLAIR.3 Based on multiple studies, FLAIR was found to be superior to both proton density (PD)- and T2-weighted images in delineating intraparenchymal lesions. In a large prospective, blinded analysis, Maubon et al. evaluated 102 patients with a multitude of neurologic presentations, including brain tumors, using turbo spin echo (TSE), turbo FLAIR, and gradient and SE (GRASE) images. They found that FLAIR was significantly superior to both GRASE and turbo SE for white matter disease (P less than 0.05), superior only to TSE (P less than 0.05) for vascular disease, but not superior to either gradient SE or TSE for tumors.4 Multiple descriptive studies with smaller numbers of patients showed more encouraging results: increased sensitivity of detection and better conspicuity of lesions using FLAIR sequences compared to T2weighted images,5 better appreciation of peritumoral edema, and better definition between edema and tumor than T2weighted and proton density-weighted images.6 In a retro-

spective analysis including only 18 patients, Bynevelt et al. found FLAIR to be superior for appreciation of the lesion (91% of studies) and for demonstration of its margin (92%) and suggested that FLAIR can replace PD- and T2-weighted spin-echo imaging in radiologic follow-up of low-grade glioma.7 All three studies, however, relied on the subjective evaluation of the quality of images by different readers. FLAIR imaging has also been used in the differentiation of intracranial epidermoid from other pathologies, related mostly to the incomplete signal suppression due to the presence of keratin and cholesterol crystals in epidermoids (Figure 27.3B). In a series of eight patients with a surgically confirmed diagnosis of epidermoid, Chen et al. compared conventional MR sequences with fast fluid-attenuated inversion recovery (fast-FLAIR) and echo-planar diffusion-weighted (DW) MR imaging. On fast-FLAIR imaging, the mean signal intensity of epidermoid tumors was significantly higher than that of CSF but significantly lower than that of the brain. The authors concluded that fast-FLAIR imaging is superior to conventional MR imaging in depicting intracranial epidermoid

FIGURE 27.2. (A) T2-weighted and (B) fast fluidattenuated inversion recovery (FLAIR) image of left frontal lobe anaplastic astrocytoma. FLAIR delineates the tumor border more clearly as a result of inherent cerebrospinal fluid (CSF) signal suppression.

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study evaluating 70 patients with cytologically proven leptomeningeal metastases, FLAIR imaging was found to have a sensitivity of only 34% for disease detection, compared to 66% for gadolinium-enhanced MR10 (Figure 27.4B). So, although FLAIR can help support the diagnosis, it alone cannot be used for the exclusion of leptomeningeal metastases, and contrast-enhanced T1-weighted imaging remains essential for that diagnosis. Contrast-enhanced FLAIR imaging, on the other hand, can improve detection of leptomeningeal disease in pediatric patients when compared to routine contrast-enhanced T1-weighted imaging, partly because of suppression of signal intensity from normal vascular structures on the surface of the brain, allowing easier visualization of abnormal leptomeninges.11 That study, however, was limited by the small number of patients with a history of medulloblastoma (n = 6). The lack of definite proof of the usefulness of enhanced FLAIR images has hampered the routine implementation of this sequence in the clinical evaluation of brain tumor patients.

Diffusion-Weighted Imaging

FIGURE 27.3. (A) T2-weighted images, (B) FLAIR images, (C) diffusion-weighted image (DWI), and (D) apparent diffusion coefficient (ADC) maps of posterior fossa epidermoid cyst eroding the bone. Note incomplete suppression of signal on FLAIR images and restricted diffusion on DWI and corresponding ADC maps.

cysts.8 Similar results confirming the superiority of FLAIR to other sequences in the evaluation of epidermoid cysts were reached by Ikushima et al.9 A recent application of FLAIR imaging is the evaluation of leptomeningeal spread of tumors, whether primary or metastatic. High signal intensity in the sulci and fissures is suggestive of tumor involvement (Figure 27.4A). In one

FIGURE 27.4. 10 year-old patient with leukemic meningeal infiltration. (A) FLAIR shows increased signal in the sulci at the brain convexity, more on the right side (arrowheads). (B) Corresponding enhanced T1-weighted images show marked meningeal enhancement compatible with the diagnosis of diffuse leukemic involvement.

Diffusion-weighted imaging (DWI) relies on the detection of the Brownian motion of water molecules between the intracellular and extracellular spaces in the brain. Such motion through tissue is a random event, the speed and direction of which is dictated by the presence of barriers such as macromolecules, cell membranes, and cellular organelles. Contrast is generated on DWI through background suppression and changes in signal intensity between images obtained at different gradient strengths (b values) that are sensitive to diffusion. Apparent diffusion coefficient (ADC) maps are then generated as the slopes of the lines derived from plotting the natural log of the signal intensity (SI) versus gradient strength. These apparent diffusion coefficient maps are essential for the visual evaluation of diffusion because the signal intensity (SI) of DWI is prone to T2 shine-through effects from heavy T2 weighting. ADC maps are independent of T1 and T2 effects, with decreased ADC values indicative of decreased diffusion.3 DWI has been evaluated for its potential in the differentiation of necrotic brain tumors from abscesses, of infiltrat-

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FIGURE 27.5. Enhanced T1-weighted images, DWI images, and ADC maps of (A) right parietal abscess and (B) left parietooccipital glioblastoma multiforme (GBM). Note restricted diffusion in the abscess cavity (increased signal on DWI and decreased signal on ADC maps) in A compared to nonrestricted diffusion of the necrotic tumor (decreased signal on DWI and increased signal on ADC maps) in B.

ing tumor from vasogenic edema, and in tumor grading. Resembling free water, necrotic or cystic portions of tumors display high ADCs whereas abscess cavities, consisting of necrotic debris, neutrophils, and bacteria, which impede free water diffusion, tend to have low ADCs12 (Figure 27.5). However, although Dorenbeck et al. found overlapping ADC values between tumors and abscesses,13 multiple other studies demonstrated the opposite. In a case-control designed study, Guzman et al. found that the ADC values in patients with brain abscesses were significantly lower than those in patients with neoplastic lesions (P less than 0.05).14 Similar confirmatory results were reached by other investigators.15–17 Besides the differences seen within the cystic/necrotic portions, Chan et al. found that the tumor wall of cystic or necrotic brain tumors had significantly lower ADCs relative to those of the abscess wall (P less than 0.005).18 In a more quantitative study in which the authors calculated ADC values based on eight gradient (b) values, the specificity of DWI in differentiating tumor from abscess was 100% using a threshold ADC value of 1.10 ¥ 10-3 mm2/s. Unfortunately, those results cannot currently be applied clinically because most available commercial systems calculate ADC based on two b values only.19 Another application of DWI is the differentiation of epidermoid tumors from arachnoid cysts, a classic diagnostic problem on conventional MRI sequences. Because cysts contain more free water than solid masses, they tend to have more restricted diffusion and higher ADC values (see Figure 27.3C,D), which proved to be the case for arachnoid cyst versus epidermoid, as proven in two preliminary studies.20,21 DWI was found to provide the best lesion conspicuity of epidermoid in comparison to FLAIR and conventional sequences.8 By implementing both FLAIR (see foregoing) and DWI, epidermoid and arachnoid cysts can be fairly easily dif-

ferentiated without cisternography, the previous clinical standard, in the majority of cases.3 The ability of DWI to differentiate between high- and lowgrade tumors has been evaluated by several groups. Sugahara et al. found that the cellularity of a variety of histologically verified gliomas correlated well with the minimum calculated ADC value of these tumors (P = 0.007) but not with the signal intensity on T2-weighted images.22 They hypothesized that the highly cellular (higher-grade) gliomas would have smaller intercellular space than tumors of lower cellularity and consequently would display lower ADCs; this is similar to the case for lymphoma and medulloblastoma, both being highly cellular CNS tumors and known to display low ADC values.23 Further support for the utility of DWI in tumor grading comes from the work of Bulakbasi et al., who evaluated 49 patients with malignant tumors. They found that ADCs were effective for grading malignant tumors (P less than 0.001) but not for distinguishing different tumor types with the same grade. In this study, high-grade malignant tumors had significantly lower ADC values than did lowgrade malignant and benign tumors.24 Two more studies further supported the previous results, showing that ADC values are significantly higher in low-grade than in high-grade tumors.25,26 As far as tumor extension is concerned, however, DWI provided no clear advantage over the conventional methods. ADC values could not separate high-grade gliomas from surrounding edema.25,27,28

Perfusion Imaging The most common MR perfusion imaging techniques exploit the spin dephasing (T2*) effect from the passage of contrast through the parenchymal capillary bed. The SI loss engendered by the passage of gadolinium-based contrast enables cal-

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culation of contrast concentration within each pixel over time, which in turn provides relative measurements of regional cerebral blood volume (rCBV). Rapid imaging is necessary to gather as much data as possible from the entire brain during the first-pass of a bolus injection of gadolinium.3 Perfusion imaging likely reflects tumor angiogenesis, a strong indicator of tumor grade. Studies employing perfusion techniques with histologic correlation agree that high rCBVs mean higher tumor grade (Figure 27.6). Specifically, rCBV correlated with areas highest in mitotic activity and vascularity but not with areas of cellular atypia or high cellularity.29 Sugahara et al. found a significant correlation between rCBV ratios of gliomas and vascularity of the tumors determined both by angiography and histology (P less than 0.001).30 In a series of 160 patients, Law et al. demonstrated increased sensitivity of detection of high-grade gliomas with rCBV values when compared to conventional imaging only. They also demonstrated a significant difference in the values of rCBV between high-grade and low-grade gliomas (P less than 0.0001).31 Similar results were reached in three other studies.32–34 Perfusion imaging has proved helpful in the preoperative diagnosis of and differentiation between different brain lesions. Recently, Hartmann et al. found significantly lower rCBVs in primary CNS lymphoma (PCNSL) compared to glioblastoma multiforme (GBM) (P less than 0.0001).35 Similarly, low rCBV measurements were found in 17 patients with gliomatosis cerebri, which is in concordance with the lack of vascular hyperplasia found at histopathologic examination in those tumors. The authors concluded that perfusion MR imaging provides useful adjunctive information to conventional MR imaging techniques in the evaluation of this relatively rare but important entity.32 In the classic problem of differentiating toxoplasmosis from lymphoma in patients with acquired immunodeficiency syndrome (AIDS), rCBV was decreased throughout the toxoplasmosis lesions whereas all active lymphomas displayed areas of increased rCBV. The difference in rCBV between those two entities was significant (P less than 0.005). Reduced rCBV in toxoplasmosis lesions is probably due to a lack of vasculature within the abscess

FIGURE 27.6. (A) T2-weighted image of glioblastoma multiforme showing necrotic changes with well-defined areas of abnormal signal intensity, compatible with tumor, anterior, medial and posterior to the cystic component as well as in the right centrum semiovale. (B) Corresponding regional cerebral blood volume (rCBV) maps show marked increased values in the posterior component (arrows) and in the wall of the necrotic tumor (small arrowheads), suggestive of a higher-grade component of the tumor.

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compared to the hypervascularity of lymphomas, especially within foci of active tumor growth.36 Finally, in a series of 51 patients, Law et al. found that peritumoral rCBV values in high-grade gliomas were significantly higher than in metastases (P less than 0.001). Mean maximum rCBV in high-grade gliomas was also significantly higher than in low-grade gliomas in a study by Yang et al.32 Whether perfusion imaging can be used to define tumor borders remains an attractive concept to be investigated.

Magnetic Resonance Spectroscopy Chemists have relied on nuclear magnetic resonance (NMR) spectroscopy for 50 years for molecular structure elucidation; magnetic resonance spectroscopy (MRS) is an in vivo extension of NMR. More than for structure determination, however, MRS is applied in medicine to determine the concentrations of a relatively few metabolites that are altered in disease. In MRS, the high-resolution morphologic imaging capabilities of MR are sacrificed to provide metabolic data that, in many cases, precede structural abnormality.3 Proton MRS is the most commonly applied technique for brain tumors because of the high natural abundance of protons in tissue. For brain tumor proton spectroscopy, the metabolites of interest include N-acetylaspartate (NAA), choline (Cho), creatine (Cr), lactate, lipids, and certain amino acids, such as alanine and succinate.37 MRS imaging (MRSI) and chemical shift imaging (CSI) provide phase encoding of spatial information and generate metabolite maps. Multislice MRSI competes with single-voxel MRS, in which a small portion of the lesion is interrogated rather than the whole tumor volume, which is more easily implemented, with brief imaging times (less than 10 min/volume element, or voxel) and commercially available software. Nevertheless MRSI, with its smaller voxel size (less than 1 cm3) and superior brain coverage, is necessary for complete characterization of heterogeneous brain tumors. The key metabolite in brain tumor MRSI is choline (Cho), the underlying causes for the alteration of which remain controversial. The majority of choline in the brain is, in normal

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FIGURE 27.7. Patient with right temporal lobe glioblastoma multiforme. Metabolite maps on the right side are notable for increased choline (Cho) in the lesion (circle). Note decreased N-acetylaspartate (NAA) peak and marked increased Cho peak in the right temporal lobe (upper spectrum) when compared to the normal contralateral temporal lobe (lower spectrum).

conditions, bound to cell membranes, myelin, and complex brain lipids. In pathologic conditions, Cho is thought to reflect cell membrane, myelin, and lipid turnover, leading to release of MRS-visible Cho.38 Cho is present primarily within glia.39 Because malignant brain tumors are glial neoplasms, it seems reasonable that Cho would be elevated within them, as is usually reported (Figure 27.7). In fact, in one study by Gupta et al., a statistically significant linear correlation between tumor to contralateral normalized Cho signal ratio (nCho) and cell density was found, although nCho did not significantly correlate with proliferative index.40 Low NAA levels in brain tumors are believed to be the result of the lack of neurons in what are essentially glial neoplasms (Figure 27.7). Increased lactate and lipids are found in brain tumors, the former believed to be associated with high tumor glycolytic rates and the latter caused by cellular breakdown and necrosis.3 Originally, MRSI was evaluated in the differentiation of normal from neoplastic tissue and its impact on decision making and surgical planning. Rand et al. found that the prospective accuracy of MRSI in the nonblinded and retrospective accuracy in the blinded discrimination of neoplastic from nonneoplastic disease were 0.96 and 0.83, respectively.41 However, preoperative diagnosis and grading remain the goals of brain tumor MRSI. Despite the stunning results obtained in one study in which Preul et al. accurately graded 90 of 91 brain tumors,42 most studies report such overlap as to make spectroscopy of marginal utility for tumor grading. In a study by Bulakbasi et al., MR spectroscopy could differentiate benign from malignant tumors but was not useful in grading malignant tumors. However, in the same study, ADC values were effective for grading malignant tumors (P less than 0.001) but not for distinguishing different tumor types with the same grade, as previously mentioned. The authors concluded that the two modalities can have a complementary effect in the differentiation and grading of brain tumors.24 Law et al. proved that the combination of rCBV, Cho/Cr, and Cho/NAA resulted in increased specificity for the detection of high-grade gliomas from 57.5% with rCBV alone to 60.0% with both modalities. No increased sensitivity, posi-

tive predictive value (PPV), or negative predictive value (NPV) was achieved, however, when the MRS findings were combined with perfusion.31 In a series of 176 patients, however, Moller-Hartmann et al. were able to establish that the additive information of proton MRSI led to a 15.4% higher number of correct diagnoses, 6.2% fewer incorrect, and 16% fewer equivocal diagnoses than with structural MRI data alone, in a multitude of pathologies, including brain tumors.43 Perhaps more clinically useful than tumor grading is the role of MRS in the planning of guided biopsies. In 29 patients in whom the preoperative metabolite levels were correlated with the histologic findings, it was found that with abnormally increased Cho and decreased NAA, biopsy invariably was positive for tumor.44 Similar results were reached by Martin et al.45 In the evaluation of tumor borders in 31 patients with diffusely infiltrating gliomas, Croteau et al. tried to determine a correlation between different proton MRS/I metabolic ratios and the degree of tumor infiltration. They correlated the metabolite ratios with the histopathologic analyses of biopsies obtained at the same location and found that the Cho to normal contralateral Cr and Cho to normal contralateral Cho ratios (Cho/nCr and Cho/nCho) were positively correlated with the degree of tumor infiltration, whereas the NAA to normal contralateral Cr ratio (NAA/nCr) was negatively correlated, for all tumor grades combined.46 The strength of this study resides in the coregistration of the biopsy sites with the metabolite values obtained from the same voxels. The potential of MRSI in the accurate delineation of tumor borders requires further investigation. Another use for MRSI is in the differentiation of primary from metastatic brain tumors. In a recent study, a significant increase in Cho concentration was found in both the peritumoral and tumoral regions of malignant gliomas, compared with metastases. Similarly, a prominent difference in the Cho/Cr ratio between gliomas and metastases (P less than 0.05) and elevated myo-inositol levels (MI/Cr) within the enhancing foci of gliomas but not in the metastases were also found (P less than 0.05). That study, however, was limited by the small number of patients (22).47

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Functional Magnetic Resonance Imaging The main use for functional magnetic resonance imaging (fMRI) in neuroimaging has been for the noninvasive study of brain activation. The most common fMRI method detects signals based on the blood oxygen level dependence (BOLD) effect. During brain activation, there is increased blood flow to the area of activation, which appears to be a direct consequence of neurotransmitter activity. Blood flow increases over a wider volume and to a greater extent than is necessary simply to provide oxygen and glucose for increased metabolism, so oxygen extraction decreases with greater neuronal activity. Consequently, the ratio of oxygenated (diamagnetic oxyhemoglobin) to deoxygenated (paramagnetic deoxyhemoglobin) blood near the corresponding areas of neuronal activation will increase, resulting in lower T2* (dephasing) effect and increased signal.48 Statistical techniques are employed or baseline images are subtracted from images obtained during activation to generate activation maps that are superimposed on MR images. In brain tumor imaging, fMRI is generally used for the preoperative localization of sensorimotor cortex, hemispheric language dominance, and other eloquent (essential) regions, locations that can be perturbed in the presence of a tumor. Cerebral reorganization (plasticity) is defined as the capacity of ipsilateral and contralateral brain regions to assume functions that are normally assumed by the damaged brain. That

FIGURE 27.8. Cerebral reorganization in righthanded patient with right paracavernous meningioma. Functional magnetic resonance imaging (MRI) demonstrates that the task of reading words activates superiorly displaced speech areas in the right hemisphere. The patient was informed of the risk of losing speech postoperatively.

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reorganization puts critical motor regions at risk if the standard anatomic techniques are used to locate motor cortex preoperatively. Functional MRI can preemptively locate that reorganized cortex (Figure 27.8). Neurosurgeons routinely perform cortical mapping intraoperatively. Cortical mapping is just that; that is, it determines function only in the cortex, which is a peripheral brain structure. Functional MRI can evaluate subcortical structures in areas far removed from the limited amount of cortex that is exposed and therefore available for intraoperative mapping.3 Functional MRI, however, is incompletely validated. Good, but not perfect, correlation between fMRI and cortical electrical stimulation has been demonstrated in several studies.49,50 Studies comparing PET and fMRI have shown much lower degrees of correlation, usually around 50%, with some patients showing no correlation of activation between the two techniques.51,52 Additionally, it remains unclear whether nonactivated brain regions may be safely resected, in part because of that spatial and temporal dispersion of blood oxygen level changes. Schreiber et al. found that the BOLD contrast can be reduced in the proximity of gliomas, but not affected by nonglial space-occupying lesions, such as vascular malformations, leading to overinterpretation of the interhemispheric reorganization in gliomas.53 Similar results were reached by Holodny et al., who suggested that this could result from loss of autoregulation in the tumor vasculature of glioblastomas and venous compression.54

376 Although fMRI is a noninvasive technique with high spatial and temporal resolution, short examination time, and wide availability, it will likely not replace intraoperative cortical mapping.

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be integrated into a neurosurgical planning system. Newer techniques decreasing the time of acquisition and minimizing image distortion are being investigated60 and could help in making diffusion tensor imaging applicable for routine clinical practice.

Diffusion Tensor Imaging Diffusion tensor imaging (DTI) is a magnetic resonance technique that is sensitive to the diffusion of water in brain tissue, thus revealing the anisotropy and orientation of white matter tracts in the brain. Myelin or protein fibers likely account for diffusion anisotropy. Measurement of ADCs along six independent axes of the tensor provides the shape of the diffusion ellipsoid, that is, fully characterizes diffusion in three dimensions. Mean diffusivity (MD) and fractional anisotropy (FA) can be calculated for each pixel, representing the magnitude and directionality of water diffusion within that pixel. Once fiber direction is known in each pixel, a three-dimensional (3-D) map can be generated that depicts patterns of connectivity throughout the brain. Display of the effects of mass lesions on large nerve fiber tracts by DTI can be used for preoperative planning. Specifically, fiber mapping enables visualization of subcortical fiber tracts that are important in motor function. Although many studies have demonstrated the usefulness of diffusion tensor imaging in the delineation of tumor infiltration, vascularity, and cellularity55–57 (Figure 27.9), in the differentiation between peritumoral edema and tumor infiltration,58 and in the differentiation between metastasis and primary brain tumors,59 more studies and well-organized clinical trials need to be performed before fiber tracking can

Positron Emission Tomography and Single-Photon Emission Tomography Positron emission tomography (PET) exploits the annihilation of positrons and electrons into photons to achieve the nuclear imaging analog of X-ray computed tomography (CT). In the decay of a positron-emitting radionuclide, the positron interacts with an electron, yielding two photons that travel in (nearly) opposite directions. By detecting those photons in coincidence, the projection data required for tomographic reconstruction are obtained. 18F-Fluorodeoxyglucose (FDG) is the most commonly used tracer in the clinic. Similar to glucose, FDG is transported into cells by a glucose transporter, but remains trapped within the cell, thus reflecting the energy metabolism within tissues. Highly malignant brain tumors usually show increased FDG uptake in comparison to the surrounding brain parenchyma (Figure 27.10). However, because of inherent limitations, such as low resolution and high background glucose metabolism of normal gray matter structures, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) use is not a part of the routine diagnostic evaluation of brain tumor patients. Other potential uses for PET in brain tumor evaluation include grading, localization for biopsy, differentiating radiation necrosis from tumor

FIGURE 27.9. Fiber tracking in brain tumors with diffusion tensor imaging (DTI). The threedimensional (3-D) relationship of the corona radiata with the tumor can be clearly appreciated. The corona radiata of the first patient (A) surrounds the surface of the tumor because of mechanical compression rather than infiltration. In the second patient’s case (B), the trajectory of the corona radiata was not changed. Instead, it projected into the core of the infiltrative tumor. (From Mori et al.,57 by permission of Annals of Neurology.)

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FIGURE 27.10. (A) CT scan, (B) 18Ffluorodeoxyglucose positron emission tomography (FDG-PET) scan, and (C) fused CT and PET scan images of left frontal lobe recurrent GBM. Note increased FDG uptake in the periphery of the necrotic mass (black arrows), compatible with tumor recurrence rather than radiation necrosis. Note the presence of another focus of increased uptake (white arrow) in the right parietal region consistent with the diagnosis of multifocal GBM.

necrosis, assessing response to therapy, predicting survival, and assessing malignant transformation of low-grade gliomas. In 47 patients with different brain tumors, the sensitivity of FDG-PET for differentiating tumor from radiation necrosis was 75% and the specificity was 81%.61 In another study yielding even lower sensitivity and specificity values, the authors concluded that the ability of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) to differentiate recurrent tumor from radiation necrosis is limited.62 FDGPET was found to be of prognostic importance in multiple studies.63,64 However, in the assessment of response to chemotherapy or radiotherapy, the role of FDG-PET remains of limited clinical utility.65 Newer tracers such as methyl-[11C]-l-methionine (MET) for measurement of amino acid transport and incorporation and 18F-3-deoxy-3-fluorothymidine (FLT) for evaluation of DNA synthesis, among others, seem to be promising in further characterization of brain tumors; however, they remain of limited clinical use currently. The use of single-photon emission tomography (SPECT) in brain tumors is limited. Thallium (Tl) is the most studied radiotracer with the longest track record. Some studies have shown a relationship between 201Tl uptake and tumor grade.66 Due to the overlap between tumor uptake and histologic grades, 201Tl cannot be used as the sole noninvasive diagnostic or prognostic tool in brain tumor patients.67,66 However, it may help in differentiating a high-grade tumor recurrence from radiation necrosis. 99mTc-Sestamibi is theoretically a better imaging agent than 201Tl, but it has not convincingly been shown to differentiate tumors according to grade.68

Intraoperative Imaging and Navigation Stereotactic Navigation Rapid 3-D MR techniques that provide thin sections (1.5 mm) can be merged with a frameless stereotactic system to improve the safety and accuracy of neurosurgical procedures. Using this technique, the surgeon’s “view” is expanded to include structures deep to the region that he or she is resecting in real time. Accurate delineation of the boundaries of the lesion is the goal with this technique, as the completeness of resection is highly correlated with survival for both low- and high-grade tumors. The usefulness and reliability of the

method was immediately recognized and allowed its widespread use. In a large series of 325 cases, the use of the frameless stereotactic viewing system was associated with minimal additional effort or time spent in setting up the procedure. The system was found to be reliable, achieving a useful registration in 95.4% of cases.69 In another case-control study, the impact of neuronavigation on glioblastoma surgery regarding time consumption, extent of tumor removal, and survival was evaluated, with and without the use of neuronavigation, in 52 cases and in 52 corresponding controls. Radical tumor resection based on radiologic evaluation was achieved in 31% of navigation cases versus 19% in conventional operations. The absolute and relative residual tumor volumes were significantly lower with neuronavigation. Radical tumor resection was associated with a highly significant prolongation in survival (P less than 0.0001). Survival was longer in patients who underwent surgery using neuronavigation (median, 13.4 versus 11.1 months).70 Similarly, stereotactic techniques have improved the efficiency of postoperative radiation of brain tumors. In stereotactic conformal radiotherapy, a computer-generated plan guides the use of a variable collimator to distribute the radiation field in such a way that the tumor may receive a very large dose, a surrounding area a moderate dose, and radiosensitive structures a minimal dose of radiation.71 Problems arise with techniques that use preoperative image coregistration, however, because the brain tends to move during the procedure due to swelling or to the introduction of air. Intraoperative acquisition of data sets eliminates the problem of brain shift in conventional navigational systems.

Intraoperative MRI Techniques Intraoperative MR devices, either with an upright double doughnut configuration or that require the patient to be moved to a magnet adjacent to the operating suite, have been developed to avoid potential image misregistration. Intraoperative MR techniques enable continual, near real-time visual feedback during the procedure.3 In one study evaluating 38 patients with high-grade gliomas, intraoperative MR imaging significantly increased the rate of complete tumor removal.72 Other uses for intraoperative MR, besides guidance to the site of an abnormality, include minimization of the size of the craniotomy, identification of adjacent structures, thus maximizing preservation of normal tissue, determination of the

378 completeness of tumor resection, and surveillance for intraoperative complications.73,74–76

Postoperative Evaluation The differentiation of tumor recurrence from radiation necrosis in patients with malignant gliomas who have been treated previously remains a challenge. Multiple imaging modalities were evaluated to address the problem, including FDG-PET, MRS, and perfusion imaging, in view of the limitations of conventional MRI in these cases. FDG-PET has been traditionally used in the differentiation of recurrence from radionecrosis. Sensitivities for detection of recurrent tumor ranged from as low as 43% to as high as 86%.61,62,77,78 Lower specificity values, however, were found, and most investigators considered the modality insufficient for the evaluation of tumor recurrence.62,77 MRS/I is finding a niche in therapeutic monitoring and has recently been applied with success to the classic problem of differentiating recurrent tumor from radiation injury. In one study (n = 56), a significant difference in metabolite ratios (Cho/Cr and Cho/NAA) emerged between neoplastic and nonneoplastic lesions after stereotactic radiotherapy.79 In another prospective study involving 27 patients, MRSI spectral patterns allowed reliable differential diagnostic statements to be made when the tissues are composed of either pure tumor or pure necrosis; however, these were less definitive in tissues composed of varying degrees of mixed tumor and necrosis.80 Perfusion imaging is also helpful in the prognostic evaluation and postoperative follow-up of patients with brain tumors. Although tumors that recur after radiation therapy tend toward lower rCBV values than native lesions, earlier diagnosis of recurrent tumor has been suggested using perfusion imaging than with serial MR imaging or with nuclear imaging techniques. In a series of 59 patients, perfusion imaging (rCBV maps) was found to predict tumor progression earlier than MR imaging in 32%, earlier than 201 Tl-SPECT in 63%, and earlier than clinical assessment in 55% of the studies.81 Sugahara et al. evaluated 20 patients with the diagnosis of recurrent tumor versus radionecrosis by a combination of perfusion imaging and thallium singlephoton emission tomography (201Tl-SPECT). The rCBV values overlapped between neoplastic and nonneoplastic lesions, and the authors suggested that 201Tl-SPECT may be useful in making the differentiation.82 In view of an improved spatial resolution in comparison to SPECT and PET,83 perfusion MRI is a promising technique that needs to be evaluated further in clinical studies.

Conclusion Clinical neuroimaging is undergoing a transformation from the purely anatomic techniques of CT and MRI to those that are functional, such as perfusion imaging and BOLD fMRI, as well as to molecular imaging techniques including MRSI and PET. Complementing the already widely available MR-based methods, the advent of PET-CT and the likely emergence of PET-MR suggest a prominent role for PET in functional brain imaging in the near future. The ultimate goal of this work is to combine multimodality and multiparametric imaging to

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gain the most relevant physiologic information for diagnosis, prognosis, and therapeutic monitoring of patients with CNSrelated cancer. An early goal is to define the true extent of tumor infiltration within the brain, that is, that which extends beyond that seen on conventional contrast-enhanced MR images. The rational combination of the parameters discussed here will likely enable that definition in the short term, with the potential to affect positively the way brain tumors are currently treated, and ultimately survival, from this now uniformly devastating disease.

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34. Lam WW, Chan KW, Wong WL, Poon WS, Metreweli C. Preoperative grading of intracranial glioma. Acta Radiol 2001;42(6): 548–554. 35. Hartmann M, Heiland S, Harting I, et al. Distinguishing of primary cerebral lymphoma from high-grade glioma with perfusion-weighted magnetic resonance imaging. Neurosci Lett 2003; 338(2):119–122. 36. Ernst TM, Chang L, Witt MD, et al. Cerebral toxoplasmosis and lymphoma in AIDS: perfusion MR imaging experience in 13 patients. Radiology 1998;208(3):663–669. 37. Grand S, Passaro G, Ziegler A, et al. Necrotic tumor versus brain abscess: importance of amino acids detected at 1H MR spectroscopy: initial results. Radiology 1999;213(3):785–793. 38. Burtscher IM, Holtas S. Proton magnetic resonance spectroscopy in brain tumours: clinical applications. Neuroradiology 2001; 43(5):345–352. 39. Fulham MJ, Bizzi A, Dietz MJ, et al. Mapping of brain tumor metabolites with proton MR spectroscopic imaging: clinical relevance. Radiology 1992;185(3):675–686. 40. Gupta RK, Cloughesy TF, Sinha U, et al. Relationships between choline magnetic resonance spectroscopy, apparent diffusion coefficient and quantitative histopathology in human glioma. J Neurooncol 2000;50(3):215–226. 41. Rand SD, Prost R, Haughton V, et al. Accuracy of single-voxel proton MR spectroscopy in distinguishing neoplastic from nonneoplastic brain lesions. AJNR Am J Neuroradiol 1997;18(9): 1695–1704. 42. Preul MC, Caramanos Z, Collins DL, et al. Accurate, noninvasive diagnosis of human brain tumors by using proton magnetic resonance spectroscopy. Nat Med 1996;2(3):323–325. 43. Moller-Hartmann W, Herminghaus S, Krings T, et al. Clinical application of proton magnetic resonance spectroscopy in the diagnosis of intracranial mass lesions. Neuroradiology 2002; 44(5):371–381. 44. Dowling C, Bollen AW, Noworolski SM, et al. Preoperative proton MR spectroscopic imaging of brain tumors: correlation with histopathologic analysis of resection specimens. AJNR Am J Neuroradiol 2001;22(4):604–612. 45. Martin AJ, Liu H, Hall WA, Truwit CL. Preliminary assessment of turbo spectroscopic imaging for targeting in brain biopsy. AJNR Am J Neuroradiol 2001;22(5):959–968. 46. Croteau D, Scarpace L, Hearshen D, et al. Correlation between magnetic resonance spectroscopy imaging and image-guided biopsies: semiquantitative and qualitative histopathological analyses of patients with untreated glioma. Neurosurgery 2001; 49(4):823–829. 47. Fan G, Sun B, Wu Z, Guo Q, Guo Y. In vivo single-voxel proton MR spectroscopy in the differentiation of high-grade gliomas and solitary metastases. Clin Radiol 2004;59(1):77–85. 48. Matthews PM, Jezzard P. Functional magnetic resonance imaging. J Neurol Neurosurg Psychiatry 2004;75(1):6–12. 49. Fandino J, Kollias SS, Wieser HG, Valavanis A, Yonekawa Y. Intraoperative validation of functional magnetic resonance imaging and cortical reorganization patterns in patients with brain tumors involving the primary motor cortex. J Neurosurg 1999;91(2):238–250. 50. Lurito JT, Lowe MJ, Sartorius C, Mathews VP. Comparison of fMRI and intraoperative direct cortical stimulation in localization of receptive language areas. J Comput Assist Tomogr 2000; 24(1):99–105. 51. Paulesu E, Connelly A, Frith CD, et al. Functional MR imaging correlations with positron emission tomography. Initial experience using a cognitive activation paradigm on verbal working memory. Neuroimaging Clin N Am 1995;5(2):207–225. 52. Krings T, Schreckenberger M, Rohde V, et al. Functional MRI and 18F FDG-positron emission tomography for presurgical planning: comparison with electrical cortical stimulation. Acta Neurochir (Wien) 2002;144(9):889–899; discussion 899.

380 53. Schreiber A, Hubbe U, Ziyeh S, Hennig J. The influence of gliomas and nonglial space-occupying lesions on blood-oxygenlevel-dependent contrast enhancement. AJNR Am J Neuroradiol 2000;21(6):1055–1063. 54. Holodny AI, Schulder M, Liu WC, Wolko J, Maldjian JA, Kalnin AJ. The effect of brain tumors on BOLD functional MR imaging activation in the adjacent motor cortex: implications for imageguided neurosurgery. AJNR Am J Neuroradiol 2000;21(8):1415– 1422. 55. Gauvain KM, McKinstry RC, Mukherjee P, et al. Evaluating pediatric brain tumor cellularity with diffusion-tensor imaging. AJR Am J Roentgenol 2001;177(2):449–454. 56. Beppu T, Inoue T, Shibata Y, et al. Measurement of fractional anisotropy using diffusion tensor MRI in supratentorial astrocytic tumors. J Neurooncol 2003;63(2):109–116. 57. Mori S, Frederiksen K, van Zijl PC, et al. Brain white matter anatomy of tumor patients evaluated with diffusion tensor imaging. Ann Neurol 2002;51(3):377–380. 58. Sinha S, Bastin ME, Whittle IR, Wardlaw JM. Diffusion tensor MR imaging of high-grade cerebral gliomas. AJNR Am J Neuroradiol 2002;23(4):520–527. 59. Lu S, Ahn D, Johnson G, Cha S. Peritumoral diffusion tensor imaging of high-grade gliomas and metastatic brain tumors. AJNR Am J Neuroradiol 2003;24(5):937–941. 60. Yamada K, Kizu O, Mori S, et al. Brain fiber tracking with clinically feasible diffusion-tensor MR imaging: initial experience. Radiology 2003;227(1):295–301. 61. Chao ST, Suh JH, Raja S, Lee SY, Barnett G. The sensitivity and specificity of FDG PET in distinguishing recurrent brain tumor from radionecrosis in patients treated with stereotactic radiosurgery. Int J Cancer 2001;96(3):191–197. 62. Ricci PE, Karis JP, Heiserman JE, Fram EK, Bice AN, Drayer BP. Differentiating recurrent tumor from radiation necrosis: time for re-evaluation of positron emission tomography? AJNR Am J Neuroradiol 1998;19(3):407–413. 63. De Witte O, Levivier M, Violon P, et al. Prognostic value positron emission tomography with [18F]fluoro-2-deoxy-dglucose in the low-grade glioma. Neurosurgery 1996;39(3):470– 476; discussion 476–477. 64. Barker FG JR, Chang SM, Valk PE, Pounds TR, Prados MD. 18Fluorodeoxyglucose uptake and survival of patients with suspected recurrent malignant glioma. Cancer (Phila)1997;79(1): 115–126. 65. Spence AM, Mankoff DA, Muzi M. Positron emission tomography imaging of brain tumors. Neuroimaging Clin N Am 2003; 13(4):717–739. 66. Sun D, Liu Q, Liu W, Hu W. Clinical application of 201Tl SPECT imaging of brain tumors. J Nucl Med 2000;41(1):5–10. 67. Oriuchi N, Tamura M, Shibazaki T, et al. Clinical evaluation of thallium-201 SPECT in supratentorial gliomas: relationship to histologic grade, prognosis and proliferative activities. J Nucl Med 1993;34(12):2085–2089. 68. Benard F, Romsa J, Hustinx R. Imaging gliomas with positron emission tomography and single-photon emission computed tomography. Semin Nucl Med 2003;33(2):148–162.

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69. Golfinos JG, Fitzpatrick BC, Smith LR, Spetzler RF. Clinical use of a frameless stereotactic arm: results of 325 cases. J Neurosurg 1995;83(2):197–205. 70. Wirtz CR, Albert FK, Schwaderer M, et al. The benefit of neuronavigation for neurosurgery analyzed by its impact on glioblastoma surgery. Neurol Res 2000;22(4):354–360. 71. Gildenberg PL, Woo SY. Multimodality program involving stereotactic surgery in brain tumor management. Stereotact Funct Neurosurg 2000;75(2–3):147–152. 72. Knauth M, Wirtz CR, Tronnier VM, Aras N, Kunze S, Sartor K. Intraoperative MR imaging increases the extent of tumor resection in patients with high-grade gliomas. AJNR Am J Neuroradiol 1999;20(9):1642–1646. 73. Tuominen J, Yrjana SK, Katisko JP, Heikkila J, Koivukangas J. Intraoperative imaging in a comprehensive neuronavigation environment for minimally invasive brain tumour surgery. Acta Neurochir Suppl 2003;85:115–120. 74. Kanner AA, Vogelbaum MA, Mayberg MR, Weisenberger JP, Barnett GH. Intracranial navigation by using low-field intraoperative magnetic resonance imaging: preliminary experience. J Neurosurg 2002;97(5):1115–1124. 75. Wirtz CR, Knauth M, Staubert A, et al. Clinical evaluation and follow-up results for intraoperative magnetic resonance imaging in neurosurgery. Neurosurgery 2000;46(5):1112–1120; discussion 1120–1121. 76. Lewin JS, Metzger A, Selman WR. Intraoperative magnetic resonance image guidance in neurosurgery. J Magn Reson Imaging 2000;12(4):512–524. 77. Thompson TP, Lunsford LD, Kondziolka D. Distinguishing recurrent tumor and radiation necrosis with positron emission tomography versus stereotactic biopsy. Stereotact Funct Neurosurg 1999;73(1–4):9–14. 78. Kahn D, Follett KA, Bushnell DL, et al. Diagnosis of recurrent brain tumor: value of 201Tl SPECT vs. 18F-fluorodeoxyglucose PET. AJR Am J Roentgenol 1994;163(6):1459–1465. 79. Schlemmer HP, Bachert P, Herfarth KK, Zuna I, Debus J, van Kaick G. Proton MR spectroscopic evaluation of suspicious brain lesions after stereotactic radiotherapy. AJNR Am J Neuroradiol 2001;22(7):1316–1324. 80. Rock JP, Hearshen D, Scarpace L, et al. Correlations between magnetic resonance spectroscopy and image-guided histopathology, with special attention to radiation necrosis. Neurosurgery 2002;51(4):912–919; discussion 919–920. 81. Siegal T, Rubinstein R, Tzuk-Shina T, Gomori JM. Utility of relative cerebral blood volume mapping derived from perfusion magnetic resonance imaging in the routine follow-up of brain tumors. J Neurosurg 1997;86(1):22–27. 82. Sugahara T, Korogi Y, Tomiguchi S, et al. Posttherapeutic intraaxial brain tumor: the value of perfusion-sensitive contrastenhanced MR imaging for differentiating tumor recurrence from nonneoplastic contrast-enhancing tissue. AJNR Am J Neuroradiol 2000;21(5):901–909. 83. Bitzer M, Klose U, Nagele T, et al. Echo planar perfusion imaging with high spatial and temporal resolution: methodology and clinical aspects. Eur Radiol 1999;9(2):221–229.

2 8

Breast Imaging Wendie A. Berg

I

n this chapter, the current status of breast imaging for both screening and diagnosis is reviewed. Mammography remains the standard for screening; however, moderate evidence supports the use of ultrasound (US) or magnetic resonance imaging (MRI) for supplemental screening of certain subgroups of women. Evaluation of a lump is highly accurate when both mammography and US are used. For the patient with nipple discharge, US appears to be an acceptable, noninvasive alternative to ductography. MRI and US also play a role in evaluating disease extent in both ipsilateral and contralateral breasts. No imaging test is sufficiently accurate compared to sentinel lymphadenectomy to preoperatively identify metastatic nodes, although US-guided fine-needle aspiration can confirm metastatic adenopathy. Positron emission tomography plays a role in restaging recurrent breast cancer.

Screening The goal of screening is early detection that will alter the natural history of the disease without harming healthy individuals. Such an intervention should also be cost-effective and practical to implement. Tabar et al.1 retrospectively examined the prognosis of breast cancers by histologic type, grade, size, and node status in the Swedish Two-County trial. Cancers were divided into those with good, intermediate, and poor prognosis. Those with good prognosis showed 20-year survival of 91%, compared to 72% for those of intermediate prognosis and 40% for those with poor prognosis. “Good” prognosis cancers had more than 90% 20-year survival and included all ductal carcinoma in situ (DCIS) as well as nodenegative invasive cancers of small size: less than 20 mm if grade I invasive ductal, less than 15 mm if grade II, less than 10 mm if grade III, and less than 10 mm invasive lobular.1 All tubular cancers had good or intermediate prognosis.1 “Poor” prognosis cancers were larger in size and node positive but fundamentally of the same histology as those of good prognosis. Mammographic screening shifts the distribution of cancers toward those with better prognosis. In the Swedish Two-County trial,1 50% of mammographic screen-detected cancers had good prognosis and 18% had poor prognosis, whereas 19% of clinically detected cancers had good prognosis and 47% poor prognosis. A report commissioned by the United States Preventive Services Task Force2 reviewed eight randomized, controlled trials of mammography and two of breast self-examination

(BSE). The Edinburgh trial was excluded for reasons of lower socioeconomic status and higher all-cause mortality in the control group and the lack of masking when evaluating cause of death. Across the seven remaining trials, in women 50 years or older, a 22% reduction in breast cancer mortality was found among women screened [95% confidence interval (CI), 13%–30%] at 14 years of observation.2 In women 40 to 49 years of age, the summary risk reduction was 15% (95% CI, 1%–27%) at 14 years of observation.2 Cancer is detected in 5 to 7 of every 1,000 women on the initial mammogram and in 2 to 3 per 1,000 on each incidence (annual) screen,3–5 with the incidence increasing with advancing age.4 In one practice, cancer detection rates on screening mammography were 6 per 1,000 when breast imaging specialists performed the interpretation and only 3.4 per 1,000 when interpreted by generalists.6 Some of the reduction in breast cancer mortality after the introduction of mammographic screening is attributable to improved treatments. In an analysis of population-based service screening in Sweden, Tabar et al.7 reported a 16% reduction in breast cancer mortality in the period 1978–1997 compared to the period 1958–1977 among women not screened, by 44% in all women 40 to 69 years of age who were screened with mammography, and by 48% in women 40 to 49 years of age who were not screened. Randomized controlled trials have not demonstrated a mortality reduction from breast self-examination (BSE). The Shanghai trial of 133,000 Chinese women randomized to receive instruction in BSE or not, found no difference in mortality; indeed, women in the BSE group were 84% more likely to undergo an unnecessary benign breast biopsy.8 Importantly, the combination of clinical breast examination (CBE, by the woman’s care provider) and mammography is more effective in lowering breast cancer mortality than mammography alone.9 Despite its effectiveness in reducing mortality from breast cancer, mammography is less sensitive when the breast tissue is dense. Breast density is classified into four categories10: fatty (less than 25% dense); minimal scattered fibroglandular density (25%–49% dense); heterogeneously dense (50%–74% dense); and extremely dense (75% or more dense). Dense tissue is especially common in younger women. Stomper et al.11 reviewed mammograms from 1,353 women and reported that approximately 62% of women in their thirties, 56% of women in their forties, 37% of women in their fifties, and 27% of women in their sixties had at least 50% parenchymal density on mammography. Kerlikowske et al.12 reported

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results on 27,281 screening mammograms and found the sensitivity to cancer was 98.4% in women 50 years of age or older with fatty breasts and 83.7% in dense breasts (P = 0.01). In women under 50, the sensitivity was 81.8% in fatty breasts and 85.4% in dense breasts (NS), although the numbers of cancers were small.12 In women under 50 with a family history of breast cancer, sensitivity decreased to 68.8%.12 Mandelson et al.13 reported sensitivity as low as 30% among women with extremely dense breasts in a Seattle screening mammography program. Among women with mutations in BRCA-1 or -2, mammography depicts fewer than half of cancers.14–17 Thus, in women with dense breasts, and particularly those at increased risk because of a family or personal history of breast cancer or atypia, methods to supplement mammography are sought. Screening does not assure a benefit to all women.18 The most aggressive cancers are often not detectable at screening but have metastasized by the time they are clinically detected. Detecting breast cancer when it is small and node negative does not assure improved survival; some of these cancers will still metastasize. Tabar1 noted that cancers manifested as branching, casting calcifications were often lethal even when less than 15 mm in size at detection. Women treated for breast cancer may still die of other causes; treatment can be unnecessary, particularly in older women as competing risks of death increase. Such “overtreatment” may even increase allcause mortality.19,20 Without treatment, the majority of DCIS will progress to invasive carcinoma, but this may occur over a period of 20 years or more.21,22 Yen et al.23 analyzed the results of the Swedish Two-County trial and estimate that at the first (prevalent) baseline screen, 37% of DCIS is nonprogressive,

28

but at subsequent (incidence) screens, only 4% of new DCIS would not progress. This finding suggests that “overtreatment” may occur at the first (prevalent) screen with any given screening test but would be uncommon if the test were performed annually. In other words, cancers that are new on subsequent (incidence) screens are almost always biologically relevant. Randomized controlled trials with death as the endpoint are considered the gold standard for assessing the impact of any screening modality on survival.24 Mammography is the only screening test to date that has been shown to reduce deaths due to breast cancer. Supplemental screening with ultrasound (US) and magnetic resonance imaging (MRI), in addition to mammography, are being considered, particularly in women with heterogeneously dense or extremely dense (hereafter referred to as dense) breast tissue who are at high risk. Indeed, dense breast tissue itself is an indicator of elevated risk of 1.8- to 6-fold, averaging 4-fold across multiple series.25 As recently reviewed,26 in single-center studies of screening US totaling 42,838 examinations in average-risk women,27–32 150 cancers had been identified (3.5 per 1,000 exams) only sonographically in 126 women (Table 28.1). Of 126 women with sonographically depicted cancers, 114 (90.5%) had dense or heterogeneously dense parenchyma. Of the 150 cancers, 141 (94%) were invasive, and 99 (70%) were 1 cm or smaller in size. More than 90% were node negative. Although these results are encouraging, these studies were not blinded to results of mammography, and variable equipment, performance, and interpretive criteria were used. Publication of minimum equipment standards for breast US,33 as well as a standardized lexicon for description of lesions and reporting

TABLE 28.1. Summary of studies of screening breast ultrasound, biopsies prompted by US, positive predictive value of biopsy, and prevalence of cancers seen only sonographically. Investigator

Gordon 199527 Buchberger28d Kaplan 200129 Kolb 200230 Crystal 200332 Leconte 200331 Overall

N

No. of biopsiesa (%)

No. malignant (%)b

Prevalence (%)

12,706 8,103 867d 1,862 13,547g 1,517 4,236i 42,838

279 (2.2)c 362 (4.5) 43 102 (5.5) 358 (2.6) 38 (2.5)h NSf 1,182/38,602 (3.1)

44/279 (16) 32/362 (8.8) 8/43 (19) 6/91 (6.6) 37/358 (10) 7/38 (18) 16/NS 134/1,171 (11.4)

44/12,706 (0.35)c 32/8,103 (0.39)e 8/867 (0.9)e 6/1,862 (0.3) 37/13,547 (0.27)g 7/1,517 (0.46)h 16/4,236 (0.38) 150/42,838 (0.35)

a

Biopsies or aspirations prompted by screening sonography.

b

Refers to cancers seen only on breast sonography, expressed as percent of biopsies (PPV).

c

All women had clinical or mammographic abnormalities. Diagnosis was by fine-needle aspiration biopsy. Numbers refer to solid masses. Sixteen cancers were found in 15 women with ipsilateral cancer.

d In this series, 867 women were evaluated because of palpable or mammographic abnormalities; 5 cancers seen only on sonography were in patients with another mammographically or clinically evident cancer. e

Cancer was found only on sonography in 0.54% of women with a personal history of cancer compared to 0.26% of women with no personal history of cancer.

f

NS, not stated.

g

Includes patients described in 1998 series.9 Number of studies, not women, as some women had more than one study. Cancer was found only on sonography in 0.48% of high-risk women compared to 0.16% of normal risk women. h

Cancer was found only on sonography in 4/318 (1.3%) women with first-degree family history or personal history of breast cancer and 3/1,199 (0.25%) women of average risk; biopsies includes 17 aspirations of which 13 yielded clear fluid.

i 1,016 had a personal history of breast cancer and 136 a palpable lesion (with the palpable lesions themselves excluded), although the number of cancers seen in women at high risk was not specified. Sixteen cancers were identified, but the number of biopsies induced by sonography was not specified: results of this study were not included in calculating the biopsy rate or the malignancy rate of biopsies.

Source: Adapted from Reference 26, with permission.

383

b r e a s t i m ag i n g TABLE 28.2. Rates of detection of cancer by magnetic resonance imaging (MRI) only in women at high risk of breast cancer.

Investigator

Kuhl39* TilanusLinthorst140 Stoutjesdijk50* Podo41 Leach141 Morris142 Kriege38* Warner143* Total

Mean age (years)

Bx (%)

PPV (%)

Cancers on MRI only (% of patients)

14/293 (5) 9 (8)

9/14 (64) 3/9 (33)

6 (3) 3 (3)

N (patients)

39 43

192 109

NS 46 >

452 This is clearly not true, as shown by Kresnik et al.,43 who demonstrated that many malignant nodules were not FDG avid, most likely because they were well differentiated. Additionally, other studies have shown that multimodular goiter44,45 or thyroiditis,46,47 predominantly lymphocytic, may have increased FDG uptake. In patients who underwent FDG-PET for some other reason, Kang et al.48 reported that thyroid incidentallomas were found in 2.2%, and among these, 27% proved to be cancer. In a larger group of patients (4,525) Cohen et al.49 reported that incidentallomas were found in 2.3% and 47% were thyroid cancers.

FDG-PET in Evaluation of Differentiated Thyroid Cancer In a large multicenter study of unselected thyroid cancer patients (n = 222), Grunwald et al.50 found that the sensitivity of FDG-PET for localizing metastatic disease in patients with DTC was 75% and that it was 85% for the group with a negative WBS (n = 166). Feine et al.51 noticed that there were tumors that accumulated only FDG, others only 131I, and some both FDG and iodine. He named this alternating pattern of either 131I or FDG uptake in thyroid cancer metastases as the “flip-flop” phenomenon. Thus, some thyroid tumors without functional differentiation for iodine (123I or 131I) uptake showed high glucose metabolism, and many differentiated papillary and follicular thyroid cancers did not have increased FDG uptake. Wang et al.52 reported that progressive dedifferentiation of thyroid cancer cells results in a loss of their ability to concentrate iodine, which results in a negative WBS in 20% of originally differentiated thyroid cancers. Thyroid cancer cells that lose their ability to concentrate radioactive iodine may exhibit increased metabolic activity, which results in enhanced glucose uptake. Many studies showed that FDGPET is more sensitive than WBS in high-grade tumors, whereas an iodine scan is more commonly positive in lowgrade carcinomas.53–55 Expression of the GLUT-1 transporter on the cell membrane is closely related to the grade of malignancy in thyroid neoplasms, with anaplastic tumors and widely invasive follicular or metastatic tumors showing a high-level of GLUT-I glucose transporter expression.56 Some studies have reported that increased TSH levels stimulate FDG uptake by thyroid cancer cells.57,58 A case report by Sisson demonstrated increased FDG uptake in a thyroid cancer metastasis imaged both before and then after withdrawal from thyroid hormone therapy. Helal et al.59 studied 37 patients with DTC who had undergone resection and ablation with radioactive iodine. He found a sensitivity of 76% in these patients and concluded that FDG-PET should be a first-line investigation in patients with elevated thyroglobulin and a negative WBS (Figure 33.2). Schluter et al.60 studied 64 patients with thyroid cancer with either elevated serum thyroglobulin or clinical suspicion of metastases and negative WBS and reported that the positive predictive value (PPV) was 83% whereas the negative predictive value (NPV) was 25%. The true positive FDG-PET findings were correlated positively with increasing thyroglobulin levels. The FDG-PET was true positive in 11%, 50%, and 93% of patients with thyroglobulin levels less than 10, 10 to 20, and more than 100 ng/dL, respectively. This

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finding suggests that the mass of thyroid cancer tissue is related to detectability, which is not surprising. The use of recombinant human thyrotropin (rhTSH) has recently been proposed to increase the sensitivity of FDGPET in the diagnosis of recurrent and metastatic cancer versus the unstimulated setting. Moog et al.61 compared imaging findings in 10 patients who were either under TSH suppression and were hyperthyroid, or were hypothyroid with stimulated TSH. Increases of 63% in the tumor-tobackground ratios were observed in the latter case. Petrich et al.62 reported that in 30 patients they found more suspicious lesions for cancer in more patients when they received rhTSH. These observations were also supported by an in vitro culture experiment.63 Wang et al.64 evaluated 125 patients with a mean of 41 months of follow-up who had a negative WBS, a positive FDG-PET study, and elevated thyroglobulin. They concluded that the single strongest predictor of survival was the volume of FDG-avid disease. Detection of tumor with FDG-PET is a volume-dependent phenomenon. In another study, the same authors65 evaluated the ability of an ablation dose of 131I to destroy FDG-avid metastatic lesions in patients with thyroid cancer who had FDG-PET scans pre- and post-131I treatment. The authors found that the total volume of FDG-avid metastases rose from a mean of 159 mL to 235 mL after 131I ablation therapy and the post-131I thyroglobulin level rose 132% above the value at baseline. In patients with a negative FDG-PET scan, the serum thyroglobulin levels decreased to 38% of baseline after 131I

A

C

B

D

FIGURE 33.2. Transverse FDG-PET scan of a young female who had a history of follicular thyroid carcinoma with lymph node and capsular involvement 3 years before this scan. She had developed an elevated serum thyroglobulin level, and her iodine scan was negative. This PET scan was performed to look for a recurrent noniodine-avid tumor. This scan was performed without recombinant thyroidstimulation hormone (rhTSH) stimulation and demonstrates increased radiotracer uptake in the left neck in level 2 lymph nodes, which were subsequently proven to be metastatic thyroid cancer (A) CT scan. (B) Fused PET/CT image. (C) Attenuation corrected PET image. (D) Nonattenuation corrected PET image.

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p o s i t ro n e m i s s i o n t o m og r a p h y i n c a n c e r TABLE 33.3. Studies comparing PET findings in different types of thyroid cancer. Author 67

Plotkin et al. Lowe et al.66 Diehl et al.69 Schluter et al.60

Year

Type of thyroid cancer

2002 2003 2001 2001

Hürthle Hürthle Medullary Papillary/follicular or mixed

Sens

Spec

Acc

PPV

NPV

92 92 78

80

89

92

80

83

25

Remarks

79 ≠ Tg level

131

I WBS(-)

Acc, accuracy; PPV, positive predictive value; NPV, negative predictive value; WBS, whole-body scan.

therapy. High-dose 131I therapy does not appear to have a tremendously beneficial effect on the viability of metastatic FDG-avid lesions. Nonresectable regional disease can be treated with external-beam irradiation or, if limited, with surgery, while widespread disease may be amenable to experimental chemotherapy.

Hürthle Cell Carcinoma Hürthle cell cancer is a histologic subtype of DTC that is clinically more aggressive and has little or no iodine uptake. In a study of 12 patients Lowe et al.66 described a sensitivity of 92% for FDG-PET. Plotkin et al.67 reported a sensitivity of 92%, a specificity of 80%, a PPV of 92%, a NPV of 80%, and an accuracy of 89% (Table 33.3).

Medullary Thyroid Cancer Medullary thyroid cancer (MTC) is a rare calcitonin-secreting tumor originating from the parafollicular C cells. At the time of initial diagnosis, most of the patients with this malignancy are noted to have lymph node metastases. The primary treatment modality is surgical resection of all malignant lesions. Brandt-Mainz et al.68 studied 20 patients and found the overall sensitivity to be 76%. In another study, Diehl et al.69 demonstrated, in 55 cases, that FDG-PET had a sensitivity of 78% and a specificity of 79%, in comparison with 131Inpentetreotide, 25% and 92%, with dimercaptosuccinic acid (DMSA), 33% and 78%, with 99mTc-MIBI (hexakis-2-methoxy2-isobutyl isonitrile), 25% and 100%, with CT, 50% and 20%, and with MRI, 82% and 67%. A reasonable imaging approach in the staging and follow-up of MTC would be a combination of FDG-PET and MRI. Novel, more-specific PET tracers, such as 18F-dihydroxyphenylalanine and 6-18F-DOPAv (dopamine), have been proposed by Hoegerle et al.70 and Courgiotis et al.,71 respectively, with promising results, especially in lymph node staging. Nonetheless, FDG-PET has assumed an increasingly important role in the management of thyroid cancer. The ability of this method to detect many non-iodine-avid tumor foci is of considerable practical utility and is changing the practice of thyroidology. Our own experience suggests that, in patients with thyroid cancer with possible recurrence of noniodine-avid disease, FDG-PET/CT (ideally under TSH stimulation) is an excellent method to precisely locate recurrent tumors and to direct the surgeon to their precise location if surgical intervention is being considered.

Esophagus Esophageal cancer is relatively infrequent, with 14,000 new cases reported in the United States in 2003. The 5-year survival rate is not more than 14%.72 The incidence of the

disease is much higher in Asia and Northern France and in some regions of the world where esophageal cancer is endemic.

FDG-PET in Staging Esophageal Carcinoma The accuracy of endoscopic ultrasonography (EUS) is lower for evaluation of T1 and T2 tumor than for T3 and T4, and the CT scan is inaccurate for identifying nonbulky lymphadenopathy. Neither EUS nor CT is able to distinguish tumor from inflammation. The introduction of FDG-PET has greatly improved the staging of esophageal carcinoma. Squamous cell and adenocarcinomas of the esophagus are both generally characterized by high FDG uptake.73,74 FDG uptake in esophageal cancer is greater than that in the normal uninflamed esophagus, and the primary tumor can be distinguished easily from background activity in most cases.75 FDG-PET false-positive results in the esophagus and nearby tissues can be caused by inflammation (reflux esophagitis), radiation-induced esophagitis, benign tumors, skeletal and adipose tissue uptake, and heterogeneous uptake in the primary, simulating periesophageal nodal metastases. FDG-PET false-negative results are the result of small tumor volume, well-differentiated tumor, and close proximity to the primary tumor. Histologic confirmation of PET findings is necessary before a patient is denied potentially curative surgery. PET is very useful in identifying a site suitable for biopsy. FDG-PET has been shown to detect primary esophageal cancer with a higher sensitivity than that of CT (95% to 100% versus 81% to 92%).73,76–78 Himeno et al.79 reported that FDG-PET has a sensitivity of 100% for the detection of primary tumors extending to the submucosa (TIb) or deeper, but cannot detect lesions confined to the mucosa (Tis or T1a). Kato et al.80 described that there is a significant relationship between FDG uptake and the depth of tumor invasion; this is most likely a relationship between tumor volume and invasion (Figure 33.3). Although PET detects most primary esophageal cancers, it is not as sensitive for nodal metastases. Yoon et al.81 evaluated 82 patients with squamous cell carcinoma and 677 lesions and found the sensitivity for PET was 30% and that for CT was 11%. This result shows the extent of the problem of nodal staging with both methods. Although PET was more sensitive than CT, both techniques failed to detect small nodal metastases that are often under 1 cm in size. There is considerable variability in the literature concerning nodal staging in esophageal cancer. The 5-year survival without lymph node involvement is 42% to 72% versus only 10% to 12%82 for patients with disease that has spread to the lymph nodes. Metastatic lymph

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node size was the strongest independent predictor of survival among several prognostic factors, such as primary tumor size, histopathologic type, number of metastatic lymph nodes.83 The combined accuracy of EUS and CT (70% to 90%) in the detection of mediastinal nodal metastases was reported to be greater than that of each modality alone,84 but limitations remained because of inability to detect tumor involvement in normal-sized lymph nodes and to differentiate metastatic from inflammatory disease. Kim et al.74 compared FDG-PET with CT and histopathologic results from esophagectomy and extensive lymph node dissection. The sensitivity, specificity, and accuracy for FDGPET to detect metastatic lymph nodes were 52%, 94%, and 84%, respectively, and those for CT were 15%, 97%, and 77%, respectively. That study showed that FDG-PET had greater sensitivity and accuracy than CT, with equal specificity in nodal staging. Flamen et al.73 compared FDG-PET (attenuation corrected with spiral CT) and EUS in 74 patients with potentially resectable esophageal cancer and showed that EUS was more sensitive (81% versus 33%) but less specific (67% versus 89%) than PET for detection of regional nodal metastases. Combined EUS and CT were more sensitive (62% versus 33%) and less specific (67% versus 89%) in the same setting. The findings from PET resulted in upstaging in 15% of patients and in downstaging in 7% of patients. PET is a better method for detection of distant metastatic disease than any other method available, but it is not as robust for locoregional disease. PET is routinely recommended before surgery for esophageal carcinoma.

A

B

C

33

A curative surgical approach is not appropriate in patients with metastases to distant foci. Distant metastatic disease most commonly occurs in distant lymph nodes, liver, and lung. FDG-PET is superior to CT and MRI for detection of distant metastatic disease.73,74,85–89 FDG-PET uncovered 3% to 37% of findings that were unsuspected. Kinkel et al.87 reported that at the specificity level of 85% the mean sensitivities of FDG-PET, ultrasound, CT, and MRI were 90%, 55%, 63%, and 76%, respectively. Flamen et al.73 demonstrated that the accuracy of FDGPET in 74 patients with stage IV disease was 82%, whereas it was only 64% for a combination of CT and EUS (P less than 0.01). The sensitivity and specificity were 74% and 90% for FDG-PET, 41% and 83% for CT, and 42% and 94% for EUS. Luketich et al.88 found, in 35 patients with potentially resectable esophageal cancer, that distant metastatic disease was identified by PET in 20% with an accuracy of 91%. The same group89 found that the sensitivity and specificity of FDG-PET for detection of distant disease were 69% and 93% for FDG-PET and 46% and 74% for CT. PET prevents ineffective radical therapies by detection of occult stage IV disease and identification of the local or distant metastases that are most accessible to confirmation by directed tissue sampling using minimally invasive procedures. Wallace et al.90 found that the combination of PET and EUS with fine-needle aspiration biopsy is the most effective strategy for staging. Table 33.4 summarizes the results of studies evaluating the sensitivity, specificity, and accuracy of CT, EUS, and FDG-PET for detecting local tumor extension (T and N stages) and systemic disease (M).73,74,81,89,91–93

D

FIGURE 33.3. Coronal PET/CT images obtained from a middle-aged male with a history of gastroesophageal reflux and biopsy-proven esophageal carcinoma. These images show intense tracer uptake in the primary lesion located at the gastroesophageal junction and extending downward into the stomach. No metastatic disease is identified. (A) CT scan. (B) Fused PET/CT image. (C) Attenuation corrected PET image. (D) Nonattenuation corrected PET image.

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p o s i t ro n e m i s s i o n t o m og r a p h y i n c a n c e r TABLE 33.4. Comparison of various modalities (CT/EUS with PET) for initial staging of esophageal cancer. Sens Author

Year

EUS

CT

Wren et al.91 T/N Hustinx et al.92 (M)

2002

90 (T) 75 (N)

50 (T) 73 (N) 46 (M)

Flamen et al.73 (N) Reanalysis Kim et al.74 (surgical extent L/N dissection) Wu et al.93 (N) Yoon et al.81 (N) Luketich et al.89 (M) Flamen et al.105 (M) Reanalysis by Lerut84

2000

2000 81 (RN)

2001

2003 2003 1999 2000 2000

68

42

62 (+ EUS) 15

77 11 46 41 46 (+ EUS)

Spec PET

EUS

CT

Acc PET

EUS

CT

PET

Remarks

85 (T) 75 (N) 69 (M) (NAC) 33 (RN) 52

74 (M) 67

75 30 69 74 77

94

67 (+ EUS) 97

79 95 74 83 69 (+ EUS)

93 (M) (NAC) 89 94

82 93 90 90

77

64 (CT + EUS)

84

82

P < 0.01 P < 0.01 P < 0.01 22% change of stage

EUS, endoscopic ultrasound; T, evaluation of T-stage; NAC, nonattenuation corrected images; N, evaluation of lymph nodes; SCT, spiral computed CT; M, distant metastases; RN, regional lymph nodes.

Luketich et al.89 also demonstrated the 30-month survival rate was 60% in patients with localized disease on PET, as compared with 20% in patients with PET evidence of distant disease. The same numbers for CT, 52% and 38%, respectively, were not significantly different.

Assessment of Response to Treatment Complete macroscopic and microscopic resection of the primary tumor is a strong independent prognostic factor. Patients with locally advanced disease (T3–T4) after complete resection have a 20% to 31% chance of 5-year survival, whereas there is essentially no chance of a 5-year survival in those with an incomplete resection.82 Randomized trials compared patients who received preoperative chemotherapy or chemoradiotherapy followed by surgery with patients who received surgical treatment alone. The results were conflicting,94 and this was attributed to the fact that the response to chemoradiotherapy was probably not uniform. Nonresponders had a poor prognosis, not only because of their disease but also because of therapy-induced side effects and the delay in surgical treatment. Anatomic imaging modalities cannot differentiate viable tumor from posttherapeutic effects in many instances. The accuracy of EUS for determination of tumor stage after therapy is less than 50%.95,96 Several studies demonstrated the usefulness of FDG-PET to predict response either shortly after initiation of therapy or after its completion. Weber et al.97 studied 40 patients with locally advanced adenocarcinomas of the gastroesophageal junction. PET imaging was performed before preoperative chemotherapy and on day 14 of the first chemotherapy cycle. Changes in tumor FDG uptake at these early time points were correlated with the clinical and histopathologic response after 3 months of chemotherapy. In clinical responders, defined as a decrease of tumor length and wall thickness by more than 50%, FDG uptake at day 14 had decreased by 54% ± 17%, compared with nonresponders, at 15% ± 21%. Using a threshold of a 35% decrease in the SUV from the baseline metabolic activity, FDG uptake predicted subse-

quent clinical response with a sensitivity and specificity of 93% and 95%, respectively. Sensitivity and specificity for predicting histopathologic response were 89% and 75%, respectively. The 2-year survival rate of “PET responders” was 49% whereas it was only 9% for “PET nonresponders.” The same authors studied98 27 patients with locally advanced squamous cell carcinomas of the esophagus before neoadjuvant chemoradiotherapy and 3 to 4 weeks after completion of therapy. Therapy-induced reduction of tumor FDG uptake was significantly higher for histopathologic responders (72% ± 11%) than for nonresponders (42% ± 22%). Using a threshold of a 51% decrease in the SUV from the baseline metabolic activity for prediction of a response to therapy resulted in a sensitivity of 100% and a specificity of 52%. Brucher et al.99 and Flamen et al.100 showed similar results, with the latter using only visual analysis (sensitivity, 71% and specificity, 81%). Downey et al.101 studied 24 patients with esophageal cancer who received induction therapy before esophagectomy. The 2-year disease-free survival (DFS) was greater when the tumor showed more than a 60% decrease in FDG uptake. Arslan et al.102 failed to distinguish residual tumor from postchemoradiation esophagitis using SUV measurements in 24 patients 4 weeks after treatment completion. PET appears to have a greater role in assessing early response than it does in assessing residual tumor (Table 33.5).

Detection of Recurrent Disease Recurrence is common despite a presumed cure after resection because of micrometastatic disease at distant sites, which can then proliferate. Fukunaga et al.103 first reported the increased FDG uptake in patients with recurrence. Yeung et al.104 and Flamen et al.105 studied recurrent disease. The latter study showed that FDG-PET was comparable to or somewhat inferior to conventional imaging. The sensitivity, specificity, and accuracy for FDG-PET were 100%, 57%, and 74%, respectively, and 100%, 93%, and 96% for conventional imaging. In the detection of regional or distant recurrence, the sensitivity, specificity, and accuracy were 94%, 82%, and

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TABLE 33.5. PET in the evaluation of response to therapy for esophageal cancer. Author

Year

No. of patients

Sens

Spec

PPV

NPV

Brucher et al.99

2001

27

100

55

72

100

Weber et al.98

2004

27

100

52

Flammen et al.100 Weber et al.97 Downey et al.101

2002 2001

36 40

71 93

81 95

2003

24

DFS (2 years)

Remarks

52% Ø SUV 3 weeks (P < 0.0001) 51% Ø SUV 3–4 weeks after therapy Visual 3–4 weeks 35% Ø SUV 67%

SUV Ø 60% (OS same)

SUV, standard uptake value; DFS, disease-free survival; OS, overall survival;

87% for FDG-PET and 81%, 82%, and 81%, respectively, for conventional imaging. In practice PET has been useful for detecting recurrent disease and is complementary to CT. In summary, PET with FDG is a useful diagnostic tool for esophageal carcinoma. It is generally used at initial diagnosis to perform whole-body staging and to determine the baseline metabolic rate of the tumors. It then can be used to follow the response to locoregional or systemic therapies. Large declines in FDG uptake after therapy are associated with a better response than a modest decline in tracer uptake. PET cannot detect microscopic disease or even disease under a few millimeters in size with current technology. This is a continuing limitation as is the uptake of FDG into inflammatory cells after treatment. Nonetheless, FDG-PET is established as an important tool at several points in the management of patients with esophageal carcinoma. PET/CT is the preferred embodiment of this application at present, but literature to strongly support the superiority of PET/CT over PET is limited at this time.

Lung Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in men and women in the United States. It has surpassed breast cancer as the number one cancer killer of women. When it is diagnosed early, the prognosis is relatively good, with greater than a 60% 5-year survival for stage I disease compared to only 14% for all patients.106 The primary treatment of lung cancer is surgery (if it is indicated), but once nodal or distant metastases have developed, the correct type of therapy is adjuvant chemotherapy or radiation therapy. Correct staging is the mainstay of appropriate clinical management. FDG-PET is a valuable noninvasive imaging test for detecting malignancy in solitary pulmonary nodules (SPNs), for staging or restaging NSCLC, for monitoring therapy, and for detecting residual or recurrent disease, and, finally, it provides prognostic information that is independent of lesion size, clinical stage, and cell type. It contributes to better informed medical decision making and more cost-effective medical care.

Diagnosis of NSCLC and Evaluation of Pulmonary Nodules In the United States, approximately 150,000 indeterminate pulmonary nodules are discovered each year and between

30% and 50% of these are malignant.107,108 The incidence of cancer is not low enough to ignore it, nor is it high enough to decide to resect all nodules. Chest radiography and CT scan can establish the benign nature of a lesion. Certain patterns of calcification (likelihood ratio, 0.07) or the presence of fat within the nodule or a low growth rate over 2 years (likelihood ratio, 0.01) are diagnostic of a benign etiology.109 CT provides some assessment of the likelihood of malignancy based on morphology and the presence of secondary findings, such as hilar or mediastinal adenopathy, but the vast majority of SPNs are indeterminate by radiographic or CT criteria.110 Biopsy by CT-guided transthoracic needle aspiration and bronchoscopy are helpful when positive, but because of sampling error, a benign result cannot exclude tumor. On the other hand, more invasive procedures, such as thoracoscopic or surgical biopsy, are associated with increased cost and morbidity.111 FDG-PET and contrast-enhanced dynamic CT (dCT) are accurate, noninvasive methods for diagnosing lung cancer. Lowe et al.112 showed that FDG-PET has an overall sensitivity of 92% and a specificity of 90% in a study of 89 patients with nodules between 0.7 and 4.0 cm in diameter using a SUV cutoff of 2.5 or greater. Another criterion is if nodules are hyperintense compared to the mediastinum. With application of these two criteria, FDG-PET is approximately 96% sensitive and 80% specific for malignancy. False-positive results may be caused by the increased glycolytic activity within activated macrophages. Active granulomatous diseases can be FDG avid, such as tuberculosis,113 sarcoidosis,114 aspergillosis,115 histoplasmosis,116 or lipoid pneumonia and talc granulomata after pleurodesis,117 and pneumonitis and necrosis after high-dose radiation therapy.118 False-negative results can occur in some low-grade tumors, including bronchoalveolar carcinoma119 and bronchial carcinoid.120 Lesions that are near the limiting spatial resolution of the PET scanner (about 6 mm on newer systems) may be falsely negative because of the effect of the volume averaging (partial volume effect). In a meta-analysis of 40 studies of 1,474 focal pulmonary lesions, Gould et al.121 reported a sensitivity of FDG-PET of 92% (95% confidence interval, range 89%–93%). They noted that in practice the sensitivity of 97% and a specificity of 78% decrease false-negative results. A nodule less than 1 cm should be considered worrisome for malignancy if any FDG accumulation is seen. Dynamic CT uses intravenous iodinated contrast material to measure nodule perfusion, and this information provides an estimate of the likelihood of malignancy. A pre-

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p o s i t ro n e m i s s i o n t o m og r a p h y i n c a n c e r SPN Thin-section CT Benign Indeterminate (fat, calcium, etc.) (< 8 mm)

Indeterminate (≥ 8 mm)

Low likelihood of malignancy

Int/High likelihood of malignancy

Dynamic CT (–) (+)

FDG-PET (–) (+)

CT follow up for stability Stable Growth

Biopsy or excision

Stop

diagnostic strategies (percutaneous needle biopsy or mediastinoscopy) and to guide appropriate therapy. One in 10 to 1 in 20 pulmonary nodules that are negative by FDG-PET imaging may, in fact, be malignant. One approach is to follow patients with a negative PET scan with serial CT examinations. A negative PET scan excludes highgrade lung carcinoma, so the risk of following patients over 1 to 2 years for nodule growth is low. Most of them are T1NOMO at the time of surgery.125 Zhuang et al.126 and Matthies et al.127 proposed dual-time PET imaging and thought this was suitable for nodules near the level of the cutoff value of 2.5 for SUV. Relative FDG uptake in malignant nodules tends to increase between the scans, whereas the relative FDG uptake in benign nodules tends to remain stable or decrease slightly. Using a threshold of a 10% increase in SUV between 1 and 3 hours led to an increase in sensitivity for FDG-PET from 80% to 100%. The specificity, however, declined from 94% to 89% (Table 33.6). Demura et al.128 reported the significance of dual time point PET imaging in the staging of disease of the mediastinum.

Staging NSCLC

FIGURE 33.4. Diagnostic algorithm for lung nodules.

contrast density measurement in Hounsfield units (HU) is obtained after a bolus injection of contrast material, and density measurements are performed at 1, 2, 3, and 4 min. Enhancing nodules are presumed to be malignant and nonenhancing nodules are presumed to be benign. Using a threshold of 15 HU, this technique has a sensitivity of 98%, a specificity of 58%, an accuracy of 77%, and a very high negative predictive value (Swensen et al.122). Nathan et al.,123 in a recent study of 36 patients, evaluated pulmonary nodules larger than 8 mm with both FDGPET and dCT. The overall sensitivity and specificity for FDG-PET were 95% and 80%, respectively (using the criteria referred to above), and for dCT (with a cutoff of 15 HU) were 100% and 27%, respectively. Rohren et al.124 suggested a diagnostic algorithm as is shown in Figure 33.4. A negative dCT scan can confidently exclude malignancy, but after a positive dCT the patients should be followed with an FDG-PET study, because one-half of them can be shown to be truly negative with PET imaging. All this staging information can be used to plan subsequent

The most standardized staging system is the TNM system. T denotes features of the primary mass, including size, location, and invasion, N denotes regional lymph node status, and M the presence or absence of metastatic disease.124 Because most patients have had a diagnostic CT before referral for FDG-PET, the PET scan is used mainly for assigning T stage (1) for the evaluation of the likelihood of malignancy in additional pulmonary nodules and to direct a confirmatory biopsy to them and (2) for the identification of malignant pleural effusions, which may be reactive or malignant, as CT cannot distinguish them. In a study of 100 patients with newly diagnosed bronchogenic carcinoma, Marom et al.129 compared staging with FDG-PET to staging obtained with a chest CT scan, a bone scan, and contrasted brain CT or MRI. For overall staging FDG-PET had an accuracy of 83%, whereas with conventional imaging it was 65% (P less than 0.005) (Table 33.7). For mediastinal lymph nodes, PET had an accuracy of 85% and for conventional imaging it was 58%. The important point here was that 9% of PET-positive studies were CT negative and 10% of PET-negative studies were CT false positive. In N3 stage disease, the sensitivity and specificity of PET were 92% and 93%, respectively, and for CT they were 25% and 98% (P less than 0.005). In M stage, the PET scan

TABLE 33.6. Representative literature of FDG-PET findings in initial diagnosis of non-small cell lung cancer (NSCLC).

Author

Year

No. of patients

Swensen et al.122 (Dynamic CT/threshold 15 HU) Nathan et al.123 Matthies et al.127 (dual time point PET) Gould et al.121 (meta-analysis)

2000

356

2003 2002

36 36

2001

1474 lesions

HU, Hounsfield units; FDG, 18F-fluoro-2-deoxy-D-glucose. Dual time point PET 1 and 3 hours after injection of FDG-PET.

PET criteria (SUV or visual)

Sens PET

Spec CT

PET

38 SUV > 2.5 + visual ≠SUV (10%)

95 100 97

100

Acc CT

58 80 89 78

27

PET

CT

77

458

chapter

33

TABLE 33.7. Studies comparing PET/CI/bone scan in staging of non-small cell lung cancer (NSCLC).

Author

Year

No. of patients

Marom et al.129

1999

100

Dwamena et al.131 1999 (meta-analysis) Bury et al.136 1999 (recurrent or residual)

Modality (PET/CI bone scan)

Sens PET

CI

Spec BS

PET

CI

PET/CI

83

65

PET/CI

85

58

91

80

25

PET

93

CI

Acc BS

PET/CI

92

PET/CI PET/BS

92

514

PET/CI

79

60

91

77

92

75

126

PET/CI

100

72

92

95

96

84

50

PPV BS

PET

CI

NPV BS

PET

CI

92

92

92

50

93

99

100

Remarks

Overall (P < 0.001) Mediastinal (P < 0.001) N3 stage (P < 0.001) M stage 92 Osseous metastases

98

99

BS

79

BS, bone scan; CI, conventional imaging.

was 91% accurate and conventional imaging was 80%. FDG PET also was superior to bone scintigraphy for evaluating osseous metastases from lung cancer: sensitivity, specificity, PPV, and NPV for FDG-PET were 92%, 99%, 92%, and 99%, respectively, and for bone scintigraphy these were 50%, 92%, 50%, and 92%. Erasmus et al.130 showed that FDG-PET was very sensitive and specific for evaluating adrenal metastases. Metastatic disease to regional lymph nodes is categorized by location in relationship to the tumor. For N0 disease, the 5-year survival is 60%, for N2 it is 20%, and for N3 it is very poor.106 The “gold standard” method for mediastinal lymph node staging is supposed to be mediastinoscopy. The overall sensitivity of the “gold standard” is approximately 90%, and it has the disadvantage of sampling errors and the technical difficulty of obtaining overall coverage with a single entry port (i.e., inaccessibility in the aortopulmonary window lymph nodes).124 On the other hand, CT uses size criteria to assess nodal metastases (1 cm in the short axis dimension). The limitation of this approach is that enlarged nodes may reflect inflammatory changes rather than metastatic involvement and small nodes may contain tumor deposits. Dwamena et al.,131 in a meta-analysis of 514 patients, reported that the sensitivity, specificity, and accuracy of FDG-PET were 79%, 91%, and 92%, respectively, and those of CT were 60%, 77%, and 75%. The average sensitivity of PET for nodal disease from a variety of studies132–135 was 88% as compared with 63% for CT, and the average specificity was 91% for PET and 76% for CT. The most common sites of metastases from lung carcinoma include lung (additional pulmonary lobes or to the contralateral lung), brain, adrenals, bone, and, less commonly, in liver and soft tissue.

Monitoring Therapy and Detection of Residual or Recurrent Disease FDG-PET provides metabolic rather than anatomic information and allows functional assessment of lung tumors during or shortly after therapy. Patients with a complete resolution of FDG uptake in their tumor following therapy have been

shown to have a good prognosis, as compared to those who have residual FDG uptake in their tumors. After treatment it is not necessary to find visible alterations in gross anatomic structure, but some posttreatment effects do occur. Tissue necrosis and concomitant macrophage-mediated inflammation after radiotherapy usually lead to the delay of a followup PET scan for 3 to 6 months. Radiographic findings usually peak within 6 to 12 weeks following completion of therapy and resolve by 6 months. The typical appearance on PET is diffuse low-grade or intermediate-grade FDG activity confined to a geographic field corresponding to the radiation port. Bury et al.,136 in a study of 126 patients with stage I to IIIB NSCLC treated with radiation therapy, showed that in detection of residual or recurrent disease FDG-PET had a sensitivity, specificity, accuracy, PPV, and NPV of 100%, 92%, 96%, 92%, and 100%, respectively, and the values for CT were 72%, 95%, 84%, 93%, and 79%. Because of its high sensitivity and negative predictive value, the investigators concluded that FDG-PET was a useful adjunct to CT in monitoring the effects of radiation therapy.

Prognostic Information and Future Trends in PET Imaging FDG-PET is used in determining planning target volumes (PTV), target coverage, and critical organ dose for radiotherapy. In one study, inclusion of a PET scan resulted in a change in PTV in approximately 30% of the patients137 because of more accurate delineation of metabolically active tumor. In another study, PTV was changed in all patients after inclusion of a PET scan in the preprocedure evaluation.138 It has been shown that FDG uptake in NSCLC correlates with the grade of the primary tumor, but it is an independent risk factor.139 Ahuja et al.140 showed that FDG-PET provides prognostic information that is entirely independent of a tumor’s size and clinical stage at the time of diagnosis. When the SUV in the primary tumor was less than 10, the median patient survival was 24.6 months. If it was greater than 10, survivals fell to 11.4 months. If the SUV was greater than 10 and the primary lesion was larger than 3 cm, survival was only 5.7 months. Dhital et al.141 reported that the 1-year survival of patients

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with tumor SUVmax less than 10 was 75% and with SUVmax greater than 20 it was only 17%. Radiolabeled thymidine, a marker of DNA synthesis, choline agents (for the evaluation of membrane synthesis and turnover), and radiolabeled amino acids (for the evaluation of protein catabolism), are many of the agents that are under investigation for potential utility in patients with NSCLC.142,143

Breast Breast cancer is the most common malignancy in women in the United States and is the second leading cause of cancer death in women. It represents 31% of all cancers in women. It is estimated that nearly 190,000 new cases appear every year and that 40,000 women die of breast cancer yearly.144,145 Brown et al.146 described the marked overexpression of the GLUT-1 glucose transporter in human breast cancer and the correlation between tumor FDG uptake and the number of viable tumor cells. Biochemical imaging using PET offers significant advantages and provides unique information about the physiologic processes associated with cancer. Early studies147–149 in patients with locally advanced breast cancer (LABC) or metastatic disease reported that FDG-PET detected the majority of the lesions, but the selection bias of patients with advanced disease did not allow determination of the specificity. Several subsequent clinical studies have shown that FDG-PET has a sensitivity ranging from 63% to 93% and specificity ranging from 73% to 94%150–154 (Table 33.8). Adler et al.155 reported a sensitivity of 96% in 27 primary lesions. Using a standard uptake value (SUV) threshold of 2 to 2.5, they were able to differentiate malignant from benign lesions with approximately 90% accuracy. Dehdashti et al.156 found a sensitivity of 88% and specificity of 100% using a SUV of 2.0 as the cutoff number to discriminate malignancy. In a recent meta-analysis154 of the PET literature, data from 606 patients indicated that FDG-PET had a sensitivity of 88% [95% confidence interval (CI), 83%–92%] and a specificity of 79% (95% CI, 71%–85%) (Figure 33.5). FDG-PET has limitations in detecting (1) tumors smaller than 1 cm), (2) more well-differentiated histologic subtypes of

tumors (tubular carcinoma and in situ carcinoma), and (3) lobular carcinomas. Avril et al.150 demonstrated that the sensitivity for detecting tumors larger than 1 cm using sensitive imaging reading criteria (definite and probable FDG uptake) was 57%, compared with 91% (with conventional image reading) for tumors larger than 1 cm. The sensitivity for detecting carcinoma in situ was even lower at 25%, and there was a significantly higher false-negative rate with infiltrating lobular carcinoma (65%) than with infiltrating ductal carcinoma (24%). In the same study, they showed that the overall sensitivity of FDGPET for detecting breast cancer was improved by using a more sensitive threshold for image interpretation compared to a conventional threshold (80% versus 64%), although the overall specificity was significantly poorer (75% versus 94%). They also reported a sensitivity of 50% for the identification of multifocal or multicentric breast cancer. Although breast conservation therapy has become standard for treating early breast cancer, it cannot be applied in these subsets of patients because up to 41% of breast cancers are multifocal or multicentric.157 Schirrmeister et al.151 demonstrated that PET was twofold more sensitive (63%) than combined mammography and ultrasound (32%) to detect multifocal lesions. The specificity was not different between these approaches. The disadvantages of FDG-PET, such as high expense, modest whole-body radiation exposure, and a low accuracy in general screening, have prompted the development of highresolution PET scanners dedicated to breast imaging with the capability of coregistering PET and mammographic images.158–160 The spatial resolution of these scanners is 2.8 mm full width at half maximum, about half that of current whole-body PET instruments, and they can utilize a lower dose of radiotracer and decreased acquisition time. The level of FDG uptake in an untreated breast cancer has prognostic information that may help to (1) stratify patients according to risk for recurrence or treatment failure and (2) target the aggressiveness of therapy for an individual patient to the aggressiveness of her tumor. FDG uptake has a strong correlation with the histologic type (higher in ductal versus lobular),161–163 tumor histologic grade,161,164,165 indices of proliferation (higher uptake with higher levels of proliferation),162,163 microscopic tumor growth

TABLE 33.8. FDG-PET results in initial diagnosis of breast cancer. Sensitivity Author

Year

Avril et al.150

2000

Schirrmeister et al.151 Walter et al.152 Heinisch et al.153 Samson et al.154 Meta-analysis (size, 2–4 cm diameter) Avril et al.150

2001 2003 2003 2001 (1993–2000) 2000

No. of patients

22 (1 cm) 12 (in situ) 117 40 36 606

144 (all sizes)

SIR, sensitive image reading; CIR, conventional image reading.

PET

57% (SIR) 91% (SIR) 25% (SIR) 93 63 76 88 (95% CI: 83%–92%) 64 (CIR) 80 (SIR)

Specificity CT/MRI

PET

CT/MRI

90

89 95

75 91 73 79 (95% CI: 71%–85%) 94 (CIR) 75 (SIR)

74 73

460

A

chapter

B

C

33

D

FIGURE 33.5. Transverse (C), coronal (A), sagittal (B), and maximum image projection (MIP) (D) (projection) PET images that demonstrate intense uptake of FDG in primary lung cancer (small cell). A previously unsuspected primary breast carcinoma is seen in the left breast.

pattern162 (nodular versus diffuse), and S phase.164,165 A weaker correlation with FDG has been reported for microvessel density, a surrogate of angiogenesis,166,167 and tumor cell density.162,167 No correlation was found between FDG uptake and tumor size,162,163,168 axillary node status,161,162,163 steroid receptor status,162,163,168,169 the presence of inflammatory cells,162 percentage of necrotic, fibrotic, and cystic components,162 or the thymidine labeling index (LI).168 Oshida et al.166 and Mankoff et al.171 found that FDG uptake in the primary tumor is predictive of response to treatment and patient outcome, even when they are treated with a variety of different protocols. Eubank et al.170 assumed that FDG uptake may be a marker of tumor cell resistance to apoptosis, and this was supported by other studies.172,173 Intermediates in the glucolytic pathway are key factors in initiating apoptosis, and alterations in these pathways limit apoptosis. Overexpression of some genes is associated with high glucolytic rates and resistance to apoptosis. An example is the P13K/Akt pathway.

Lymph Node Staging The single most important prognostic factor in early stage breast cancer is the status of the axillary lymph nodes. The 10-year survival rate of patients with histologically negative axillary nodes (65% to 80%) is significantly higher than that of those with involvement of one to three nodes (38% to 63%) or more than three axillary nodes (13% to 27%).174 The extent of axillary disease influences the choice of the therapeutic

regimen for individual patients. Many studies using FDG-PET for axillary staging showed a sensitivity of 40% to 94% and a specificity of 80% to 100%.154,175–180 Because neither physical examination nor conventional imaging can detect axillary nodal metastases, lymph node dissection (either conventional or limited with the use of sentinel node localization) is routinely performed to assess axillary nodal status in all patients with invasive cancers of 20 mm or less (80% or more of these patients have negative axillary lymph nodes). The risk of axillary nodal metastases is reported to be less than 5% in patients with tubular carcinoma less than 1 cm in diameter, grade I tumors less than 5 mm in diameter, or tumors with a single focus of microinvasion. With the introduction of step sectioning and immunohistochemical staining, micrometastases can be detected in up to 45% of cases.181 Microscopic nodal involvement may be important for prognosis and treatment planning, and FDGPET will miss this.182 Avril et al.180 found that the sensitivity of FDG-PET for detecting axillary disease in patients with T1 tumors (33%) was significantly less than for patients with tumors larger than 2 cm (94%). The specificity (100%) was the same for both subgroups. It has also been shown that the number of nodes involved with tumor at dissection influenced the sensitivity of PET (Table 33.9). In preclinical studies of several types of tumors, including rat mammary tumors, Wahl et al.183 showed that FDG uptake in lymph nodes involved by metastatic tumor is greater than FDG uptake in normal lymph nodes. In a recent multicenter study involving 308 axilla sites, the same investigators reported a moderate accuracy of FDG-PET and a

461

p o s i t ro n e m i s s i o n t o m og r a p h y i n c a n c e r TABLE 33.9. FDG-PET results for detection of axillary lymph node metastases. Study 175

Wahl et al. Kumar et al.176 Zornoza et al.177 Greco et al.178 Schrirrmeister et al.179 Avril et al.180

Year

No. of patients

Sens

2004 2004 2004 2001 2001 1996 all sizes

308 49 100 167 113 51

61 40 84 94 [68/72] 79 [27/34] 79 [19/24]

80 100 98 86 [82/95] 92 [73/79] 96 [26/27]

18 23

33 [2/6] 94 [17/18]

100 [12/12] 100 [5/5]

Stage T1 Stage >T1

Spec

Numbers in brackets are patient numbers used to derive sensitivity and specificity values.

mean sensitivity and specificity of 61% and 80%, respectively, when at least one focus of abnormal axillary uptake was detected.185 A recent meta-analysis found that FDG-PET has a higher sensitivity for predicting lymph node metastases in the axilla of patients with palpable axillary nodes, 90%, than for those having nonpalpable nodes, 69%, but lower specificity, 88% versus 94%.154 Greco et al.178 showed that in primary breast cancers, the detection rate for axillary nodal disease by FDG-PET depended on the size of the primary lesion, with an overall sensitivity and specificity of 94% and 86%, respectively. Sentinel lymph node mapping is now a validated, minimally invasive technique that includes histologic analysis of the primary draining nodes in the axilla identified at surgery after perilesional injection of 99mTc-sulfur colloid and/or blue dye.186 FDG-PET has been reported to have a sensitivity in the range of 20% to 50%185–187 in patients with pathologic results from sentinel lymph node (SLN) biopsy. In more advanced disease, however, especially with palpable axillary nodes, a large volume of disease (“packed” SLN) may not be visualized at mapping because lymph flow is diverted around it, and this may potentially result in a false-negative examination.188 Lymphatic spread of tumor to the internal mammary (IM) nodes occurs in up to 25% of patients at the time of initial diagnosis and more commonly in recurrence.189 IM nodes are not as accessible as axillary nodes, and radiotherapy and lymphadenectomy did not seem to improve patient survival.157 For these reasons, they are not sampled, although the presence of IM-FDG uptake predicts treatment failure.

Detection of Distant Metastatic Disease and Recurrence The most common sites of locoregional recurrence among patients following mastectomy, axillary node dissection, and radiation therapy are the chest wall and supraclavicular nodes.190 FDG-PET is a sensitive method for detecting metastases in the brachial plexus in patients with breast cancer.191,192 Eubank et al.,193 in a study of 73 patients with recurrent or metastatic breast cancer, demonstrated that FDG uptake in mediastinal or IM nodes was two times more prevalent than suspiciously enlarged nodes by CT. The sensitivity of FDG-PET was 85%, much higher than CT (50%), with nearly the same specificity (90% for PET and 83% for CT). Of these, 30% of patients suspected of having only locoregional recurrence by conventional imaging and clinical examination had mediastinal or IM-FDG uptake. Moon et al.194 reported an overall lesion-by-lesion sensitivity of 85% for FDG-PET and a specificity of 79%. Gallowitsch et al.195 reported sensitivity, specificity, PPV, NPV, and accuracy of 97%, 82%, 87%, 96%, and 90%, respectively, for FDG-PET, compared with 84%, 60%, 73%, 75%, and 74%, respectively, for CT. Lonneux et al.,196 in a study of 39 patients (asymptomatic) with a rise in tumor makers, showed that FDG-PET detected recurrences with 94% sensitivity, whereas conventional imaging had a sensitivity of 18%. Kamel et al.,197 in a study of 60 similar patients, found an overall sensitivity, specificity, and accuracy of 89%, 84%, and 87%, respectively, for locoregional recurrence and found it more sensitive than the serum tumor marker CA15-3 (Table 33.10). Inoue et al.198 demonstrated that the patients

TABLE 33.10. FDG-PET results for detection of recurrent/distant metastases. Sens

Spec

Acc

PPV

NPV

Study

Year

No. of patients

PET

CT/MRI

PET

CT/MRI

PET

CT/MRI

PET

CT/MRI

PET

CT/MRI

Moon et al.194 Eubank et al.193 Gallowitch et al.195 Lonneux et al.196 (clinical suspected recurrence) Kamel et al.197

1998 2001 2003 2000

57 73 62 39

85 85 97 94

— 50 84 18

79 90 82 50

— 83 60

— 88 90

— 73 74

82

—

92

—

87

73

96

75

2003

60

89

84

87

462 with a higher SUV had a significantly poorer prognosis than those patients with lower values. The skeleton is the most common site of distant metastases in breast cancer. Bone scintigraphy is considered the most sensitive method for detecting and determining the extent of skeletal metastases. However, purely lytic lesions or metastases confined to the marrow cavity may be difficult to detect on a bone scan, due to the lack of a sufficient osteoblastic response.199 Cook et al.200 reported that the level of FDG uptake in lytic lesions was significantly greater compared with osteoblastic lesions and that the prognosis of patients with predominantly lytic disease was significantly worse. Osseous metastases are a frequent finding in breast cancer; approximately 70% of patients with advanced disease have an osseous metastasis, which is a major contributor to morbidity and treatment cost.201 The median survival for these patients is 24 months and the 5-year survival is 20%. Breast cancer causes osteolytic more often than osteoblastic metastatic lesions, although osteoblastic changes often develop after treatment. The reported higher sensitivity of FDG-PET for detection of osteolytic lesions likely reflects the ability of FDG-PET to detect metastatic deposits in the bone marrow before the development of a significant reactive bone formation that is necessary for detection by bone scintigraphy. FDG-PET detection of osseous metastatic disease appears to be unrelated to reactive bone formation, but rather is related to detection of the metabolic activity of the tumor cells. 18 F-Fluoride PET may provide improved detection of bone metastases in breast cancer, and in other tumors, because its concentration is approximately twofold greater than that of 99m Tc-methylene disphosphonate (99mTc-MDP) and its clearance is faster, resulting in a higher bone to background ratio. Schirrmeister et al.202 compared a whole-body 18F-PET scan with a whole body 99mTc-MDP scan and demonstrated that the former detected more lesions in more patients than the conventional bone scan. Finally, it was found that FDG-PET changed the clinical stage in 36% of patients with breast cancer and the management in 58%.203

Monitoring Treatment Response Neoadjuvant chemotherapy (NACT) is the standard therapy for patients with locally advanced breast cancer (LABC). NACT is associated with a good response rate in more than 70% of the patients, including a complete pathologic remission in about 10% to 15%.204 It has been used to improve primary tumor resectability (including the use of breast-conserving surgery) and to assess chemosensitivity to selected chemotherapeutic agents. It can also be used as an alternative therapy for patients who are unresectable or chemoresistant. Conventional imaging methods are limited in assessing response to therapy, and often a delay of several weeks after completion of therapy is required before the effectiveness of the treatment can be assessed. Wahl et al.205 reported that metabolic changes could be detected as early as 8 days posttreatment in responders. Persistent FDG uptake is seen in nonresponding patients. Schelling et al.206 and Smith et al.207 were able to separate responders from nonresponders with sensitivities of 90% and 100% and specificities of 74% and 85% after the first course

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of chemotherapy. Their results were similar although they used a different SUV cutoff. In assessing the response to chemotherapy, Vranjesevic et al.208 noted, in a study of 61 patients using FDG-PET and conventional imaging (CT/MRI/US), that the former was more accurate (90% versus 75%). Other biologic and physiologic tumor properties may be responsible for clinical prognosis. For example, imaging with 15 O-water can estimate regional blood flow within a tumor. Low perfusion may be responsible for a poor response to intravenous chemotherapy.209 Mankoff et al.210 showed that blood flow declined an average of 32% in responders and increased an average of 48% in nonresponders. The posttherapy blood flow measurement was the only statistically significant variable associated with improved disease-free survival. Using PET in this way may help to identify the physiologic manifestations of drug resistance. Patients with breast cancer undergoing chemotherapy often receive the hematopoietic cytokines, granulocyte colony-stimulating factor (G-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF). The use of these agents results in an increase in bone marrow uptake of FDG, which may be misinterpreted as diffuse bone marrow involvement by breast cancer. The higher bone marrow background activity after cytokine therapy may make it more difficult to detect osseous metastases. Sugawara et al.211 studied the effects of G-CSF and GM-CSF on the biodistribution of FDG in rats and found that SUVlean (SUV corrected for lean body mass) of the bone marrow was greater during G-CSF treatment than the baseline level. Markedly increased FDG uptake is also often seen in the spleen because of extramedullary hematopoiesis in the spleen.211,212 Smith et al.213 and Gennari et al.214 showed by quantitative methods that a significant reduction in axillary nodal FDG uptake after neoadjuvant chemotherapy could predict a complete microscopic pathologic response, and that may be an even more important marker for prognosis because nodal disease is thought to reflect the presence of occult disseminated disease. Stafford et al.215 evaluated the response of skeletal metastases to therapy using serial FDG-PET and found a strong correlation between the quantitative change in FDG SUV and the overall clinical assessment of response, assessed with physical examination, conventional imaging, and change in tumor markers. Mortimer et al.216 reported a series of 40 patients who underwent FDG-PET for the evaluation of response to tamoxifen 7 to 10 days after institution of therapy. FDG uptake predicted a subsequent response to therapy consistent with a “metabolic flare.”

Other PET Tracers Energy metabolism is associated not only with tumor growth, but also with a variety of other biologic processes, such as inflammation or tissue repair. Other PET tracers have been used for staging and guiding treatment by identifying therapeutic targets, by identifying factors associated with resistance to therapy, and by making early assessments of therapeutic response. Decreased tumor proliferation is an early event in response to successful treatment.217 Thymidine is incorporated into

p o s i t ro n e m i s s i o n t o m og r a p h y i n c a n c e r

DNA but not RNA, so its uptake and retention in the tumor serves as a specific marker of cell growth. Shields et al.218 showed that 11C-thymidine could be used in assessing early response to treatment. The 18F analogue of thymidine (FLT) has been used because its longer half-life is an advantage.219–221 FLT has been used to measure the response to treatment in several different tumor types, including breast cancer. Tumor hypoxia has been established as a resistance factor for radiotherapy, and evolving evidence indicates that it promotes tumor aggressiveness and resistance to a variety of systemic treatment modalities.222,223 Hypoxia could not be reliably predicted by FDG uptake,224 although it contributes to increased rates of glycolysis, as was shown by Clavo et al.225 The most widely used PET agent for imaging hypoxia is 18Ffluoromisonidazole.226 PET imaging of hypoxia holds great promise for identifying the subset of breast cancers with significant hypoxia, where alternative therapeutic strategies that can overcome the resistance associated with hypoxia will likely be needed. The majority of breast cancers express estrogen receptors (ER) and progesterone receptors (PR), and their expression is an indicator of prognosis and predicts the likelihood of responding to antiestrogen therapy.227 Most breast cancers are hormone sensitive, requiring estrogen for proliferation. Currently, tumor ERs and PRs are evaluated by in vitro assays, but these assays provide limited information about the functional status of the receptors and the likely responsiveness of the tumor to hormone therapy. Only 55% to 60% of patients with ER(+) disease actually respond to hormonal therapy [versus fewer than 10% of patients with ER(-) disease].228,229 Furthermore, ER expression can be heterogeneous in large or metastatic breast cancers, and biopsy can be misleading as a result of sampling error. The most extensively studied compound is 16a-18F-fluoro17b-estradiol (FES), which showed an excellent correlation between tumor FES uptake measured on PET images and the ER concentration of the tumor determined by conventional quantitative ligand binding assays230 or by immunohistochemistry,231 either in the primary tumor or in metastatic lesions. FES-PET has been shown to be highly sensitive (93%) for detection of ER(+) metastatic foci232 at an acceptable radiation dose to the patient.233 Mankoff et al.234 showed heterogeneous FES uptake within the same tumor and between metastatic lesions, both qualitatively and quantitatively, which can help in establishing prognosis and in guiding treatment selection. In patients with known metastatic breast cancer, FES uptake decreased after the initial therapeutic dose of tamoxifen, and this is presumably related to the nonavailability of ERs to interact with FES because the receptors were occupied by tamoxifen and its bioactive metabolites. This finding shows that the tumor uptake of FES appears to be a receptormediated process. Dehdashti et al.235 found no significant relationship between FDG uptake and either ER status or FES uptake. FES-PET and in vitro ER assays agreed in 88% of patients. Mortimer et al.236 reported that patients with FES(+) disease had longer survival than those with FES(-) tumors. When there is a high degree of ER blockade in the primary tumor (about 50% decrease in SUV from baseline), a good response to therapy is predicted.237

463

Within 7 to 10 days after the initiation of hormonal treatment, a small number of patients (5% to 20%) experience a phenomenon known as the hormonal flare reaction, with pain in osseous metastatic lesions, pain and erythema in soft tissue lesions, hypocalcemia, and apparent disease progression on bone scintigraphy.237 The percent change in FDG uptake and the baseline FES uptake were the best predictors of response to therapy. The PPV for response to tamoxifen with a metabolic flare (an increase in tumor FDG uptake of 10% or more as the cutoff criterion) was 91% and the NPV was 94%. The PPV and NPV for the baseline FES uptake (with a cutoff SUV of 2.0) were 79% and 88%, respectively.237 The flare reaction is a strong predictor of response because nearly 80% of the patients who develop this reaction respond to hormonal therapy.238 Hormonal flare is presumed to represent an initial agonist effect of the drug on the tumor before its antagonist effects supervene.239 PET can be used to guide therapy by showing characteristics of the tumor at the biochemical level before therapy or early during therapy.

Gastric Cancer Gastric cancer is the second most common cause of cancer death in the world, with an overall 5-year survival rate less than 25%.240 The leading cause for the development of gastric cancer is repeated infection with Helicobacter pylori. There two different types: the intestinal type, which predominantly involves the distal stomach (most common in Asia), and the diffuse or signet-ring type, which mainly involves the proximal stomach (most common in Western countries). Tumors consisting of signet-ring cells or with large amounts of mucin are frequently false negative by FDG-PET, probably because of a lower expression of glucose transporters in these types of tumors and a lower tumor cell density.241,242 Even large tumors with a diameter of several centimeters can be falsely negative on FDG-PET if the tumor cells demonstrate low metabolic activity.243 Yeung et al.244 studied 23 patients with gastric cancer and found that FDG-PET had a sensitivity of 93% for detection of gastric cancer, a specificity of 100% for detection of local recurrence, but low sensitivity (22%) and high specificity (97%) for detection of metastatic disease in intraabdominal lymph mode stations. Stahl et al.241 reported higher detection rates in the intestinal type (83%) compared with the nonintestinal type (41%). The SUV was greater in the intestinal type (6.7 ± 3.4) than in the nonintestinal type (4.8 ± 2.8). Nonmucinous tumors had higher SUVs (7.2 ± 3.2) than the mucinous ones (3.9 ± 2.1), and the same was true for grade 2 tumors, which had higher FDG uptake than the grade 3 tumors. Mochiki et al.245 described the existence of a relationship between the intensity of FDG uptake and survival, which did not agree with the results of Stahl and coworkers.241 Yoshioka et al.246 demonstrated the usefulness of FDG-PET in detecting metastatic disease in the liver, lungs, and lymph nodes, but it was not useful for detection of osseous metastases and peritoneal or pleural carcinomatosis. De Potter et al.243 reported in a study of 33 patients that the sensitivity, speci-

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TABLE 33.11. Representative literature of PET findings in the initial diagnosis, recurrence, and response to therapy for gastric cancer. Author

Year

No. of patients

Sens

Yeung et al.244

1999

23

22

97

Stahl et al.241

2003

40

De Potter et al.243 (recurrence) Ott et al.247 (prediction of response)

2002 2003

33 35

83 41 70 77

(intestinal type) (nonintestinal type) 69 86

Spec

PPV

NPV

SR (2-year)

Remarks

Abdominal lymph node detection P < 0.01 78

60 90

SUV Ø 35% (cutoff)

SR, survival rate.

ficity, PPV, and NPV of FDG-PET were 70%, 69%, 78%, and 60%, respectively, in the detection of recurrent disease. Ott et al.247 have used a 35% decrease from the baseline metabolic activity on day 14 of preoperative chemotherapy to predict tumor response in patients with gastric cancer (Table 33.11). The sensitivity and specificity of FDG-PET for prediction of histopathologic response were 77% and 86%, respectively, and the 2-year overall survival of “responders” compared with that of “nonresponders” was 90% and 25%, respectively.

Colorectal Carcinoma Colorectal cancer is the third most common cause of cancer in men and women, and it affects 5% of the population in the United States and other Western countries. Approximately 106,000 new cases of colon cancer, 40,570 new cases of rectal cancer, and 57,000 deaths (10% of all cancer deaths) were expected to occur in 2004 in the United States.248 Most patients (70%) diagnosed with colorectal cancer undergo surgery with curative intent, and the overall survival of 5 years is less than 60%. The recurrence rate is close to 40% within the 5 years following surgery, with up to 80% of the recurrence appearing in the first 2 years. The most common sites of recurrence are in the liver (20%), in the original local site (12.5%), and in the lungs (8%). Only 20% of patients are amenable to a second surgery with curative intent, and long-term survival is expected in only 30% of these.249,250 The diagnosis of colorectal carcinoma is based on colonoscopy and biopsy. Most follow-up strategies include carcinoembryonic antigen (CEA) testing and liver imaging. The use of frequent colonoscopy is still being investigated.

FDG-PET in the Diagnosis and Initial Staging of Colorectal Carcinoma FDG-PET can usually differentiate benign from malignant lesions (hepatic and pulmonary lesions, indeterminate lymph nodes) and can play an important role in the evaluation of patients with rising tumor markers in the absence of a known source of disease. When these lesions (or metastases) are found with FDG-PET, they may lead to a cancellation of surgery in these patients. Abdel-Nabi et al.251 and Kantorova et al.252 demonstrated that FDG-PET had a high sensitivity for detection of distant metastases, particularly in the liver, but neither FDG-PET nor

CT was sensitive enough to reliably detect local lymph node involvement. FDG-PET was, however, superior to CT for detecting hepatic metastases, with a sensitivity and specificity of 88% and 100%, respectively, compared with 38% and 97% for CT.251 Mukai et al.253 reported that FDG-PET changed the treatment modality in 8% of patients and the extent of surgery in 13%. In a study of 110 patients, Yasuda et al.254 showed that precancerous adenomatous polyps could be detected with a sensitivity of 24% for lesions from 5 to 30 mm in size and of 90% for lesions greater than 13 mm. Although there are false-positive findings such as abscesses, fistulas, diverticulitis, and adenomas, the identification of focal uptake should not be ignored. However, the impact on patient management is not high because most patients will undergo surgery anyway, and staging is usually performed with preoperative liver ultrasound and during surgery. PET results may have a role in changing the type of surgery (curative versus palliative or concomitant liver metastases resection).

FDG-PET in the Diagnosis and Staging of Recurrent Colorectal Cancer Early detection of recurrent disease is of primary importance because it may lead to a cure in up to 25% of patients. Surgical or medical treatment with the intent to improve survival and the quality of life should be guided by the accurate staging of disease. The size and number of hepatic metastases and the presence of extrahepatic disease affect the prognosis. The prognosis is poor if extrahepatic metastases are present, and this is believed to be a contraindication to hepatic resection.255 Iterative measurement of CEA is a useful, albeit imperfect, method to monitor the detection of recurrence, with a sensitivity of 59% and specificity of 84%.256 Barium studies have been reported to be only 49% sensitive, 85% specific, and 80% accurate for overall recurrence.257 A strategy in which increased CEA levels trigger the ordering of a PET study is limited by the diagnostic performance of CEA itself, which is far from optimal. CT has an accuracy of 25% to 73% for localizing recurrence, but it fails to demonstrate hepatic metastases in up to 7% of patients and underestimates the number of lobes involved in up to 33% of patients. Metastases to the peritoneum, mesentery, and lymph nodes are commonly missed on CT, as well as the differentiation of postsurgical changes from local tumor recurrence.258,259 CT portography (superior mesenteric arterial portography) is more sensitive (80% to 90%) than CT (70% to 80%) for detection of hepatic metas-

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tases, but there are many false-positive findings, which lower the positive predictive value.260,261 There are also limitations in accurate operative staging because of adhesions or the site of the surgical incision (transverse upper abdominal for liver resection). Shiepers et al.262 studied 76 patients and found that the accuracy of FDG-PET and CT were 95% and 65%, respectively, for differentiation of scar from local recurrence. Huebner et al.,263 in a meta-analysis review of 11 articles, reported that the sensitivity and specificity for detecting recurrent colorectal cancer with FDG-PET were 97% and 76%, respectively, and for liver and local pelvic recurrences FDG-PET had specificities of 99% and 98%. Whiteford et al.264 demonstrated that the sensitivity of FDG-PET imaging for detection of mucinous adenocarcinoma was significantly lower than for nonmucinous adenocarcinoma, 58% and 92%, respectively, mainly because of the relative hypocellularity of these tumors.265 The high diagnostic accuracy of FDG-PET for detecting liver metastases was confirmed by Kinkel et al.,266 who compared noninvasive imaging modalities (US, CT, MRI, and FDG-PET) for the detection of hepatic metastases from colorectal, gastric, and esophageal cancers. They found that FDG-PET had the highest sensitivity (90%), compared with 76% for MRI, 72% for CT, and 55% for US. Delbeke et al.267 reported that FDG-PET had a higher accuracy (92%) than CT (78%) and CT portography (80%) for detection of hepatic metastases. Although the sensitivity of FDG-PET (91%) was lower than that of CT portography (97%), the specificity was much higher, particularly at postsurgical sites. Ogunbiyi et al.268 compared the sensitivity of FDG-PET and CT in local recurrence (91% versus 52%) and in hepatic lesions (95% versus 74%). Rydzewski et al.269 found that the PPV of FDG-PET for characterizing liver lesions was similar to that of intraoperative ultrasonography (US) (93% and 89%, respectively) and superior to CT and MRI imaging (Table 33.12). A major advantage of FDG-PET is its ability to detect extrahepatic disease not discovered by the other modalities. Valk et al.270 compared the sensitivity of FDG-PET and CT for specific anatomic locations and found that FDG-PET was more sensitive than CT in all locations except the lung, where the two modalities were equivalent. The largest difference between PET and CT was found in the abdomen, pelvis, and retroperitoneum, where more than one-third of PET-positive lesions were negative by CT. PET was also more specific than CT at all sites except the retroperitoneum. Delbeke et al.267 concluded that, outside of the liver, FDGPET was especially helpful in detecting nodal involvement, differentiating local recurrence from postsurgical changes, evaluating the malignancy of indeterminate pulmonary nodules, and detecting distant metastases in the chest, abdomen, or pelvis. Gambhir et al.,271 in a review of 2,244 patient studies, reported that the sensitivity and specificity for FDG-PET were 94% and 87%, respectively, compared with 79% and 73% for CT. Flanagan et al.272 reported the use of FDG-PET in 22 patients with unexplained elevation of CEA serum levels after resection of colorectal carcinoma with no abnormal findings on conventional workup, including CT. The sensitivity of FDG-PET in these patients was 100%, the specificity 71%, and the PPV 89%. Valk et al.270 reported a sensitivity of 93% and a specificity of 92% in a similar group of 18 patients.

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Flamen et al.273 used FDG-PET to study 50 patients with elevated CEA and negative (n = 31) or equivocal (n = 19) findings on conventional imaging and found a sensitivity of 79% for the patients and 75% for the lesions. Cohade et al.,274 in a study of 45 patients, showed that PET/CT integrated imaging reduced the frequency of equivocal and probable lesion characterization by 50% compared with PET alone. This hybrid modality increased the number of definite locations by 25% and increased the overall correct staging from 78% to 89%.

Impact of FDG-PET on Patient Management FDG-PET imaging allows the detection of unsuspected metastases in 13% to 36% of patients and has a clinical impact in 14% to 65%.267,268,270,272,273,275–279 In the study by Delbeke et al.,267 PET altered surgical management in 28% of the patients, in one-third by initiating surgery and in two-thirds by avoiding surgery. Meta et al.280 analyzed the answers to questionnaires that were sent to 60 referring physicians and concluded that PET had an impact on the clinical management in 65% of their patients (80% upstaged and 20% downstaged). In a study of 51 patients Ruers et al.281 found that clinical management decisions based on conventional diagnostic methods were changed in 20% of patients based on the findings of FDG-PET imaging, especially by detecting unsuspected extrahepatic disease. Strasberg et al.282 demonstrated a higher long-term overall survival (OS) at 3 years (70%) and higher disease-free rates in patients selected for curative resection who had a PET study than those who did not have PET included in their workup (30% to 64%). Current PET/CT fusion images can further affect clinical management283–287 by guiding therapy toward a less invasive and more efficient surgical procedure or by guiding a biopsy to an FDG-avid region of the tumor. Additionally, it can provide better maps than CT alone to modulate the field and dose of radiation therapy.

Monitoring Therapy The ability of PET to differentiate scar tissue from recurrent tumor in the pelvis was recognized very early.288,289 Increased FDG uptake can be present immediately after radiation because of inflammatory changes, and this is not always associated with residual tumor. Moore et al.290 found a sensitivity of 84% and specificity of 88% for the detection of local pelvic recurrence 6 months after external-beam radiation therapy for rectal cancer. In contrast, Schiepers et al.291 concluded that there was no correlation between FDG uptake and cell kinetics in patients with primary rectal cancer treated by irradiation. Guillem et al.292 demonstrated in a study of 15 patients treated with combined chemoradiation that FDGPET added useful information. In a study of 25 patients with rectal cancer, Calvo et al.293 described SUVs that were significantly decreased after treatment, but no correlation was found between postradiation metabolic activity and the 3-year survival rate. Hepatic metastases can be treated with either systemic chemotherapy or regional therapy to the liver. A variety of

2244 47

2001

2002

CI, conventional imaging.

2002

18 577

1999 2000

Valk et al.270 Heubner et al.263 (meta-analysis) Gambhir et al.271 (review) Rydzewski et al.269

54

90

94

93 97

72

79

52 74

CT

Others

76 (MRI) 55 (US)

97 (CT portography)

59 (CEA)

Sens

87

92 76

100 100

PET

73

80 85

CT

Spec Others

84 (CEA)

92

PET

78

CT

Others

80 (CT portography)

Acc

93

PET

78

CT

PPV

89 (intraoperative US)

Others

Specificity >85% Colorectal, gastric, and esophageal cancers

For detection of hepatic metastases CEA≠/CI(-)

P < 0.005

Remarks

chapter

Kinkel et al.266 (hepatic metastasis)

91

1997

Delbeke et al.267 52

91 95

58

1997

58 92

Moertel et al.256 Whiteford et al.264 Mucinous Nonmucinous Ogunbiyi et al.268 Local recurrence Hepatic

PET

417 109

Year

1993 2000

Author

No. of patients

TABLE 33.12. FDG-PET results in detection and staging recurrent colorectal carcinoma.

466 33

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regional therapies exist, including chemotherapy administered through the hepatic artery using infusion pumps, selective chemoembolization, radiofrequency ablation, cryoablation, alcohol ablation, and radiolabeled 90Ymicrospheres. Findlay et al.294 showed that, in patients with hepatic metastases, responders can be discriminated from nonresponders after 4 to 5 weeks of chemotherapy with fluorouracil by measuring FDG uptake before and during therapy. Some results reported by Vitola et al.,295 Torizuka et al.,296 and Langenhoff et al.,297 showed that 3 weeks after radiofrequency ablation and cryoablation, 51 of the 56 metastatic sites became FDG negative and there was no recurrence during 16 months follow-up. Wong et al.298 compared FDG-PET imaging, CT, MRI, and serum levels of CEA to monitor the therapeutic response of hepatic metastases to 90Y-glass microspheres. They found that FDG uptake correlated best with the changes in serum levels of CEA.

New PET Tracers for Clinical Use 18

F-Fluoride has a mechanism of uptake similar to that for other bone imaging radiopharmaceuticals, but because of the better spatial resolution and routine acquisition of tomographic images, 18F-fluoride PET imaging offers potential advantages over conventional bone scintigraphy for detecting metastases. Schirrmeister et al.299 demonstrated that twice as many benign and malignant lesions were detected with 18 F-fluoride PET compared to planar scintigraphy. Higashi et al.300 demonstrated that the in vitro uptake 11 of C-thymidine or 18F-fluorothymidine correlates with the tumor proliferation rate and that these radiopharmaceuticals are assessing the rate of DNA synthesis. Dittman et al.301 compared FDG with FLT uptake and showed that FLT-PET accurately visualized thoracic tumors and cerebral metastases, but that high physiologic uptake in the liver and bone marrow prevents detection of metastases in these locations.

Summary FDG-PET is indicated as the initial test for diagnosis and staging of recurrence, for preoperative staging (N and M) of known recurrence, for the differentiation of benign from malignant lesions (indeterminate lymph nodes, hepatic and pulmonary lesions), for the differentiation of posttreatment changes from recurrent tumor, for the evaluation of patients with rising tumor markers in the absence of a known source, for a subgroup of patients at high risk (elevated CEA levels), for patients with a normal CT in whom surgery could be avoided if FDG-PET shows metastases, and for screening for recurrence in patients at high risk. It also affects the clinical management by guiding further procedures (biopsy, surgery, and radiation therapy) and excluding the need for additional procedures.

Lymphoma Lymphoma is a general term that refers to a group of malignancies originating in the lymphoid tissue, including Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma

467

(NHL).302 The first evaluations of PET for staging in large cohorts of patients with lymphoma were performed by Moog et al.303,304 (mixed populations with HD and NHL). For nodal staging, Moog et al.303 evaluated 60 patients with CT and PET and verified discordant results by biopsy whenever possible. A total of 160 nodal regions were positive by both modalities, and 25 were positive by PET alone. Nine of these were verified histologically, and PET was true positive in 7 cases and false positive in 2 cases. Six regions were positive by CT only, and in the 3 in which verification was obtained, the CT result was false positive. There was a change in management in 10% to 15% of the patients. For extranodal staging, Moog et al.304 also evaluated 81 patients. Forty-two disease sites were detected by both modalities, and PET detected an additional 24 sites, of which 15 were verified pathologically, including 9 sites in bone marrow, 3 in the spleen, and 2 elsewhere, and in 14 sites PET was true positive. Six of 7 lesions detected only by CT were verified, and 5 of these were false positive. FDG-PET was found to be of value in the diagnosis of HD and aggressive NHL.305,306 It is generally accepted that FDGPET may have a role in diagnosis and staging of low-grade follicular NHL. For other subtypes of low-grade lymphoma (small cell lymphocytic and probably mantle cell lymphoma), it seems that FDG-PET has no value for staging and followup.305,307 Similar discouraging results have been demonstrated in a small group of patients with follicular lymphoma of the duodenum.308 In contrast, marginal zone B-cell lymphoma, an entity that was initially considered to originate from mucosaassociated lymphoid tissue (MALT) lymphoma, but in recent reports is classified as a distinctive histologic type, was shown to take up FDG only in the involved lymph nodes. From the studies of Moog et al.309 and Carr et al.,310 it appears that both PET and iliac crest biopsy should be performed to stage the bone marrow. It is probable that some patients with diffuse involvement have homogeneous uptake on PET, whereas some patients with focal involvement are missed by random biopsy. FDG-PET can be useful in guiding the biopsy to a site of active disease. An additional study evaluated FDG-PET as a predictor of prognosis. Aggressive and treatment resistant tumors showed a trend toward higher uptake of FDG, with an inverse relationship between the survival rate of patients and the degree of FDG uptake.311 The complementary role of FDG-PET to conventional staging of 45 patients with newly diagnosed HD and NHL was investigated by Delbeke et al.312 In addition to the positive impact of PET, these authors report that false-negative FDG imaging understaged 3 patients (7%), including 2 patients with low-grade NHL and 1 with HD. They concluded that FDG-PET is an efficient method for staging of lymphoma but should be used in conjunction with conventional staging as a complementary modality. Recently, Hong et al.313 evaluated the clinical value of FDG-PET for the staging of malignant lymphoma. The sensitivities and specificities for detection of nodal involvement for PET, CT, and 67Ga scanning were determined to be 93.3%, 98.9%, and 25.8%, and 100%, 99.1%, and 99.8%, respectively. In detecting extranodal lymphoma, the sensitivities and specificities of the PET, CT and 67Ga scanning were 87.5%, 87.5%, and 37.5%, and 100%, 100%, and 100%, respectively. Sasaki et al.314 showed a specificity of 99% for

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TABLE 33.13. Representative recent literature of PET findings in lymphoma.

Author 313

Hong et al. Nodal evaluation Extranodal evaluation Sasaki et al.314 Wirth et al.319 Stumpe et al.315 HD NHL Shen et al.318 Rini et al.320 (HD + splenic involvement)

Sens

Year

No. of patients

No lesions

PET

CT

2003

30

—

93 88

2002 2002 1998

46 50 50

152 117

2002 2003

25 32

111

Spec 67

Ga

PET

CT

98 88

26 38

100 100

99 100

92 82 86

65 68 81

69

99 — 96

99 — 41

89 96 92

86

100

67

72 50

67

Ga

100 100

100

95

HD, Hodgkin’s disease; NHL, non-Hodgkin’s lymphoma.

both CT and PET, whereas the sensitivity of CT was 65% and that of PET was 92%. An older study including 50 patients compared FDG-PET for staging of HD and NHL to CT.315 The sensitivity and specificity of PET were 86% and 96% for HD and 89% and 100% for NHL. The sensitivity and specificity of CT were 81% and 41% for HD and 86% and 67% for NHL. In comparison to 67Ga, PET showed better performance than 67Ga, as was reported by Paul et al.316 (the first report on FDG uptake in five patients with lymphomas) and Okada et al.317 Of course, their mechanism of uptake by malignant tissue is based on different principles. FDG, as mentioned before, is incorporated into malignant cells with a high glucolytic metabolism due to intracellular trapping of FDG phosphate. 67Ga is taken up by malignant cells, lymphoma in particular, probably based on an intracellular transferrinrelated transport mechanism. Inside the cells, the tracer is incorporated in lysosome-like granules and shows a slower clearance from malignant as compared with normal tissues. A study comparing PET and 67Ga evaluated 111 sites of disease in 25 patients with different types of lymphoma at diagnosis and relapse.318 The sensitivity of PET was 96% versus 72% for 67Ga. The false-negative 67Ga studies were attributed to poor detection of low-grade NHL, bone and bone marrow involvement, and lesions smaller than 12 mm in diameter. The differences in the performance rate of PET, 67Ga, and CT for staging of HD and NHL were evaluated in 50 patients.319 On a site-based analysis, PET showed superior values, 82%, as compared with both 67Ga, 69%, and CT, 68%. Diagnosis of splenic involvement is difficult using nuclear medicine techniques, because both 67Ga and FDG are physiologically taken up in variable amounts by the normal spleen. Lymphomatous splenic involvement is, as a rule, diffuse, thus increasing the diagnostic challenge. The sensitivity, specificity, and accuracy of PET were 92%, 100%, and 97%, respectively, as compared with 50%, 95%, and 78% for 67Ga320 (Table 33.13). Buckmann et al.321 found that PET is 10% to 20% more accurate than CT in detecting and staging of malignant lymphoma. They also reported that PET is better than CT in detecting bone marrow involvement and is useful as a guide for bone marrow biopsy. A change in staging is more likely to result in a change in treatment strategy for lymphoma subtypes in which treatment is given with a curative intent. For example, upstaging from an early (stage I–II) to an advanced stage (III–IV) in HD

or large cell lymphoma will probably result in the selection of a longer course of chemotherapy as the exclusive treatment, as opposed to a shorter course of chemotherapy followed by radiation therapy (Figure 33.6). A similar upstaging in patients with follicular lymphoma will also influence treatment and follow-up of the disease. Schoder et al.322 demonstrated that PET findings led to a change in the clinical stage in 44% of 46 patients: in patients with NHL and HD, 21% were upstaged and 23% were downstaged. In a recent prospective study of 88 patients with HD, Naumann et al.323 demonstrated a change in staging in 18 patients (20%). FDG-PET appears to be a noninvasive, efficient, and costeffective whole-body imaging modality with a high sensitivity, specificity, and accuracy for staging patients with most histologic types of HD and NHL (Figure 33.7). It is generally

A

C

B

D

FIGURE 33.6. Transaxial PET/CT images obtained with FDG in a patient in the mid-twenties with a new diagnosis of Hodgkin’s lymphoma. Intense focal tracer uptake is seen in multiple lymph nodes in the right neck and axillary region. (A) CT scan. (B) Fused PET/CT image. (C) Attenuation corrected PET image. (D) Nonattenuation corrected PET image.

p o s i t ro n e m i s s i o n t o m og r a p h y i n c a n c e r

A

B

FIGURE 33.7. (A) Coronal PET/CT images of a 60+-year-old woman with recurrent follicular nonHodgkin’s lymphoma. Intense focal uptake is noted in the right supraclavicular area that is attributed to recurrent disease. (B) Coronal PET/CT images of the patient noted in (A) at 12 weeks after radioimmunotherapy with Bexxar (131I-tositumomab and unlabeled tositumomab therapy). The dramatic decrease in FDG uptake in the right supraclavicular area indicates an excellent response to therapy.

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TABLE 33.14. Representative literature of PET in monitoring response to treatment of lymphoma. DFS Authors

Year

No. of patients

FDG evaluation after first-line treatment: Kostakoglu et al.331 2002 Spaepen et al.336 2003 Weihrauch et al.329 2001 Spaepen et al.343 2003 FDG evaluation during treatment: Torizuka et al.337 2004 Zijlstra et al.335 2003 Spaepen et al.336 2003

Type of disease

PPV (%)

NPV (%)

OS

(-) PET

(+) PET

(-) PET

(+) PET

30 93 28 60

NHL + HD NHL HD HD

83 100 60 —

65 83 100 —

65 85 95 91

17 4 40 4

— — — —

— — — —

20 (1–2 cycles)

NHL + HD NHL NHL

63

100

—

—

24–34 mo 64 92

8–16 mo 25 10

100

60

— 92%

— 88%

96 — 62

23 — 32

100 — — —

55 — —

26 (2nd cycle) 70 (3–4 cycles)

FDG evaluation before stem cell transplantation: Spaepen et al.343 2003 60 Filmont et al.342 2003 43 Schot et al.341 2003 46

NHL + HD NHL + HD NHL + HD

Cycles, cycles of chemotherapy. Mo = months.

accepted today that FDG-PET is a clinically valuable tool that should be added to conventional staging modalities.329,330

FDG-PET for Predicting Treatment Response Evaluation of PET for assessment of treatment response has been studied more extensively in HD and NHL than in any other tumor. Differentiation of viable tumor from fibrosis in a residual posttreatment mass is a common problem in lymphoma that is seen in more than 85% of patients with HD and approximately 40% of the patients with NHL. Initial studies have assessed response to treatment in heterogeneous populations including both HD and NHL patients. Cremerius et al.324 reported better specificity and positive predictive value (PPV) for FDG-PET (92% and 94%, respectively) as compared with that of CT (17% and 60%) in 27 patients. Zinzani et al.325 studied 44 patients with HD or aggressive NHL who had residual abdominal disease and showed that the 2-year progression-free survival (PFS) rate was 95% for the PET-negative group and 0% for the PET-positive group. A PPV of 100% for PET, as compared with 42% for CT, was found in 54 patients with HD and aggressive NHL assessed after therapy by Jerusalem et al.326 The negative predictive values (NPV) of PET (83%) and CT (87%) were not significantly different. Recurrence was noticed in the same study, with both positive PET and CT in 26% of patients and with negative PET and positive CT in only 10%. The PFS (2-year) rate with negative PET and negative CT was 87%, with positive CT and negative PET only 60%, and finally, with positive PET regardless of the CT, 0%. Mikhaeel et al.327 also found in 45 patients with aggressive NHL that the relapse rate was 17% for PET-negative patients and 100% for PET-positive patients compared with 25% for CT-negative patients and 41% for CT-positive patients. The progression-free survival (PFS ) for 1 year was 83% for PET-positive and 0% for PET-negative patients.

Spaepen et al.328 evaluated 93 patients with NHL and reported that all patients who had persistent FDG uptake relapsed, with a 2-year PFS rate of 85% of patients with negative PET findings. The 2-year PFS rate was 4% in patients with positive PET findings. Weihrauch et al.329 studied the predictive value of PET in 28 patients with HD who had residual masses after treatment. The 1-year PFS was 95% for the PET-negative group as compared with 40% for the positive group. Spaepen et al.330 evaluated 60 patients with HD with or without masses at the end of first-line treatment; the 2-year disease free survival (DFS) rate was 4% for the PETpositive group and 85% for the PET-negative group. Kostakoglu et al.331 compared FDG-PET after the first cycle of chemotherapy and after completion of chemotherapy. PET had greater sensitivity and PPV for predicting relapse after the first cycle. PET after the first cycle had a lower falsenegative rate (13%) than the posttherapy PET (35%), possibly reflecting the presence of a small but still detectable tumor load of resistant cells early, but not late, in the therapy course (Table 33.14). In general, in NHL and high-grade HD, a positive PET at the end of first-line therapy is highly suggestive of disease and requires intensive confirmatory investigation. A negative PET does not exclude the presence of minimal residual disease or future relapse and requires close follow-up. However, in early HD, a negative PET can be used to define complete response (CR) with favorable prognosis, even in the presence of residual masses on CT (see Figure 33.7A,B). A positive PET, especially if located in a site different from the residual mass, should be assessed with caution, and benign or inflammatory etiologies should also be considered in the differential diagnosis of persistent disease.330

Evaluation During Treatment Many studies have been conducted to evaluate the extent and time course of changes in FDG metabolism in response to chemotherapy. The rapidity of response during treatment

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appears to be an accurate predictor of overall response, with early tumor regression indicating higher cure rates.332 Accurate early assessment of response allows for timely institution of aggressive second-line protocols. If resistant tumor burden is identified, additional treatment-related toxicity might be prevented. Romer et al.333 found that a single PET study performed after two cycles of chemotherapy was predictive of long-term prognosis. Mikhaeel et al.334 reported the results of 23 patients with NHL who had FDG-PET after two to four cycles of chemotherapy. No relapse was seen in patients with minimal or no FDG uptake, whereas 88% of patients who had persistent FDG uptake relapsed. The same group also found that in 23 patients with HD during treatment, the relapse rate was 100% in the PET-positive group and 8% in the PET-negative group. Zijlstra et al.335 studied the prognostic value of FDG-PET in 26 patients with aggressive NHL after two cycles of chemotherapy. At a median follow-up of 16 months, the PFS rate was 64% in patients who had negative FDG-PET findings and was 25% in patients who had positive FDG-PET findings. Spaepen et al.336 evaluated 70 patients with aggressive NHL and found that visual interpretation of FDG-PET, performed after three to four cycles of first-line chemotherapy, predicted PFS and OS independently from and better than the international prognostic index. Torizuka et al.337 reported that FDG-PET may be predictive of clinical outcome and could differentiate short-term responders from nonresponders in a group of 17 patients, most of them with advanced-stage lymphoma.

Prognostic value of FDG-PET Before Stem Cell Transplantation High-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) has been shown to improve survival in patients with relapsed aggressive NHL or HD.338 A number of studies indicate that FDG-PET performed during or after salvage chemotherapy has a high predictive value for relapse after HDT/ASCT.339,340 Schot et al.341 evaluated 46 patients with recurrent or persistent NHL/HD lymphoma after HDT/ASCT. The PFS for 2 years was 62% for PET-negative studies versus 32% for PET-positive patients. Filmont et al.342 showed that PPV (92%) and NPV (88%) in 43 patients with NHL/HD were very similar if the PET study was obtained 2 to 5 weeks after initiation of salvage chemotherapy, before ASCT, or within a median interval of 2.4 months. Spaepen et al.343 assessed the prognostic value of FDG-PET after salvage chemotherapy before HDT/ASCT in 60 patients with NHL and HD. The 2-year PFS and OS rates for patients with negative FDG-PET scans were 96% and

100%, respectively, as compared with 23% and 55% for those with positive FDG-PET results.

FDG-PET for the Detection of Recurrence Although early diagnosis of relapse will lead to early administration of salvage therapy, the crucial question is whether a lesion is metabolically active, because two-thirds of patients with HD present with fibrotic or recurrent mass lesions, and 20% of these relapse.344 Fifty percent of patients with highgrade NHL present with a mass lesion and only 25% of them relapse.344 67Ga will not accurately indicate whether a tumor is metabolically active, and it has limitations in detection of intraabdominal and low-grade lymphoma.345 False-positive PET studies may be the result of FDG uptake in a hyperplastic thymus, in the gastrointestinal tract, or in an inflamed lung lesion.346 False-negative results may also arise from the absence of an FDG-avid lesion within small tumor lesions, possibly because of low glucose metabolism after therapy or acquisition problems, such as spatial resolution and partial volume effect. The value of the sensitivity and specificity of FDG-PET and CT to predict the relapse of malignant lymphoma were described in several studies.347,348 Jerusalem et al.349 evaluated the recurrence rate in 45 NHL/HD patients with residual tumor masses and positive FDG-PET results, and it was only 26% in patients with residual tumors and negative FDG-PET results. The 1-year PFS and OS rates were 86% and 92%, respectively, for the PET-negative group, and only 0% and 55%, respectively, for the PET-positive group. Guay et al.350 compared the diagnostic accuracy of FDGPET and CT in detecting residual disease or relapse during the posttherapy period in 48 patients with HD. The sensitivity, specificity, PPV, and NPV of FDG-PET for predicting relapse were 79%, 97%, 92%, and 92%, respectively. The accuracy of FDG-PET was 92%, higher than the accuracy of CT (56%). Freudenberg et al.351 described the advantages of PET/CT fusion imaging in 27 patients with lymphoma and evaluated the clinical significance of combined PET/CT and compared the staging results of PET/CT with those of FDGPET and CT alone (Table 33.15).

Summary FDG-PET provides an excellent tool in the initial staging of lymphomas, in restaging lymphoma after initial treatment, in predicting response during and at the end of therapy, and during follow-up for diagnosis of recurrence. A pretreatment FDG-PET study is essential for accurate assessment of residual masses and early monitoring of response to the treatment. A baseline PET will help detect

TABLE 33.15. Recent literature of PET findings in recurrence of lymphoma. Sens Authors 351

Freudenberg et al. Guay et al.350 Filmont et al.342

Spec

PPV

NPV

ACC

Year

No. of patients

PET

CT

PET

CT

PET

CT

PET

CT

PET

CT

2004 2003 2003

27 48 78

86 79 87

78 — 94

100 97 80

54 — 56

100 92 95

65 — 72

87 92 83

70 — 67

93 92 90

67 56 71

472 relapse or residual disease, because relapse occurs most often in the region of previous disease.352

Melanoma Cutaneous melanoma is the seventh most common newly diagnosed cancer in the United States: 55,100 new cases were diagnosed in 2004 and 7,910 patients will have died of systemic disease.353 Wahl et al.354 and Kern et al.355 demonstrated that radiolabeled glucose analogues were preferentially taken up in murine melanomas and human melanoma xenografts, establishing the rationale for the potential use of FDG in patients with melanoma. There is no defined role for PET in the initial diagnosis of melanoma, as has been shown by Wagner et al.,356 because the inherent spatial resolution of PET reduces the sensitivity for detection of lesions less than 80 mm2 and it is unlikely that this technique (as currently performed) will ever be effective in the initial diagnosis of small, surgically curable melanoma in situ.

Initial Staging of Clinically Localized Disease In intermediate- and high-risk lesions greater than 1 mm in thickness, assessment of the SLN draining the tumor site is very important. Rinne et al.357 studied 52 patients with primary melanoma greater than 1.5 mm in depth who had no evidence of local or distant metastases; they found that the accuracy of PET for identification of regional or distant metastases was 95% per lesion and 94% per patient and that for CT was 68% per lesion and 77% per patient. Macfarlane et al.358 found that PET accurately predicted regional nodal status in 88% of 23 patients with primary melanoma more than 1.5 mm thick. Wagner et al.359 performed a large prospective trial containing 70 patients with primary thick melanoma (more than 1.0 mm) and 4 patients with recurrent melanoma in or adjacent to the surgical scar who underwent PET and SLN biopsy. They demonstrated a sensitivity of 11% to 17% (depending on reading threshold) and a specificity of 94% to 100%. This is one of the first articles to suggest that PET is not sensitive for staging regional nodes in patients with newly diagnosed thick melanomas. Acland et al.360 found that FDG-PET failed to identify all 14 positive SLNs found in 50 patients who underwent sentinel node biopsy for primary melanomas more than 1 mm in thickness. Fink et al.361 found, in 48 patients with stage I or II disease, that FDG-PET identified only one metastatic node, and they concluded that this result was likely “due to the small size of the metastatic deposits in the sentinel node.” There is now strong evidence that FDG-PET is not useful in the initial staging of primary melanoma when there is no clinical evidence of local or distant metastatic spread. This finding is attributed to the small size of most nodal metastases and the low prevalence of nodal disease in patients with primary melanoma.

Local Recurrence and Satellite or In-Transit Metastases There are no studies that specifically examine the efficacy of FDG-PET in the evaluation of patients with locally recurrent

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primary melanoma tumors, and there are only two studies that evaluated satellite and in-transit metastases. Acland et al.362 studied 9 patients with satellite metastases adjacent to the primary tumor excision site and found a sensitivity of 93% and a specificity of 50% for the ability of FDG-PET to detect locoregional metastatic disease. Stas et al.363 described a change in clinical management in patients with varying types of recurrent melanoma with adjacent metastases or distant in-transit lesions. These findings suggest a possible role for PET in this population, but very small tumor volume of disease will not be detected. The sensitivity of FDG-PET may be low in patients with small metastases in adjacent lymph nodes,379,380 but patients with suspected regional metastases based on physical examination or other imaging modalities may have greater detectability with PET. The majority of patients (80% or greater) with clinically localized tumors never develop distant disease. Blessing et al.364 found a sensitivity of 74% and a specificity of 93% for the evaluation of 20 clinically suspicious lymph node basins imaged with FDG-PET. Crippa et al.,365 in a study of 38 patients, found the accuracy of FDG PET to be 91% for clinically or radiographically enlarged lymph nodes. Sensitivity dropped off rapidly for lymph nodes less than 5 mm, but was 100% and 83% for nodes that were greater than or equal to 10 mm and 6 to 10 mm, respectively. Tyler et al.366 attempted to show the utility of FDG-PET in a study of 95 patients with clinically evident stage III lymph node and/or in-transit melanoma. The sensitivity was 87%, the PPV (with the integration of pertinent clinical information) was 91%, the specificity was 44% (although few prophylactic lymph node dissections were performed), and the findings led to a change in clinical management in 15% of the patients. These findings argue that FDG-PET has a useful role in the patient with suspected regional lymph node metastases (Table 33.16). In the case of confirmed lymph node metastases beyond the SLN, the value of FDG-PET is to localize occult distant metastases that might be amenable to surgical resection or to exclude metastatic disease in patients with equivocal findings on conventional anatomic images. Wagner et al.367 and Acland et al.362 showed that in this group of patients it was unknown distant disease that may have altered patient management.

Identification of Distant Metastases FDG-PET can be used in patients with recently diagnosed melanoma and those who have clinical, laboratory, or radiologic evidence of distant metastases, in patients with previously resected melanoma with findings suspicious for recurrent disease in the form of distant metastases, and, finally, in patients with previously treated distant metastases requiring restaging to plan future surgical or medical management. Gritters et al.368 studied 12 patients with various stages of melanoma (thick primaries, palpable lymph nodes, or presumed metastases on CT), and they found intraabdominal visceral and lymph node metastases that were not seen on CT. Steinert et al.369 found a 92% sensitivity for FDG-PET in 33 patients with known metastatic melanoma or high-risk primaries (greater than 1.5 mm).

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p o s i t ro n e m i s s i o n t o m og r a p h y i n c a n c e r TABLE 33.16. Representative literature of FDG-PET findings in melanoma.

Author

Year

No. of patients

Wagner et al.359 Crippa et al.365

1999 2000

70 38

Wagner et al.356

2001

45

Eigtved et al.371 Swetter et al.372 Hafner et al.377 Havengna et al.378 Rinne et al.370 Tyler et al.366

2000 2002 2004 2003 1998 2000

Sensitivity

Specificity

PET

CI

95

38 104 100 53 48

11–17 100 (10 mm diameter) 83 (6–10 mm diameter) 23 (5.3 mm diameter) 14 ( or = N2, M0) undifferentiated nasopharyngeal carcinoma: a positive effect on progression-free survival. International Nasopharynx Cancer Study Group. VUMCA I trial. Int J Radiat Oncol Biol Phys 1996;35:463–469. Cummings C, Frederickson J, Harker L, Krause C, Schuller D. Otolaryngology—Head & Neck Surgery, vol 4. St. Louis: Mosby, 1998:2908–2933. Bhattacharyya N, Fried MP. Nodal metastasis in major salivary gland cancer: predictive factors and effects on survival. Arch Otolaryngol Head Neck Surg 2002;128:904–908. Hocwald E, Korkmaz H, Yoo GH, et al. Prognostic factors in major salivary gland cancer. Laryngoscope 2001;111:1434– 1439. Regis De Brito Santos I, Kowalski LP, Cavalcante De Araujo V, Flavia Logullo A, Magrin J. Multivariate analysis of risk factors for neck metastases in surgically treated parotid carcinomas. Arch Otolaryngol Head Neck Surg 2001;127:56–60. Zbaren P, Schar C, Hotz MA, Loosli H. Value of fine-needle aspiration cytology of parotid gland masses. Laryngoscope 2001;111:1989–1992. Urquhart A, Hutchins LG, Berg RL. Preoperative computed tomography scans for parotid tumor evaluation. Laryngoscope 2001;111:1984–1988. Greene F, Page D, Fleming I, et al. TNM Classification of Malignant Tumours. AJCC Cancer Staging Handbook. New York: Springer-Verlag, 2002:145–153. Dulguerov P, Marchal F, Lehmann W. Postparotidectomy facial nerve paralysis: possible etiologic factors and results with routine facial nerve monitoring. Laryngoscope 1999;109: 754–762. Terrell JE, Kileny PR, Yian C, et al. Clinical outcome of continuous facial nerve monitoring during primary parotidectomy. Arch Otolaryngol Head Neck Surg 1997;123:1081–1087. Reddy PG, Arden RL, Mathog RH. Facial nerve rehabilitation after radical parotidectomy. Laryngoscope 1999;109:894– 899. Govindaraj S, Cohen M, Genden EM, Costantino PD, Urken ML. The use of acellular dermis in the prevention of Frey’s syndrome. Laryngoscope 2001;111:1993–1998. Guntinas-Lichius O. Increased botulinum toxin type A dosage is more effective in patients with Frey’s syndrome. Laryngoscope 2002;112:746–749. Arad-Cohen A, Blitzer A. Botulinum toxin treatment for symptomatic Frey’s syndrome. Otolaryngol Head Neck Surg 2000; 122:237–240.

544 185. Laskawi R, Drobik C, Schonebeck C. Up-to-date report of botulinum toxin type A treatment in patients with gustatory sweating (Frey’s syndrome). Laryngoscope 1998;108:381–384. 186. Blitzer A, Sulica L. Botulinum toxin: basic science and clinical uses in otolaryngology. Laryngoscope 2001;111:218–226. 187. A phase III randomised trial of cisplatinum, methotrexate, cisplatinum + methotrexate and cisplatinum + 5-FU in end stage squamous carcinoma of the head and neck. Liverpool Head and Neck Oncology Group. Br J Cancer 1990;61:311–315. 188. Jacobs C, Lyman G, Velez-Garcia E, et al. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 1992;10:257–263. 189. Clavel M, Vermorken JB, Cognetti F, et al. Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck. A phase III study of the EORTC Head and Neck Cancer Cooperative Group. Ann Oncol 1994;5:521–526. 190. Forastiere AA, Shank D, Neuberg D, Taylor SGt, DeConti RC, Adams G. Final report of a phase II evaluation of paclitaxel in patients with advanced squamous cell carcinoma of the head and neck: an Eastern Cooperative Oncology Group trial (PA390). Cancer (Phila) 1998;82:2270–2274. 191. Dreyfuss AI, Clark JR, Norris CM, et al. Docetaxel: an active drug for squamous cell carcinoma of the head and neck. J Clin Oncol 1996;14:1672–1678. 192. Couteau C, Chouaki N, Leyvraz S, et al. A phase II study of docetaxel in patients with metastatic squamous cell carcinoma of the head and neck. Br J Cancer 1999;81:457–462. 193. Catimel G, Verweij J, Mattijssen V, et al. Docetaxel (Taxotere): an active drug for the treatment of patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group. Ann Oncol 1994;5:533–537. 194. Buesa JM, Fernandez R, Esteban E, et al. Phase II trial of ifosfamide in recurrent and metastatic head and neck cancer. Ann Oncol 1991;2:151–152. 195. Huber MH, Lippman SM, Benner SE, et al. A phase II study of ifosfamide in recurrent squamous cell carcinoma of the head and neck. Am J Clin Oncol 1996;19:379–382.

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196. Sandler A, Saxman S, Bandealy M, et al. Ifosfamide in the treatment of advanced or recurrent squamous cell carcinoma of the head and neck: a phase II Hoosier Oncology Group trial. Am J Clin Oncol 1998;21:195–197. 197. Cervellino JC, Araujo CE, Pirisi C, Francia A, Cerruti R. Ifosfamide and mesna for the treatment of advanced squamous cell head and neck cancer. A GETLAC study. Oncology 1991;48:89–92. 198. Degardin M, Oliveira J, Geoffrois L, et al. An EORTC-ECSG phase II study of vinorelbine in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol 1998;9:1103–1107. 199. Saxman S, Mann B, Canfield V, Loehrer P, Vokes E. A phase II trial of vinorelbine in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Am J Clin Oncol 1998;21:398–400. 200. Catimel G, Vermorken JB, Clavel M, et al. A phase II study of Gemcitabine (LY 188011) in patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group. Ann Oncol 1994;5:543–547. 201. Samlowski WE, Gundacker H, Kuebler JP, et al. Evaluation of gemcitabine in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a Southwest Oncology Group phase II study. Invest New Drugs 2001;19:311– 315. 202. Schrijvers D, Johnson J, Jiminez U, et al. Phase III trial of modulation of cisplatin/fluorouracil chemotherapy by interferon alfa-2b in patients with recurrent or metastatic head and neck cancer. Head and Neck Interferon Cooperative Study Group. J Clin Oncol 1998;16:1054–1059. 203. Forastiere AA, Leong T, Rowinsky E, et al. Phase III comparison of high-dose paclitaxel + cisplatin + granulocyte colonystimulating factor versus low-dose paclitaxel + cisplatin in advanced head and neck cancer: Eastern Cooperative Oncology Group Study E1393. J Clin Oncol 2001;19:1088–1095. 204. Gilson MK, Li Y, Murphy B, et al. Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the eastern cooperative oncology group. J Clin Oncol 2005;23:3562–3567.

3 7

Lung Cancer Hak Choy, Harvey I. Pass, Rafael Rosell, and Anne Traynor

Etiology Lung cancer is the leading cause of cancer death in the United States and throughout the world.1 In the United States, the manufactured cigarette emerged as the tobacco product of choice shortly after the turn of the 20th century. Lung cancer surfaced after years of inhalation of cigarette smoke, first among men and then among women. From 1995 to 1999, cigarette smoking and exposure to environmental tobacco smoke (ETS) accounted for approximately 160,000 annual deaths in the United States. Each year, 127,813 Americans die from smoking-attributable lung cancer deaths.

Smoking Active Cigarette Smoking Worldwide, approximately 4 million people die annually of tobacco-attributable diseases; the number of tobaccoattributable deaths is projected to rise to 8.4 million by 2020. China, with 20% of the world’s population, smokes 30% of the world’s cigarettes. Men smoke more than women, and the proportion of male deaths at ages 35 to 69 years attributable to tobacco has been predicted to rise over the next few decades from 13% (in 1988) to about 33%.2 In Hong Kong, cigarette consumption reached its peak 20 years earlier than in mainland China. In the general population of Hong Kong, in 1988, tobacco caused about 33% of all male deaths at ages 35 to 69, plus 5% of all female deaths, and hence 25% of all deaths at these ages.2 A highly significant trend of increasing lung cancer mortality has been observed with increasing cigarette consumption. Smoking was considered causally related to cancers of the trachea, lung and bronchus, larynx, and lip by the first Surgeon General’s Report in 1964.3 In studies conducted through the 1960s, cigarette smoking was strongly associated with squamous and small cell cancers of the lung, but less so with adenocarcinoma. However, during the past two decades, there has been a noticeable shift in lung cancer histology patterns. The relative frequency of squamous cell carcinoma has decreased, whereas that of adenocarcinomas, often of peripheral origin, is clearly increasing. This shift has been attributed to changing cigarette design, in which filters removed much of the tar from inhaled tobacco smoke. The tar fraction contains most of the polycyclic aromatic hydrocarbons (PAH), including numerous carcinogens known to produce squamous cell lung cancer in animals. However, filters also retain

some nicotine. As the use of filtered cigarettes has become predominant, smokers have inhaled more deeply and have retained smoke longer in the deep lung to satisfy nicotine craving.4 The mainstream smoke emerging from the mouthpiece of a cigarette is an aerosol containing about 1,010 particles/mL and 4,800 compounds. Experimentally, vapor-phase components of the smoke can be separated from the particulate phase by a glass fiber filter. The vapor-phase comprises more than 90% of the mainstream smoke weight. Potentially carcinogenic vapor-phase compounds include nitrogen oxides, isoprene, butadiene (BD), benzene, styrene, formaldehyde, acetaldehyde, acrolein, and furan. The particulate phase contains at least 3,500 compounds and many carcinogens including PAH, N-nitrosamines, aromatic amines, and metals.5,6 A key aspect of the link between cigarette smoke and lung cancer is the chronic exposure of DNA to multiple metabolically activated carcinogens, leading to multiple DNA adducts and mutations (Figure 37.1). PAH and other aromatics are also found in ambient and indoor air and in the diet. PAH, a major class of carcinogens present in ETS, leads to the formation of DNA adducts, which cause mutagenic events involving chromosomal aberrations, DNA strand breaks, oncogene activation, and tumor suppressor gene inactivation. Several epidemiologic and experimental studies have shown a good correlation between PAH and aromatic DNA adducts in blood and lung tissue from the same subjects. Genetic susceptibility plays an important role in the risk of developing lung cancer, and at present there are multiple biomarker assays to predict exposure risk7 (Table 37.1).

Passive Smoking/Environmental Tobacco Smoke Active cigarette smoking, passive smoking, various occupational exposures, and carcinogens in heavily polluted air are causally related to lung cancer. Environmental tobacco smoke (ETS) is a form of indoor air pollution resulting from the mixture of sidestream smoke, emitted from the smoldering of the distal part of the cigarette in between puff drawing, and the portion of mainstream smoke that is released into ambient air by actively smoking individuals. Most epidemiologic studies support the view that exposure to ETS involves a carcinogenic risk to humans. In rats treated with very high doses of a mixture of sidestream smoke and mainstream smoke, mimicking exposure to ETS, the formation of DNA adducts was observed in different organs and tissues.8 The poor persistence of smoke-related adducts in the lung sug-

545

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chapter 0

Cigarette Smoking

Carcinogenesis

Metabolic Activation

DNA Adducts

Persistence Miscoding

Normal Tissue tions Muta

Nicotine Addiction

37

Repair

Detoxification

Apoptosis

Normal DNA

Hyperplasis Metaplasia

Carcinogenesis

Metabolic Activation

DNA Adducts

Persistence Miscoding

Excretion

Normal DNA

Apoptosis

Dysplasia

, RB , FHIT

, p16 MYC

Repair

Detoxification

P53, AS, T es-KR

hang

Nicotine Cigarette Addiction Smoking

15

ears) oking (y

n of sm Duratio

cc eneti ther g and o

Excretion

Carcinoma in situ

Carcinogenesis

Metabolic Activation

DNA Adducts

Persistence Miscoding

enes

Nicotine Cigarette Addiction Smoking

ther g

and o

30

Invasive Cancer

Repair

Detoxification Excretion

Normal DNA

Apoptosis

FIGURE 37.1. Genotoxicity of tobacco smoke.

gests that a continuative exposure is needed for fixation of DNA damage. It has been demonstrated that spending an average period of 3 hours in a smoky pub results in a considerably high exposure to carcinogenic ETS. In one study, the mean ambient air concentration of benzo[a]pyrene, a widely known representative of carcinogenic PAH, was 6.3 ng/m3. The mean concentrations of this compound in smoking and nonsmoking homes were 1.0 and 0.4 ng/m3, respectively. The values in commercial buildings were 1.07 ng/m3 for smoking zones and 0.39 ng/m3 for nonsmoking zones. In the ambient air of Silesia, Poland, a highly polluted industrial city, the mean concentrations of benzo[a]pyrene were 60 to 90 ng/m3 in winter and 5 to 20 mg/m3 in summer.9 Significantly, formation of DNA adducts was observed in the induced sputum of 3 of 15 healthy nonsmokers consequent to ETS exposure, establishing a plausible link between ETS and lung cancer.9 The hypothesis that ETS is more potent

than mainstream tobacco smoke as a lung carcinogen is supported by observations that cigarette sidestream smoke condensate is more carcinogenic in skin painting studies than full-smoke condensate. ETS-induced lung tumor risk in A/J mice occurs by a predominantly genotoxic mechanism of action, which may be suppressed partially by sustained highlevel ETS exposure.

Trends in Lung Cancer Risk After Smoking Cessation In both men and women, the age-related increase in lung cancer risk is lowest in people who have never smoked, intermediate in those who have quit at various ages, and highest in those who continue smoking. Among former smokers, the age-related increase is smaller the earlier the age of quitting.3 Widespread cessation of smoking in the United Kingdom has

TABLE 37.1. Classification and examples of biomarkers for lung cancer. Category

Examples

External exposure Biomarker of exposure

Questionnaire data, Federal Trade Commission (FTC) yield Polycyclic aromatic hydrocarbon in lung tissue Urinary measurement of tobacco constituent or metabolite, exhaled CO; carboxyhemoglobin, urinary mutagenicity Carcinogen–DNA adducts in human lung tissue Carcinogen–DNA hemoglobin adducts, chromosomal aberrations in cultured lymphocytes, lipid peroxidation Changes in RNA or protein expression, somatic mutations and LOH in normally or abnormally appearing tissue; change in methylation or gene control; mitochondrial mutations, mRNA expression arrays or proteomics Osteoporosis, hypertension, hyperplasia, dysplasia, lipids, blood coagulant pathways, mRNA expression arrays or proteomics Leukocytosis, hprt mutations, mRNA or protein expression via microarrays in cultured blood cells Genetic polymorphisms for genes involved in disease pathways Enzyme induction of metabolizing enzymes

Biologically effective dose Biomarker of harm

Effect modifiers LOH, loss of heterozygosity.

lung cancer

approximately halved the lung cancer mortality that would have been expected if former smokers had continued to smoke.10 However, for some individuals, such as those of advanced age and heavy smoking exposure, the risk of lung cancer may exceed 10% within 10 years even if they stop smoking.11 The risk for lung cancer is increased for both current and former female smokers compared with female nonsmokers and declines for former smokers with increasing duration of abstinence.12

Occupational Exposure and Polluted Air Workers in graphite-electrode manufacturing, as well as in coke-oven plants, are exposed to PAH by inhalation of volatile PAH and PAH bound to respiratory particulate matter. Mean 8-oxo-7,8-dihydro-2¢-deoxyguanosine in white blood cells of exposed workers was between 1.38 and 2.15 times higher than levels found in control samples. An alkaline single-cell gel electrophoresis (Comet assay) was used to study DNA strand breaks that were found in exposed workers. These biomarkers may be appropriate for surveillance of workers exposed to PAH13 (see Table 37.1). Vehicles powered by diesel engines are a major source of suspended particulate matter, which is a suspected cause of lung cancer and allergic respiratory disease, including bronchial asthma. Diesel exhaust contains potent carcinogens and mutagens, such as PAH and nitrated PAH. PAH released from diesel exhaust particulates also generate DNA adducts that cause mutations in oncogenes and tumor suppressor genes and act as initiators of carcinogenesis. DNA adducts were identified in rats after both short-term (12 weeks) and long-term (30 months) exposure to diesel exhaust, and the level of DNA adducts was shown to be higher in lung tumor tissues than in normal tissues after chronic exposure.14 Formation of DNA adducts is catalyzed by CYP1A1 and CYP1A2, which are inducible by PAH. CYPs oxidize PAH to reactive electrophilic metabolites, which bind to DNA bases to form DNA adducts. The level of cytochrome P-450 1A1 mRNA was shown by Northern blot analysis to be significantly increased in the lungs of rats exposed to 6 mg/m3 of diesel exhaust.14 1,3-BD is a major commodity chemical used in the manufacture of synthetic rubber and various plastics.15 Global consumption of BD was 6.1 million metric tons in 1995, with consumption expected to rise to more than 7.5 million metric tons in the year 2000. BD is also a common air contaminant found in auto emissions and cigarette smoke. It is a component of automotive exhaust and of the vapor phase of environmental smoke (~400 mg/cigarette). BD is carcinogenic in rodent bioassays, and exposure of mice to BD at 20 parts per million for 4 days induced mutations in spleen lymphocytes at the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus. Coexposure to cadmium, cobalt, lead, and other heavy metals occurs in many occupational settings, such as pigment and batteries production, galvanization, and recycling of electric tools.16 The lifetime excess lung cancer risk for cadmium fumes of 100 mg/m3 was estimated to be approximately 50 to 111 lung cancer deaths per 1,000 workers exposed to cadmium for 45 years. The principal mechanisms of cadmium genotoxicity, mutagenicity, and carcinogenicity are generation of reactive oxygen species, inhibition of DNA repair,

547

depletion of glutathione, and possibly also suppression of apoptosis.

Diet and Lung Cancer Risk Numerous epidemiologic studies have demonstrated a protective effect of vegetable or fruit consumption on cancer risk.17–22 Statistically significant inverse associations were found with total vegetables and most vegetable groups in a Netherlands study.17 The strongest effect was found for vegetables from the Brassica group (Brussels sprouts, cauliflower, cabbage, kale). Based on the results, it was calculated that a male current smoker who smoked 25 cigarettes per day for 40 years has a risk of lung cancer that is 18 times higher than that of a never-smoker. By eating 286 g vegetables per day, instead of 103 grams, he may reduce his risk by 29%.17 The mechanisms underlying a cancer protection by fruit and vegetables are still uncertain. The possible protective compounds in vegetables and fruits include a wide variety of phytochemicals. Among them are the carotenoids, colorful compounds that are abundant as pigments in plants. The main carotenoids are a-carotene, b-carotene, lutein, zeaxanthin, bcryptoxanthin, and lycopene. They are potent quenchers of free radicals, which are by-products of metabolic processes originating from environmental pollutants such as cigarette smoke.23 Blood levels of micronutrients and vitamins including beta-carotene have been inversely correlated with lung cancer risk.24 However, large intervention studies with b-carotene supplementation found no clear protection against cancer or cardiovascular disease, and two studies were terminated because mortality or lung cancer incidence increased in the supplemented group.25–27 Subsequent analyses suggested that the deleterious effect might occur primarily among heavy current smokers and/or alcohol drinkers and asbestosexposed subjects.28 It has been speculated that this represents a pro-oxidant interaction effect of b-carotene with such exposures or that it could be related to a high supplementation dose and unnaturally high serum levels.

Lung Cancer Susceptibility Gender It has been stated that females are more susceptible than males to tobacco carcinogenesis. Activation of gastrinreleasing peptide receptor (GRPR) in airways has been related to a proliferative response of bronchial cells to gastrinreleasing peptide and to long-term tobacco exposure. The GRPR gene is located on the X chromosome and escapes Xchromosome inactivation, which occurs in females. GRPR mRNA expression was detected in airway cells and tissues of more female than male nonsmokers and short-term smokers. Female smokers showed expression of GRPR mRNA at a lower mean pack-year (number of packs of cigarettes smoked per day multiplied by number of years of smoking) exposure than male smokers. These findings indicate that women may have a higher risk of developing lung cancer than men.29 However, in a different study, the risk of lung cancer was comparable in women and men.30 Estrogen and progesterone receptors have been found to be present in resected lung cancers, regardless of the sex of

548 the patient, although a female patient with squamous cell carcinoma showed an estrogen receptor level of 301 fmol/mg.31 Catechol estrogens may act as carcinogens either by forming DNA adducts or by acting as oxidative intermediates. The CYP1B1*3 polymorphism, which can cause enhanced conversion of estradiol to 4-hydroxy-estrogen and its catechol estrogen metabolite, was found frequently among 203 lung cancer cases in comparison with 205 controls (odds ratio, 2.6). Gene–gene interactive associations were observed among females, but not among males, with the CYP1B1*3 allele, including increased adjusted odds ratios for coinheritance of at least one copy of the CYP1B1*3 allele and the DNA repair enzyme XPD exon 23 (Gln) allele (odds ratio, 5.7), or for coinheritance of CYP1B1*3 and the high or intermediate activity alleles of epoxide hydrolase (odds ratio, 9.1). The microsomal epoxide hydrolase enzyme could activate catechol estrogens to reactive intermediate.32 Lung cancer is the leading cause of cancer death in Taiwanese women, although less than 10% of female lung cancer patients are smokers. Half of the 141 lung tumors in these patients had human papillomavirus 16/18, compared with 26% of 60 noncancer control subjects. It is thought that the human papillomavirus infection is related to lung cancer development in nonsmoking females.33 An aggregation of lung cancer was seen in first-degree relatives of more than 800 lung cancer probands, and a significantly lower intake of dietary folate, critical for maintaining DNA integrity and synthesis, was observed in lung cancer cases compared with controls.34

Genetic ALTERATIONS IN MINISATELLITES AND VARIABLE NUMBER OF TANDEM REPEATS Microsatellite instability, defined as changes in the number of short tandem DNA repeats in microsatellites, mainly associated with CA dinucleotides, has been reported in non-small cell lung cancer (NSCLC).35 Genetic susceptibility to lung cancer is multifactorial, including alterations in minisatellites and variable number of tandem repeats (VNTR). The HRAS1 VNTR region, which maps 1 kb downstream from the canonical polyadenylation signal of the human protooncogene H-ras-1, consists of four common progenitor alleles, in addition to several rare variants that are thought to derive from germ-line mutations of the nearest common alleles. A higher percentage of rare HRAS1 VNTR alleles was found in lung cancer patients than in controls,36 and a meta-analysis37 showed suggestive but not statistically significant association for these alleles with lung cancer. Minisatellite alterations may cause dysregulation of gene expression. HRAS1 VNTR binds at members of the NF-kB family of transcriptional regulatory factors, and some HRAS1 VNTR alleles show a tendency to bind more avidly to transcriptional regulatory factors. Frequent allele loss for the marker HRAS on chromosome 11p (deleted region designated LOH11B) has been associated with cigarette consumption and gender. None of the nonsmokers had allele loss, as compared with 28% of the patients with low and 43% of those with high cigarette consumption. Allele loss was also more frequent in men (43%) than in women (11%). Median survival was lower for patients with allele loss.38

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ADDUCTS DNA adducts are markers not only of exposure but also of risk for cancer development. Healthy current smokers who had elevated levels of DNA adducts in leukocytes were approximately three times more likely to be diagnosed with lung cancer 1 to 13 years later than current smokers with lower adduct concentrations.39 A recent meta-analysis found an overall 83% excess of adducts in cases compared to controls in current smokers.40 DNA adducts have been found to be higher in women than in men with the same level of smoking. S-TRANSFERASE Glutathione S-transferase (GST) M1 is deleted in about half of Caucasians, and a GSTP1 polymorphism at codon 105 (Ile to Val) has been identified. The combined GSTM1 null/GSTP1 Val genotypes were associated with lung cancer before and after adjusting for adducts.41 In addition, a metaanalysis of 43 published case-control studies including more than 18,000 subjects found a slight excess risk for lung cancer in individuals with the GSTM1 null genotype.42 INSULIN-LIKE GROWTH FACTOR A case-control analysis of plasma insulin-like growth factor (IGF) levels from lung cancer patients revealed that elevated plasma IGF-I was associated with an increased risk of lung cancer. An increased risk of lung cancer was also associated with reduced levels of IGF-binding protein (IGFBP)-3, which moderates the effect of IGF-I but also inhibits all growth and induces apoptosis.43 Elevated levels of IGF-II are associated with a poor prognosis in human lung adenocarcinoma. Transgenic overexpression of IGF-II in lung epithelium induces lung tumors in mice. These tumors display morphologic characteristics of human pulmonary adenocarcinomas, such as expression of prosurfactant protein C, surfactant protein B, and thyroid transcription factor 1. Moreover, IGF-II induced proliferation and CREB phosphorylation in human lung cancer cell lines.44 POLYMORPHISMS IN DNA REPAIR CAPACITY (DRC) GENES Host-specific factors modulate susceptibility to tobacco carcinogenesis, including variations in DNA repair, which may influence the rate of removal of DNA damage and of fixation of mutations. In a seminal study, DRC was measured in peripheral blood lymphocytes by means of the host-cell reactivation assay, which measured cellular reactivation of a reporter gene damaged by exposure to 75 mM benzo[a]pyrene diol epoxide. The mean level of DRC in lung cancer cases (3.3%) was significantly lower than in controls (5.1%). Younger cases (less than 65 years) and smokers were more likely than controls to have reduced DRC.45 This finding was confirmed in a case-control study of 316 newly diagnosed lung cancer patients and 316 cancer-free controls. Case patients who were younger at diagnosis, female, or lighter smokers, or who reported a family history of cancer, exhibited the lowest DRC, suggesting that these subgroups may be especially susceptible to lung cancer.46 Reduced DRC and increased DNA adduct levels are associated with increased risk of lung cancer. Nucleotide excision repair (NER) is one of the principal pathways for repair of DNA adducts induced by smokingrelated carcinogens. NER is also the main mechanism for

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removing cisplatin adducts.47 The NER molecular machinery includes proteins that are mutated in xeroderma pigmentosum (XP) and Cockayne syndrome (CS) patients. In the global genome repair pathway, the protein complex XPC-HHR23B, which appears to be essential for the recruitment of all subsequent NER factors in the preincision complex, binds to damaged DNA. Then, the multicomponent transcription factor TFIIH, which is responsible for unwinding the damaged region of the DNA, is recruited. Next, XPG nuclease cleaves the DNA on the 3¢-end. Following cleavage on the DNA, XPA/RPA proteins join the complex and recruit the ERCC1XPF complex, which cleaves the 5¢-end.47,48 Polymorphisms of a number of DNA repair genes involved in the NER pathway have the potential to affect protein function and subsequently DRC. In lung cancer patients, reduced expression levels of XPG and CSB have been observed in peripheral lymphocytes.49 Moreover, ERCC1 and XPD mRNA levels in lymphocytes have been shown to correlate with DRC and could thus be useful surrogates of DRC.50 A reduction in DRC was more significant in lung cancer patients who were homozygous for two XPD (also known as ERCC2) polymorphisms (Asp312Asn at exon 10 and Lys751Gln at exon 23) (-12.3% and -18.3%, respectively) than in controls (-3.3% and -5.4%, respectively). Lung cancer patients who were homozygous for XPD Asn312Asn or Gln751Gln had an increased risk of suboptimal DRC (odds ratios, 1.57 and 3.50, respectively), compared to those who were wild-type homozygous.51 The intron 9 polymorphism of XPC [an 83-bp poly(AT) insertion] has also been correlated with DRC. XPC PAT+/+ homozygous subjects exhibited lower DRC than those with other XPC PAT genotypes, suggesting that XPC PAT+/+ is an adverse genotype.52 A common single-nucleotide polymorphism (A to G) in the 5¢-noncoding region of the XPA gene has been related to lung cancer. The presence of one or two copies of the G allele was associated with a reduced lung cancer risk. Control subjects with one or two copies of the G allele demonstrated more efficient DRC than those homozygous for the A allele.48 Polymorphisms in other pathways have been identified also. The XRCC3 (belonging to the homologous recombination repair pathway) Thr241Met at exon 7 and the XRCC1 (belonging to the base excision repair pathway) Arg399Gln at exon 10 have been related to lung cancer. The XRCC3 241Met allele was associated with higher DNA adduct levels, while

the XRCC1 399Gln allele was associated with higher DNA adduct levels only in nonsmokers.53 Gene–smoking interaction associations have been found for the XPD Asp312Asn and Lys751Gln and for the XRCC1 Arg399Gln polymorphisms. The odds ratios decreased as pack-years increased. For nonsmokers, the adjusted odds ratio was 2.4, whereas for heavy smokers (more than 55 pack-years), the odds ratio decreased to 0.5. When the three polymorphisms were evaluated together, the adjusted odds ratios for individuals with five or six variant alleles versus individuals with no variant alleles were 5.2 for nonsmokers and 0.3 for heavy smokers.54

Basic Science Lung cancers are believed to arise after a series of progressive pathologic changes (preneoplastic lesions). Many of these preneoplastic changes are frequently detected in the respiratory mucosa of smokers. The molecular abnormalities involved in the multistep pathogenesis of lung carcinomas have been examined in lung cancer cell lines, microdissected primary lung tumors, respiratory epithelium from patients with lung cancer, and respiratory epithelium from nonsmokers55 (Figure 37.2). Historically, the carcinogenesis sequence for squamous cell carcinomas shows that invasive lung cancer develops through a series of stages from mild, moderate, and severe atypia, carcinoma in situ, and then invasive cancer. The genetic changes of preneoplastic lesions can be analyzed in cytologic specimens, including sputum samples, bronchial brushes and bronchoalveolar lavage fluids (BAL) from smokers. Atypical adenomatous hyperplasia (AAH) is considered to be the preinvasive lesion of adenocarcinoma. AAH is valued as a good target for delineating the timing and sequence of genetic alterations in the development of lung adenocarcinomas. Activation of the K-ras oncogene seems to be an early event involved in the initiation of AAH. Progression of AAH through increasing degrees of morphologic dysplasia requires the silencing of key tumor suppressor genes, such as p16. Ultimately, activation of telomerase and inactivation of the p53 tumor suppressor gene appear to be important in triggering invasive tumor growth. Importantly, as discussed later, alterations of LKB1 function may represent one of the critical steps in the transition

Late

Intermediate

Early Normal Epithelium Hyperplasia

Dysplasia

In situ Carcinoma Invasive Carcinoma

3p/9p LOH Genomic instability Telomerase Dysregulation 8p LOH FHIT Gene Inactivation Gene Methylation TP53 Gene Inactivation K-RAS Gene Mutation (Codon 12) FIGURE 37.2. Sequential molecular changes during the multistage pathogenesis of squamous cell lung carcinoma.

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from a benign to a potentially malignant proliferation of pneumocytes. Loss of LKB1 expression was more frequent (21%) in the high-grade AAH lesions (severe atypia) than in low-grade lesions (5%). Therefore, loss of LKB1 expression is associated with severe dysplasia.56

Genetic Oncogenes and Tumor Suppressor Genes In general, mutations follow a sequence. Allelic losses at chromosomes 3p, 9p, and 8p occur relatively early. Losses and inactivation of the retinoblastoma and p53 genes are intermediate, and losses at 5q are late events.55 The losses at 3p are progressive, and advanced lesions and tumors have often lost most of the arm or the entire arm, whereas early lesions have more focal lesions.57 In contrast, loss of heterozygosity (LOH) at 5q21 (APC-MMC region) and K-ras mutations are detected at the carcinoma in situ stage.55 Some of the genetic changes involved in the pathogenesis of lung cancer are depicted in Table 37.2. Mutations of the K-ras proto-oncogene are found in about 20% of the tumors with a mutation hot spot at codon 12. However, the mutation frequencies are significantly different among histologic subtypes of lung cancer. Most K-ras mutations are detected in lung adenocarcinoma.58,59 ras mutations are not observed in small cell lung cancer (SCLC).60 K-ras mutations are not correlated with sex of the patient, tumor extent, or prior therapy status.60 The p53 tumor suppressor gene is inactivated by mutations in more than 50% of NSCLC patients and in 90% of SCLC patients. p53 gene mutations in NSCLC cell lines with ras mutations tended to cluster at exon 8.61

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receptor’s catalytic site, activation of the receptor’s tyrosine kinase, and autophosphorylation of C-terminal tyrosine residues, which in turn recruit several cytoplasmic signal transducers. These effector molecules include Ras-MEKMAPK, phosphatidylinositol-3 kinase (PI3K) and its target Akt, p70S6 kinase, Src, and STATs, among others. Active Akt phosphorylates a number of substrates involved in apoptosis, cell-cycle regulation, protein synthesis, and glycogen metabolism, which include the Bcl-2 family member Bad, forkhead transcription factors, caspase 9, IKB kinase, p21, p27, mTOR, and nitric oxide synthase. Akt activity has been shown to be upregulated by loss of function of the phosphatase and tensin homologue (PTEN) phosphatase.62 In addition, the activation of receptor tyrosine kinases and Src also leads to activation of the signal transducers and activators of the transcription (STAT) pathway. Tyrosine kinase growth factor receptors are overexpressed in a large number of human lung cancers, with NSCLCs demonstrating overexpression of EGFR and its ligands EGF, amphiregulin, and tumor necrosis factor-alpha (TGF-a), whereas some SCLCs demonstrate c-Kit overexpression. STAT activation leads to increased transcription of cyclin, D1, and Myc. In NSCLC cells, Stat3 DNA-binding capacity is upregulated by EGF, interleukin 6 (IL-6), and the hepatocyte growth factor (HGF).63 A model proposed in NSCLC is that either EGF, IL-6, or the HGF-Src-Stat3 signaling cascade may protect lung cancer cells from death signals through the upregulation of Stat3 activity. Interestingly, no constitutive Stat3 activity was found in a human lung carcinoma cell line that had constitutive Akt activity. Therefore, Stat3 signaling may be dispensable for tumors that have upregulated other survival signals such as Akt.63 An increased understanding of molecular biology is necessary to piece together all the critical factors in lung cancer cell growth.

Epidermal Growth Factor Pathway Overexpression and/or hyperactivity of the epidermal growth factor receptor (EGFR) has been shown to play a causal role in the progression of lung tumors. EGFR is activated by the binding of ligands to its extracellular domain, which leads to receptor homodimerization or heterodimerization with any of the other three members of this family of transmembrane tyrosine kinases: HER2 (erbB2), HER3, and HER4. This results in the binding of adenosine triphosphate (ATP) to the

Angiogenesis Angiogenesis is essential for tumor growth in vivo. Cytokines and growth factors, such as TGF-b, TGF-a, platelet-derived growth factor, basic fibroblast growth factor, and vascular endothelial growth factor (VEGF), are known to promote angiogenesis. VEGF expression is induced in cancer cells as a result of hypoxia and multiple genetic alterations, including p53 and PTEN loss-of-function, RAS and SRC gain-of-

TABLE 37.2. Summary of the histopathologic and molecular abnormalities of the major types of lung cancer. Abnormality histopathology

Precursor Lesion Theory of development Molecular Gene abnormalities LOH Frequency Chromosomal regions Genetic instability Frequency

Small cell lung cancer (SCLC)

Squamous cell carcinoma

Adenocarcinoma

Unknown Normal epithelium and hyperplasia Parallel

Known Squamous dysplasia and CIS Sequential

Probable Adenomatous atypical hyperplasia (AAH) Probably sequential

myc overexpression TP53 LOH and mutation High 90% 5q21, 8p21–23, 9p21, 17p/TP53 High 68%

TP53 LOH and mutation

K-ras mutation

Intermediate 54% 8p21–23, 9p21, 17p/TP53 Intermediate 10%

Low 10% 9p21, 17p/TP53 Low 13%

lung cancer

function and autocrine tyrosine kinase signaling pathways involving EGFR, HER-2/neu, and insulin growth factor 1 receptor (IGF-1R). In each case, VEGF expression is activated by hypoxia inducible factor 1 (HIF-1).64 Cyclooxygenase (COX)-2, a catalyst in prostaglandin synthesis from arachidonic acid, also increases VEGF expression. Another angiogenesis modulator, nitric oxide synthase (NOS-2), stimulates VEGF as well. Immunohistochemical protein expression levels of COX-2, NOS-2, and VEGF correlated with microvessel density at the tumor-stromal interphase. NOS-2 and COX-2 levels correlated positively with VEGF status.65

Gene and Protein Expression Patterns Comprehensive analysis of gene expression patterns could provide detailed molecular portraits including differences in gene expression profiles among lung adenocarcinomas. Thyroid transcription factor 1, as well as several surfactantrelated genes, was identified as one of the genes whose expression is primarily restricted to lung adenocarcinomas.66–69 High-resolution two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) analysis allows the simultaneous assessment of hundreds of known and unknown polypeptides. Protein expression profiles (proteomic analysis) of lung adenocarcinomas identified triosephosphate isomerase, a key component of the glycolytic pathway that converts dihydroxyacetone phosphate to glyceraldehyde 3-phosphate, to be significantly elevated in more advanced lung adenocarcinomas.70 A glucose-regulated (GRP58) protein that was increased in tumors with K-ras mutations was also elevated.70,71 Proteomic profiling of tumor tissue has the potential to uncover aberrantly expressed proteins resulting, in part, from numerous posttranslational modifications that may be altered in lung cancer.

Aberrant Methylation To determine the extent of RASSF1A promoter methylation, sputum samples from lung cancer patients and from current and former smokers were examined using the common procedure of methylation-specific PCR. Fifty percent of SCLC and 21% of NSCLC patients had RASSF1A methylation, whereas 1 of 2 former smokers and 4 of 13 current smokers showed RASSF1A methylation in sputum. Furthermore, 2 of the 4 current smokers and 1 former smoker showing RASSF1A methylation in their sputum developed lung cancer within 12 to 14 months of bronchoscopy.72 Methylation status of p16, DAPK, and GSTP1 has been studied in bronchial brush samples from former smokers.73 A total of 32% of the samples had methylation in at least one of the three genes tested.73 Interestingly, in a study where DNA was isolated from sputum, bilateral BAL, and brushing taken at bronchoscopy, p16 promoter methylation and p53 mutations were observed in chronic smokers before any clinical evidence of neoplasia. However, K-ras mutations were exclusively seen in lung cancer patients.74

Genetic Alterations in Serum/Plasma Elevated levels of free DNA in the serum of lung cancer patients were reported more than 25 years ago.75 The cancer fingerprint in the form of microsatellite alterations in plasma DNA was found in 50% of SCLC patients. A microsatellite

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alteration was present in 76% of SCLC tumors and in 71% of plasma samples.76 Microsatellite alterations, either as a shift (changes in the size of the microsatellite sequence), LOH, or both, have been found in tumor and serum/plasma DNA paired samples in NSCLC, using microsatellite markers at chromosome 3p.77,78 Intriguingly, plasma DNA abnormalities were found in 45% of tumors up to 2 cm in maximum diameter.78 Similarly, findings indicate that quantification and molecular characterization of plasma DNA in lung cancer patients are valuable noninvasive tools for discriminating patients from unaffected individuals and for detecting early recurrence during follow-up.79 LOH in plasma samples also predated a diagnosis of lung cancer by several months.80 Other studies have reported p53 and K-ras mutations in serum DNA. Aberrant methylation of at least one of p16, DAPK, GSTP1, or MGMT was noted in 15 of 22 (68%) NSCLC tumors but not in any paired normal lung tissue. In these primary tumors with methylation, 11 of 15 (73%) samples also had abnormal methylated DNA in the matched serum samples.81 Other genes are also methylated in primary tumors and paired preoperative serum samples from lung cancer patients.

Genetic and Molecular Alterations in Sputum Sputum is the most commonly utilized biologic material to detect lung cancer cells in a noninvasive manner. Cancer cells harboring point mutations of oncogenes such as K-ras82 and p53 might be detected in sputum of patients with early-stage lung cancer. Bronchoalveolar lavage has also been used as biologic material for the detection of lung cancer.83 Microsatellite alterations might be detectable in cytologically negative sputum from patients with lung cancer.82 In lung cancer, aberrant promoter methylation is frequently found in tumor suppressor genes.84,85 Aberrant methylation of the p16 and/or O-6-methyl-guanine-DNA methyltransferase (MGMT) promoter can be found in 100% of patients with squamous cell lung carcinoma up to 3 years before clinical diagnosis.86 Aberrant promoter methylation of p16 has also been seen in normal bronchial epithelium.87

Pathology Premalignant Lesions Bronchial preneoplastic lesions may be divided into three broad categories: reactive changes (histologically normal epithelium, hyperplasia, and metaplasia) having no increased risk other than smoke exposure; intermediate changes (mild and moderate dysplasia) having moderately increased risk; and high-risk lesions (severe dysplasia and carcinoma in situ) having considerably increased risk. The proportion of individuals with mild, moderate, or severe sputum cell atypia who will develop invasive lung cancer within 10 years was found to be 4%, 10%, and 40%, respectively.88 In a study of high-risk subjects enrolled because of a cigarette-smoking history of at least 30 pack-years, an airflow obstruction, and either an abnormal sputum cytology or a previous or suspected lung cancer, laser-induced fluorescence endoscopy (LIFE) was more sensitive than white-light bronchoscopy (WLB) in detecting preneoplastic bronchial

552 changes.89 LIFE was also better at identifying angiogenic squamous dysplasia (ASD) lesions than WLB. ASD is a unique lesion consisting of capillary blood vessels closely juxtaposed to and projecting into metaplastic or dysplastic squamous bronchial epithelium. ASD represents a qualitatively distinct from of angiogenesis in which there is architectural rearrangement of the capillary microvasculature. LOH at chromosome 3p was observed in 53% of ASD lesions. ASD was described in 34% of high-risk smokers without carcinoma and in 6 of 10 patients with squamous cell carcinoma who underwent LIFE.90 Atypical adenomatous hyperplasia (AAH) is considered to be the preinvasive lesion of adenocarcinoma. These lesions are usually less than 7 mm in diameter and are detected on computed tomography (CT) scan as small, ground-glass densities. In resected lungs, the incidence of AAH was estimated to be 9% to 21% in patients with primary lung cancer and 4% to 10% in patients without lung cancer.88 The mere presence of AAH does not necessarily indicate sure and unremitting progression to adenocarcinoma. Lung cancer is classified into two major clinicopathologic groups: small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC). Squamous cell carcinoma (SCC), adenocarcinoma, and large cell carcinoma are the major histologic types of NSCLC.

Non-Small Cell Lung Cancer (NSCLC) Squamous Cell Carcinoma (SCC) SCC (epidermoid carcinoma) of the lung is a malignant epithelial tumor with the differentiating features of squamous epithelium: keratinization, intercellular bridges, or both. SCC varies from small endobronchial obstructive tumors to large cavitated masses that can replace an entire lung. The masses are gray-white or yellowish, often with a dry flaky appearance that reflects the keratinization. Necrosis and hemorrhage are common; cavitation is seen in one-third of cases. Secondary infections may occur in cavitated masses. SCC of the lung may be divided into welldifferentiated, moderately differentiated, and poorly differentiated subtypes depending on the degree of squamous differentiation present. Intercellular bridges and keratinization are most marked in well-differentiated tumors. SCCs tend to grow as nests of cells with surrounding stroma that may be desmoplastic and infiltrated by acute or chronic inflammatory cells. The nuclei are hyperchromatic, sometimes with prominent nucleoli and thick chromatin condensation along the nuclear membrane. SCC typically stains for both high and low molecular weight keratins. Other intermediate filaments may also be present, including vimentin and synaptophysin. SCC may also stain positively for epithelial membrane antigen (EMA), human milk fat globule (HMFG-2), S-100 protein, Leu-M1, and carcinoembryonic antigen (CEA).91

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hepatoid differentiation. Adenocarcinomas are generally peripheral, well-circumscribed masses often associated with overlying pleural fibrosis or puckering. On cut section, they are gray-white, sometimes lobulated, and often have central scarring that may contain anthracotic pigment. The cells comprising adenocarcinoma are large, cuboidal, columnar, or polygonal with large vesicular nuclei and prominent nucleoli. Solid adenocarcinomas may be virtually indistinguishable from large cell carcinomas except for the mucin production. Mucin stains (mucicarmine, periodic acid–Schiff diastase, Alcian blue) are required for diagnosis. Mucin production varies from occasional positive cells to large pools containing nests of tumor cells. Some pleomorphic adenocarcinomas have foci of spindle cells. Pulmonary adenocarcinomas may be positive for a number of neuroendocrine markers.91

Bronchoalveolar Carcinoma Bronchoalveolar carcinoma (BAC), also called alveolar cell carcinoma or bronchoalveolar tumor, is a subset of pulmonary adenocarcinoma in which cylindrical tumor cells grow upon the walls of preexisting alveoli. The key feature is the preservation of the underlying architecture of the lung. BACs are separated into two major subtypes: nonmucinous, comprising two-thirds of cases, and mucinous, comprising most of the remainder. Nonmucinous BACs are composed of cells with Clara cell or type 2 cell differentiation or both. Mucinous BACs are composed of goblet or mucin-producing cells and are usually very well differentiated.91

Large Cell Carcinoma Large cell carcinoma, also called large cell anaplastic carcinoma and large cell undifferentiated carcinoma, is defined as a malignant epithelial tumor with large nuclei, prominent nucleoli, and usually well-defined cell borders without the characteristic features of SCC, small cell, or adenocarcinoma. This definition is one of exclusion and is dependent on extensive sampling of a given tumor.91

Small Cell Lung Cancer The International Association for the Study of Lung Cancer (IASLC) proposed that small cell carcinoma be divided into three categories: small cell carcinoma; mixed small cell/large cell carcinoma; and combined small cell carcinoma, which also has components of squamous cell and/or adenocarcinoma.92 Small cell carcinoma is composed of small tumor cells with a round to fusiform shape, scant cytoplasm, finely granular nuclear chromatin, and absent or inconspicuous nucleoli. The tumor has a very hyperchromatic appearance because the cells have little cytoplasm and are situated very close to each other. Nuclear molding may be conspicuous but is more difficult to visualize in histologic sections than in cytologic preparations. Mitotic rates are characteristically high, sometimes exceeding 10 per single high-power field.91

Adenocarcinoma Adenocarcinoma of the lung is a glandular epithelial malignancy manifesting tubular, papillary, or acinar growth patterns or a solid growth pattern with mucin production. Unusual patterns include signet-ring adenocarcinoma, spindle cell adenocarcinoma, and adenocarcinoma showing

Neuroendocrine Tumors SCLC and large cell neuroendocrine (NE) carcinomas are high-grade NE tumors, whereas typical carcinoid and atypical carcinoid are low and intermediate grade, respectively. Large cell NE carcinoma is defined as a tumor with NE mor-

lung cancer

phology, including organoid nesting, palisading, trabecular pattern, and rosette-like structures. A mitotic count of 11 or more mitoses per 2 mm2 is the main criterion for separating large cell NE carcinoma and SCLC from atypical carcinoid. Large cell NE carcinoma and SCLC usually have very high mitotic rates, with an average of 70 to 80 per 2 mm2. Large cell NE carcinoma and SCLC also generally have more extensive necrosis than atypical carcinoid. Large cell NE carcinoma is separated from SCLC using a constellation of criteria, which include larger cell size, abundant cytoplasm, prominent nucleoli, vesicular or coarse chromatin, polygonal rather than fusiform shape, less-prominent nuclear molding, and less-conspicuous DNA encrustation of blood vessel walls.93 Clinically, approximately 20% to 40% of patients with both typical and atypical carcinoids are nonsmokers, whereas virtually all patients with SCLC and large cell NE carcinoma are cigarette smokers. In contrast to SCLC and large cell NE carcinoma, both typical and atypical carcinoids can occur in patients with multiple endocrine neoplasia (MEN) type I. Histology heterogeneity with other major histologic types of lung carcinoma (squamous cell carcinoma, adenocarcinoma) occurs with both SCLC and large cell NE carcinoma but not with typical or atypical carcinoids. Furthermore, large cell NE carcinomas and SCLC have a high frequency of retinoblastoma direct inactivation related to retinoblastoma loss of protein expression. However, the typical carcinoids remain the only tumor type in the spectrum of neuroendocrine tumors that retain an intact retinoblastoma pathway. Moreover, p53 mutations leading to immunohistochemical aberrant overexpression of p53 protein are observed in 60% of large cell NE carcinomas and SCLC, in 20% of atypical carcinoids, and in no typical carcinoids. E2F1 regulated by p53retinoblastoma pathways is overexpressed, as well as all its transcriptional target genes, in the majority of SCLC and large cell NE carcinomas, but not in carcinoids.94

Biologic Differences Between Histologic Subtypes EGFR expression varies according to histologic subtypes. Squamous cell carcinoma expressed EGFR in 84% of tumors, adenocarcinoma in 65%, large cell carcinoma in 68%, and SCLC in 0%. Interestingly, a study of a small number of patients with bronchioloalveolar carcinoma (BAC) found that the large majority had either intermediate or high expression of EGFR by immunostaining. There was also a significant correlation between nonmucinous BAC and EGFR expression, while mucinous BAC histology was more frequently related to HER2 overexpression.95 In addition to differences in K-ras and p53 mutation frequencies between SCLC and NSCLC, there are other significant genetic distinctions. RASSF1A is inactivated by promoter methylation in more than 90% of SCLCs and in 40% of NSCLCs. Retinoblastoma is inactivated in more than 90% of SCLCs but only 15% of NSCLCs. p16 is almost never abnormal in SCLCs but is inactivated in more than 50% of NSCLCs. A study of hypermethylation in lung cancer for eight genes (p16, APC, CDH13, GSTP1, MGMT, RARb, CDH1, RASSF1A) revealed that the profile of methylated genes in SCLC was different from that of NSCLC.84 Further details on methylation, including FHIT and DAPK, have been reviewed elsewhere.85

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Prognostic Factors Clinical In a retrospective analysis of 2,531 NSCLC patients treated in the Southwest Oncology Group (SWOG) with extensive disease defined either as distant metastases or locoregional recurrence after definitive radiotherapy, a Cox modeling and recursive partitioning and amalgamation (RPA) was performed to determine independent predictive factors of outcome.96 Patients were treated between 1974 and 1988. Performance status (PS) was defined as good (SWOG 0–1, no symptoms or with symptoms but fully ambulatory) or poor (SWOG 2–4, nonambulatory). Good performance status (PS), female sex, and age greater than 70 years were significant independent predictors. In a second Cox model for patients with good PS, hemoglobin levels above 11 g/dL, normal calcium, and a single metastatic site were significant favorable factors. The use of cisplatin was an additional independent predictor of improved outcome. An RPA performed in 904 patients from more-recent SWOG trials, almost all of whom were treated with cisplatin, revealed three distinct subsets based on PS, age, hemoglobin, and lactate dehydrogenase (LDH); 1-year survivals were 27%, 16%, and 6%, respectively. Until 1980, additional variables, such as weight loss (less than 10 or more than 10 pounds), were not included. In the multivariate survival analyses by prognostic variables and therapy discriminants, significant favorable SWOG factors were PS 0 to 1, female sex, age greater than 70 years, and then greater than 45 years in females, single metastatic lesion, less than 10 pounds of weight loss, normal LDH, normal alkaline phosphatase, and hemoglobin above 11 g/dL. Median survival was 1 to 3 months better for the good PS, female, singlelesion, and cisplatin-based therapy categories.96 Intriguingly, LDH was important in the poor PS subset; patients with a normal LDH level and poor PS had a survival outcome similar to other subsets with a good PS.96 In the analysis of 1,052 patients included in clinical trials conducted by the European Lung Cancer Working Party (ELCWP), a Cox regression model found the following variables: Karnofsky PS (greater than 80 = SWOG 0–1; less than 70 = SWOG 2–4), neutrophil counts, metastatic involvement of skin, serum calcium level, age, and gender, as well as disease extent, because patients with stages I to III were included in the analysis. According to an RPA model, the best subgroup of patients was defined as female with limited disease and Karnofsky PS above 80.97 In a third, smaller analysis including a homogenous group of stage III unresectable or inoperable patients receiving cisplatin 120 mg/m2 plus vinca alkaloid combination chemotherapy, a multivariate analysis disclosed the following parameters associated with outcome: initial PS, with patients having a good PS displaying an increased objective response and survival; bone metastases, which were adversely predictive of response rate and survival; elevated LDH and male sex, both of which were associated with shortened survival; and the presence of two or more extrathoracic metastatic organ sites, which was associated with shortened survival.98 When objective response with chemotherapy was included in the analysis, it was also strongly associated with longer survival.98 In a prospective Spanish Lung Cancer Group (SLCG) study99 including 557 cisplatin combination-treated NSCLC

554 patients, PS, gender, and weight loss were significant prognostic factors. Second, weight loss in lung cancer patients is associated with both impaired therapy outcome and reduced survival.97 In studies of multimodality treatment in stage IIIA (N2) and IIIB NSCLC, the SWOG study of concurrent cisplatin plus etoposide and chest radiotherapy followed by surgery observed that the strongest predictor of long-term survival after thoracotomy was absence of tumor in the mediastinal lymph nodes at surgery (median survivals, 30 versus 10 months and 3-year survival rates, 44% versus 18%).100 Some of these predictive markers of survival, such as PS, hemoglobin level, and bone, liver, or skin metastases, are understandable; however, why gender, LDH, or weight loss influence survival remains unclear. New pieces of information should shed light on these prognostic factors. First, there are interindividual differences in DRC that are accentuated according to age and gender, with females having a reduced DRC.46 Based on this difference in DRC, females would have greater chemosensitivity than males. In vitro intrinsic cisplatin resistance was associated with elevated DRC in NSCLC cells.101 DRC is a surrogate of the NER pathway, which eliminates cisplatin adducts,47,50 and it has been demonstrated that NSCLC patients with effective systemic (host) DRC have poorer survival than patients with suboptimal DRC.102 Patients who were in the top DRC quartile of the group (DRC greater than 9.2%) had a risk of death more than two times that of patients in the bottom quartile (DRC less than 5.8%). Median survival was 8.9 months for patients in the top DRC quartile, compared with 15.8 months for those in the bottom quartile (P = 0.04).102 Earlier findings suggest that the formation and persistence of cisplatin or carboplatin adducts in buccal cells or in leukocytes predict better response.103,104 Cisplatin DNA adducts in nuclei of buccal cells were studied in a small group of patients who received radical radiotherapy and daily administration of low-dose cisplatin for inoperable NSCLC.105 Nuclear staining was performed in buccal cells collected 1 hour after cisplatin on the fifth treatment day (after five daily doses of cisplatin 6 mg/m2). Cisplatin DNA adduct staining remained a significant independent predictor of survival. Patients with low levels of induced DNA adducts in buccal cells showed a meager median survival of 5 months, in contrast with 30 months for patients with elevated DNA adduct levels.106 Beyond the stratification for gender in future clinical trials, measuring DRC by functional assays or surrogates such as ERCC1 or XPD mRNA in peripheral lymphocytes50 could help to predict responders.98

Metabolism In contrast to normal mammalian cells, which use oxygen to generate energy, cancer cells rely on glycolysis for energy. Lung cancer patients with weight loss have elevated 3phosphoglycerate and phosphoenolpyruvate, components of the glycolysis pathway107 (Figure 37.3). Furthermore, c-Myc and HIF-1 overexpression deregulate glycolysis through the activation of the glucose metabolic pathway, which regulates lactate dehydrogenase and induces lactate overproduction108 (Figure 37.3). Elevated serum LDH was associated with shortened survival and remission duration.98 Elevated mRNA levels of phosphofructokinase, glyceraldehyde-3-phosphate

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dehydrogenase, phosphoglycerate kinase, and enolase were also reported.108 Systematic identification of lung adenocarcinoma proteins using 2-D PAGE and mass spectrometry found that at least four proteins (phosphoglycerate kinase 1, phosphoglycerate mutase, alpha enolase, and pyruvate kinase M1), all of which are components of the glycolysis pathway (see Figure 37.3), were increased in expression and associated with poor survival in resected lung adenocarcinoma.109 Expression of phosphoglycerate kinase 1, the sixth enzyme of the glycolytic pathway (Figure 37.3), reflects increased glycolysis in the tumor cells and is related to the induction of a multidrug resistant phenotype distinct from MDR1. The hypoxic nature of solid tumor triggers VEGF expression, which stimulates angiogenesis and glycolytic enzymes, including phosphoglycerate kinase, which facilitates anaerobic production of ATP.110 A surrogate of the cancer glycolytic pathway could be positron emission tomography (PET) reflecting the biochemical and physiologic processes occurring in the tissues being imaged. The most frequently used positron-emitting radiopharmaceutical is 18-fluor, labeled 2-deoxy-d-glucose (18FFDG), a radioactively labeled glucose analogue. The clinical use of 18F-FDG-PET is based on the premise that cancer cells exhibit a higher glycolytic rate than do nonneoplastic cells. It is reasonable to speculate that a higher tumor uptake of the radiolabeled glucose analogue could be a surrogate of the glycolytic pathway. PET imaging has been used to assess changes in tumor glucose use during chemotherapy. In NSCLC, median time to progression and overall survival were significantly longer for 18FDG-6-PET metabolic responders in the interval before and after the first chemotherapy cycle.111

Overexpression of ERCC1 mRNA and Other NER Genes Moving toward a new prognostic classification, overexpression of ERCC1 mRNA and other NER genes has been associated with repair of cisplatin-induced DNA damage and clinical resistance to cisplatin. In a small study of cisplatin/gemcitabine-treated metastatic NSCLC patients, performance status, weight loss and low ERCC1 mRNA expression were independent prognostic factors. ERCC1 mRNA levels were even more significant than that of performance status.112 Median survival for patients with low ERCC1 expression was 15 months in contrast to only 5 months for those harboring high expression.

M2 Subunit of Ribonucleotide Reductase Also to be considered as a potential new predictive and prognostic marker is the ribonucleotide reductase activity, which is increased in cancer cells. The subunit M2 (or RRM2) is directly involved in a number of signaling pathways.113 Among other drugs, gemcitabine decreases ribonucleotide reductase activity. In a retrospective analysis, better time to progression and survival were observed in gemcitabine/ cisplatin-treated metastatic NSCLC patients who had low ribonucleotide reductase subunit M1 (or RRM1) mRNA expression.114 Interestingly, retinoblastoma is sequentially phosphorylated by cyclin D-CDK4/6 and cyclin E/CDK2 during G1/S cell-cycle transition. This modification leads to the dissociation of retinoblastoma from E2F/DP heterodimers, leaving them in a transcriptionally active state

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lung cancer Glucose Hexokinase

Legend Glycolysis Gluconeogenesis Unfavorable for survival (protein) Unfavorable for survival (mRNA) GAP: Glyceraldehyde-3-phosphate GOT: Aspartate aminotransferase MOH: Malate dehydrogenase

Glucose-6-phosphatase

Glucose-6-phosphate Glucose-6-phosphate isomerase Fructose-6-phosphate Phosphofructokinase

Fructose-1,6-hisphosphatase

Fructose-1,6-bisphosphate Aldolase GAP

Triosephosphate isomerase

Dihydroxyacetone phosphate

Glyceraldehyde-3-PO4 dehydrogenase 1,3-Bisphosphoglycerate Phosphoglycerate kinase 3-Phosphoglycerate Phosphoglycerate mufase 2-Phosphoglycerate

Enolase

Cytosol

Phosphoenolpyruvate

Asparate

PEP Carboxykinase

GOT. cyto

Mitochondrion Asparate GOT. mt

Pyruvate kinase Oxaloacetate MDH. cyto

Pyruvate

Malate Lactate dehydrogenase

Oxaloacetate MDH. mt Malate

Pyruvate Pyruvate carboxylase Lactate

Pyruvate dehydrogenase

TCA cycle

Acetyl-CoA FIGURE 37.3. Glycolysis and gluconeogenesis pathway.

that regulates several DNA synthesis enzymes also involved in chemotherapy response, such as dihydrofolate reductase (DHFR), thymidylate synthase (TS), and ribonucleotide reductase.115 In SCLC and NSCLC, p16/INK4A and retinoblastoma are reciprocally inactivated, resulting in the inactivation of the same p16/INK4A/RB pathway.116 Therefore, in prospective studies the predictive and/or prognostic value of certain transcripts should be kept in mind. For example, in ribonucleotide-dependent chemotherapy combinations, the role of RRM1 and TS mRNA levels could influence response and survival, as proposed in the model in Figure 37.4.

Genetic Since the first article describing K-ras mutations in lung adenocarcinomas,51 a continual list of new genetic markers has been described, predicting disease-free survival and overall survival, mainly in surgically resected stage I NSCLC (Table 37.3). Tumors with K-ras mutations tend to be smaller and less differentiated than those without. The normal DNA sequence GGT at codon 12 is commonly switched to TGT.52 K-ras mutations in NSCLC cell lines were related to poor survival in stage IIIB–IV.117 Numerous reports have pointed out

556

chapter In 1990’s

To be validated

PS DRC (ERCC1 and XPD mRNA) in lymphocytes

Gender

LDH Weight loss

Enhanced glycolysis: ™6-phosphofructokinase mRNA ™Triosephosphate isomerase rnRNA ™Phosphoglycerate kinase in mRNA/ protein ™Phosphoglycerate mutase protein ™Enolase protein ™Pyruvate kinase protein PET metabolic response

Intratumoral ERCC1 mRNA

HIF-1a/VEGF mRNA EGFR mRNA PI3K/Akt mRNA

RNR-dependant drugs RRM1 mRNA TS mRNA FIGURE 37.4. Factors associated with impaired therapy outcome and reduced survival.

the prognostic value of K-ras codon 12 mutations in stage I NSCLC.52,118–120 However, in a recent report, neither K-ras nor p53 mutations influenced survival in all patients, although in patients receiving adjuvant chemotherapy, those without K-

37

ras mutations had a median survival of almost 42 months, whereas for those with mutations, median survival bottomed out at nearly 25 months (P = 0.09; risk ratio = 0.59).121 Such differences were not seen in patients who did not receive adjuvant chemotherapy. In a randomized neoadjuvant trial, Kras mutations were more often found in the surgery-alone arm than in the neoadjuvant arm.122 In a small neoadjuvant chemotherapy study of stage III NSCLC, the presence of Kras mutations in the surgical specimens was a significant predictor of poor disease-free survival.123

Retinoic Acid Receptor and COX-2 In several retrospectively analyzed surgical series, high retinoic acid receptor-b mRNA levels by in situ hybridization correlated with poor survival in stage I NSCLC.124 A significant relationship between elevated expression of cyclooxygenase 2 (COX-2) and worse survival has also been observed in stage I disease.125,126

Aberrant Methylation Hypermethylation of death-associated protein kinase (DAPK) was found in 44% of tumors and linked to significantly poorer survival.127 Similarly, hypermethylation of RASSF1A was linked to worse survival.128 However, in a recent study, neither DAPK nor RASSF1A methylation in tumor or

TABLE 37.3. Genetic markers in resected non-small cell lung cancer (NSCLC). No. of patients

Biomarker 53

K-ras mutation wt RAR-b mRNA124 COX-2125,126 DAPK127 RASSF1A128 CRMP-1 mRNA130 IL-8 mRNA131 IL-10132 MIF mRNA133 RANTES134 IGFBP-3135 11p15.5 LOH136 ERCC1 mRNA137 128-gene set138

High Low High Low Methyl Unmethyl Methyl Unmethyl Low Normal High Normal Low High Low High Low High Methyl Unmethyl Present Absent Low High With

NSCLC

Survivala

P

19 50 45 115 57 24 59 76 32 75 40 40 61 61 44 94 4 6 36 27 51 32 26 50 NS

Adenocarcinoma

ª18 months NR

0.002

Stage I

Worse

0.045

Stage I

0.034

NS

Adenocarcinoma

66% 88% 46% 68% 37 months 49 months 28 months leveled off at 52% Shorter Longer 40.9% 56% Longer Shorter Shorter Longer 53% 86% 24.9 months 36 months 35.5 months 94.6 months Shorter

Stage I Stage I Stage I Stage I SCC SCC Stage I Stage I Stage I Stage I

wt, wild-type; NS, not specified; SCC, squamous cell carcinoma; NR, not reached. a

Percentages indicate 5-year survival rates; months indicate median survival.

b

Another study found no survival differences according to methylation patterns.

0.007b 0.046b 0.016 6 months

Total 802 410 392

Treatment

Response

Paclitaxel 175 mg/m2 Cyclophosphamide 500 mg/m2 Doxorubicin 50 mg/m2 Cisplatin 50 mg/m2 Carboplatin Carboplatin + epidoxorubicin

45%

Median DFS

Median survival

9.7 months 15.9 months

25.8 months 34.7%

P = 0.08

P = 0.16

14 months 17 months

NR

P value

55%

55% 58%

NS

Pfisterer

178

2004

>6 months

Total 365 178 178

Gordon

133

2001

>6 months

Total 220 109 111

Platinum-based therapy Paclitaxel and platinum

NR

Carboplatin AUC 5 day 1 Carboplatin AUC 4 day 1 + Gemcitabine 1000 mg/m2 Days 1 and 8

30.9%

Liposomal Doxorubicin Topotecan

31%

28.9 weeks

108 weeks

32%

23.3 weeks P = 0.037

71 weeks P = 0.008

topotecan, and liposomal doxorubicin have very modest response rates and median survival of less than 1 year.131,133,136,137 Randomized studies of these agents against supportive care have not been performed, although the superiority of intravenous topotecan to oral topotecan for overall survival implies a modest survival advantage for intravenous

9 months

24 months

12 months HR = 0.76

29 months HR = 0.82

5.8 months

47.2%

P < 0.02 (survival) P < 0.0004 (DFS) DFS P < 0.0031

NR 8.6 months HR = 0.72

topotecan therapy.136 A number of agents have been also examined in Phase II single-agent studies. In this setting, etoposide and gemcitabine stand out as two agents with modest activity.138–143 Gemcitabine is often favored over etoposide, based on the small incidence of acute leukemia associated with etoposide treatment. Special mention should

TABLE 52.11. Recurrent disease: platinum-resistant disease. Author

ten Bokkel Huinink

Reference

Year

131

1997

No. of patients

Total 226 112 114

Bolis

Piccart

179

137

1998

2000

Gordon

133

2001

Gore

136

2002

Total 81 40 41

Total 87 41 45 Total 254 130 124 Total 266 135 131

Treatment

Response

Median DFS

Median survival

P value

P = 0.002 for DFS

Topotecan 1.5 mg/m2 daily ¥ 5 Paclitaxel 175 mg/m2 over 3 h

20.5%

23 weeks

61 weeks

13.2%

20 weeks

43 weeks

Paclitaxel 175 mg/m2 Paclitaxel 150 mg/m2 + epidoxorubicn 120 mg/m2

17.1% 34.1%

NR

Paclitaxel 175 mg/m2 Oxaliplatin 130 mg/m2 Liposomal Doxorubicin 50 mg/m2 Topotecan 1.5 mg/m2 ¥ 5 days Total 266 Oral topotecan 2.3 mg/m2 ¥ 5 days Topotecan 1.5 mg/m2 ¥ 5 days

17% 16% 16% 8% 13% 20%

Two-year survival 18% 10%

P = 0.10 for response

14 weeks 12 weeks 9.1 weeks

37 weeks 42 weeks 35 weeks

NS for all

13.6 weeks

41 weeks

13 weeks 17 weeks

51 weeks 58 weeks

NS for all

P = 0.033 for survival

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be made of the taxanes in this setting. Weekly paclitaxel has a response rate in excess of 20% for patients previously resistant to an every-3-week cycle, and this schedule enjoys an excellent side effect profile.138,144 There is also some suggestion that docetaxel is not completely cross reistant with paclitaxel in ovarian cancer treatment.145–147 The choice among these agents can be based on toxicity preferences. No data exist for a preferred sequence, and it appears that there is little cross-resistance among agents.132,148 It is also of note that a “platinum-resistant” cohort will contain some patients who may respond to additional platinum-based therapy. The GINECO investigators reviewed their experience with platinum-based chemotherapy for patients classified as “platinum resistant” by the standard definition. In that presentation, there was still a modest (but statistically significant) survival advantage to platinum-based chemotherapy.149 In the Memorial Sloan Kettering experience, most of the platinum responders in “platinum-resistant” cohort are patients with early relapse following platinumbased therapy.150

Appropriate Follow-Up Interventions Interval The ideal follow-up of asymptomatic patients who have completed primary surgery and chemotherapy has yet to be determined. Typically, patients are followed at 3- to 4-month intervals for the first 2 years. Using a 15-question survey, Barnhill et al. illustrated the practice patterns for patient follow up after primary treatment of gynecologic cancers among 94 gynecologic oncologists.151 The majority of the physicians surveyed recommended visits every 3 months for the first year, every 3 to 4 months for the second year, every 6 months for years 3 to 5, and annually thereafter. The National Comprehensive Cancer Network (www.NCCN.org) has published their guidelines for monitoring patients with epithelial ovarian cancer who have had a complete response. Visits are every 2 to 4 months for the first 2 years, then every 6 months for the third year, followed by annual visits. Physical examination with pelvic exam and CA 125 (if initially elevated) is performed at each visit, and a complete blood count is obtained annually. Other testing is performed only if indicated. Olaitan et al. recently reviewed their follow up protocols for 81 patients with gynecologic cancers at a tertiary referral center.152 This regimen was similar to the one previously mentioned in that patients have visits with the specialists every 3 months for the first 2 years, every 6 months for the next 2 years, and then annually. There was a total of 14 recurrences, of which 8 (57.1%) were diagnosed at the scheduled appointments, and the remainder were diagnosed by either unscheduled visits to the general practitioner or emergency room. There were 10 cases of recurrent ovarian cancer of which 7 were diagnosed at scheduled clinic visits. Four of the 7 had symptoms of recurrence for at least 1 month before their scheduled visit, and 1 patient had symptoms for 4 months. Two recurrences were detected by CA 125 elevations, 2 patients presented to the general practitioners with several days of symptoms of recurrence, and 1 patient presented to the emergency room with a bowel obstruction. In total, 354 visits were required to diagnose 8 recurrences. The authors identified that patients with scheduled visits may

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delay reporting symptoms until the visit. They suggested an open-access system according to patient need may be a more cost-effective model and are currently performing a prospective randomized trial for follow-up.153

Appropriate Examinations In Barnhill’s survey, examination of the breasts, pelvis, lymph nodes, and abdomen were performed by the majority of physicians at each exam.151 Physical examination by itself is limited in its ability to detect subclinical or persistent disease, but on occasion, a pelvic mass may be detected. The other test that is routinely performed in the follow-up of patients with ovarian cancer is CA 125. According to a survey of gynecologic oncologists, the median recommended number of times the CA 125 level was checked in patients with epithelial ovarian cancer was four during the first 2 years, two over the next 3 years, and either none, one, or two times annually after the fifth year. The accuracy of CA 125 for determining recurrence was illustrated by Niloff et al.154 Serum levels of CA 125 were obtained from 55 women with epithelial ovarian cancer both before and after second-look surgery. Patients were clinically and radiologically disease free and were followed until clinical recurrence. Patients with an elevated CA 125 at time of second look had a 60% chance of recurring within 4 months compared to only a 5% chance in patients with a normal CA 125. Elevation in serial CA 125 during the monitoring period was associated with recurrence in 94% of cases with a median lead time of 3 months. The accuracy of CA 125 in determining relapse illustrates its importance for ovarian cancer follow-up. However, given that there may be a lead time before detectable recurrence, ideal treatment for an elevated CA 125 alone raises a new question that is being addressed in a multicenter Medical Research Council/European Organization for Research and Treatment of Cancer (MRC/EORTC) prospective trial. The primary endpoint for this trial is overall survival, with quality of life and health economics designated as secondary endpoints.

Surgery in Relapse Secondary Debulking The value of primary cytoreductive surgery is well recognized. Removal of large tumors reduces the tumor load, and thus the number of chemotherapy cycles needed to eradicate residual tumor is also reduced. This concept of reducing tumor burden has also been applied to patients who have already undergone a primary cytoreductive surgery followed by chemotherapy. The data on this remain retrospective in nature and include a mixed population of patients. Secondary operations for ovarian cancer can be grouped into four different clinical situations: 1. Recurrent disease: those patients with at least a 6-month disease-free interval. 2. Second-look laparotomy: patients who are clinically without evidence of disease and are found to have gross disease at second-look surgery. 3. Interval debulking: patients with bulky, unresectable disease at initial surgery who undergo neoadjuvant chemotherapy.

922 4. Progressive disease: patients with disease progression on primary chemotherapy. Secondary surgery for recurrent disease is addressed in this section. Because the majority of patients with advanced-stage ovarian cancer will eventually have a recurrence of their disease in spite of a period of clinical remission, the question of whether cytoreductive surgery is of therapeutic benefit at time of relapse remains. A number of retrospective studies have addressed this question of secondary cytoreduction at time of relapse. Berek et al. described their experience with secondary cytoreductive surgery for ovarian cancer,155 which included 32 patients who underwent secondary cytoreduction at the time of second-look laparotomy, at surgery for clinically detected disease, or at the time of bowel obstruction surgery. The median interval between primary and secondary surgery was 12 months, and optimal resection (defined as residual disease less than 1.5 cm) was accomplished in 38% of patients. When patients undergoing second-look surgery were excepted, 6 (29%) underwent optimal cytoreduction and had a median survival of 18 months compared to the 15 suboptimally debulked patients who had a median survival of 5 months. Although this series contained a heterogeneous group of patients, several poor prognostic variables were identified, including greater residual disease after primary surgery, disease-free interval less than 1 year, large tumor size at recurrence, ascites, and greater residual disease after secondary surgery. Several other series have reviewed the impact of residual disease on survival, and most have shown a benefit if residual disease is of small volume. Although the majority of studies regarding the utility of secondary cytoreduction are retrospective, a prospective study was conducted by Eisenkop et al. that evaluated the feasibility and benefit of secondary cytoreduction.156 Thirty-six patients who had undergone primary cytoreduction followed by platinum-based chemotherapy and who had relapsed at least 6 months after primary therapy were enrolled for secondary cytoreduction. All patients had disease greater than 1 cm at recurrence, and complete cytoreduction was achieved in 30 (83%) of patients using an aggressive surgical approach. Morbidity occurred in 30.1% of patients, and there was 1 (2.8%) postoperative mortality. Although there was not a control group who did not undergo secondary cytoreductive surgery, median survival in the group was significantly better in the patients completely resected before salvage therapy compared to those with macroscopic residual disease (43 versus 5 months; P = 0.03, respectively). Based on these retrospective series, secondary cytoreduction appears to be beneficial in patients with resectable recurrent disease and a reasonable disease-free interval. It should be kept in mind that the retrospective series published on secondary cytoreduction included heterogeneous groups of patients and surgeons, involved tumors with different biologic behavior, and had strong selection bias in the authors’ criteria for surgical interventions. The GOG (Protocol 213) is currently conducting a prospective bifactorial randomized trial addressing the use of sequence-dependent chemotherapy and secondary cytoreductive surgery in platinum-sensitive, recurrent ovarian and primary peritoneal cancers. Patients will be randomized to either treatment with

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52

topotecan or carboplatin or secondary cytoreduction followed by treatment with topotecan or carboplatin.

Value and Impact of Surgery for Obstruction Progression of ovarian cancer results in symptoms of diffuse intraabdominal spread and can lead to progressive encasement of the bowel and its mesentery, resulting in symptoms of mechanical obstruction. This is a common finding among patients with recurrent ovarian cancer, and many will eventually succumb to this problem. In a study to determine the incidence of bowel obstruction in patients with ovarian cancer, Lund et al.139 followed the clinical courses of 310 consecutive patients with ovarian cancer. With a median observation time of 46 months, the estimated incidence of intestinal obstruction was 26% at 5 years. The complication rate associated with surgery for obstruction was high, and only 32% of patients had a survival of greater than 60 days with palliation of symptoms. The most commonly associated variables included initial stage III or IV disease, suboptimal (larger than 2 cm tumor nodules) tumor debulking at initial surgery, and the presence of intestinal carcinomatosis at initial surgical exploration. Initial management of patients with obstruction is typically a trial of conservative management with nasogastric drainage. However, Krebs and Goplerud reported that such an approach results in sufficient improvement for discharge in only about one-third of cases, and the majority of these patients return with a subsequent obstruction within a mean of 5.5 weeks.157 In cases that do not resolve with conservative management, surgical correction may be considered. This option is associated with a high rate of morbidity and mortality, and the chances of successful palliation, risk of reobstruction, and quality of life after the surgery must be taken into consideration. A number of retrospective studies have examined the role of surgery for obstruction in patients with ovarian cancer. Pothuri et al. reported. from Memorial Sloan-Kettering Cancer Center 64 patients who underwent 68 operations.158 The obstruction was surgically corrected in 57 (84%) of the 68 procedures. Of this group, 71% were able to tolerate a regular or low-residue diet at least 60 days postoperatively, and 79% were able to receive more chemotherapy. The surgical morbidity was 22% and the perioperative mortality was 6%. Median survival was significantly longer in the patients who had successful palliation compared to those who did not, 11.6 months and 3.9 months, respectively (P less than 0.01). A number of other studies have demonstrated that surgical correction is possible; however, these studies include a patient pool that is heavily preselected. Successful palliation, defined as survival greater than 60 days from surgery, was achieved for 51% to 80% of patients; however, perioperative mortality (4%–32%) and morbidity (7%–64%) can be significant. In an attempt to better define patients who may benefit from a surgical procedure, Krebs and Goplerud used age, nutritional status, tumor spread, ascites, previous chemotherapy, and previous radiation to formulate a prognostic index.159 Using a scoring system of 0–2 for each variable, they reported that 84% of patients with a score of 6 or less survived at least 60 days postsurgery compared to 0% of patients with a score of 7 or more. It would be beneficial to identify patients who would not benefit from surgery, and other series have con-

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firmed the validity of using a prognostic index.160 Not all reports, however, have been able to demonstrate that such variables are predictive of successful palliation or improved survival.161

Supportive Care Total Parenteral Nutrition The role of total parenteral nutrition is a question that may arise in patients with malignant intestinal obstruction. Due to the predilection for intraabdominal spread, intestinal obstruction in patients with advanced ovarian cancer is not an uncommon situation. Many patients may present with or develop bowel obstruction related to unresectable disease. In such cases which do not appear amenable to surgical correction, supportive care should be the focus of treatment. The extent of supportive efforts can be a difficult topic to address. Many patients or families suffering from altered gastrointestinal function from unresectable ovarian cancer may raise the possibility of using total parenteral nutrition (TPN). In spite of decreased oral intake, more than 60% of terminally ill cancer patients experience no hunger or thirst.162 Thus, the value of TPN in patients with end-stage ovarian cancer remains questionable. The potential risks associated with TPN and the training required for home administration may justify its use in patients with expected survivals of more than 3 months.163 With the exception of certain situations, such as patients who are undergoing surgical correction for obstruction or being administered TPN in conjunction with systemic chemotherapy for newly diagnosed ovarian cancer, TPN is not routinely recommended. A review of patients with small bowel obstruction and advanced ovarian cancer demonstrated some of the rare indications for the use of TPN in advanced ovarian cancer patients. Abu-Rustum et al. identified 21 patients (3 newly diagnosed and 18 heavily treated for persistent or recurrent disease) who received chemotherapy in an attempt to restore bowel function.164 All patients had a drainage gastrostomy placed. Eleven patients also received TPN (all newly diagnosed and 8 recurrent/persistent). Two of the 3 chemotherapy-naïve patients had relief of their bowel obstruction, compared to none of the patients with recurrent or persistent disease. Median survival for patients who received TPN with chemotherapy was 89 days compared to 71 days in patients who received chemotherapy alone (P = 0.031). However, the authors did not believe that the additional 18 days justified the routine administration of TPN and discouraged its use.

Percutaneous Endoscopic Gastrostomy Tube Drainage Patients with malignant obstruction who either choose not to undergo a surgical procedure or who are poor candidates for surgical correction can be managed with percutaneous endoscopic gastrostomy (PEG) drainage of the stomach and small bowel. PEG has many advantages over a nasogastric tube, including patient comfort, lack of damage to the gastric mucosa, more efficient drainage due to a wide tube, and providing the satisfaction of oral liquids in spite of obstruction. PEG can be placed without necessitating a surgical procedure

923

that may be associated with increased morbidity. Retrospective studies have demonstrated that PEG tubes can be placed in the majority of patients with success rates of 89% to 100%.165,166 Complications rates are typically low, with the major risks being leakage of gastric contents, intestinal perforation, and peritonitis. After successful placement of the PEG tube, patients can resume a liquid or soft diet in 84% to 100% of cases.165,166 Because improvement in comfort of the terminally ill cancer patient should be the major goal, PEG drainage should be considered in patients with malignant bowel obstruction.

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recurrent ovarian cancer: an updated series. Gynecol Oncol 2003;89(2):306–313. Krebs HB, Goplerud DR. The role of intestinal intubation in obstruction of the small intestine due to carcinoma of the ovary. Surg Gynecol Obstet 1984;158(5):467–471. Larson JE, Podczaski ES, Manetta A, Whitney CW, Mortel R. Bowel obstruction in patients with ovarian carcinoma: analysis of prognostic factors. Gynecol Oncol 1989;35(1):61– 65. Rubin SC, Hoskins WJ, Benjamin I, Lewis JL, Jr. Palliative surgery for intestinal obstruction in advanced ovarian cancer. Gynecol Oncol 1989;34(1):16–19. McCann RM, Hall WJ, Groth-Juncker A. Comfort care for terminally ill patients. The appropriate use of nutrition and hydration. JAMA 1994;272(16):1263–1266. Cozzaglio L, Balzola F, Cosentino F, et al. Outcome of cancer patients receiving home parenteral nutrition. Italian Society of Parenteral and Enteral Nutrition (S.I.N.P.E.). JPEN J Parenter Enteral Nutr 1997;21(6):339–342. Abu-Rustum NR, Barakat RR, Venkatraman E, Spriggs D. Chemotherapy and total parenteral nutrition for advanced ovarian cancer with bowel obstruction. Gynecol Oncol 1997;64(3):493–495. Herman LL, Hoskins WJ, Shike M. Percutaneous endoscopic gastrostomy for decompression of the stomach and small bowel. Gastrointest Endosc 1992;38(3):314–318. Cunningham MJ, Bromberg C, Kredentser DC, Collins MB, Malfetano JH. Percutaneous gastrostomy for decompression in patients with advanced gynecologic malignancies. Gynecol Oncol 1995;59(2):273–276. Jacobs I, Davies AP, Bridges J, et al. Prevalence screening for ovarian cancer in postmenopausal women by CA 125 measurement and ultrasonography. Br Med J 1993;306(6884): 1030–1034. Grover S, Quinn MA, Weideman P, et al. Screening for ovarian cancer using serum CA 125 and vaginal examination: report on 2550 females. Int J Gynecol Cancer 1995;5(4): 291–295. Adonakis GL, Paraskevaidis E, Tsiga S, Seferiadis K, Lolis DE. A combined approach for the early detection of ovarian cancer in asymptomatic women. Eur J Obstet Gynecol Reprod Biol 1996;65(2):221–225. Sato S, Yokoyama Y, Sakamoto T, Futagami M, Saito Y. Usefulness of mass screening for ovarian carcinoma using transvaginal ultrasonography. Cancer (Phila) 2000;89(3): 582–588. DePriest PD, Gallion HH, Pavlik EJ, Kryscio RJ, van Nagell JR, Jr. Transvaginal sonography as a screening method for the detection of early ovarian cancer. Gynecol Oncol 1997;65(3):408–414. Sell A, Bertelsen K, Andersen JE, Stroyer I, Panduro J. Randomized study of whole-abdomen irradiation versus pelvic irradiation plus cyclophosphamide in treatment of early ovarian cancer. Gynecol Oncol 1990;37(3):367–373. Dembo AJ. Radiotherapeutic management of ovarian cancer. Semin Oncol 1984;11(3):238–250. Muggia FM, Braly PS, Brady MF, et al. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecologic oncology group study. J Clin Oncol 2000;18(1):106–115. Colombo N, Maggioni A, Vignali M, Parma G, Mangioni C. Options for primary chemotherapy in advanced ovarian cancer: the European perspective. Gynecol Oncol 1994;55(3 pt 2):S108–S113.

ova r i a n c a n c e r

176. Sorbe B. Consolidation treatment of advanced (FIGO stage III) ovarian carcinoma in complete surgical remission after induction chemotherapy: a randomized, controlled, clinical trial comparing whole abdominal radiotherapy, chemotherapy, and no further treatment. Int J Gynecol Cancer 2003; 13(3):278–286. 177. Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed

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ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet 2003;361(9375):2099–2106. 178. Pfisterer J, Plante M, du Bois A, Wagner U, Hirte H, al E. Gemcitabine/carboplatin vs. carboplatin in platinum sensitive disease. Proc ASCO 2004;23:450s (abstract 5005). 179. Bolis G, Parazzini F, Scarfone G, et al. Paclitaxel vs epidoxorubicin plus paclitaxel as second-line therapy for platinumrefractory and -resistant ovarian cancer. Gynecol Oncol 1999;72(1):60–64.

5 3

Uterine Malignancies Gini F. Fleming, Anthony C. Montag, Arno J. Mundt, and S.D. Yamada

Etiology, Epidemiology, and Risk Factors The American Cancer Society estimates that, in 2004, endometrial cancer will be the most common gynecologic malignancy in North America, accounting for 40,320 new cases and 7,090 deaths. Endometrial cancer is primarily a disease of postmenopausal women, with the incidence peaking between the ages of 55 and 65 years. Among Caucasian women, the incidence of uterine cancer is about twice that of African-American women; however, AfricanAmerican women are less likely to survive this disease. Between 1992 and 1999, the 5-year survival for Caucasian women was 86% as compared to 60% for African-American women.1 This disparity in survival has persisted over the past 25 years and may reflect the preponderance of tumors in African-Americans with unfavorable histology, higher grade and, possibly, more-advanced stage at diagnosis. It is believed that there are two types of endometrial cancer: estrogen related and non-estrogen related. More than 80% of early-stage endometrial cancers are endometrioid and, most likely, estrogen related.2 The majority of these cases develop from preexisting endometrial hyperplasia and reflect the effect of endogenous or exogenous estrogen stimulation. The risk and rate of progression to cancer are not well defined, although it has been estimated that endometrial hyperplasia with nuclear atypia has a 25% risk of progression to endometrial carcinoma, in contrast to hyperplasia without cytologic atypia, which has an exceedingly low rate of progression.3 Numerous factors, many related to estrogen stimulation, have been associated with the development of endometrial hyperplasia and, subsequently, endometrial cancer. Estrogen without concurrent progestin use increases the risk of endometrial carcinoma by four- to eightfold. This risk increases with both duration and amount of estrogen exposure.4 In the PEPI trial (Postmenopausal Estrogen and Progesterone Intervention Trial), 75 of 119 (62%) women who used unopposed estrogen 0.625 mg/day (conjugated equine estrogen) over the course of 3 years developed endometrial hyperplasia. Atypical endometrial hyperplasia occurred in a statistically higher percentage of women taking unopposed estrogen as opposed to placebo: 11.8% versus 0% (P less than 0.001).5 Progestins used in conjunction with estrogen reduce the risk of endometrial cancer and should be prescribed to all women with an intact uterus receiving hormone replacement

928

therapy. In the HOPE trial (Women’s Health, Osteoporosis, Estrogen, Progestin Trial), doses of 0.625 mg conjugated equine estrogen (CEE) or 0.45 mg CEE with medroxyprogesterone 2.5 mg daily did not produce any cases of hyperplasia.6 As a result of prolonged exposure of the endometrium to estrogen stimulation, obesity, nulliparity, and late menopause increase the risk of endometrial cancer development, as do feminizing ovarian tumors (granulosa cell tumors) and polycystic ovarian syndrome. Diabetes and hypertension are also associated with increased risk of disease development but may be surrogates for other risk factors such as obesity. Tamoxifen use in women with breast cancer also increases the relative risk of endometrial cancer six- to sevenfold, with the risk being most pronounced after 2 years of use.7 Tamoxifen inhibits the action of estradiol by competitively binding to the estrogen receptor, but it inherently also has a weak estrogenic effect. In the NSABP B-14 study, the use of tamoxifen was associated with a rate of 1.6 cases of endometrial cancer in 1,000 women as compared to 0.2 cases per 1,000 women in the placebo group. The relative risk for the development of endometrial cancer increases with prolonged use: the relative risk is 2.0 [95% confidence interval (CI) 1.2–3.2) with 2 to 5 years of use and 6.9 (95% CI, 2.4–19.4) for 5 years or more of use as compared to nonusers. Although the vast majority of uterine cancers found in association with tamoxifen use are low-grade endometrial carcinomas, the long-term use of tamoxifen has been associated with the development of poor prognostic subtypes such as carcinosarcomas.8 Although the majority of uterine cancer cases develop in an environment of estrogen stimulation, some cases develop in the absence of hyperplasia or significant risk factors such as obesity. These endometrial cancers are often found to be of higher grade and may contain poorer prognostic histologic subtypes than their estrogen-related counterparts. Endometrial cancer is infrequently associated with a genetic component; however, members of families with the Lynch II syndrome or hereditary nonpolyposis cancer syndromes, where there are mutations in the DNA mismatch repair genes hMSH2 and hMLH1, have a lifetime risk of 25% to 50%9 of developing endometrial cancer in addition to colon, breast, and ovarian cancer. Finally, pelvic radiation has also been associated with the development of certain poor prognostic cancers such as sarcomas.

uterine malignancies

Diagnosis and Screening The diagnosis of uterine cancer is most frequently established through an office endometrial biopsy, usually instituted as a result of postmenopausal vaginal bleeding. In the absence of bleeding, endometrial cancer occasionally presents with abdominal pain as a result of an obstructed, blood-filled uterus, or, rarely, with abnormal endometrial cells on routine Pap smear screening. When atypical endometrial cells are seen on a Pap smear, the risk that an endometrial adenocarcinoma will be found is approximately 20%. This risk increases to approximately 41% in women who are at least 60 years old. Grossly normal endometrial cells in a Pap smear of a postmenopausal woman should also raise suspicion for malignancy. Approximately 10% of postmenopausal women less than 60 years old and up to 20% of those who are older with endometrial cells on Pap smear have an underlying adenocarcinoma, the majority of which are grade 1 or 2 endometrioid adenocarcinomas.10 An office endometrial biopsy will diagnose endometrial cancer with certainty in nearly 95% of cases. With small tissue samples it is sometimes difficult to distinguish complex hyperplasia from adenocarcinoma. In this case, a dilatation and curettage (D&C) may be necessary. In fact, in women with complex hyperplasia with atypia found on biopsy, up to 43% of patients in a prospective Gynecologic Oncology Group study correlating findings on biopsy with final hysterectomy diagnosis were found to have endometrial carcinoma.11 Once a uterine cancer is found, a careful pelvic examination is performed to determine if there is clinically apparent extension of the tumor beyond the confines of the uterus. In more than 75% of patients there will be no clinical evidence of extrauterine disease, and preoperative studies would then include a chest X-ray and routine blood tests. In patients with evidence of extrauterine spread or in patients with known aggressive histologic subtypes of tumor (see following), a computed tomography (CT) scan or magnetic resonance imaging (MRI) may delineate other areas of disease extension. For the general population, there is no benefit to routine screening (transvaginal ultrasound and/or endometrial sampling) for endometrial cancer in asymptomatic women, even those on hormone replacement therapy.12 Screening for women who have an increased risk for the development of endometrial cancer, such as patients on tamoxifen, has been studied extensively using a variety of techniques including transvaginal ultrasound (TVUS), sonohysterography, and hysteroscopy. The results of key prospective studies including studies of breast cancer patients on tamoxifen and controls not on tamoxifen are shown in Table 53.1. The majority of patients with abnormalities on ultrasound have benign disease in the form of atrophy, polyps, or simple hyperplasia. Tamoxifen has also been shown to cause stromal condensation that may be misinterpreted as a thickened endometrial lining on ultrasound. It is not cost-effective to screen asymptomatic breast cancer patients on tamoxifen. Most patients with significant abnormalities will manifest their disease with signs of vaginal bleeding. Only patients who experience vaginal bleeding on tamoxifen, therefore, should be further evaluated by endometrial tissue sampling. Screening even in patients with higher risk of development of endometrial cancer, such as members of hereditary nonpolyposis colon cancer syndrome (HNPCC) families, has been shown to be of

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limited value. Forty-one women in an HNPCC cohort, the majority of whom were postmenopausal, underwent annual TVUS exams with a median follow-up of 5 years. A total of 179 TVUSs led to 17 endometrial biopsies in which 3 patients with complex hyperplasia and 1 patient with endometrial cancers were identified.13

Pathology of Neoplasia of the Uterine Corpus: Carcinomas Uterine lesions can be broadly divided into lesions that take their origin from the epithelium, from the stroma (whether endometrial stroma or myometrial smooth muscle), or mixed tumors containing both epithelial and stromal elements. Mixed tumors may contain a benign epithelial and malignant stromal component (adenosarcoma), the converse (carcinofibroma), or two malignant components (carcinosarcoma).

Endometrioid Adenocarcinoma Most endometrial carcinomas are adenocarcinomas, displaying glandular differentiation mimicking one of the Mullerianderived epithelia: endometrial, tubal, or cervical (Figure 53.1). Endometrioid carcinoma is the most common histology, comprising approximately 60% of endometrial carcinomas. Endometrioid tumors mimic normal endometrial glands to varying degrees; well-differentiated tumors form glands with several layers of cells that retain some of the normal polarity of proliferative endometrium. More poorly differentiated tumors lose the tendency to form glands, taking on a moresolid architecture, with loss of nuclear polarity and increasing cytologic atypia. The endometrioid histology and its subtypes are estrogen related, frequently accompanied by adenomatous hyperplasia, express estrogen and progesterone receptors, and tend to present at a lower stage and grade. Grading is according to the International Federation of Gynecology and Obstetrics (FIGO) system, based on the amount of solid growth pattern (excluding squamous areas): grade I is 5% or less solid, grade II is 6% to 50% solid, and grade III is more than 50% solid. If significant nuclear atypia is present, the grade should be increased by one degree. Diffuse nuclear atypia may indicate serous or clear cell histology.

Serous and Clear Cell Adenocarcinoma In the early 1980s Bokhman14 proposed two clinically and histologically distinct forms of endometrial carcinoma: type I or endometrioid and its variants, and type II, including serous and clear cell histologies. The latter frequently arise in a background of relative atrophy, are not associated with estrogenrelated risk factors, occur in an older population, and are clinically more aggressive lesions. Hendrickson et al.15 presented similar clinicopathologic support for two forms of endometrial carcinoma in their description of papillary serous carcinoma of the endometrium and its delineation from the villoglandular variant of endometrioid carcinoma. Patients with papillary serous carcinoma were on average 5 years older, had more-advanced tumors, more-frequent lymphatic involvement, and a tendency to recur in the upper abdomen. Serous tumors of the endometrium are considered to be highgrade lesions by definition and are not further graded by histology.

1998

1996

161

162

163

164

165

166

167

168

169

Gerber

Vosse

Fong

Strauss

Barakat

Seoud

Love

Timmerman Cecchini

737 (T)

53 (T)

357 (T) 130 (C)

80 (T)

159 (T)

20 or 40 mg/day 20 mg/day

20 mg/day

Not noted

20 mg/day

20 mg/day

Not noted

20–30 mg/day

20 mg/day

TVUS, hysteroscopy TVUS, EMB

TVUS, hysteroscopy if abnormal

TVUS, EMB

EMB on entry

TVUS (138), hysterosonography (133), hysteroscopy (117) TVUS

TVUS, EMB

TVUS

TVUS with CFDI, EMB

Screening method

Abnormal >6 mm

Abnormal >4 mm

Abnormal ≥5 mm (postmenopausal)

Baseline biopsy, TVUS, EMB q 6 months

All

Abnormal ≥10 mm or bleeding

All

Abnormal ≥8 mm

Abnormal ≥10 mm

Normal 50% MI, grade 2 any MI, grade 3 < 50% MI) Pathologic stage IB, IC, occult II

Comments

Chronic toxicities: pelvic RT (1.8%) versus. no pelvic RT (0.8%) P < 0.001 (pelvic recurrence); P = 0.31 (survival)

P = 0.007 (recurrence); P = 0.56 (survival)

TAH-BSO, total abdominal hysterectomy and bilateral salpingo-oophorectomy; VB, vaginal brachytherapy; RT, radiation therapy; MI, myometrial invasion. a

Deep myometrial invasion patients only.

invasion and more than 1–3 myometrial invasion, (2) at least 50 years of age with any two of the above factors, or (3) at least 70 years of age with any one of the above factors. Overall, irradiated patients had a better 4-year overall survival (92% versus 86%); however, this difference failed to reach significance (P = 0.56). Significantly higher rates of hematologic, gastrointestinal, genitourinary, and cutaneous toxicities were seen in the irradiated group; however, acute and chronic toxicities were combined in the analysis. Creutzberg and coworkers reported the results of the PORTEC trial.51 All patients underwent primary surgery without nodal sampling. Eligible women had grade 1 tumors with more than 50% myometrial invasion, grade 2 tumors, or grade 3 tumors with less than 50% invasion. Seven hundred fifteen women were randomized to receive either pelvic RT or no further therapy. At a median follow-up of 52 months, irradiated patients had a superior 5-year pelvic control (96% versus 86%; P less than 0.001). However, no difference was noted in overall survival (81% RT group, 85% control group). As in the GOG trial, treatment sequelae were more common in irradiated patients (25% versus 6%; P less than 0.001). Although these trials consistently demonstrate that RT reduces the risk of pelvic failure in patients with adverse pathologic features, it is unclear whether survival is improved. This is far from being an academic issue, for the lack of a survival benefit has led some to withhold RT. However, none of these trials is well suited to answer this question. First, their follow-up is limited. Longer observational times are needed to assess outcomes of patients who relapse following surgery. Second, only two include a no-RT control arm, for all women in the Norwegian trial received brachytherapy. Finally, the GOG included many low-risk patients (58% IB, 82% grades 1–2), whereas PORTEC excluded high-risk women (stage IC grade 3, stage II). The former thus included women the least likely to benefit whereas the latter excluded those the most likely to benefit. Although the GOG analyzed “high”-risk patients separately, the small number of such patients significantly limited the power of the analysis. The optimal approach in early-stage patients who do receive postoperative RT is unclear. It is noteworthy that

most pelvic recurrences in the GOG surgery-alone arm were in the vagina.50 Such a failure pattern suggests that, at least in surgically staged patients, vaginal brachytherapy may be as efficacious as pelvic RT. The more-favorable toxicity profile of vaginal brachytherapy is certainly appealing. The ongoing PORTEC-2 study randomizes between external-beam radiotherapy and vaginal brachytherapy. The decision whether to irradiate an individual patient rests on a careful assessment of the benefits and risk of treating (and of not treating). The likelihood of cure and toxicity following adjuvant RT needs to be weighed against the likelihood of salvage and toxicity if treatment is withheld. If administered, the approach that maximizes tumor control while minimizing toxicity should be selected. The least aggressive approach should always be used if outcome is not compromised, for example, vaginal brachytherapy instead of pelvic RT in surgically staged patients. It is difficult to give clear guidelines regarding the use of adjuvant RT in early-stage endometrial cancer, given the lack of consensus between investigators. In general, most investigators do not administer adjuvant RT in women with stage IA grade 1–2 or stage IB grade 1 disease. Stage IA grade 3 patients usually receive either vaginal brachytherapy or pelvic RT. Patients with stage IB grade 2 tumors undergo pelvic RT or vaginal brachytherapy. Given the excellent pelvic control and low toxicity associated with brachytherapy alone, it is the preferred approach, particularly in surgically staged patients. Women with stage IB grade 3 tumors typically undergo both pelvic RT and brachytherapy. However, pelvic RT alone is associated with excellent control rates and less toxicity.52 In surgically staged patients, brachytherapy alone appears to results in equally favorable outcomes with low rates of toxicity.53 At most centers, patients with stage IC tumors receive pelvic RT. At others, they undergo both pelvic RT and vaginal brachytherapy. However, this practice should be discouraged. In a review of 541 stage I patients with deep myometrial invasion from 12 published studies, Weiss et al. noted vaginal recurrences in 1.04% of patients undergoing pelvic RT alone versus 0.97% of patients receiving pelvic RT and vaginal brachytherapy.54 Moreover, toxicity is more common with

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the combined approach.52 In surgically staged patients, brachytherapy alone results in an excellent pelvic control rate with a low risk of sequelae.53 Interest has emerged recently in whether surgically staged patients with stage IC disease can be observed without adjuvant radiation. One study comparing two cohorts of patients with stage IC (all grades) disease with and without RT demonstrated a 6% chance of recurrence in the RT cohort and 12% in the observation cohort but with similar 5-year overall survivals in both groups (92% versus 90%, respectively; P = 0.717). Five-year diseasefree survival was improved only in the grade 1 tumor group receiving RT (100% versus 80%; P = 0.036). However, studies such as these have been retrospective in nature with observation groups chosen by physician preference.55 Patients with stage II disease typically receive both pelvic RT and brachytherapy. However, stage IIA tumors can be treated with pelvic RT alone or, if surgically staged, vaginal brachytherapy.56 Patients with stage IIB disease should receive both pelvic RT and vaginal brachytherapy.

Definitive Radiotherapy Although most endometrial cancer patients are treated with surgery, a subset of patients with multiple medical comorbidities and/or advanced age are considered medically inoperable. Such patients are often treated with RT, with curative intent. In addition, patients with locally advanced disease may undergo RT alone. The most favorable outcomes following RT alone are seen in clinical stage I patients, with 5-year survival rates ranging from 48% to 66%.57,58 After correcting for intercurrent deaths, 5-year cause-specific survivals in these women range from 72% to 87%, with survivals in many series exceeding 80%. Less-favorable outcomes have been reported in clinical stage II and III patients.57 Pelvic/uterine control rates are high in most patients treated with definitive RT, particularly in those with stage I disease (more than 80%).59

Systemic Therapy There are currently no data supporting the addition of systemic therapy to adjuvant RT in early-stage endometrial cancer. Older randomized trials of adjuvant progestins showed no benefit.60 The highest risk group are those with high-grade, deep myometrial invasion and no lymph node

53

sampling. A recent registration trial from the PORTEC group followed 99 women with stage IC grade 3 tumors who did not undergo pelvic/paraaortic node dissection. All received postoperative pelvic radiotherapy. There were 13 vaginal/ pelvic relapses and 31 distant relapses, with 30 deaths due to endometrial cancer.36 The Radiation Therapy Oncology Group (RTOG) recently completed a Phase II trial evaluating chemoradiotherapy in high-risk patients (grade 2–3 tumors with more than 50% invasion, cervical stromal invasion, or pelvic-only extrauterine disease).61 All patients received pelvic RT with cisplatin (50 mg/m2, days 1 and 28), vaginal brachytherapy, and then four cycles of cisplatin (50 mg/m2) and paclitaxel (175 mg/m2). Although the regimen was thought to be feasible, severe (grade 3–4) acute and chronic toxicities were noted in 29% and 18% of patients, respectively. At 24 months, the pelvic recurrence, distant recurrence, disease-free survival, and overall survival of the entire group were 2%, 17%, 83%, and 90%, respectively. A recent randomized trial launched by the RTOG using this cisplatin/paclitaxel chemotherapy in stage I/II disease failed to accrue. Patients with high-risk tumors who have lymph node staging performed, and are known to be node negative, have a lower risk of recurrence than those in whom lymph node assessment is not performed, and it is not likely that adequately powered randomized trials in this subgroup will be feasible. Patients with stage I/II serous/clear cell tumors do merit consideration for adjuvant chemotherapy, as discussed next. In the future, molecular markers may aid in the selection of patients for adjuvant chemotherapy trials.

Therapy for Stage III and “Optimally Debulked” Stage IV Disease Radiation Therapy Adjuvant RT has been used in the postoperative treatment of stage III–IV endometrial cancer patients for many years. Patients with disease limited to the pelvis received pelvic RT with and without vaginal brachytherapy, analogous to stage I–II disease. Those with more-extensive disease were treated with more comprehensive fields, such as extended-field and whole abdominal RT. Table 53.7 summarizes representative recent adjuvant RT series in stage III–IV disease.62–68 Unsurprisingly, outcomes

TABLE 53.7. Surgery and postoperative radiotherapy: stage III–IV endometrial carcinoma (series after 1997). Reference

Year

N

Stage

Site(s)

Radiation therapy

Onda Connell Nelson Nicklin

62 63 64 65

1997 1999 1999 2000

30 12 17 14

IIIC IIIA IIIC IIIB

Pelvic/PA nodes Adnexa only Pelvic nodes Vagina

P/E P ± VB P/WA ± VB P ± VB

84% 70.9% (DFS) 72% 13%

Smith Ashman Mundt

66 67 68

2000 2001 2001

22 15 30

III-IV IIIA IIIC

Various Serosa Pelvic/PA nodes

WA ± VB P ± VB P/E/W ± VB

89% (3-year) 41.5% (DFS) 55.8% (DFS)

Author

Five-year survival

Comments

Includes some nonirradiated patients

DFS, disease-free survival; PA, paraaortic; P, pelvic RT; E, extended-field RT; WA, whole abdominal RT; VB, vaginal brachytherapy.

uterine malignancies

vary widely, with the best results seen in stage IIIA disease, particularly in patients with isolated adnexal or peritoneal fluid involvement. In contrast, less-favorable outcomes are seen in stage III–IV patients with involvement of multiple extrauterine sites and residual upper abdominal disease. Considerable interest formerly existed for intraperitoneal 32 P in patients with isolated involvement of the peritoneal cytology. Today, interest has waned in light of reports questioning the prognostic significance of positive cytology in the absence of other adverse features.69 Moreover, significant gastrointestinal toxicities may occur in patients receiving both 32 P and external-beam RT. In the past, stage IIIA patients with isolated adnexal involvement received aggressive therapy, including whole abdominal RT. However, pelvic RT is most likely sufficient. Similarly, recent data have called into questions the role of whole abdominal RT in stage IIIA patients with isolated serosal involvement.67 Stage IIIB disease is rare. These patients are usually clinically staged and undergo preoperative (or definitive) irradiation. Limited data are available to guide therapeutic decisions.65 Adjuvant irradiation in stage IIIC disease has received considerable attention. Numerous authors have reported long-term cures in women with positive paraaortic nodes following extended-field RT, with 5-year survivals ranging from 36% to 84%.62,68 Patients with pelvic nodal involvement alone represent a favorable group. Nelson and coworkers treated 17 stage IIIC patients with positive pelvic (and negative paraortic) nodes with pelvic (n = 13) or whole abdominal (n = 4) RT. The 5-year disease-free and overall survivals of the entire group were 81% and 72%, respectively.64 Patients with involvement of multiple extrauterine sites pose a therapeutic challenge. In a review of stage III patients, Greven et al. noted abdominal failures in 10% and 25% of women with involvement of one versus three or more extrauterine sites (P = 0.03), providing a rationale for whole abdominal RT in the latter group.70 Promising results have been reported using whole abdominal RT in these as well as in stage IV patients. A GOG phase II trial (GOG 94) of whole abdominal RT included 77 optimally debulked stage III–IV patients. The 3-year progression-free and overall survival of this group was 35% and 31%, respectively.71 No prospective Phase III trial has been performed comparing surgery versus surgery plus postoperative RT in any subgroup of stage III–IV disease. Thus, the benefit of any form of adjuvant RT in these patients remains unclear. Today, interest is shifting increasingly away from postoperative RT toward systemic chemotherapy. Recently, the GOG completed a randomized trial (GOG 122) comparing adjuvant whole abdominal RT versus chemotherapy (doxorubicin/cisplatin) in optimally (less than 2 cm residual disease) debulked stage III/IV patients. This trial has not yet been published in full; at a median follow-up of 52 months, chemotherapy patients had a superior 2-year disease-free (59% versus 46%) and overall (70% versus 59%) survival. Recurrences were frequent, predominantly in the pelvis and abdomen, in both groups.72 A concern was the high rate of vaginal cuff recurrences in the RT group because vaginal brachytherapy was not routinely delivered. Little interest today remains for whole abdominal RT alone except at select centers.66 However, whole abdominal RT is currently being evaluated combined with either con-

939

comitant (GOG 9907) or sequential (GOG 9908) chemotherapy. An earlier phase I trial (GOG 9001) demonstrated the feasibility of concomitant chemoradiotherapy in this setting.73 Given the heterogeneity of stage III–IV disease, it is unlikely that a single approach is appropriate in all patients. Unfortunately, the limited numbers of locally advanced patients preclude the ability to define the optimal approach in every subgroup.

Systemic Therapy As discussed above, the only randomized trial evaluating chemotherapy in stage III disease is GOG 122, which compared whole abdominal radiotherapy to cisplatin/doxorubicin chemotherapy. About 73% of the patients had stage III disease. Survival benefit with chemotherapy was seen for both the stage III patients [hazard ratio (HR) 0.67, 0.47–0.95] and the stage IV patients (HR 0.64, 0.42–0.99). A small number (about 15%) of these “optimally debulked” stage IV patients appear to be disease free at 5 years. Fifty percent to 60% of stage III patients were disease free at 5 years.72 Although select stage III patients may benefit from RT alone, current interest focuses on combined chemoradiotherapy approaches. The addition of radiotherapy to chemotherapy is supported by the high rate of locoregional failure both in GOG 122 and in retrospective series of patients treated with chemotherapy alone.74 A subsequent GOG stage III trial, GOG 184, prescribed “involved field” (pelvic ± para-aortic ± intravaginal) radiotherapy to all patients; this was followed by either cisplatin/doxorubicin or paclitaxel/doxorubicin/ cisplatin chemotherapy. Results of this trial are not yet available. Growth factor (granulocyte colony-stimulating factor, G-CSF) is required for most patients when pelvic radiotherapy precedes chemotherapy to maintain reasonable dose intensity. Cisplatin/doxorubicin is the only chemotherapy combination for which any positive randomized trial data exist for use in the adjuvant setting. However, based on preliminary results in metastatic disease and ongoing adjuvant clinical trials, other regimens, such as paclitaxel/doxorubicin/cisplatin or carboplatin/paclitaxel, may be used in the future.75

Advanced/Recurrent Disease With the exception of isolated vaginal recurrences or the occasional solitary, resectable pulmonary nodule, therapy for metastatic or recurrent endometrial carcinoma remains palliative.

Salvage Surgery After radiation therapy, patients with localized central recurrences have been treated surgically with a complete pelvic exenteration for curative intent. Although the complication rate is high, 5-year disease-free survival in this small group of patients was 45%.76

Salvage Radiotherapy Approximately 50% of endometrial cancer patients who relapse following surgery fail in the pelvis, of whom 50%

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53

recur in the vaginal vault. Patients with recurrent disease limited to the pelvis often undergo salvage, particularly those with isolated vaginal recurrences. Numerous investigators have reported the outcome of patients with recurrent endometrial cancer following salvage RT.77–79 Survival rates vary considerably between the published reports, ranging from 18% to 71%. Patients with isolated vaginal recurrences represent a favorable group. Pai and coworkers evaluated the outcome of 20 patients with isolated vaginal involvement treated with salvage RT. The 10-year actuarial local control and cause-specific survival of the entire group were 74% and 71%, respectively.79 In contrast, others have reported poor survivals (24%–33%) in patients with isolated vaginal recurrences.77 Additional favorable prognostic factors include long disease-free intervals, low-grade disease, adenocarcinoma histology, and no prior RT. Local control is achieved in 35% to 92% of patients treated with salvage RT, with most series reporting control rates between 40% and 70%.78 A major determinant of local control is tumor size. Wylie and coworkers reported 5-year local control rates of 80% and 54% in tumors of 2 cm or less and more than 2 cm, respectively (P = 0.02).80 Others have reported similar results.

women with metastatic/recurrent disease found 0.8 mg/m2/day ¥ 5 (versus the FDA-approved dose of 1.5 mg/m2/day ¥ 5 for second-line therapy for ovarian cancer) to be the tolerable dose in women with prior pelvic radiotherapy for endometrial cancer.87 Table 53.8 shows randomized trials of combination therapy. In general, combinations have been shown to produce higher response rates than single-agent therapy and have therefore become standard for healthy patients. Most recently, the three-drug combination of paclitaxel, doxorubicin, and cisplatin showed a survival advantage over the two-drug combination of doxorubicin and cisplatin, but it produced more neurotoxicity88 and required growth factor support. As treatment in the setting of metastatic disease is generally palliative, decisions about choice of regimen should be based on individual needs and wishes of the patient. The median survival from time of entry onto a chemotherapy protocol for measurable recurrent disease is about a year.

Hormonal Therapy

Because of the rarity of these subtypes, many publications represent small retrospective single-institution series that include patients diagnosed over several decades with a conglomerate of stages and treatments. Often uterine papillary serous carcinomas (UPSC) and clear cell carcinomas (CCC) are analyzed together.

Endometrial cancers frequently express both estrogen (ER) and progesterone (PR) receptors, and high levels of PR expression have been shown to correlate inversely with stage and grade, as well as being an independently favorable prognostic indicator in some series of early-stage disease.81 About 20% of unselected patients with metastatic endometrial carcinoma will respond to therapy with progestins. Other hormonal agents may also have some activity. Factors that have been found to predict for response to progestins and, to a limited extent, to other hormonal therapies include well-differentiated tumors, a long interval between diagnosis and tumor recurrence, and high levels of estrogen receptors (ER) and progesterone receptors (PR).82 However, these criteria are imperfect; for example, high-grade tumors sometimes respond to hormonal therapy. Attempts have been made to standardize definitions of ER and PR positivity so that endometrial cancer patients could be selected for hormonal therapy in a manner similar to breast cancer patients, but this has not occurred. Concern exists over the fact that some patients defined as “receptor negative” by various cutoff criteria nonetheless respond to hormones, that there can be heterogeneity between the hormone receptor status of the primary tumor and the metastatic sites, and that various metastatic sites can be discordant.83,84 Moreover, PR-specific antibodies may fail to detect PRB in formalinfixed, wax-embedded tissue despite their ability to do so by immunoblot analysis,85 and PRB may be important in response to hormonal therapy.86

Cytotoxic Chemotherapy Taxanes, anthracyclines, and platinum agents have shown the most activity as single agents to date. It should be kept in mind that dose intensity in some single-agent trials is limited by the older age and prior pelvic radiotherapy of many patients. For example, the Eastern Cooperative Oncology Group (ECOG) trial of topotecan in chemotherapy-naïve

Unfavorable Histology Papillary Serous/Clear Cell

Surgery Because of the propensity for lymphatic and hematogenous spread, patients with papillary serous and clear cell carcinomas should be surgically staged. This procedure should include a total abdominal hysterectomy, bilateral salpingooophorectomy, cytologic washings, pelvic and paraaortic lymph node assessment, and an omentectomy, as 37% to 50% of patients believed to have cancer confined to the uterus will have extrauterine involvement found upon surgical staging.89,90 Twenty-six of 34 (76%) patients from selected retrospective studies who were surgically staged and shown to have disease confined to the endometrium (stage IA) were observed without adjuvant radiation or chemotherapy. Five of these 26 patients (19%) developed a recurrence in either the pelvis or abdomen. The majority, however, remain disease free.89–92 Other retrospective studies of presumptive stage IA patients have shown higher recurrence rates (30%) but are difficult to interpret given the lack of surgical staging.93

Radiotherapy The role of RT in patients with unfavorable histologies (papillary serous, clear cell) is controversial. Because papillary serous tumors have a propensity to relapse in the upper abdomen, attention has focused primarily on whole abdominal RT. In a study of 26 patients (80% papillary serous) treated with abdominopelvic radiotherapy, Smith et al. noted a 3-year disease-free and overall survival of 87% and 87% in stage I–II and 32% and 61% in stage III–IV patients, respectively.66 A Phase II study of whole abdominal RT conducted by the GOG (GOG 94) enrolled 88 papillary serous/clear cell patients, 49

941

uterine malignancies TABLE 53.8. Randomized chemotherapy trials (first-line). Median OS (months)

Author

Reference

Year

Regimen

N

RR%

Ayoub

176

1988

Aapro

177

2003

20 23 87 90

15% 43% 17% 43%

Thigpen

178

2004

CAFa CAF + MPA/tamoxifenb Doxorubicin 60 mg/m2 q 4 weeks Doxorubicin 60 mg/m2 + Cisplatin 50 mg/m2 q 4 weeks Doxorubicin 60 mg/m2 q 3 weeks (dox 45 mg/m2 if prior RT or age >65) Doxorubicin 60 mg/m2 + cisplatin 50 mg/m2 q 3 weeks (dox 45 mg/m2 if prior RT or age >65) Doxorubicin 60 mg/m2 q 3 weeks Doxorubicin 60 mg/m2 + cyclophosphamide 500 mg/m2 q 3 weeks (25% dose reduction if prior RT or age >65) Doxorubicin 60 mg/m2 + cisplatin 60 mg/m2 q 3 weeks (dox 45 mg/m2 if prior RT or age >65) Doxorubicin 60 mg/m2 (6 AM) + cisplatin 60 mg/m2 (6 PM) q 3 weeks (dox 45 mg/m2 if prior RT or age >65) Doxorubicin 60 mg/m2 + cisplatin 50 mg/m2 q 3 weeks (dox 45 mg/m2 + cis 40 mg/m2 if prior RT or age >65) Doxorubicin 50 mg/m2 + Paclitaxel 150 mg/m2/24 h + G-CSF (dox 40 mg/m2 + paclitaxel 120 mg/m2 if prior RT or age >65) Doxorubicin 60 mg/m2 + cisplatin 50 mg/m2 q 3 weeks (Dox 45 mg/m2 if prior RT or age >65) Dox 45 mg/m2 + cisplatin 50 mg/m2 + paclitaxel 160 mg/m2 + G-CSF Doxorubicin 60 mg/m2 + cisplatin 50 mg/m2 Paclitaxel 175 mg/m2 + carboplatin AUC 5

122

25%

9.2

101

42%

9.0

132 144

22% 30%

6.7 7.3

No significant difference in unadjusted RR or OS

169

46%

11.2

No difference between standard and “circadiantimed” chemotherapy

173

49%

13.2

157

40%

12.6

160

43%

13.6

132

34%

12.3

134

57%

15.3

29

28%

—

34

35%

—

Thigpen

179

1994

Gallion

180

2003

Fleming

Fleming

Weber

181

88

75

2004

2004

2003

11 14 7 9

a

CAF = Dox 30 mg/m2 on day 1, plus Ctx 400 mg/m2 on days 1 and 8, plus 5-FU 400 mg/m2 on days 1 and 8, q 4 weeks.

b

MPA/TAM = medroxyprogesterone acetate 200 mg/day ¥ 3 weeks, alternating with tamoxifen 20 mg/day ¥ 3 weeks.

of whom were pathologic stage I/II. The 5-year disease-free survival of stage I–II papillary serous (n = 31) and clear cell (n = 18) patients were 35% and 61%, respectively.71 Some others have also reported less-favorable results with whole abdominal RT.71 No prospective Phase III trial evaluating whole abdominal RT in papillary serous tumors has been conducted. Its benefit thus remains unclear, particularly in pathologic stage I–II patients. In a review of 193 stage I–II patients from nine studies, Mehta et al. noted abdominal failures in 6 of 68 patients (9%) treated with versus 10 of 125 patients (8%) treated without whole abdominal RT. A benefit in pelvic control was seen, however, with the use of pelvic and/or

Comments

OS difference not significant P = 0.06 for OS

P = 0.004 for RR

No difference between arms

Significant difference in RR and OS No initial dose reduction in three-drug arm

Preliminary report

vaginal irradiation (11% irradiated, 73% nonirradiated patients).94 Given the high risk of distant failure, a reasonable approach may be chemotherapy combined with pelvic and/or vaginal RT.95 Fewer data are available evaluating the role of RT in clear cell carcinoma. These tumors are often grouped with papillary serous tumors and treated with whole abdominal RT, even when confined to the uterus.66 However, it remains unclear whether whole abdominal RT is beneficial. Murphy and colleagues reviewed the outcome of 38 clear cell patients treated with primary surgery.96 Pelvic recurrence was seen in 0 of 22 patients treated with versus 8 of 16 (50%) without adjuvant RT (P less than 0.0001). Although no patient

942 received whole abdominal RT, only 1 (2%) failed in the upper abdomen.

Systemic Therapy: Recurrent/Metastatic Disease The worse prognosis associated with USPC and CCC appears to be related to the very high rates of advanced stage at presentation. Once a tumor has spread outside the uterus, there is no evidence that the chemotherapeutic treatment for women with UPSC or CCC should be different from that for women with high-grade endometrioid carcinomas, despite the different molecular pathways involved. UPSC and CCC do not usually express hormone receptors97 and should not generally be treated with hormonal therapies such as progestins. Response rates and overall survival for UPSC did not differ from that for all other histologies in two large randomized trials of patients with advanced or recurrent endometrial cancer using cisplatin, paclitaxel, and doxorubicin (GOG 163 and GOG 177). Clear cell carcinoma is less common than UPSC, and it is difficult to arrive at meaningful conclusions about how well it responds to chemotherapy. Abeler et al. reported that four of six patients treated with platinum-containing chemotherapy showed a response.98 Three of 10 and 3 of 8 patients with clear cell carcinoma treated on GOG 163 and GOG 177, respectively, had a major response.

Adjuvant Systemic Therapy Twenty-one percent of patients on GOG 122 had UPSC and 4% had CCC.72 As discussed earlier, this trial demonstrated an overall superiority for chemotherapy; this was true regardless of histology, and chemotherapy therefore appears to be appropriate therapy for women with stage III and debulked stage IV endometrial cancer of all histologic subtypes, UPSC and CCC included. The particular dilemmas in the systemic treatment of CCC and UPSC arise in the stage I and II patients. First, was the patient adequately staged? What criteria should be used to determine if the patient had an adequate surgical procedure to exclude more-advanced disease? Second, what is the prognosis of a true extensively surgically staged stage I UPSC or CCC patient? Given the rarity of these histologic subtypes, adequately powered randomized trials testing adjuvant treatment strategies are not feasible. Decisions about adjuvant chemotherapy must be made on a best estimate of risk of recurrence in the absence of systemic treatment and the assumption that if chemotherapy can reduce the risk of recurrence in stage III disease, it can also do so in high-risk stage I/II disease. GOG 94 prospectively treated patients with clinical stage I/II UPSC/CCC with whole abdominal radiotherapy.99 A preliminary report noted only a 35% 5-year progression-free survival (PFS) for stage I/II UPSC patients (n = 31) and a 61% PFS for stage I/II CCC patients (n = 18). On the other hand, as already discussed, a number of small single-institutional series using very extensive surgical staging have reported 85% to 100% 5-year survivals using no adjuvant therapy for patients with stage Ia disease.91,100,101 Patients with UPSC who have disease limited to a polyp or the endometrium and who have no further disease found in the hysterectomy specimen or by surgical staging probably have excellent survival and would not benefit from chemotherapy. This is a fairly rare situation. Those who have

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53

stage Ia disease based on extensive surgical staging, with a reasonable number of nodes dissected, the omentum and peritoneum sampled, and washings taken, probably also have survivals of 80% or more and will have limited benefit from adjuvant chemotherapy. Most series suggest that the remainder of stage I patients have a risk of recurrence of at least 20%, and they may benefit from chemotherapy. UPSC and CCC have been suggested to have a higher frequency of HER2 amplification than endometrioid endometrial cancers.102 The GOG reported results of HER2/neu evaluation on patients from GOG 177. A 3+ level of immunohistochemical staining was detected in 46 of 236 (20%) of cases overall; 10 of 38 USPC (26%), and 36/198 for all others (18%).103 One complete response to trastuzumab was reported in a 2003 ASCO abstract.104 However, a GOG trial of singleagent trastuzumab in patients with endometrial cancers staining 2+ or 3+ by immunohistochemical analysis noted no responses in the first stage of accrual.105 That trial was amended to include only patients with HER2/neu gene amplification [i.e., fluorescence in situ hybridization (FISH) positive] patients of any histologic subtype, and accrual is ongoing.

Carcinosarcomas Carcinosarcomas, similary to uterine papillary serous carcinomas, have a high rate (75%) of unsuspected metastatic disease.106 These patients should be surgically staged, if possible, for counseling with regard to prognosis and for recommendations with regard to adjuvant therapy. Survival is directly related to stage of disease. In patients with disease truly confined to the uterus based upon staging, 5-year survival is as high as 74%, in contrast to patients who have known extrauterine disease where survival is only 24% (P = 0.0013).107 However, even in patients left with no gross residual disease, 44% of patients have been shown to develop recurrent disease.108

Radiotherapy Controversy exists regarding the role of RT in carcinosarcoma. Unfortunately, the available outcome data are difficult to interpret because many older reports fail to distinguish between carcinosarcomas and other uterine sarcomas (leiomyosarcoma, endometrial stromal sarcoma) in their analyses. Of note, most,109 but not all, studies that group the various sarcoma histologies together report improved pelvic control with adjuvant RT. Moreover, most 109–111 but not all112 note improved survival as well. Hornback and coworkers evaluated the impact of pelvic RT in uterine sarcoma patients enrolled on GOG-20 (a randomized trial of adjuvant doxorubicin). In this study, pelvic RT was optional. Of 109 stage I–II patients (87% carcinosarcoma), the pelvis was the first site of failure in 10% and 23% of irradiated and nonirradiated patients, respectively.113 In a separate GOG study, irradiated clinical stage I–II patients had a lower rate of first relapse in the pelvis (17%) than nonirradiated patients (24%).114 Most studies focusing solely on carcinosarcoma have reported better pelvic control rates in irradiated patients, particularly in stage I–II disease.115–117 Impact on survival has been mixed, with a benefit seen in some but not all reports.

943

uterine malignancies

Based on studies that noted a predominance of failures in the upper abdomen,118 increasing attention has been focused on the use of whole abdominal RT in carcinosarcomas. Currently, the GOG is conducting a randomized trial (GOG 150) of adjuvant whole abdominal RT versus chemotherapy in optimally debulked stage I–IV carcinosarcoma patients. The results of this trial may help define the optimal approach to these patients.

Adjuvant Systemic Therapy The effects of adjuvant chemotherapy have not been well studied. The only randomized trial performed (GOG 20) tested single-agent doxorubicin versus no chemotherapy after surgery, and demonstrated no difference between the arms in recurrence rate, progression-free survival, or overall survival.119 This trial included stage I/II uterine carcinosarcomas, leiomyosarcomas, and sarcomas of other histologies, and the numbers in each histologic subset were too small for definitive analysis. Moreover, as discussed, use of pelvic irradiation was at the discretion of the investigator. Forty-five percent of the patients with carcinosarcoma treated on GOG 20 recurred. The current GOG adjuvant trial (GOG 150) randomizes women with optimally debulked stages I–IV carcinosarcoma to whole abdominal radiotherapy versus combination ifosfamide/cisplatin chemotherapy.

Systemic Therapy in Advanced/Recurrent Disease In advanced or recurrent disease, the number of agents studied is limited, and older trials tended to study carcinosarcomas along with leiomyosarcomas and other sarcomas. Paclitaxel, ifosfamide, and cisplatin clearly produce response rates above 10%, with the highest response rates documented for ifosfamide, although these have also been the most doseintense and toxic regimens. No randomized trials (Table 53.9) have proven any survival benefit for chemotherapy with

advanced/recurrent disease, and median survival for this group of patients remains less than 1 year.

Uterine Mesenchymal Tumors (Sarcomas) Uterine sarcomas, in general, are rare. However, leiomyosarcomas are responsible for a disproportionate number of deaths from uterine malignancy (40%–50% of stage I–II cancers will recur). As is the case for other soft tissue sarcomas, grade is prognostically very important.120–122 The overall incidence of uterine malignancies including endometrial carcinomas is lower in black patients (15.31 per 100,000 woman-years; 95% CI, 14.61–16.04) than in white non-Hispanic patients (23.43 per 100,000 woman-years; 95% CI, 23.06–23.81). However, based on SEER (Surveillance, Epidemiology, and End Results) data from 1992–1998, blacks had significantly higher incidence rates of the poorer prognostic histologic types such as carcinosarcoma and sarcoma as compared to white nonHispanics. The comparison rate ratios for blacks were 2.33 (95% CI, 1.99–2.72) for carcinosarcomas and 1.56 (95% CI, 1.31–1.86) for sarcomas. Mortality attributable to these rare aggressive tumor types accounted for 53% of mortality among black patients as compared to 36% among white patients.123 Although there is no specific staging system for uterine sarcomas, some clinicians utilize the surgical staging system for endometrial corpus cancers to classify sarcomas.

Pathology Uterine mesenchymal neoplasms can be broadly classified into those associated with endometrial stroma and those arising from the smooth muscle of the myometrium.

Endometrial Stromal Tumors Endometrial stromal tumors are characterized by an appearance similar to the stroma of proliferative endometrium, being

TABLE 53.9. Randomized chemotherapy trials in advanced uterine carcinosarcoma. Author

Sutton

Reference

182

Year

2000

Prior chemotherapy

N

Muss

183

1985

N

Omura

184

1983

Mixed

N evaluable

Regimen 2

Ifosfamide 1.5 g/m d ¥ 5 d q 21 d vs. Ifosfamide 1.5 g/m2 d ¥ 4–5 d + CDDP 20 mg/m2/d ¥ 4–5 d q 21 d Ifosfamide 1.2 g/m2 if prior RT both arms Doxorubicin 60 mg/m2 q 21 days vs. doxorubicin 60 mg/m2 + cyclophosphamide 500 mg/m2 q 21 days Doxorubicin dose 45 mg/m2 in patients with prior RT, age >65 years, or PS 2–3, both arms Doxorubicin 60 mg/m2 q 21 days vs. doxorubicin 60 mg/m2 + DTIC 250 mg/m2/day ¥ 5 q 21 days Chemotherapy doses reduced 25% for prior RT, both arms

DTIC, dacarbazine; PS, performance status; CNS, central nervous system; gr, grade.

RR% (n)

Median OS

102

36% 7.6 (37) months

92

54% 9.4 (50) months 25% — (5)

20

41

10% (4)

—

31

23% (7)

—

Comments

P = 0.07 for survival, 17% gr 3–4 CNS toxicity Doses reduced to 4 days in combination arm because of toxicity; 6 deaths before dose reduction Part of a trial including uterine leiomyosarcoma Response rates given for patients with measurable disease, both arms combined

Part of a trial including uterine leiomyosarcomas

944 composed of short blue spindle cells and small arterioles. Based on the pattern of growth, they are separated into benign stromal nodules, low-grade endometrial stromal sarcoma, and undifferentiated endometrial sarcoma. The latter was formerly classified as high-grade endometrial stromal sarcoma, but as it is histologically, immunophenotypically, and cytogenetically distinct and has a dismal prognosis by comparison, it is best considered as a different entity rather than a less-differentiated example of stromal sarcoma.124 Endometrial stromal nodules are uncommon lesions, usually presenting as an intramural or polypoid well-circumscribed round or oval lesion less than 5 cm in diameter. They are most often discovered as incidental findings on hysterectomy. Microscopically they have an expansile, noninfiltrative growth pattern and are composed of bland stromal cells with variable mitotic activity. Stromal nodules are benign, and tend not to recur even if treated with simple excision.125 Low-grade endometrial stromal sarcoma may appear circumscribed or infiltrative on gross examination, but classically presents with a worm-ridden appearance to the myometrium. Areas of cystic degeneration and necrosis may be present. Microscopically, most cases have broad tongues of infiltrating tumor peculating through the myometrium and involving lymphatic spaces. Cells are uniform, nuclear atypia is minimal, and mitotic activity is usually low, although the latter is no longer a diagnostic criterion.126 Stromal sarcoma typically expresses estrogen and progesterone receptors, CD10, and smooth muscle actin, but lacks expression of desmin.127,128 Most endometrial stromal sarcomas have at (7 : 17) translocation involving JAZF1 and JJAZ1.129 Survival data from many studies are biased by the inclusion of cases of undifferentiated endometrial sarcoma; however, nearly half of stromal sarcoma patients will experience recurrence, often more than 5 years from initial diagnosis. Hormonal therapy has been effective in treating metastatic disease.130 Undifferentiated endometrial sarcoma, formerly known as high-grade endometrial stromal sarcoma, occurs in an older population than low-grade endometrial stromal sarcoma and has a dismal prognosis: most patients present with advanced stage and the median survival is less than 2 years. The tumor is composed of spindle or polygonal pleomorphic mesenchymal cells that bear little resemblance to endometrial stromal cells. Mitotic activity is typically brisk and necrosis is often present. Undifferentiated endometrial sarcoma rarely expresses estrogen or progesterone receptors, lack CD10 expression, and has a complex karyotype.131 Because of the marked difference in behavior, histology, and immunoprofile, it is recommended that the term high-grade endometrial stromal sarcoma be replaced by undifferentiated endometrial sarcoma.132

Smooth Muscle Tumors Leiomyomas are the most common uterine neoplasm, present in as many as 25% of women over 30. Grossly they are usually well circumscribed, white, and firm to rubbery, although when degenerative changes are present they may range from deep red to yellow and have a soft consistency. Microscopically, they are composed of fascicles of smooth muscle cells with bland cytology. Mitotic activity is usually low, although in reproductive years an otherwise typical leiomyoma may have up to 20 mitoses per 10 high-power fields (mitotically active

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53

leiomyoma) and still be benign. Although areas of hyalinization, red or carneous degeneration, or even necrosis may be present, they are different form the geographic coagulative tumor necrosis associated with leiomyosarcoma. Variants of leiomyoma include symplastic leiomyoma, with markedly atypical bizarre cells; epithelioid leiomyoma, with polygonal cells rather than spindled cells; and cellular leiomyoma, composed of cells with scant cytoplasm. Leiomyomas that have undergone treatment with gonadotropin-releasing hormone analogues may display coagulative necrosis or apoptosis.133 Leiomyosarcoma is the most common uterine sarcoma, with an incidence of approximately 1 per 105 population. Grossly the tumors are more likely to be poorly circumscribed, soft, fleshy, and necrotic or hemorrhagic. Microscopically, compared to leiomyomas, they are more cellular, more mitotically active, and frequently have coagulative necrosis. The histologic spectrum ranges from lesions that have recognizable smooth muscle differentiation to high-grade tumors that bear little resemblance to their cell of origin. The separation of lowgrade leiomyosarcoma from leiomyoma is problematic. Taylor and Norris in 1966,134 reporting on 63 highly cellular smooth muscle tumors, found that cases with fewer than 10 mitoses per 10 high-power fields (hpf) did not metastasize. They also noted that 74% of sarcomas had necrosis, as compared to 12% of leiomyomas. Kempson and Bari135 studied 29 cases of problematic smooth muscle tumors and found that 6 of 7 cases with 5 to 9 mitoses/hpf recurred when associated with atypia. The malignant criteria of greater than 10 mitoses/10 hpf without atypia and greater than 5 mitoses/hpf with atypia were used for decades based on these studies. In 1988 Perrone and Dehner136 found that mitotic index did not predict poor prognosis in cases that otherwise lacked atypia. They also noted that infiltrative margins and coagulative necrosis were seen in tumors with malignant behavior. Bell et al.137 reported their experience with 213 “problematic” smooth muscle tumors in 1994, finding in a multivariant analysis that coagulative tumor necrosis, atypia, and mitotic activity were the important predictors of malignant behavior. When some but not all of these criteria are present, the diagnosis of atypical leiomyoma is made, which carries a small risk of malignant behavior. This expansion of malignant criteria to include coagulative necrosis is especially important in two circumstances: women with mitotically active smooth muscle tumors that lack atypia and necrosis, and tumors with necrosis and atypia that lack significant mitotic activity. The former, mitotically active leiomyomas, occur in women in the reproductive years, particularly under the influence of progesterone, and are benign even if mitotic activity is greater than 10 mitoses/10 hpf. The latter are sarcomas or atypical leiomyomas with some risk of recurrence, even if the mitotic index is low. Although a clear sequence of neoplastic progression from precursor lesion to fully malignant tumor is seen in other organs, such as colonic adenocarcinoma, there are only anecdotal examples of leiomyosarcoma developing from preexisting leiomyomas. Indeed, the presence of multiple leiomyomas does not increase the risk of sarcoma, and the tumors have different cytogenetic and molecular characteristics.138

Surgery The standard surgical procedure for patients with sarcomas of the uterus is a total abdominal hysterectomy and bilateral

uterine malignancies

salpingo-oophorectomy. Often, the diagnosis will be made incidentally in a patient believed to have a benign leiomyoma. The incidence of ovarian metastasis is relatively low (5%), even in patients with high-grade sarcomas. In patients with low-grade sarcomas, there were no patients with ovarian metastases in a cohort of 108 patients. The role of lymphadenectomy and surgical staging is not of proven benefit in leiomyosarcomas of the uterus. The only patients (n = 3 of 37) with positive nodes (8%) in one study from Memorial Sloan Kettering had grossly enlarged lymph nodes. No patients with disease confined to the uterus or cervix had positive nodes.139 Therefore, there is no documented benefit to taking a patient back to surgery for extended surgical staging. A young patient who underwent a myomectomy only, however, may benefit from undergoing a completion hysterectomy if high-grade leiomyosarcoma was found as there may be residual sarcoma remaining in the uterus.140

Radiation Therapy Limited data are available regarding the role of RT in uterine leiomyosarcomas and endometrial stromal sarcomas. Although some investigators have reported a benefit to adjuvant RT in endometrial stromal sarcoma,118 others have not.141 Weitman et al. evaluated 15 endometrial stromal sarcoma patients (80% stage I–II) treated with surgery and adjuvant RT. The 5-year pelvic control and overall survivals were 93% and 79%, respectively.142 Results have been mixed in leiomyosarcomas, with a benefit seen in terms of pelvic control143,144 and survival144 in some reports. Others have noted no benefit to adjuvant irradiation.121

Systemic Therapy Uterine Leiomyosarcomas: Adjuvant Therapy Neither adjuvant chemotherapy nor adjuvant radiotherapy has been proven to produce a survival benefit, but adequately powered randomized trials do not exist. Results for those patients with leiomyosarcoma entered on the one published randomized trial (doxorubicin versus no chemotherapy) suggest a possible modest benefit from adjuvant deoxorubicin.119

Uterine Leiomyosarcomas: Advanced/Recurrent Disease As is the case for other leiomyosarcomas, ifosfamide and doxorubicin have single-agent activity in metastatic disease. The combination of these two agents has been reported to produce a response rate of 29%145 but is toxic, and the median survival of 9.5 months observed is similar to that seen in a variety of single-agent studies. Cisplatin, which has reproducible activity in uterine carcinosarcomas, is not effective in the treatment of leiomyosarcomas. Interestingly, the GOG has recently reported a response rate of 19% to single-agent gemcitabine,146 which has not demonstrated activity against advanced sarcomas or leiomyosarcomas in general.147 A study by Hensley et al.148 used the combination of docetaxel and gemcitabine and reported an overall response rate of 53% with a median overall survival of 17.9 months in a group of patients with leiomyosarcoma (85% had uterine leiomyosar-

945

coma, and half had prior chemotherapy). A confirmatory trial is underway in the GOG.

Low Grade Endometrial Stromal Sarcoma (ESS): Systemic Therapy Although low-grade ESS (previously known as endolymphatic stromal myosis) has a relatively good prognosis, it may recur late. It has been reported that 30% to 50% of tumors localized to the uterus at the time of diagnosis eventually recur.149 Aubry et al. described 16 patients with lung metastases from metastatic low-grade ESS. In that series, the diagnosis of ESS had been made an average of 9.8 years previously.150 Lowgrade ESS frequently expresses ER and PR. It has been suggested that the ovaries should be removed in premenopausal women with low-grade ESS and/or that adjuvant progestins should be given,149 but data to support these recommendations are insufficient. There are, however, multiple case reports documenting responses of low-grade ESS to various hormonal manipulations, including aromatase inhibitors such as aminoglutethimide130 and letrozole,151 progestins such as megestrol acetate,152,153 and, preoperatively, to gonadotropin-releasing hormone (GnRH) agonists such as leuprolide.154 Because the tumor is indolent, resection of metastases is also an option. Among the 16 patients with lung metastases described by Aubry et al.,150 14 were alive and 7 were without evidence of disease at a median follow-up of 4.1 years after diagnosis of lung metastases. The interventions used consisted primarily of resection of lung nodules and hormonal therapy.

Undifferentiated Endometrial Sarcoma Undifferentiated endometrial sarcoma (high grade) is less common than uterine leiomyosarcoma but has a similar prognosis.122,155,156 In recurrent undifferentiated endometrial sarcoma, chemotherapy is generally tried. A prospective trial of ifosfamide in 22 patients with recurrent or disease yielded a response rate of 32%.157 Multiple case reports have documented responses to doxorubicin,158 and a complete response to paclitaxel and carboplatin has also been reported.159

References 1. http://www.cancer.org/downloads/STT/CAFF_ finalPWSecured.pdf. Accessed 4/8/04. 2. Pecorelli S. FIGO annual report on the results of treatment in gynaecological cancer. J Epidemiol Biostat 1998;3:41. 3. Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia. A long-term study of “untreated” hyperplasia in 170 patients. Cancer (Phila) 1985;56:403–412. 4. Grady D, Gebretsadik T, Kerlikowske K, Ernster V, Petitti D. Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol 1995;85:304–313. 5. Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1996;275:370–375. 6. Weiderpass E, Adami HO, Baron JA, et al. Risk of endometrial cancer following estrogen replacement with and without progestins. J Natl Cancer Inst 1999;91:1131–1137. 7. Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin WM. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical

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8.

9.

10.

11.

12.

13.

14. 15.

16.

17.

18.

19.

20.

21.

22.

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145. Sutton G, Blessing JA, Malfetano JH. Ifosfamide and doxorubicin in the treatment of advanced leiomyosarcomas of the uterus: a Gynecologic Oncology Group study. Gynecol Oncol 1996;62: 226–229. 146. Look KY, Sandler A, Blessing JA, Lucci JA III, Rose PG. Phase II trial of gemcitabine as second-line chemotherapy of uterine leiomyosarcoma: a Gynecologic Oncology Group (GOG) Study. Gynecol Oncol 2004;92:644–647. 147. Okuno S, Ryan LM, Edmonson JH, Priebat DA, Blum RH. Phase II trial of gemcitabine in patients with advanced sarcomas (E1797): a trial of the Eastern Cooperative Oncology Group. Cancer (Phila) 2003;97:1969–1973. 148. Hensley ML, Maki R, Venkatraman E, et al. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol 2002;20:2824–2831. 149. Chu MC, Mor G, Lim C, Zheng W, Parkash V, Schwartz PE. Lowgrade endometrial stromal sarcoma: hormonal aspects. Gynecol Oncol 2003;90:170–176. 150. Aubry MC, Myers JL, Colby TV, Leslie KO, Tazelaar HD. Endometrial stromal sarcoma metastatic to the lung: a detailed analysis of 16 patients. Am J Surg Pathol 2002;26:440–449. 151. Maluf FC, Sabbatini P, Schwartz L, Xia J, Aghajanian C. Endometrial stromal sarcoma: objective response to letrozole. Gynecol Oncol 2001;82:384–388. 152. Sabini G, Chumas JC, Mann WJ. Steroid hormone receptors in endometrial stromal sarcomas. A biochemical and immunohistochemical study. Am J Clin Pathol 1992;97:381–386. 153. Wade K, Quinn MA, Hammond I, Williams K, Cauchi M. Uterine sarcoma: steroid receptors and response to hormonal therapy. Gynecol Oncol 1990;39:364–367. 154. Schilder JM, Hurd WW, Roth LM, Sutton GP. Hormonal treatment of an endometrial stromal nodule followed by local excision. Obstet Gynecol 1999;93:805–807. 155. Nordal RR, Thoresen SO. Uterine sarcomas in Norway 1956–1992: incidence, survival and mortality. Eur J Cancer 1997;33:907–911. 156. Brooks SE, Zhan M, Cote T, Baquet CR. Surveillance, Epidemiology, and End Results analysis of 2677 cases of uterine sarcoma 1989–1999. Gynecol Oncol 2004;93:204–208. 157. Sutton G, Blessing JA, Park R, DiSaia PJ, Rosenshein N. Ifosfamide treatment of recurrent or metastatic endometrial stromal sarcomas previously unexposed to chemotherapy: a study of the Gynecologic Oncology Group. Obstet Gynecol 1996;87:747–750. 158. Berchuck A, Rubin SC, Hoskins WJ, Saigo PE, Pierce VK, Lewis JL Jr. Treatment of endometrial stromal tumors. Gynecol Oncol 1990;36:60–65. 159. Szlosarek PW, Lofts FJ, Pettengell R, Carter P, Young M, Harmer C. Effective treatment of a patient with a high-grade endometrial stromal sarcoma with an accelerated regimen of carboplatin and paclitaxel. Anticancer Drugs 2000;11:275–278. 160. Fung MF, Reid A, Faught W, et al. Prospective longitudinal study of ultrasound screening for endometrial abnormalities in women with breast cancer receiving tamoxifen. Gynecol Oncol 2003;91:154–159. 161. Gerber B, Krause A, Muller H, et al. Effects of adjuvant tamoxifen on the endometrium in postmenopausal women with breast cancer: a prospective long-term study using transvaginal ultrasound. J Clin Oncol 2000;18:3464–3470. 162. Vosse M, Renard F, Coibion M, Neven P, Nogaret JM, Hertens D. Endometrial disorders in 406 breast cancer patients on tamoxifen: the case for less intensive monitoring. Eur J Obstet Gynecol Reprod Biol 2002;101:58–63. 163. Fong K, Kung R, Lytwyn A, et al. Endometrial evaluation with transvaginal US and hysterosonography in asymptomatic postmenopausal women with breast cancer receiving tamoxifen. Radiology 2001;220:765–773. 164. Strauss HG, Wolters M, Methfessel G, Buchmann J, Koelbl H. Significance of endovaginal ultrasonography in assessing tamox-

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5 4

Evidence-Based Management of Breast Cancer Lisa A. Newman and Daniel F. Hayes

T

he magnitude of the worldwide breast cancer burden is substantial and is increasing. Known to be a disease of greatest prevalence in heavily industrialized nations, its incidence and mortality rates are rising internationally as the populations of relatively less developed countries adopt the lifestyle and commercialism that characterize Western communities. Breast cancer has therefore been the subject of numerous clinical trials designed to improve our ability to screen for, to treat, and even to prevent the disease. This chapter reviews the highest levels of evidence that have been published for the major categories of interest in the contemporary management of breast cancer: 1. 2. 3. 4. 5.

Screening/early detection Primary surgery Medical/systemic therapy Radiation issues Primary medical management (neoadjuvant chemotherapy) 6. Management of ductal carcinoma in situ (DCIS) 7. Risk reduction/prevention 8. Evaluation and treatment of metastatic disease

Breast Cancer Screening The most commonly-accepted age-specific breast cancer screening recommendations regarding breast selfexamination (BSE), clinical breast examination (CBE), and mammography are as follows: 20–40 years old: monthly BSE (optional); CBE every 1–3 years 40 years old and older: monthly BSE (optional); CBE annually; mammogram annually BSE is generally perceived as a cost-efficient means of promoting breast health awareness, but data to document its efficacy in reducing breast cancer mortality are lacking.1–3 Some clinicians have even criticized this approach because of concerns that it creates excessive cancerphobia in some women, and one meta-analysis revealed that it tended to result in an excess of unnecessary biopsies for benign fibrocystic changes.2 On the other hand, it may represent the only viable alternative for women who do not meet screening eligibility requirements or for whom mammography services are

simply unavailable.4,5 Furthermore, Shen and Zelen6 analyzed data from selected mammography screening trials and found the sensitivity of BSE (39%–59%) to be appreciable. Utilization of annual mammographic screening in women beginning at age 40 is promoted by the majority of medical societies and advocacy organizations, such as the American Cancer Society, the American College of Surgeons, the American Society of Clinical Oncology, and the Susan G. Komen Breast Cancer Foundation. One issue that has generated substantial controversy involves the role of screening mammography in women 40 to 49 years old. In contrast to the annual mammography recommendation espoused by the majority of societies, the American Academy of Family Physicians and the American College of Preventive Medicine recommend that annual surveillance mammography should not begin until age 50. The U.S. Preventive Services Task Force7 has compiled a comprehensive evidence-based analysis of published screening trials and concluded that mammographic surveillance (with or without clinical breast examination) is appropriate at 1- to 2-year intervals for women beginning at age 40, and they also reported that data are inadequate to fully assess the value of BSE. The history of breast imaging dates back to the early 1900s, and it has evolved into the sophisticated technology of contemporary mammographic screening. Between 1963 and 1990, eight different prospective randomized studies were conducted worldwide in an attempt to define the optimal standards for breast cancer surveillance with screening mammography. Breast cancer mortality was the endpoint for all these studies, and participants were randomized to receive either periodic mammographic imaging or “routine” health care. The design of the various studies is shown in Table 54.1,7–14 demonstrating notable differences between them regarding patient populations, screening intervals, and type of mammogram offered. Most of the studies were designed to be population based, and the women in the study arm were “invited” to undergo mammography, but the only trials with 100% uptake on initial screen were the two national programs coordinated in Canada. Uptake in the other six trials averaged approximately 80%. Furthermore, compliance with return for the second screen in the mammography arms ranged from only 54% to 90%, and many studies had significant contamination (13%–25%) of the control arms by patients who received mammography despite their random-

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TABLE 54.1. Phase III studies of screening mammography. No. randomized Trial

Screening period

Mammography screening

No mammography

Age at accrual (years)

1963–1969 1976–1990 1977–1985 1979–1988 1980–1987 1980–1987 1981–1985 1982–1988

30,239 21,088 77,080 28,628 25,214 19,711 40,318 20,724

30,256 21,195 55,985 26,015 25,216 19,694 19,943 28,809

40–64 45–70 40–74 45–64 40–49 50–59 40–64 39–59

HIP7,8 Malmo7,9 Swedish Two-County7,9–11 Edinburgh7,12 CNBSS-17,13 CNBSS-214 Stockholm7,9 Gothenberg7,9

Mammography interval (months)

No. of views

12 18–24 24–33 24 12 12 24–28 18

2 1–2 1 1–2 2 2 1 1–2

HIP, Health Insurance Plan of Greater New York; CNBSS, Canadian National Breast Screening Study.

ization assignment. The “intent-to-treat” statistical design of these studies mandated that all participants were analyzed according to their randomization assignment, regardless of whether the assignment was fulfilled. Nonetheless, a 21% to 26% lower breast cancer mortality rate was seen among the women randomized to receive screening mammography in these studies (Table 54.2). It is likely that the survival benefit associated with mammography is underestimated by these studies as a consequence of the suboptimal compliance and contamination issues. Subset analysis based on age from these trials has revealed that most of the mammography-associated reduction in breast cancer mortality was seen among patients age 50 and older, where the magnitude of protection was 23%. To some extent this is an expected finding: breast cancer incidence is substantially lower for women aged 40 to 49 years, and the relatively greater breast density of younger women can complicate the interpretation of mammographic images. The

Canadian National Breast Screening Study (CNBSS) represented an attempt to specifically address the question of mammography efficacy in younger women. In this study, 50,000 Canadian women aged 40 to 49 years were randomized to annual mammography versus routine health care and, with an average follow-up of 13 years, breast cancer mortality was unaffected by screening (rate ratio, 1.06; 95% confidence interval, 0.80–1.40).13 A parallel study conducted in Canadian women aged 50 to 59 years yielded similar 13-year results (rate ratio, 1.02; 95% confidence interval, 0.78–1.33).14 However, the validity of these results has been questioned because of criticisms regarding trial conduct. A fourfold excess of advanced disease was seen in the screened cohort, leading to allegations of bias in the CNBSS patient selection and randomization process.15,16 Additional screening-related controversy has been generated by investigators Gotzsche and Olsen, from the Cochrane Collaboration. Their interpretations that the methods

TABLE 54.2. Mammography screening trials: outcome and results. Participants 2 cm size) Premenopausal Node-negative (any ER statusf)

Premenopausal ER-positive

9.6

9.5

7

3.6

5

FAC ¥ 6 FAC ¥ 6 + goserelin ¥ 5 years FAC ¥ 6 + goserelin + tamoxifen ¥ 5 years

OA/OS + CTXg CTXg

Goserelin ¥ 2 years CMF ¥ 6 CMF ¥ 6 + goserelin ¥ 1.5 years

CMF ¥ 6 Goserelin ¥ 3 years + tamoxifen ¥ 5 years Oophorectomy + tamoxifen ¥ 5 years Observation

9-year DFS 68%; 9-year OS 76%h

9-year DFS 57%; 9-year OS 70% 9-year DFS 60%; 9-year OS 73%

10-year DFS 48%; 10-year OS 65% 10-year DFS 49%; 10-year OS 68% (no significant differences in DFS or OS)

5-year DFS 58%; 5-year OS 70% (P < 0.05; significant for DFS and OS in favor of adjuvant therapy) DFS significantly superior in favor of CMF for ER-negative tumors (5-year DFS 84% for CMF alone and 88% for CMF + goserelin vs. 73% for goserelin alone) DFS similar for all three arms in ER-positive tumors (5-year DFS 81% for either goserelin or CMF alone; and 86% for CMF + goserelin)

5-year DFS 75%; 5-year OS 78%

5-year DFS 76% 5-year DFS 81% (P = 0.37; significant in favor of endocrine therapy)

Trial closed in 1989 because of poor accrual, with 153 evaluable patients.

Approximately 30% of participants were ER negative; these were evenly distributed between the two trial arms.

f

h

Outcome differences not significantly different, but trends favoring OS in women who did not become amenorrheic with CTX, and favoring tamoxifen in women who did become amenorrheic.

Approximately 24% of participants were ER negative; these were evenly distributed between the two trial arms; the adjuvant CTX delivered included an anthracycline in 77%; OA/OS was via irradiation or LHRH agonists.

g

Reported data on 227 evaluable patients from interim analysis.

Approximately 20% of participants were ER negative; these were evenly distributed between the two trial arms.

e

Surgical oophorectomy, 6 patients; radiotherapeutic oophorectomy, 31 patients; goserelin, 87 patients.

d

c

Pooled results from similar trials conducted by the Cancer Research Campaign; the Breast Cancer Trials Group; the Stockholm Breast Cancer Study Group; the South-East Sweden Breast Cancer Group; and the Gruppo Interdisciplinare Valutazione Interventi in Oncologia (GIVIO); adjuvant chemotherapy use varied by individual protocols and participating centers.

b

a

OA, ovarian ablation; CMF, cyclophosphamide, methotrexate, 5-fluorouracil; ER, estrogen receptor; PR, progesterone receptor; FAC, 5-fluorouracil, doxorubicin, cyclophosphamide; CTX, chemotherapy; DFS, disease-free survival; OS, overall survival; CI, confidence interval.

1,063

709

Love 2002206

CastiglioneGertsch 2003207

1,034

Jakesz 2002205

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TABLE 54.7. Table of selected Phase III trials evaluating adjuvant chemotherapy. Study

Eligibility 210

N

Median follow-up

CALGB 9344

Node-positive

3,121

69 months

NSABP B-28211

Node-positive

3,060

64 months

BCIRG 001212

Node-positive

1,491

55 months

CALGBa 9741213

Node-positive

2,005

36 months

Randomization

AC AC + paclitaxel Significance AC AC + paclitaxel Significance TAC FAC Significance Conventional (q 3 weeks) ACP Dose-dense (q 2 weeks) ACP + G-CSF Significance

DFS

OS

65% 70% P = 0.0023 72% 76% P = 0.008 75% 68% P = 0.001 75% 82% P = 0.010

77% 80% P = 0.0064 85% 85% P = 0.46 87% 81% P = 0.008 90% 92% P = 0.013

CALGB, Cancer and Leukemia Group B; NSABP, National Surgical Adjuvant Breast Project; BCIRG, Breast Cancer International Research Group; TAC, taxol (paclitaxel), adriamycin (doxorubicin), cytoxin (cyclophosphamide); AC, adriamycin (doxorubicin), cytoxin (cyclophosphamide); FAC, fluorouracil, adriamycin (doxorubicin), cytoxin (cyclophosphamide); ACP, adriamycin (doxorubicin), cytoxin (cyclophosphamide), paclitaxel (taxol). a

The CALGB Trial 9741 also evaluated sequential adriamycin ¥ 4 followed by paclitaxel ¥ 4 followed by cytoxin ¥ 4 versus concurrent adriamycin and cytoxin ¥ 4 followed by paclitaxel ¥ 4 and found no significant effect on outcome based on these schedule variations.

Radiation Therapy for Breast Cancer Radiation therapy and surgery are the primary modalities for treatment of locoregional manifestations of breast cancer. Radiation therapy alone can sterilize some breast tumors, but at the expense of excessively toxic doses. The standard rationale is therefore to rely on surgery to control grossly apparent breast lesions and to utilize irradiation to eliminate residual microscopic disease. Results from the Phase III studies of BCT summarized in Table 54.3 demonstrate the success of this approach. Adjuvant breast radiation delivered after surgical lumpectomy will effectively decrease the incidence of in-breast tumor recurrences. Most trials, however, have demonstrated equivalent overall survival rates following lumpectomy regardless of whether radiation was delivered. This finding suggested that breast cancer outcome was largely determined by ability to control progression of micrometastases and that irradiation would make a marginal or negligible contribution to survival. In contrast, the Guy’s Hospital BCT Trials67 used a breast XRT regimen that would be considered inferior to contemporary radiation schedules, and this resulted in significantly inferior survival rates. Level I evidence therefore supports the inclusion of appropriate radiation therapy (5,000–6,000 rads) into the management of conservatively treated breast cancer patients. A recent meta-analysis68 of Phase III clinical trials involving breast irradiation has motivated additional consideration of the survival benefits associated with radiation therapy in BCT patients. Vinh-Hung and Verschraegen pooled the outcomes of 13 trials involving more than 8,000 patients. The mortality hazard for patients treated by lumpectomy without radiation therapy was 1.086 (95% confidence interval, 1.003–1.175). This corresponds to a possible 8% survival benefit conferred by radiation. The issue of postmastectomy chest wall irradiation (PMRT) has generated extensive controversy over the past few decades. Clinical trials conducted thus far have failed to render a consistent answer to the question of whether sterilization of microscopic disease on the chest wall of a mastectomized patient yields a worthwhile outcome advantage to all breast

cancer patients. The EBCTCG studied this question indirectly in their meta-analysis of radiation for early-stage breast cancer patients.69,70 Although this study revealed a reduced breast cancer mortality risk associated with adjuvant XRT (by 13%), it was at the expense of a 21% increase in nonbreast cancerrelated mortality. This pooled analysis, however, involved studies whose primary design involved mastectomy versus BCT, systemic therapy versus no systemic therapy, and variable axillary management strategies. This heterogeneity precludes the ability to draw well-defined conclusions. Table 54.8 summarizes the results from Phase III prospective randomized trials conducted internationally that have contributed data regarding PMRT in women whose management has also included ALND as well as adjuvant systemic therapy. The results of these trials suggest that patients with four or more metastatic axillary lymph nodes represent the subset most likely to derive a benefit from PMRT, primarily because of their inherently increased risk for chest wall recurrence (range, 20%–40%). The ability to reduce locoregional relapses (to rates of 6%–14%) in these patients with the delivery of PMRT appears to improve the overall survival as well. The National Cancer Institute, the American Society of Clinical Oncology, and the American Society of Therapeutic Radiation Oncology have all issued position statements recommending PMRT for breast cancer patients with four or more metastatic nodes. The Danish Breast Cancer Group71,72 reported survival benefits from PMRT in women with one to three metastatic axillary nodes as well; however, this trial has been criticized because of the surgical treatment rendered. The average number of nodes retrieved from the ALND specimens (six) was somewhat lower than would be expected in a standard level I and II dissection. This finding prompts the concern that inadequate regional surgery may have contributed to the increased incidence of locoregional failures. Unfortunately, a clinical trial designed by the Radiation Therapy Oncology Group designed to address the question of PMRT in patients with one to three metastatic axillary lymph nodes was recently closed because of poor accrual, and this question therefore remains unanswered.

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TABLE 54.8. Randomized trials of postmastectomy irradiation in patients treated with axillary lymph node dissection and adjuvant systemic therapy, including subset analyses based on extent of nodal metastases (where available) and randomized trials of postmastectomy irradiation in patients treated with axillary lymph node dissection and adjuvant systemic therapy, including subset analyses based on extent of nodal metastases (where available).

Study

DBCG 82b71

DBCG 82c72

Glasgow214

BC215

DFCI216a SECSG217b

Year

All 1–3 Nodes Positive ≥4 Nodes Positive All 1–3 Nodes Positive ≥4 Nodes Positive All 1–3 Nodes Positive ≥4 Nodes Positive All 1–3 Nodes Positive ≥4 Nodes Positive 1–3 Nodes Positive ≥4 Nodes Positive

≥4 Nodes Positive South Sweden (Tamoxifen)218 South Sweden (Cyclophosphamide)218 ECOG219 Mayo220–223 German BCG224 Israel222,223,225 Portugal223,226 M.D. Anderson222,223 Helsinki227 Piedmont228 Köln (Germany)223,229

1997

1999

1986

1997

1987 1992 1993 1993 1997 1984 2000 2000 1998 2001 1987 1991 1982

LRF

OS (%)

No. of patients

Median follow-up (months)

No PMRT

PMRT

No PMRT

PMRT

1,708 1,061 510 1,375 794 448 219 141 72 318 183 112 83 123

114 114 114 123 123 123 63 63 63 150 150 150 53 45

32% 30% 42% 35% 31% 46% 25% NR NR 33% 33% 46% 5% 20%

9% 7* 14% 8% 6% 11% 11% NR NR 13% 13% 21% 2% 6%

45% 54% 20% 36% 44% 17% 57% 68% 46% 46% NR NR 85% 63%

54% 62% 32% 45% 55% 24% 61% 76% 54% 54% NR NR 77% 59%

120 96 96 109 (min) (mean) NR NR NR NR (min) (mean)

23% 18% 17% 24% 30% NR 24% NR NR 60% 35% NR

13% 6% 6% 15% 10% NR 4% NR NR 13% 18% NR

44% NR NR 47% 66% 84% 71% 35% 56% 69% 48% 84%

55% NR NR 46% 68% 96% 61% 33% 35% 94% 61% 96%

295 483 287 312 217 71 112 112 97 79 76 71

48 36

132 36

DFCI, Dana Farber Cancer Institute; DBCG, Danish Breast Cancer Group; BC, British Columbia; SECSG, Southeast Cancer Study Group; NR, not reported; ECOG, Eastern Cooperative Oncology Group; German BCG, German Breast Cancer Group. a

DFCI Trial patients with 1–3 nodes positive received CMF adjuvant chemotherapy; patients with four or more positive nodes received AC adjuvant chemotherapy. b

All SECSG Trial patients had at least 4 positive nodes.

Primary Chemotherapy for Breast Cancer Implementation of preoperative chemotherapy protocols (also commonly referred to as neoadjuvant or induction chemotherapy) revolutionized the management of locally advanced breast cancer (LABC) cases, and this approach is now considered the standard of care for patients with bulky breast and/or axillary disease. Early skepticism regarding this treatment sequence was based on concerns that preoperative chemotherapy would exert an adverse effect on (i) surgical complication rates, (ii) the prognostic value of the axillary nodal status, and (iii) overall survival as a consequence of delayed surgery. Nonetheless, the generally dismal results of treating LABC with primary surgery, radiation alone, or chemotherapy alone motivated investigations of multimodality therapy, and the benefits as well as the safety of preoperative downstaging of disease to improve respectability became apparent. Broadwater et al.73 demonstrated comparable operative morbidity among nearly 200 LABC patients treated with mastectomy, approximately half of whom received preoperative doxorubicin-based chemotherapy. The induction chemotherapy patients in fact had a lower rate of postoperative seroma

formation. Danforth et al.74 similarly reported that preoperative chemotherapy had no adverse effect on surgical complication rates and did not result in delayed delivery of any postoperative cancer care. Most patients will be ready to undergo surgery approximately 3 weeks after the last chemotherapy treatment, when the absolute neutrophil and platelet counts have normalized (greater than 1,500 and 100,000, respectively). McCready et al.75 confirmed that the axillary nodal status retains its prognostic value in the neoadjuvant chemotherapy setting. Their study of 136 LABC undergoing modified radical mastectomy following induction chemotherapy revealed that patients with no axillary metastases in the postchemotherapy mastectomy specimen had an excellent outcome, with nearly 80% surviving 5 years. In contrast, less than 10% of patients with 10 or more positive nodes survived 5 years, and patients with an intermediate number of residual metastatic nodes had an intermediate survival rate. The third issue, regarding induction chemotherapy and its relative impact on breast cancer survival in comparison to conventional postoperative adjuvant therapy, remains controversial. It is clear, however, that preoperative treatment and deferral of surgery do not increase rates of unresectabil-

964 ity. On the contrary, approximately 80% of patients will have at least 50% shrinkage of the primary tumor mass, and only 2% to 3% will have signs of progressive disease.76–78 Fears that the surgeon will lose a “window of opportunity” to resect chest wall disease are therefore unfounded, and preoperatively treated patients are likely to be rendered improved operative candidates. A surgical resection is essential in accurately documenting chemotherapy response and in achieving durable locoregional control of disease, as the clinical assessment of response will overestimate the actual pathologic extent by two- to threefold.79,80 The induction CTX benefits of tumor downstaging and the ability to rapidly identify chemoresistant disease by in vivo observation motivated expanded applications of this treatment to the setting of early-stage disease. Accordingly, outcomes from prospective clinical trials have now been reported in which preoperative chemotherapy has been compared directly to postoperative chemotherapy in women with LABC as well as early-stage disease. Some of these Phase III clinical trial results are shown in Table 54.9.81–88 All have demonstrated overall survival equivalence for the two treatment sequences, confirming the oncologic safety of the neoadjuvant approach. Subset analyses of the Phase III studies, however, reveal that patients found to have a complete pathologic response (pCR) do have a statistically significant survival benefit, substantiating the concept that primary breast tumor response is a reliable surrogate for chemoeffect on micrometastases. In the NSABP B-18 trial,88 patients with stage I–III breast cancer who were randomized to receive four cycles of doxorubicin and cytoxin preoperatively and who experienced a pCR had a 5-year overall survival of 86%, which was statistically superior to the outcome seen in all other study participants. Similarly, the University of Texas M.D. Anderson Cancer Center89 reported an overall survival rate of 89% for pCR patients treated on preoperative chemotherapy protocols designed specifically for LABC, and this outcome also represented a statistically significant benefit compared to patients with a lesser response. Unfortunately, both studies found that only 12% to 13% of patients experience a pCR when treated with a doxorubicin-based regimen, and this proportion is simply insufficient in yielding a survival benefit for the entire pool of preoperatively treated patients. Predictors of a pCR include relatively smaller size primary breast tumors, estrogen receptor negativity, and high-grade lesions.89 The latter two features probably characterize rapidly cycling tumors that may be particularly sensitive to chemotherapy effects. The ability to downsize the primary breast tumor, thereby facilitating attainment of a margin-negative lumpectomy with a smaller-volume lumpectomy, is a major advantage of the neoadjuvant CTX sequence. A feasibility study reported by Singletary et al.90 addressed many of the concerns that induction CTX might leave a field of microscopic satellite lesions, with a resulting increased risk of margin failure and/or excessive local recurrence rates. The Singletary study involved a pathology review of the mastectomy specimens in 143 LABC cases that had been treated with preoperative CTX; approximately one-quarter had adequate shrinkage of tumor and adequate eradication of disease in surrounding breast tissue as well as skin, such that they would have been candidates for successful lumpectomy. Table 54.9 demonstrates the overall comparability of local recurrence rates in subse-

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54

quent clinical trials of women receiving BCT with versus without neoadjuvant CTX. The NSABP B-18 trial87,88,91 randomized more than 1,500 women with stages I–IIIA breast cancer to receive preoperative versus postoperative chemotherapy. This study demonstrated a statistically significant increase in breast conservation therapy utilization for the preoperative chemotherapy arm (68% versus 60%). With a median followup of 72 months, the local recurrence rates were 7.9% and 5.8% (no statistically significant difference) following BCT in the preoperative and postoperative chemotherapy arms, respectively. The conversion rate to BCT eligibility was greatest in the patients with T3 tumors at diagnosis. The NSABP also reported that local recurrence was somewhat higher in the subset of lumpectomy patients who were downstaged to become BCT eligible in comparison to the BCT patients who were BCT candidates at presentation.88 However, this subset of downstaged BCT cases was predominantly composed of T3 tumors, and because local recurrence is one manifestation of underlying tumor biology, it would be expected that the more advanced stage lesions might have increased local recurrence rates regardless of surgery type and treatment sequence. Also, radiation boost doses were not consistently used in the lumpectomy patients, and tamoxifen therapy was only used in patients over 50 years of age. Both these interventions, if implemented uniformly, might have influenced local recurrence rates in downstaged tumors. Last, the NSABP requires that margin-negative lumpectomies be free of any tumor cells at an inked margin; a more-aggressive approach to margin control might be necessary for lumpectomies in tumors that have been downsized by preoperative CTX. Newman et al.92 analyzed a series of 100 patients treated at the M.D. Anderson Cancer Center on a prospective protocol of preoperative sequential taxotere and adriamycin-based chemotherapy in patients with stage I–III breast cancer. These investigators reported that 34% of patients initially ineligible for BCT were converted to lumpectomy candidates with this preoperative chemotherapy regimen. Final pathology review of all surgical specimens revealed that clinical assessment of BCT eligibility following induction chemotherapy was inaccurate for invasive lobular cancers, multicentric disease, and diffuse microcalcifications. Difficulties with assessment of chemoresponse in lobular cancers have also been noted by Mathieu et al.93 Induction chemotherapy is a reasonable and safe treatment approach for patients with breast cancer of any stage if the clinician is certain that chemotherapy would be recommended in the postoperative setting. The risk of overtreatment can be minimized by obtaining multiple diagnostic core biopsy specimens to confirm that a lesion is predominantly invasive, as it would clearly be inappropriate to treat large-volume or palpable DCIS tumors (with or without microinvasion) with CTX in any setting. Patients presenting with multiple tumors or extensive calcifications on initial mammogram should be counseled that preoperative chemotherapy will not convert them to BCT eligibility, regardless of extent of their primary tumor shrinkage. If the tumor is not associated with any microcalcifications, then a radiopaque clip should be inserted (preferably under ultrasound guidance) either before delivery of the neoadjuvant CTX or within the first couple of cycles. In the event that the patient should have a complete clinical response to the preoperative chemotherapy, this clip will serve

1983–1990

Institut Curie230–232

2001

ECTO235 423

892

698

1,523

309

414

272

N

I-IIIB

I-IIIA

I-IIIA

I-IIIA

I-IIIB

IIA-IIIA

II-IIIA (T > 3 cm)

Stages

NR

23

56

108

48

66

124

67%

71%

37%

60%

89%

82%

63.1%

Preoperative CTX

60%

35%

21%

68%

78%

77%

0%

Postoperative CTX

NR

d

NR

NR

10.7%

3%

b

24%

XRT: 34% L/ALND/XRT: 23%

Preoperative CTX

b

NR

d

NR

NR

7.6%

4%

18%

NA

Postoperative CTX

Local recurrence after BCT

a

NR

d

NR

NR

69%c

80%

86%

55%a

Preoperative CTX

NRd

NR

NR

70%c

80%a

78%

55%a

Postoperative CTX

Overall survival at median follow-up

Local recurrence rates reported for lumpectomy and mastectomy patients combined.

Overall survival rate at 9 years.

Recurrence and survival rates not reported, but relapse-free survival noted to be lower in neoadjuvant CTX arm, while overall survival similar for the two study arms.

c

d

Rate estimated from graph.

b

a

NSABP, National Surgical Adjuvant Breast Project; EORTC, European Organization for Research and Treatment of Cancer; ECTO, European Cooperative Trial in Breast Cancer; ABCS, Austrian Breast and Colorectal Study Group.

XRT, radiation; L, lumpectomy; ALND, axillary lymph node dissection; NA, not applicable; NR, not reported.

ABCSG

1991–1996

1991–1999

EORTC234

236

1988–1993

NSABP87,88,91

Royal Marsden

1990–1995

1985–1989

Institut Bergonie81,82

85,86,233

Accrual years

Study

Median follow-up (months)

BCT rate

TABLE 54.9. Randomized trials of neoadjuvant versus adjuvant chemotherapy for breast cancer.

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as the target for subsequent mammography-assisted wire localization lumpectomy when the patient is ready for surgery. Lesions associated with microcalcifications have an inherent target for subsequent localization. There is ongoing debate regarding the optimal method for integrating sentinel node staging of the axilla into induction CTX protocols. The standard treatment sequence for neoadjuvant CTX patients involves a percutaneous needle biopsy for establishment of the cancer diagnosis, delivery of chemotherapy, breast/axillary surgery, followed by irradiation in selected cases, and endocrine therapy for hormone receptor-positive disease. It was therefore logical for initial investigations to evaluate the results of sentinel lymph node biopsy performed after the delivery of preoperative CTX and concomitantly with the breast surgery. Concerns arose early in these discussions that the lymphatic mapping concept might be compromised by the following: i. Lymphatic obstruction by tumor emboli from the relatively larger tumors that are more likely to be managed with neoadjuvant CTX; ii. CTX effect on axillary metastases might not be uniform; and/or iii. CTX might obliterate intramammary lymphatic channels. Any combination of these factors could result in higher rates of sentinel node nonidentification or false negativity. Studies reported by Bedrosian et al.94 and Chung et al.95 documented the accuracy of lymphatic mapping for T2 and T3 breast

54

cancers. Breslin et al.96 reported the first series of patients undergoing sentinel lymph node biopsy and completion ALND after neoadjuvant CTX in a 2000 study from the M.D. Anderson Cancer Center, and these investigators demonstrated that the lymphatic mapping technology is indeed feasible in these cases, but accuracy rates are optimized when the surgical team has progressed through the learning curve of mapping in the setting of CTX-treated axillary tissue. As shown in Table 54.10, several other investigators have now reported varying success rates with lymphatic mapping performed after delivery of neoadjuvant CTX. Identification rates range from 85% to 97%, and false-negative sentinel nodes are identified in 0% to 33% of cases. One feature supporting the biologic rationale for this approach is the persistent observation that even after neoadjuvant CTX, the sentinel node is frequently the isolated site of axillary metastases. A meta-analysis of reported studies conducted by Xing et al.97 revealed an overall accuracy of 95% for sentinel node biopsy in this setting. Nonetheless, the suboptimal false-negative results have prompted many surgeons to perform sentinel node biopsy for axillary staging before delivery of neoadjuvant CTX. The disadvantage to this approach is that some women will be subjected to unnecessary ALNDs, because the node-positive patients identified at presentation will be committed to a completion ALND after induction CTX, despite the fact that the sentinel node(s) may have been the only sites of disease for some cases, and for others the CTX may have eliminated any residual axillary metastases.

TABLE 54.10. Studies of sentinel lymph node biopsy performed after neoadjuvant chemotherapy. Study

T status

Sample size

Breslin96 (2000)

2, 3

51

Nason237 (2000)

2, 3

15

Haid238 (2001)

1–3

33

Fernandez239 (2001)

1–4

40

Tafra240 (2001)

1, 2

29

Stearns241 (2002)

3, 4

T4d (inflammatory) 8 Noninflammatory 26

Julian242 (2002)

1–3

34

Miller243 (2002)

1–3

35

Brady244 (2002)

1–3

14

Piato245 (2003)

1, 2

42

Balch246 (2003)

2–4

32

Schwartz247 (2003)

1–3

21

Reitsamer248 (2003)

2, 3

30

Mamounas249 (2002)

1–3

428

Sentinel node identification rate

False-negative rate

Metastases limited to sentinel node(s)

85% (42/51) 87% (13/15) 88% (29/33) 90% (36/40) 93% (27/29) 75% (6/8) 88% (23/26) 91% (31/34) 86% (30/35) 93% (13/14) 98% (41/42) 97% (31/32) 100% (21/21) 87% (26/30) 85% (363/428)

12% (3/25) 33% (3/9) 0% (0/22) 20% (4/20) 0% (0/15) 40% (2/5) 6% (1/16) 0% (0/12) 0% (0/9) 0% (0/10) 17% (3/18) 5% (1/19) 9% (1/11) 7% (1/15) 11% (15/140)

40% (10/25) ≥11%* (≥1/9) 50% (11/22) 20% (4/20) NR 24% (5/21)

42% (5/12) 44% (4/9) 60% (6/10) 0% (0/18) 56% (10/18) 64% (7/11) 53% (8/15) 50% (70/140)

e v i d e n c e - b a s e d m a n ag e m e n t o f b r e a s t c a n c e r

Management of Ductal Carcinoma In Situ Because DCIS is largely a disease whose manifestations are confined to in-breast pathology, management strategies focus on various combinations of local therapy: mastectomy, lumpectomy, and breast irradiation. Axillary metastases are sufficiently rare with DCIS that nodal staging with the conventional level I/II lymph node dissection and its associated risk of lymphedema is generally considered unnecessary. However, in cases of extensive DCIS, where the risk of coexisting invasive disease is significant, information regarding the axillary nodal status becomes more relevant. The advent of lymphatic mapping and sentinel lymph node biopsy has greatly facilitated the handling of this dilemma. Adjuvant systemic therapy provides no survival benefit for pure DCIS because of the exceedingly low risk of micrometastases. However, hormonally active medical therapies such as selective estrogen receptor modulators and aromatase inhibitors exert a suppressive effect on abnormal proliferative activity in the breast, and these agents can therefore be useful in contributing to local control of disease as well as prevention of new breast primary cancerous events. Table 54.1198–103 summarizes the results reported by Phase III studies designed to compare DCIS treatment options.

Local Therapy Mastectomy was the standard management approach for DCIS until approximately 25 years ago. During the 1980s, two developments provided the impetus for expanded surgical options in the treatment of this condition: (i) publication of prospective, randomized clinical trials from the United States and from Europe confirming the safety of breast conservation therapy as management for early-stage invasive breast cancer; and (ii) implementation of widespread screening mammography programs and the resulting increased rates of detection for localized foci of DCIS. Despite concerns that DCIS represented a diffuse pattern of disease in the breast, it became increasingly difficult for clinicians to support the paradox of offering breast-sparing treatment to women with invasive palpable breast cancer while women with mammographically detected DCIS were penalized with a routine recommendation for mastectomy. Hence, breast conservation strategies were explored and have been proven to be oncologically safe for appropriately selected DCIS cases. Nonetheless, mastectomy remains a reasonable treatment option for DCIS, resulting in prolonged disease-free survival. Advances in plastic surgery techniques for immediate or delayed breast reconstruction have further improved the results achieved by mastectomy for DCIS. In certain clinical scenarios, mastectomy remains the preferred approach: 1. Patients with diffuse, suspicious-appearing microcalcifications in the breast 2. Inability to obtain margin control by lumpectomy and/or reexcision(s) 3. Patients with a contraindication to chest wall irradiation (XRT) or who lack access to an XRT facility, in cases in which it has been determined that breast XRT would be a necessary adjunct to lumpectomy 4. Patients with a primary personal preference for mastectomy

967

5. Patients with multiple, clinically apparent foci of DCIS that are not amenable to resection within a single marginnegative lumpectomy 6. Suboptimal tumor-to-breast size ratio, where a marginnegative lumpectomy will yield an unacceptable cosmetic result (as defined by the patient) Mastectomy and lumpectomy have never been directly compared in a prospective, randomized trial designed for DCIS patients. However comparable survival has been confirmed by indirect comparisons from retrospective studies and from DCIS patients who were incidentally included in the NSABP B-06 trial.98 The B-06 trial was designed to evaluate the outcome of approximately 1,800 stage I and II breast cancer patients randomized to treatment by breast conservation therapy (with versus without breast irradiation) or by mastectomy. Centralized pathology review subsequently identified 78 cases of DCIS that were randomized as well98 and equally divided between the three study arms. The overall survival for all three arms was similar (approximately 96% at 6 years), but the addition of breast irradiation to lumpectomy decreased local recurrence (LR) from 43% to 7% (see Table 54.11). As shown by Table 54.11, lumpectomy alone results in consistently higher rates of LR (range, 20%–43%) in comparison to patients treated by lumpectomy and breast radiation (range, 7%–12%). Commonly cited risk factors for LR have included suboptimal margin control, young age at diagnosis, and high-grade tumors with comedo-necrosis. Although margin status is frequently implicated in risk for developing LR, there is no consensus regarding the optimal extent of a negative margin. Furthermore, as noted in a meta-analysis of BCT for DCIS by Boyages et al.,104 studies published before 1998 often neglected to include margin status in their analyses. In the more-recent studies, a negative margin was variously defined as a minimum of 1, 2, or 3 mm of microscopically normal tissue at the inked lumpectomy borders. Another consistent finding between studies was that approximately half of all locally recurrent lesions are in the form of invasive disease. The decision to be treated by breast preservation therefore involves a different category of risk that is assumed by the DCIS patient compared to the patient undergoing lumpectomy for invasive cancer. In the latter case, the risk for distant micrometastases is present from the time of diagnosis, and decisions regarding the need for adjuvant systemic therapy are addressed at that time. In the former case, however, there would be no need to consider treatment of micrometastases, because DCIS biologically would not be expected have the ability to extend beyond the local tissue environment of the breast. The development of a local recurrence alters this prognostically favorable situation, and affected patients then face the risk of breast cancer mortality from distant spread. The proportion of invasive LR was similar for the patients treated by lumpectomy alone versus lumpectomy and XRT. Because the risk of LR is lower for the radiated patients, however, the assumption would be that radiation reduces the incidence of a potentially lifethreatening pattern of disease progression. One could further postulate that mastectomy is the safest treatment for DCIS patients because of the exceptionally low rate of LR. Although low, this risk is not nonexistent,105,106 indicating

Lack of XRT following lumpectomy Comedonecrosis

96%

96%

96%

0 (0%) NA

28

Mastectomy

97%

54 (12.4%) 23/54 (45%)

437

Lump + XRT

Lack of XRT Age £40 years Symptomatic DCIS Involved margins Solid/cribriform/ comedo patterns

97%

83 (19.5%) 37/83 (44%)

426

Lump

65

96%

47 (11.4%) 17/47 (36%)

411

Lump + XRT

Lack of XRT Calcifications on mammogram

97%

104 (25.8%) 53/104 (51%)

403

Lump

90

a

There were 76 cases randomized in NSABP B-06 that were found to be pure DCIS on retrospective pathology review.

Lump, lumpectomy; XRT, breast irradiation; Tam, tamoxifen; Symptomatic DCIS, palpable mass,; nipple discharge.

Risk factors for local recurrence

2 (7.4%) 1/2 (50%)

27

Lump + XRT

9 (42.8%) 5/9 (45%)

21

Lump

• Designed to evaluate lumpectomy with versus without breast XRT

NSABP B-17100,102

• Mammographically • DCIS detected by detected DCIS mammogram or £5 cm physical exam • No margin • Inked margin specification tumor-free

• Designed to evaluate lumpectomy with versus without breast XRT

EORTC99,103

97%

63 (7.0%) 23/63 (37%)

902

Lump + XRT + Tam

Lack of tamoxifen Age 60 years S/p hysterectomy

Eligibility criteria

Mean, 64 years

NA

Accrual not yet completed 28–67

Median, 66.5

35–70 NA

35–70

35

30–70

Age range (years)

Arimidex vs. Tam vs. Tam + arimidex

Tam vs. no adjuvant therapy

4-HPR vs. placebo

Tam vs. raloxifene

Raloxifene vs. placebo

Tam vs. placebo Tam vs. placebo

Tam vs. placebo

Tam vs. placebo

Tam vs. placebo

Randomization

5

≥5 (average, 5)

7

5

4

5 NA

5

5

5–8

Intended treatment duration (years)

33.3 months

5 years

Accrual not yet completed 97 months

50 months 70.6 ¥ 103 womenyears 3 years

81.2 months

54.6 months

70 months

Median follow-up

Breast cancer hazard

0.42 (0.22–0.79)

0.54 (0.43–0.69)

Premenopausal: 0.66 (0.41–1.07) Postmenopausal: 1.32 (0.82–2.15)

NA

0.28 (0.17–0.46)

All: 0.75 (0.48–1.18) No HRT: 0.99 (0.59–1.68) HRT: 0.36 (0.14–0.91) 0.68 (0.50–0.92) 0.62 (0.54–0.72)

1.06 (0.7–1.7) Tam. vs. placebo 0.51 (0.39–0.66)

chapter

Accrual goal 19,000 1,574

7,705

7,139 28,406

5,408

13,388

2,471

Yes

Study

N

Primary chemoprevention study?

TABLE 54.12. Phase III trials of breast cancer chemoprevention.

972 54

e v i d e n c e - b a s e d m a n ag e m e n t o f b r e a s t c a n c e r

Prediction For most patients, careful selection of the optimal therapy can result in considerable and often relatively long-lasting palliation. Expression of estrogen and progesterone receptors (ER, PgR) is highly predictive of response to endocrine treatments.141,142 HER-2 is the protein product of the erbB-2 gene, a member of the epidermal growth factor receptor family that consists of four members: epidermal growth factor receptor (EGFR, also called HER1), HER2 (also called erbB-2 and cneu), HER3, and HER4. HER2 is amplified and/or overexpressed in 25% to 40% of breast cancers, and the humanized monoclonal anti-HER2 antibody, trastuzumab, appears to be effective only in patients with HER2-positive breast cancer.143–145 There are no good predictive factors for individual chemotherapy agents. Chemotherapy resistance assays have been studied for more than two decades, but none of these technologies has been shown in rigorous studies to be sufficiently accurate for routine clinical use.146–148 Therefore, selection of specific chemotherapy is empiric. For example, patients who relapse within 1 year of adjuvant therapy are very unlikely to respond to the same agents again. Moreover, cumulative toxicities, especially cardiac failure with the anthracyclines, may preclude additional treatment even if the agent is likely to be effective.

Selection of Therapy: Local Versus Systemic Local therapies (surgery, radiation, hyperthermia) often preclude concurrent systemic therapy and therefore are most appropriate for patients who have isolated metastases and/or who have impending crises, such as long bone fracture, spinal cord metastases, or intracranial metastases.

973

Fulvestrant, similar to tamoxifen, binds to the ER. However, instead of modulating ER dimerization and binding to estrogen response elements in the nucleus, fulvestrant prevents dimerization and induces downregulation of the receptor. Prospective randomized trials have demonstrated that fulvestrant is as effective as anastrozole as second-line therapy and, recently, more effective than tamoxifen as firstline therapy157–159 (see Table 54.13). Premenopausal women with hormone receptor-positive metastatic breast cancer are probably best treated with ovarian function cessation, either by surgical oophorectomy or by chemical cessation of ovary function with the use of luteinizing hormone-releasing hormone antagonists such as goserelin. Addition of either tamoxifen, an aromatase inhibitor, or fulvestrant to ovarian cessation appears to improve outcome, but the side effects are greater. However, because the aromatase inhibitors appear more effective than tamoxifen in postmenopausal women, it is not unreasonable to combine ovarian ablation with an aromatase inhibitor.160,161 Side effects of endocrine treatments are generally related to antiestrogenic effects, including hot flashes, moodiness, and vaginal dryness and dysparunia. The aromatase inhibitors all seem to have a small rate of arthralgias and of gastrointestinal upset. Because tamoxifen has estrogenic properties in the liver, it increases thrombogenesis, with consequent increased risk of deep venous thrombosis and cerebral vascular accident. Long-term use of aromatase inhibitors is associated with increased risk of osteoporosis and fracture, whereas tamoxifen has estrogenic effects in bone and is therefore protective from this effect. However, in women with metastatic disease, this is rarely an issue because they rarely remain on the agent for more than a few months due to progression, and they are frequently treated with bisphosphonates (see following).

Systemic Therapy: Endocrine Therapy For most patients with metastatic disease, selection of systemic therapy is preferable. Patients with ER- and/or PgRpositive tumors should receive endocrine therapy. There is no role for combined endocrine and chemotherapy; there are some preclinical and adjuvant data suggesting that they may be antagonistic.149,150 Regardless, because palliation is the goal, if endocrine treatment alone is appropriate it is more likely to induce palliation. If not, then there is no reason to use it, and chemotherapy should be initiated alone. For the past 20 years, tamoxifen has been the first-line endocrine treatment of choice, because it is equally or more effective and has fewer side effects than previously available therapies. However, because most hormone receptor-positive patients receive tamoxifen in the adjuvant setting, secondline endocrine therapy, in fact, becomes “first line” if patients recur on tamoxifen. Several prospective randomized trials have demonstrated that for postmenopausal women with ERpositive metastatic breast cancer, the selective aromatase inhibitors are more effective with fewer side effects than older second-line therapies, such as megestrol acetate or aminoglutethimide151–154 (Table 54.13). Recently, similar studies have demonstrated that survival is superior for women treated with AIs compared to tamoxifen as first line therapy for metastatic disease136,155,156 (Table 54.13). Because they do not inhibit ovarian estrogen production, aromatase inhibitors should not be used in premenopausal women.

Systemic Therapy: Chemotherapy Of the common solid tumor malignancies, breast cancer is one of the most sensitive to chemotherapy, although, as noted, metastatic breast cancer exhibits a fundamental pattern of resistance that ultimately, and nearly universally, leads to death. Nonetheless, responses, and one therefore hopes improvement in symptoms, occur in 20% to 60% of patients when treated with single-agent alkylating agents, antimetabolites (purine and pyrimidine analogues), anthracyclines and anthraquinones, and taxanes. Of these, the anthracyclines (doxorubicin, epirubicin) and taxanes (paclitaxel, docetaxel) appear to have the highest single-agent activity. Through the 1980s, combination chemotherapy was widely applied in metastatic breast cancer, cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) and cyclophosphamide, doxorubicin (adriamycin), and 5-fluorouracil (CAF).162,163 In the 1990s, use of sequential singleagent therapy was more widely applied to avoid overlapping toxicities of combination therapy.164–169 Results of two recently published studies have suggested a modest survival advantage for combination therapy using either docetaxel and capecitabine or paclitaxel and gemcitabine.138,170 These two studies notwithstanding, in the absence of rapidly progressive visceral disease, it seems just as reasonable to treat patients with single-agent chemotherapy, offering the next therapy if the first is either ineffective or intolerable.

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TABLE 54.13. Prospective randomized trials of endocrine therapy for metastatic breast cancer. Comparison

Reference

Clinical benefit*

Selective aromatase inhibitors versus aminoglutethimide Letrozole vs. 153 36.3% aminoglutethimide 28.9% (NS) Selective aromatase inhibitors versus megestrol acetate Anastrozole vs. megestrol 151 42.2% acetate 40.3% (NA) Letrozole vs. megestrol 152 34.5% acetate 31.7% (NS) Letrozole vs. megestrol 251 26.7% acetate 23.4% (NA) Exemestane vs. megestrol 252 37.4% acetate 34.6% (NS) One selective aromatase inhibitor versus another Letrozole vs. anastrozole 253 27% 23%

TTP (HR for progression)

Overall survival (HR for death)

0.72 (P = 0.008)

0.64 (P = 0.002)

0.94 (NS)

0.78 (P = 0.025)

0.80 (P = 0.07)

0.82 (P = 0.15)

0.99 (NS)

0.92 (P = 0.49)

0.82 (P = 0.04)

NA (P = 0.04)

1.0 (P = 0.92)

0.95 (P = 0.62)

Selective estrogen receptor downregulator versus selective aromatase inhibitor Fulvestrant vs. anastrozole 158 42.2% 0.92 36.1% (P = 0.43) (P = 0.26) Fulvestrant vs. anastrozole 157 44.6% 0.98 45% (P = 0.84) (NS) Selective aromatase inhibitors versus tamoxifen (selective estrogen receptor modulator) Anastrozole vs. tamoxifen 254 56.2% 0.99 55.5% (P = 0.94) (NS) Anastrozole vs. tamoxifen 255 59% 0.69 46% (P = 0.005) (P = 0.01) Letrozole vs. tamoxifen 155 49% 0.70 38% (P = 0.0001) (P = 0.001) Exemestane vs. tamoxifen 156 57% NA 42% (P = NA)

In summary, chemotherapy can induce quite satisfactory palliation, in spite of its side effects, if applied judiciously. There does not appear to be an optimal regimen, schedule, or dose, although general guidelines can be drawn from a number of well-performed prospective randomized trials.

Novel Targeted Therapies Trastuzumab is a humanized monoclonal antibody that selectively binds HER2. Phase II trials have shown it to induce responses in 10% to 25% of patients with HER2-positive breast cancers.144,171,172 Perhaps more importantly, a single prospective randomized clinical trial has demonstrated that response rates, progression-free survival, and even overall survival are improved by chemotherapy (either CAF or paclitaxel) plus trastuzumab versus chemotherapy alone.139

NA

NA

NA

NA

NA

NA

These exciting findings have led to combination studies of trastuzumab with several chemotherapeutic agents, with the suggestion of increased response rates than might be expected from historical controls.173–175 There are two important caveats regarding trastuzumab therapy. First, in the pivotal metastatic trial, congestive heart failure was observed in more than 25% of patients treated with combination doxorubicin and trastuzumab and in more than 10% of those who received paclitaxel and trastuzumab.139 Currently combination therapy with trastuzumab and an anthracycline should be considered contraindicated. Second, HER2 is most commonly evaluated in breast cancer tissue by immunohistochemistry (IHC). The only IHC test for HER2 testing that is approved by the FDA is the so-called Herceptest. Substantial data suggest that, using the recommended readout scale of 0–3+, only those

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patients whose tumors are read as “3+” are likely to benefit from trastuzumab.176 Likewise, it also appears that HER2 amplification, which is evaluated by fluorescent in situ hybridization (FISH), is also an accurate predictor of benefit from trastuzumab.176 A reasonable algorithm is to perform IHC first. Patients with tumor HER2 scores of 0–1+ are unlikely to benefit, whereas those who are 3+ are good candidates for trastuzumab. For patients whose tumors are 2+, FISH should be performed to distinguish those who should receive trastuzumab from those who should not. Other novel therapies that appear to have some benefit include bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor (VEGF) and the orally available inhibitors of the EGFR-family tyrosine kinases.177–179 However, none of these has been studied in a sufficiently rigorous manner to determine if it has a role in routine clinical care.

Monitoring Patients with Metastatic Breast Cancer Palliative therapy should be continued so long as it appears to be successful and tolerated, as determined by history, physical examination, radiographs, and serologic/blood testing. Commonly a patient is followed for several cycles of therapy, lasting weeks to months, until progression is obvious and therapy should be changed. During this period of time, the patient may have been exposed to the toxicities of the therapy needlessly, if it was of little or no value in reducing the cancer burden. Serial plain radiographs, computerized tomography, magnetic resonance imaging, and bone scintigraphy can provide evidence of response or, more importantly, progression. It is critical that the clinician be aware of causes of false-positive evidence of progression, in particular the so-called scintigraphic healing flare associated with response of bone metastases and conversion from lytic to sclerotic lesions. Because more than 50% of patients with metastases may have bonepredominant or bone-only metastases, monitoring may be quite difficult. The value of positron emission tomography for monitoring metastatic breast cancer has not been shown in prospective, well-designed clinical trials, although this technology appears to have substantial promise. Serial circulating tumor markers, in particular carcinoembryonic antigen (CEA) and products of the MUC1 gene (identified by the commercially available assays CA 15-3 or CA 27.29), appear reasonably accurate for monitoring patients with metastatic disease.180 However, approximately 25% of patients may experience a false-positive increase, or “tumor marker spike,” during the first 30 to 60 days of therapy, and the clinician also needs to be aware of other reasons for nonmalignant tumor marker elevation, for example, as observed with acute hepatic dysfunction. Recently, results of a prospective clinical trial have suggested that circulating tumor cell (CTC) levels, as evaluated by an automated immunomagnetic technique, may be strongly associated with clinical outcome of patients with metastatic breast cancer.181,182 These data, and the potential benefits of changing therapy very early for patients with elevated CTC, require validation in future studies. In summary, high levels of evidence support the benefits of careful application of systemic therapies for patients with metastatic disease. Prospective randomized clinical trials

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have demonstrated the benefits of various endocrine treatments for those with hormone receptor-positive disease, for specific chemotherapeutic regimens for patients with very poor prognosis or those with hormone-refractory metastases, and for the use of trastuzumab alone or in combination with chemotherapy for patients with HER2-positive breast cancer. Ongoing research offers promise to further improve quality of life and even survival for patients who suffer with distant disease, and it is hoped that future investigations may even result in cure rates approaching those of Hodgkins’ disease, non-Hodgkins’ lymphoma, and testicular cancer.

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244. Brady EW. Sentinel lymph node mapping following neoadjuvant chemotherapy for breast cancer. Breast J 2002;8:97–100. 245. Piato JR, Barros AC, Pincerato KM, Sampaio AP, Pinotti JA. Sentinel lymph node biopsy in breast cancer after neoadjuvant chemotherapy. A pilot study. Eur J Surg Oncol 2003;29:118– 120. 246. Balch GC, Mithani SK, Richards KR, Beauchamp RD, Kelley MC. Lymphatic mapping and sentinel lymphadenectomy after preoperative therapy for stage II and III breast cancer. Ann Surg Oncol 2003;10:616–621. 247. Grunwald Z, Moore JH, Schwartz GF. Bilateral brachial plexus palsy after a right-side modified radical mastectomy with immediate TRAM flap reconstruction. Breast J 2003;9:41–43. 248. Reitsamer R, Peintinger F, Rettenbacher L, Prokop E. Sentinel lymph node biopsy in breast cancer patients after neoadjuvant chemotherapy. J Surg Oncol 2003;84:63–67. 249. Mamounas E, Brown A, Smith R, et al. Accuracy of sentinel lymph node biopsy after neoadjuvant chemotherapy in breast cancer: Updated results from NSABP B-27. Proc Am Soc Clin Oncol 2002;21: abstract 140. 250. Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Wolmark N. The study of tamoxifen and raloxifene: preliminary enrollment data from a randomized breast cancer risk reduction trial. Clin Breast Cancer 2002;3:153–159. 251. Buzdar A, Douma J, Davidson N, et al. Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. J Clin Oncol 2001;19:3357–3366. 252. Kaufmann M, Bajetta E, Dirix LY, et al. Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group. J Clin Oncol 2000;18:1399–1411. 253. Rose C, Vtoraya O, Pluzanska A, et al. An open randomised trial of second-line endocrine therapy in advanced breast cancer. Comparison of the aromatase inhibitors letrozole and anastrozole. Eur J Cancer 2003;39:2318–2327. 254. Bonneterre J, Thurlimann B, Robertson JF, et al. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol 2000;18:3748–3757. 255. Nabholtz JM, Buzdar A, Pollak M, et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol 2000;18:3758–3767.

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Thyroid and Parathyroid Gerard M. Doherty

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hyroid and parathyroid diseases combine the focuses of endocrinology and oncology, as one must consider both the hormonal function effects of the tumor and its treatment and the management of the malignancy, or potential malignancy. This chapter addresses the malignant forms of thyroid and parathyroid diseases and their epidemiology, diagnosis, treatment, and follow-up.

Thyroid Nodule A palpable solitary nodule caused by a carcinoma in the neck is often impossible to distinguish from a benign nodule. However, a hard and firm consistency in especially a relatively fast growing nodule indicates a higher risk for malignancy than a soft slowly growing nodule, and multinodular disease is associated with lower risk of malignancy compared with a solitary nodule.1 A solitary nodule is best investigated by fine-needle aspiration (FNA), as well as ultrasound (Figure 55.1). FNA, however, is limited in its ability to differentiate benign from malignant disease for follicular tumors, because the diagnostic criteria rely on thorough examination of capsular invasion. Ultrasound-guided FNA may improve the diagnostic yield of FNA, but interpretation problems of the aspirate remain. FNA biopsy has a sensitivity and specificity of 95% and 97.5%, respectively, in the diagnosis of thyroid cancer. The diagnostic accuracy of FNA cytology is more than 95% for papillary thyroid cancer (PTC). FNA cytology in patients with PTC commonly shows psammoma bodies, papillary structure, and the nuclear features of PTC (Figure 55.2). The FNA cytology may be suspicious or indeterminate, including follicular and Hürthle cell neoplasms, and in such cases patients should undergo thyroidectomy because about 20% prove to be thyroid cancer. In cases in which the FNA biopsy is nondiagnostic the FNA should be repeated; this is important because about 10% of these neoplasms are malignant. Diagnostic 131I- or technetium-thallium scintigraphy was used in the past to identify hypofunctional areas in the thyroid corresponding to a palpable lesion—cold nodules. However, this method has very low specificity and should only be used for patients with suppressed thyroid-stimulating hormone (TSH). There is no indication for scintigraphy in a euthyroid patient with a thyroid nodule. There are no available diagnostic approaches that can distinguish follicular carcinoma from follicular adenoma, other than diagnostic lobectomy and histologic evaluation. There-

fore, for follicular thyroid neoplasms by cytology, diagnostic lobectomy is generally indicated. If the thyroid nodule is large or otherwise suspicious for a carcinoma, the patient should have a total thyroidectomy, at the discretion of the surgeon and the patient.

Thyroid Cancer Epidemiology Thyroid cancer is the most common endocrine malignancy; it also has the highest mortality among endocrine neoplasms. According to estimates by the American Cancer Society, about 23,600 new cases of thyroid cancer will occur in 2004 in the United States and about 1,460 people will die of thyroid cancer. In addition, although thyroid cancer is more common in women than in men (M : F ratio, 5,960 : 17,640), death from thyroid cancer occurs in a higher proportion of the men (M : F, 620 : 840).2 The lifetime risk of developing thyroid carcinoma is 0.33% for men and 0.9% for women, according to U.S. Surveillance, Epidemiology and End Results (SEER) data estimates.3 Thyroid cancers have a wide range of aggressiveness, from relative indolence for most papillary thyroid cancer (PTC) to near-uniform lethality for anaplastic thyroid cancer. Fortunately, PTC accounts for about 80% of all thyroid cancer cases in iodine-sufficient areas and is associated with a relatively good prognosis. Significant advances in our knowledge of the molecular biology, diagnosis, and prognosis of thyroid cancer have been made over the past three decades. The treatment of differentiated thyroid cancer remains controversial, with debates among experts regarding the most appropriate extent of thyroidectomy, the use of postoperative radioactive iodine ablation, and the need for thyroid hormone for TSH suppression. In addition, the understanding of the molecular changes leading to papillary thyroid cancer and medullary thyroid cancer have created optimism that specific therapies will be developed.

Follicular Cell-Derived Thyroid Cancer The normal thyroid gland consists mainly of follicular cells. These specialized cells concentrate iodide from circulating blood through the sodium iodide symporter (NIS), synthesize thyroid hormone and thyroglobulin, and respond to thyroidstimulating hormone (TSH) by both growth and hormone

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Figure 55.1. Algorithm for the evaluation of a solitary thyroid nodule. All patients should have thyroid function tests. Ultrasound is extremely helpful in the characterization of the nodule, and in the guidance of percutaneous interventions. Fine-needle aspiration cytology is the mainstay of thyroid nodule assessment and is very reliable. Thyroid scintigraphy does not have a place in the routine evaluation of a thyroid nodule unless the patient is hyperthyroid.

release. Follicular cell-derived thyroid cancer (FCDTC) cells lose some of the normal signals that control cell growth and division, but often maintain some of the functions of normal thyroid follicular cells. The function that is most frequently lost is the ability to synthesize thyroid hormone. Very few thyroid carcinomas make thyroid hormone or cause hyperthyroidism. However, the NIS is present and functional in most FCDTC, and forms the basis for the use of radioiodine therapy in its management. Most FCDTC also retain the ability to synthesize thyroglobulin, which allows the use of serum levels of thyroglobulin after treatment as a tumor marker for follow-up. Finally, most FCDTC continue to express the TSH receptor and to respond to TSH with growth and increased thyroglobulin release. This understanding is important in the treatment of FCDTC, as suppression of TSH with thyroid hormone can decrease the recurrence rate. In addition, during follow-up, administration of TSH can increase the sensitivity of thyroglobulin tumor marker measurement. FCDTC includes several related histologic and clinical subtypes. The main types are papillary thyroid cancer (about 80%), follicular thyroid cancer (about 15%), and Hürthle cell cancer. A variety of subcategories also exist, some of which have prognostic implications (Table 55.1).

Papillary Thyroid Carcinoma Clinical Features Almost all patients (98% or more) who present with clinical evidence of PTC present with a mass located in the thyroid

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Figure 55.2. Papillary thyroid cancer histology. The classic papillary thyroid cancer has thin vascularized stalks lined by follicular cell-derived thyroid cancer (FCDTC) cells with typical nuclear changes. These can be diagnosed on cytology by the nuclear changes and by the fragments of papillary architecture that are sometimes identifiable.

gland (67%), a mass associated with cervical lymphadenopathy (13%), and only with cervical lymphadenopathy (20%).4 Children and young adults more frequently present with palpable nodal metastases.5 The peak incidence of PTC is in the third and fourth decade of life, and there is a female-to-male ratio of 3 : 1. Depending on the series and whether prophylactic neck node dissection was performed, the rate of cervical node metastases is 11% to 80%. Most studies from the United States report a rate of 30% to 40% cervical node metastases when therapeutic neck node dissections are done.6 Distant metastasis is less common (2%–14%). The most common sites of distant metastases are to the lung and bone, and less commonly to the soft tissue, central nervous system, and liver. Papillary thyroid cancer is the most common tumor that occurs in patients with Graves’ disease, accounting for about 75% of the thyroid cancers associated with Graves’ disease.7 Some investigators report more-aggressive thyroid cancers in patients with Graves’ disease whereas others do not.7,8 Confounding factors that cloud the debate regarding whether patients with Graves’ disease have more-aggressive tumors are (1) whether the thyroid cancer was diagnosed clinically or on histologic evaluation, (2) whether surgical or medical treatment was used, (3) history of radiation to the head and neck, and (4) level of microscopic histologic evaluation for the presence of thyroid cancer. The similarity of the thyroidstimulating antibodies, present in Graves’ patients, and TSH

TABLE 55.1. Histologic variants of follicular cell-derived thyroid carcinoma. Variants with similar clinical behavior

Variants with more aggressive behavior

Follicular variant of papillary Minimally invasive follicular thyroid carcinoma (FTC) Encapsulated Solid/trabecular

Tall cell Diffuse sclerosing Columnar Oxyphil (Hürthle) Oncocytic papillary thyroid cancer (PTC) (similar to Hürthle) Clear cell FTC InsularMixed MTC/FTC (behaves like medullary thyroid carcinoma, MTC)

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is clearly documented. The fact that TSH promotes tumor growth, invasion, angiogenesis, and inhibits apoptosis in vitro supports the possibility that thyroid cancer may be more aggressive in these patients. It appears that patients who present with clinical evidence of thyroid cancer and who have Graves’ disease have more-aggressive tumors, whereas patients with occult thyroid cancers who are treated for Graves’ disease have an excellent prognosis.

Pathologic Features PTC is typically firm with an irregular border, has a whitish color, and may contain microcalcifications. However, there is variation in the tumor gross characteristics related to the different morphologic variants of PTC. For example, the encapsulated follicular variant of PTC may have a well-defined margin with a fleshy appearance similar to a follicular adenoma. Depending on the evaluation of the entire thyroid gland, a microscopic examination, and the thickness of histologic section, up to 80% tumor multicentricity is reported for PTC. Carcangiu and associates found 22% of PTC were multifocal on routine histologic examination whereas Katoh et al., on thin (0.5-mm) microscopic section evaluation, found 78% of PTC were multifocal.4,9 Overall, most studies report 20% to 30% of PTC are multicentric. Vascular invasion by PTC is uncommon compared with follicular thyroid cancer, occurring rarely. The presence of papillae and unique nuclear features are the defining characteristic of PTC. The papillae appear as fibrovascular stalks lined by the neoplastic epithelial follicular cells. The nuclear features are hyperchromatic nuclei, absent nucleoli, nuclear grooves, and intranuclear inclusions. Several variants of PTC exist, and their diagnosis is established by the presence of these distinct nuclear features of PTC. Some variants behave similar to typical PTC whereas others have a more-aggressive behavior. In 1960, Lindsay made the initial observation that some “follicular carcinoma” had papillae and a less-aggressive clinical course than typical follicular carcinoma.10 Subsequent studies confirmed these observations, and the follicular variant of PTC is now regarded as a variant of PTC. This variant is characterized by the presence of ground-glass (clear nucleoli) nuclei and may have some or no papillary elements on histology. The micropapillary, “occult,” or “minimal” variant of PTC is smaller than 10 mm by definition and is commonly found incidentally. Patients with occult PTC (less than 1 cm) have a near-normal life expectancy. The encapsulated variant of PTC accounts for about 10% of all PTC and is characterized by a total surrounding fibrous capsule that may have focal invasion but has the nuclear features consistent with PTC. In the solid/trabecular variant of PTC are foci of solid and/or trabecular growth pattern in most (more than 50%) or all of the tumor with the typical nuclear features of PTC. The presence of this morphologic variant is important to recognize to avoid misclassification as a poorly differentiated thyroid cancer. The tall cell variant of PTC has a typical appearance with the height of the follicular cells greater than twice the width with an intense eosinophilic cytoplasm lining the glandular and papillary structures.11 In this variant, nuclear grooves and intranuclear invaginations are commonly present. Hazard and Hawk observed that these tumors occurred in older patients

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and were larger in size (greater than 5 cm), with frequent extrathyroid extension and a higher incidence of vascular invasion.12 Studies by Johnson et al. and Moreno-Egea et al. comparing patients with the tall cell variants to patients with typical PTC, which matched patients for age and gender, found a higher recurrence rate and mortality in patients with the tall cell variant of PTC.11,14 Vickery and associates were the first to describe the diffuse sclerosing variant of PTC, which is characterized by dense intrathyroidal lymphocytic invasion, severe fibrosis, squamous metaplasia, and numerous psammoma bodies involving one or both thyroid lobes.15,16 Importantly, this morphologic variant was associated with a slightly worse prognosis and occurred more frequently in children. Compared with typical PTC, most subsequent studies have shown a higher rate of nodal and distant metastases, and also a higher recurrence rate for the diffuse sclerosing variant, but not a significant difference in mortality. According to the World Health Organization thyroid histologic classification, oxyphil or Hürthle cell carcinomas that display classic papillary architecture on histology are considered a variant of PTC. Herrera and associates have reported that this morphologic variant compared with typical PTC is associated with a higher recurrence rate and mortality.17

Risk Factors and Associated Hereditary Conditions Several hereditary conditions and environmental factors increase the risk of developing thyroid cancer. A history of radiation exposure increases the risk of developing differentiated thyroid cancer. Most of the external radiation exposure was used in children to treat them for tinea capitus, hypertrophic thymus, tonsillitis, acne, and external otitis in the 1940s and 1950s. Large case-control retrospective studies by Shore et al. and Ron et al. confirmed the increased risk of thyroid cancers and benign thyroid nodules in children exposed to low-dose therapeutic radiation.18–21 Shore and colleagues reported among 2,650 children exposed to therapeutic low-dose radiation, there is an increased relative risk of 45 for malignant thyroid tumors and a relative risk of 15 for benign thyroid tumors. Ron and associates found a relative risk of 4 for malignant thyroid tumors and 2 for benign thyroid tumors in a cohort of 10,834 children exposed to therapeutic radiation for tinea capitus. A linearly increased risk of thyroid cancer to dose of radiation exposure has been observed with an even higher risk among those exposed at a young age. A minimum 3- to 5-year latency period has been observed between radiation exposure and tumor development. The number of cases continues to increase for at least three decades after exposure and then decreases. About 90% of the radiation-associated thyroid cancers reported have been PTC. Today, radiation-induced thyroid cancer accounts for about 9% of all thyroid cancers. In addition to age and dose of radiation exposure, other environmental or genetic factors may play a role in which individuals develop thyroid neoplasm. Perkel and associates, in a study of 286 sib pairs, reported a significant (P = 0.05) familial concordance for thyroid neoplasms (benign and malignant) but not for thyroid cancer.22 Schneider et al. have followed 2,634 children in Chicago and 40% have developed thyroid neoplasms (all types) and 12% thyroid cancer.23 The use of low-dose radiation treatment in patients with benign conditions has been

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abandoned in the past 40 years because of the recognized increased risk for thyroid cancer. Radiation exposure from diagnostic radiation or therapeutic high-dose external-beam radiation accounts for the medical-related exposure in patients today. Investigations in children exposed to nuclear fallout accidents in the Marshall Islands, Nevada test sites, and Chernobyl clearly document an increased risk of thyroid cancer among patients exposed to acute ionized radiation.24–26 As in the studies of patients exposed to low-dose therapeutic radiation, age at exposure and dose of radiation exposure were significant factors in the increased relative risk. Other risk factors such as dietary, sex hormones, goitrogens, and environmental factors have also been identified but not all studies show an increased risk of thyroid cancer (Table 55.2). Epidemiologic studies show that both high-iodine and low-iodine diets can increase the risk of thyroid cancer. Patients with familial adenomatous polyposis (FAP) have an increased risk of benign and malignant thyroid neoplasms27,28; they can develop either papillary or follicular tumors.

Diagnosis of Papillary Thyroid Cancer The majority of patients with PTC present with a neck mass originating from the thyroid gland or from a cervical node metastasis. When there is significant local tumor invasion, patients may have local symptoms such as hoarseness, changes to the singing voice, or difficulty swallowing. A careful history and physical examination with emphasis on a history of head and neck radiation or familial thyroid disorders is important. If a patient has had previous neck surgery or has had any change in his or her voice, indirect or direct laryngoscopy can evaluate the status of the vocal cords. Although hyperfunctioning PTC are rare, careful evaluation for symptoms or signs of hypothyroidism with serum TSH level determination should be done. A diagnosis of PTC is usually established by fine-needle aspiration (FNA). FNA cytology is highly accurate for diagnosing PTC. Simultaneous thyroid ultrasonography may be used during FNA biopsy, especially if the thyroid nodule is cystic, to obtain cellular element from the solid component (Figure 55.3). Intraoperative frozen section in patients with PTC is not necessary for patients with PTC by cytologic examination. In patients who have enlarged lymph nodes or when there is a question of lymph node metastases, a frozen section can be helpful in confirming nodal metastases and for confirming the diagnosis intraoperatively. TABLE 55.2. Risk classification systems for patients with papillary follicular cell-derived thyroid cancer (FCDTC). System

Prognostic factors included

AGES

Age, tumor grade, extrathyroidal invasion, distant metastases, tumor size Age, extrathyroidal invasion, distant metastases, tumor size Gender, tumor histology type, extrathyroidal invasion, distant metastases Age, extrathyroidal invasion, distant metastases, completeness of resection, tumor size

AMES EORTC MACIS

EORTC, European Organization for Research and Treatment of Cancer.

Figure 55.3. Thyroid ultrasound. Ultrasound is extremely useful for the characterization of cervical anatomy and thyroid nodules. This nodule in the lower pole of the right lobe of the thyroid gland is well circumscribed, slightly hypoechoic, and deforms the surface of the thyroid gland. Upon resection, this was a tall cell carcinoma of the thyroid. J, jugular vein; C, carotid artery.

Treatment of Papillary Thyroid Cancer Controversy remains regarding optimal treatment of patients with differentiated thyroid cancer. The controversy persists because there are no prospective randomized control studies evaluating the merit of extent of thyroidectomy, postoperative radioactive iodine therapy, and TSH suppressive therapy. Such a trial would require a large multicenter trial with a long follow-up time required because of the relatively good prognosis and low incidence of thyroid cancer. EXTENT OF THYROIDECTOMY Thyroidectomy is safe and effective and it is the primary treatment in patients with PTC. In patients who have bilateral lobe tumors, extrathyroidal tumor extension, and/or high-risk PTC, there is a general consensus that total thyroidectomy is warranted. However, in low-risk patients con-

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flicting points of view by experts persist. Generally, three surgical approaches have been advocated among experts: (1) thyroid lobectomy or hemithyroidectomy (total removal of one lobe and isthmus), (2) near-total (total lobectomy and subtotal resection on the contralateral side leaving less than 1g thyroid tissue), and (3) total thyroidectomy. The most important reasons for performing a total or near-total thyroidectomy in patients with PTC are (1) a lower dose of radioactive iodine can be used to identify and ablate residual thyroid cancer, and (2) the serum thyroglobulin level following total thyroidectomy is a more accurate marker of recurrent/persistent PTC. Up to 80% of PTC are multicentric and tumor foci may occur in the contralateral lobe, thus representing a potential site of recurrence. There is about a 1% risk of a differentiated thyroid cancer progressing to anaplastic thyroid cancer, which is uniformly lethal. Hay et al. from the Mayo clinic also specifically studied local recurrence and nodal and distant metastases in patients with low-risk PTC based on the AMES prognostic classification system, finding those patients who had unilateral procedure (lobectomy only) had a higher local recurrence rate (14%) and nodal metastases (19%) than those patients treated with bilateral procedures.29 However, there was no significant difference in survival rate and distant metastases. Although advocates of lesser procedures contend that there is a higher risk of complications after total thyroidectomy, numerous surgeons with experience in total thyroidectomy report complication rates of less than 2%. The risk of complication from thyroidectomy depends primarily on the extent of thyroid disease, the experience of the surgeon, and anatomic variation of the parathyroid glands, recurrent laryngeal nerves, and external laryngeal nerves. The most common and serious complications of thyroidectomy are injury to the recurrent laryngeal nerves or parathyroid glands. It seems obvious that the risk of complication is higher with total thyroidectomy because of dissection on the side contralateral to the tumor. However, comparable complication rates for total thyroidectomy, near-total thyroidectomy, and lesser procedures are achieved by many surgeons.30,31 Even among the less than 2% of patients who had complications, these patients were more likely to have more-invasive tumors involving the recurrent laryngeal nerve. Although the evidence suggests that total thyroidectomy should be associated with little or no higher complication rate than lesser procedures, these data are based upon the outcomes of experienced surgeons. The public policy issue of whether it is preferable to advocate a less-effective approach (lobectomy) that is more applicable by the occasional thyroid surgeon is made moot if patients are cared for by those with experience performing these operations. Total thyroidectomy is the treatment of choice for virtually all patients with PTC when postoperative radioactive iodine is considered. This group includes virtually all patients except those with the very best prognosis, that is, small tumor (less than 1 cm), confined to the thyroid without evident metastases, in an otherwise healthy woman under 45 years. Even in patients with low-risk PTC, total or near-total thyroidectomy is associated with a lower recurrence rate and mortality.6,29 Serum thyroglobulin levels after total thyroidectomy are a more accurate marker for follow-up of patients with PTC, and postoperative radioactive iodine scanning and ablation is more effective. If a total thyroidectomy

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cannot be performed without injury to the recurrent laryngeal nerve or parathyroid glands, a near-total thyroidectomy can be done with a small amount of thyroid tissue left behind that can subsequently be ablated with radioactive iodine. LYMPH NODE DISSECTION Up to 80% of patients with PTC have cervical lymph node metastases; however, the prognostic significance of lymph node metastases is controversial. Patients with PTC and matted lymph nodes or tumor extending through the lymph node capsule have a worse prognosis.6,32,33 When patients are matched for age and sex, lymph node metastases also appears to be associated with a higher recurrence rate. Patients with PTC treated with prophylactic node dissection compared with only therapeutic node dissection (removal of palpable enlarged lymph nodes) have essentially the same survival rate. Even though up to 80% of patients with PTC have occult cervical lymph node metastases, most of these metastases can be ablated with radioactive iodine treatment postoperatively and some do not appear to grow. Lymph node dissection during thyroidectomy has a higher complication rate, probably because it is associated with more tumor, especially around the parathyroid glands. Therapeutic lymph node dissection with removal of the ipsilateral central neck nodes and perithyroid lymph nodes (Delphian node and lymph nodes medial to the carotid sheath) is important for clinically involved nodes. If there are clinically involved lateral neck nodes, then a compartment-based resection, rather than a “node-plucking” operation, has a better rate of control of the nodal disease. A functional modified radical neck dissection removing all fibrofatty tissue with lymph nodes but preserving all motor (phrenic, vagus, and spinal accessory nerves) and sensory nerves as well as the sternocleidomastoid muscle and internal jugular vein unless invaded by tumor is the best approach. Contralateral lymph node dissection should also be performed for gross evidence of lymph node metastases. The superior mediastinal lower nodes and periesophageal nodes are often involved, and can often be removed through the cervical excision. RECURRENT AND PERSISTENT PTC Most patients with PTC are diagnosed with persistent or recurrent disease by an elevated serum Tg level and/or by a positive radioactive iodine scan. Some patients with recurrent PTC may have an elevated Tg with a negative radioactive iodine scan. In this situation, a therapeutic dose of 131I (100–200 mCi) may help some patients by showing uptake (diagnostic benefit) or by response to this therapy (therapeutic benefit).34 Local recurrences are often associated or precede distant metastases in patients with PTC; an evaluation for metastatic disease is important to define the extent of the recurrence. When recurrent PTC is identified in the neck by radioiodine scan, computed tomography (CT) scan, magnetic resonance imaging (MRI), or ultrasound with a positive FNA biopsy, a neck dissection can eliminate disease. Patients with solitary metastases (usually to the bone and rarely to the lung, which tend to be multiple) can benefit from operative resection. About two-thirds of patients with lung or bone metastases from differentiated thyroid cancer respond to 131I therapy. In patients who are not operative candidates, and for most patients after resection of isolated metastasis to bone, external-beam radiation can be helpful in local tumor control

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or for symptomatic relief. In those patients with PTC that fail 131 I ablation or external-beam radiotherapy and who are not surgical candidates, cytotoxic chemotherapy may be useful in patients with progressive PTC.35

Follicular Thyroid Carcinoma Clinical Features The clinical presentation of follicular thyroid carcinoma (FTC) is very similar to PTC. Most patients present with a mass in the thyroid. However, FTC is less likely to be associated with cervical lymph node metastases than is PTC, so it is unusual to have a lateral neck mass as the presenting sign. FTC can be associated with distant metastases, particularly in older patients. In contrast to patients with follicular adenoma, patients with follicular thyroid cancers are more likely to have local symptoms; these can include difficulty swallowing, dysphonia, stridor, or pain. Patients can also present with evidence of distant metastases, most typically metastases in the bone, lung, brain, or liver. Apparently because of its propensity for vascular invasion, follicular tumors often metastasize via hematogenous pathways, and only rarely via cervical lymph nodes as would be more typical of papillary cancer. Biopsy at these distant sites may demonstrate relatively benign-appearing follicular tumor; however, by its behavior it has defined itself as an invasive malignant variety. Thus, follicular cancers typically present as a slowly growing solitary thyroid mass in a middle-aged to older person. About 25% of the patients have extrathyroidal invasion at the time of presentation. Between 10% and 33% of patients have distant metastasis at the time of initial diagnosis. Most follicular cancers are nonfunctional (“cold”) by radioiodine thyroid scan. Occasionally, a follicular cancer retains the ability to concentrate iodine to a degree similar to adjacent thyroid tissue (“warm”) or even to a greater degree then the normal thyroid (“hot”). The rare “functional” thyroid cancer is nearly always a follicular carcinoma rather than a papillary tumor. Follicular thyroid cancers can occur in any age group, but the median age of groups with follicular cancers is typically higher than groups with papillary cancers. The median age at presentation is in the sixth decade of life. Similar to papillary cancer, the female to male ratio is between 2 : 1 and 5 : 1.36

Pathologic Features The important features that distinguish FTC from follicular adenomas are vascular and capsular invasion.37 Follicular carcinomas can appear very similar to follicular adenoma on cytology and gross examination and therefore impossible to identify by either the cytologist, surgeon, or pathologist before complete pathologic assessment. The well-differentiated follicular carcinomas are identified by signs of minimal invasion such as microscopic evidence of capsule discontinuity. Other follicular tumors may be less differentiated, widely invading surrounding thyroid or even extrathyroidal tissues. The tumor cells vary in their histologic differentiation, but are generally bland, monomorphic cells lacking nuclear changes typical of PTC. Thus, follicular carcinoma cells can appear differentiated and may resemble normal

Figure 55.4. Follicular variant of papillary thyroid cancer. This variant has the follicular architecture of follicular thyroid carcinoma (FTC) (black arrows) without papillary structures, but has the nuclear features of papillary thyroid cancer (PTC) (white arrows) with nuclear grooves, clearing, and clumped chromatin.

thyroid tissue even when recurrent or metastatic; this can be misinterpreted as a “thyroid remnant” and not treated properly. The precise histologic pattern may be described as follicular, trabecular, or solid or display combinations of these. In the widely invasive forms, the tumor demonstrates areas of solid growth, frequent mitoses, and atypical cells. Signs of dedifferentiation are frequent as the disease proceeds. Tumors with a mix of papillary and follicular features often show follicular differentiation, expressing follicular structures, but have nuclear features of papillary carcinoma (for example, psammoma bodies, or nuclear grooves or pseudoinclusions) (Figure 55.4). They can be difficult to diagnose on cytology, but once recognized they have the clinical course and prognosis of PTC rather than FTC.

Risk Factors and Associated Hereditary Conditions In areas with sufficient intake of iodine, most of the differentiated thyroid carcinomas are papillary. In areas with iodine deficiency and endemic goiter, the total incidence of thyroid carcinoma is similar, with a relative increase in follicular thyroid carcinoma that are sometimes even more frequent than papillary carcinomas. A substantial intake of vegetables from the cruciferous family that block iodine uptake (goitrogenic food) can contribute to these findings. The stimulatory factor in the low-iodine areas leading to thyroid tumors appears to be TSH, although no clear correlation has been documented. Nevertheless, iodine supplementation coincides with an increase in the incidence of papillary carcinomas, with reduction in follicular and especially poorly differentiated and anaplastic carcinomas.38 External radiation has not been associated with follicular carcinoma. Investigations after the Chernobyl accident generally support these earlier findings, although there are occasional reports of follicular thyroid carcinomas.39 Nearly all follicular thyroid carcinomas are sporadic, but may in rare cases also be associated with familial colon polyposis or Gardner’s syndrome, as well as Cowden’s syndrome.

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Treatment of Follicular Thyroid Cancer Surgical resection is the only available method for FTC in the thyroid. As for PTC, the choice of hemithyroidectomy or total thyroidectomy as the procedure of choice for FTC has been debated. Hemithyroidectomy or total thyroidectomy with extirpation of central lymph nodes without radioiodine are both adequate for survival outcomes in patients with invasive follicular carcinoma confined to the thyroid, that is, T1–T2N0M0. However, for larger tumors (above T2), total thyroidectomy with at least central lymph node dissection is appropriate for a number of reasons. This treatment allows postoperative 131I ablation, as well as diagnostic scintigrams for follow-up. Arguments against total thyroidectomy have been increased risk for surgical complications such as injury to the recurrent laryngeal nerve or permanent hypoparathyroidism. However, for experienced surgeons, total thyroidectomy is a safe procedure, with minor complication rates. Therefore, in T3–4 tumors, a more-extensive treatment is mandatory. Although follicular tumors metastasize to lymph nodes in the neck less frequently than papillary tumors (approximately 35% versus 67%), therapeutic modified neck dissection should be performed when clinically apparent disease is present, followed by postoperative 131I diagnostic procedures and radioiodine ablation therapy.

Hürthle Cell Carcinoma Hürthle cell carcinoma is a variant of follicular carcinoma, which is sometimes called an oxyphilic or oncocytic carcinoma. These tumors may be remarkably similar on gross examination but are microscopically characterized by an acidophilic cytoplasm with small pyknotic central nuclei. It is important to distinguish these tumors from each other, because the oncocytic carcinomas have a much lower capacity for uptake of iodine, which makes postoperative diagnostic and therapeutic 131I scintigrams difficult. They have a natural history and prognosis similar to FTC, which supports similar treatment.40

Postoperative Management of Differentiated Thyroid Carcinoma Prognosis FCDTC is the direct cause of death of more patients than all other endocrine malignancies combined. Nevertheless, with a crude mortality rate of only around 7%, the vast majority of patients with FCDTC are either cured, or lives with cancer, often for many years. Overall recurrence rates after apparent surgical cure of the primary tumor range from 10% to 35%,41,42 depending on histologic subtype and stage at diagnosis.41–45 Recurrence may sometimes occur many years after the initial, apparently successful, treatment.46 Thyroid carcinomas exhibit among the widest range of malignant potential of any human cancer. They range from the almost benign, incidentally discovered, papillary microcarcinoma, which probably has no impact on long-term survival, to extremely aggressive poorly differentiated carcinomas with a median life expectancy of only a few months. Within the FCDTC group, life expectancy and the likelihood of cure vary widely.

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There have been many attempts to identify prognostic factors for patients with FCDTC. Unfortunately, there are no randomized, prospective trials of any aspect of thyroid cancer management, largely because of the relative rarity of the tumor, its generally slow clinical course with long survivorship, and the difficulty and expense of mounting large multicenter studies over prolonged periods. Nevertheless, a great deal of information is available from large retrospective reviews from a number of centers that can be used to influence all aspects of management of the patient with differentiated thyroid cancer (DTC). To select appropriate therapy and follow-up, and to provide prognostic information to the patient, the initial step in the postoperative care of the patient with FCDTC is to categorize the patient’s risk of recurrence and death from disease. AMERICAN JOINT COMMITTEE ON CANCER (AJCC) STAGING Pathologists apply the pTNM classification system to tumors of all types, providing a convenient shorthand method to describe the tumor extent (Table 55.3).47 Using this system, the tumor is assessed according to the size of the primary tumor mass, with T1 representing tumors of 1 cm or less, T2 those between 1 and 4 cm in maximum diameter, T3 those greater than 4 cm, and T4 represents tumors of any size exhibiting local extrathyroidal invasion. The presence (N1) or absence (N0) of lymph node spread, and the presence (M1) or absence (M0) of distant metastases are similarly easily defined at the time of the original diagnosis, and the pTNM classification is generally straightforward to determine within a few hours of operation. Although the prognosis for many tumor types is determined largely or exclusively by the extent of disease, described efficiently by the pTNM classification, FCDTC are unique, in that the strongest influence on prognosis is patient age at diagnosis. As a result, the AJCC staging system uses patient age in defining stage for follicular cellderived thyroid carcinoma. In this staging system, all patients under the age of 45 with FCDTC have stage I disease unless they have evidence of distant metastases, which makes them stage II. Moreadvanced stages are restricted to patients over the age of 45, with locally invasive tumors (stage III), or with evidence of nodal (stage III) or distant (stage IV) metastases. The pTNM system is the most widely accepted tool to describe the extent of disease for staging in thyroid carcinoma. The AJCC stage correlates well with outcome of FCDTC, in both retrospective and prospectively collected data, with stage I and II disease exhibiting a less than 1% overall mortality at 5 years.48 In contrast, more-advanced stages of disease, limited to those patients over the age of 45 with locally invasive or metastatic disease, carry a less-favorable prognosis. For stage III disease, the 5-year mortality was 6% for PTC and 18% for FTC, whereas stage IV disease had a 5-year mortality in excess of 50% in both tumor types. Despite its simplicity and utility, however, the AJCC staging does not provide all the information a clinician may need to adequately classify a patient with DTC and to assist in making therapeutic decisions. It does not use several additional independent prognostic variables and may therefore risk misclassification of a significant number of patients. For this reason, several other classification schemes remain in clinical use that may permit more accurate decision making, at least for patients with FCDTC.

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TABLE 55.3. American Joint Committee on Cancer (AJCC) thyroid cancer staging. Primary tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Tumor 2 cm or less in greatest dimension limited to the thyroid T2 Tumor more than 2 cm but not more than 4 cm in greatest dimension limited to the thyroid T3 Tumor more than 4 cm in greatest dimension limited to the thyroid or any tumor with minimal extrathyroid extension (e.g, extension to sternothyroid muscle or perithyroid soft tissues) T4a Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve T4b Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels All anaplastic carcinomas are considered T4 tumors. T4a Intrathyroidal anaplastic carcinoma—surgically resectable T4b Extrathyroidal anaplastic carcinoma—surgically unresectable Regional lymph nodes (N) NX Regional lymph nodes cannot be assessed. N0 No regional lymph node metastasis N1 Regional lymph node metastasis N1a Metastasis to Level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes) N1b Metastasis to unilateral, bilateral, or contralateral cervical of superior mediastinal lymph nodes Distant metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1

Distant metastasis a

Stage grouping

Papillary or Follicular Under 45 years Stage I Any T Stage II Any T

Medullary Carcinoma Any N Any N

M0 M1

Stage I Stage II Stage III

T1 T2 T3 T1 T2 T3 T4a T4a T1 T2 T3 T4a T4b Any T

N0 N0 N0 N1a N1a N1a N0 N1a N1b N1b N1b N1b Any N Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

Stage IVA

T4a

Any N

M0

Stage IVB Stage IVC

T4b Any T

Any N Any N

M0 M1

Stage IVA

Papillary or Folicular 45 years and older Stage I T1 Stage II T2 Stage III T3 T1 T2 T3 Stage IVA T4a T4a T1 T2 T3 T4a Stage IVB T4b Stage IVC Any T

N0 N0 N0 N1a N1a N1a N0 N1a N1b N1b N1b N1b Any N Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

Stage IVB Stage IVC Anaplastic Carcinoma All anaplastic carcinomas are considered Stage IV

a

Separate stage groupings are recommended for papillary or follicular, medullary, and anaplastic (undifferentiated) carcinoma.

Source: Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, sixth edition (2002), published by Springer-Verlag New York, www.springer-ny.com.

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CLINICOPATHOLOGIC PROGNOSTIC SCHEMES FOR FCDTC For patients with FCDTC, age at initial treatment, tumor size, the presence of extrathyroidal invasion, and the presence of distant metastases at diagnosis are the most important risk factors for recurrence and for cause-specific mortality. However, unlike almost any other cancer type, the presence of lymph node metastases in PTC has little influence on cause-specific mortality from this disease, although it increases the risk of locoregional recurrence. Several other factors, not included in the AJCC staging scheme, are also independent prognostic variables in rigorous multivariate analyses, including tumor grade in PTC, which is rarely assessed in routine histologic examination; extent of microinvasion of capsule or of blood vessels in FTC; DNA aneuploidy in Hürthle cell cancer and PTC, but not in nonoxyphilic FTC; delay to initial surgical intervention; and completeness of surgical resection of the primary tumor. These prognostic factors are not of equal importance in predicting mortality or recurrence, with the most predictive factors generally being regarded as the presence of distant metastases, the age of the patient, and the extent of the tumor.49 Several prognostic systems have been developed that include a number of these variables, weighted according to their importance in predicting outcomes, in multivariate analyses, of retrospectively analyzed large cohorts of patients (see Table 55.2). Each of these schemes permits classification of patients with FCDTC (particularly PTC, the most common type) into low-, medium-, and high-risk groups, accurately predicting long term outcome for these patients. Each of the prognostic schemes includes a slightly different group of variables, weighted in slightly different ways. However, all have certain features in common, and all include both tumor and patient variables, emphasizing the likely importance of host–tumor interaction in the behavior of this group of cancers. Almost all the schemes, except the Ohio State University system, include the patient’s age as an important variable predicting outcome. The size of the primary tumor, its histologic type, the presence of extrathyroidal invasion, and the presence of distant metastases are almost universally included. Controversy remains about the importance of nodal metastases and of patient gender. Tumor grade (and DNA ploidy in certain tumor types) is almost certainly an important independent prognostic variable but is rarely assessed. The MACIS score (named for its predictive variables of Metastases, Age, Completeness of surgical excision, local Invasion, and tumor Size) was derived from a retrospective review of almost 1,800 patients with PTC treated at one institution over a period of up to 50 years (median, 17 years followup).50 Approximately half of the patients (from 1940 to 1964) were selected to represent the “training” group, and a formal multivariate analysis was performed on this group to identify the independently predictive prognostic variables from the data set. Each of these variables had a significant predictive value on outcomes in univariate analysis, but also remained significantly correlated with outcome in multivariate analysis. The MACIS equation was generated to weight the importance of each of the predictive variables, generating a single score for patient classification (Table 55.4). This equation was tested on the remaining 1,015 patients in the original data set

TABLE 55.4. The MACIS score. Metastasis Age Completeness of resection Invasion (local) Size (primary tumor) MACIS = 3.0 (for distant metastases at presentation) + 3.1 (for age less than 40 years) or (0.08 ¥ age) + 1.0 (for incomplete tumor resection) + 1.0 (if locally invasive) + 0.3 ¥ tumor size (in centimeters) MACIS score

8

20-year cause-specific mortality

4 cm

< 4 cm

+ Size Repeat Adrenalectomy CT Q 6 mo ¥ 2 years + cancer

–

Cancer History FNA Localized site – catecholamines FIGURE 56.2. Flow chart for the management of incidentally discovered adrenal tumors. –

FIGURE 56.1. Computed tomography (CT) of left adrenal aldosteronoma shows a normal right adrenal gland and a small (2-cm) tumor in the left adrenal that was an aldosteronoma.

Plasma-free metanephrine normetanephrine Serum K 24 h urine free cortisol Low-dose dexamethasome

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TABLE 56.4. Staging of adrenal cancer. Stage

Tumor size (cm)

1 2 3 4

Less than 5 More than 5 Any Any

Lymph nodes

Local invasion

Distant metastases

+ +

+ +

+

Virilization/Feminization Virilization or feminization may be combined with hypercortisolism, or the tumor may produce only estrogen or testosterone. Sex hormone secretion is often associated with adrenal cancer. In children, the clinical signs of increased androgen production include excessive growth, premature pubic and facial hair, acne, genital enlargement, increased muscle mass, and deep voice. In women, the clinical signs of excess androgen production include hirsutism, acne, amenorrhea, infertility, increased muscle mass, deep voice, and temporal balding. In adult men, hyperestrogenism presents with gynecomastia, decreased sexual drive, impotence, and infertility. In premenopausal women, hyperestrogenism presents with irregular menses. In postmenopausal women, it causes dysfunctional uterine bleeding. The workup includes 24-hour urinary 17-ketosteroids, 17-hydroxysteroids, urinary free cortisol, and, depending on virilization or feminization, serum determination of testosterone or estrogen.

Adrenal Carcinoma Seventy-five percent of adrenal carcinomas present with excessive glucocorticoid or mineralocorticoid hormone secretion; however, some may be nonfunctional.15 The mainstay of treatment of adrenal cortical carcinoma is complete surgical resection. If the carcinoma cannot be effectively removed without removing the ipsilateral kidney, concomitant nephrectomy is necessary. CT or MR can image the extent of disease and should include the chest to rule out pulmonary metastases. If the inferior vena cava is involved, imaging studies such as cavography are useful to assess extent of tumor. Tumor size, hemorrhage, and mitotic count each correlate with survival rates for patients undergoing curative resection. Tumors less than 12 cm, mitotic rate less than 6 per high-power field, and absence of hemorrhage are associated with improved survival.16 Radical, complete resection of all cancer is critical for prolonged survival and potential cure. There is no clearly effective adjuvant therapy.17 Recurrent or metastatic tumor should also be resected. Recent reports suggest that radiofrequency ablation may be able to control recurrent tumor both inside and outside the liver.18 Adrenal carcinoma may occur in children. It occurs in children younger than 6 years, with a higher incidence in girls than boys. The median age in children is 4 years. Virilization is the most common presenting feature (93%), followed by hypercortisolism.19 The overall 5-year survival rate for children with adrenal cancer is 49%, and following complete resection 70%. Adrenal cancer occurs in adults. The second peak age is between 40 and 50 years, and most present with hormonal syndromes. The staging of patients with adrenal carcinoma is as follows: 20% of patients have stage I, II, and III disease at diagnosis, whereas 80% have metastases20 (Table 56.4). Many

Five-year survival (%)

More than 80 50–75 50 10

patients (70%) present with stage III or IV disease. The definitive treatment for localized disease including stage III is en bloc resection. Even tumor thrombus within the inferior vena cava is not a contraindication to resection.21 Surgical resection of localized disease can be curative. The overall 5-year survival rate is between 20% and 35%. In a recent series, the 6-year survival following complete resection of all tumor is 60%.22 Complete resection of recurrent tumor is also useful and, if achieved, it is associated with a 6-year survival of 40%.23,24 Patients should undergo monitoring of steroid hormone levels postoperatively to assess for recurrence. CT and MRI are also able to detect local recurrences and pulmonary metastases. If a localized recurrence is detected, it should be removed surgically. Prolonged remissions have been reported after resection of hepatic, pulmonary, and cerebral metastases. Patients with recurrent adrenal cortical carcinoma who can be surgically resected have 5-year survival rates of 50% versus 8% for nonoperated cases. Control of recurrent tumor can be achieved by radiofrequency ablation.18 Palliation of bony metastases may be achieved by radiation therapy. Op-DDD (mitotane) is the most commonly used chemotherapy drug for adrenal cancer (Table 56.5). It is administered at a dose of 2 to 6 g daily, and the dose is increased until toxicity occurs. Toxicity includes gastrointestinal, neuromuscular, and skin symptoms. Mitotane prolongs bleeding time and inhibits platelet aggregation. A decrease in urinary steroid excretion is seen in most patients. Partial responses occur in one-third of patients and a few complete responses have been reported. Because mitotane inhibits the multidrug-resistant gene, chemotherapy has been given with mitotane. Patients with metastatic adrenal cortical carcinoma have been given etoposide, cisplatin, and mitotane. The response rate was 33% with some complete responses. Further, when combined with etoposide, doxorubicin, and cisplatin, it had an overall response rate of 22% to 54%.24,25 Docetaxel and gemcitabine failed to demonstrate a response in 2 patients treated.26 Irinotecan (CPT-11) at 250 mg/m2 has been ineffective in 12 patients with metastatic adrenal cortical carcinoma who failed other therapies.27

TABLE 56.5. Chemotherapy for adrenal cancer. Drug

Mitotane Suramin Doxorubicin 5-Fluorouracil (5-FU) + doxorubicin + cisplatin Etoposide + doxorubicin + cisplatin Oncovin + cisplatin + epipodophyllotoxin Mitotane + etoposide + doxorubicin + cisplatin

Response rate (%)

30–60 15–30 19 20 100 (3/3) 100 (1/1) 50

1009

tumors of the endocrine system

Pheochromocytoma Pheochromocytomas are rare tumors that secrete excessive catecholamines. They arise from chromaffin cells in the adrenal medulla and elsewhere. They occur in about 1 per 100,000 per year.28 In autopsy series, only 0.005% to 0.1% of persons have unsuspected pheochromocytomas. When urinary catecholamines are measured in hypertensive patients, pheochromocytoma is present in only 0.1% of patients. Pheochromocytomas may be intraadrenal, extraadrenal, benign, or malignant. Early diagnosis and therapy improve the prognosis. Incidence of malignancy is as low as 5% and as high as 46% in different series. Extraadrenal tumors are more likely to be cancerous. Pheochromocytomas may be associated with endocrine and nonendocrine inherited disorders. Bilateral adrenal medullary pheochromocytomas are components of MEN 2a and MEN 2b. Some families have bilateral adrenal pheochromocytomas and no other manifestation of MEN. In other families, only extraadrenal pheochromocytomas have been reported. Pheochromocytomas occur in approximately 25% of patients with von Hippel–Lindau (VHL) disease and in 1% of patients with neurofibromatosis and von Recklinghausen’s disease. Further, recent studies indicate that many patients with apparently sporadic pheochromocytomas really have either MEN-2 (RET gene) or VHL. Among 271 patients, 66 (24%) were found to have mutations of VHL and RET. This finding suggests that patients who present with apparently sporadic nonfamilial pheochromocytoma should be screened for RET and VHL mutations as 25% will have them.29 Germ-line mutations in three of the succinate dehydrogenase subunits (SDHD, SDHB, and SDHC) cause susceptibility to head and neck paragangliomas (extraadrenal pheochromocytomas).30,31 Pheochromocytomas cause intermittent, episodic, or sustained hypertension. Pheochromocytomas also cause insulin resistance and diabetes.32 Following resection of the tumor, insulin sensitivity improves.33 Further, pheochromocytomas may produce other hormones, including ectopic ACTH and Cushing’s syndrome. Pheochromocytomas arise from chromaffin cells. Chromaffin cells are widespread and associated with sympathetic ganglia during fetal life. After birth, most chromaffin cells degenerate, and the majority remain in the adrenal medulla; this may explain why approximately 90% of pheochromocytomas are in the adrenal medulla. Extraadrenal pheochromocytomas may arise anywhere, including the carotid body, intracardia, along the aorta (both thoracic and abdominal), and within the urinary bladder. The most common extraadrenal location is the organ of Zuckerkandl that is near the origin of the inferior mesenteric artery to the left of the aortic bifurcation. Data from series of patients with sporadic pheochromocytomas indicate that the right adrenal gland more often harbors a tumor than the left gland. Pheochromocytomas usually measure between 3 and 5 cm in diameter and weigh 100 g. Tumors are tan to gray in color and have a soft consistency. Larger tumors are cystic and have necrosis or calcification. Microscopically, pheochromocytomas are usually arranged in cords or alveolar patterns. Tumors are generally clearly separated from the adrenal cortex by a thin band of fibrous tissue. Extension into the cortex or vascular invasion may occur.

TABLE 56.6. Management of patients with pheochromocytoma. Step

Goal

Method

1

Diagnosis

2

Localization

3 4

Preparation Resection

5

Recurrence

24-h urine for vanyl-mandelic acid (VMA), metanephrines, and catecholamines: plasma free metanephrine, normetanephrine CT MRI Metaiodobenzylguanidine (MIBG) scan Phenoxybenzamine ± propranalol Laparoscopic adrenalectomy (open for extraadrenal and/or large tumor) Plasma-free metanephrine, normetanephrine

The pathologic distinction between benign and malignant pheochromocytomas is not clear. The only absolute criterion for malignancy is the presence of secondary tumors in sites where chromaffin cells are not usually present and visceral metastases. Malignant tumors tend to be larger and weigh more. Staining for the nuclear proliferation marker MIB-1 is positive in 50% of malignant pheochromocytomas and negative in benign tumors. Benign pheochromocytomas may demonstrate marked nuclear pleomorphism, whereas, paradoxically, malignant ones demonstrate less. Malignant pheochromocytomas usually have many more mitoses, but capsular and vascular invasion occurs with equal frequency in both. Nuclear DNA ploidy may be a predictive indicator of malignant potential. Flow cytometry has been used to identify tetraploidy, polyploidy, and aneuploidy, which are associated with malignancy. Neuropeptide Y gene expression is more common in benign tumors. Patients with pheochromocytomas can present with a range of symptoms, from mild labile hypertension to sudden death secondary to severe hypertension, myocardial infarction, or cerebral vascular accident. The classic patient describes “spells” of paroxysmal headaches, pallor, palpitations, hypertension, and diaphoresis. In 50% of patients, the hypertension is intermittent, but it may be sustained. In children, hypertension is sustained. Patients may have lactic acidosis. Patients may have weight loss and hyperglycemia. The diagnosis of pheochromocytoma is based on measuring catecholamines and metabolites in the urine (Table 56.6), which previously required a 24-hour urine for metanephrines and catecholamines.34 However, plasma free metanephrines and normetanephrines have been used recently to reliably diagnose pheochromocytoma.35 Certainly the blood measurement greatly facilitates the workup, and it is accurate. Measurements of urinary total metanephrines or VMA are not as reliable as plasma free levels of metanephrines and normetanephrine.36 If a pheochromocytoma is suspected, the best study is plasma free levels of metanephrine and normetanephrine.37 Older studies suggest that urinary measurement of catecholamines, VMA, and metanephrine levels are best. It is now clear that plasma free samples have replaced urinary studies as indicated in patients with suspected pheochromocytoma. CT and MRI are the two nonnuclear medicine procedures of choice to localize pheochromocytomas. Both are noninvasive and sensitive, being able to reliably detect tumors 1 cm in diameter. MRI may be more specific because of findings with different sequences. CT detects more than 95% of

1010 pheochromocytomas, including 9 of 10 bilateral tumors. CT also detects most extraadrenal retroperitoneal tumors. However, MRI is similar and may be better. MRI also imaged all pheochromocytomas demonstrated on CT, plus metastases to the chest, retroperitoneum, and liver that were not seen. Because it has no radiation exposure, MRI can be used to image during pregnancy. In one analysis, CT imaged 16 of 19 pheochromocytomas (84%) whereas MRI imaged 12 of 15 (75%) for comparable sensitivity.38 In addition, MRI successfully imaged an intrapericardial pheochromocytoma and distinguished it from the cardiac chambers and surrounding great vessels, which could not be determined by CT. The single best technique for localization of pheochromocytomas is nuclear scanning after the administration of labeled metaiodobenzylguanidine (MIBG). The compound is similar to norepinephrine and is taken up by vesicular monoamine transporters.39 The sensitivity of MIBG scanning with 131I for pheochromocytoma is 100% and the specificity is 95%.40 It appears that MIBG scanning is safe, noninvasive, and efficacious for the localization of pheochromocytomas, including those that arise in nonadrenal sites, and malignant disease. Bone metastases are best imaged by bone scan. Because MIBG scan is a total body study, it can image tumors wherever they are including unusual locations.40 Although CT and MRI reflect changes in morphology, scintigraphic imaging relies on tissue function. False-positive results with MIBG are rare, which accounts for the high specificity (98% to 100%). False-negative results do occur, which lowers sensitivity. For patients with suspected pheochromocytoma and negative MIBG, 18F-FDG PET may be useful. Metastases from a predominantly dopamine-secreting pheochromocytoma that did not take up MIBG were imaged with FDG-PET.41 Further, 18FDOPA PET has imaged 17 pheochromocytomas in 17 patients. It is highly sensitive and specific and may be very useful if other studies are negative.41 It has imaged a malignant bladder pheochromocytoma.42 It may be superior to MIBG for localization of metastatic pheochromocytoma.43 It is not commonly available, but it can be useful.44 Once the diagnosis is established and the tumor localized, preoperative preparation includes a-adrenergic blockade. Patients are started on phenoxybenzamine, 10 mg orally two or three times daily. If tachycardia develops, a-adrenergic blocking agents (propranolol) are added. Propranolol should never be started before a-blockade because unopposed vasoconstriction may worsen hypertension. Phenoxybenzamine increases the total blood and plasma volume and reduces lactic acidosis. Appropriately used calcium channel antagonists and selective alpha1-receptor blockers are also effective and safe.45 Small (less than 6 cm) intraadrenal pheochromocytomas are removed using laparoscopic techniques.46 However, others report that laparoscopic adrenalectomy should still be performed for large tumors (greater than 6 cm). They point out that the operative time, blood loss, and length of stay are the same for either small or large adrenal tumors.47,48 Laparoscopic procedures appear to decrease pain and shorten the time to recovery.49 Most pheochromocytomas are well localized, which facilitates laparoscopic removal. Laparoscopic adrenalectomy for familial pheochromocytomas is especially useful because these tumors are small and within the adrenal gland.50 Adrenal cortical-sparing surgery may be indicated for patients with familial pheochromocytomas who require bilat-

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eral adrenalectomy.51 However, iatrogenic pheochromocytomatosis has been described as a possible complication of laparoscopic removal. Numerous tumor cells are deposited throughout the retroperitoneum near the site of the primary tumor, which may have been caused by laparoscopic excision of a malignant tumor or by spilling benign tumor cells at the time of laparoscopic excision. Despite the exact etiology, this is a rare complication that must be considered if it continues to occur.52 Malignant pheochromocytomas are present in approximately 10% of patients with pheochromocytoma. Malignant tumors have high mitotic rate, aneuploidy and high S-phase fraction.53 EM66 is a novel secretogranin II-derived peptide that is present in the chromaffin cells of the human adrenal gland. EM66 has a higher concentrations in benign pheochromocytomas than malignant tumors.54 Expression of hTERT, HSP90, and telomerase activity may also be used to detect more-aggressive tumors.55 SDHB gene is a tumor suppressor gene. Detection of a germ-line SDHB mutation in patients with apparently sporadic pheochromocytomas appears to be associated with a tumor that is high risk for malignancy and recurrence.56 The basic principles in the treatment of malignant pheochromocytoma have been to surgically resect recurrences or metastases whenever possible and to treat hypertensive symptoms by catecholamine blockade. Surgical resection of metastatic and recurrent pheochromocytoma has been shown to prolong survival. Soft tissue masses or bony masses may be treated with radiation therapy if doses of 40 Gy or more can be administered.57 Serum levels of chromogranin A can be used to measure response to therapy.58 Survival data of patients with malignant pheochromocytoma are difficult to obtain because of the rarity and indolence of the tumor. The 5-year survival rate is between 36% and 60%. Because of the high sensitivity (85%) and specificity (100%) of 131I-MIBG to image pheochromocytomas, it has been used at higher doses to treat recurrent or metastatic pheochromocytomas. A beneficial response to treatment is observed in 42% to 60% of patients. Paedial remissions as measured by decrease in catecholamine secretion and tumor size have been observed in approximately one-third of patients treated. However, complete responses with 131IMIBG have been rare.59 Recently, very high dose (800 mCi) 131 I-MIBG resulted in complete antitumor responses in 2 of 12 patients with skeletal and soft tissue metastases from pheochromocytoma and partial responses in most.60 Combinations of cyclophosphamide, vincristine, and dacarbazine have been used in patients with metastatic pheochromocytoma. However, the regimen has been abandoned because of toxicity and variability in response rate with few complete responses. Single cases have been reported to have complete responses with cyclophosphamide, vincristine, and dacarbazine (CVD). Long-acting octreotide (sandostatin-LAR) has been used to treat malignant pheochromoctyoma without success. Even tumors that were positive on octreoscan did not respond to LAR.61 Combination chemotherapy with cyclophosphamide, vincristine, dacarbazine, doxorubicin, and epirubicin resulted in a complete response in a single patient with metastatic pheochromocytoma.62

tumors of the endocrine system

Pancreatic Islet Cell Tumors Endocrine tumors of the pancreas are classified primarily according to the associated clinical syndrome.63 Signs and symptoms are caused by uncontrolled excessive secretion of hormone. For example, patients with insulinoma have altered mental status, confusion, seizures, and other neuroglycopenic symptoms related to hypoglycemia caused by excessive uncontrolled insulin secretion.64 Pancreatic endocrine tumors share a number of common features including similar microscopic appearance, hormonal symptoms, special issues in patients with multiple endocrine neoplasia type 1,65 and malignant growth affecting survival. Pancreatic endocrine tumors are usually slow growing, and even patients with extensive tumor may still live for long periods. However, if liver metastases occur, survival will be affected by the malignant nature of the tumor. Effective treatment must address the symptoms associated with the clinical syndrome and the malignant potential of the tumor.

Epidemiology Endocrine tumors of the pancreas are rare, having an incidence of less than 10 per million people per year.63 Insulinomas are the most common islet cell tumor with a prevalence of approximately 1 per million per year, and gastrinomas are a close second. The remaining islet cell tumors are less common.

Pathology Pancreatic neuroendocrine tumors arise from cells that have been termed APUDomas (APUD means amine precursor uptake and decarboxylation). Pancreatic neuroendocrine tumors are composed of monotonous sheets of small round cells with uniform nuclei and cytoplasm. Mitotic figures are unusual. Tumors have dense secretory granules. When stained by immunohistochemistry, most pancreatic neuroendocrine tumors are positive for more than one hormone. However, in most instances only one peptide is secreted into the circulation. Pancreatic neuroendocrine tumors are hypervascular, solid, and reddish-brown in color. They occur not only within the pancreas as they have been described in ectopic pancreas tissue.66 They are usually solid, but cystic and papillary insulinomas have been described.67 Neuroendocrine tumors may have a “rhabdoid” appearance, which means sheets of monotonous tumor cells with uniform round nuclei.68 Tumors may be caused by mutations of the tumor suppressor gene DPC4 located on chromosome 18q21 that have been found in 5 of 9 (55%) nonfunctional pancreatic neuroendocrine tumors.69 X-chromosome loss of heterozygosity is common in gastrinomas from women, and its presence indicates more-aggressive growth and behavior.70 Aberrant methylation of the APC promoter is strongly involved in the molecular pathogenesis of pancreatic neuroendocrine tumors.71 Raf-1 activation causes morphologic changes and decrease in secretory granules.72 One study showed that methylation of the p16INK4a gene is the most common gene alteration in gastrinomas, and it appears to occur early in the time sequence of these tumors and may be a central process in the molecular pathogenesis.73

1011

In general, microscopic pathologic analysis of pancreatic endocrine tumors has failed to predict the growth pattern of the tumor and is not able to determine whether a tumor is benign or malignant. In addition, there is no correlation between histologic pattern and clinical syndrome. At present, the only clear determination of malignancy is detection of metastases, either in lymph nodes or liver. However, lymph node metastases do not negatively affect survival, whereas liver metastases clearly do.74 Microscopic invasion of blood vessels and surrounding pancreas is another indicator of malignancy, but it is not as precise as the detection of distant metastatic disease. Because of this, it is unclear exactly which pancreatic neuroendocrine tumors are malignant. The true nature of an individual tumor can only be determined by careful long-term follow-up studies. In general, few (less than 10%) insulinomas are cancerous,75 60% of gastrinomas are malignant (lymph node or liver metastases),76 and the majority (50% to 90%) of all other islet cell tumors are malignant. Neuroendocrine tumors of the gut are similar and have a similar prognosis. Five-year survival rates for localized neuroendocrine tumors are approximately 80% or greater, whereas for metastatic tumors the rates decrease to 50%.77 Survival of patients with pancreatic neuroendocrine tumors has been shown to decrease when liver metastases occur. However, surgical excision of liver tumors has salvaged some patients and improved prognosis.78 Functional (hormone-producing) pancreatic neuroendocrine tumors are usually malignant (except for insulinomas), but patients have an excellent survival. Most patients who undergo surgery to remove tumor have a 5-year survival of more than 75%.79 Nonfunctional pancreatic neuroendocrine tumors commonly present as a pancreatic mass lesion. These tumors may be detected incidentally on CT scan ordered for another reason (Figure 56.3). They may cause intestinal bleeding if they invade into the bowel or stomach or they obstruct the splenic vein and cause gastric varices. They may cause gastrointestinal obstruction if they obliterate the lumen of the small bowel or colon. Nonfunctional tumors are distributed evenly throughout the head, body, and tail of the pancreas. The 2-year survival for surgically removed node-negative nonfunctional pancreatic neuroendocrine tumor (NET) is 78%, for node-positive tumors is 72%,

FIGURE 56.3. CT of a large nonfunctional pancreatic neuroendocrine tumor within the head.

1012 and for liver metastases is 36%.80 Pancreatic neuroendocrine tumors do not usually obstruct the pancreatic duct, but they can be a cause of focal, recurrent pancreatitis.81,82 The size of an individual islet cell tumor does not appear to correlate with the severity of the hormonally mediated symptoms. There is, however, a clear correlation between the size of the tumor and the occurrence of malignancy; the larger the tumor, the greater the probability of metastases, especially liver metastases. Insulinomas, similar to duodenal gastrinomas, are generally small tumors, less than 2 cm. However, duodenal gastrinomas still have a 60% chance of nodal metastases, whereas small insulinomas seldom spread. Glucagonomas, somatostatinomas, pancreatic polypeptidomas, and other islet cell tumors are frequently large at the time of detection, more than 5 cm, and are usually malignant. Most pancreatic endocrine tumors are solitary, encapsulated, and within the pancreas. However, islet cell tumors may also occur in the duodenum and other extrapancreatic locations. Primary gastrinomas have been described within the duodenum (Figure 56.4), pancreas, heart, liver, stomach, and ovary. When metastases occur, they are usually found in peripancreatic lymph nodes (60%) or liver (30%). Late in the course of disease, tumor spreads to lung, bone, and even heart. Pancreatic endocrine tumors occur in either a nonfamilial (sporadic) form or in a familial form associated with multiple endocrine neoplasia type 1 (see section on MEN-1). The exact proportion of patients with pancreatic islet cell tumors who manifest MEN-1 varies in different series from less than 5% to 25%. The recognition of MEN-1 syndrome is impor-

FIGURE 56.4. Gross (A) and microscopic (B) photographs of a duodenal gastrinoma.

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tant because these patients always have multiple pancreatic neuroendocrine tumors. Furthermore, screening of other family members is indicated. Finally, the presence of one hormonal abnormality in MEN-1 patients may affect another. Primary hyperparathyroidism worsens the manifestations of Zollinger–Ellison syndrome and should be corrected first. Functional islet cell tumors are the second most frequent abnormality in MEN-1 and are present in approximately 80% of individuals. Gastrinomas, insulinomas, glucagonomas, and vasoactive intestinal peptide tumors (VIPomas) occur in decreasing prevalence in MEN-1 patients with gastrinomas in 54% and insulinomas in 20%. In addition to MEN-1, studies suggest that pancreatic islet cell tumors are found more commonly in patients with von Recklinghausen’s disease, von Hippel–Lindau syndrome, and tuberous sclerosis. In patients with von Recklinghausen’s disease, duodenal somatostatinomas and gastrinomas have been reported. In patients with von Hippel–Lindau syndrome, 17% of patients have pancreatic endocrine tumors, including both adenomas and carcinomas. However, it is unusual for these tumors to be functional and few have a clinical hormonal syndrome. Patients with tuberous sclerosis have insulinomas and nonfunctional pancreatic islet cell tumors.

Specific Islet Cell Tumors Insulinomas occur in the pancreas and are evenly distributed among the head, body, and tail.75 Insulinomas are most often benign, but they can metastasize and be malignant.83 Glucagonomas also occur within the pancreas (Table 56.7). In contrast, primary gastrinomas usually occur within the duodenum (50%), and the second most common site is the pancreas (20%–40%). Further, approximately 80% to 85% of primary gastrinomas are found within the gastrinoma triangle, an area that includes the head of the pancreas and the duodenum.84 Vasoactive intestinal peptide-secreting tumors (VIPomas) are usually in the pancreas, but they may also occur within the duodenum. Somatostatinomas are commonly in the pancreas, but may be extrapancreatic. In a recent review of 48 primary somatostatinomas, 56% were in the pancreas and 44% were in the duodenum or jejunum. Similar to glucagonomas, somatostatinomas usually are large, greater than 5 cm, and metastases are present at the time of diagnosis.85 Patients with insulinoma or gastrinoma have symptoms of hypoglycemia and ulcer diathesis with or without diarrhea, respectively. The diagnosis is established biochemically based on the results of standardized tests. Insulinoma is diagnosed by a 72-hour fast with the development of neuroglycopenic symptoms. Insulinoma is proven by hypoglycemia (glucose less than 45 mg/dL) and hyperinsulinism (insulin more than 5 mU/mL). Close supervision is necessary to exclude factitious hypoglycemia, use of medications to falsely decrease blood glucose levels. Zollinger–Ellison syndrome (ZES) is diagnosed by measurement of elevated fasting serum levels of gastrin (more than 100 pg/mL) and elevated levels of basal acid output (BAO greater than 15 mEq/h). All antiacid medications should be discontinued during testing as these drugs may falsely elevate serum gastrin levels. The secretin stimulation test is also used to diagnose ZES; 2 U/kg of secretin is given intravenously and serum levels of gastrin are measured before and

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tumors of the endocrine system TABLE 56.7. Pancreatic neuroendocrine tumor, incidence of multiple endocrine neoplasia (MEN)-1, diagnosis, location, and malignant potential. Tumor

MEN-1 (%)

Diagnosis

Location

Malignant (%)

Insulinoma

10

Pancreas

5–0

Gastrinoma

20

Fasting glucose Insulin C-peptide Pro-insulin Fasting gastrin Basal acid output (BAO) Secretin test

Glucagonoma Somatostatinoma

Rare Rare

Glucagon Somatostatin

Vasoactive intestinal polypeptide-secreting tumors (VIPoma) Ppoma (nonfunctional tumor)

Rare

VIP

Common

Pancreatic polypeptide

after. An increase of 200 pg/mL over basal levels of gastrin is consistent with ZES. After the diagnosis of insulinoma is made based on the results of the fast, localization studies are used to try to image and identify the insulinoma. CT correctly images approximately 50% of these tumors. In a recent study with multiphasic helical CT, 19 of 30 insulinomas were correctly identified; there were no false positives.86 Most experts agree that multiphasic CT is the imaging study of choice for pancreatic neuroendocrine tumors. It can image all large tumors (more than 2 cm) and it images approximately 50% of tumors as small as 1 cm. Tumors appear as a blush on CT because of increased vascularity.87 MRI localized 7 of 8 neuroendocrine tumors in one study.88 Somatostatin receptor scintigraphy (SRS) is the imaging study of choice for all pancreatic neu-

FIGURE 56.5. Somatostatin receptor scintigraphy (octreoscan) of a pancreatic tail neuroendocrine tumor with bilobar liver metastases.

Duodenum Pancreas Extrapancreatic Extraintestinal Pancreas Pancreas Duodenum Jejunum Pancreas Duodenum Pancreas

60

100 100

60

60

roendocrine tumors except insulinomas (Figure 56.5). Recent studies suggest that FDG-PET may also be useful, but it is not as good as SRS.89 SRS is generally believed to be inaccurate for the localization of insulinomas compared to all other pancreatic neuroendocrine tumors. However, in one recent study it was able to identify most insulinomas, and when combined with endoscopic ultrasound (EUS) it correctly demonstrated 15 of 16 insulinomas.90 EUS is able to identify most insulinomas, more preoperatively than all other studies. However, occasionally it may have false-positive results that lead to misguidance of the surgery. Pancreatic nodules and accessory spleens have been confused with insulinoma. EUS is not a substitute for careful preoperative evaluation and biochemical testing that should be done in every patient.91 EUS specificity can be improved by needle biopsy, which can be done for primary pancreatic tumors or lymph nodes92 (Figure 56.6). The best results are seen when one combines thin-section helical CT with EUS. In one study of 18 consecutive patients, this combination identified an insulinoma in each patient.93

FIGURE 56.6. Endoscopic ultrasound (EUS) of a large nonfunctional neuroendocrine tumor within the head of the pancreas. During EUS, the tumor was aspirated for cells, making the diagnosis of pancreatic neuroendocrine tumor. This tumor is the same tumor seen on CT scan in Figure 56.3.

1014 Because insulinomas are generally benign and located within the pancreas, the goal of surgery is to precisely identify the tumor and remove it preserving as much pancreas as possible. Intraoperative ultrasound has been useful for precise operative localization. It can identify the tumor and its relationship to vital structures such as the common bile duct and the pancreatic duct. It allows the surgeon to decide the best way to remove the tumor and avoid complications. A preoperative calcium angiogram has been shown to localize most (more than 90%) of insulinomas to the head, body, or tail of the pancreas.94 Similar studies have been done with secretin injection for gastrinomas. However, recently calcium angiogram has been shown to effectively localize most gastrinomas as well.95 Further, modern methods have allowed laparoscopic enucleation of insulinomas based on laparoscopic ultrasound done during the surgery. If it can be done, this procedure results in less pain and more rapid recovery.96 However, similar complications such as pancreatic fistula and abscess may occur with laparoscopic pancreatic operations and must be considered. Because of this fact, the length of stay with laparoscopic surgery for NET has not been dramatically different than open operations.97,98 The glucagonoma syndrome is a specific hormonally mediated clinical syndrome that includes a characteristic pruritic migratory red excoriating rash called necrolytic migratory erythema (NME), diabetes mellitus, weight loss, anemia, stomatitis, thromboembolic complications, hypoaminoacidemia, and gastrointestinal and neuropsychiatric disturbances.99 Some patients also have evidence of tachycardia, heart failure, and a dilated cardiomyopathy.100 These signs and symptoms are relieved by resection of the tumor. Infusions of zinc, amino acids, and total parenteral nutrition have each relieved the NME skin rash in certain cases.101 It is most likely caused by a nutritional deficiency related to chronic excess levels of glucagon. CT scan and octreoscan image most glucagonomas. PET scan images some tumors as well.102 Patients commonly have clinical manifestations of the hypercoagulable state, including pulmonary embolus and deep venous thrombosis.103,104 Vasoactive intestinal polypeptide-secreting tumors (VIPoma) are rare pancreatic neuroendocrine tumors with remarkable symptoms of severe diarrhea.105 Most tumors that produce VIP are found within the pancreas, but they can also be extrapancreatic. These tumors are usually malignant. Patients may have liver metastases at the time of diagnosis. MRI is the best imaging study to visualize liver neuroendocrine tumor.106,107 Octreoscan can also image tumor. VIPoma leads to a syndrome of watery diarrhea, hypokalemia, hypercalcemia, and achlorhydria. It is also called the Verner–Morrison syndrome or the pancreatic cholera syndrome. Dehydration, renal failure, and electrolyte and acid–base abnormalities are so severe that death may ensue if these are not corrected. Octreotide can reverse the diarrhea and correct the fluid–base disturbances and may be lifesaving in some patients. It has few side effects and can be used in the elderly without complications.108 Interferonalpha and 5-fluorouracil have been used to treat metastatic VIPoma and have resulted in a dramatic response in one patient.109 Nonfunctioning pancreatic islet cell tumors are usually large (more than 5 cm), and symptoms are related to tumor mass. Patients may present with incidentally imaged pancre-

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atic neuroendocrine tumor seen on a CT done for another reason. They may have intestinal bleeding or obstruction or pain. Other less-common functioning islet cell tumors such as those associated with acromegaly (GRFoma), hypercalcemia, or ectopic ACTH production are usually quite large, with liver metastases at diagnosis. Recently, a ghrelin-producing pancreatic neuroendocrine tumor was described. It was not associated with clinical features of acromegaly.110

Radiologic Imaging Despite the fact that there are numerous studies to image pancreatic neuroendocrine tumors, some patients will still have no imageable tumor. CT has been an excellent study for identifying large tumors within the pancreas and liver. It can reliably visualize tumors that are greater than 2 to 3 cm in diameter; however, smaller tumors may be missed. CT is indicated in all patients with suspected islet cell tumors, especially to exclude liver metastases. Multidetector CT has been able to image many neuroendocrine tumors including those within lymph nodes. When coupled with somatostatin receptor scintigraphy, it can reliably detect the majority of neuroendocrine tumors.111 The results with MRI are similar to CT. MRI has the advantage that no radiation is used; however, it is much more expensive and is not routinely recommended unless small liver metastases are a concern. MRI correctly imaged 29 of 31 neuroendocrine tumors in 19 patients.112 Somatostatin receptor scintigraphy (SRS) or octreoscan images neuroendocrine tumors based on the density of type 2 somatostatin receptors. The high density of sst2 on pancreatic neuroendocrine tumors and carcinoid tumors makes radiolabeled somatostatin analogues excellent for tumor imaging. If the tumor is imaged by these analogues, the peptide inhibits tumor growth and hormone secretion, making it useful for treatment. Studies are under way to label octreotide with other isotopes to use it for tumor cell destruction.113 It is an excellent study at identifying both primary and metastatic tumors. It has a sensitivity and specificity of approximately 85% to 90%. It is the imaging study of choice for nearly all neuroendocrine tumors except insulinomas. However, it must be realized that it may fail to identify small tumors within the duodenum. It has been combined with echo-enhanced power Doppler sonography to better image pancreatic neuroendocrine tumors.114 Endoscopic ultrasound is best for imaging small pancreatic islet cell tumors within the pancreas such as insulinoma. It has a sensitivity and specificity of 85% for pancreatic islet cell tumors. However, it is observer dependent and not all institutions have had excellent results. Occult insulinomas and gastrinomas can be regionally localized by calcium and/or secretin angiogram. Arteries that perfuse the pancreas are injected with an agent that causes the tumor to secrete hormone that can be measured in the hepatic vein. Calcium is used for both insulinoma and gastrinoma, whereas secretin is only for gastrinoma. These studies provide correct regional localization in approximately 90% of patients. These studies provide less information in gastrinoma, because occult tumors are generally within the gastrinoma triangle, and more information in insulinoma that are uniformly distributed throughout the entire pancreas.

tumors of the endocrine system

Treatment Treatment should be designed to control the signs and symptoms of excessive hormone secretion and the malignant growth and spread of the tumor. The only curative treatment is complete surgical resection of all tumor. Gastrinomas are most commonly within the duodenum. Duodenotomy (opening the duodenum) identifies more tumors and results in a greater cure rate, indicating that it should be done routinely in all operations for gastrinoma. These tumors are frequently small, most commonly found in the proximal duodenum, and associated with lymph node metastases in 60% of patients.115–117 Resection of primary gastrinoma has been shown to decrease the probability of liver metastases. Even localized liver metastases can be removed for apparent amelioration of symptoms and prolongation of survival.118 Serum levels of chromogranin A and secretory hormones can be used to assess curative resection, but minor changes in levels are not sensitive enough to assess tumor regression or progression.119 Repetitive imaging with CT and SRS can be used to follow tumor response to therapy. Aggressive surgery including Whipple pancreaticoduodenectomy has been performed for neuroendocrine tumors (NET) of the pancreas. However, because the prognosis is good with pancreatic neuroendocrine tumors, the operative death rate and morbidity of surgery should be acceptable. A recent report shows that the Whipple for NET had an operative mortality of 10% and a complication rate of 30%. However, the long-term survival was also excellent in that 81% and 70% were alive at 5 and 10 years, respectively.120 Chemotherapy treatment is based on tumor differentiation. Differentiation can be assessed by octreoscan and biopsy. Well-differentiated NET are usually positive on SRS, suggesting that somatostatin analogues will be useful in treatment to inhibit both tumor growth and hormone secretion. If the SRS is negative and the tumor is poorly differentiated, chemotherapy treatment is indicated. Drugs such as cisplatin and etoposide are especially useful and have 50% response rates with some dramatic responses.121 Medical management of the gastric acid hypersecretion in patients with gastrinoma can usually be achieved with 20 to 40 mg of omeprazole twice a day. The hypoglycemic symptoms of insulinoma are treated by more-frequent feedings. Drugs such as diazoxide, octreotide, and verapamil may occasionally be helpful. However, in general, the hypoglycemia of insulinoma is unable to be controlled with drugs. The symptoms of glucagonoma (rash) and VIPoma (diarrhea) can be controlled with octreotide, the long-acting somatostatin analogue. Dopamine agonists have been used to treat the hormonal secretion by some pancreatic NET. Elevated serum levels of pancreatic polypeptide and prolactin have been significantly reduced by either cabergoline or bromocyptine.122 The malignant tumoral process of islet cell tumors can seldom be controlled with chemotherapy.123 Approximately 30% to 40% of tumors respond to doxorubicin, 5-FU, and streptozotocin as single drugs or in combination. Interferon-alpha has also produced some partial responses. Chemoembolization of liver metastases using interventional radiology techniques and doxorubicin has had a significant partial response rate. However, there have been no complete responses, and it does not appear to prolong survival. Patients with untreated liver

1015

metastases have a 20% 5-year survival. On the other hand, octreotide therapy using long-acting depot slow-release-form sandostatin LAR 20 mg IM every 3 weeks or sandostatin LAR 30 mg IM every 4 weeks does inhibit tumor growth and progression of NET that have high-density somatostatin receptors. This hormonal treatment plus surgical resection and/or radiofrequency ablation of liver neuroendocrine tumors increases the 5-year survival to 80% to 90%.124,125 Liver transplantation has also been used for patients with metastatic liver NET who do not have tumor outside the liver. In general, the results have been good. Patients are seldom cured by liver transplantation as tumor generally recurs. However, the 5-year survival is between 36% and 83%.126–128 Bone metastases are usually treated with external-beam radiation therapy. They have also been successfully treated with indium-labeled pentetreotide.129 Patients may live for many years with distant metastases from neuroendocrine tumors because tumor progression may be slow.

Carcinoid Tumors Carcinoid tumors are neuroendocrine tumors derived from the diffuse neuroendocrine system. They are composed of monotonous sheets of small round cells with uniform nuclei and cytoplasm. Pathologists cannot differentiate benign from malignant tumors based on histology. Malignancy can only be determined based on the detection of metastases to either lymph nodes or distant sites. Carcinoid tumors synthesize numerous bioactive amines and peptides including neuronspecific enolase (NSE), 5-hydroxytryptamine (serotonin), 5hydroxytryptophan, synaptophysin, chromogranin A and C, substance P, tachykinins. and hormones such as ACTH, calcitonin, and growth hormone-releasing hormone. Carcinoid tumors are fairly common in autopsy series and are present in approximately 21 per million autopsies. Similarly, 1 in 300 appendectomies will have a carcinoid tumor. Carcinoid tumors occur with greater frequency in patients with the MEN-1 syndrome. Carcinoid tumors generally originate in four sites: bronchus, appendix, rectum, and small intestine (Table 56.8). Carcinoid tumors most commonly occur in the appendix (40%), small intestine (27%), rectum (13%), and bronchus (12%). Carcinoid tumors may also be divided into foregut, midgut, and hindgut. Foregut tumors include the bronchus, stomach, and thymus, which most commonly produce peptide hormones such as ACTH and calcitonin. These tumors also cause the atypical carcinoid syndrome because they secrete 5-hydroxytryptophan and lack the enzyme to convert it to 5-hydroxytryptamine or serotonin. Midgut carcinoid tumors include the appendix and small intestine (Figure 56.7). These tumors most commonly secrete serotonin that causes the typical carcinoid syndrome. However, because the liver metabolizes serotonin, signs and symptoms of the carcinoid syndrome are not present without liver metastases and the release of serotonin into the systemic circulation. Hindgut carcinoid tumors occur in the rectum and generally secrete no hormones. Foregut carcinoid tumors most commonly occur in the bronchus and are a common cause of ectopic ACTH syndrome (Cushing’s syndrome). The tumors occur in the major bronchi. They appear cherry-red on bronchoscopy because of

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TABLE 56.8. Carcinoid tumors: location, metastases, and carcinoid syndrome. Location

Site

Incidence (%)

Metastases (%)

Carcinoid syndrome

Foregut

Stomach Duodenum Bronchus Thymus Jejunum Ileum Appendix Ovary Rectum

2 3 12 2 1 23 38 Less than 1 13

22 20 50 25 35 35 2 6 3

10 3 13 0 9 9 Less than 1 50 0

Midgut

Hindgut

increased vascularity. Biopsy is contraindicated because of the risk of uncontrolled hemorrhage. MRI of the chest is the best method to diagnose bronchial carcinoid tumors because it can distinguish a tumor from hilar vessels. Lobectomy is the surgical procedure of choice as 50% have lymph node metastases. Thymic carcinoid tumors are another potential cause of ectopic ACTH syndrome. These tumors are commonly malignant. CT and MRI are excellent studies to image the extent of disease and make the diagnosis. The tumor appears as a mass within the anterior superior mediastinum and the thymus. Radical thymectomy is the procedure of choice. Care should be taken to avoid injury to one or both phrenic nerves. Stomach carcinoid tumors equal only 3 of every 1,000 gastric neoplasms (Figure 56.8). Recent studies suggest that not all gastric carcinoid tumors are similar. Some are associated with chronic hypergastrinemic states such as achlorhydria and Zollinger–Ellison syndrome. These tumors arise from the enterochromaffin cells (ECL) cells, are small, multiple and seldom malignant (9% overall). These are contrasted to sporadic carcinoid tumors of the stomach, which are large, single, and atypical on histology and are associated with the carcinoid syndrome in 15% to 50% of cases. These tumors cause the syndrome without liver metastases as the bioactive substances can enter the systemic circulation; 55% to 66% of these large gastric carcinoid tumors are malignant based on the detection of nodal or liver metastases. Midgut carcinoid tumors most commonly occur within the appendix. Most carcinoid tumors occur at the tip of the appendix and are totally removed by an appendectomy.

FIGURE 56.7. CT of an ileal carcinoid tumor (T). (From Norton et al.,76 with permission.)

Appendiceal carcinoid tumors are usually smaller than 1 cm in diameter, and simple appendectomy is adequate. Tumors between 1 and 2 cm are more worrisome, especially when present at the base of the appendix. These tumors have a 50% chance of lymph node metastases and are best treated by right hemicolectomy. Tumors greater than 2 cm in size have a high probability of nodal spread and are also treated by right hemicolectomy. However, most appendiceal carcinoids are smaller than 1 cm, at the tip of the appendix, and only require simple appendectomy. Primary small intestinal carcinoid tumors may be multiple and most occur within the ileum. In fact, 40% are within 2 feet of the ileocecal valve. Unlike appendiceal carcinoid tumors, which are usually benign, these tumors are generally malignant. They spread to local lymph nodes and cause a dense fibrotic reaction that distorts the gut and may cause symptoms of small bowel obstruction. This fibrosis may obliterate venous outflow and result in venous mesenteric infarction. The incidence of nodal metastases from ileal carcinoid tumors is dependent on the size of the tumor. If the tumor is less than 1 cm, nodal metastases are present approximately 15% of the time. If the tumor is between 1 and 2 cm, nodal metastases occur 60% to 80% of the time. If the tumor is larger than 2 cm, metastases nearly always occur. Liver metastases also occur and, if present,

FIGURE 56.8. Multiple stomach carcinoid tumors (nodules) seen on endoscopy. This patient also has thickened gastric folds secondary to Zollinger–Ellison syndrome.

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tumors of the endocrine system

patients have symptoms of the malignant carcinoid syndrome. Duodenal carcinoid tumors may also occur, but most are asymptomatic and are found on endoscopy as an incidental finding. A duodenal carcinoid tumor less than 1 cm is clinically insignificant, whereas approximately one-third of larger tumors spread to lymph nodes. Thus, duodenal carcinoid tumors are rarely clinically significant, but they must be differentiated from gastrinomas and somatostatinomas that can appear like a small duodenal carcinoid. Immunoperoxidase staining for various hormones helps to differentiate the various tumors. In approximately 1 in every 2,500 sigmoidoscopies, a hindgut carcinoid tumor is identified. Rectal carcinoids occur submucosally on the anterior or lateral walls of the rectum between 4 and 13 cm from the dentate line. Approximately 80% of these tumors are less than 1 cm in size and never metastasize. Tumors greater than 2 cm almost always metastasize. These larger tumors are locally invasive and have a large number of mitoses. Either simple resection with negative margins or low anterior resection is the procedure of choice for rectal carcinoid tumors. Abdominoperineal resection is not recommended as small tumors are seldom malignant and large tumors are usually not cured by surgery. Rectal carcinoid tumors seldom cause the carcinoid syndrome.

Carcinoid Syndrome The carcinoid syndrome is associated with severe flushing attacks. Flushing attacks are characterized by the sudden onset of a deep red color over the upper part of the body, primarily the neck and face, and an unpleasant feeling of warmth, lacrimation, itching, palpitations, and diarrhea. Flushing spells may be precipitated by stress, certain foods such as cheese or wine, exercise, and drugs. Attacks are generally brief, lasting 2 to 5 minutes, and episodic. Typical flushing attacks are most commonly seen with carcinoid tumors that originate in the midgut and have liver metastases. Diarrhea is also associated with carcinoid syndrome. Ovarian carcinoid tumors also commonly cause the carcinoid syndrome (see Table 56.8). Diarrhea usually occurs with the flushing but it may also occur alone. Typically the stools are watery with the number of movements ranging from 3 to 30 per day. Patients commonly develop wheezing and airway constriction during an attack. Cardiac manifestations are also part of the carcinoid syndrome. The cardiac disease is typically caused by fibrosis that involves primarily the right side of the heart. Fibrous deposits tend to cause constriction of the tricuspid and pulmonic valve that results in regurgitation. In the atypical carcinoid syndrome, the flushing may be prolonged, lasting several days. It is more diffuse over the entire body, and may be a constant red or cyanotic color. The atypical rash

is frequently provoked by food and may be associated with intense pruritis. In general, the signs and symptoms of the carcinoid syndrome are caused by serotonin (5-HT) secretion by the tumor. Most patients (more than 85%) with the carcinoid syndrome have elevated urinary levels of 5-hydroxyindolacetic acid (5HIAA), the major metabolite of serotonin. The carcinoid syndrome is diagnosed by measurement of elevated urinary levels of 5-HIAA. It is also important to remember that foregut carcinoid tumors may produce the atypical carcinoid syndrome. These tumors lack the appropriate decarboxylase enzyme to convert 5-hydroxytryptophan to serotonin (5-hydroxytryptamine). Therefore, in patients with the atypical carcinoid syndrome, urinary levels of 5-HIAA may be normal but urinary metabolites of tryptophan are elevated. Further, platelet levels of serotonin will be elevated because platelets have the enzyme to convert 5-hydroxytryptophan to serotonin. However, most patients with carcinoid syndrome have midgut carcinoid tumors with liver metastases, and these patients have elevated urinary levels of 5-HIAA.

Localization Studies Patients with the carcinoid syndrome typically have a mass in the small bowel on CT with cicatrization and narrowing of the bowel with partial obstruction. These patients usually have liver metastases. Tumor is best imaged by somatostatin receptor scintigraphy that has approximately a 90% sensitivity and specificity for the tumor. SRS is especially useful because it will also image bone and other distant metastases. SRS has been shown to be superior to imaging with MIBG.130

Prognosis and Treatment For all patients with the carcinoid syndrome, the 5-year survival is approximately 25% (Table 56.9). The prognosis varies with the site of origin and extent of disease. Patients with the carcinoid syndrome usually have distant metastases. The most immediate life-threatening complication is the carcinoid crisis that may occur during chemotherapy, surgery, or anesthesia. The crisis only happens in patients with 24-hour urinary 5-HIAA levels greater than 200 mg per 24 hours. The crisis initially presents with upper body flush, hypertension, and tachycardia, and subsequently severe hypotension and death may develop. Treatment with intravenous octreotide (long-acting somatostatin analogue) ameliorates the symptoms and signs and can be lifesaving. The manifestations of the carcinoid syndrome should be managed medically. The flush is initially controlled by avoiding precipitating agents, diarrhea by antidiarrheal drugs, wheezing by bronchial dilators, and valvular heart disease by

TABLE 56.9. Five-year survival (%) with carcinoid tumors by site and stage. Location

Site

Foregut

Bronchus Stomach Appendix Ileum Rectum

Midgut Hindgut

Primary with no metastasis

Nodal metastases

Distant metastases

96 93 99 75 92

71 23 99 60 44

11 0 27 20 7

1018 inotropic drugs and diuretics. However, the syndrome may not be completely controlled by these measures and eventually patients become more symptomatic. At this point, patients are treated by the somatostatin analogue octreotide 100–150 mg SC TID, which markedly improves all symptoms. After 1 to 2 weeks of octreotide, the patient can be given sandostatin LAR 20–30 mg IM every 3 to 4 weeks to control the syndrome long term. Patients who are treated chronically with this drug may become refractory to it and require larger and larger doses. Interferon-alpha has also been used to treat the carcinoid syndrome and may be helpful in some patients. Carcinoid tumors are best managed surgically. However, in patients with liver or locally advanced tumor, surgery is seldom curative. Patients with distant metastases may have symptoms related to a partial small bowel obstruction that warrant surgery. Further, in some reports aggressive surgery to debulk the primary and metastatic tumor is associated with amelioration of symptoms and prolongation of survival. Hepatic metastases may also be treated with chemoembolization, cryotherapy, radiofrequency ablation, and liver transplantation. Each of these procedures may improve symptoms, but none has been shown to clearly prolong survival. Control of liver metastases by surgery is associated with a 5year survival of 80%.131 Chemotherapy with adriamycin, 5fluorouracil, and streptozotocin has a 30% partial response rate. However, there have been no complete responses and no improvement in survival. Immunotherapy with interferonalpha has also decreased tumor size and may improve symptoms. In general, patients with carcinoid tumors live for long periods (see Table 56.9), and treatments are used to provide specific goals such as relief of symptoms and prolongation of survival. Recent data continue to document that chemotherapy has not been effective in gastroenteropancreatic neuroendocrine tumors. Somatostatin analogues such as sandostatin LAR in doses of 20–30 mg IM every 3 to 4 weeks have been able to control the signs and symptoms of carcinoid syndrome and appear to have decreased tumor growth, causing stabilization of disease.132 A prospective trial of interferon-alpha, lantreotide, or both in 80 patients with metastatic carcinoid tumors demonstrated that each of the drugs and the combination had antitumor activity that decreased symptoms and appeared to prolong survival. However, no treatment group was significantly better than the other groups.133 Other investigators have criticized this study based on inadequate numbers of patients and the use of lantreotide instead of other somatostain analogues.134 A new approach that shows promise is based on inhibition of the epidermal growth factor receptor by gefitinib, which induced apoptosis and cell-cycle arrest in in vitro studies of malignant neuroendocrine tumors.135

Multiple Endocrine Neoplasia Multiple endocrine neoplasia type 1 (MEN-1) is an inherited endocrine disorder that includes hyperplasia of the parathyroid glands, tumors of the pancreatic islets and anterior pituitary, and occasionally carcinoid tumors and lipomas. It is inherited as an autosomal dominant disorder with variable penetrance, meaning that 50% of the offspring will develop the disease, but each may not express all the components (Table 56.10).

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TABLE 56.10. Multiple endocrine neoplasias: genetics and clinical syndromes.

Chromosome Gene Autosomal dominant Phenotype MTC Virulence of MTC Pheochromocytoma Pancreatic NET 1° HPT Pituitary tumor

MEN-1

MEN-2A

MEN-2B

FMTC

11 Menin + ----+ + +

10 RET + -+ ++ + -+ -

10 RET + + + ++++ + ----

10 RET + -+ + -----

MEN, multiple endocrine neoplasia; MTC, medullary thyroid carcinoma; FMTC familial medullary thyroid carcinoma; NET, neuroendocrine tumor; 1° HPT, primary hyperparathyroidism.

Genetic Abnormalities in MEN-1 The causative gene in MEN-1 has been mapped to the long arm of chromosome 11 (see Table 56.10). The exact gene has been identified and named menin. Menin is a tumor suppressor gene, but its exact function is unknown.136 Screening for the presence of disease should begin during the second or third decade of life. Individuals at risk should be questioned and examined for kidney stones, lipomas, hypercortisolism, hypoglycemia, peptic ulcer disease, headaches, acromegaly, and visual field defects. Blood levels of calcium, glucose, prolactin, gastrin, and pancreatic polypeptide are measured.

Parathyroid Hyperplasia in MEN-1 Primary hyperparathyroidism (HPT) is the most common endocrine disorder in patients with MEN-1.137,138 The manifestations are similar to those seen in non-MEN-1 patients with HPT and include asymptomatic hypercalcemia, weakness, fatigue, kidney stones, and bone pain from decreased bone density. The prevalence of HPT in MEN-1 increases with age and is nearly 100% after age 50. The age of onset is 25 years, which is younger than sporadic HPT. Primary hyperparathyroidism is diagnosed by measurement of elevated serum levels of total calcium, ionized calcium, and parathyroid hormone (PTH). The intact PTH assay has seldom given false-positive results and is very specific for HPT. These patients always have parathyroid hyperplasia, but at surgery there can be some asymmetry in size.139 The operation of choice is currently three and one-half gland parathyroidectomy. Half the most normal-appearing parathyroid gland is left intact and marked with a clip. The cervical thymus should also be removed, as supernumerary glands may occur and are usually within the thymus.

Pancreatic Islet Cell Tumors in MEN-1 MEN-1 patients also develop pancreatic or duodenal neuroendocrine tumors. Tissue microdissection techniques show that pancreatic neuroendocrine tumors in MEN-1 originate from the ductal acinar system and not the islets.140 Endoscopic ultrasound has been used in MEN-1 patients to detect pancreatic neuroendocrine tumors at an early stage before the development of metastases. EUS was able to diagnose the

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presence of pancreatic neuroendocrine tumors in 14 of 15 MEN-1 patients before they had signs or symptoms of islet cell tumors.141 These tumors may be malignant, and there is a correlation between the size of the tumor and the chance of metastases.142 Pancreatic islet cell tumors may be nonfunctional or produce excessive hormones that cause a characteristic clinical syndrome. The most common functional islet cell tumor in MEN-1 is gastrinoma. Moreover, any islet cell tumor can occur in patients with MEN-1, including gastrinoma, insulinoma, glucagonoma, VIPoma, GRFoma, somatostatinoma, and nonfunctional tumor or PPoma. Surgery is indicated to remove a potentially malignant islet cell tumor and ameliorate hormonal effects. At surgery these patients commonly have multiple pancreatic islet cell tumors and also multiple duodenal neuroendocrine tumors.143 Recent studies indicate that tumors that produce insulin, glucagon, and VIP are more commonly within the pancreas, whereas tumors that secrete gastrin are usually within the duodenum.144 The goal of surgery is to remove tumor without excessive morbidity and mortality. Surgical resection seldom cures patients of Zollinger–Ellison syndrome,145 but it reduces the probability of liver metastases. The concept of early diagnosis of pancreatic neuroendocrine tumors in MEN-1 patients is not supported by the low cure rate and the fact that MEN1 patients with resected metastatic tumors have the same survival as patients with resected localized tumors.146

Pituitary Tumors in MEN-1 The most common pituitary tumor in MEN-1 is a prolactinoma. Elevated serum levels of prolactin are diagnostic and are used as a screening study. Prolactinomas cause galactorrhea and impotence. Pituitary tumors in MEN-1 may also secrete other hormones including corticotropin (ACTH), growth hormone, and thyroid stimulating hormone (TSH). These tumors are associated with Cushing’s disease, acromegaly, and hyperthyroidism, respectively. Biochemical diagnosis of each is based on recognition of the clinical signs and symptoms. MRI or CT of the sella and visual field examination are ordered for patients suspected to have pituitary tumors. Bitemporal hemianopsia may occur when large tumors compress the optic chiasm. Pituitary adenomas that produce prolactin are usually treated with bromocryptine. Pituitary tumors can also be removed surgically or less commonly are treated with irradiation.

Less-Common Tumors in MEN-1 Less-common tumors that may be occur with MEN-1 include bronchial or thymic carcinoids, intestinal carcinoids, gastric carcinoids, lipomas, benign adenomas of the thyroid gland, benign adrenocortical adenomas, and rarely adrenocortical carcinomas. Carcinoid tumors should be removed surgically when identified. Cortical adenomas of the thyroid gland and benign cortical adenomas of the adrenal cortex usually require no treatment, unless there is evidence of excessive hormonal function. Lipomas are usually large and should be excised when symptomatic. Adrenal cortical carcinomas commonly present with signs and symptoms of hypercortisolism and are identified as a large adrenal tumor on CT (6 cm). Surgical resection is the treatment of choice.

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Multiple Endocrine Neoplasia Type 2A, 2B, and Familial Medullary Thyroid Carcinoma Multiple endocrine neoplasia type 2A (MEN-2A) is an autosomal dominant inherited endocrine syndrome that is characterized by medullary thyroid carcinoma (MTC), adrenal pheochromocytoma(s), and parathyroid hyperplasia (see Table 56.10). Multiple endocrine neoplasia type 2B (MEN-2B) is an autosomal dominant inherited endocrine syndrome that is characterized by MTC, adrenal pheochromocytoma(s), and a characteristic phenotype that includes mucosal neuromas, puffy lips, bony abnormalities, marfanoid habitus, intestinal ganglioneuromas, and corneal nerve hypertrophy.147 Unlike MEN-2A, parathyroid disease is not associated with MEN-2B. Familial medullary thyroid carcinoma (FMTC) is characterized by an autosomal dominant inheritance of only medullary thyroid carcinoma without any other endocrine abnormalities.148

Gene Defect in MEN-2 The gene for MEN-2A, MEN-2B, and FMTC has been localized to the pericentromeric region of chromosome 10 (see Table 56.10). The responsible gene is a transmembrane protein kinase receptor called RET.149,150 RET is an oncogene in that mutations enhance cellular growth. The exact mechanism by which RET enhances cellular growth is unknown. Recent studies have detected missense mutations in RET in all individuals with MEN-2A, MEN-2B, and FMTC.149,150 MEN-2A and FMTC mutations have been identified within the extracellular portion of the molecule, whereas MEN-2B mutations have been identified within the intracellular domain.

Medullary Thyroid Carcinoma In patients with MEN-2A, MTC generally appears between the ages of 5 and 25 years before the development of pheochromocytoma or primary hyperparathyroidism.150 Recently, detection of RET mutations in the peripheral white blood cells of patients from kindreds with MEN-2A has been used as a screening procedure to diagnose an affected individual.150,151 Because 100% of individuals with MEN-2A will develop MTC, total thyroidectomy has been performed when RET mutations are detected. Before thyroid surgery, it is important to rule out the presence of a pheochromocytoma by measuring 24-hour urine levels of VMA, metanephrines, and total catecholamines. When total thyroidectomy has been performed based solely on genetic testing, either premalignant C-cell hyperplasia or in situ MTC has been identified. Individuals with MEN-2B have a characteristic phenotype.147 These patients have prognathism, puffy lips, poor dentition, mucosal neuromas, corneal nerve hypertrophy, and multiple bony abnormalities. The presence of MEN-2B can be ascertained by the observation of corneal nerve hypertrophy on slit-light examination. Patients with MEN-2B usually have locally advanced MTC at presentation.147 These patients are seldom cured by thyroidectomy and usually die of the MTC. Individuals with FMTC have the best prognosis.148 In these patients, MTC occurs at an older age and patients seldom die of MTC. Thus, in the three different familial settings, although the same oncogene is affected, the virulence of the MTC is different. The most virulent form is MEN-2B,

1020 the intermediate form is MEN-2A, and the least virulent is FMTC. Total thyroidectomy is indicated for the familial types of MTC as each involves both lobes of the gland.

Pheochromocytoma in MEN-2A and 2B Individuals with either MEN-2A or MEN-2B may develop bilateral benign intraadrenal pheochromocytomas.150 The diagnosis of pheochromocytoma is made by detection of elevated 24 hour urinary levels of VMA, metanephrines, or total catecholamines. Urinary metanephrines are the single best diagnostic study. Imaging studies can identify which adrenal gland is involved. CT, MRI, and MIBG scan each have utility. Both MRI and CT can image pheochromocytomas as small as 1 cm. There is controversy as to the extent of adrenalectomy in patients with MEN-2. Some recommend bilateral adrenalectomy for all individuals with biochemical evidence of pheochromocytoma, because studies have shown that 70% are bilateral and sudden death can be caused by an untreated pheochromocytoma. Others remove only the adrenal gland in which a tumor is seen. If a unilateral adrenalectomy is performed, careful follow-up is warranted as some patients may develop another tumor in the contralateral gland. Recent studies have demonstrated that laparoscopic adrenalectomy is the method of choice to remove these tumors. Resection should be performed after the patient has been prepared preoperatively with alpha-adrenergic-blocking drugs such as phenoxybenzamine. Adrenal surgery should be performed before thyroidectomy.

Parathyroid Disease in MEN-2A Patients with MEN-2A may also develop symptomatic primary hyperparathyroidism (HPT).152 The diagnosis is ascertained by measurement of elevated serum levels of calcium and parathyroid hormone. HPT is caused by multiple gland disease or parathyroid hyperplasia (see Table 56.10). The proper surgical treatment is three and one-half gland parathyroidectomy.

Gastrointestinal Manifestations of MEN-2A or MEN-2B Some individuals with MEN-2A may also have Hirschsprung’s disease. Recent evidence suggests that Hirschsprung’s disease is also associated with RET mutations; however, these mutations are inactivating for RET. Individuals with MEN-2B commonly complain of severe constipation, and megacolon or diverticulosis has been described. MEN-2B patients are known to have abnormal gut motility secondary to intestinal ganglioneuromatosis. Constipation should be treated as symptoms arise. As the MTC becomes metastatic, patients may develop severe secretory diarrhea. MTC can secrete a wide variety of peptide hormones that cause diarrhea. Octreotide has been used to inhibit the diarrhea in this setting.

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docrine tumors: identification of one pancreatic ghrelinoma. J Clin Endocrinol Metab 2003;88:3117–3120. Nguyen BD. Scintigraphic and computed tomographic imaging of isolated peripancreatic nodal gastinomas. Clin Nucl Med 2003;28:47–48. Owen NJ, Sohaib SAA, Peppercorn PD, et al. MRI of pancreatic neuroendocrine tumours. Br J Radiol 2001;74:968–973. deHerder WW, Hofland LJ, van der Lely AJ, Lamberts SWJ. Somatostatin receptors in gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer 2003;10:451–458. Rickes S, Unkrodt K, Ocran K, Neye H, Wermke W. Differentiation of neuroendocrine tumors from other pancreatic lesions by echo-enhanced power Doppler sonography and somatostatin receptor scintigraphy. Pancreas 2003;1:76–81. McIntyre TP, Stahfels KR, Sell HW Jr. Gastrinoma. Am J Surg 2002;183:666–667. Norton JA, Alexander HR, Fraker D, Venzon D, Gibril F, Jensen RT. Does the use of routine duodenotomy (DUODX) affect rate of cure, development of liver metastases or survival in patients with Zollinger-Ellison Syndrome (ZES)? Ann Surg 2004;239(5):617–625; discussion 626. Zogakis TG, Gibril F, Libutti SK, et al. Management and outcome of patients with sporadic gastrinoma arising in the duodenum. Ann Surg 2003;238:42–48. Norton JA, Sugarbaker PH, Doppman JL, et al. Aggressive resection of metastatic disease in selected patients with malignant gastrinoma. Ann Surg 1986;203:352–359. Abou-Saif A, Gibril F, Ojeaburu JV, et al. Prospective study of the ability of serial measurements of serum chromogranin A and gastrin to detect changes in tumor burden in patients with gastrinomas. Cancer (Phila) 2003;98:249–261. Sarmiento JM, Farnell MB, Que FG, Nagorney DM. Pancreaticoduodenectomy for islet cell tumors of the head of the pancreas: long-term survival analysis. World J Surg 2002;26: 1267–1271. Fjallskog ML, Granberg DPK, Welin SLV, et al. Treatment with cisplatin and etoposide in patients with neuroendocrine tumors. Cancer (Phila) 2001;92:1101–1107. Pathak RD, Tran TH, Burshell AL. A case of dopamine agonists inhibiting pancreatic polypeptide secretion from an islet cell tumor. J Clin Endocrinol Metab 2004;89:581–584. Modlin IM, Lewis JJ, Ahlman H, Bilchik AJ, Kumar RR. Management of unresectable malignant endocrine tumors of the pancreas. Surg Gynecol Obstet 1993;176:507–518. Saito F, Naito H, Funayama Y, et al. Octreotide in control of multiple liver metastases from gastrinoma. J Gastroenterol 2003;38:905–908. Norton JA, Kivlen M, Li M, Schneider D, Chuter T, Jensen R. Morbidity and mortality of aggressive resection in patients with advanced neuroendocrine tumors. Arch Surg 2003;138: 859–866. Ringe B, Lorf T, Dopkens K, Canelo R. Treatment of hepatic metastases from gastroenteropancreatic neuroendocrine tumors: role of liver trasplantation. World J Surg 2001;25:697–699. Ahlman H, Friman S, Cahlin C, et al. Liver transplantation for treatment of metastatic neuroendocrine tumors. Ann NY Acad Sci 2004;1014:265–269. Olausson M, Friman S, Cahlin C, et al. Indication and results of liver transplantation in patients with neuroendocrine tumors. World J Surg 2002;26:998–1004. van der Hiel B, Stokkel MPM, Chiti A, et al. Effective treatment of bone metastases from a tumour of the pancreas with high activities of indium-111-pentetreotide. Eur J Endosc 2003;149: 479–483. Kaltsas G, Korbonits M, Heintz E, et al. Comparison of somatostain analog and metaiodobenzylguanidine radionuclides in the diagnosis and localization of advanced neuroendocrine tumors. J Clin Endocrinol Metab 2001;86:895–902.

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131. Norton JA, Warren RS, Kelly MG, Zuraek MB, Jensen RT. Aggressive surgery for metastatic liver neuroendocrine tumors. Surgery (St. Louis) 2003;134:1057–1065. 132. Pelley RJ, Bukowski RM. Recent advances in systemic therapy for gastrointestinal neuroendocrine tumors. Curr Opinion Oncol 1999;11:32–38. 133. Faiss S, Pape UL, Bohmig M, et al. Prospective randomized multicenter trial on the antiproliferative effect of lantreotide, interferon-alpha, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors: the international lanreotide and interferon alfa study group. J Clin Oncol 2003;21:2689–2696. 134. Volter V, Peschel C. Is lantreotide and/or interferon alfa an adequate therapy for neuroendocrine tumors? J Clin Oncol 2004;22:573–574. 135. Hopfner M, Sutter AP, Gerst B, Zeitz M, Scherubi H. A novel approach in the treatment of neuroendocrine gastrointestinal tumours. Targeting the epidermal growth factor receptor by gefitinib (ZD 1839). Br J Cancer 2003;89:1766–1775. 136. Chandrasekharappa SC, Guru SC, Manickam P, et al. Positional cloning of the gene for multiple endocrine neoplasia type 1. Science 1997;276:404–407. 137. Friedman E, Larsson C, Amorosi A, et al. Multiple endocrine neoplasia type 1 pathology, pathophysiology, molecular genetics and differential diagnosis. In: Bilezikian JP, Levine MA, Marcus R (eds). The Parathyroids. New York: Raven Press, 1994: 647–680. 138. Metz DC, Jensen RT, Bale AE, et al. Multiple endocrine neoplasia type 1 clinical features and management. In: Bilezikian JP, Levine MA, Marcus R (eds). The Parathyroids. New York: Raven Press, 1994:591–646. 139. Marx SJ, Menczel J, Campbell G, Aurbach GD, Spiegel AM, Norton JA. Heterogeneous size of the parathyroid glands in familial multiple endocrine neoplasia type 1. Clin Endocrinol 1991;35:521–526. 140. Vortmeyer AO, Huang S, Lubensky I, Zhuang Z. Non-islet origin of pancreatic islet cell tumors. J Clin Endocrinol Metab 2004;89: 1934–1938. 141. Gauger PG, Scheiman JM, Wamsteker EJ, et al. Role of endoscopic ultrasonography in screening and treatment of pancreatic endocrine tumours in asymptomatic patients with multiple endocrine neoplasia type 1. Br J Surg 2003;90:748–754. 142. Weber HC, Venzon DJ, Jaw-Town L, et al. Determinant of metastatic rate and survival in patients with Zollinger-Ellison syndrome: a prospective long-term study. Gastroenterology 1995;108:1637–1649. 143. Veldhuid JD, Norton JA, Wells SA Jr, Vinik AI, Perry RR. Surgical vs. medical management of multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 1997;82: 357–364. 144. Pipeleers-Marichal M, Somers G, Willems G, et al. Gastrinomas in the duodenums of patients with multiple endocrine neoplasia type 1 and the Zollinger-Ellison syndrome. N Engl J Med 1990;322:723–727. 145. MacFarland MP, Fraker DL, Alexander HR, Norton JA, Lubensky I, Jensen RT. Prospective study of surgical resection of duodenal and pancreatic gastrinomas in multiple endocrine neoplasia type 1. Surgery (St. Louis) 1995;118:973–980. 146. Norton JA, Alexander HR, Fraker DL, et al. Comparison of surgical results in patients with advanced and limited disease with multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome. Ann Surg 2001;234:495–506. 147. Norton JA, Fromme LC, Farrell RE, Wells SA Jr. Multiple endocrine neoplasia type 2B: the most aggressive form of medullary thyroid carcinoma. Surg Clin N Am 1979;59: 109–119. 148. Farndon JR, Leight GS, Dilley WG, et al. Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity. Br J Surg 1986;73:278–282.

1024 149. Mulligan LM, Eng C, Healey CS, et al. Specific mutations of the RET proto-oncogene are related to the disease phenotype in MEN2A and FMTC. Nat Genet 1994;6:70–74. 150. Santoro M, Carlomagno F, Romano A, et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science 1995;267: 381–383.

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151. Lips CJM, Landsvater RM, Hoppener JWM, et al. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med 1994;331:828–835. 152. Howe JR, Norton JA, Wells SA Jr. Prevalence of pheochromocytoma and hyperparathyroidism in multiple endocrine neoplasia type 2A: results of long-term follow-up. Surgery (St. Louis) 1993;114:1070–1077.

5 7 S

Sarcomas of Bone Randy N. Rosier and Susan V. Bukata

arcomas of bone have a number of distinguishing features that set them apart from primary cancers of many other organ systems. First, they are extremely rare in comparison with other types of cancer, a fact that has impeded the ability of treatment in this field to evolve rapidly in an evidence-based manner because of the small numbers of patients available for studies. Progress in this field has been possible only with multicenter and oncology group trials that can provide sufficient numbers of patients for study. Even so, clinical trials are generally limited to prospective case series at best, and much of the literature is based on retrospective case series. True controlled randomized prospective trials are extremely rare. Nevertheless, a number of clinically useful observations defining the behavior of these tumors and their responses to treatments have derived from the analyses of the numerous case series that have been published, and these results and the associated levels of evidence are reviewed here. Bone sarcomas are generally characterized by a solitary primary focus with initial local growth being followed by hematogenous patterns of metastasis, with the lungs as the most common initial metastatic site. Metastases to other bones also can occasionally occur, although lymphatic, central nervous system, and other solid organ metastases are distinctly rare. The annual incidence of primary bone malignancies is less than 3,000 cases/year in the United States, excluding marrow cell malignancies such as lymphoma and myeloma.1 The majority of bone sarcomas fall into three histogenic types: osteosarcoma, Ewing’s sarcoma, and chondrosarcoma. Osteosarcoma and Ewing’s sarcoma preferentially affect children and young adults, whereas chondrosarcoma is seen more commonly in later adulthood. Far less common sarcomas of bones include fibrosarcoma, malignant fibrous histiocytoma, and extremely rare lesions such as adamantinoma. Because of the extreme rarity and lack of clinical trials with these uncommon lesions, the following material focuses on the three most common tumor types. Bone sarcomas typically evolve in a single focus, with local centrifugal growth and invasion of the bone and surrounding soft tissues. Although metastases are typically pulmonary in location, metastases within a single bone (so-called skip metastases2) or to other bones can occur occasionally.3 Before the advent of chemotherapy, treatment was generally by surgical amputation proximal to the lesion, and the prognosis for these sarcomas was extremely poor. Use of chemotherapy, in particular for osteosarcoma and Ewing’s sarcoma, has markedly improved survival in comparison with

historical results. While osteosarcoma and chondrosarcoma are relatively resistant to radiation, Ewing’s sarcoma is radiosensitive, and radiation has been used as both a primary or adjuvant treatment for this disease in the past.4 However, because of late recurrences in bone at the primary site and other complications such as pathologic fracture, the treatment paradigm for this disease has evolved over the past two decades to surgical resection and adjuvant chemotherapy, similar to the approach for osteosarcoma.5 For chondrosarcoma, because of resistance to both chemotherapy and radiation, surgery remains the only method of treatment.6 In addition to the use of adjuvant chemotherapy and radiation, the treatment of bone sarcomas has evolved surgically during the past two to three decades as well. There has been a progressive and well-supported change from amputations to limb-sparing types of surgical procedures for the majority of bone sarcomas.5,7 A number of factors have contributed to this change, many related to technologic advances. Examples include accurate imaging techniques such as magnetic resonance imaging (MRI), which enable far better assessment of the anatomic location of the tumor than was available previously; free tissue microvascular transfers, enabling coverage of problematic soft tissue defects; and availability of osteochondral allografts and complex prosthetic bone and joint replacement devices for limb reconstruction. These advances have dramatically enhanced the ability to perform limb salvage procedures with preservation of limb function while not compromising treatment of the malignancy. Instruments for limb functional outcomes assessment have been developed8 and are widely used to evaluate local treatment outcomes, in addition to the traditional measures of disease presence or absence, quantification of disease extent, and performance status. There are currently two slightly different staging systems used by orthopedic oncologists for bone sarcomas.9 The surgical staging system of Enneking10,11 is based on the grade, anatomic extent, and presence of metastases, and has been widely used by musculoskeletal oncologists for many years. It has been adopted by the Musculoskeletal Tumor Society and is also known as the MSTS staging system.9 The staging correlates well with survival and facilitates surgical planning for the primary lesion. Tumors are graded as either low or high grade (stage I or II, respectively), and as either confined to a single anatomic compartment (A) or involving more than one anatomic compartment (B). Stage III refers to any tumor with metastases. More recently, the American Joint Committee on Cancer has developed a bone tumor staging system

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TABLE 57.1. Musculoskeletal Tumor Society staging system. Stage

Grade

Local extent

Metastases

I-A I-B II-A II-B III

Low Low High High Any

Intracompartmental Extracompartmental Intracompartmental Extracompartmental Any

None None None None Present, any site

Data from Enneking et al.10

that is also in use, the major differences being that tumor size is considered as well as location of metastases.9 Tables 57.1 and 57.2 outline the bone sarcoma staging systems. Several considerations borne out by both staging systems are that higher-grade tumors, tumors with metastases, and large or anatomically more extensive tumors have worse prognoses. In a recent comparison of the two staging systems, no significant difference in prognosis prediction was found, indicating that at present either system remains acceptable.9 Clinical presentation of bone sarcomas usually involves pain, often at rest or at night, and presence of swelling or a mass at the primary site. Systemic symptoms are rare. Occasionally pathologic fracture can occur, although this is fortunately relatively uncommon, presumably because bone sarcomas are generally quite painful and may cause the patient to seek medical attention before bone destruction is sufficient to cause fracture. The most useful study in developing differential diagnosis of the lesion remains the radiograph of the primary site. Osteosarcomas usually exhibit destructive patterns with disorganized bone formation, periosteal reaction, and often extension into the adjacent soft tissues. Ewing’s sarcomas tend to have a permeative lytic pattern on radiographs, with periosteal reaction and also with soft tissue extension. Chondrosarcomas may be identified or suspected because of the combination of a destructive radiographic appearance with presence of calcifications. Threedimensional imaging, generally with MRI, enables evaluation of the anatomic extent, the soft tissue involvement, and proximity to critical neurovascular structures, and helps to determine feasibility of limb-sparing surgical treatment of the tumor. Diagnosis is most commonly achieved by needle biopsy, although occasionally an open biopsy may be necessary to obtain adequate tissue for definitive diagnosis. Biopsy is best performed by an experienced orthopedic oncologist who will ultimately provide the surgical treatment of the primary tumor, because placement of the biopsy site has important anatomic considerations relevant to the definitive resection, and outcomes have been shown to be better in TABLE 57.2. The American Joint Committee on Cancer (AJCC) staging system for bone tumors. Stage

Grade

Local extent

Metastases

IA IB IIA IIB III IVA IVB

Low Low High High Any Any Any

£8 cm ≥8 cm £8 cm ≥8 cm Any Any Any

None None None None Skip metastases Pulmonary metastasis Other metastases

Data from AJCC Cancer Staging Manual, sixth edition (2002), published by Springer-Verlag New York, www.springer-ny.com.

57

this circumstance.12 Additional staging studies besides the imaging of the primary lesion should include computed tomographic (CT) scan of the lungs to detect pulmonary metastases and a whole-body bone scan to help identify bony metastases or skip metastases. Following confirmation of diagnosis and staging, either surgical treatment (for chondrosarcoma) or preoperative adjuvant chemotherapy (for osteosarcoma or Ewing’s sarcoma) is initiated. For those tumors treated with adjuvant chemotherapy, surgical resection and reconstruction (if feasible) is carried out after several cycles of preoperative “neoadjuvant” treatment. Following surgical treatment, chemotherapy is resumed for a predetermined number of cycles, depending on the protocol in use. Metastatic pulmonary lesions persisting after chemotherapy or appearing later during posttreatment follow-up may be resected by thoracotomy with salvage of some patients.13 After successful completion of therapy, patients are monitored periodically with radiographs and other local imaging modalities at the primary site, as well as with chest CT scans and bone scans. The role of positron emission tomography (PET) scans in evaluation and follow-up of bone sarcomas is still in evolution, and this modality is not yet a component of most standardized protocols. PET scan activity has been shown in chondrosarcoma to correlate with grade and outcome,14 although CT scans have been shown to be superior to PET scans in detection of pulmonary metastasis of osteosarcoma.15 PET scan activity has also been shown to correlate with response to chemotherapy for bone sarcomas.16 However, the role of PET scans in diagnosis and follow-up of bone sarcomas remains to be determined.

Osteosarcoma Osteosarcoma is by definition a sarcoma composed of boneforming cells and is the most common of the primary bone sarcomas. Osteosarcoma is characterized by the production by the tumor cells of the matrix of bone, osteoid, which may mineralize to a variable extent. Osteosarcomas may also contain other tissues of mesenchymal origin, such as cartilage and fibrous tissue. Osteosarcoma most commonly affects individuals in the second and third decades and preferentially involves the major long bones, that is, the femur, tibia, and humerus, although essentially any bone can be involved. There are a number of histologic variants of osteosarcoma, including typical central high-grade osteosarcoma, telangiectatic osteosarcoma, parosteal osteosarcoma, periosteal or juxtacortical osteosarcoma, fibroblastic osteosarcoma, chondroblastic osteosarcoma, intramedullary low-grade osteosarcoma, and secondary osteosarcoma (most commonly arising in irradiated bone or in Paget’s disease).17 Parosteal osteosarcomas are low-grade lesions with low metastatic potential arising adjacent to the periosteum, usually of the posterior distal femur, proximal tibia, or of the proximal humerus. These tumors differ from most other osteosarcoma subtypes in that the treatment is generally surgical resection alone.18 Studies of prognosis versus histogenic subtypes of osteosarcomas have shown that telangiectatic and fibroblastic osteosarcomas have a relatively better prognosis and chondroblastic variants a worse prognosis.19–22 The approach to treatment of osteosarcoma for the past two decades has consisted of induction multiagent chemotherapy, surgical resection (whether amputation or

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limb salvage surgery with reconstruction), and then postoperative chemotherapy. The approach arose from the Rosen T10 protocol, which produced markedly enhanced survival compared with the prior dismal historical results of amputation alone.23 Although a number of different protocols have been used, the most commonly included drugs in the multiagent regimens have been doxorubicin, methotrexate, cisplatin, cyclophosphamide, and ifosfamide (Table 57.3.13,24–38 Although other agents have been employed, there has not been a dramatic difference among protocols in outcomes. The recent evidence in the literature is summarized in Table 57.3. Many series consist of small numbers of patients, and most are retrospective or prospective case series, with true randomized clinical trials being extremely rare except for a few Phase III comparative studies. Overall, however, the survival rates with this tumor have not changed dramatically beyond original chemotherapeutic protocols. Comparative studies have determined that local recurrence and survival rates do not differ whether the patient has had limb salvage or amputation.5 Some of the major advances in the past decade relate to improved ability to salvage functional extremities, with custom and modular prosthetics, enhanced soft tissue reconstructions, and allografting technologies. Recent develop-

ments in lengthening prosthetics have enabled salvage of extremities in younger children, despite a relatively high complication rate.39,40 However, prevention and treatment of metastatic disease remain the major challenges. Evidence from the literature summarized in Table 57.3 and site-specific evidence presented in Table 57.441–45 lead to consensus on a number of issues, which are summarized by the following: 1. Prognosis is worse with metastasis or with local recurrence. 2. Good response to neoadjuvant chemotherapy (greater than 90% necrosis) is associated with a better prognosis. 3. Pelvic and spinal primary sites are associated with a worse prognosis. 4. Older patients have a worse prognosis with osteosarcoma. 5. Pathologic fracture is not associated with a worse prognosis and is no longer believed to be an absolute indication for amputation. 6. Outcome varies among osteosarcoma subtypes. 7. Aggressive treatment with multiagent chemotherapy and surgical resection carries a better prognosis than lessaggressive approaches.

TABLE 57.3. Clinical studies of osteosarcoma. Study

Reference

Year

N

Type

Study specifics

Lin Bacci

24 25

2003 2003

50 185

RCS RCS

Wilkins

26

2003

47

PCS

Smeland Kager

27 28

2003 2003

113 202

PCS RCS

Goorin

29

2003

100

PRCT

Grimer

30

2003

481

RCS

Tsuchiya

31

2002

280

RCS

Bacci

32

2002

72

PCS

Multiagent + surg Cisplatin, dox, ifos, mtx Mets vs. nonmet Dox, intraarterial cisplatin preop Mtx, cisplatin, dox Multiagent, varied regimens; w/mets Neoadjuvant vs postop chemo Pt age >40 years; surg + multiagent Stratified by time of met presentation Ifos added to dox, mtx, cisplatin

Thompson

13

2002

85

RCS

Multiagent + surg

Carsi Goorin

33 34

2002 2002

47 43

Berend

35

2001

54

RCS phase II/III RCS

Bacci

36

2001

162

PCS

Ferrari

37

2001

300

RCS

Pt age >40 years Etopo/ifos; pts presenting w/mets Neoadj, surg ± postop chemotherapy Mtx, dox, cisplatin, ifos Mtx, dox, cisplatin, ifos

Petrilli

38

1999

33

PCS

Intraarterial carboplatin + multiagent, + mets

F/U; other

EFS

OS

47.1 mo w/mets nonmet 92 mo

7 years 51% 2 years 21% 2 years 75% 10 years 84%

7 years 68% 2 years 55% 2 years 90% 10 years 92%

83 mo 1.9 years

5 years 63% 5 years 18% 10 years 16% 5 years 61% 5 years 65% NR

5 years 74% 5 years 29% 10 years 24% 5 years 78% (combined) 5 years 46%

Early Late 5 years

All metastatic 5 years 73%

5 years 18% 5 years 31% 5 years 87%

4 years

4 years 51%

4 years 67%

5 years 32% Lung met Bone met NR

5 2 2 5

5 years 56%

5 years 71%

9.2 years

8 years 59%

NR

No mets + mets

3 years 65% 3 years 14%

3 years 71% 3 years 17%

Neoadj Postop

10%CR 49%PR Chemo None 6.5 years

years years years years

Conclusions

42% 39% 58% 54%

Prog worse w/mets Better prog. w/intraart Rx Supports surg for lung mets Neoadj Rx same as postop Rx Worse prog. older pts Late mets better prog Increased toxicity; incr. survival # mets, early mets worse Worse prog Effective but high toxicity No difference Ifos no difference Tumor vol, hi alk phos, poor prognosis 73%–81% good response to carboplatin

RCS, retrospective case series; PCS, prospective case series; PRCT, prospective randomized clinical trial; EFS, event-free survival; OS, overall survival; NR, not reported; F/U, follow-up; pts, patients; dox, doxorubicin; mtx, methotrexate; etopo, etoposide; ifos, ifosfamide; surg, surgery; mets, metastasis; prog, prognosis; vol, volume; incr, increased; alk phos, alkaline phosphatase.

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TABLE 57.4. Site-specific clinical studies of osteosarcoma. Study

Reference

Year

Site

N

Type

Intervention

F/U; other

Ozaki

41

2003

Pelvis

67

RCS

Multiagent chemo, surg

Wittig

42

2002

Humerus

23

RCS

Chemo, surg

Ozaki

43

2002

Spine

22

RCS

Chemo, surg, ± XRT

Ham

44

2000

Pelvis

40

RCS

Variable

Grimer

45

1999

Pelvis

36

RCS

Variable

EFS

OS

5 years 19%

5 years 27%

Med 10 years

10 years 65%

10 years 65%

6 years

6 years 14%

6 years 27%

NR

2 years 35% 5 years 26% 5 years 41% 5 years 18%

Chemo + surg Surgery only

NR

Conclusions

Poor prog; worse w/mets or poor surgical margins Good function w/limb salvage; similar survival to other sites Prog better w/surg or XRT than chemo only Worse prog. than other sites; best w/chemo + surg Worse prog than other sites; best w/chemo + surg

RCS, retrospective case series; EFS, event-free survival; OS, overall survival; NR, not reported; F/U, follow-up; XRT, radiotherapy; surg, surgery; mets, metastasis; prog, prognosis; alk phos, alkaline phosphatase.

Overall survival with osteosarcoma treated with multiagent chemotherapy and surgery has remained in the 60% to 70% range over the past two decades. Limb salvage has become more prevalent and has not shown an adverse effect on survival, even in the context of pathologic fracture.5,39,40,46–49 Survival in relapsed or metastatic osteosarcoma is distinctly worse (see Table 57.3) and ranges from 18% to 55%. The prognosis is worse in axial skeletal locations, such as the spine and pelvis (see Table 57.4),41,43–45 which may relate in part to the technical difficulty of obtaining wide surgical margins in these locations. Prognosis for skip metastases has also been extremely poor.2 There has been considerable interest in identifying prognostic markers in osteosarcoma. The RB and p53 genes have long been associated with the pathogenesis and growth dysregulation in osteosarcoma but have not found utility prognostically.50 Multidrug resistance genes, such as MDR1 (P-glycoprotein), a cellular detoxifying plasma membrane efflux pump that can confer chemotherapeutic resistance on tumor cells, have been fairly widely investigated in osteosarcoma. However, the issue of prognostic relevance remains unresolved, with some studies showing correlation with prognosis51,52 whereas others have not.53,54 Bone morphogenetic proteins (BMPs) have been studied, with findings of BMP4 and 7 expression in all osteosarcomas and BMP6 in chondroblastic subtypes.55,56 Other markers that have been investigated include Her2/neu,57,58 tenascin,59 ezrin,60 LRP5,61 and telomerase.62 Although one study suggested overexpression of Her2/neu correlated with poor prognosis,57 a more-recent study has contradicted that finding.58 Tenascin, ezrin, LRP5, and telomerase have each been found to correlate with metastasis and worse prognosis in recent single studies.59–62 A number of newer agents have been tested for activity against osteosarcoma, including carboplatin, ecteinascidin, liposomal doxorubicin, etoposide, gemcitabine, interleukin 12, topotecan, paclitaxel, and the combination of retinoic acid and interferon alpha, generally in the setting of metastatic and/or recurrent tumor refractory to standard regimens.38,63–72

Although the studies have been small, ecteinascidin, topotecan, and paclitaxel have exhibited minimum activity.64,67,71 Ifosfamide, etoposide, and carboplatin have been evaluated in several studies and antitumor efficacy demonstrated, although results are similar to previous multiagent regimens.34,63,65,69,73 Gemcitabine and interleukin 12 have shown activity against metastatic disease in animal models,70,74 but interleukin 12 has not been evaluated in clinical trials, and response to gemcitabine in one Phase II trial with refractory disease was modest.66 Preoperative intraarterial cisplatin has demonstrated improved survival of 92% in a single clinical study,26 whereas in another study with intraarterial carboplatin the 3-year survival was similar to other multidrug protocols at 71%.38 Unfortunately, overall the results with newer agents have not shown promise of significantly altering the treatment outcomes with this disease, and further studies are needed.

Ewing’s Sarcoma Ewing’s sarcoma is an aggressive, non-matrix-producing primary bone sarcoma that affects individuals mainly in the second and third decades. Many of these tumors are characterized by presence of a specific chromosomal translocation (11:22), resulting in an abnormal transcription factor, EWSFLI-1, which may contribute to their pathogenesis. Ewing’s sarcoma can occur in the soft tissues as well, and both bone and soft tissue lesions often exhibit features of neuroectodermal differentiation, previously termed peripheral neuroectodermal tumors (PNET).4 The presence of neural differentiation features has not been shown to affect outcome.75,76 Currently, the term Ewing’s sarcoma family of tumors (ESFT, or EFT) is used to encompass the variations of this sarcoma. Ewing’s sarcoma is characterized by a permeative pattern of bone destruction, often associated with a periosteal reaction and soft tissue mass. As with other bone sarcomas, the presenting complaint is usually pain at the site

sarcomas of bone

of the primary lesion. Involvement of the major long bones is most common, although pelvic, spinal, and rib primary sites also occur.77 Metastases are hematogenous and usually pulmonary, with bone as a much less common metastatic site. Diagnosis is generally accomplished by needle biopsy, although occasionally an open surgical biopsy may be necessary. The use of immunohistochemistry to identify markers of neural differentiation, cell-surface markers such as CD99, and the specific fusion protein, EWS-FLI-1, which results from the characteristic chromosomal translocation found in most cases of the disease, has made diagnosis more accurate with small tissue specimens.78–81 The staging studies are similar to those of other bone sarcomas, with magnetic resonance imaging (MRI) of the primary site for surgical planning, CT scan of the chest to assess pulmonary metastasis, and whole-body bone scanning to rule out bone metastases.77 Treatment consists of multiagent chemotherapy regimens similar to those used for osteosarcoma, followed by surgical resection and reconstruction if feasible, with or without local radiotherapy, depending on the response of the tumor to neoadjuvant therapy and achievement of wide surgical margins. This regimen represents a shift in approach over the past two decades as previously chemotherapy with local radiation was the most common treatment paradigm. However, late recurrences in irradiated bone in the past led to increasing use of surgical treatment of primary lesions, with improved results.82–85 In unresectable lesions in difficult locations, such as the spine, chemotherapy with adjuvant radiation treatment remains an acceptable alternative to surgical treatment. Postoperative chemotherapy is then utilized, as for osteosarcoma, with subsequent follow-up using MRI, CT, and bone scan assessments periodically to monitor for recurrent disease. The published clinical studies of Ewing’s family tumors are summarized in Table 57.575,82–84,86–101 and Table 57.6,102–107 and the issues of consensus based on evidence presented in these studies are as follows: 1. Surgical treatment of the primary lesion is associated with a better prognosis than radiotherapy alone. 2. The prognosis of patients presenting with metastatic disease is much worse than those without. 3. Late complications such as relapse and second malignancies occur and must be monitored through long-term follow-up. 4. Addition of etoposide and ifosfamide improves outcome in patients without metastasis but not in those with metastasis at presentation. 5. Pathologic fracture is not associated with worse prognosis and does not necessarily mandate amputation. 6. Chemotherapeutic response of tumor to neoadjuvant chemotherapy is highly correlated with outcome. 7. Prognosis in spinal and pelvic locations is worse than with extremity tumors. 8. Tumor volume is inversely correlated with outcome. 9. Improved survival with stem cell transplantation has not been as yet demonstrated. The problems associated with interpretation of the data on Ewing’s tumors relates in large part to the rarity of the disease. Thus, most of the reported evidence is at the case series level, with few randomized trials. In addition, much of the literature is based on relatively small numbers of cases, with patient and treatment heterogeneity. Furthermore,

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many reported series have been collected over significant periods of time, introducing the confounding variables of changing treatment paradigms and diagnostic and staging technologies. As can be seen from Table 57.5, reported overall survival rates at 5 years generally are in the range of 50% to 70% for nonmetastatic disease presentation and 20% to 30% for metastatic disease, thus reinforcing the strong prognostic significance of early metastasis. Longer time to relapse has also correlated with improved survival.92 Surgical treatment of the primary has yielded better outcomes than radiotherapy alone in several studies,64,83,100,102,108,109 leading to the current shift in paradigm favoring surgical resection whenever possible. Incorporation of surgical treatment for relapsed disease has also been shown to improve survival.92,110,111 Pathologic fractures occur in Ewing’s tumor, particularly in the femur, but have had similar outcomes to disease without fracture whether or not amputation was undertaken.112,113 Additional factors that have been found in some studies to correlate with a worse prognosis include tumor volume greater than 100 mL,94,113,114 nonextremity sites such as the spine and pelvis,102,103,106,115 elevated serum lactase dehydrogenase (LDH) levels,76,82,116 and systemic symptoms such as fever and anemia.116 Apart from the presence of metastatic disease, however, the strongest predictor of prognosis is response to neoadjuvant chemotherapy.85,94,97,107,113,116,117 A number of issues remain controversial, such as the prognostic significance of age at diagnosis, concerning which conflicting data have been reported.97,118 The treatment of metastatic disease does not appear to have improved much over time despite numerous changes in chemotherapeutic protocols, although the value of surgical treatment of the primary lesion has been well supported.64,83,100,119 Several studies have reported on improved outcomes in nonmetastatic patients with more-recent protocols incorporating ifosfamide and etoposide over previous protocols that did not incorporate these agents.87,101,120 Some experimental drug regimens evaluated in recent small Phase II studies for relapsed disease include cyclophosphamide + topotecan and irinotecan.64,121 Although the cyclophosphamide/topotecan study yielded a 35% response rate, further study of larger numbers of patients will likely be needed to determine the possible role of this regimen. Responses in the irinotecan study were minimal,121 and a Phase II study of pyrazoloacridine yielded no responses.122 Although allogeneic and autologous stem cell transplantation for relapsed or advanced disease have not shown improved outcomes over chemotherapy alone,93,95 a high rate of tumor cell contaminants in autologous stem cells has been reported93,123 and may be a contributing factor to failures. One of the serious late complications of Ewing’s sarcoma is the occurrence of second malignancies, which ranges from 1 to 6.5% in several series.82,124–126 The outcomes of secondary osteosarcomas have been reported, with overall survival of the secondary sarcoma 41% at 8 years follow-up.127 The late surgical complication rates for pelvic Ewing’s and limb reconstruction with expanding prostheses in young children have also been high and constitute a longer-term problem requiring ongoing follow-up.39,104,128,129 Functional studies have supported rotation plasty lower extremity procedures for younger children over prosthetic reconstructions,130 although multiple reconstructive options have decreased indications for amputation even in younger children.129,131 One additional

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TABLE 57.5. Clinical studies of Ewing’s sarcoma family tumors. Study

Reference

Year

N

Type

Study specifics

Zogopoulos

86

2004

72

RCS

Bacci

82

2004

402

RCS

Multiagent chemo + surg or XRT Multiagent chemo

Miser

87

2004

120

PRCT

Bacci

83

2004

268

RCS

Grier

88

2003

518

PRCT

Dox, vincr, cyclo, dactin vs. etopo, ifos; ± met groups

Kolb

89

2003

68

PCS

Schuck

90

2002

153

RCS

Marcus

91

2002

144

RCS

RodriguezGalindo

92

2002

71

RCS

Sluga

84

2001

86

RCS

Surgical margins

Meyers

93

2001

32

PCS

Paulussen

94

2001

301

RCS

Burdach

95

2000

36

RCS

Cotterill

75

2000

975

RCS

Elomaa

96

2000

88

RCS

TBI, autol. Stem cells in metastatic Ewings Ifos vs. cyclo in high- vs. lowrisk pts (by tumor volume) Stem cell transplant for advanced disease Standard multiagent; ± mets Vincr/dox/ifos + cisplatin/dox/ifos

Bacci

97

2000

23

RCS

Frolich

98

1999

131

RCS

Rosito

99

1999

160

RCS

Givens

100

1999

85

RCS

Craft

101

1998

243

RCS

F/U; other

EFS

OS

7 years 66%

7 years 72%

18 years

18 years 44%

5 years 57% 10 years 49% 15 years 45% 20 years 38%

STD Etopo/ifos

8 years 20% 8 years 20%

8 years 32% 8 years 29%

All pts Surgery XRT STD Etopo/ifos

5 5 5 5 5

62% 80% 48% 54% 69%

5 years 69%

5 years 61% 5 years 73%

Dox, cyclo, vincr, etopo, ifos

w/mets no mets

4 years 12% 4 years 82%

4 years 18% 4 years 89%

Postop XRT timing Various multidrug regimens Time to relapse ± surgery for mets

60 days Various Rx groups

5 years 64% 5 years 64% NR

Dox, vincr, cyclo, dactin vs. etopo, ifos in pts w/mets XRT vs. surgery

years years years years years

2 years Surgery No surg Wide Nonwide

5 years 50–63% 18% 35% 30% 9% 60% 40% 0%

Nonmetastatic, extremity best outcomes Late relapses and 2° malignancies; long-term F/U needed No difference

Outcomes better with surgery No diff w/mets; etopo/ifos better nonmet Metastasis is major prog determinant LR 2% LR 8% No large diff. with regimens; mets poor prog Better outcome with late relapse & surgical Rx Wider margin better No benefit over chemo

2 years 24%

5 5 5 5 5 5 2

5 years 52%

5 years 57%

5 years 24%

5 years 24%

No mets + mets Nonmet Met

5 5 5 5

55% 22% 58% 27%

NR 5 years 70% 5 years 28%

Age >39 years

8.8 years

5 years 53%

5 years 59%

High-dose melphalan, etopo in relapsed pts Vincr, dact, dox, cyclo + etopo, ifos Multiagent chemo, XRT, ± surgery Dox, vincr, dact, ifos

3.7 years

5 years 19%

5 years 27%

37 months

3 years 78%

3 years 84%

10–20 years

NR

5 years 46% 10 years 37%

Results better with surgery

58 months

5 years 56%

5 years 62%

Ifos better compared with historical protocol

years years years years

years years years years years years years

Conclusions

No difference; vol >200 mL, poor response worse prognosis Survival not improved +mets, earlier relapse worse Best prog with nonmetastatic, extremity sites No difference from age 50 years 90% grI; 10% grII

Indolent course, late mets High grade, LR correlated with worse prog High grade poor prog Worst results in dediff CS Poor prognosis, better w/chemo

XRT no benefit High grade poor prog; no benefit chemo, XRT LR higher in shoulder, pelvis

RCS, retrospective case series; EFS, event-free survival; LR, local recurrence; OS, overall survival; NR, not reported; F/U, follow-up; XRT, radiotherapy; surg, surgery; mets, metastasis; prog, prognosis; vol, volume; incr, increased.

needle biopsy can be used to confirm the histogenesis of the tumor, the results with a small sample can be misleading in terms of the grade of the tumor. Open biopsy may be more helpful in ascertaining absence of higher-grade areas, which may influence the extent of the surgical procedure.139,145 Published clinical studies of chondrosarcoma are unfortunately limited to retrospective case series, many with relatively small numbers of patients. There have been no randomized clinical trials involving radiotherapy or

chemotherapy, although limited evidence from the few published case series is not encouraging with regard to use of adjuvant modalities. The issues on which there would appear to be consensus in the literature are summarized as follows (see also Table 57.7)139,141,143,149–159: 1. Surgical excision of the primary is the accepted method of treatment. 2. Tumor grade is the most significant prognostic variable.

sarcomas of bone

3. Local recurrence is higher than with other bone sarcomas. 4. Progression of disease is often slow, and long-term followup is necessary. 5. Prognosis is excellent for the primary lesions in the hand. 6. Wide surgical margins are associated with lower local recurrence rates. 7. Prognosis in surgically difficult areas, such as the spine, scapula, and pelvis, may be worse. The most striking findings from the published literature, as demonstrated in Table 57.7, are the high local recurrence rates of chondrosarcoma following surgical treatment and the correlation of higher-grade tumors with worse prognoses. The higher local recurrence rate than with osteosarcoma or Ewing’s sarcoma may be related to the lack of effective adjuvant therapies such as radiotherapy or chemotherapy. The MDR1 gene and its product P-glycoprotein have been shown to be constitutively expressed in cartilage neoplasms and may account for the lack of sensitivity to chemotherapeutic agents.160–162 As with other bone sarcomas, current technologic improvements in prosthetic implants for bone and joint reconstruction, availability of allografts, and microvascular techniques enabling free tissue transfer to handle soft tissue coverage problems have led to a shift over the past two decades from amputations to limb salvage procedures for extremity and pelvic chondrosarcomas. Although some studies have found a worse prognosis with pelvic chondrosarcoma,158 others have not corroborated this,154,155 so this issue remains unclear. However, there is consensus in the literature that wider margins are associated with lower local recurrence rates and better prognosis, and therefore the difficulty of achieving wide margins in surgically difficult locations such as the pelvis, scapula, and spine may affect outcomes with primaries at these sites.159 The published case series examining scapular and spinal primaries specifically would support this conclusion.149,157 In contrast, two series that studied primary chondrosarcomas of the hand both showed an excellent prognosis in all patients in terms of lack of metastasis and long-term survival, regardless of tumor grade.150,151 Secondary chondrosarcomas arising in osteochondromas or hereditary multiple exostoses appear to have overall an excellent prognosis, likely because of the preponderance of low-grade lesions.153 Specific mutations in the EXT1 and EXT2 genes have been identified in more than 80% of individuals with multiple exostoses and in the chondrosarcomas that arise in this condition163 and may contribute to the pathogenesis of the neoplasm. It is fairly well accepted that the rate of malignant degeneration is substantially higher in patients with multiple exostoses or multiple enchondromas (enchondromatosis, Ollier’s disease) than in patients with solitary intraosseous or surface cartilage lesions, although a recent study of a large number of families failed to find an association with disease severity and development of chondrosarcoma.163 Possibly because of the diagnostic difficulty in distinguishing between benign and low-grade malignant tumors, considerable investigation of possible markers of malignancy in chondrosarcoma has been undertaken. A number of markers have been associated with increased grade of malignancy, including urokinase-like plasminogen activator,164,165 cathepsinB,165 MMP1,166,167 PTHrP and its receptor,168,169 INK4A/

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p16,170 tenascin-C splice variants,171 and telomerase reverse transcriptase.172 Although all these markers are more highly expressed in higher grades of malignancy, none definitively differentiates between benign and malignant low-grade lesions. Her2/neu has been studied and shown no correlation with chondrosarcoma grade.173 A recent study has found that cyclooxygenase 2 (COX-2) is expressed in all high- and lowgrade malignant cartilage tumors whereas it is absent in benign tumors.174 Although this study involved a small number of specimens (n = 29), the absence of expression in benign lesions is in contrast to the continuum of expression from benign to higher-grade tumors observed in all the other published marker studies. This finding could have potential therapeutic as well as diagnostic significance, because prostaglandins stimulate chondrocyte proliferation and COX-2 inhibitors are widely available, but this area requires further study. Because PTHrP also drives chondrocyte proliferation and has been shown in several studies to be more highly expressed in highergrade lesions,168,169 potential therapeutic use of antibodies to PTHrP or its receptor has been proposed, and efficacy of this approach in induction of chondrosarcoma cell apoptosis has been demonstrated in vitro.175 At present, however, use of diagnostic markers has not assumed a place in clinical practice, and new therapeutic options remain theoretical.

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74. Jia SF, Worth LL, Turan M, et al. Eradication of osteosarcoma lung metastasis using intranasal gemcitabine. Anti-Cancer Drugs 2002;13:155–161. 75. Coterill SJ, Ahrens S, Paulussen M, et al. Prognostic factors in Ewing’s tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing’s Sarcoma Study Group. J Clin Oncol 2000;18:3108–3114. 76. Luksch R, Sampietro G, Collini P, et al. Prognostic value of clinicopathologic characteristics including neuroectodermal differentiation in osseous Ewing’s sarcoma family of tumors. Tumori 1999;85:101–107. 77. McCarthy E, Frassica F. Primary bone tumors. In: Pathology of Bone and Joint Disorders. Philadelphia: Saunders, 1998:258–261. 78. Lee CS, Southey MC, Waters K, et al. EWS/FLI-1 fusion transcript detection and MIC2 immunohistochemical staining in the diagnosis of Ewing’s sarcoma. Pediatr Pathol Lab Med 1996;16: 379–392. 79. Machen SK, Fisher C, Gautam RS, et al. Utility of cytokeratin subsets for distinguishing poorly differentiated synovial sarcoma from peripheral primitive neuroectodermal tumour. Histopathology (Oxf) 1998;33:501–507. 80. Halliday BE, Slagel DD, Elsheikh TE, et al. Diagnostic utility of MIC-2 immunocytochemical staining in the differential diagnosis of small blue cell tumors. Diagn Cytopathol 1998;19: 410–416. 81. Collins BT, Cramer HM, Frain BE, et al. Fine-needle aspiration biopsy of metastatic Ewing’s sarcoma with MIC2 (CD99) immunocytochemistry. Diagn Cytopathol 1998;19:382–384. 82. Bacci G, Forni C, Longhi A, et al. Long-term outcome for patients with non-metastatic Ewing’s sarcoma treated with adjuvant and neoadjuvant chemotherapies: 402 patients treated at Rizzoli between 1972 and 1992. Eur J Cancer 2004;40:73–83. 83. Bacci G, Ferrari S, Longhi A, et al. Role of surgery in local treatment of Ewing’s sarcoma of the extremities in patients undergoing adjuvant and neoadjuvant chemotherapy. Oncol Rep 2004; 11:111–120. 84. Sluga M, Windhager R, Lang S, et al. The role of surgery and resection margins in the treatment of Ewing’s sarcoma. Clin Orthop 2001;392:394–399. 85. Sluga M, Windhager R, Lang S, et al. A long-term review of the treatment of patients with Ewing’s sarcoma in one institution. Eur J Surg Oncol 2001;27:569–573. 86. Zogopoulos G, Teskey L, Sung L, et al. Ewing sarcoma: farourable results with combined modality therapy and conservative use of radiotherapy. Pediatr Blood Cancer 2004;43:35–39. 87. Miser JS, Krailo MD, Tarbell MJ, et al. Treatment of metastatic Ewing’s sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide—a Children’s Cancer Group and Pediatric Oncology Group study. J Clin Oncol 2004;22:2873–2876. 88. Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 2003;348:694–701. 89. Kolb EA, Kushner BH, Gorlick R, et al. Long-term event-free survival after intensive chemotherapy for Ewing’s family of tumors in children and young adults. J Clin Oncol 2003;21:3423–3430. 90. Schuck A, Rube C, Konemann S, et al. Postoperative radiotherapy in the treatment of Ewing tumors: influence of the interval between surgery and radiotherapy. Strahlenther Onkol 2002;178: 25–31. 91. Marcus RB, Berrey BH, Graham-Pole J, et al. The treatment of Ewing’s sarcoma of bone at the University of Florida: 1969–1998. Clin Orthop 2002;397:290–297. 92. Rodriguez-Galindo C, Billups CA, Kun LE, et al. Survival after recurrence of Ewing tumors: the St Jude Children’s Research Hospital experience, 1979–1999. Cancer (Phila) 2002;94: 561–569.

1036 93. Meyers PA, Krailo MD, Ladanyi M, et al. High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing’s sarcoma does not improve prognosis. J Clin Oncol 2001;19:2812–2820. 94. Paulussen M, Ahrens S, Dunst J, et al. Localized Ewing tumor of bone: final results of the cooperative Ewing’s Sarcoma Study CESS 86. J Clin Oncol 2001;19:1818–1829. 95. Burdach S, van Kaick B, Laws HJ, et al. Allogeneic and autologous stem-cell transplantation in advanced Ewing tumors. An update after long-term follow-up from two centers of the European Intergroup study EICESS. Stem-cell transplant programs at Dusseldorf University Medical center, Germany, and St. Anna Kinderspital, Vienna, Austria. Ann Oncol 2000;11:1451–1462. 96. Elomaa I, Blomqvist CP, Saeter G, et al. Five-year results in Ewing’s sarcoma. The Scandinavian Sarcoma Group experience with the SSG IX protocol. Eur J Cancer 2000;36:875–880. 97. Bacci G, Ferrari S, Comandone A, et al. Neoadjuvant chemotherapy for Ewing’s sarcoma of bone in patients older than thirty-nine years. Acta Oncol 2000;39:111–116. 98. Frolich B, Ahrens S, Burdach S, et al. High-dosage chemotherapy in primary metastasized and relapsed Ewing’s sarcoma (EI)CESS. Klin Paediatr 1999;211:284–290. 99. Rosito P, Mancini AF, Rondelli R, et al. Italian Cooperative Study for the treatment of children and young adults with localized Ewing sarcoma of bone: a preliminary report of 6 years of experience. Cancer (Phila) 1999;86:421–428. 100. Givens SS, Woo SY, Huang LY, et al. Non-metastatic Ewing’s sarcoma: twenty years of experience suggests that surgery is a prime factor for successful multimodality therapy. Int J Oncol 1999;14:1039–1043. 101. Craft A, Cotterill S, Malcolm A, et al. Ifosfamide-containing chemotherapy in Ewing’s sarcoma: The Second United Kingdom Children’s Cancer Study Group and the Medical Research Council Ewing’s Tumor Study. J Clin Oncol 1998;16:3628–3633. 102. Bacci G, Ferrari S, Longhi A, et al. Local and systemic control in Ewing’s sarcoma of the femur treated with chemotherapy, and locally by radiotherapy and/or surgery. J Bone Joint Surg 2003; 85B:107–114. 103. Talac R, Yaszemski MJ, Currier BL, et al. Relationship between surgical margins and local recurrence in sarcomas of the spine. Clin Orthop 2002;397:127–132. 104. Ozaki T, Hoffmann C, Hillmann A, et al. Implantation of hemipelvic prosthesis after resection of sarcoma. Clin Orthop 2002;396:197–205. 105. Shamberger RC, Laquaglia MP, Krailo MD, et al. Ewing sarcoma of the rib: results of an intergroup study with analysis of outcome by timing of resection. J Thorac Cardiovasc Surg 2000; 119:1154–1161. 106. Sucato DJ, Rougraff B, McGrath BE, et al. Ewing’s sarcoma of the pelvis. Long-term survival and functional outcome. Clin Orthop 2000;373:193–201. 107. Hoffmann C, Ahrens S, Dunst J, et al. Pelvic Ewing sarcoma: a retrospective analysis of 241 cases. Cancer (Phila) 1999;85: 869–877. 108. Paulussen M, Ahrens S, Burdach S, et al. Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. European Intergroup Cooperative Ewing Sarcoma Studies. Ann Oncol 1998;9:275–281. 109. San-Julian M, Dolz R, Garcia-Barrecheguren E, et al. Limb salvage in bone sarcomas in patients younger than age 10: a 20-year experience. J Pediatr Orthop 2003;23:753–762. 110. Bacci G, Ferrari S, Longhi A, et al. Therapy and survival after recurrence of Ewing’s tumors: the Rizzoli experience in 195 patients treated with adjuvant and neoadjuvant chemotherapy from 1979 to 1997. 111. Briccoli A, Rocca M, Ferrari S, et al. Surgery for lung metastases in Ewing’s sarcoma of bone. Eur J Surg Oncol 2004;30:63–67.

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112. Fuchs B, Valenzuela RG, Sim FH. Pathologic fracture as a complication in the treatment of Ewing’s sarcoma. Clin Orthop 2003;415:25–30. 113. Wunder JS, Paulian G, Huvos AG, et al. The histological response to chemotherapy as a predictor of the oncological outcome of operative treatment of Ewing sarcoma. J Bone Joint Surg 1998;80A:1020–1033. 114. Hense HW, Ahrens S, Paulussen M, et al. Factors associated with tumor volume and primary metastases in Ewing tumors: results from the (EI)CESS studies. Ann Oncol 1999;10:1073–1077. 115. Ahrens S, Hoffmann C, Jabar S, et al. Evaluation of the prognostic factors in a tumor volume-adapted treatment strategy for localized Ewing sarcoma of bone: the CESS 86 experience. Cooperative Ewing Sarcoma Study. Med Pediatr Oncol 1999;32:186–195. 116. Bacci G, Ferrari S, Bertoni F, et al. Prognostic factors in nonmetastatic Ewing’s sarcoma of bone treated with adjuvant chemotherapy: analysis of 359 patients at the Istituto Ortopedico Rizzoli. J Clin Oncol 2000;18:4–11. 117. Abudu A, Davies AM, Punsent PB, et al. Tumour volume as a predictor of necrosis after chemotherapy in Ewing’s sarcoma. J Bone Joint Surg 1999;81B:317–322. 118. Baldini EH, Demetri GD, Fletcher CD, et al. Adults with Ewing’s sarcoma/primitive neuroectodermal tumor: adverse effect of older age and primary extraosseous disease on outcome. Ann Surg 1999;230:79–86. 119. Paulussen M, Ahrens S, Craft AW, et al. Ewing’s tumors with primary lung metastases: survival analysis of 114 (European Intergroup) Cooperative Ewing’s Sarcoma Studies patients. J Clin Oncol 1998;16:3044–3052. 120. Krasin MJ, Rodriguez-Galindo C, Davidoff AM, et al. Efficacy of combined surgery and irradiation for localized Ewings sarcoma family of tumors. Pediatr Blood Cancer 2004;43:229–236. 121. Cosetti M, Wexler LH, Calleja E, et al. Irinotecan for pediatric solid tumors: the Memorial Sloan-Kettering experience. J Pediatr Hematol Oncol 2002;24:101–105. 122. Berg SL, Blaney SM, Sullivan J, et al. Phase II trial of pyrazoloacridine in children with solid tumors: a Pediatric Oncology Group phase II study. J Pediatr Hematol Oncol 2000;22:506– 509. 123. Leung W, Chen AR, Klann RC, et al. Frequent detection of tumor cells in hematopoietic grafts in neuroblastoma and Ewing’s sarcoma. Bone Marrow Transplant 1998;22:971–979. 124. Fuchs B, Valenzuela RG, Inwards C, et al. Complications in longterm survivors of Ewing sarcoma. Cancer (Phila) 2003;98:2687– 2692. 125. Fuchs B, Valenzuela RG, Petersen IA, et al. Ewing’s sarcoma and the development of secondary malignancies. Clin Orthop 2003; 415:82–89. 126. Paulussen M, Ahrens S, Lehnert M, et al. Second malignancies after Ewing tumor treatment in 690 patients from a cooperative German/Austrian/Dutch study. Ann Oncol 2001;12:1619– 1630. 127. Tabone MD, Terrier P, Pacquement H, et al. Outcome of radiation-related osteosarcoma after treatment of childhood and adolescent cancer: a study of 23 cases. J Clin Oncol 1999;17: 2789–2795. 128. Grimer RJ, Belthur M, Carter SR, et al. Extendable replacements of the proximal tibia for bone tumours. J Bone Joint Surg 2000; 82B:255–260. 129. Neel MD, Wilkins RM, Rao BN, et al. Early multicenter experience with a noninvasive expandable prosthesis. Clin Orthop 2003;415:72–81. 130. Hillmann A, Hoffmann C, Gosheger G, et al. Malignant tumor of the distal part of the femur or the proximal part of the tibia: endoprosthetic replacement or rotationplasty. Functional outcome and quality-of-life measurements. J Bone Joint Surg 1999; 81A:462–468.

sarcomas of bone 131. Kumta SM, Cheng JC, Li CK, et al. Scope and limitations of limb-sparing surgery in childhood sarcomas. J Pediatr Orthop 2002;22:244–248. 132. Azcona C, Burghard E, Ruza E, et al. Reduced bone mineralization in adolescent survivors of malignant bone tumors: comparison of quantitative ultrasound and dual-energy X-ray absorptiometry. J Pediatr Hematol Oncol 2003;25:297–302. 133. Wagner LM, Neel MD, Pappo AS, et al. Fractures in pediatric Ewing sarcoma. J Pediatr Hematol Oncol 2001;23:568–571. 134. Rorie CJ, Thomas VD, Chen P, et al. The Ews/Fli-1 fusion gene switches the differentiation program of neuroblastomas to Ewing sarcoma/peripheral primitive neuroectodermal tumors. Cancer Res 2004;64:1266–1277. 135. Takahashi A, Higashino F, Aoyagi M, et al. EWS/ETS fusions activate telomerase in Ewing’s tumors. Cancer Res 2003;63: 8338–8344. 136. Chansky HA, Barahmand-Pour F, Mei Q, et al. Targeting of EWS/FLI-1 by RNA interference attenuates the tumor phenotype of Ewing’s sarcoma cells in vitro. J Orthop Res 2004;22:910–917. 137. Merchant MS, Woo CW, Mackall CL, et al. Potential use of imatinib in Ewing’s sarcoma: evidence for in vitro and in vivo activity. J Natl Cancer Inst 2002;94:1673–1679. 138. Rossi S, Orvieto E, Furlanetto A, et al. Utility of immunohistochemical detection of FLI-1 expression in round cell and vascular neoplasms using a monoclonal antibody. Mod Pathol 2004; 17:547–552. 139. Reith JD, Horodyski MB, Scarborough MT. Grade 2 chondrosarcoma: stage I or stage II tumor? Clin Orthop 2003;415:45–51. 140. Welkerling H, Kratz S, Ewerbeck V, et al. A reproducible and simple grading system for classical chondrosarcomas. Analysis of 35 chondrosarcomas and 16 enchondromas with emphasis on recurrence rate and radiological and clinical data. Virchows Arch 2003;443:725–733. 141. Mitchell AD, Ayoub K, Mangham DC, et al. Experience in the treatment of dedifferentiated chondrosarcoma. J Bone Joint Surg 2000;82B:55–61. 142. Brown RE, Boyle JL. Mesenchymal chondrosarcoma: molecular characterization by a proteomic approach, with morphogenic and therapeutic implications. Ann Clin Lab Sci 2003;33: 131–141. 143. Kawaguchi S, Wada T, Nagoya S, et al. Extraskeletal myxoid chondrosarcoma: a multi-institutional study of 42 cases in Japan. Cancer (Phila) 2003;97:1285–1292. 144. Collins MS, Koyama T, Swee RG, et al. Clear cell chondrosarcoma: radiographic, computed tomographic, and magnetic resonance findings in 34 patients with pathologic correlation. Skeletal Radiol 2003;32:687–694. 145. Marco RA, Gitelis S, Brebach GT, et al. Cartilage tumors: evaluation and treatment. J Am Acad Orthop Surg 2000;8:292–304. 146. Schreuder HW, Pruszczynski M, Veth RP, et al. Treatment of benign and low-grade malignant intramedullary chondroid tumors with curettage and cryosurgery. Eur J Surg Oncol 1998; 24:120–126. 147. Ozaki T, Lindner N, Hillmann A, et al. Influence of intralesional surgery on treatment outcome of chondrosarcoma. Cancer (Phila) 1996;77:1292–1297. 148. Murphey MD, Walker EA, Wilson AJ, et al. From the archives of the AFIP: imaging of primary chondrosarcoma: radiologicpathologic correlation. Radiographics 2003;23:1245–1278. 149. Schneiderbauer MM, Blanchard C, Gullerud R, et al. Scapular chondrosarcomas have high rates of local recurrence and metastasis. Clin Orthop 2004;426:232–238. 150. Mittermayer F, Dominkus M, Krepler P, et al. Chondrosarcoma of the hand: is a wide surgical resection necessary? Clin Orthop 2004;424:211–215. 151. Patil S, deSilva MV, Crossan J, et al. Chondrosarcoma of the small bones of the hand. J Hand Surg 2003;28:602–608.

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152. Soderstrom M, Ekfors TO, Bohling TO, et al. No improvement in the overall survival of 194 patients with chondrosarcoma in Finland in 1971–1990. Acta Orthop Scand 2003;74:344– 350. 153. Ahmed AR, Tan TS, Unni KK, et al. Secondary chondrosarcoma in osteochondroma: report of 107 patients. Clin Orthop 2003; 411:193–206. 154. Fiorenza F, Abudu A, Grimer RJ, et al. Risk factors for survival and local control in chondrosarcoma of bone. J Bone Joint Surg 2002;84B:93–99. 155. Pring ME, Weber KL, Unni KK, et al. Chondrosarcoma of the pelvis. A review of sixty-four cases. J Bone Joint Surg 2001;83A: 1630–1642. 156. Bruns J, Elbracht M, Niggemeyer O. Chondrosarcoma of bone: an oncological and functional follow-up study. Ann Oncol 2001;12:859–864. 157. York JE, Berk RH, Fuller GN, et al. Chondrosarcoma of the spine: 1954 to 1997. J Neurosurg 1999;90(suppl 1):73–78. 158. Lee FY, Mankin HJ, Fondren G, et al. Chondrosarcoma of bone: an assessment of outcome. J Bone Joint Surg 1999;81A:326–338. 159. Bjornsson J, McLeod RA, Unni KK, et al. Primary chondrosarcoma of long bones and limb girdles. Cancer (Phila) 1998;83: 2105–2119. 160. Rosier RN, O’Keefe RJ, Teot LA, et al. P-glyprotein expression in cartilaginous tumors. J Surg Oncol 1997;65:95–105. 161. Wyman JJ, Hornstein AM, Meitner PA, et al. Multidrug resistance-1 and p-glycoprotein in human chondrosarcoma cell lines: expression correlates with decreased intracellular doxorubicin and in vitro chemoresistance. J Orthop Res 1999;17: 935–940. 162. Terek RM, Schwartz GK, Devaney K, et al. Chemotherapy and P-glycoprotein expression in chondrosarcoma. J Orthop Res 1998;16:585–590. 163. Porter DE, Lonie L, Fraser M, et al. Severity of disease and risk of malignant change in hereditary multiple exostoses. A genotype-phenotype study. J Bone Joint Surg 2004;86:1041– 1046. 164. Kobayashi H, Suzuki M, Kanayama N, et al. CD44 stimulation by fragmented hyaluronic acid induces upregulation of urokinase-type plasminogen activator and its receptor and subsequently facilitates invasion of human chondrosarcoma cells. Int J Cancer 2002;102:379–389. 165. Hackel CG, Krueger S, Grote HJ, et al. Overexpression of cathepsin B and urokinase plasminogen activator is associated with increased risk of recurrence and metastasis in patients with chondrosarcoma. Cancer (Phila) 2000;89:995–1003. 166. Berend KR, Toth AP, Harrelson JM, et al. Association between ratio of matrix metalloproteinase-1 to tissue inhibitor of metalloproteinase-1 and local recurrence, metastasis, and survival in human chondrosarcoma. J Bone Joint Surg 1998;90A:11–17. 167. Jiang X, Dutton CM, Qi W, et al. Inhibition of MMP-1 expression by antisense RNA decreases invasiveness of human chondrosarcoma. J Orthop Res 2003;21:1063–1070. 168. Kunisada T, Moseley JM, Slavin JL, et al. Co-expression of parathyroid hormone-related protein (PTHrP) and PTH/PTHrP receptor in cartilaginous tumours: a marker for malignancy? Pathology 2002;34:133–137. 169. Pateder DB, Gish MW, O’Keefe RJ, et al. Parathyroid hormonerelated peptide expression in cartilaginous tumors. Clin Orthop 2002;403:198–204. 170. van Beerendonk HM, Rozeman LB, Taminiau AH, et al. Molecular analysis of the INK4A/INK4A-ARF gene locus in conventional (central) chondrosarcomas and enchondromas: indication of an important for tumour progression. J Pathol 2004;202:359–366. 171. Ghert MA, Jung ST, Qi W, et al. The clinical significance of tenascin-C splice variant expression in chondrosarcoma. Oncology 2001;51:306–314.

1038 172. Martin JA, DeYoung BR, Gitelis S, et al. Telomerase reverse transcriptase subunit expression is associated with chondrosarcoma malignancy. Clin Orthop 2004;426:117–124. 173. Park HR, Kim YW, Jung WW, et al. Evaluation of HER-2/neu status by real-time quantitative PCR in malignant cartilaginous tumors. Int J Oncol 2004;24:575–580.

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174. Sutton KM, Wright M, Fondren G, et al. Cyclooxygenase-2 expression in chondrosarcoma. Oncology 2004;66:275–280. 175. Miyaji T, Nakase T, Onuma E, et al. Monoclonal antibody to parathyroid hormone-related protein induces differentiation and apoptosis of chondrosarcoma cells. Cancer Lett 2003;199: 147–155.

5 8 S

Soft Tissue Sarcoma T. Christopher Windham and Vernon K. Sondak

arcomas are malignant tumors arising from mesenchymal cells. These tumors are usually—but not always— located in muscle, fat, and connective tissues. Sarcomas have varying clinical courses based on their histologic subtype, grade, location and size. These tumors are rare, with approximately 9,400 soft tissue sarcomas diagnosed annually in the United States, representing less than 1% of all newly diagnosed malignancies. In pediatric patients, sarcomas account for a greater percentage of malignancies, 15% of cancer cases. Deaths from soft tissue sarcomas exceed 3,400 and are 1,200 for bone sarcomas.1 Sarcomas affect both genders equally. Approximately two-thirds of soft tissue sarcomas are high-grade tumors, and histologic subtypes encountered vary by anatomic location.2 The rarity of sarcomas, plus the vast array of histologic subtypes, have complicated our understanding of these tumors and impeded the development of effective therapies, as well as hindered efforts to establish “evidence-based” principles of diagnosis, treatment, and follow-up. For example, only 400 to 500 liposarcomas of the thigh (one relatively common histologic type in its most common anatomic site) are diagnosed per year in the United States, and literally only a handful of these patients ever enter onto prospective clinical trials, virtually none of which are randomized trials. Therefore, nearly all recommendations about sarcoma management are based on limited and often anecdotal evidence. Unfortunately, 50% of patients diagnosed with sarcomas ultimately succumb to their disease, and treatment is often associated with significant acute and longterm morbidity and limited if any benefit. Despite these limitations, significant progress has been made in our understanding and treatment of sarcomas. Information about molecular events involved in the development and progress of sarcomas has advanced dramatically during the past 15 years. Improvements in surgical techniques have resulted in significant decreases in morbidity of resection, allowing moreaggressive operations, and active chemotherapeutics have been identified, including the development of biologically targeted therapies. In this chapter, we attempt to take an evidence-based view of all aspects of sarcoma management. It will be readily apparent, however, that much of our clinical practice is based on very scanty, often conflicting data.

Risk Factors for the Development of Sarcomas Hereditary Syndromes Several hereditary genetic syndromes have been associated with the development of sarcomas (Table 58.1). Neurofibromatosis type I (c) is the most commonly encountered hereditary genetic syndrome associated with soft tissue sarcoma development. Affected patients usually present early in life with cutaneous findings of café-au-lait spots and freckling in skin folds, particularly in the axilla. These patients go on to develop benign tumors of the soft tissues (dermal neurofibromas) and tumors derived from perineural cells. In a longterm follow-up study of 212 patients with neurofibromatosis type I. Sorenson et al. found that malignant neoplasms or benign central nervous system tumors occurred in 45% of these patients.3 Neurofibromatosis type I is associated with mutations in the tumor suppressor gene NF1 on chromosome 17, which acts through the negative regulation of ras.4 The protein product of the NF1 gene is neurofibromin. Neurofibromin contains a functional GAP domain, which acts on GTP-ras.5 Homozygous deletion of NF1 in mice is lethal during embryologic development. Heterozygous NF1 knockout mice are viable; however, these mice develop leukemias and pheochromocytomas. Other functions of neurofibromin have yet to be elucidated. The clinically related syndrome of neurofibromatosis type II (NF2) is less common than NF1. This syndrome is associated with mutations of the NF2 gene on chromosome 22. Tumors most commonly encountered in NF2 are schwannomas, ependymomas, and gliomas. The protein product of the NF2 gene is the cytoskeletal protein merlin (also called schwannomin) that acts to link cellsurface glycoproteins to the cytoskeleton.6,7 Li and Fraumeni identified an autosomal dominant inheritable syndrome associated with the development of soft tissue and bone sarcomas, breast cancer, brain tumors, acute leukemia, germ cell tumors, and adrenocortical cancer.8 Subsequent work identified a mutation of the tumor suppressor gene p53 associated with the Li–Fraumeni syndrome.9 Patients with germ-line inherited mutations of the p53 gene develop cancers at younger ages and at a significantly higher frequency than seen in the general population. The spectrum

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TABLE 58.1. Major genetic syndromes associated with sarcoma development. Syndrome

Tumors observed

Genetic abnormality

Studies

Neurofibromatosis type 1 (von Recklinghausen’s disease)

Neurofibromas Gliomas Malignant peripheral nerve sheath tumors Nonlymphocytic leukemia Pheochromocytoma Schwannoma Ependymoma Meningioma Glioma Bone and soft tissue sarcomas Breast cancer (often phyllodes) Adrenocortical cancer Melanoma Gastric cancer Lung cancer Pancreatic cancer Retinoblastoma

Mutation of NF1 gene Protein product-neurofibromin

—Cohort/epidemiologic —Molecular studies of small groups of tumor samples and cell lines —Knockout mouse studies

Mutation of NF2 gene Protein product–Merlin (schwannomin)

—Cohort/epidemiologic —Molecular studies of small groups of tumor samples and cell lines —Knockout mouse studies —Cohort/epidemiologic —Molecular studies of small groups of tumor samples and cell lines —Knockout mouse studies

Colon cancer Desmoid tumors

Mutation of adenomatous polyposis coli gene

Neurofibromatosis type 2

Li–Fraumeni and other p53 mutations

Retinoblastoma

Gardner syndrome

Mutation of p53 gene Protein product p53

Mutation of Rb1 gene Protein product p105 Rb

—Cohort/epidemiologic —Molecular studies of small groups of tumor samples and cell lines —Knockout mouse studies —Cohort/epidemiologic —Molecular studies of small groups of tumor samples and cell lines —Knockout mouse studies

Source: Data from references 3–5, 7–14, 13, 15.

of cancer formation varies by the location of mutation within the p53 gene.10 Another tumor suppressor gene has been associated with the development of retinoblastoma, a rare neoplasm arising in the epithelium of the retina. Retinoblastoma represents the prototype for inheritable genetic disease involving tumor suppressor genes. As observed by Knudson, patients who inherit a single mutation of the Rb1 gene are at higher risk for developing retinoblastoma in the event of a sporadic mutation of the Rb1 gene occurring in a somatic cell.11 The Rb1 gene product, p105 protein, plays multiple important regulatory roles in the regulation of cell cycle, survival, proliferation, DNA repair, and DNA replication. The p105 protein has direct interactions with the p53 regulatory pathway.12 In an analysis of risk of second malignancy in long-term retinoblastoma survivors, Fletcher et al. observed a 69% incidence of second malignancies commonly associated with ionizing radiation or agents causing DNA damage.11 Alterations in the adenomatous polyposis coli (APC) gene are found in patients with familial adenomatous polyposis (FAP). These patients have multiple polyps (usually more than 100) of the colon and rectum, as well as variable numbers of polyps in the stomach and small bowel.13 A subset of patients with FAP has a constellation of findings that has been termed Gardner’s syndrome. In addition to the intestinal polyps characteristic of FAP patients, these individuals also have mandibular osteomas and intraabdominal desmoid tumors. Available evidence indicates that Gardner’s syndrome is not a distinct entity. Instead, patients with germline APC mutations show a phenotypic spectrum of some or all of the manifestations of classic Gardner’s syndrome, and this spectrum correlates with the specific site of the mutation within the APC gene.14 The APC gene acts to down regulate b-catenin, a regulator of cell proliferation.13,15

Current studies of hereditary syndromes rely on cohort reports, epidemiologic studies, and molecular biologic investigations. The validity of these syndromes has been bolstered by the genetic alterations identified through molecular genetic studies identifying specific associations with clinical presentations. Future advances will allow us to better understand genetic alterations involved in sarcomagenesis and assist patients in genetic counseling and also shed light on the biology of sporadic sarcoma cases.

Radiation The development of sarcomas following radiation exposure was first suggested in the early 1900s. One of the earliest reports was that of Martland, who in 1929 documented the development of bone sarcomas in young girls who painted radioactive luminescent paints onto watch dials.16 During the past century, other reports relating radiation exposure to sarcoma development began to emerge. Cahan et al. catalogued studies demonstrating the ability to create sarcomas in numerous animal models following treatment with radiation.17 They further summarized studies documenting development of sarcomas in humans following treatment with radiation therapy and added 11 additional patients from their experience. This was one of the first efforts to describe clinical characteristics of radiation-associated sarcomas. They noted a latent period from 5 to more than 20 years between radiation exposure and the development of sarcoma. Unlike radiation-associated carcinomas, development of sarcomas was primarily seen after higher doses were administered.18 In this work, Cahan and colleagues set forth criteria still used today for the diagnosis of a “radiation-induced” sarcoma:

soft tissue sarcoma

1. There must have been microscopic or radiographic evidence of the nonsarcomatous nature of the initial condition. 2. The sarcoma must have arisen in the area included within the radiation field. 3. A relatively long latent period must have elapsed after irradiation before the clinical appearance of the sarcoma, in most cases longer than 5 years. 4. All sarcomas must have been proved histologically.18–24,25–33 Sarcomas have been seen after radiation therapy for the treatment of breast cancer, gynecologic malignancies, head and neck diseases, and lymphoma. The incidence of sarcoma following irradiation has been estimated to range from 0.03% to 0.8%.21,34–36 These sarcomas are frequently high grade, clinically aggressive, and difficult to treat.19 Histologic sarcoma subtypes most frequently observed following radiation exposure include osteosarcomas, malignant fibrous histiocytomas, and angiosarcomas.19 From the 1920s through the early 1950s, the alpha particle-emitting radioactive contrast agent thorium dioxide (Thorotrast) was commonly used in radiologic studies. This compound is selectively taken up by the reticuloendothelial cells of the liver and spleen, where it deposits a very high dose of radiation over many years as a consequence of its very long half-life. Several case-control studies of patients exposed to Thorotrast have found a much higher than expected incidence of liver disease, leukemias, and liver cancers.37–39 In an updated report summarizing a Japanese Thorotrast follow-up study, Mori et al. reported increased mortality primarily as a result of liver cancers, of which 15% were hemangiosarcomas.38 In their study, dos Santos Silva and colleagues also found an increased incidence of liver cancers; however, specific histology was not reported.37 Platz and associates observed increased chromosomal aberrations in the peripheral blood of a group of eight patients exposed to Thorotrast when compared with five patients exposed to nonradioactive contrast during the same time period.40 The studies to date strongly suggest an association between Thorotrast exposure and the development of sarcomas of the liver. Although most studies have demonstrated a consistent association between irradiation and sarcoma formation, other factors besides radiation may account for the actual tumor development. Frequently, patients are treated with chemotherapy agents as part of their therapies. A number of studies have documented an increased risk of second malignancy formation following treatment with chemotherapy. Neglia et al., in a large retrospective cohort study, reported 60 bone and soft tissue sarcomas developing as a second malignancy (of 298 second malignancies) in children treated with chemotherapy.41 Of note, these results were not adjusted to account for patients also treated with radiation therapy. Tucker et al. evaluated bone sarcoma development in children previously treated with chemotherapy or radiation therapy compared with untreated matched controls. They reported an excess number of bone sarcomas in patients who received alkylating agents with or without radiation therapy.22 In a nonhuman primate study evaluating the effects of procarbazine, Sieber and associates identified 4 sarcomas in 55 monkeys following treatment.42 Moreover, it is likely that a significant percentage of patients who develop sarco-

1041

mas after treatment with chemotherapy and/or radiation have underlying genetic susceptibility, as was first observed in sarcomas developing after irradiation for retinoblastoma.

Lymphedema Sarcoma development has also been associated with chronic lymphedema. A clinical scenario was recognized by Stewart and Treves in which lymphangiosarcoma develops following mastectomy, axillary nodal dissection, and radiation therapy in a chronically lymphedematous limb.43 Because lymphedema may be associated with radiation therapy, the ultimate association of causation can be difficult or impossible. However, lymphangiosarcomas have been noted to arise in congenitally lymphedematous extremities as well as other settings where no radiation was given, demonstrating that lymphedema alone is sufficient to result in sarcoma formation in some cases.

Foreign Body Sarcoma formation secondary to the presence of a foreign body has been the subject of numerous case reports. Foreign bodies associated with sarcomas have ranged from shrapnel to medical implants such as vascular conduits and orthopedic hardware.44–53 Experimental studies have demonstrated foreign body carcinogenesis, identifying a mesenchymal pleuripotent cell lineage in sarcomas arising in association with foreign bodies.54 Other studies have demonstrated that foreign body tumorigenesis requires a solid material of at least 5 mm and the prolongation of a dense fibrous capsule.55 Activation of surrounding macrophages, as seen in chronic inflammatory reactions, results in a failure in fibrous capsular formation and subsequent tumor formation.55 Laboratory studies have demonstrated that surface shape characteristics are important in determining carcinogenic potential; this appears to be a result of variable induction of a dense fibrous capsule by differing surfaces of foreign bodies.56 The strength of clinical evidence implicating foreign bodies in the development of sarcomas is limited to case reports and small series. Despite these limitations, experimental evidence supports a causative role for foreign body reactions in the induction of rare cases of soft tissue sarcoma.

Viruses The first viral oncogene, Src, was described by Rous in 1911 and has been confirmed to be tumorigenic.57 Its significance in humans, however, remains uncertain. The elevated risk for the development of Kaposi’s sarcoma in patients diagnosed with acquired immunodeficiency syndrome (AIDS) prompted investigators to determine if viruses could play a causative role in the development of these cancers. Recent studies have implicated the development of Kaposi’s sarcoma in AIDS patients who have the herpes simplex virus type 8 (HSV-8). This etiology appears to be secondary to unregulated vascular endothelial cell proliferation in immunosuppressed patients. Dictor et al. found 88% of classical forms of Kaposi’s sarcoma and 100% of AIDS–Kaposi’s sarcomas with HSV-8.58 Epstein–Barr virus (EBV) has been linked to sarcoma development in immunosuppressed patients. McClain and

1042 colleagues found evidence of EBV infection in five leiomyosarcomas and two leiomyomas from six human immunodeficiency virus (HIV)-infected patients. They did not find evidence of EBV infection in smooth muscle tumors tested from HIV-negative patients.59 In a large retrospective study of patients who received a polio vaccine contaminated with simian virus 40 (SV-40), Engels and associates failed to identify an increase in cancer formation.60 The evidence from case reports, epidemiologic studies, and molecular biology studies supports an association of HSV-8 infection and Kaposi’s sarcoma development in HIV-infected patients and probably in sporadic cases as well, and a minor role of EBV infection in other sarcoma formation in HIV-infected patients. Outside the clinical setting of HIV infection and/or immunosuppression, there is a lack of compelling data to support a viral etiology of sarcomas.

Chemical Exposure A number of studies have evaluated a possible association of chemical exposure and the development of sarcomas. Chemicals implicated by case-control and epidemiologic studies include phenoxy herbicides, chlorinated aromatic compounds (e.g., dioxins), and vinyl chloride. There exist certain limitations inherent in many of these studies. Reporting of visceral sarcomas is often placed under the International Classification of Diseases (ICD) codes assigned to that particular organ rather than as a soft tissue sarcoma.61 Several large epidemiologic studies of exposed workers have identified an association with chemical exposure, although others have not.61–71 Public concern surrounding exposure of Vietnam veterans to phenoxy herbicides (“Agent Orange”) and subsequent health risks has been addressed through a number of studies. These herbicides contain dioxin, widely reputed to be highly carcinogenic. However, a study by Greenwald and colleagues found no increased risk of sarcomas in veterans exposed to Agent Orange.72 Subsequent studies, reviewed by Frumkin, have not demonstrated an increase in the development of soft tissue sarcomas in veterans exposed to these herbicides.73 Further, Cole and colleagues summarized work evaluating dioxin and cancer, concluding that this agent is not a human carcinogen.74 Another chemical reported to be associated with the development of sarcomas is vinyl chloride. Case-control, retrospective cohort, and epidemiology studies have linked vinyl chloride exposure with a variety of cancers.75–79 However, subsequent review by McLaughlin indicated that the increased cancer risk after vinyl chloride exposure was limited to angiosarcomas of the liver.80 Subsequent review of epidemiologic literature by Bosetti and associates concluded that the only increased cancer risk was that of liver cancers, which they speculate may in fact represent angiosarcomas.81 At present, studies evaluating exposure to vinyl chloride support an association with the development of angiosarcomas of the liver.

Pathology There is a wide variety of histologic subtypes of sarcomas, and clinical behavior can be subtly or significantly different depending on histologic type. Pathologists use histogenetic

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classification schemes, which broadly distinguish soft tissue tumor subtypes based on the tissues they contain or are forming. Light microscopic evaluation is used to seek evidence of specific differentiation as the first step in classification. High-grade sarcomas are poorly differentiated, complicating classification. With advances in immunohistochemistry, cytogenetics, and electron microscopy, non-tissuespecific diagnoses, such as the once-common diagnosis of malignant fibrous histiocytoma, are increasingly being replaced by tissue-specific diagnoses based on direct or indirect evidence of characteristic tissue formation. However, many pleomorphic sarcomas are sufficiently undifferentiated that the tumors cannot be further classified or can only be classified after an extensive (and variably performed clinically) set of tests.

Molecular Pathology The ultimate evidence of differentiation is provided at the molecular level, and molecular techniques have the potential to profoundly influence our notions regarding the classification and characterization of sarcomas. Our conceptual model of sarcomagenesis has evolved over recent years. Sarcomas are believed to arise de novo in nearly all instances. They rarely arise from preexisting benign neoplasms (one important exception being sarcomas arising within plexiform neurofibromas in patients with neurofibromatosis type I). Sarcomas are thought to develop from mesenchymal stem cells residing in muscle, fat, and connective tissues. The origin of these stem cells remains unclear, and sometimes even their mesenchymal derivation is in question (as for nerve or nerve sheath sarcomas, gastrointestinal stromal tumors, and primitive neuroectodermal tumors (Ewing’s sarcomas). Two prevailing theories suggest that mesenchymal stem cells are found in local tissue pools or arise from the bone marrow.82 Advances in molecular pathology have enabled us to distinguish two general groups of sarcomas. One group consists of those tumors with simple karyotypes and specific reciprocal chromosomal rearrangements. Specific chromosomal translocations have been identified in a number of pathologic subtypes and may provide a specific diagnosis in the absence of other identifiable evidence of differentiation. Tumors in this group typically occur in younger patients, rarely have p53 mutations, and are not usually associated with genetic syndromes such as Li–Fraumeni syndrome. The second group consists of those tumors with complex karyotypes and random nonreciprocal chromosomal rearrangements; these are typically seen in older patients, frequently have p53 mutations, and are generally the ones seen associated with genetic syndromes. Molecular signatures, such as provided by cDNA microarray analysis, are increasingly being used to investigate the genetic basis of the histogenetic classification scheme employed for sarcomas. Perhaps not surprising, those sarcomas characterized by specific translocations or mutations have well-defined signatures that correlate strongly with the histopathologic diagnosis. Conversely, the molecular signatures of other sarcomas, notably liposarcomas, leiomyosarcomas, and malignant fibrous histiocytomas, overlap to a significant degree.83 This finding calls into question the validity of many of the pathologic distinctions that have been

soft tissue sarcoma

1043

FIGURE 58.1. Certain histologic types of soft tissue sarcoma have a strong predilection for specific anatomic sites. (Pisters, P-Soft Tissue Sarcoma in Surgery Basic Science and Clinical Evidence, New York, Springer 2001. Norton JA, Bollinger R, Chang A, et al. eds.)

made over the years and further suggests that there may be hitherto unrecognized sarcoma categories of clinical relevance.

Patterns of Growth and Anatomic Distribution Soft tissue sarcomas grow by direct local extension, infiltrating adjacent tissues and structures, occasionally with skip areas. They generally extend along tissue planes and uncommonly transverse or invade major fascial planes or bone. However, on gross inspection, many sarcomas demonstrate a characteristic pattern defined by a pseudocapsule, an apparently circumscribed tumor seemingly surrounded by a rim of compressed normal tissue. In fact, this pseudocapsule does not indicate the anatomic extent of the tumor, and removing the main mass from within the pseudocapsule invariably leaves tumor tissue behind. A minority of sarcomas, particularly dermatofibrosarcoma protuberans and cutaneous angiosarcoma, rarely if ever show a pseudocapsule and are instead characterized by very insidious infiltration of surrounding normal tissues that can greatly complicate attempts at complete resection. Soft tissue sarcomas occur at all anatomic sites of the body, but the majority arise in the extremities.2 At any given

anatomic location, the most commonly encountered histologic subtypes vary. Certain histologic types of soft tissue sarcoma have a strong predilection for specific anatomic sites (Figure 58.1). For example, 40% to 50% of epithelioid sarcomas arise on the forearm or hand, compared to only 14% of soft tissue sarcomas overall presenting anywhere in the upper extremity.84 There exist a number of staging systems for soft tissue sarcomas. The most widely used system is the American Joint Commission on Cancer (AJCC) (Table 58.2). This system incorporates the traditional tumor size (T), lymph node status (N), and metastasis (M) categories as well as histologic grade (G). The incorporation of histologic grade reflects the observation that grade is a significant prognostic factor, with survival decreasing with increasing tumor grade.85 A recent refinement in the staging of soft tissue sarcomas is the distinction of superficial and deep lesions, based on the location of the tumor relative to the investing muscular fascia. Sarcomas arising entirely above the investing fascia (i.e., cutaneous or subcutaneous) are “superficial” and designated in the AJCC system with the T modifier “a.” Sarcomas involving the fascia or arising entirely below it are “deep” and given the T modifier “b.” The majority (67%) of soft tissue sarcomas are high grade, deep, and more than 5 cm in greatest dimension. The evidence base for the AJCC staging system is reviewed subsequently.

1044 TABLE 58.2. American Joint Committee on Cancer (AJCC) GTNM classification and stage grouping of soft tissue sarcomas. Tumor grade GX Grade cannot be assessed G1 Well differentiated G2 Moderately differentiated G3 Poorly differentiated G4 Poorly differentiated or undifferentiated (four-tiered systems only) Primary tumor TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Tumor 5 cm or less in greatest dimension T1a Superficial location T1b Deep tumor T2 Tumor more than 5 cm in greatest dimension T2a Superficial location T2b Deep tumor Regional lymph node involvement NX Regional lymph nodes cannot be assessed N0 No known metastases to lymph nodes N1a Regional lymph node metastasis Distant metastasis MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis Stage grouping Stage IA Low grade, small (G1–2, T1a or b, N0, M0) Stage IB Low grade, large, superficial (G1–2, T2a, N0, M0) Stage IIA Low grade, large, deep (G1–2, T2b, N0, M0) Stage IIB High grade, small (G3–4, T1b, N0, M0) Stage IIC High grade, large, superficial (G3–4, T2a, N0, M0) Stage III High grade, large, deep (G3–4, T2b, N0, M0) Stage IV Nodal or distant metastases (any G, any T) a

Note: Presence of positive nodes (N1) is considered Stage IV.

Source: Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, sixth edition (2002), published by Springer-Verlag New York, www.springer-ny.com.

Prognostic Features Characterization of the heterogeneous group of tumors called sarcomas has been hampered by the relative rarity of each specific subtype. Our understanding of the clinical features and natural history of sarcomas is largely limited to case reports, single-institutional experiences, and a few large-scale surveys of national cancer registries using different methodologies in data collection and reporting. To obtain sufficient numbers of patients with sarcomas, these reports generally combine the data from patients treated over several decades. This practice often results in the inclusion of patients who underwent markedly different treatment regimens, inclusion of bone sar-

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comas with soft tissue sarcomas, and inclusion of histologic subtypes that are known to have dramatically different clinical behavior. Despite these limitations, we are able to identify a number of salient features associated with sarcomas that are generally supported by studies involving large, often prospectively collected databases. These reports provide the foundation for current grading systems. The strongest recognized prognostic factors are tumor grade, size, and depth; these key components of widely used clinical staging systems are discussed next (Table 58.3). Other prognostic factors have variably been identified as statistically significantly associated with either local recurrence or metastasis and survival. Local extension of tumor to involve blood vessels and bone has been shown to be associated with decreased survival, as has microscopic vascular invasion.86,87 Some studies have related worse survival and increased local recurrence rates with increasing age.88–92 A number of studies have identified that tumor location is of clinical importance.86,93–95 LeVay and associates noted that local recurrence was higher in patients with sarcomas of the head and neck, likely reflecting difficulties in obtaining negative surgical margins. They also noted higher rates of metastasis in patients with trunk and head and neck sarcomas when compared with extremity sarcomas. In virtually all major studies, patients with extremity tumors fare better than those with sarcomas arising on the trunk, head, neck, or retroperitoneum. Other prognostic factors associated with adverse outcomes identified by researchers in separate studies include skin involvement, lymph node metastasis, pain at presentation, and postoperative fever following resection.90,95–98 Another area of controversy is the impact of isolated local recurrence on ultimate prognosis. Presentation with local recurrence has been shown to decrease overall survival in a number of studies.86,89,92,99 Other studies have indicated a similar outcome for locally recurrent lesions compared to primary sarcomas of the same grade, size, and depth. The available evidence does not clearly support a contention that local recurrence is, in and of itself, an independent negative prognostic factor. Rather, the weight of evidence supports managing most cases of isolated local recurrence of sarcoma in a fashion analogous to the same case presenting for primary treatment. Histologic grade, widely regarded as the predominant prognostic factor for localized sarcomas, is a subjective determination based on a number of individual microscopic features: these include tumor cellularity, pleomorphism, mitotic rate, degree of differentiation, and the presence or absence of spontaneous necrosis. Some authors have separately evaluated these features and shown them to be independent prognostic factors.87,88,93,98,100,101 Newly identified molecular markers will likely play an important role in the future. Several molecular markers, such as c-Kit in gastrointestinal stromal tumors, have demonstrated their clinical utility in the diagnosis and treatment of specific sarcomas. Some molecular markers that have been associated with adverse prognosis are ras, c-myc, Ki-67, murine double minute 2 (MDM2), Rb1, and p53.102–113 Further studies involving larger numbers of patients are required before any of these markers can be regarded to have documented independent prognostic significance.

1045

soft tissue sarcoma TABLE 58.3. Major studies evaluating prognostic features of soft tissue sarcomas. Statistically significant factors Author

Study design

Coindre et al., 199696

Retrospective review of prospectively collected data

N

Sites

Size

Grade

Depth

Histology

546

All

(+)*

(+)* **

(+)†

(+)**

†

†

†

Pisters et al., 199689 Zagars et al., 2003322

Retrospective review of prospectively collected data Retrospective case series

LeVay et al., 199386

Retrospective case series

323

Abbas et al., 1981 Tsujimoto et al., 198893 Trojani et al., 198488

Retrospective case series Retrospective case series Retrospective case series

1,041

Extremity

(+)**

(+)**

(+)**

(+)*

1,225

All

(+)* ** (+)* **

(+)* ** (+)* **

NR NS

(+)* ** NR

NR (+)† (+)†

(+)† NR NR

(+)**

NR

389

251 236 155

All except retroperitoneal and visceral All All All

†

†

†

†

(+) NS NS

(+) (+)† (+)** †

94

Ravaud et al., 1992

El-Jabbour et al., 1990100 Mandard et al., 198987

Ruka et. al., 198995 Lack et al., 1989101 Collin et al., 198790

Retrospective case series Retrospective case series Retrospective case series

Retrospective case series Retrospective review of prospectively collected data Retrospective case series

144 125 109

267 300

All except visceral

(+)**

All All except retroperitoneal and visceral All except retroperitoneal Extremity

(+)† (+)**

†

†

(+)** †

(+)†

Weitz et al., 2003

423

Extremity

Ueda et al., 198897

Retrospective review of prospectively collected data Retrospective review of prospectively collected cata Retrospective case series

Rööser et al., 198798

Retrospective case series

144

Extremity and Trunk Extremity

Shiu et al., 1975324 Markhede et al., 198299

Retrospective case series Retrospective case series

297 97

Extremity Extremity

Singer et al., 199492

†

(+)† (+)** †

NR, all high grade (+)**

†

(+)† (+)**

(+)† NR

†

NR

NR

NR

NS

NS

(+)**

†

(+)** †

91

(+)**

(+)** †

†

1,706

Extremity

(+)**

(+)**

(+)**

(+)**

182

Extremity

(+)†

(+)†

NR

(+)†

163

(+)†

(+)†

(+)†

NR

(+)**

NR

NR

(+)† NS

(+)** All intermediate and high grade (+)† (+)*

NR NS

NR (+)**

(+), statistically significant by univariate or multivariate analysis; NR, not reported; NS, not statistically significant. *Local recurrence-free survival. **Disease-free survival. †

Overall survival.

Staging The importance of staging systems is severalfold. These systems serve as a means to evaluate prognosis, base clinical treatment decisions, and allow comparisons of studies. A staging system needs to be able to discriminate patient outcome in a meaningful and reproducible way. Staging of soft tissue sarcomas remains a work in evolution. Attempts to develop staging systems for soft tissue sarcomas began in earnest in the 1970s. Enneking and colleagues established a staging system for extremity soft tissue sarcomas based on

tumor localization within muscular anatomic compartments, histologic grade and metastasis.114 Subsequent investigators have created new or refined staging systems, each with its strengths and weaknesses.85,115 Currently, the most widely use staging system is that of the American Joint Committee on Cancer (AJCC), which modifies the familiar TNM system by the addition of grade (G) as a separate component (see Table 58.2).85 Important caveats related to the AJCC staging system are that it does not apply to Kaposi’s sarcoma, dermatofibrosarcoma, infantile fibrosarcoma, and angiosarcomas, as these tumors are known to have unique but often poorly

1046 characterized prognostic features. The framers of this staging system also point out that it does not adequately stage sarcomas arising in all anatomic locations. Specifically, sites with unique prognostic features are those sarcomas arising in the dura, brain, parenchymatous organs, gastrointestinal tract, and retroperitoneum. A great deal of evidence forms the basis for the AJCC staging system, but there is also evidence pointing to weaknesses or inadequacies of the current system. From the studies to date, it is clear that prognosis is inversely proportional to tumor size. The AJCC staging system characterizes size as a dichotomous variable with a breakpoint at 5 cm maximum dimension. Available evidence indicates, however, that size should be a considered as a continuous variable. For example, survival with a 6-cm tumor is significantly better than that of a 15-cm sarcoma despite both tumors being staged T2 in the AJCC system. At the very least, it would be appropriate to recognize additional breakpoints (e.g., 10 cm, 15 cm, 20 cm) as defining progressively poorer prognosis categories. Recently, depth was incorporated into the AJCC staging system as a factor secondary in importance to size. Available evidence is inconclusive as to whether depth is truly an independent factor: the apparent prognostic significance of depth may be a reflection of the fact that deeper lesions more often reach larger size (frequently well in excess of the 5-cm cutoff) before diagnosis. The use of histologic grade as an integral part of the AJCC system is one of the most accepted and time-tested aspects of sarcoma staging, but even this has not been without controversy. Evidence clearly supports that three-part systems (defining low, medium, and high grade) provide additional prognostic information compared to two-part systems.116 The evidence is much less clear that there is additional information conveyed by four-part systems. The AJCC system uses a four-part grading system but collapses this into a two-part system for assignment of the G classification (that is, grade 1 or 2 sarcomas are G1 while grade 3 or 4 sarcomas are G2). Clinically, it is a widely accepted principle that intermediateand high-grade sarcomas (in three-part systems) are treated similarly. The rationale for collapsing grade 1 and 2 sarcomas into the same category, especially given how most pathologists discriminate grade 1 and 2 lesions, requires further prospective evaluation and perhaps even revision in future iterations of the system. The relative significance assigned to grade in stage assignment has also been brought into question. Ramanathan and associates observed that AJCC stage III patients in their study in fact had a higher overall survival than stage II patients.117 Other investigators similarly found survival rate discrepancies between stages.118–120 Lymph node metastasis has been identified as a significant negative prognostic finding,121,122 as reflected in stage IV assignment in the face of N1 disease, indicating that prognosis for node-positive sarcoma patients is considered similar to those who present with metastatic disease. The frequency of lymph node metastasis has been reported to range from 2% to 13%, with the true incidence likely closer to 5%.122–126 Although lymph node metastasis is a rare event in soft tissue sarcomas, higher incidence of lymph node metastasis is observed in synovial cell sarcoma, rhabdomyosarcoma, clear cell sarcoma, and alveolar soft parts sarcoma.126 It remains unclear, based on available data, whether nodal metastasis conveys similarly poor prognosis for all these tumor types and

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whether the prognosis after nodal metastasis in contemporary series is truly equivalent to metastatic disease beyond the regional nodes. Validation of the AJCC staging system has been performed through a number of studies. As already discussed, problems with stage discrimination have been identified in several studies. From these reports, it is clear that further modifications will be needed in future iterations. Treatment decisions should incorporate anatomic site, tumor histology, actual tumor size, and, where appropriate, molecular markers rather than restricting decisions to only AJCC stage assignment.

Clinical Evaluation Extremity Sarcomas The clinical presentation of patients with soft tissue sarcomas varies by anatomic site. The most common locations for these tumors are shown in Figure 58.1. Patients with soft tissue sarcomas arising in the extremities usually present with a painless mass that is larger than 5 cm (Table 58.4). ElJabbour et al. reported a median duration of symptoms of 6 months before presentation.100 In a survey of more than 5,800 sarcoma patients, Lawrence and colleagues reported that about half waited at least 4 months before seeing a physician and 20% experienced delays of 6 months or more after seeking treatment before a correct diagnosis was made.127 Often sarcoma patients are diagnosed clinically as having a “chronic hematoma” or “pulled muscle” and undergo prolonged observation or treatment for these conditions. In fact, nonathletic adults rarely develop persistent soft tissue masses from either of these causes in the absence of a history of unusually strenuous activity or significant trauma, unless they are on chronic anticoagulant therapy. When a soft tissue mass arises in a patient with no history of trauma or persists more than 6 weeks after local trauma, further evaluation is indicated. Virtually all soft tissue masses arising in the extremity that are more than 5 cm in diameter and any new, enlarging, or symptomatic lesions should be biopsied. Only small subcutaneous lesions that have persisted unchanged for many years should be considered for observation rather than biopsy.

TABLE 58.4. Major studies reporting clinical presentation of extremity soft tissue sarcomas. Study

Age

Gender (% male)

Pain (%)

Less than 5 cm (%)

Donohue et al., 1988325 Ueda et al., 198897 Weitz et al., 200391 Pisters et al., 199689 El-Jabbour et al., 1990100

58a 46a 55a 51a 58c

46 56 53 53 53

22 30 NR 19 20

44 38 52 41 33

NR, not recorded. a

Median age with metastasis, 48 years without metastasis.

b

Median.

c

Mean.

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soft tissue sarcoma TABLE 58.5. Major studies reporting clinical presentation of retroperitoneal sarcomas. Study

Lewis et al., 1998129 Stöckle et al., 2001251 Ferrario et al., 2003256 Alvarenga et al., 1991249 Dalton et al., 1989247 Jaques et al., 1990239 Hassan et al., 2004254 Karakousis et al., 1995246 Zornig et al., 1992250 Wang et al., 1996255 Makela et al., 2000252 Pirayesh et al., 2001253 Solla et al., 1986248

N

Age

Gender (% male)

Size greater than 5 cm (%)

High grade (%)

500 165 130 50b 116 114 97 90 51 40 32 22 20

58b 54b 57b 50 57a 57b 59a 58b 44a 55a 58a 53a 53a

57 50 53 90 47 59 56 50 45 67 50 59 40

94 94 95 43 98 100 97 97 100 100 91 100 100

60 43 44 54 57 69 40 42 NR NR 46 NR

NR, not recorded. a

Mean.

b

Median.

The best way to avoid undue diagnostic delay during evaluation of a soft tissue mass is for the physician always to remain cognizant of the possibility of malignancy. During the physical examination attention should be given to tumor location, size, mobility, tenderness, vascular exam, skin changes, and inspection of all lymphatic basins. It is also relevant to identify often subtle neurologic changes that can result from the mass. If a deep-seated extremity mass is to be biopsied, we prefer that appropriate imaging studies be performed before biopsy; this ensures no tissue distortion that could complicate the interpretation of the study and may assist in the planning of the biopsy to ensure the highest yield samples.

Retroperitoneal and Visceral Sarcomas Sarcomas arising in the retroperitoneum and from abdominal viscera most commonly present as an abdominal mass often without other symptoms (Table 58.5). Although the median age is around 50, retroperitoneal sarcomas can occur at any age. These tumors usually do not come to the attention of the patient until they are large. Retroperitoneal sarcomas smaller than 5 cm are rarely seen.128,129 When present, symptoms relate to mass effect of the tumor or local invasion. Early satiety, gastrointestinal obstruction or bleeding, lower extremity swelling, or pain can be the first symptoms leading to the discovery of a retroperitoneal sarcoma. The most useful tool in the evaluation of retroperitoneal tumors is a computed tomographic (CT) scan; this allows assessment of tumor location and relationship to adjacent organs, and can identify metastatic lesions in the liver or peritoneal cavity. Once the initial evaluation identifies a retroperitoneal tumor, the clinician must consider a number of clinical entities, including functioning and nonfunctioning adrenal tumors, renal tumors, pancreatic tumors, advanced gastrointestinal carcinomas, germ cell tumors, and soft tissue sarcomas. Detailed history and physical examination can help distinguish many of these entities and prompt further studies. Serum betahuman chorionic gonadotropin (b-hCG), alpha (a-)fetoprotein,

and testicular examination and ultrasonography are indicated in cases of suspected testicular cancer with retroperitoneal metastasis. In patients with lymphadenopathy, either core needle or excisional biopsy of enlarged lymph nodes may be diagnostic for lymphoma. When tumors appear to be arising from the stomach, pancreas, or duodenum, upper gastrointestinal endoscopy with biopsy may be diagnostic. Similarly, colonoscopy with biopsy can be useful in tumors arising from the colon. If these diagnoses are ruled out or low in the differential and sarcoma is the most likely diagnosis, the role of biopsy is controversial. Pisters and colleagues suggest that surgical exploration is the most appropriate next step for a retroperitoneal mass suspected of being a sarcoma.130 We advocate a more-cautious approach, as new treatment options may be considered based on the results of a percutaneous biopsy. Examples include the use of imatinib mesylate (Gleevec) in the treatment of gastrointestinal stromal tumors or primary chemotherapy in germ cell tumors or lymphomas. Often the distinction between these diagnoses can be difficult with nonspecific physical findings and imaging studies. Our approach is to have patients undergo CT-guided biopsy of retroperitoneal tumors before treatment planning if the diagnosis is unable to be established through less-invasive means. It is important to note that nondiagnostic biopsies are not uncommon; in such cases, we proceed to surgery.

Head and Neck Sarcomas The majority of head and neck cancers are epithelial tumors, followed by lymphomas with sarcomas comprising only 1% to 11% of these malignancies.131 Sarcomas of the head and neck can occur at any age; however, median ages from series are usually in the fourth and fifth decades (Table 58.6). From several series, we observe that the majority of these tumors are less than 5 cm, and they are less often high grade than sarcomas arising in other sites. Bentz et al. reported a series of 111 head and neck sarcomas, noting that half these patients

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TABLE 58.6. Major studies reporting clinical features of sarcomas arising in the head and neck. Study

Webber et al., 1986133 Farhood et al., 1990134 Eeles et al., 1993140 Bentz et al., 2004132 Le Vay et al., 1994135 Dudhat et al., 2000178 Kraus et al., 1994139

N

Age

Size less than 5 cm (%)

High grade (%)

Distant metastastes (%)

188 176 130 111 73 72 60

50b 48a 36 47a 50a 37b 49b

59 52 78 72 42 29 72

NR 59 48 46 NR 38 58

40 23 1 33 16 7 NR

NR, not recorded. a

Mean.

b

Median.

presented with a painless enlarging mass; the remainder reported pain or neurologic dysfunction on presentation.132 The neck, face, and scalp represent the most frequent subsites for sarcoma formation; however, tumors can arise in the oral cavity, sinuses, orbit, pharynx, and nasopharynx.131–143

Imaging Great advances have occurred during the past two decades through the widespread use of CT and magnetic resonance (MR) scanning. The two modalities have continued to evolve, further refining the quality of these studies. As discussed previously, we strongly encourage imaging of deep soft tissue tumors before any biopsy procedure; this is important in characterizing the lesion before distortion that may accompany the biopsy. Planning the most appropriate biopsy technique, target area, and approach is also facilitated by prebiopsy imaging. Magnetic resonance images are excellent at delineating tissue planes, neurovascular structures, and characterization of soft tissue tumors without the use of radiation (Figure 58.2). A number of studies have demonstrated the ability of magnetic resonance imaging (MRI) to characterize benign and

FIGURE 58.2. Magnetic resonance imaging (MRI) of lower extremity high-grade undifferentiated pleomorphic sarcoma with encasement of the sciatic nerve.

malignant soft tissue tumors accurately in a high percentage of cases.144–147 Totty et al. compared MRI with CT scanning for evaluating soft tissue tumors of the extremities.144 They noted that T1-weighted MR images better delineated extension of tumors into surrounding fatty tissue. They found that T2-weighted and spin-density MR images were superior in detecting tumor extension into muscle. Overall, they found MR to yield superior resolution images to CT scanning in 33% of comparisons and equal results in 67%. In their study, MRI never yielded inferior results compared to CT. The only deficiency they identified was the limited ability of MRI to demonstrate soft tissue calcification and gas. In a study comparing MRI with CT in the evaluation of 27 extremity soft tissue tumors, Weeks and associates found that MRI was able to adequately assess neurovascular involvement in 80% of cases compared with 62% of CT scans.148 Verstraete and colleagues utilized contrast-enhanced techniques in MRI, demonstrating an improved ability to depict tissue vascularization and perfusion.147 This advantage is relevant in biopsy planning, where the highest yield specimens are more likely to be obtained from viable, well-perfused areas. When bony involvement or destruction is of concern, CT scanning is better suited than MRI (Figure 58.3). Imaging of the head and neck can be accomplished through either CT or MRI. We have usually relied on CT as our initial imaging modality and added MRI when further characterization is required. In imaging the chest, trunk and abdomen, CT scanning is the most commonly employed technique (Figure 58.4). Obtaining high-quality MR scans of the chest and abdomen can be difficult, whereas CT is less sensitive to motion artifact.149 Characterization of fatty tumors, tumor proximity to adjacent organs, and detection of intraabdominal metastasis are all possible with CT scanning of the abdomen. In the pelvis, all these features of CT are relevant, as well as excellent characterization of bony invasion. Granstrom and Unger reviewed the techniques and interpretation of MR in the evaluation of retroperitoneum.150 They emphasized the importance of axial images in addition to sagittal and coronal views. Although MR has been investigated in the evaluation of specific organs such as pancreas and adrenal glands, large studies comparing MRI of retroperitoneal sarcomas with CT scanning are lacking. At present, we rely primarily on CT scanning in the evaluation of soft tissue tumors arising in the abdomen and pelvis.

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FIGURE 58.3. Computed tomography of a pelvic Ewing’s sarcoma showing destruction of the right iliac bone.

Biopsy The technical details of biopsy in the evaluation and treatment of soft tissue tumors remain the subject of debate, fueled by a surprising lack of high-quality evidence. Concerns surround the technique employed, pathologic interpretation, and treatment implications. Following the initial history and physical examination and appropriate radiologic investigations, the decision regarding biopsy must be carefully considered. Although the technical aspects of the actual performance of the biopsy are not necessarily complex, the decision making can be challenging for even the most experienced surgeon. As Mankin and colleagues pointed out in two similar studies conducted 14 years apart, missteps at this stage can have grave consequences.151,152 Their initial report identified a 17% complication rate resulting from the biopsy. More concerning was the finding that, in 18% of patients, the

FIGURE 58.4. Computed tomography of abdominal wall solitary fibrous tumor.

treatment or outcome was altered because of some difficulty related to the biopsy. Factors implicated included poorly oriented incisions, made without due regard to the subsequent surgical approach required for definitive resection, and wound complications such as infection or hematoma formation. Perhaps the most distressing finding was that nearly 5% of patients went on to have amputations who might otherwise have been candidates for limb-sparing procedures. The authors concluded that the planning of a biopsy, technique employed, incision orientation, and pathologic interpretation could have significant treatment implications. They also found that patients biopsied at outside referring institutions experienced complications with skin, soft tissue, or bone in 31% whereas only 7% of biopsies performed at specialty centers had similar complications. There was an alteration in treatment as a result of the biopsy in 32% of referring institutions who performed these biopsies and 8% in those performed at the specialty centers. When the authors repeated this study, they found very little had changed in these results despite prior warnings. These issues serve to alert us to the significance a biopsy plays in patients presenting with soft tissue tumors. In lesions of the extremity, a number of methods can be employed to obtain diagnostic tissue, including fine-needle aspiration (FNA) cytology, core needle biopsy, incisional biopsy, and excisional biopsy. Each technique has its advantages and disadvantages and requires expertise in its performance and, equally importantly, in the pathologic interpretation. FNA is the least invasive, associated with a low complication rate, and can be performed in an outpatient setting. Tumors in both superficial and deep locations can be biopsied using this technique. A number of studies have been able to establish the diagnosis of malignancy in more than 90% of cases; in some series, the majority could be assigned to a specific histologic subtype.153–157 In a prospective series of 365 consecutive FNA biopsies of soft tissue lesions, Akerman et al. reported correct diagnosis of malignancy in 89% and correct diagnosis of a benign lesion in 96% of lesions.155 A major concern with the use of FNA remains the occurrence of false-positive diagnoses of malignancy in small numbers of

1050 patients in virtually every large series. In Akerman’s series, two patients had their care altered as a result of a false diagnosis. The application of ancillary techniques (cytogenetics, immunohistochemistry, flow cytometry, electron microscopy) can achieve a diagnostic accuracy approaching 95% in identifying malignancy.156 Reported rates of false positives and false negatives range from 1% to 4% with adequate sampling.153,156,158,159,160–161 Needle tract seeding following FNA biopsy has been reported; however, it appears to be exceptionally rare.155,157,161–163 It must also be noted that the majority of studies reporting excellent results with FNA are performed in centers with large volumes of soft tissue tumors, expert cytologists, and individuals with expertise and interest in the cytologic evaluation of soft tissue tumors. Whether these results can be reproduced in institutions without dedicated specialized cytopathologists is doubtful. We currently employ FNA in the evaluation of lesions suspicious for recurrence or metastatic disease, where the prior histology is available and can aid in confirmation, but not for primary extremity lesions. Core needle biopsy has emerged as the most commonly employed biopsy technique in recent years. Several advantages have been identified when using this approach. This procedure can generally be performed in the outpatient setting with local anesthesia. The complication rate is similar to that of FNA, approximately 1% to 2% in several series.164–166 Core needle biopsy provides a 1 mm ¥ 10 mm tissue sample, preserving tumor architecture to facilitate pathologic diagnosis and the assignment of histologic grade.166 Ball and associates evaluated 52 consecutive core needle biopsies of soft tissue tumors, reporting accurate diagnosis in 98% of malignant tumors.165 They reported correct histologic subtype diagnosis in 85% and correct histologic grade assignment in 88% of sarcomas. In a report comparing 570 core needle and open biopsies, Hoeber and colleagues reported sensitivities of 99.4% and 97.4%, respectively.166 They found a specificity of 98.7% for core needle biopsy and 100% for incisional biopsy. They were able to assign the histologic subtype and grade in 80% of core needle biopsies. Heslin and associates evaluated 164 primary extremity soft tissue tumors comparing first biopsy attempts of core needle biopsy, incisional biopsy, frozen section, and excisional biopsy,167 finding that 93% of core needle biopsy samples were adequate to establish the diagnosis. Core needle biopsy was able to identify malignancy in 95%, histologic grade in 88%, and subtype in 75% of biopsies. Taken together, these studies support the accuracy, safety, and utility of core needle biopsy in the evaluation of soft tissue tumors. We utilize core needle biopsy for the initial diagnostic study in most patients presenting with soft tissue tumors larger than 5 cm in both superficial and deep locations. Incisional biopsies play an important role in evaluation of soft tissue tumors, but decisions regarding when and where to employ this technique require significant experience in the treatment of musculoskeletal tumors. As tumor seeding is a concern, excision of the biopsy scar and tract is required if a sarcoma is diagnosed. Poorly planned incisions may result in added morbidity for sarcoma patients when they undergo definitive resection (Figure 58.5).168–170 Incisions oriented along the long axis of the extremity do not necessarily yield the best cosmetic result, but they minimize future problems in the event a sarcoma is diagnosed. The incision should be

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FIGURE 58.5. Poorly oriented biopsy of anterior shoulder with interrupted sutures, hematoma, and infection.

placed directly over the most superficial part of the tumor whenever possible, allowing a surgical approach that avoids crossing through uninvolved compartments to minimize contamination of normal tissues (Figure 58.6).154 The accuracy in distinguishing benign from malignant tumors is greater than with core needle biopsy; however, risks of hematoma and wound complications are also higher.151,152,166 Meticulous hemostasis to avoid hematoma and possible contamination of adjacent muscle compartments is imperative. Because the zone of compressed, reactive tissue around a sarcoma can

Incision for subsequent tumor removal Biopsy incision Tumor within muscle

FIGURE 58.6. When making an incision, the incision should be placed directly over the most superficial part of the tumor whenever possible, allowing a surgical approach that avoids crossing through uninvolved compartments to minimize contamination of normal tissues.

soft tissue sarcoma

look like malignant tumor tissue, we utilize frozen section to ensure adequate tissue for diagnosis has been obtained. The limitations of frozen section histopathology are significant, however, and radical procedures are generally not carried out based on a frozen section diagnosis obtained during incisional biopsy. Excisional biopsy is reserved for small, superficial lesions. Although most such lesions are benign, the same careful planning is required as described in performing incisional biopsies. The biopsy incision should be oriented in such a way as to allow for uncompromised wide reexcision in the unlikely event of a malignant diagnosis. When considering biopsy of a large or deep soft tissue tumor, the input of a surgical specialist experienced in the treatment of sarcomas can avoid many of the potential pitfalls reported by Mankin et al.151,152 Sarcoma treatment centers continue to see patients who have undergone excisional biopsy for large or deep sarcomas. Unplanned excisional biopsy (the so-called oops phenomenon) carries with it a very high risk of leaving gross or microscopic tumor behind, even when the biopsy surgeon believes a complete excision of all tumor has been carried out. Randall and associates reviewed 104 unplanned resections of soft tissue sarcomas referred to a specialty center and found that 82% of excisional biopsies had positive histologic margins.171 In a retrospective review of 65 patients referred to a specialty care center after unplanned excision of soft tissue sarcomas, Noria and associates documented that 39% of these patients had residual disease when subsequent reresection was performed.172 None of the patients in this series had identifiable disease on physical examination or by imaging. Noria et al. were unable to identify predictive factors to identify those patients who were most likely to have residual disease. When Davis et al. evaluated their experience performing reexcision in 239 patients after soft tissue sarcoma excisional biopsies, they identified residual disease in 35% to 40% of reresected specimens.173 Other investigators have similarly found a high incidence of residual disease on reresection.174,175 Increased local recurrence rates have also been associated with excisional biopsy of soft tissue sarcomas in some but by no means all series.172,173

Treatment Available evidence regarding prognostic and treatmentrelated factors suggests that treatment decisions for patients with clinically localized soft tissue sarcomas be based on the site and histologic grade of the primary tumor. Traditionally, the mainstay of treatment for soft tissue sarcomas has been surgery.176–178 Increasingly, it is now recognized that a multidisciplinary, multimodality approach including radiation and at times systemic chemotherapy is associated with improved outcomes for most patients with soft tissue sarcomas. Multimodality therapy in properly selected patients can improve local control rates, decrease the morbidity and quality of life impairment associated with surgery (particularly by decreasing the need for amputation to control extremity sarcomas), and increase the duration of relapse-free survival. Available evidence is insufficient to conclude that multimodality therapy results in increased overall survival durations, but at least some data suggest that it may.

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Surgery The most effective single-modality treatment for localized soft tissue sarcoma in any site is complete resection with histologically negative margins. Because many soft tissue sarcomas manifest a pseudocapsule, “shell out” procedures where tumors are removed from within this apparent capsule are associated with local recurrence rates that approach 100%. Historically, this led to the adoption of extensive radical procedures, frequently in the form of amputations, to ensure adequate local control. Sarcoma resections are categorized as intracapsular, marginal, wide, or radical.179 Intracapsular resections are usually a result of “shell out” of an apparently encapsulated tumor when a malignant diagnosis was not anticipated. In a marginal resection, the plane of dissection is outside the pseudocapsule but before or within the surrounding reactive zone. Wide resection consists of resection of surrounding normal tissue outside the reactive zone. In a radical resection, there must exist a natural barrier interposed between the tumor and the margin in all directions. This approach is best illustrated in compartmental resections, where an entire muscle group is resected at its origin and insertion with the fascia intact throughout (Figure 58.7).179 In this categorization, radical resections are associated with lower local recurrence rates than other procedures when surgery is the sole modality of therapy. In multimodality approaches, however, evidence of the superiority of true radical resections is lacking, and indeed they may be associated with increased complication rates and poorer functional outcomes. For most sarcomas treated with a multimodality approach, wide excisions are the procedure of choice. The emergence of radiation and systemic chemotherapy as potentially active agents for unresectable sarcomas led to the development of combined modality approaches that could preserve the limb with reasonable function and acceptable local control rates. Rosenberg and associates reported a prospective 2 : 1 randomized trial of 43 patients comparing limb-sparing surgery (wide excision) and postoperative radiation to amputation; all patients received postoperative systemic chemotherapy.180 They found that the local recurrence rate was marginally higher in the group undergoing limbsparing surgery (P = 0.06), but a large majority of patients in the limb-sparing surgery group had successful local control of their tumors. There was no statistical difference in overall survival between the two arms, but the study was far too small to reliably detect such a difference. Based on these limited data, multimodality limb-sparing approaches have become the accepted norm for the management of nearly all extremity soft tissue sarcomas. Subsequent studies evaluating limb-sparing surgery in the treatment of soft tissue sarcomas are shown in Table 58.7. Surprisingly, evidence demonstrating that limb-sparing approaches are associated with measurably improved functional outcomes and/or quality of life compared to amputation is largely nonexistent. Functional outcome comparing patients who had amputation with those who underwent limb-sparing procedures was addressed in a study by Davis et al.,181 who noted a trend toward increased disability in those patients undergoing amputation versus those who had limbsparing procedures. Conversely, a study by Sugarbaker and associates found that quality of life assessments failed to

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FIGURE 58.7. A compartmental resections is where an entire muscle group is resected at its origin and insertion with the fascia intact throughout.

support a benefit to limb-sparing procedures over amputations.182 Following radical limb-sparing procedures, many patients have significant functional disability, although most are able to ambulate remarkably well.183–185 Stinson and colleagues evaluated acute and long-term effects of limb function following limb sparing therapy,183 reporting that 84% of patient were able to ambulate without assist devices with mild or no pain.

Encasement of nerves or blood vessels by soft tissue sarcomas is uncommon but is not in and of itself an indication for amputation. Complete resection of the sciatic nerve results in loss of knee flexion and dorsiflexion of the foot. With aggressive physical therapy and the use of an ankle-foot orthosis, however, these patients can ambulate. Brooks et al. evaluated functional status of patients following resection of the sciatic, peroneal, or tibial nerves.186 They reported a post-

TABLE 58.7. Major studies evaluating limb-sparing surgery for soft tissue sarcomas. Study

N

Chemo*

XRT**

Study design

84 81

Yes Yes

Yes No

Prospective Randomized

4 14

88 91

Yes Yes

Yes No

Prospective Randomized

0 10

75 74

Yes Yes

Yes No

Prospective Randomized

0 15

88 83

Yes Yes

Yes No

Prospective Randomized

6 15

NR

Yes

Yes

33

6

88

Yes

Yes

Rydholm et al., 1991192

67

12

82

Yes

No

Pao et al., 1990195

50

8

68

Yes

Yes

Retrospective Database Review Retrospective Review Retrospective Review Retrospective Review

Pisters et al., 199689 Brachytherapy No brachytherapy Brennan et al., 1987193 Brachytherapy No brachytherapy Yang et al., 1998196 Radiation No radiation Rosenberg et al., 1982180 Amputation Limb salvage Williard et al., 1991326 Amputation Limb salvage

164

Henshaw et al., 2001191

117 52 65 91 47 44 47 27 16 649 92 557

LR (%)

OS (%)

18 31

NR, not recorded; LR, local recurrence; OS, overall survival; chemo, chemotherapy; XRT, radiation therapy. *Variations in timing, doses, and regimens in different studies. **Variations in dose, timing, and use in different studies.

soft tissue sarcoma

operative leg function score of 8 of 10 and added that all patients surveyed preferred their status to amputation. A number of reports have documented the feasibility of en bloc resection of arteries and veins with autologous or prosthetic graft reconstructions.187,188 Current multimodality approaches can result in limb preservation with useful function and very high rates of local tumor control. Even though evidence of clear-cut superiority in functional outcome or equivalence in local control and survival when compared to amputation is lacking, sarcoma patients will almost never accept a major amputation if a nonamputative surgery is feasible. This general acceptance of the concept of limb preservation is reflected in the fact that only 5% of patients currently presenting to major centers with primary soft tissue sarcoma of the extremity are treated with amputation.127 The weight of current evidence supports the use of limb-sparing surgery as part of the multimodality management of soft tissue sarcoma of the extremities. The optimal techniques for limb-sparing treatment have not been defined, and it is undoubtedly true that multiple effective options exist. Matching the proper combination and sequence of therapies to the needs of the individual patient remains one of the major challenges in the treatment of soft tissue sarcomas and often requires the skills of a dedicated multidisciplinary team of physicians and allied health personnel.

Radiation Therapy Limb-sparing resection alone, particularly marginal or wide excision, has been associated with local recurrence rates up to 50% to 70%,189,190 which sparked an interest in decreasing local recurrence with the application of radiation. Controversy continues regarding the necessity, type, and timing of radiation therapy; as in so many other situations, prospective comparative clinical trials are few, limited in statistical power, and often contradictory.118,191,192 Although most patients with extremity sarcomas do receive some form of radiation along with surgery, available evidence suggests that for some patients, particularly those with small, superficial, or low-grade tumors, wide excision alone is adequate treatment. In a review of 56 patients with extremity sarcoma, Rydholm and associates reported their experience using limb-sparing surgery without radiation.192 They reported a local recurrence rate of 7%. From their experience, they questioned the necessity of radiation therapy in all extremity sarcoma patients. In contrast, other investigators have demonstrated improved local control rates with the addition of radiation therapy.119,193–196 Confounding the impact of radiation therapy is the variability in the timing of radiation, surgical margin status, and use of adjuvant chemotherapy. From the studies to date there appears to be a decrease in local recurrence by adding radiation to resection. Studies have generally supported the omission of radiation for lowgrade soft tissue sarcomas when surgical margins are widely free of tumor.118,192,196 It may be the case that aggressive systemic and/or regional chemotherapy can replace the need for radiation in some cases. In a study by Henshaw and associates, 33 patients were treated with preoperative intraarterial cisplatin and systemic doxorubicin.191 Ifosfamide was added in the later part of the study. Included in this study were 18 patients with high-grade soft tissue sarcomas of the extremities and pelvis that were

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deemed unresectable, with the remainder of patients having large but potentially resectable high-grade soft tissue sarcomas in the extremities and pelvis. Variability in the definition of unresectability for extremity sarcomas is a major limitation when comparing studies or trying to generalize results to other institutions. In any event, only 2 of the 18 patients who initially were deemed unresectable actually underwent amputation after receiving chemotherapy. All the remaining patients were able to have limb-sparing resections. Twelve of the patients received radiation therapy, which was reserved for those with close surgical margins or limited degrees of chemotherapy-induced necrosis on histologic evaluation of the resected specimen. Two patients had local recurrences; interestingly, these occurred in the higher-risk patients treated with radiation. Disease-free survival in this study was 88% and 80% at 5 and 10 years, respectively. The authors of this study questioned the need for routine use of adjuvant radiation therapy when using aggressive intraarterial and systemic preoperative chemotherapy. The timing of radiation relative to surgery has also been investigated in terms of local disease control, effects on wound complications, and long-term morbidity. The use of preoperative external-beam radiation takes advantage of the presence of an intact tumor mass to delineate and limit the field of treatment. A theoretical advantage of preoperative radiation is the treatment (and presumptive sterilization) of tumor cells outside the pseudocapsule, which might otherwise seed the operative site and result in local recurrence. Potential disadvantages are that it requires delay of the definitive surgery, which can create a psychologic stress for some patients, and that it may result in higher wound complication rates. Postoperative radiation therapy has the advantages of providing the entire tumor specimen to the pathologist for evaluation before deciding on the need for adjuvant therapy, potentially fewer wound complications, and no delay in surgery. Taken as a whole, studies have failed to demonstrate that preoperative radiation therapy is superior to postoperative radiation. What has been identified is that preoperative radiation therapy is associated with higher wound complications whereas postoperative radiation has been found in some studies to result in increased fibrosis.83,197–201 In a prospective randomized trial of 94 patients comparing pre- and postoperative radiation in extremity soft tissue sarcomas, O’Sullivan and colleagues197 identified wound complications in 35% of the preoperative radiated patients versus 17% of the postoperatively treated patients, a statistically significant difference and strong evidence that wound complication rates are indeed increased after preoperative radiotherapy. No statistically significant difference in local recurrence rates was identified between the two treatment groups. Overall disability was similar between the two groups when assessed one year following therapy. The overwhelming majority of wound complications seen in the preoperatively treated patients occurred in the treatment of lower extremity tumors; wound complication rates were low after preoperative radiation for upper extremity sarcomas. The highest incidence of wound complications (45%) was seen in upper leg tumors treated with preoperative radiation therapy. A confounding element in analyzing wound complications in patients receiving radiation therapy can be the effect of chemotherapy that many patients receive during their treatment. Meric and associates performed a retrospective review of 309 patients and failed to

1054 identify an association between chemotherapy use and wound complications.202 The optimal method of radiation delivery has not yet been defined. The most commonly used methods are brachytherapy (implanted radiation) and external-beam radiation. Each approach has its advantages and disadvantages. To date there has not been a prospective randomized trial comparing brachytherapy to external-beam radiation. In randomized trials compared to surgery alone, the application of radiation using each technique has been associated with reduction in local recurrences. As such, the primary issues in choosing the best technique is balancing the advantages and disadvantages of each approach for individual patients. Proponents of brachytherapy cite delivery of a high dose of radiation directly to the surgical bed, limited treatment time, limited radiation to surrounding uninvolved tissues, and decreased overall costs.203,204 Another advantage lies in its potential for use in treatment of recurrent disease in previously radiated tissues. Limitations of brachytherapy lie in its requirement for dedicated surgical and radiation oncologists with experience with this technique and limitations in the ability to treat extremely large resection beds.119 Because brachytherapy delivers its radiation over a few days instead of many weeks, there is evidence to support the concern that low-grade tumors, with their relatively lower rates of DNA synthesis and cell division, are not well treated by brachytherapy. With these considerations in mind, the current evidence to date would support preoperative and postoperative external-beam and postoperative brachytherapy radiation as effective methods for local tumor control in large, high-grade soft tissue sarcomas. Our current approach is to tailor therapy to the tumor location, patient ability to complete prescribed therapy, and, most importantly, patient preference.

Adjuvant Systemic Chemotherapy As with most major issues in the treatment of localized soft tissue sarcomas, the role of chemotherapy remains controversial and the quality of available evidence is variable. Patients with localized soft tissue sarcomas are generally able to achieve local control through surgery and radiation. Unfortunately, roughly 50% will go on to develop distant metastasis, and most of those will die as a direct consequence.190 Patients with large (more than 5 cm) and high-grade sarcomas are clearly more likely to develop metastatic disease and die than those with smaller or low-grade tumors. Some investigators have observed that local recurrence also places patients at higher risk of distant metastasis, even when all visible disease can be removed by reresection or amputations.205, 206 This finding suggests but does not prove that lowering local recurrence rates can ultimately enhance relapse-free and overall survival rates. Importantly, adjuvant systemic therapy for osteosarcoma has been shown repeatedly to significantly and markedly improve local control and relapse-free and overall survival rates. Experience in the treatment of measurable metastatic sarcoma has identified doxorubicin and ifosfamide to have the highest response rates, and the response rates for osteosarcoma and soft tissue sarcoma are relatively similar.190,207,208 Extrapolating from experience in osteosarcoma, first-generation clinical trials of adjuvant therapy for soft tissue sarcomas were usually doxorubicin based (often with single-agent

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doxorubicin) and used relatively low doses. Factors that often varied between studies were drug doses, tumor histologic subtypes, anatomic sites, methods of delivery, and timing of therapy. These studies gave inconsistent results; however, there appeared to be some evidence of improvement in relapse-free survival. A meta-analysis was performed evaluating 14 trials composed of 1,568 patients with localized resectable soft tissue sarcomas, including both extremity and nonextremity primary sites.209 The analysis revealed a 27% relative reduction in local recurrence in patients treated with chemotherapy, translating to an absolute benefit of 6% fewer local recurrences at 10 years. The relative reduction in distant metastasis-free survival was 30%, with an absolute benefit of 10% at 10 years. Adjuvant chemotherapy resulted in a 25% relative reduction in relapse-free survival, with a resultant 10% absolute benefit at 10 years; this corresponded to an overall improvement in recurrence-free survival from 45% without adjuvant chemotherapy to 55% with its use. Overall survival, however, was not improved significantly by the use of chemotherapy. There was a trend toward improved survival with a potential absolute benefit of 4%, which translated to an overall survival improvement from 50% to 54%. Several criticisms of this meta-analysis have been raised.190,207,210 The first relates to the time frame of these studies compared to contemporary treatment practices: the most recent study included in the meta-analysis completed accrual in 1990. Since that time, higher doses of chemotherapy and more-effective agents such as ifosfamide have become standard for adjuvant therapy. By grouping patients with extremity and nonextremity sarcomas together, the meta-analysis may have been biased against detecting an impact of adjuvant therapy in extremity sarcoma patients, where surgery and radiation eradicate all local tumor in a higher percentage of patients. Nonetheless, as the primary goals of adjuvant chemotherapy are to improve relapse-free and overall survival, the modest absolute relapse-free survival increase of 10% at 10 years and questionable benefit in overall survival are concerning. These findings suggest that 90% of patients treated with chemotherapy would not gain any advantage from adjuvant treatment compared to providing the same or similar chemotherapy upon relapse; this is an important consideration, in that chemotherapy can result in significant toxicities, diminished overall quality of life, and even in rare cases treatment-related deaths. In the face of the limitations of the meta-analysis, a subsequent trial from Italy has been widely touted as more contemporary support for the use of chemotherapy in the treatment of soft tissue sarcomas. In this prospective randomized trial of 104 patients with large high-grade soft tissue sarcomas of the extremities, Frustaci and associates evaluated the adjuvant use of epirubicin (an anthracycline cytotoxic drug similar in efficacy and toxicity to doxorubicin) and ifosfamide.211 The study was closed early secondary to an interim analysis revealing a statistically significant improvement in relapse-free survival in the patients in the chemotherapy arm. The median follow-up was 59 months at the time of this interim analysis, which demonstrated a 41% relative reduction in the risk of disease relapse, translating to an absolute benefit of 27% from chemotherapy at 2 years and 13% at 4 years. Local disease-free survival was not found to be statistically significant between the treatment groups, with the treatment arm having 9 local recurrences and 11 in the

soft tissue sarcoma

control arm (P = 0.07). Overall survival favored the treatment arm, with an absolute improvement at 4 years of 19%. Early termination of a randomized trial due to a highly significant treatment effect requires exceeding a stringent threshold and is the strongest possible evidence of superior efficacy for an investigational therapy. In essence, it means it would be unethical to continue to treat patients on the study with the control regimen (in this case surgery and radiation without systemic adjuvant chemotherapy), and by strong and direct implication, similar patients in the nonprotocol setting as well. Once early termination of a trial takes place, subsequent follow-up of the trial data may be compromised by the smaller than anticipated number of study patients and/or by cross-over of control arm patients to the now recognized superior treatment arm. Indeed, longer-term follow-up of the patients on this study reported at a median of 89 months of follow-up, indicated that the statistically significant survival advantage observed at the interim analysis was no longer present.212 Time to disease progression, median survival, and survival at 4 years still favored the treatment arm in the extended analysis, which for the reasons described above cannot be considered to invalidate the interim analysis finding. What are we to take from this body of literature when considering adjuvant chemotherapy for patients with localized disease? The current evidence supports the contention that doxorubicin and ifosfamide are the most active agents currently available and appear to be most effective at relatively high doses, although there is likely a plateau beyond which further dose escalation is not helpful and may be harmful.190,211–218 These high-dose chemotherapy regimens are toxic and frequently require dose reduction and/or hematopoietic growth factor support to complete therapy. From data compiled through meta-analysis and more-contemporary reports, the benefit from the use of adjuvant chemotherapy may be real. However, this benefit will be confined to a minority of treated patients; others will be cured by local therapy alone or relapse despite the addition of chemotherapy. These factors must be considered when weighing the risks and benefits in adjuvant chemotherapy for an individual patient. At present, the use of adjuvant chemotherapy in the treatment of intermediate- and high-grade soft tissue sarcomas likely confers a small advantage in local control, time to disease progression, and overall survival when high-dose doxorubicin- and ifosfamide-based regimens are used. Our preference is to provide adjuvant chemotherapy treatment of soft tissue sarcomas under strict protocol-based regimens or in the context of prospective clinical trials. Preoperative or neoadjuvant chemotherapy may have practical advantages over postoperative chemotherapy, not the least of which is the ability to monitor response or lack thereof and alter or terminate therapy in patients who do not appear to be deriving any benefit. Preoperative and postoperative chemotherapy have never been directly compared in randomized trials, however.

Regional Chemotherapy The fact that so many sarcomas arise in the extremities has prompted investigation of cytotoxic chemotherapeutic agents administered intraarterially. This method has the theoretical

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advantage of maximizing the dose of drug to the tumor and minimizing the dose delivered systemically to the patient. The relative pharmacologic advantage of intraarterial therapy compared to intravenous administration depends on the degree of “first-pass” extraction of the drug in the perfused tissues. Doxorubicin has a high degree of first-pass extraction in peripheral tissues, conveying a moderate advantage in tumor to systemic drug levels compared to intravenous administration of the same dose. Cisplatin, another drug commonly used for intraarterial therapy of sarcomas, has a much lower degree of first-pass extraction and hence there is relatively little pharmacologic advantage to its intraarterial administration.219 Intraarterial administration has significant complexity and risks, requires inpatient hospitalization, and results in limiting the systemic antitumor effects of the drug to the same extent that it augments the regional intratumoral effects. Evidence directly supporting the use of intraarterial chemotherapy in extremity soft tissue sarcomas is minimal, essentially anecdotal. One small, randomized trial (90 patients total) compared intravenous to intraarterial doxorubicin when identical doses were administered as part of a preoperative chemoradiation strategy. This trial was only published in abstract form, but insufficient advantage for intraarterial administration was noted and the authors (hitherto the primary advocates for intraarterial doxorubicin administration) abandoned the technique.220 Several investigators have attempted to increase the therapeutic advantage of intraarterial drug administration by the use of isolated limb perfusion, a technique commonly applied in the treatment of extremity-confined melanomas. In this technique, surgical isolation of the extremity vasculature and directed circulation of most or all the blood of the extremity through an extracorporeal membrane oxygenator and pump (“heart bypass” machine) minimizes the systemic administration of drug and allows for very high, even otherwise potentially lethal, doses of drug to be circulated intraarterial for a period of time and then extracted in the venous effluent and discarded. Many soft tissue sarcomas present in advanced stages, adjacent to neurovascular structures or with local recurrences where resection may be difficult. From experimental evidence and experiences in the treatment of melanoma patients, most investigators have employed melphalan, tumor necrosis factor-alpha (TNF-a) or occasionally doxorubicin in the treatment of extremity soft tissue sarcomas.221–231 A multi-institutional experience of 186 patients treated with isolated limb perfusion with TNF-a and melphalan (plus gamma interferon in some cases) for primary or recurrent extremity soft tissue sarcomas was reported by Eggermont and colleagues.231 Eighty-two patients had an objective tumor response. At a median follow-up of 2 years, the limb salvage rate was 82%. TNF-a is not available in the United States, and results with melphalan or other drugs in the isolation perfusion of sarcomas have been much less encouraging. Studies evaluating the use of isolated limb perfusion are summarized in Table 58.8. At present evidence supports a possible role for isolated limb perfusion with TNF-a in carefully selected patients with locally advanced or multifocal soft tissue sarcomas when amputation is the only surgical alternative. Whether limb perfusion is worthwhile for sarcoma patients if only melphalan is available is less clear, but it is still advocated by some.232

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TABLE 58.8. Major studies evaluating isolated limb perfusion for soft tissue sarcomas. Study

N 231

Agents

Hyperthermia (°C)

Limb salvage (%)

Eggermont et al., 1996

186

TNF, melphalan

39–40

82

McBride et al., 1974222

79

NR

83

Lev-Chelouche et al.,228

53

Melphalan, dactinomycin TNF, melphalan

39–40

85

Lejeune et al., 2000230

22

TNF, melphalan

38–40

86

Rossi et al., 1999225

27

TNF, doxorubicin

40.5–41.5

85

Design

Review of multiinstitutional experience Review of institutional experience Review of institutional experience Review of institutional experience PhaseI/II prospective trial

NR, not recorded; TNF, tumor necrosis factor.

Treatment of Localized Retroperitoneal Soft Tissue Sarcoma Surgery Retroperitoneal soft tissue sarcomas have unique clinical characteristics and pose distinct clinical challenges, which distinguish them from the more-common extremity sarcomas. Patients typically present with very large tumors, often with minimal symptoms. Although the most common site of first recurrence for patients with extremity sarcomas is in the form of distant metastatic disease, patients with retroperitoneal sarcomas are more prone to recur within the abdominal cavity. The overall survival for patients with extremity sarcomas is superior to that of patients with retroperitoneal sarcomas. Local failure is evident in nearly 90% of patients

who die of retroperitoneal sarcomas,233 a fact that reflects the large tumor size on presentation, inability to achieve wide surgical margins, and limitations of adjuvant radiation and chemotherapy. Local failure continues to occur beyond 5 and 10 years following resection, leading to some to estimate the overall recurrence rate for resectable retroperitoneal sarcomas exceeds 70%.234,235 As for extremity primaries, surgery is the mainstay of treatment for retroperitoneal sarcomas. Because of the limitations of adjuvant therapy, including the inability to deliver high doses of radiation secondary to limited tolerance of bowel, kidneys, liver, and the spinal cord, surgery is somewhat more likely to be used as the only modality for treatment of these tumors. Reports describing experience in the surgical management of primary retroperitoneal soft tissue sarcomas are summarized in Table 58.9. The data in this table

TABLE 58.9. Major studies of the treatment of primary retroperitoneal soft tissue sarcomas.

Study

N* 129

Complete** resection (%)

LR*** (%)

OS† 5-year (%)

OS‡ 10-year (%)

Lewis et al., 1998

500

80

59

70

NR

Jaques et al., 1990239

114

65

49

NR

NR

Stoeckle et al., 2001251 Cody et al., 1981243 Alvarenga et al., 1989249 Dalton et al., 1990247 Catton et al., 1994244 Hassan et al., 2004254 Karakousis et al., 1995246 Bevilacqua et al., 1991245 Kilkenny et al., 1996237 Zornig et al., 1991250 McGrath et al., 1984241 Salvadori et al., 1986242 Wang et al., 1996255 Pirayesh et al., 2001253 Solla et al., 1986248

165 158 120 116 104 97 90 80 63 51 47 43 40 22 20

65 66 30 54 43 78 100 65 78 59 38 42 70 41 35

48 33 46 68 50 44 25 29 40 24 61 39 68 45 43

46 40 29 40 55 51 66 57 56 35 70 NR 42 22 43

NR NR NR 22 22 NR 57 NR NR 15 58 NR NR NR NR

NR, not reported. *Total patients in study including some presenting with recurrent disease. **Percent resected with primary retroperitoneal sarcomas. ***Percent local recurrences in those who had complete surgical resection for primary retroperitoneal sarcoma. †

Five-year overall survival of those who had complete surgical resection for primary retroperitoneal sarcoma.

‡

Five-year overall survival of those who had complete surgical resection for primary retroperitoneal sarcoma.

Study design

Retrospective review of prospectively collected data Retrospective review of prospectively collected data Registry review Retrospective case series Retrospective case series Retrospective case series Retrospective case series Retrospective review Retrospective case series Retrospective case series Retrospective case series Retrospective case series Retrospective case series Retrospective case series Retrospective review Retrospective review Retrospective case series

soft tissue sarcoma

focus on primary retroperitoneal sarcomas that have no evidence of metastatic disease. These reports have consistently documented the significance of complete resection of all gross disease in improving local control and disease-specific survival. In most reports, complete excision is achieved less than 70% of the time, with local recurrence occurring in approximately half of patients undergoing complete resection. The impact of local recurrence is reflected in diminished overall survival despite attempts at further resections.129,236 Results for resection of recurrent retroperitoneal sarcomas are notably worse, in both the percentage of patients who can be resected free of all disease and those who remain recurrence free long term. With the possible exception of low-grade retroperitoneal liposarcomas, no survival benefit has been observed when incomplete resection is undertaken.129,237–240 Major complication rates are identical, however, for partial and complete resections. Thus, patients undergoing incomplete resection procedures are exposed to all the morbidity with none of the potential survival benefit of their counterparts who undergo complete excision. This result emphasizes the need for careful preoperative planning as well as determination of unresectability early in the operative procedure so that incomplete resections are not mandated because the surgeon has passed “the point of no return.” Retroperitoneal liposarcomas represent a distinct situation where a more-aggressive surgical approach, including multiple resections for repeated recurrences and even occasionally incomplete resections, may be justified. Liposarcomas in this location have been observed to have a lower incidence of distant metastases (7%) when compared to 15% to 34% for other histologic subtypes.236,239,241 Shibata and associates observed prolongation in survival in patients with partial resection in patients with liposarcomas when compared with those who only had biopsy.236 Further, they reported effective palliation of symptoms in 75% of symptomatic patients who underwent debulking procedures. Identification of prognostic factors other than the adequacy of resection has been inconsistent across studies. Tumor size has not been identified as a predictor of survival, with the recognition that virtually all retroperitoneal sarcomas are larger than 5 cm at presentation. Tumor grade has been found to be significant in some studies but not in others, with the weight of evidence supporting shorter recurrencefree and overall survival for patients with high-grade tumors.129,233,235,237,239,241–256 The clinical presentation and imaging evaluation of retroperitoneal sarcomas were discussed previously. Important in the next step is determining resectability from these studies. It is often difficult to determine preoperatively if adjacent vascular structures or organs are involved with tumor. Vascular involvement was noted in 34% of patients undergoing resection in a review by Kilkenny and colleagues.237 In cases where tumor is near major vessels but routine CT scanning cannot resolve whether the vessels are in fact involved, we have turned to MR angiography or CT angiography. Multivisceral resections are required in the majority of cases (63%–86%), most frequently involving the kidney, colon, small bowel, pancreas, and bladder.129,237,239,243,248,254 Our experience and that of others have shown that it can difficult to determine whether adjacent organs will be attached or freely separable based on preoperative imaging. In planning resection one must be prepared for the high likelihood of exten-

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sive en bloc resections to achieve this goal. No surgeon should operate on a retroperitoneal mass unless he or she is prepared for the magnitude of the resection that may be required.

Radiation Several investigators have explored methods to decrease the incidence of local failure following resection. Extrapolating from evidence supporting improved local disease control with the use of radiation therapy in the trunk and extremities, radiation therapy is widely used as an adjunct to surgery in retroperitoneal sarcomas. There are important differences, however, that make radiation therapy more problematic and call into question its value for patients with retroperitoneal tumors. To date, no randomized trial has documented the value of adjuvant radiation for retroperitoneal sarcomas, so evaluations of its benefit are confined to retrospective analyses. Proponents of preoperative radiation therapy cite the theoretical advantages of using the tumors bulk to displace uninvolved intrabdominal viscera, thereby decreasing local toxicity and increasing the ability to administer therapeutic doses.234,235,257 This approach also allows the target volume to be easily delineated for treatment planning, and treating the tumor before manipulation at the time of surgery could theoretically decrease the likelihood of tumor implantation. Resection is usually performed between 4 to 6 weeks after the completion of radiation. Postoperative external-beam radiation at doses that are most likely to be effective258,259 can be associated with significant acute and delayed bowel toxicity.233,260 After removal of the large tumor mass that had been displacing adjacent viscera, the bowel tends to fall into the resection bed and often becomes fixed there by postoperative adhesions. However, as in the extremities, postoperative radiation has advantages, including the ability to examine the entire tumor and the excision margins pathologically before deciding on the need for radiation as well as allowing for the completion of healing and recovery from surgery and complications thereof before instituting radiation. The areas of greatest concern for residual tumor and/or the closest surgical margins can be delineated and given focally higher doses of radiation in many cases. Contrary to some reports, we have successfully used postoperative radiation for retroperitoneal sarcomas over nearly two decades with acceptable acute toxicity and very little in the way of severe chronic toxicity. Radiation should not be automatically withheld from patients who have undergone complete resection, especially with close or involved margins, merely because they are postoperative. That notwithstanding, the limitations of deliverable dose and the large volumes of the abdomen and pelvis that need to be radiated, whether preoperatively or postoperatively, have led many investigators to explore techniques to augment the effectiveness and/or minimize the toxicity of delivered radiation. Cytotoxic chemotherapy may be combined with radiation, but this combination is often poorly tolerated in patients with a large intraabdominal tumor or convalescing from its recent removal. As reviewed by Storm, studies have generally relied on doxorubicin-based regimens and have not demonstrated convincing improvements in disease-free or overall survival.261 Nonetheless, a growing body of evidence suggests the combination can be administered to carefully selected patients.262 The current evidence for the use of adju-

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TABLE 58.10. Major studies of the treatment of retroperitoneal soft tissue sarcomas with intraoperative radiation therapy. Study*

N

Sindelar et al., 1993** IORT No IORT Gieschen et al., 2001*** IORT No IORT Alektiar et al., 2000*** Bobin et al., 2003*** Gunderson et al., 1993*** Willet et al., 1991***

35 15 20 37 20 17 32 22 19 10

Local recurrence (%)

Preoperative XRT

Postoperative XRT

40 80

No No

Yes Yes

17 51 38 50 15 10

Yes Yes No Yes No Yes

No No Yes Yes Yes No

IORT, intraoperative radiation therapy. *Studies frequently included primary and recurrent retroperitoneal soft tissue sarcomas. Some patients also treated with chemotherapy regimens. **Prospective randomized trial. ***Prospective nonrandomized trial. Sources: References 265, 327–331.

vant chemotherapy in the treatment of sarcomas is reviewed in the section on treatment of extremity sarcomas. Other approaches have also been evaluated. In a Phase I/II trial using preoperative radiation therapy and the radiosensitizer idoxuridine (also known as IUdR or iododeoxyuridine), which does not have direct antitumor effects, in the treatment of retroperitoneal soft tissue sarcomas, Sondak and associates treated 16 patients with alternating weeks of continuous intravenous infusional iododeoxyuridine and twicedaily radiation therapy before surgery. Patients received a total of five cycles of therapy, either entirely preoperatively or split with three cycles before and two afterward.263 This effort resulted in an overall local control rate of 45% at 24 months; local control was achieved in 5 of the 8 patients who had complete resection with acceptable toxicity. An alternative approach to intensifying the radiation dose to the tumor bed was conducted in a trial by Jones and associates in which 55 patients with resectable primary or recurrent retroperitoneal sarcomas were treated with preoperative externalbeam and postoperative brachytherapy.264 Forty-six patients had complete resections, with 41 completing preoperative radiation therapy and 23 having brachytherapy. Preoperative radiation therapy was well tolerated, but those treated with brachytherapy experienced significant toxicity, including 1 death. Sondak et al. reported overall 2-year relapse-free and overall survival of 80 and 88%, respectively. Another approach that has been investigated is the use of intraoperative radiation. Once an enormously complicated undertaking wherein anesthetized surgical patients needed to be transported to treatment machines in the Radiation Oncology Department with their abdomens open, intraoperative radiation is now practically achieved at a number of centers with specially designed and shielded operating rooms equipped with built-in radiation devices. With this technique, the resection bed can be directly targeted to a high dose while nearby radiosensitive tissues are mechanically retracted out of the treatment field. A summary of studies investigating the use of intraoperative radiation therapy is shown in Table 58.10. Unfortunately, the weight of evidence, including one

small randomized trial,265 suggests that intraoperative radiation increases in-field tumor control but not recurrence-free or overall survival, as patients recur just outside the treatment field, and that it adds significant late toxicity.

Local Recurrence In the absence of metastatic disease, repeat resection when able to remove all gross disease is the treatment of choice for locally recurrent retroperitoneal sarcomas. Many studies have shown that a significant number of patients experience prolonged disease-free survival when all gross disease can be resected. The addition of chemotherapy or radiation in the treatment of locally recurrent disease remains the subject of debate. Given the extremely high risk of further local and distant recurrence, all patients who have not previously received adjuvant therapy should be considered for it after resection of recurrent disease. Subsequent recurrences have progressively diminishing chances for resection. Evidence for the benefit of third and subsequent resections of retroperitoneal sarcomas is scant and largely limited to studies of patients with low-grade liposarcomas. Such aggressive attempts at disease control should almost always be relegated to centers with significant expertise in the management of retroperitoneal tumors.

Treatment of Gastrointestinal Stromal Tumors Gastrointestinal stromal tumors (GIST) are uncommon tumors believed to originate from the interstitial cells of Cajal in the alimentary tract. These cells form a smooth muscle cellular network to function as a pacemaker of gut motility.266,267 Gastrointestinal stromal tumors are most commonly found in the stomach (39% to 70%), small intestine (20% to 32%), colon and rectum (5% to 15%), and esophagus (less than 5%) (Figure 58.8).266–269 The true incidence of these tumors is unclear, because population studies frequently fail to distinguish GIST from gastrointestinal carcinomas.

soft tissue sarcoma

Traditionally, GIST have been considered to be benign, malignant, or “borderline.” The evidentiary basis for this distinction is suspect, but it is clearly difficult to determine if a GIST will metastasize by its light microscopic appearance alone. Studies investigating features most associated with malignant behavior have found tumor size (more than 5 cm), mitotic count (more than 1–5 per 10 high-power fields), tumor necrosis, and most recently immunohistochemical identification of c-Kit (CD117) mutation to be important.266–270 In most studies that have attempted to use this type of classification, approximately one-third of GIST are classified as “malignant.”271 In nearly all studies, however, tumors classified as “benign” or “borderline” manifest unequivocally malignant behavior (i.e., metastasis) in a small percent of cases. Hence, available evidence would suggest that all GIST should be considered to be malignant neoplasms at low, intermediate, or high risk for developing metastatic disease. Whether there is a subset of GIST that are unequivocally benign, with no propensity whatsoever to metastasize, remains to be proven. Treatment of GIST has traditionally relied on complete resection. Complete resection of GIST has been reported in the range of 48% to 89% of cases; long-term disease-free survival has been reported to be 18% to 35% and overall survival from 28% to 43%.271,272 Metastatic GIST are virtually resistant to standard chemotherapeutic agents. Therefore, it is not surprising that the use of adjuvant chemotherapy with cytotoxic agents has been disappointing. In a retrospective review of a multicenter experience in the treatment of GIST with chemotherapy, De Pas and associates found no evident survival benefit from the addition of chemotherapy.273 The addition of radiation therapy has similarly been limited in its effectiveness in the treatment of GIST.268 Identification of c-Kit mutations in GIST has been the focus of extensive recent attention. The Kit protein is a transmembrane protein receptor that is structurally similar to the macrophage colony-stimulating factor receptor. A gain-offunction mutation of exon 11 of the c-Kit gene in GIST tumors was described by Hirota and colleagues, corresponding to the intracellular juxtamembrane region of the c-Kit protein.274 Additional sites of mutation have been identified

FIGURE 58.8. Bisected gastrointestinal stromal tumor arising from the lesser curvature of the stomach.

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within the c-Kit gene in GIST tumors, with the observation that mutated Kit protein products are constitutively activated in the absence of its stem cell factor ligand.267,275 Alternatively, the platelet-derived growth factor receptor (PDGFR)-a has been found to be mutated and activating in a significant percentage of GIST that lack activating mutations in c-Kit.276 Experimental results demonstrated that the use of the tyrosine kinase inhibitor imatinib mesylate (Gleevec) targets the BCR-ABL fusion protein found in chronic myeloid leukemia and is available in an oral formulation.277 Additional studies of imatinib demonstrated activity against other protein tyrosine receptors including PDGFR-a and Kit. With this background, Joensuu and associates treated a patient with rapidly progressive, chemotherapy-resistant metastatic GIST with imatinib.278 This protocol resulted in a dramatic response that was sustained for more than 11 months with minimal toxicity. This observation prompted clinical trials using imantinib in the treatment of GIST.279,280 Results of these studies demonstrated an effective initial dose range of 400 to 800 mg per day, which has since been approved by the U.S. Food and Drug Administration for the treatment of metastatic and/or unresectable GIST.281 It remains to be determined whether it is better to initiate treatment at the lower end of the effective dose range and increase the dose if necessary because of inadequate efficacy, or to start at the high end of the dose range and decrease the dose in case of toxicity. It is clear, however, that some patients who progress on lower doses of imatinib respond to higher doses, whereas other patients who have prohibitive toxicity at higher doses still derive clinical benefit from doses lower than the usual starting range. Several investigators have noted that reliance on traditional clinical parameters for measurement of response to imatinib therapy may not be ideal in the treatment of GIST. Benjamin et al. found that time to progression following treatment did not correlate with RECIST criteria of change in size.208 Instead, these investigators were able to correlate time to progression with changes in glucose uptake detected by positron emission tomography (PET) scanning. They found PET achieved a sensitivity of 94% and specificity of 100% in identifying response to treatment, and was more predictive of time to progression, than CT assessment of tumor size. Other investigators have also highlighted the usefulness of PET in evaluating response to imantinib therapy.282 Tumors may manifest little if any change in size on CT scans yet show dramatic decreases in activity on PET scans (Figure 58.9). Unfortunately, even tumors that have shown dramatic responses to imatinib eventually progress in most cases, sometimes after several years. Second-line tyrosine kinase inhibitors are in active clinical investigation; if these prove useful, it would be logical to investigate combination therapy with imatinib in future clinical trials. Although GIST is a rare tumor, it represents an important model for the use of biologically targeted therapy, where an identified molecular alteration is targeted by a specific therapy with clinically relevant results. Another approach currently under investigation is the use of imatinib in the adjuvant and neoadjuvant setting. Whether adjuvant approaches can decrease recurrence, improve survival, and turn unresectable tumors into those that can be completely resected requires prospective testing in clinical trials.

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FIGURE 58.9. Positron emission tomography (PET) studies with [18F]fluorodeoxyglucose as the tracer. (A) Before STI571 therapy, multiple metastases are seen in the liver and upper abdomen, with marked retention of [18F]fluorodeoxyglucose in the right renal pelvis and ureter, a finding suggestive of hydronephrosis. (B) After 4 weeks of treatment, no abnormal uptake of tracer is seen in the liver or right kidney.278

Treatment of Localized Soft Tissue Sarcomas of Selected Other Sites Trunk, Heart, and Great Vessels Sarcomas arising in the soft tissues of the trunk/body wall have been found to follow a clinical course similar to that observed in the extremities. Sarcomas arising in this location account for approximately 10% to 20% of newly diagnosed sarcomas; they are usually over 5 cm in size and can involve underlying viscera (Figure 58.10). Treatment principles are derived from the experience with extremity sarcomas, with aggressive attempts at wide excision to achieve clear margins and consideration of chemotherapy and radiation for large high-grade tumors. Soft tissue sarcomas arising from chest wall musculature and diaphragm are quite rare. Treatment of these tumors is based on the general principle of wide resection with clear margins. Radiation therapy can be considered for large lesions, particularly when high grade; however, underlying lung tissue may limit the dose that can be delivered. Sarcomas are the most common primary malignant neoplasm arising in the heart and are usually angiosarcomas.189 They may arise from the heart or the pericardium and may be asymptomatic. These tumors are usually advanced when identified, and curative resection is difficult. Surgical removal has been the mainstay of therapy.283 The rarity of these tumors has not allowed the role of adjuvant therapies to be extensively evaluated. Often surgery is aimed at alleviating symptoms rather than cure. Cardiac allotransplantation, alone or with lung transplantation as well, has been performed in anecdotal cases, but seems to be associated with poor results for high-grade tumors.284 The aorta and vena cava are occasionally involved by direct extension of retroperitoneal sarcomas; however,

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sarcomas arising de novo from the great vessels are rare. Leiomyosarcomas are the predominant histologic type encountered arising from the vena cava and other named veins. Treatment is again based on complete resection with clear surgical margins.285,286 Mingoli and colleagues reported the results of resection of 218 patients compiled from an international registry of inferior vena cava leiomyosarcomas.287 Of 120 patients who underwent radical resection with complete removal of all gross disease and clear microscopic margins, caval wall resection with autologous vein or prosthetic patch repair was performed in 44%, and segmental caval resection was performed in 56%. Of the 67 patients who underwent caval resection, 27 had infrarenal caval ligation and 23 had supracaval ligation. The authors reported 3 postoperative deaths, 21 deep venous thromboses, and 7 major complications. There was a local recurrence rate of 57% (mean follow-up of 32 months). These results support a role for resection to clear margins. We have utilized patch repair following caval wall resection or segmental resection with prosthetic graft placement and avoid ligation of the cava if possible (Figure 58.11). The role of adjuvant therapies in the treatment of tumors in this location remains undefined.

Breast Primary breast sarcomas comprise less than 5% of all soft tissue sarcomas and can be subdivided into two categories. So-called monophasic or stromal sarcomas are identical to their counterparts arising elsewhere in the body. The most commonly encountered histologic types of these primary breast sarcomas are malignant fibrous histiocytoma, angiosarcoma, and liposarcomas.189,288–290 The second category are sarcomas specific to the breast, entitled cystosarcoma phyllodes or, more generically, phyllodes tumors. Because the pathologic and clinical characteristics of phyllodes tumors are quite distinct from other histologic types they are addressed separately. From retrospective series, primary breast sarcomas have a peak incidence during the fourth and fifth decades and most commonly present as a painless breast mass. These tumors

FIGURE 58.10. Computed tomography of high-grade undifferentiated pleomorphic sarcoma arising from the left abdominal wall musculature.

soft tissue sarcoma

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FIGURE 58.11. Left: Leiomyosarcoma (arrowhead) arising from the anterior wall of the inferior vena cava (arrow). Right: Patch repair of inferior vena cava following resection.

are often mistaken for a fibroadenoma as lymphadenopathy, skin changes, nipple discharge, and other signs typical of breast malignancy are almost always absent. Treatment of primary breast sarcomas is based on experience with extremity and trunk soft tissue sarcomas. Surgical treatment is tailored to breast conservation if the volume of normal breast would be adequate to allow a wide resection of the sarcoma with a 1- to 2-cm circumferential margin. In cases in which breast conservation would not result in a cosmetically acceptable appearance, simple mastectomy is appropriate. Postoperative radiation is often added to decrease local recurrence, particularly if the margin of excision was less than 2 cm (regardless of whether the breast was conserved). Local recurrence, disease-free survival, and overall survival rates following resection are similar to those observed in soft tissue sarcomas arising in other locations. Also, such considerations regarding the addition of adjuvant chemotherapy are the same as discussed in the treatment of extremity sarcomas. As lymph node metastases are exceeding rare in primary breast sarcomas, axillary dissection is not warranted unless clinically palpable nodes are present.189,288,289 Phyllodes tumors are fibroepithelial or “biphasic” tumors that arise exclusively in breast tissue. They also have a peak incidence during the fourth and fifth decades of life, typically presenting as a painless breast mass. Some patients report a long-standing mass that begins to grow rapidly. Analogous to gastrointestinal stromal tumors, the propensity to metastasize is often difficult to determine histologically. It has been estimated that 25% of cases are “malignant,” but cases deemed to be benign have been associated with the development of distant metastasis. Thus, the evidence would suggest that phyllodes tumors span a spectrum from very low to very high risk of metastasis. Whether any phyllodes tumors can be unequivocally considered to be benign, with no possibility whatsoever of distant metastasis, remains a matter of debate. Local recurrence of phyllodes tumors is common (16%–22%), so that wide excision with a 1- to 2-cm margin, by mastectomy if necessary, is appropriate therapy.189,291,292 Radiation and chemotherapy can be considered for cases deemed at high risk of recurrence or metastasis, but the role of each modality is as yet poorly defined in the treatment of phyllodes tumors.

Treatment of Metastatic Disease Half of all patients with soft tissue sarcomas ultimately develop metastatic disease. Metastases are present in about 10% of patients at time of initial presentation.127,293 The predominant site of first recurrence is in the lung, seen in 52% of patients who developed local or distant disease (70% of patients with extremity primaries). Patients with retroperitoneal sarcomas have a greater tendency for local recurrence and disseminated disease throughout the abdomen. As reported by Potter and colleagues, 80% of recurrences occur within 5 years.294 Approximately 80% of patients with extremity and trunk soft tissue sarcomas who have distant disease have isolated pulmonary metastases.2,130 The detection of pulmonary metastatic disease is accomplished by either plain film radiographs or CT scanning of the thorax. CT scans have a greater sensitivity in detecting small (3–10) mm pulmonary nodules than plain film radiographs, which has led many clinicians to use CT rather than plain films when evaluating for pulmonary metastases.189 On the other hand, this greater sensitivity to small nodules means that many subcentimeter benign nodules are identified on CT scans, especially in older patients. Proving these nodules to be benign can be difficult, and their detection often leads to concern for metastasis for patient and physician alike. PET scans were evaluated by Lucas et al. in comparison with CT scans,295 who reported a sensitivity in detecting pulmonary disease of 87% with a specificity of 100%. Conversely, CT scans had a sensitivity of 100% and a specificity of 96%. PET scanning does poorly at detecting subcentimeter pulmonary nodules and cannot always distinguish malignancy from inflammation or postoperative changes. The available evidence does not support a role for PET in the routine screening for or evaluation of pulmonary metastases, particularly given its limited availability and high cost. Once detected, pulmonary metastases have associated with median survival rates of 6 to 12 months.2,296 Because of the strong predilection for sarcoma to metastasize to the lungs and only to the lungs, resection of even multiple pulmonary metastases (metastasectomies) has been shown in multiple reports to be associated with prolonged relapse-free

1062 survival in a small but significant percentage of patients (probably at least 25%).189,293,297–299 Several prognostic features associated with long-term survival in patients undergoing pulmonary metastasectomy have been identified. In an evaluation of soft tissue sarcoma pulmonary metastases, Billingsley and associates observed a more favorable prognosis for those who had complete resection of all metastases, a disease-free interval of more that 12 months or a low-grade primary tumor.298 Adverse findings included histologies of liposarcomas and malignant peripheral nerve sheath tumors as well as age greater than 50. A relationship between outcome and time interval from initial diagnosis to the development of pulmonary metastases has been observed in multiple studies, although this may be largely or entirely a surrogate for histologic grade of the primary tumor.189,296–300 Greater numbers of metastatic nodules and rapid tumor doubling times have been associated with diminished survival following resection of soft tissue sarcoma pulmonary metastases.189 Reported survival rates following complete resection of pulmonary metastases (sometimes with repeated thoracotomies) range from 25% to 39% at 5 years.189,293,297,299 From published reports to date, an aggressive approach to resection of pulmonary metastases is warranted. Resection of soft tissue sarcoma hepatic metastases has also been evaluated. Survival rates following hepatic resection have generally been less than observed in pulmonary resections for metastatic disease. One series of soft tissue sarcoma patients undergoing hepatic resections of metastases reported a 100% recurrence rate.301 Despite this, a median survival time of 30 months for resected patients compared with 11 months for unresected patients was found. The inclusion of many patients with what are now recognized to be gastrointestinal stromal tumors in most series describing sarcoma metastatic to the liver makes interpretation of these series more complex. The role of chemotherapy in the treatment of unresectable metastatic disease has been extensively reviewed.190,302 Doxorubicin, ifosfamide, and dacarbazine have all been shown to have significant single-agent activity in the treatment of metastatic soft tissue sarcomas. Although published reports of various combinations of available drugs have suggested them to be superior to single-agent therapy,303 to date there is little evidence from prospective randomized trials to support that contention. One randomized trial is representative: the addition of ifosfamide to doxorubicin increased response rates at the expense of significantly greater toxicity but did not result in any detectable difference in time to progression or overall survival.304 The influence of drug dose intensity has been studied in numerous retrospective and prospective evaluations. There is considerable evidence to support the contention that the two most active drugs, doxorubicin and ifosfamide, yield better results in terms of response rates and time to progression if given at high doses. The range over which increased dose leads to increased benefit is fairly narrow, however, and not entirely defined. One recent report is sobering: patients randomized to receive doxorubicin plus 6 g/m2 ifosfamide actually had slightly superior survival compared to patients randomized to the same dose of doxorubicin plus 12 g/m2 ifosfamide.218 Reports of even higher doses of chemotherapy along with stem cell rescue have demonstrated the feasibility of this approach; however, its role in the treat-

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ment of metastatic soft tissue sarcomas has yet to be determined.305–307 There is no consensus whatsoever regarding the ideal second-line chemotherapy regimen for patients with metastatic disease refractory to combination therapy with doxorubicin and ifosfamide. Higher doses of ifosfamide (in the range of 12–14 g/m2) have been associated with objective responses in patients who failed or progressed after chemotherapy with lower doses of ifosfamide, with synovial sarcomas appearing to be particularly responsive to this approach.308,309 The toxicity of ifosfamide in this range of doses mandates careful patient selection and excludes many older patients and those with impaired renal function. Recently, the combination of gemcitabine and docetaxel in specific sequence has been associated with high objective response rates, even in patients with prior doxorubicin and ifosfamide chemotherapy. This regimen appears to be particularly effective for patients with leiomyosarcomas,310 but responses in other histologies have been seen as well.311 Low doses of chemotherapy administered more chronically have received some evaluation in sarcoma subtypes. Low-dose paclitaxel has been used for angiosarcomas312 and low-dose methotrexate and vinblastine for desmoid tumors.313,314 Although substantial data attest to differential sensitivities of various sarcoma subtypes to particular chemotherapy regimens, prospective evaluations of specific regimens for individual subtypes have been limited, and it is likely that hitherto unrecognized patterns of susceptibility and resistance exist. Clinical trials remain a highly appropriate option for patients with metastatic soft tissue sarcomas of all histologic subtypes. Novel approaches to clinical trials design are also worthy of exploration, given the multiple potential interactions of drug type, dose, and schedule with histologic subtype and prior treatment status.315

Specialty Centers Several investigators have highlighted the importance of early referral to centers with specialists with experience in treating soft tissue sarcomas.151,152,316,317 Soft tissue masses are common, with benign soft tissue masses exceeding malignant tumors 100 to 200 fold.316 As such, physicians frequently treat benign tumor without significant consequence. Unfortunately, malignant soft tissue tumors are more often than not approached with the same lack of concern and are not taken as seriously as masses arising in other locations. In a regional audit of the management of soft tissue sarcomas in England, Clasby and associates found only 21% of patients were investigated adequately and only 60% were treated with wide excision or surgery with radiation.318 They reported that in 331 patients who had undergone resections, only 104 had a preoperative biopsy and 26% of patients had not had any form of radiologic investigation. They found junior surgeons initially treated two-thirds of soft tissue sarcoma patients, whereas senior surgeons in 80% of cases performed second operations. In an similar audit conducted in France, RayCoquard et al. found only 42% of patients had a preoperative biopsy.319 They identified deficiencies in the initial evaluation in 48% of patients where MRI, chest radiographs, and clinical record of tumor size were frequently omitted. No more than 7% of patients in this study had biopsies planned and performed after formal multidisciplinary review. These studies illustrate a number of difficulties associated with the

soft tissue sarcoma

evaluation and referral of soft tissue tumors. As Clasby and colleagues observed, only 17% of patients were treated with an initial wide margin, with 67% left with an unacceptable margin.318 Similarly, Ray-Coquard et al. found 74% with inadequate initial resections. As discussed previously, initial failure to achieve clear surgical margins will result in higher local recurrence rates, with the associated poor prognostic implications associated with local recurrences.319 Referral to a specialty center with experience in soft tissue sarcomas should be initiated for subfascial masses of any size, tumors greater than 3 to 5 cm, masses that are noted to be changing in size, or any physical findings worrisome for malignancy. These findings may include proximity to neurovascular structures, painful masses, and tumors that are firm or fixed to underlying structures. When evaluating any soft tissue mass one should always consider these factors to maintain an index of suspicion for such lesions. With better education and early referral, we can expect improved oncologic outcomes with less morbidity associated with surgical treatment.

Surveillance Guidelines When deciding the appropriate surveillance plan for an individual following treatment for soft tissue sarcoma, several considerations arise. The impact of early detection on therapy and patient outcome varies by anatomic location of the recurrent disease. In cases of local recurrence of extremity soft tissue sarcomas, reresection can result in prolonged survival, improved quality of life, and cure in a significant number of patients. The majority (90%) of extremity local recurrences occur during the first 5 years after treatment, of which up to two-thirds are detected during the first 2 years.300 In a retrospective review of surveillance for follow-up of patients with high-grade extremity sarcomas, Whooley and associates evaluated the efficacy and cost-effectiveness of chest radiographs, CT scans of chest, imaging of the affected extremity, and blood tests.320 Follow-up evaluations were performed every 3 months during the first 2 years, every 4 to 6 months during the third posttreatment year, every 6 months for years 4 to 5, and annually thereafter. Their review found that physical examination was the most common method of detection of local recurrence (97%), with only one recurrence detected solely by surveillance MR (3%). Pulmonary metastasis was

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identified in 40% of patients, but only 37% of these patients with pulmonary had symptoms as a basis for detection. Asymptomatic patients had their pulmonary metastasis initially detected with chest radiographs in 83% of cases. In the remainder of patients, pulmonary metastases were detected solely with CT scanning. Metastasectomy was performed on 24 of 36 asymptomatic patients with pulmonary recurrence. Blood tests did not contribute to the detection of any local or distant recurrence. From their analysis of cost to effectiveness, Whooley et al. concluded that chest radiographs and physical examination were the most useful and cost-effective methods for the detection of local or distant metastasis.320 They recommended a surveillance program intensified during the early portion of the posttreatment period. They also recommended crosssectional imaging (CT or MR) every 6 months in cases of deep lesions or in radiated regions where physical examination is difficult. Similar studies delineating the most useful and cost-effective methods for the detection of local recurrence and distant metastases for other disease sites have not been performed. For soft tissue sarcomas in sites such as head, neck, and trunk, where patterns of failure are similar to those for extremity primaries, it would appear reasonable to follow a similar approach. For intraabdominal and retroperitoneal sarcomas, failure is primarily within the abdomen as in the liver; an additional 20% to 30% of recurrences will occur in the lungs. With this in mind, it would seem appropriate to have the patient undergo physical examination, CT scanning of the abdomen, and chest radiographs as a surveillance strategy. Early detection of local recurrence, metastases to the liver, and pulmonary metastases occasionally results in surgical intervention; it is assumed but not proven that such interventions may prolong survival and improve quality of life.129,298,299,301 Time to recurrence for intraabdominal and retroperitoneal sarcomas is also highest in the early posttreatment period, and a similar schedule of evaluation used in extremity sarcomas would seem reasonable. These sarcoma surveillance strategies remain to be proven in prospective trials, but are widely used and almost universally recommended, with some controversy remaining as to the incremental value of chest CT scans over radiographs alone. The current National Comprehensive Cancer Network (NCCN) guidelines for the surveillance of soft tissue sarcomas arising in the extremity and retroperitoneum are summarized in Table 58.11.

TABLE 58.11. Surveillance guidelines for extremity soft tissue sarcomas. Stage I

Stage II, III

-H&P every 3–6 mo for 2–3 y, then annually -Consider imaging surgical site with scan annually based on estimated risk of locoregional recurrence -Consider baseline imaging after primary therapy

-H&P every 3–4 mo for 3 y, then every 6 mo for next 2 y, then annually -Imaging of primary site (MRI, CT, consider US) -Chest imaging (plain radiograph or chest CT) every 3–6 mo for 5 y, then annually

-Consider chest X-ray every 6–12 mo Surveillance Guidelines for Retroperitoneal Soft Tissue Sarcomas Low grade

High grade

Physical exam with imaging (chest/abdomen/pelvis CT) every 3–6 mo for 2–3 y, then annually

Physical exam with imaging (chest/abdomen/pelvis CT) every 3–4 mo for 3 y, then every 6 mo for next 2 y, then annually

MRI, magnetic resonance imaging; CT, computed tomograpy; mo, months; y, years. Source: Reference 332.

1064 The use of PET scanning in the evaluation and surveillance of GIST is currently under investigation. At present, guidelines do not incorporate PET scans for the routine surveillance of GIST; however, this may change due to the advent of effective therapy (imatinib). To date, there are no compelling data to suggest that PET scanning has a routine role in the initial management or posttreatment surveillance of soft tissue sarcomas other than GIST.

Conclusion The evaluation and treatment of soft tissue sarcomas remains challenging. Advances in pathology and molecular biology have greatly improved our understanding of this complex and heterogeneous group of tumors. Since the 1980s, aggressive treatment approaches by experienced multidisciplinary teams have improved the outlook for these patients. The widespread acceptance of limb-sparing procedures, the identification of active chemotherapy regimens, and improvements in local disease control from the use of radiation therapy are all examples of the strides that have been made in the treatment of patients with soft tissue sarcoma. Despite these advances, areas of concern remain. Most distressing is the fact that approximately half of patients diagnosed with soft tissue sarcomas will succumb to their disease. Local recurrence remains a difficult problem, with increased associated morbidity and psychologic stress for affected patients. Through improved education, we hope that early biopsy and referral of soft tissue sarcomas will become the norm, and that patients will derive the benefits of multidisciplinary evaluation and treatment of their disease.

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5 9

Cutaneous Melanoma Mark R. Albertini, B. Jack Longley, Paul M. Harari, and Douglas Reintgen

Epidemiology The incidence of melanoma has increased dramatically during the past several decades among Caucasian populations.1 Mortality rates continue to rise overall, but in some populations, such as females, the mortality rate has plateaued or even fallen. The reasons for these trends are not altogether obvious, but may involve changes in attitudes and behaviors with regard to sun exposure or an increased public awareness to the early signs of melanoma diagnosis. Incidence rates vary from a low of 0.2 (females and males) in China to 34.9 per 100,000 among females in New Zealand and 40.5 per 100,000 among males in Australia.1 There were 23.1 new cases per 100,000 population in the United States (incidence rate adjusted to the 2000 United States population). Approximately 59,580 new cases of malignant melanoma and 7,770 deaths due to melanoma are predicted for the United States in 2005.2 Over the past 30 years, the incidence rate has tripled, particularly in the Caucasian male population. Recent data would suggest that the largest proportion contributing to the increased incidence are “thin” melanomas. People born before 1950 show an increased risk of developing melanoma whereas those whose birthdays are after 1950 show stable or declining rates.1 Melanoma is a tumor that occurs in the relatively young, with the mean age of diagnosis being 50 years of age, 10 to 15 years before the mean age of diagnosis of some of the morecommon cancers such as breast, lung, and colon. In the United States, there has been an increase in the diagnosis of thin melanomas in the young and an increase in the diagnosis of thick lesions in men over the age of 65.1

Dermatopathology of Melanoma The classification of cutaneous melanomas depends on an interaction between the clinical and pathologic features. The commonly recognized melanomas include (1) lentigo maligna melanoma, (2) superficial spreading melanoma, (3) nodular melanoma, and (4) acral lentiginous melanoma. We begin with a discussion of precursors of melanoma followed by a description of the histopathologic features of the various types of melanoma.

Precursors of Malignant Melanoma It is widely accepted that many if not most melanomas of the superficial spreading type arise in preexisting junctional or

compound melanocytic nevi, and benign melanoctic nevi are therefore a risk factor for malignant melanoma.3 Determining the exact percentage of melanomas arising in nevi is problematic because many melanomas are probably not detected until they have overrun small precursor nevi and because the terminology for early melanoma (in situ) arising in nevi is not standardized (please see following discussion of “dysplastic” nevi). However, most studies that are based on histologic features alone report finding remnants of a preexisting nevus in about 22% of melanomas of the superficial spreading type.4,5 Studies that include clinical as well as histopathologic criteria report precursors in as many as 39.5% of melanomas.6 Several subgroups of precursor nevi have been identified including preexisting congenital nevi, sporadic acquired nevi, and nevi associated with the familial melanoma syndrome. It is commonly accepted that melanomas may arise in large congenital nevi, but a separate study that specifically addressed the size of congenital precursor lesions established that a significant percentage of melanomas may also arise in small congenital nevi less than 1.5 cm in diameter.4 A representative histologic study found that 59% of the precursor nevi showed features of acquired nevi, 39% showed features of congenital nevi, and the remaining few nevi were not further categorized.5 Of all these nevi, 54% also showed histologic features of so-called dysplastic nevi, a designation that is controversial. “Dysplastic nevi” were originally described as a cutaneous marker of familial melanoma.7 The term “dysplastic nevus” has since been used to describe syndromes of multiple atypical nevi occurring in association with either familial melanomas or sporadic melanomas, and the term has also been used to describe individual atypical nevi occurring in patients without a personal or familial history of melanoma. Several studies have shown a lack of inter-observer reproducibility in the histologic diagnosis of dysplastic nevi, and it is now widely accepted that there is a continuum from ordinary benign (banal) nevi through nevi with moderate and severe dysplasia, to nevi with developing melanoma in situ.8 Furthermore, the NIH consensus conference recommended excising nevi with histologic features of a dysplastic nevus and moderate to severe cytologic atypia with the 0.5 cm margins, the same margins that they recommended for treatment of melanoma in situ, because developing melanoma in situ may show overlapping histologic characteristics with these nevi.

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Types of Malignant Melanoma Lentigo Maligna and Lentigo Maligna Melanoma Lentigo maligna is by definition the in situ phase of lentigo maligna melanoma (LMM). Lentigo maligna occurs in chronically sun-exposed skin, usually of the head and neck but occasionally in other sun-exposed areas. Lentigo maligna typically evolves over many years as an unevenly pigmented macular lesion that expands peripherally and that eventually may measure several centimeters in diameter. The histopathologic features in lentigo maligna may be subtle, and partial biopsies may not be diagnostic. Early lentigo maligna may show only epidermal hyperpigmentation and a subtle increase in the number of melanocytes, features that are not easily distinguishable from changes seen in chronically sun-damaged skin. Helpful histologic features include extension of atypical melanocytes down follicular epithelium and spread of melanocytes above the dermal epidermal junction, so-called pagetoid spread of melanocytes.9–11 When the dermis is invaded, the lesion is called lentigo maligna melanoma. Dermal invasion is a focal process and may be difficult to recognize. Invasive cells of lentigo maligna melanoma usually have abundant cytoplasm and are epitheliod or spindle shaped in character but may rarely appear as small round cells. Occasionally, lentigo maligna melanoma invades as cells that have spindle-shaped nuclei and relatively little cytoplasm, and induces a fibrotic or “desmoplastic” response in the underlying stroma. This variant, called desmoplastic malignant melanoma, may also show neurotropism and may be very difficult to recognize, requiring a high degree of suspicion and the use of immunoperoxidase studies to establish the diagnosis.12 This morphologic variant of lentigo malignant melanoma is important because it may be difficult to recognize, but it is not associated with a difference in prognosis, compared to other primary melanomas, when adjusted for tumor thickness.13

Superficial Spreading Melanoma Superficial spreading melanomas (SSM) often arise in melanocytic nevi and must be distinguished histologically from normal or atypical nevi. Architecturally, normal nevi are usually symmetric and show relatively uniform nests of cytologically typical melanocytes occurring at the tips and sides of rete ridges. Criteria for a diagnosis for superficial spreading melanoma include both architectural and cytologic features. Architectural features favoring a diagnosis of melanoma include asymmetric growth, a lack of circumscription, and large size. A major criterion for the diagnosis of melanoma is the spread of melanocytes throughout the epidermis as individual cells or nests of cells. Poorly circumscribed lesions also show individual cells at their edges, which are irregularly distributed at and above the dermal epidermal junction.10,11 With early invasion, atypical melanocytes extend from the epidermis into the most superficial (papillary) dermis as individual cells, where they start to form nests. Melanoma cells are typically round or polygonal in shape. The dermal component of benign melanocytic nevi is typically composed of melanocytes arranged in nests that are larger in the upper dermis and that gradually decrease in size in the deeper por-

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tions of the dermis. Melanocytes of benign nevi may also be arranged in single file, splayed between dermal collagen bundles, and arranged around neurovascular or adnexal structures. In contrast, invasive melanoma cells usually do not decrease in size in the deeper portions of the dermis, a characteristic that distinguishes them from the cells of benign melanocytic nevi. Invasive melanoma more typically grows as irregularly sized and shaped nests of cytologically atypical cells, as irregularly distributed single cells, or as sheets of atypical cells.

Acral Lentiginous Melanoma The term acral lentiginous melanoma (ALM) refers mainly to melanomas occurring in the hairless skin of the palms and soles but also includes those arising in the nail unit and the surrounding periungual areas.10,11 They are called lentiginous because their early pattern of growth consists of a proliferation of individual cells along the dermal–epidermal junction, a pattern that resembles melanocytic growth in benign lentigines. Features that distinguish ALM from lentigines include the presence of cytologically atypical cells that tend to confluence and the formation of irregularly distributed junctional nests without a benign dermal component. Cytologically, cells in early ALM may be relatively bland and it may be very difficult to establish the diagnosis, particularly if the specimen is a partial biopsy from the edge of a lesion that may show only an increase in pigment and a subtle increase in the number of melanocytes. Invasive ALM usually grows as epitheliod or spindle-shaped cells, or as smaller melanoma cells with less cytoplasm. As with LMM, ALM may show a desmoplastic growth pattern and may preferentially invade and grow along nerves.

Nodular Melanoma The histologic features of a nodular melanoma (NM) are those of expansile dermal growth with relatively little involvement of the epidermis.10,11 The epidermal component is often described as spreading no more than three rete ridges beyond the dermal component of the tumor, so whereas the overall architecture of SSM is horizontally oriented as the tumor cells spread within the epidermis and invade the papillary dermis, the orientation of nodular melanoma is vertical and NM typically appear deeper than they do wide. The dermal nests and masses of nodular melanoma cells should be larger than any of the nests present within the epidermis. NM often grow in sheets and may show marked focal differences in pigmentation and cell morphology in different parts of the tumor. Cytologically, the cells of NM are often epithelioid or spindle shaped, but may also be small with a high nuclear to cytoplasmic ratio.

Histologic Features of Prognosis in Cutaneous Melanomas The only histologic features of primary melanomas that have been consistently shown to be correlated with prognosis in multivariate (Cox regression and Tree structured survival) analyses have been tumor thickness, micrometasases, ulceration, mitotic activity, and incomplete removal of the original lesion with the presence of melanoma on the margins of

cutaneous melanoma

the primary resection specimen.13–17 These histologic features are of prognostic significance independent of the age of the patient, the type of the melanoma, or the anatomic location, and it is therefore recommended that these features be specifically mentioned in pathology reports.18

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interpretation, and various proposals have been made for the prognostic significance of certain patterns of regression or for stratifying regression based on the percentage of the melanoma that appears to be affected. However, regression of a primary melanoma does not appear to be a robust indicator of clinical outcome.24

Tumor Thickness and Level The concept that the depth of invasion of a melanoma into the dermis and subcutaneous fat could be related to prognosis was first suggested by Allen and Spitz,19 and was modified by Clark et al.,20 who proposed descriptive levels including an in situ level, and levels of invasion involving the papillary dermis, the reticular dermis, and the subcutaneous fat. These studies clearly established the concept that the depth of the tumor was more significant prognostically than its diameter, but these methods resulted in a stepwise classification and were not highly reproducible. In 1970, Alexander Breslow proposed determining the thickness of primary cutaneous melanomas by measuring from the top of the granular layer of the epidermis to the greatest depth of the invasion into the dermis, using an eyepiece micrometer.15 The resultant continuous variable, usually reported to the hundredth of a millimeter, is variously referred to as the Breslow depth or Breslow thickness, and has been found to be a reproducible and statistically significant prognostic variable in the evaluation of primary cutaneous melanoma.15

Vascular Invasion and Micrometastases The presence of invasion of tumor cells within blood or lymphatic vessels has been shown to be associated with a poor prognosis21,22 and is generally accepted as a poor prognostic feature. Similarly, micrometastases, defined as discrete masses of tumor cells measuring greater than 0.05 mm in diameter and located in the reticular dermis or subcutaneous fat, separated from the main tumor mass by normal tissue, has been identified as a histologic prognostic feature, and is also generally accepted as an indicator of a poor prognosis.

Ulceration and Other Tissue Reaction Patterns Spontaneous ulceration of the epidermis has been identified as an independent indicator of poor prognosis in a number of studies.14,16,17 A second tissue reaction pattern that has been described is the presence or absence of tumor-infiltrating lymphocytes (TILs), which are lymphocytes that infiltrate between the individual melanocytes making up nests and clusters of melanoma cells invading the dermis.23 Histologic identification of TILs requires interpretation, and the usefulness of this feature has not been as widely validated as have tumor thickness, ulceration, mitoses and margins. A third commonly studied variable is the presence of regression. The histologic feature of partial regression of a primary melanoma are usually observed in the papillary dermis, where there is fibrosis characterized by delicate collagen bundles in the papillary dermis, usually associated with melanophages and lymphocytes, and with melanoma present in the overlying epidermis and/or adjacent papillary dermis. There is also frequently flattening of the overlying epidermis. However, the histologic diagnosis of regression in thin melanomas requires

Mitoses and Proliferative Indices The presence of mitosis in the invasive component of a melanoma, usually reported as the mitotic rate per millimeter squared (mm2) or the number of mitoses per 10 high-power fields, has consistently shown to be an independent variable for predicting prognosis.16 Mitoses are obviously an expression of the proliferative rate of the tumor, and the proliferative capacity has also been estimated by immunohistochemical staining for Ki-67, also known as proliferating nuclear antigen (PNAC).25,26 Conversely, the level of cyclin A, a cell-cycle regulator, has been reported to be positively associated with disease-free survival.25

Melanoma Genetics Familial Melanoma Syndromes Two general types of genetic abnormalities are observed in families whose members are at increased risk for melanoma. In one type of abnormality, seen in the multiple primary melanoma syndrome, family members carry an abnormal CDKN2A tumor suppressor gene. This gene, which is located on 9p21, encodes the cell-cycle progression regulator p16, which is part of the cyclin D1/CDK 4/p16/pRb signaling pathway. This cyclin signaling pathway controls proliferation in many cell types,27–30 and loss of function of genes in this pathway affects individual cells, placing them at increased risk for transformation. In contrast, the mechanism of the second type of familial melanoma susceptibility functions on the level of the whole organism by affecting the ability of pigmented keratinocytes to protect epidermal melanocytes from transformation by ultraviolet irradiation. In this second type of susceptibility, variation in the melanocortin I receptor (MCI R) has been identified as the probable basis for high-risk phenotypes such as pale (type 1) skin, the lack of ability to tan in response to ultraviolet (UV) exposure, and red hair.31 Thus, these mutations work at the level of the entire organism by decreasing the natural protection afforded by normal epidermal melanin and increasing the risk of damage to melanocytes when the individual is exposed to ultraviolet light.

Genetic Abnormalities in Sporadic Melanoma In general, sporadic human melanomas show genetic instability, characterized by multiple chromosomal gains and losses, when examined by comparative genomic hybridization,32–35 but no specific individual gene changes have been associated with the development of sporadic melanomas, other than those directly affecting the cyclin pathway. In sporadic melanomas, loss of the tumor suppressor genes INK 4a/ARF, which are also components of the cyclin pathway, is

1076 frequently found.36 Overexpression of HDM2 is found in 56% of invasive primary and in metastatic melanomas, 27% of melanomas in situ, and in only 6% of “dysplastic nevi,” a finding that suggests that this gene may play a role in progression of individual melanomas.37 Although in vivo animal models of melanoma have been developed by overexpressing HRAS, mutations and increases in copy number of this gene have been found in humans only in Spitz nevi and not in melanomas.

Risk Factors and Prevention Risk Factors The identification of risk factors and high-risk populations for melanoma provides opportunities for both primary prevention and early diagnosis. A greatly elevated melanoma risk is present for a changing nevus as well as for dysplastic nevi in the setting of familial melanoma.38,39 Individuals with a familial melanoma syndrome, as discussed in the previous section on melanoma genetics, are high-risk individuals. An individual with a personal history of melanoma has a lifetime risk of at least 3% of having another primary melanoma.39,40 Individuals with precursor lesions such as atypical or dysplastic nevi, giant congenital nevi, or numerous common nevi have an increased melanoma risk.38,39 An elevated risk is also present for patients receiving immunosuppression.41 There are numerous studies that suggest the importance of ultraviolet radiation (UVR) on the development of melanoma.39,42 Geographic location near the equator, especially for individuals with a fair complexion, is associated with an increased risk of melanoma. The phenotype of the typical melanoma patient (fair complexion, tendency to sunburn rather than tan, blond or red hair color, blue or green eyes) is well described.39 Blistering sunburns, especially in childhood and adolescence, is an identified risk factor. Outdoor recreational habits that include intermittent high ultraviolet radiation (UVR) exposure are associated with an increased melanoma risk. Individuals with the genetic disorder xeroderma pigmentosum, a condition with defective cellular DNA repair mechanisms following UVR, have a significantly increased risk for melanoma compared with age-matched controls.43

Prevention Strategies to prevent melanoma have primarily emphasized primary prevention strategies that target high-risk individuals.44,45 Because UVR is considered an important modifiable risk factor, efforts have focused on avoidance of excessive sun exposure. The wearing of protective clothing, avoiding blistering sunburns, minimizing peak hours of sun exposure, avoiding tanning parlors, and use of sunscreen with a sun protection factor (SPF) of 15 or higher, are all examples of this sun protective behavior. The topic of sunscreens and melanoma risk remains controversial.46,47 Several factors confound interpretation of studies evaluating use of sunscreens and melanoma risk. Individuals with a fair complexion and at increased risk for problems with UVR may be more likely to use sunscreens. Sunscreen use may be higher in individu-

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als with a prior history of sunburns. In addition, individuals using sunscreens may allow themselves to have increased UVR. A meta-analysis of 18 case-controlled studies recently addressed this topic, and no association was seen between melanoma and sunscreen use.48 Direct proof that sunscreens reduce the risk for melanoma is lacking. However, significant indirect evidence supports the recommendations by the American Academy of Dermatology that includes regular use of a broad-spectrum high-SPF sunscreen along with protective clothing and avoiding midday sun as measures to reduce melanoma risk. A prospective randomized study to determine the efficacy of sunscreens would be informative, but this study is unlikely to be performed. Strategies aimed at chemoprevention of melanoma in individuals with high-risk lesions are also being developed.49 The possible molecular mechanisms for UV melanogenesis, as well as preliminary data from clinical and preclinical studies, were recently reviewed.49 Molecular and histologic markers are being identified as surrogate endpoints for melanoma chemoprevention studies. Agents currently receiving clinical testing include retinoids, lovastatin, nonsteroidal antiinflammatory agents, and vitamin E. Many other agents including green tea, perilyl alcohol, COX-2 inhibitors, selinium, and others are receiving preclinical testing. The results of these studies are eagerly awaited, and additional clinical testing is anticipated for melanoma chemoprevention of highrisk precancerous lesions.

Melanoma and Pregnancy or Exogenous Hormone Administration Melanoma and Pregnancy A number of clinical observations suggest that pregnancy might have an effect on melanocytes.50–52 Increased pigmentation is often associated with pregnancy. An increase in levels of melanocytic-stimulating hormone has also been measured in some pregnant women, and receptors that bind the female hormone estrogen can be found on some melanomas. These observations have raised the possibility that the hormonal and other physiologic changes associated with pregnancy may influence the development and course of melanoma. Thus, several investigators utilized available prognostic factors to study women diagnosed with melanoma during their pregnancy as well as evaluate the effect pregnancy might have on women who have previously been diagnosed with melanoma. When patients who are pregnant are compared with patients who are not pregnant and the known prognostic factors are comparable, the outcome of the patients are very similar.50–52 In addition, the majority of available evidence indicates that women who became pregnant after being previously treated for melanoma do not have a worse outcome or an earlier reactivation of previously diagnosed melanoma.52

Melanoma and Exogenous Hormone Administration The estrogen receptor has been identified in approximately one of five melanomas, which has led some to speculate that

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the presence of estrogens might influence the course of the disease.51 However, current studies have not demonstrated any convincing association, either favorable or unfavorable, between the use of oral contraceptives before the diagnosis of melanoma and survival.51 There are no large, well-conducted studies that have addressed the issue of birth control pills or hormone replacement therapy following the diagnosis of melanoma. Therefore, recommendations are usually made on the basis of clinical need and with the understanding that no evidence currently requires that oral contraceptives or hormone replacement therapy be withheld from these patients.

Classification and Staging: The 2002 AJCC Staging System The American Joint Committee on Cancer (AJCC) melanoma task force first published the most recent revisions to the melanoma staging system and companion validation prognostic factor analyses in 2001.53,54 This updated melanoma staging system represents a significant change from the previous system (Table 59.1). These changes are based on a better understanding of the melanoma-associated prognostic factors, derived from an extensive body of literature as well as from the largest melanoma prognostic factor analysis ever conducted, involving complete raw data from 17,600 patients.54 The most important criteria for T classification are tumor thickness followed by tumor ulceration (Table 59.2). Analyses of large prospective databases confirmed the importance of tumor thickness as a prognostic factor and found that Clark

level of invasion was significant only for melanoma lesions 1 mm thick or less.54 In the revised melanoma staging system, four criteria were established as significant prognostic factors for survival in patients with regional metastases: (1) the number of lymph nodes harboring metastatic disease, (2) microscopic versus macroscopic tumor burden in the lymph nodes, (3) the presence of satellite or in-transit metastases, and (4) the presence of ulceration in the primary lesion. These criteria require pathologic confirmation of nodal or regional metastatic disease (see Table 59.2). Within the M classification there is only one group, M1, because no breakpoints in this classification stratify patients into groups with survival differences sufficient to warrant further subgroupings. Within the M1 group, however, there are three subcategories, “a,” “b,” and “c,” reflecting survival differences that have been reported in other studies or were apparent in 1-year analyses, although not on longer-term analyses, in the AJCC prognostic factors study (see Table 59.2). M1a includes distant skin, subcutaneous, or lymph node metastases; these manifestations of distant disease have been associated with a better prognosis than distant metastases in other anatomic locations.54 Lung metastases are included in a separate category, M1b, because of the survival advantage at 1 year in the AJCC analysis for patients with lung metastases compared to patients with other visceral metastases (57% versus 41%, P less than 0.0001). Finally, M1c includes all other visceral metastases and cases with any distant metastases and an elevated serum lactate dehydrogenase level. Serum lactate dehydrogenase level is included in the M1c category because it has been identified as one of the

TABLE 59.1. Differences between the previous (1997) version and the present (2002) version of the melanoma staging system. Factor

Old system

New system

Comments

Thickness Level of invasion

Secondary prognosis factor; thresholds of 0.75, 1.50, 4.0 mm Primary determinant of T staging

Ulceration

Not included

Primary determinant of T staging; thresholds of 1.0, 2.0, 4.0 mm Used only for defining T1 melanomas Included as a second determinant of T and N staging

Satellite metastases Thick melanomas (>4.0 mm) Dimensions of nodal metastases Number of nodal metastases Metastatic tumor burden

In T category Stage III

In N category Stage IIC

Dominant determinant of N staging Not included

Not used

Correlation of metastatic risk is a continuous variable Correlation only significant for thin lesions; variability in interpretation Signifies a locally advanced lesion; dominant prognostic factor for grouping stages I, II, and III Merged with in-transit lesions Stage III defined as regional metastases No evidence of significant prognostic correlation Thresholds of 1 vs. 2–3 vs. ≥4 nodes

Not included

Included as a second determinant of N staging

Merged with all other visceral metastases Not included

Separate category as M1b

Lung metastases Elevated serum lactate dehydrogenase (LDH) Clinical vs. pathologic staging

Did not account for sentinel node technology

Primary determinant of N staging

Included as a second determinant of M staging Sentinel node results incorporated into definition of pathologic staging

Clinically occult (“microscopic”) vs. clinically apparent (“macroscopic”) nodal volume Has a somewhat better prognosis than other visceral metastases

Large variability in outcome between clinical and pathologic staging; pathologic staging encouraged before entry into clinical trials

Source: Adapted from Balch et al.53 Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, sixth edition (2002), published by Springer-Verlag New York, www.springer-ny.com.

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most important predictors of poor prognosis in patients with metastatic disease.54 The clinical and pathologic stage groupings for the current staging system are shown in Table 59.3. Stage I includes thin primary lesions with low associated melanoma-specific mortality. The 10-year survival rates for patients with stage IA and IB disease are 88% and 81%, respectively.53 Stage II includes lesions associated with an intermediate and somewhat higher risk of metastatic disease and melanoma-specific

59

mortality. The 10-year survival rates for patients with stage IIA, IIB, and IIC disease are 64%, 52%, and 32%, respectively.53 Because of the significant heterogeneity of prognoses in patients with stage III disease, three substages were defined: IIIA, IIIB, and IIIC. The 5-year survival rates for patients with stage IIIA, IIIB, and IIIC disease are 67%, 53%, and 26%, respectively.53 For patients with stage IV disease, the 1-year survival rates in the M1a, M1b, and M1c groups are 59%, 57%, and 41%, respectively.53

TABLE 59.2. Definition of TNM in the 2002 American Joint Committee on Cancer staging system for cutaneous melanoma. Primary TX T0 Tis T1 T1a T1b T2 T2a T2b T3 T3a T3b T4 T4a T4b

tumor (T) Primary tumor cannot be assessed (e.g., shave biopsy or regressed melanoma) No evidence of primary tumor Melanoma in situ Melanoma £1.0 mm in thickness with or without ulceration Melanoma £1.0 mm in thickness and level II or III, no ulceration Melanoma £1.0 mm in thickness and level IV or V or with ulceration Melanoma 1.01–2 mm in thickness with or without ulceration Melanoma 1.01–2.0 mm in thickness, no ulceration Melanoma 1.01–2.0 mm in thickness, with ulceration Melanoma 2.01–4 mm in thickness with or without ulceration Melanoma 2.01–4.0 mm in thickness, no ulceration Melanoma 2.01–4.0 mm in thickness, with ulceration Melanoma >4.0 mm in thickness with or without ulceration Melanoma >4.0 mm in thickness, no ulceration Melanoma >4.0 mm in thickness, with ulceration

Regional lymph nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in one lymph node N1a Clinically occult (microscopic) metastasis N1b Clinically apparent (macroscopic) metastasis N2 Metastasis in two to three regional nodes or intralymphatic regional metastasis without nodal metastases N2a Clinically occult (microscopic) metastasis N2b Clinically apparent (macroscopic) metastasis N2c Satellite or in-transit metastasis without nodal metastasis N3 Metastasis in four or more regional nodes, or matted metastatic nodes, or in-transit metastasis or satellite(s) with metastasis in regional node(s) Distant MX M0 M1 M1a M1b M1c

metastasis (M) Distant metastasis cannot be assessed No distant metastasis Distant metastasis Metastasis to skin, subcutaneous tissues, or distant lymph nodes Metastasis to lung Metastasis to all other visceral sites or distant metastasis at any site associated with an elevated serum lactic dehydrogenase (LDH)

Source: Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, sixth edition (2002), published by Springer-Verlag New York, www.springer-ny.com.

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cutaneous melanoma TABLE 59.3. Clinical and pathologic stage grouping in the 2002 American Joint Committee on Cancer staging system for cutaneous melanoma. Clinical stage grouping a T

Stage 0 Stage IA Stage IB Stage IIA Stage IIB Stage IIC Stage III

Tis T1a T1b T2a T2b T3a T3b T4a T4b Any T

Pathologic stage grouping b

N

N0 N0 N0 N0 N0 N0 N0 N0 N0 N1 N2 N3

M

T

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0

Stage IIIA Stage IIIB

Stage IIIC

Stage IV

Any T

Any N

Any M1

N

M

Tis T1a T1b T2a T2b T3a T3b T4a T4b

N0 N0 N0 N0 N0 N0 N0 N0 N0

M0 M0 M0 M0 M0 M0 M0 M0 M0

T1–4a T1–4a T1–4b T1–4b T1–4a T1–4a T1–4a/b T1–4b T1–4b Any T Any T

N1a N2a N1a N2a N1b N2b N2c N1b N2b N3 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 Any M1

a

Clinical staging includes microstaging of the primary melanoma and clinical/radiological evaluation for metastases. By convention, it should be used after complete excision of the primary melanoma with clinical assessment for regional and distant metastases.

b Pathologic staging includes microstaging of the primary melanoma and pathologic information about the regional lymph nodes after partial or complete lymphadenectomy. Pathologic stage 0 or stage IA patients are the exception; they do not require pathologic evaluation of their lymph nodes.

Source: Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, sixth edition (2002), published by Springer-Verlag New York.

Surgical Considerations All lesions with characteristics that are concerning for melanoma should be biopsied. An “ABCD” rule is available to help identify pigmented lesions at risk for melanoma: Asymmetry, Border irregularity, Color inhomogeneity, and diameter greater than 6 mm (the size of a pencil eraser).55 Any pigmented lesion that demonstrates a change in size, color, or shape should be considered clinically suspicious. Although the majority of lesions needing biopsy can be identified by careful visual inspection, additional tools are available to assist in the evaluation of pigmented skin lesions. Serial photography can be used to help follow individuals with a large number of atypical appearing nevi. The use of digital photography especially allows for careful sequential assessment of individual pigmented lesions.56,57 Lesions that change over time can be identified for diagnostic biopsy. Epiluminescence, or surface microscopy, can be used to examine individual pigmented lesions for features suggestive of malignancy.56,58,59 Any pigmented lesion with changes or features suggestive of melanoma should be biospied expeditiously.

survival. The corollary to this is that it is important to biopsy the suspicious pigmented lesion with the proper technique. Shave biopsies should not be performed when a melanoma is suspected because of the risk of cutting through the depth of the lesion and having a positive deep margin. If this occurs, a true tumor thickness cannot be ascertained and prognosis and treatment decisions are hampered; this is particularly pertinent when a shave biopsy straddles the tumor thickness of 0.76–1.0 mm. Patients with melanomas less than 0.76 mm in thickness have “thin” melanomas and have a high likelihood of cure with simple surgical techniques [1.0-cm-wide local excision (WLE)]. Patients with melanomas thicker than this have a defined rate of nodal and systemic metastases and are candidates for a wide local excision and nodal staging with the new lymphatic mapping techniques. Patients are done a disservice if a true tumor thickness cannot be ascertained. The proper biopsy technique for suspicious pigmented lesions is an excisional biopsy with a 1.0-mm margin. For larger lesions that cannot be completely excised, a 6.0-mm punch or incisional biopsy of the most nodular-appearing area that reaches into the subcutaneous fat beneath the lesion is indicated to make the diagnosis.

Biopsy Techniques The most powerful predictor of survival for primary melanoma is tumor thickness. There is almost a linear relationship between increasing tumor thickness and decreasing

Surgical Treatment of the Primary Melanoma Local management of primary melanoma necessitates wide excision of the lesion with a margin of normal-appearing skin.

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TABLE 59.4. Completed prospective randomized trials evaluating surgical excision margins. No. of patients

Tumor thickness (mm)

Excision margins

French Cooperative Group64

362

£2

World Health Organization, Melanoma Program, trial 1065–67

612

Swedish Melanoma Group68,69 Intergroup Melanoma Surgical Trial70,71 U.K. Melanoma Study Group72,73

Trial

a

Overall local recurrence

Overall survival

2 cm vs. 5 cm

NSDa

NSD

£2

1 cm vs. 3 cm

NSDb

NSD

989

£2

2 cm vs. 5 cm

NSD

NSD

486

1–4

2 cm vs. 4 cm

NSD

NSD

900

>2

1 cm vs. 3 cm

NSDc

NSD

Comments

Margins of 2 cm are safe for melanomas £2 mm Margins of 1 cm are safe for melanomas £1 mm Follow-up for local failures is ongoing for 1- to 2-mm melanomas Margins of 2 cm are safe for melanomas £2 mm Margins of 2 cm are safe for melanomas 1–4 mm A percentage of nodal or other local/regional events may be reduced by margins >1 cm for melanomas >2 mm

No significant difference.

b

Trend toward an increase in the absolute number of local recurrences in the narrow excision group for patients in the 1–2 mm subset.

c

The patients who received a 3-cm excision had an improved relapse-free survival when all local and regional events were grouped together.

Previously, the surgical standard of care was a 3- to 5-cm-wide local excision (WLE) and a split-thickness skin graft. Increasingly, it has become evident that the risk of local recurrence coincides more with the thickness of the lesion and whether it is ulcerated rather than the extent of the surgical margins.60–62 It may seem more rational, then, to use surgical margins that vary with the ulceration and thickness of the lesion, as these factors seem to correlate best with the risk for local recurrence. The least advanced form of the disease is melanoma in situ. Although the natural history of this noninvasive melanoma is not completely understood, failure to reexcise the biopsy site may result in a local recurrence as either an invasive melanoma or an in situ lesion.63 Therefore, it is recommended that the biopsy site of an in situ melanoma be reexcised with at least a 0.5- to 1-cm margin of skin. For “thin” melanomas (less than 1.00 mm in thickness), only a minimum local recurrence rate has been reported in observed patient series,60–62 despite varying surgical margins. In other words, survival is not influenced by the size of the resection margins. At the present time, a wide excision consisting of no less than 1 cm minimum margin of skin is recommended by many melanoma surgeons.61 This procedure may be performed as a generous elliptical excision and a primary skin closure. Results from five completed prospective randomized studies, summarized in Table 59.4, have established guidelines for excisional margins for invasive melanomas less than 4.0 mm in thickness.64–73 Current recommendations are for 1-cm margins for melanomas up to 1 mm, 1- or 2-cm margins for melanomas between 1 and 2 cm, and 2-cm margins for melanomas between 2 and 4 mm.61 The risk of local recurrence may exceed 10% to 20% for those melanomas more than 4 mm in thickness.60–62,73 Thus, at least 2-cm margins are recommended for these deep primary melanomas.

Intraoperative Lymphatic Mapping and Sentinel Node Biopsy A new procedure has been developed to assess the status of the regional lymph nodes more accurately and decrease the morbidity and expense of a complete elective lymph node dissection (ELND). The technique, termed intraoperative lymphatic mapping and selective lymphadenectomy, relies on the concept that regions of the skin have specific patterns of lymphatic drainage, not only to the regional lymphatic basin but also to a specific lymph node (sentinel lymph node, SLN) in the basin.74 Morton et al. initially proposed the technique75,76 using a vital blue dye method and showed, in animals and initial human trials, that the SLN is the first node in the lymphatic basin into which the primary site drains. They showed that the SLN histology reflected the histology of the remainder of the nodal basin, so that complete nodal staging could be obtained with a SLN biopsy.74 These data have been confirmed by many other institutions, including the Lakeland Regional Cancer Center (LRCC) and Moffitt Cancer Center (MCC),77 M.D. Anderson Cancer Center,78 and the Sidney Melanoma Unit.79 These studies have demonstrated an orderly progression of melanoma nodal metastases. Preoperative lymphoscintigraphy is performed to provide a roadmap for the surgeon as to what basins are at risk for metastatic disease. This nuclear medicine study involves the injection of technetium sulfur colloid into the skin around the melanoma and imaging the patient to ascertain the direction of cutaneous lymphatic flow (Figure 59.1). Two mapping agents are then routinely used intraoperatively, a vital blue dye and a radiocolloid that has the right particle size to be taken up by the cutaneous lymphatics to migrate to the SLN. Upon exposing the lymph nodes in the basin, the SLN will be stained blue and will become “hot” compared to

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cutaneous melanoma

FIGURE 59.1. Preoperative lymphoscinitigraphy in a patient with an intermediatethickness melanoma around the umbilicus. This region of the skin is a watershed area of the body that can show multidirectional lymphatic flow with more than one basin at risk for metastases. This particular primary melanoma drains to both superficial groins as well as the left axilla.

surrounding neighboring non-SLNs and other tissue in the basin. These hot spots can then be used to direct the dissection with a hand-held gamma probe to the SLN. This SLN concept was demonstrated in a study involving patients with a primary melanoma tumor thickness greater than 0.76 mm and who were considered candidates for an elective lymph node dissection.76 The SLN was harvested and submitted separately to pathology, followed by a complete node dissection. In this study, 42 patients met the criteria for SLN biopsy based on prognostic factors of their primary melanoma.76 Thirty-four patients had histologically negative SLNs, with the rest of the nodes in the basin also being negative. Thus, there were no “skip” metastases documented. Eight patients had positive SLNs, with 7 of the 8 having the SLN as the only site of disease. Nodal involvement was compared between the SLN and non-SLN groups based on the binomial distribution. Under the null hypothesis of equality in distribution of nodal metastases, the probability that all seven unpaired observations would demonstrate involvement of the SLN was 0.008. The data presented demonstrates that nodal metastases from cutaneous melanoma are not random events. The SLNs in the lymphatic basins can be mapped and individually identified, and they have been shown to contain the first evidence of melanoma metastases. These findings demonstrate effective pathologic staging, no decrease in standards of care, and a reduction of morbidity with a lessaggressive, rational surgical approach and lower costs for the healthcare system.74

Several prospective national trials are in progress to assess whether this surgical strategy provides a survival benefit for patients. In addition, the Florida Melanoma Trial, with the central office and laboratory located at the Lakeland Regional Cancer Center, is a regional industry-sponsored trial that will examine whether all patients with a positive SLN need to undergo a complete lymph node dissection of the affected basin. The results of these ongoing trials will help determine the final role of radioguided surgery in patients with malignant melanoma.

Surgical Management of Regional Metastases Elective Lymph Node Dissection Results from four completed prospective randomized studies are available to assess potential survival benefit for patients with clinically negative lymph nodes who receive elective lymph node dissection (ELND) as part of their primary tumor management (Table 59.5).80–86 These studies clearly demonstrate no overall survival benefit for all patients receiving ELND.87 However, findings from prospectively stratified subgroups of patients suggest that patients with intermediatethickness melanomas (1–4 mm) that are not ulcerated appear to have a survival advantage with ELND.84–87 Although surgical management of these patients has been largely replaced with SLN evaluation, these results suggest the potential cura-

TABLE 59.5. Completed prospective randomized trials evaluating elective lymph node dissection (ELND). Subset survival benefit

Sites

Tumor thickness (mm)

World Health Organization Melanoma Program Trial 180,81 Mayo Clinic Surgical Trial82,83

553

Extremities

All thicknesses

NSDa

Nob

171

Extremities

All thicknesses

NSD

Nob

Intergroup Melanoma Surgical Trial84,85 World Health Organization Melanoma Program Trial 1486

737

All

1–4

NSD

Yesc

227

Trunk

≥1.5

NSD

Yesd

Trial

No. of patients

Overall group survival benefit

a

No significant difference.

b

Prospective stratified subgroup analysis was not performed.

Comments

All melanoma patients do not benefit from ELND All melanoma patients do not benefit from ELND Defined subsets may benefit from ELNDc Defined subsets may benefit from ELNDd

c

Among the prospectively stratified subgroups of patients, 10-year survival rates were improved in patients who received ELND and had the following characteristics: nonulcerated melanomas, tumor thickness of 1–2 mm, extremity melanomas.

d

Among the prospectively stratified subgroups of patients, overall survival was improved in patients with a tumor thickness of 1.5–4.0 mm.

1082 tive potential of surgery for defined subsets of patients with regionally metastatic disease.87

Therapeutic Lymph Node Dissection In patients with gross nodal metastases, the standard of care is to perform a complete lymph node dissection. The 5-year survival of patients with a nonulcerated melanoma and one, microscopically involved lymph node in the regional basin is approximately 75%. For patients with resected gross nodal disease in the regional basin, the 5-year survival rate drops to 25%. Thus, even in the face of gross nodal disease, surgery in and of itself in the nodal basin can cure approximately 25% of the patients.53,54

Isolated Limb Perfusion Isolated limb perfusion (ILP) refers to the regional intravascular delivery of chemotherapeutic agents to an extremity that has had involvement with melanoma.88 The concept behind ILP is that administration of high drug concentrations is possible with ILP, and the goal with this approach is to improve treatment outcome while limiting systemic toxicities. Major toxicities with ILP have included systemic toxicities related to the infused agent as well as regional toxicities including skin toxicity, limb edema, myopathy, peripheral neuropathy, and vascular toxicity, including arterial embolic events and deep venous thrombosis.88 The application of ILP for extremity melanoma has included both adjuvant ILP as well as ILP for established metastatic disease. Unfortunately, most of the literature describing ILP involves nonrandomized single-institution studies that often use a variety of treatment regimens as well as include heterogeneous patient populations.88 A randomized trial involving 852 patients was performed by an intergroup including the European Organization for Research and Treatment of Cancer (EORTC), World Health Organization (WHO), and the North American Perfusion Group (NAPG) to evaluate the benefit of prophylactic ILP with melphalan for patients with high-risk extremity melanoma.89 Study results published with a median follow-up of more than 6 years demonstrate an improvement related to disease-free survival, with a decrease in both in-transit metastases (6.6% to 3.3%) as well as a decrease or delay in regional lymph node metastases in the ILPtreated patients.89 Unfortunately, no benefit in decreasing distant metastases or improving survival was identified. Thus, routine use of adjuvant ILP cannot be recommended for patients with resected high-risk extremity melanoma. ILP with melphalan has also been administered at normothermic or hyperthermic (HILP) temperatures to melanoma patients who have disease consisting of established in-transit metastases, either with or without additional regional lymph node disease.88 Results from a number of uncontrolled studies report complete responses ranging from 7% to 82% and overall response rates that range from 48% to 100%.88 To improve these results, tumor necrosis factor (TNF) alone or with interferon-gamma has been added to melphalan.88,90,91 Initial results have demonstrated high response rates, and a multiinstitutional Phase III study by the American College of Surgeons Oncology Group (ACSOG) is now in progress to compare ILP using melphalan plus TNF with ILP using melphalan alone.88 The use of ILP is a treatment of choice for some highly selected patients with in-transit metas-

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tases involving an extremity. The optimal treatment agent, treatment time, and limb temperature have not been clearly identified. Palliation can be a goal of this therapy for patients with bulky, symptomatic melanoma of the extremity.

Surgery for Stage IV Melanoma Patients Patients with systemic metastases (AJCC stage IV) have poor prognoses.53 Selection of surgery as a treatment option should take into account the general medical condition of the patient, the potential for prevention or relief of symptoms, and improvement in the quality of life. Surgery may be an effective palliative treatment for isolated metastases, especially because melanoma often metastasizes sequentially and effective chemotherapy is not presently available. Surgical excision of metastatic melanoma may give the patient the best, quickest, and longest lasting palliation. On some occasions, the palliative effect can last for 5 to 10 years.92,93 The obvious limitation of surgery is that it is a local form of treatment, and the patient will very likely die of metastatic disease in another location. Careful patient selection is therefore important.

Mucosal Melanoma Primary melanomas arising from the mucosal epithelia lining the respiratory, alimentary, and genitourinary tracts are rare, accounting for 3% to 4% of all melanomas diagnosed annually. The lack of large numbers of cases is responsible for the lack of insight into the pathogenesis, natural history, and treatment of mucosal melanomas. Mucosal melanomas are considered to be more aggressive with a worse prognosis than melanomas of the skin, and there are no microstaging data applicable for prognosis for patients with mucosal melanomas. The anatomic sites at which these melanomas originate are the head and neck, followed by vulvar and vaginal mucosa, followed by the anorectum.94,95 Similar to the primary melanomas that originate in the skin, mucosal melanomas are more common in the Caucasian population and are diagnosed in an older age group. The presence of melanocytes in the mucous membranes is well established, and thus the mucosal melanomas are considered true primary lesions and not metastases. The characteristic growth pattern of cutaneous melanoma is probably not applicable to mucosal melanoma, which is characterized by a rapid vertical growth phase and metastases. Mucosal melanomas act more like the thick, ulcerated cutaneous melanomas. For this reason, the treatment of the primary melanoma should be as conservative as possible, with total excision obtaining clear margins, but avoiding radical resections. For instance, patients with rectal melanoma should be treated with local excisions obtaining clear margins if possible instead of the more radical abdominoperineal resection.94 A focus in these patients should be on systemic therapy, because many will have systemic metastases at the time of diagnosis. Five-year survival for patients with mucosal melanoma is uncommon regardless of primary site.95

Radiation Therapy Considerations There are several clinical settings in which radiation can provide important benefits for patients with melanoma, the most common involving the palliation of symptomatic

cutaneous melanoma

regional and distant metastases. Palliative settings frequently include patients with painful bony or soft tissue metastases, as well as patients with metastases to the brain and spinal axis. Furthermore, there are several adjuvant therapy settings for which the role of radiation remains of potential value in an effort to diminish locoregional disease recurrence.

Radiotherapy for Symptomatic Treatment Focal radiation generally provides excellent pain palliation for patients with metastatic melanoma.96,97 High rates of palliative pain response for bone metastases have been routinely identified as exemplified by a randomized trial comparing fractionation regimens of 9 Gy ¥ 3 fractions versus 5 Gy ¥ 8 fractions delivered in a twice-weekly schedule. An overall response rate greater than 90% was identified without significant difference between the two arms.98 Similarly, patients with metastatic melanoma will often have painful soft tissue or in-transit metastases that contribute directly to a reduced quality of life. Symptomatic lesions often can be successfully palliated with small-field electron beam or shallow photon tangent beams for pain relief. In addition, there is a rich literature regarding the use of hyperthermia as an adjuvant to radiation therapy in the treatment of malignant melanoma.99,100 These reports include studies employing focal hyperthermia with microwave, ultrasound, and interstitial heating devices. Both retrospective and prospective studies suggest an advantage in clinical response for some patients treated with combined hyperthermia and radiation compared with patients treated with radiation alone.100 Patients with central nervous system metastases involving the brain or spinal cord present special circumstances for which the emergent use of radiation therapy is often warranted. The heterogeneity of melanoma responsiveness to radiation means that selected patients will have prompt regression of brain metastases following palliative radiotherapy, whereas others will not demonstrate clear response. The combination of high-dose corticosteroids with whole-brain radiation therapy provides effective symptom palliation in one-half to two-thirds of patients as measured by transient improvement in performance status and small extensions in median survival.101 Despite several studies, no clear benefit of altered fractionation regimens has been clarified, and a convention of 3 Gy ¥ 10 fractions or 4 Gy ¥ 5 fractions is common throughout much of North America. There are emerging reports regarding the potential additional value of stereotactic radiosurgery for patients with one to three melanoma brain metastases, particularly those with lesions of less than 3 cm and no active disease progression in other systemic sites.102

Role of Adjuvant Radiotherapy There are selected circumstances in which locoregional radiotherapy in the adjuvant setting appears particularly promising.96,103,104 The best described data set examining the use of adjuvant radiotherapy for localized melanoma involves patients with intermediate to thick tumors of the head and neck, with or without regional nodal spread.96,103 Prospective nonrandomized trials suggest a marked reduction in locoregional disease recurrence in comparison with historic controls treated at the same institution.103,105 A similar approach has been advocated for melanoma patients with axillary nodal

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disease, specifically including those patients with extracapsular disease, multiple metastatic nodes, or recurrent disease in a previously dissected axilla. Reports from the M.D. Anderson Cancer Center with more than 5-year median follow-up suggest that the addition of axillary radiation in these highrisk settings can substantially reduce the likelihood of subsequent axillary failure over historical outcome at the same institution.106

Adjuvant Interferon Therapy The only U.S. Food and Drug Administration (FDA)-approved adjuvant therapy following resection of high-risk melanoma remains interferon alpha-2b (IFN-a-2b).107 Vaccines remain experimental for melanoma patients, and vaccine considerations are presented in a later section of this chapter. Interleukin-2 has been evaluated alone and with other biologic response modifiers and/or chemotherapy in numerous advanced-disease studies (see following sections). Unfortunately, there remains no established adjuvant therapy benefit for high-risk melanoma patients following interleukin-2based therapy. Although historically controlled studies have suggested benefit for adjuvant therapy with granulocytemacrophage colony-stimulating factor (GM-CSF),108 this benefit remains unproven and is now receiving prospective randomized clinical trial testing. Numerous other adjuvant therapies including bacillus Calmette–Guérin (BCG), Corynebacterium parvum, dacarbazine, levamisole, megestrol acetate, and interferon-gamma have been evaluated and shown to have limited or no benefit in both randomized and nonrandomized adjuvant therapy trials for melanoma patients.109–111 Although high-dose therapy with IFN-a-2b is the only FDA-approved adjuvant treatment for patients with resected high-risk melanoma, significant debate and controversy continue regarding interpretation of the completed interferon adjuvant studies.112–115 The results of studies evaluating high-dose IFN-a-2b are summarized in Table 59.6. In E1684, the 5-year overall survival rate of patients randomized to observation was 37% and the 5-year overall survival rate of patients randomized to receive IFN-a-2b was 46%.107 This difference was statistically significant and resulted in FDA approval of high-dose adjuvant IFN-a-2b for melanoma patients following resection of high-risk (stage IIB and III) melanoma. The intergroup trial E1690 was performed to confirm results from E1684, as well as to concurrently compare high-dose IFN-a-2b and low dose IFN-a-2b with observation following resection of high-risk melanoma.116 Regional lymph node evaluation was not required for patients with T4N0 disease. The 5-year relapse-free survival rate for high-dose IFN-a-2b was 44%, the relapse-free survival rate for low-dose IFN-a-2b was 40%, and the relapse-free survival rate for observation was 35%. However, no significant improvement in overall survival was achieved by either high-dose or low-dose IFN-a-2b in comparison with observation.116 The E1694 study compared high-dose IFN-a-2b with a GM2 vaccine based on earlier data suggesting benefit in stage III melanoma patients having GM2 antibodies following vaccination with a GM2 ganglioside vaccine.117 An independent data monitoring committee evaluated results from the E1694

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59

TABLE 59.6. Completed randomized trials evaluating high-dose interferon alpha-2b (IFN-a-2b) as adjuvant therapy of melanoma. No. of patients

Eligibility

E1684107

287

T4 N1-3

E1690116

642

T4 N1-3

E1694118

851

T4 N1-3

Trial

Treatment regimens

HDI vs. observation HDI vs. LDIb vs. observation

HDI vs. GMK vaccinec

HDIa overall survival benefit

HDI relapsefree survival benefit

Yes

Yes

No

Yes

Yes

Yes

Comments

IFN-a-2b prolonged median survival from 2.8 to 3.8 years compared to observation There was no difference in the estimated 5-year overall survival rates of 52%, 53%, and 55% for HDI, LDI, and observation, respectively IFN-a-2b is superior to GMK vaccine

a

High-dose interferon-a-2b (HDI) given at 20 MU/m2/day IV 5 days per week for 4 weeks, then 3 times weekly at 10 MU/m2/day subcutaneously for 48 weeks.

b

Low dose interferon-a-2b (LDI) given 3 times weekly at 3 MU subcutaneously for 2 years.

c

GMK vaccine (modified GM2 ganglioside vaccine (Progenics, Inc., Tarrytown, NY) given subcutaneously on a weekly basis for 4 weeks, then every 12 weeks for the next 84 weeks.

study following 16 months of median follow-up. Results from that analysis demonstrated that treatment results had crossed the stopping boundaries specified by the study. The estimated 1- and 2-year relapse-free survival rates for the IFN-a-2btreated patients were 71% and 62%, and the GM2KLH/QS21-treated group had 1- and 2-year relapse-free survival rates of 62% and 49%.118 These results resulted in the recommendation for discontinuation of GM2-KLH/QS21 for patients still receiving it, as it was determined to be inferior to interferon.118 The clinical toxicity and economic cost of adjuvant therapy with this high-dose IFN-a-2b regimen are significant. Although the clinical toxicity of high-dose IFN-a-2b is substantial, overall clinical benefit from this treatment has been reported following quality of life adjusted survival analysis.119 In addition, several investigators are attempting to identify strategies to decrease some of the interferon-associated toxicities.120 Consensus is not present regarding the “standard” use of this treatment for patients with resected high-risk melanoma.112,121

Systemic Chemotherapy The success of various chemotherapy strategies for patients with metastatic melanoma has been very limited.110,122–125 Although some patients have certainly benefited from current treatments, additional improvements are critically needed.

Single Agents The use of single-agent dacarbazine (dimethyl-triazanoimidazol carboxamide, DTIC) has been a “standard” treatment and remains the only FDA-approved cytotoxic drug for metastatic melanoma patients. However, the modest response rate of 15% to 20%, with most of the responses being of brief duration, certainly leaves ample room for improvement.63,126 The median response duration is only 4 to 6 months, and the likelihood of a complete response is less than 5%. Many other drugs have been evaluated for singleagent activity against melanoma. Overall response rates complete response (CR) + partial response (PR) between 13% and 24% have been reported in single-agent chemotherapy studies utilizing a variety of doses and schedules for temozolomide,127,128 cisplatin,129 carboplatin,130 paclitaxel,131 docetaxel,132 carmustine (BCNU),133 lomustine (CCNU),134

fotemustine (FTMU),135 vindesine,136 vinblastine,136 and the dihydrofolate-reductase inhibitor piritrexim.137 Most of these responses are partial, and median response duration is usually measured in units of a few months. Although results from several single-agent Phase II chemotherapy studies appear better than single-agent DTIC, none have been confirmed as superior in a prospective randomized Phase III study.122,123,128 Thus, combination treatments and novel agents with new mechanisms of action are being actively investigated.

Combination Chemotherapy or Chemohormonal Therapy Combination chemotherapy regimens have attempted to either combine agents with distinct single-agent activity and/or add tamoxifen as a means to enhance activity of the treatment regimen. A randomized Italian study evaluated treatment with DTIC, either alone or in combination with tamoxifen, for patients with metastatic melanoma.138 This study reported an improved response rate (28% versus 12%; P = 0.03) and an improved median survival (48 weeks versus 29 weeks; P = 0.02) in patients receiving DTIC combined with tamoxifen compared with patients receiving DTIC alone (Table 59.7). However, a more-recent study from the Eastern Cooperative Oncology Group (ECOG) randomized 258 eligible patients with metastatic melanoma to receive treatment with dacarbazine either alone or combined with tamoxifen, IFN-a-2b or both tamoxifen and IFN-a-2b. There was no difference between time to treatment failure (median, 2.6 months) or overall survival (median, 8.9 months) between any of the four treatment groups.139 Thus, neither tamoxifen, IFNa-2b, nor the combination of tamoxifen and IFN-a-2b was able to improve response rate, time to treatment failure, or survival of melanoma patients when these treatments were added to single-agent therapy with dacarbazine (see Table 59.7). Several studies have reported promising results of tamoxifen in combination with cytotoxic agents including cisplatin,140 navelbine,141 and others.125 Subsequent Phase III testing to determine impact of tamoxifen on the combination treatment either has been negative or has not been performed.125 Although tamoxifen is still being administered as part of published Phase II protocols, existing data do not demonstrate improved therapeutic outcome with addition of tamoxifen to cytotoxic regimens for melanoma patients. The three-drug combinations of cisplatin, vinblastine, and DTIC or cisplatin, vindesine, and DTIC achieved response

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TABLE 59.7. Randomized Phase III trials comparing chemohormonal or combination chemotherapy with DTIC for patients with advanced melanoma. No. of patients

Author 138

Cocconi et al.

Falkson et al.139 Buzaid et al.142 Chapman et al.146

60 52 124 126 46 45 108 118

Treatment regimens

DTIC/TAM DTIC DTIC ± IFN-a + TAM DTIC ± IFN-a Cisplatin/vinblastine/DTIC DTIC Cisplatin/DTIC/BCNU/TAM DTIC

CR + PR (%)

17 6 25 24 11 5 20 12

(28) (12) (20) (19) (24) (11) (18) (10)

Median survival (months)

11 7 9 9 6 5 7 7

Comments

Major benefit of DTIC/TAM appeared to be in women This 2 ¥ 2 factorial design showed no advantage for the addition of IFN-a or TAM to DTIC No convincing evidence to support combination chemotherapy No convincing evidence to support combination chemotherapy

DTIC, dacarbazine; TAM, tamoxifen; IFN-a, interferon-alpha; BCNU, carmustine; CR + PR, complete response + partial response.

rates between 35% and 40% in Phase II testing. Unfortunately, no benefit in response duration or overall survival was seen in subsequent randomized comparison with DTIC (see Table 59.7).142 The treatment combination of cisplatin, dacarbazine, carmustine, and tamoxifen (CDBT; also known as the Dartmouth regimen) has been suggested for many years to have significant activity for patients with metastatic melanoma. Many of these studies reported response rates up to 30% to 50%, and some of these responses seemed to be durable.143–145 However, a more recently completed prospective randomized trial compared CDBT with single-agent therapy with DTIC and found no difference in overall survival with either of these treatments (Table 59.7).146 Although several phase II studies have suggested potential benefit for combination chemotherapy over single agent chemotherapy, results from subsequent phase III testing have been disappointing. Additional agents are also receiving investigation in combination with standard cytotoxic agents. Thalidomide is an orally bioavailable agent that has both antiangiogenic as well as some immunomodulatory properties. Use of thalidomide as single-agent therapy in melanoma has had limited activity.147 The combination of thalidomide and temozolomide was tested for patients with metastatic melanoma, as melanoma is a highly vascular tumor that could benefit from this combined approach.148,149 Current results demonstrate this treatment to be well tolerated and to have some antitumor activity. Overall response rates in small Phase II studies have ranged from 15% to 32%, and durable responses have been reported.148,149 Further study is needed to determine if this combination regimen offers improved outcome over either single agent alone. Other approaches being tested clinically include the combinaton of chemotherapy with the antisense BCL2 oligonucleotide to inhibit antiapoptotic pathways as well as the combination of chemotherapy with novel agents such as Raf kinase inhibitors. It is anticipated that increased understanding of the many pathways involved in melanoma tumorigenesis will provide new opportunities for melanoma treatment strategies.150

Cytokines and Other Immune Activators Many cytokines and other immune activators are being actively evaluated as therapy for patients with metastatic melanoma.151 Treatment with high-dose bolus IL-2 is

approved by the FDA for the treatment of metastatic melanoma, and many studies are in progress to improve efficacy and/or decrease toxicity of cytokine-based regimens for advanced melanoma patients.

Interferons As outlined earlier, treatment with IFN-a-2b has received extensive testing as adjuvant therapy for patients with resected stage III melanoma. In addition, measurable responses have been seen with IFN therapy for melanoma patients with advanced metastatic disease.151 Although the dose and schedule of IFN utilized in the metastatic setting have been quite varied, about 15% of patients have had tumor regression and 5% have been CRs. Although most of these responses last for only a few months, some can be more durable.

Interleukin 2 When peripheral blood mononuclear cells are cultured together with high concentrations of IL-2, a striking proliferation of natural killer (NK) cells and some T cells is observed, with induction of dramatically augmented cytolytic function.152 This IL-2-induced cytolytic function allows destruction of most cultured tumor cell lines and most populations of fresh tumor cell suspensions. For at least some patients with melanoma, measurable shrinkage of grossly evident tumor metastases can be induced by IL-2 treatment.153,154 Approximately 6% of these patients achieved complete remission and 10% of patients achieved partial remission in numerous Phase II studies using high-dose bolus IL-2.151,154,155 These clinical data supported the approval by the FDA of high-dose bolus IL-2 as a treatment for patients with metastatic melanoma. IL-2 treatment induces NK cell activation, the release of cytokines, and a cytokine syndrome that is associated with capillary leak. This IL-2 therapy has a dose-dependent toxicity profile and has significant toxicity when administered in the approved high-dose bolus regimen.156 The approved regimen is for administration of IL-2 at 600,000 to 720,000 IU/kg every 8 hours, up to a maximum of 15 doses, on days 1 through 5 and 15 through 19 of a treatment course. Data supporting approval and use of high-dose bolus IL-2 are based on nonrandomized Phase II data.155 In addition, protocols

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using lower-dose outpatient regimens of IL-2 have generally had lower response rates as well as few long-term survivors.151,154 However, the limitations of decision making based on Phase II data for advanced melanoma patients were emphasized with the recently reported results of the randomized Phase III study of combination chemotherapy and biochemotherapy.157 Thus, use of high-dose bolus IL-2 as a single agent has been primarily at specialized centers with experience in administration of this treatment. Studies involving administration of lymphokine-activated killer (LAK) cells as well as tumor-infiltrating lymphocytes (TILs) together with IL-2 did not demonstrate sufficient additional activity to support noninvestigational use of these approaches.151 More-recent studies are investigating use of nonmyeloablative chemotherapy before adoptive transfer of cloned T cells and high-dose IL-2 therapy.158 These studies, as well as integration of vaccine-based approaches given together with IL-2, will receive intense investigation in upcoming years.

Biochemotherapy Several nonrandomized, single-institution Phase II studies have evaluated combination chemotherapy given together with IL-2 and IFN-a as biochemotherapy for patients with metastatic melanoma. Both inpatient and outpatient regimens have been evaluated, and response rates of 40% to 60% have been reported.159–162 In addition to the high response rates reported, up to 10% of these patients have achieved a durable complete response. The frequent finding of high response rates in separate Phase II studies, as well as the consistent reporting of durable complete responses in a minority of responders, led to high expectations as well as great enthusiasm for this approach. The potential benefit of IL-2/cisplatinbased biochemotherapy has been investigated in at least six randomized trials (Table 59.8).157,163–167 The recent intergroup

59

Phase III randomized study was conducted to determine in a definitive fashion whether biotherapy (IL-2, IFN-a-2b, and GCSF) added to the results of chemotherapy consisting of dacarbazine, cisplatin, and vinblastine when administered in a concurrent fashion. A total of 416 patients without prior treatment for metastatic melanoma were enrolled into the study, and results demonstrated increased toxicity without additional clinical benefit following treatment with the concurrent biochemotherapy regimen (see Table 59.8).157 It remains unknown whether clinical benefit over chemotherapy alone can be achieved with other biochemotherapy regimens, such as use of some of the sequential biochemotherapy regimens. However, the disappointing result of this carefully performed intergroup study emphasizes the need for Phase III testing of promising approaches before accepting them as standard therapy.

Vaccine Therapy Numerous advances in molecular biology and immunology provide opportunities for the design and analysis of vaccinebased therapies for melanoma patients.168–171 Although melanomas contain antigens that can stimulate T-cell responses, the antigen(s) that can stimulate effective in vivo T-cell activation and an antitumor response are not known. Potential sources for antigens to use in melanoma vaccines, listed in Table 59.9, include whole melanoma cells as well as defined melanoma antigens or genes for defined melanoma antigens. The use of melanoma cellular vaccines has included both autologous as well as allogeneic melanoma cells.172–175 Dr. Berd and colleagues have been investigating strategies to enhance the immunogenicity of autologous melanoma cell vaccines.176 A recent update of this nonrandomized experience described 214 clinical stage III (N2 and N3) patients treated adjuvantly with an autologous tumor cell vaccine

TABLE 59.8. Randomized Phase III trials evaluating IL-2/cisplatin-based biochemotherapy for metastatic melanoma patients. No. of patients

Author 163

Treatment regimens

CR + PR (%)

Median survival (months)

Keilholz et al.

66 60

IL-2/IFN-a CDDP + IL-2/IFN-a

18 33

9 9

Rosenberg et al.164

52 50

CDDP/DTIC/TAM CDDP/DTIC/TAM + IL-2/IFN-a

27 44

15.8 10.7

Dorval et al.165

49 52

CDDP/IL-2 CDDP/IL-2 + IFN-a

16 24

10.4 10.9

Eton et al.166

92 91

CVD Sequential CVD + IL2/IFN-a CDDP/DTIC/IFN-a CDDP/DTIC/IFN-a + IL-2 CVD Concurrent CVD + IL-2/IFN-a

25 48

9.2 11.9

23 21

9.0 9.0

11 17

8.7 8.3

Keilholz et al.167

Atkins et al.157

363 randomized 201 204

Comments

Addition of CDDP to cytokine treatment with IFN-a and IL-2 improves response rate without improving survival Addition of immunotherapy to combination chemotherapy increased toxicity without improving survival with these treatment regimens Addition of IFN-a to this CDDP/IL-2 regimen increased toxicity without improving survival Cytokines improved antitumor activity at the expense of considerable toxicity Addition of IL-2 to this CDDP/DTIC/IFN-a regimen increased toxicity without improving survival Addition of immunotherapy to combination chemotherapy increased toxicity without improving survival with these treatment regimens

IL-2, interleukin-2; IFN-a, interferon alpha; CDDP, cisplatin; DTIC, dacarbazine; TAM, tamoxifen; CVD, cisplatin/vinblastine/dacarbazine.

cutaneous melanoma TABLE 59.9. Sources of antigen for melanoma vaccines. Autologous melanoma cells Allogeneic melanoma cells Autologous heat shock protein–peptide complexes Ganglioside antigens Antiidiotypic monoclonal antibody Peptides for melanoma-associated antigens DNA encoding protein containing melanoma-associated antigens

modified with the hapten dinitrophenol (DNP).177 The 5-year overall survival rate of 44% was better than expected from historical controls, and the 47% of patients with an induced delayed-type hypersensitivity (DTH) to unmodified autologous melanoma had an overall survival that was twice that of the DTH-negative patients (59.3% versus 29.3%; P less than 0.001). Additional approaches designed to augment the immunogenicity of autologous melanoma cells include the use of oncolysates of melanoma cells with vaccinia virus and the use of irradiated gene modified melanoma cells as a melanoma vaccine.173,178–180 Other investigators are utilizing vaccines based on allogeneic cell lines, as this strategy offers many practical advantages over the use of autologous cells as a cancer vaccine.173–175 An allogeneic melanoma cell lysate vaccine (Melacine) was compared with combination chemotherapy with the Dartmouth regimen in a randomized clinical trial for patients with metastatic melanoma.181 Although both treatments had low but similar median survivals (7.2 months for the Dartmouth regimen compared with 6.8 months for Melacine), the improved toxicity profile for Melacine resulted in its approval in Canada. In addition, Melacine was investigated as adjuvant therapy for patients with intermediatethickness, node-negative melanoma.182 Although no overall survival benefit for this vaccine was seen in all treated patients, the patient subset with a specific histocompatibility leukocyte antigen (HLA) expression (HLA-A2 and/or HLAC3) had improved relapse-free and overall survival compared to control patients.183 Another allogeneic cellular vaccine with promising results in adjuvant studies as well as some antitumor activity in metastatic disease is CancerVax.184 This vaccine is currently receiving expanded testing in a Phase III adjuvant study comparing CancerVax (with BCG) versus BCG alone for patients with resected stage III melanoma. Several gangliosides on melanoma cells have been characterized, and these gangliosides provide a target for an antibody response to melanoma.117 Unfortunately, the GM2-KLH/QS-21 vaccine was inferior to interferon when evaluated in a prospective randomized trial as adjuvant therapy for patients with resected high-risk melanoma.118 Another approach to stimulate an antibody response to melanoma uses an antiidiotypic antibody as an immunogen. Clinical trials are in progress, and some patients have been shown to develop an antiantiidiotypic antibody following vaccination with an antiidiotypic antibody.185 Several clinical studies are now in progress either utilizing immunodominant peptides for melanoma-associated antigens or using DNA-encoding proteins containing melanoma-associated antigens.186–189 Additional studies are

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combining these defined vaccines with cytokines or other immune activators. Rosenberg and colleagues reported antitumor activity in HLA-A2-positive melanoma patients receiving GP-100 peptide in combination with IL-2,190 and Nestle and colleagues reported antitumor activity and antigen-specific T-cell immunity in melanoma patients treated with peptide or tumor lysate pulsed dendritic cells.191 Thus, ongoing clinical studies will determine the immunogenicity and antitumor activity of defined antigen vaccines given alone or with other immunotherapies. Initial Phase I and Phase II studies will determine promising approaches, but prospective, randomized Phase III studies will be needed to determine clinical benefit.

Imaging and Follow-Up of Melanoma Patients The use of intensive follow-up of melanoma patients receiving definitive surgical management of primary melanoma is without demonstrated benefit.192–194 The majority of recurrences for patients with resected melanoma occur in the skin, soft tissues, or lymph nodes. Thus, careful physical examination remains of primary importance in the follow-up of these patients. In addition, the majority of recurrences amenable to surgical resection will be in these regions. Because most recurrences occur in the first 2 years following surgery, the frequency of follow-up is typically greater during the first 2 years following definitive surgery. Typical intervals are every 6 months for patients with melanomas less than 1 mm in thickness and every 3 to 4 months for patients with deeper primary melanomas and/or regional lymph node involvement. Addition of chest X-rays and laboratory studies typically does not take place for patients with melanomas less than 1 mm, but often are obtained at intervals from 3 to 6 months for patients with deeper primary melanomas and/or regional lymph node involvement. Follow-up intervals then become gradually longer between years 3 and 5, and yearly follow-up typically takes places after year 5. Because recurrences can take place more than 10 years from initial resection, some ongoing follow-up is appropriate for these patients. The use of molecular tumor markers in the blood as early predictors of melanoma recurrence or disease outcome for melanoma patients is also receiving intense investigation.195,196 The strategy receiving the most intensive investigation involves use of a multiple-marker reverse transcription polymerase chain reaction (RT-PCR) to predict disease outcome. The markers being evaluated include the presence of melanoma-associated mRNA for tyrosinase, melanoma antigen recognized by T cells (MART-1), and the melanoma antigen MAGE. Although preliminary studies suggest potential benefit for this technology, additional evaluation and validation of assay characteristics are needed before incorporation into routine clinical monitoring. Acknowledgements. Dr. Mark Albertini thanks the Steve Leuthold Family Foundation (Jay Van Sloan Memorial) and Kathy Eagle (Tim Eagle Memorial) for gifts to the University of Wisconsin Comprehensive Cancer Center supporting our research on melanoma immunotherapy. The authors thank Kathy Neish for assistance with manuscript preparation.

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cutaneous melanoma 44. Goggins WB, Tsao H. A population-based analysis of risk factors for a second primary cutaneous melanoma among melanoma survivors. Cancer (Phila) 2003;97:639–643. 45. Geller AC. Screening for melanoma. Dermatol Clin 2002;20: 629–640, viii. 46. Rigel DS. The effect of sunscreen on melanoma risk. Dermatol Clin 2002;20:601–606. 47. Huncharek M, Kupelnick B. Use of topical sunscreens and the risk of malignant melanoma: a meta-analysis of 9067 patients from 11 case-control studies. Am J Public Health 2002;92:1173– 1177. 48. Dennis LK, Beane Freeman LE, VanBeek MJ. Sunscreen use and the risk for melanoma: a quantitative review. Ann Intern Med 2003;139:966–978. 49. Demierre MF, Nathanson L. Chemoprevention of melanoma: an unexplored strategy. J Clin Oncol 2003;21:158–165. 50. MacKie RM, Bufalino R, Morabito A, Sutherland C, Cascinelli N. Lack of effect of pregnancy on outcome of melanoma. For The World Health Organisation Melanoma Programme. Lancet 1991;337:653–655. 51. MacKie RM. Pregnancy and hormones. In: Balch CM, Houghton AN, Sober AJ, Soong S-J (eds). Cutaneous Melanoma. St. Louis: Quality Medical, 2003:319–326. 52. Slingluff CL Jr, Reintgen DS, Vollmer RT, Seigler HF. Malignant melanoma arising during pregnancy. A study of 100 patients. Ann Surg 1990;211:552–557; discussion 558–559. 53. Balch CM, Buzaid AC, Soong SJ, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001;19:3635–3648. 54. Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001;19:3622–3634. 55. Friedman RJ, Rigel DS, Silverman MK, Kopf AW, Vossaert KA. Malignant melanoma in the 1990s: the continued importance of early detection and the role of physician examination and self-examination of the skin. CA Cancer J Clin 1991;41: 201–226. 56. Naeyaert JM, Brochez L. Clinical practice. Dysplastic nevi. N Engl J Med 2003;349:2233–2240. 57. Rhodes AR. Intervention strategy to prevent lethal cutaneous melanoma: use of dermatologic photography to aid surveillance of high-risk persons. J Am Acad Dermatol 1998;39:262–267. 58. Pehamberger H, Binder M, Steiner A, Wolff K. In vivo epiluminescence microscopy: improvement of early diagnosis of melanoma. J Invest Dermatol 1993;100:356S–362S. 59. Argenziano G, Fabbrocini G, Carli P, De Giorgi V, Sammarco E, Delfino M. Epiluminescence microscopy for the diagnosis of doubtful melanocytic skin lesions. Comparison of the ABCD rule of dermatoscopy and a new 7-point checklist based on pattern analysis. Arch Dermatol 1998;134:1563–1570. 60. Haddad FF, Costello D, Reintgen DS. Radioguided surgery for melanoma. Surg Oncol Clin N Am 1999;8:413–426. 61. Ross MI, Balch CM, Cascinelli N, Edwards MJ. Excision of primary melanoma. In: Balch CM, Houghton AN, Sober AJ, Soong S-J (eds). Cutaneous Melanoma. St. Louis: Quality Medical, 2003:209–230. 62. Day CL Jr, Mihm MC Jr, Sober AJ, Fitzpatrick TB, Malt RA. Narrower margins for clinical stage I malignant melanoma. N Engl J Med 1982;306:479–482. 63. Balch CM, Reintgen DS, Kirkwood J, Houghton A, Peters L, Ang KK. Cutaneous melanoma. In: Devita VT, Hellman S, Rosenberg SA (eds). Cancer: Principles and Practice of Oncology, 5th ed. Philadelphia: Lippincott-Raven, 1997:1947–1997. 64. Banzet P, Thomas A, Vuillemin E. Wide versus narrow surgical excision in thin (2x ULN: 800 mg/m2 IV over 30 min days 1, 8, 15 q 28 d R: PCr 1.6–5.0: 650 mg/m2 IV Over 30 min days 1, 8, 15 q 28 d H: Studies ongoing, no recommendations R: Studies ongoing, no recommendations H: Tbili 1.5–3.0 ¥ ULN: 200 mg/m2 IV over 90 min, q 21 d H: Tbili 40: 500 mg/m2 IV q 21 d R: CrCl 25–65: 50% dose reduction H: Tbili >1.2 ¥ ULN: 100% of dose R: CrCl 20–39: 0.5–0.75 mg/m2/d ¥ 5, q 21 d No recommendations H: No recommendations possible No recommendations

R, renal dysfunction; H, hepatic dysfunction; ULN, upper limit of laboratory normals; CrCl, creatinine clearance, as measured by mL/min; PCr, serum creatinine, as measured by mg/dL; Tbili, total bilirubin, as measured by mg/dL; AST, aspartate serum transaminase.

c h e m o t h e r a p y i n pat i e n t s w i t h o r g a n dy s f u n c t i o n

These patients had a greater AUC but similar terminal halflife as those with normal hepatic function. The antitumor efficacy was similar (2/11 evaluable patients) in each group. The patients with hyperbilirubinemia were significantly more likely to have leukopenia on day 7, however. Subsequent explorations have involved liposomal formulations of anthracyclines. Hong et al.76 reported a single case of a patient with inoperable hepatocellular cancer, and severe hepatic dysfunction, as indicated by an abnormally increased indocyanine green clearance (ICG) study: 30 mg/m2 of pegylated liposomal doxorubicin was given every 3 to 4 weeks. The patient tolerated therapy well, with grade 2 stomatitis and grade 2 and 3 leukopenia, and he was able to receive therapy for eight cycles, with an initial partial response. The pharmacokinetic studies were compared to results from eight patients with normal hepatic function and found that the volume of distribution and clearance of doxorubicin were higher, and AUC lower, in this patient. Based on this result, the authors then performed a Phase II study with this drug and dose in this population. Forty patients with hepatocellular cancer were enrolled; they were required to have a total bilirubin of 3.0 mg/dL or less. The overall response rate was 10%, with a median survival of 3.0 months. The toxicity was acceptable, with severe neutropenia in 9% of cycles and stomatitis in 7% of cycles. The results from the pharmacokinetic studies were variable, with no clear correlation to toxicity. Hepatic function as determined by ICG studies also did not correlate with pharmacokinetic or toxicity results. Compared to the results from a Phase I study, the results from this study again suggested a lower initial concentration of doxorubicin, larger volume of distribution, and more rapid clearance of doxorubicin in these patients with hepatocellular carcinoma. Daniele et al.77 planned a dose-escalation study of liposomal daunorubicin in patients with hepatocellular carcinoma and cirrhosis. However, because of the toxicity encountered in this study, dose deescalation, from 80 to 60 to 40 mg/m2 every 21 days, occurred. Indeed, even at the lowest level, three of the four patients encountered dose-limiting toxicity. No objective responses were noted. The primary toxicity in this study, however, was elevations in bilirubin and other hepatic biochemical studies. This study was ultimately also discontinued in part because of the finding of significant uptake of the liposomes in the “normal” liver parenchyma. Specific recommendations based on the previous discussion are presented in Table 98.4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

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41. Roth BJ, Dreicer R, Einhorn LH, et al. Significant activity of paclitaxel in advanced transitional-cell carcinoma of the urothelium: a phase II trial of the Eastern Cooperative Oncology Group. J Clin Oncol 1994;12(11):2264–2270. 42. Dreicer R, Gustin DM, See WA, et al. Paclitaxel in advanced urothelial carcinoma: its role in patients with renal insufficiency and as salvage therapy. J Urol 1996;156(5):1606–1608. 43. Dimopoulos MA, Deliveliotis C, Moulopoulos LA, et al. Treatment of patients with metastatic urothelial carcinoma and impaired renal function with single-agent docetaxel. Urology 1998;52(1):56–60. 44. Bekele L, Vidal Vazquez M, et al. Systemic chemotherapy in patients with renal failure. Am J Clin Oncol 2001;24(4):382–384. 45. Vaughn DJ, Malkowicz SB, Zoltick B, et al. Paclitaxel plus carboplatin in advanced carcinoma of the urothelium: an active and tolerable outpatient regimen. J Clin Oncol 1998;16(1):255–260. 46. Vaughn DJ, Manola J, Dreicer R, et al. Phase II study of paclitaxel plus carboplatin in patients with advanced carcinoma of the urothelium and renal dysfunction (E2896): a Trial of the Eastern Cooperative Oncology Group. Cancer 2002;95(5): 1022–1027. 47. Small EJ, Lew D, Redman BG, et al. Southwest Oncology Group Study of paclitaxel and carboplatin for advanced transitional-cell carcinoma: the importance of survival as a clinical trial end point. J Clin Oncol 2000;18(13):2537–2544. 48. Stadler WM, Kuzel T, Roth B, et al. A phase II study of single-agent gemcitabine in previously untreated patients with metastatic urothelial cancer. J Clin Oncol 1997;15(11): 3394–3398. 49. Lorusso V, Pollera CF, Antimi M, et al. A phase II study of gemcitabine in patients with transitional cell carcinoma of the urinary tract previously treated with platinum. Italian CoOperative Group on Bladder Cancer. Eur J Cancer 1998;34(8): 1208–1212. 50. von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III Study. J Clin Oncol 2000;18(17):3068–3077. 51. Llado A, Bellmunt J, Kaiser G, et al. A dose finding study of carboplatin with fixed doses of gemcitabine in “unfit” patients with advanced bladder cancer. ASCO 2000;19:344a (abstract 1354). 52. Shannon C, Crombie C, Brooks A, et al. Carboplatin and gemcitabine in metastatic transitional cell carcinoma of the urothelium: effective treatment of patients with poor prognostic features. Ann Oncol 2001;12(7):947–952. 53. Carles J, Nogue M, Domenech M, et al. Carboplatin-gemcitabine treatment of patients with transitional cell carcinoma of the bladder and impaired renal function. Oncology 2000;59(1):24–27. 54. Carles J, Nogue M. Gemcitabine/carboplatin in advanced urothelial cancer. Semin Oncol 2001;28(3 suppl 10):19–24. 55. Nogue-Aliguer M, Carles J, Arrivi A, et al. Gemcitabine and carboplatin in advanced transitional cell carcinoma of the urinary tract: an alternative therapy. Cancer (Phila) 2003;97(9): 2180–2186. 56. Ricci S, Galli L, Chioni A, et al. Gemcitabine plus epirubicin in patients with advanced urothelial carcinoma who are not eligible for platinum-based regimens. Cancer (Phila) 2002;95(7): 1444–1450. 57. Maisonneuve P, Agodoa L, Gellert R, et al. Cancer in patients on dialysis for end-stage renal disease: an international collaborative study. Lancet 1999;354:93–99. 58. Watanabe R, Takiguchi Y, Moriya T, et al. Feasibility of combination chemotherapy with cisplatin and etoposide for hemodialysis patients with lung cancer. Br J Cancer 2003;88:25–30. 59. Kiani A, Kohne CH, Franz T, et al. Pharmacokinetics of gemcitabine in a patient with end-stage renal disease: effective clearance of its main metabolite by standard hemodialysis treatment. Cancer Chemother Pharmacol 2003;51(3):266–270.

c h e m o t h e r a p y i n pat i e n t s w i t h o r g a n dy s f u n c t i o n 60. Motzer RJ, Niedzwiecki D, Isaacs M, et al. Carboplatin-based chemotherapy with pharmacokinetic analysis for patients with hemodialysis-dependent renal insufficiency. Cancer Chemother Pharmacol 1990;27:234–238. 61. Kurata H, Yoshiya N, Ikarashi H, et al. Pharmacokinetics of carboplatin in a patient undergoing hemodialysis. Jpn J Cancer Chemother 1994;21:547–550. 62. Niikura H, Koizumi T, Ito K, et al. Carboplatin-based chemotherapy in patients with gynecological malignancies on long-term dialysis. Anti-Cancer Drugs 2003;14:735–738. 63. Chatelut E, Rostaing L, Gualano V, et al. Pharmacokinetics of carboplatin in a patient suffering from advanced ovarian carcinoma with hemodialysis-dependent renal insufficiency. Nephron 1994;66:157–161. 64. Watanabe M, Aoki Y, Tomita M, et al. Paclitaxel and carboplatin combination chemotherapy in a hemodialysis patient with advanced ovarian cancer. Gynecol Oncol 2002;84(2):335–338. 65. Furuya Y, Takihana Y, Araki I, et al. Pharmacokinetics of paclitaxel and carboplatin in a hemodialysis patient with metastatic urothelial carcinoma—a case report (Japanese). Gan To Kagaku Ryoho 2003;7:1017–1020. 66. Weirnik PH, Schwartz ELLL, Strauman JJ, et al. Phase I clinical and pharmacokinetic study of taxol. Cancer Res 1987;47: 2486–2493. 67. Longnecker SM, Donehower RC, Cates AE, et al. High performance liquid chromatographic assay for taxol in human plasma and urine pharmacokinetics in a phase I trial. Cancer Treat Rep 1987;71:53–59. 68. Woo MH, Greggornik D, Shearer PD, et al. Pharmacokinetics of paclitaxel in an anephric patient. Cancer Chemother Pharmacol 1999;43:92–96. 69. Tomita M, Kurata H, Aoki Y, et al. Pharmacokinetics of paclitaxel and cisplatin in a hemodialysis patient with

70.

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76.

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recurrent ovarian cancer. Anti-Cancer Drugs 2001;12:485– 487. Kamizuru M, Iwata H, Terada T, et al. Chemotherapy in hemodialysis patient with metastatic testicular cancer; pharmacokinetics of etoposide and cisplatin. Nippon Hinyokika Gakkai Zasshi 2000;91:599–603. Tokunaga J, Kikukawa H, Nishi K, et al. Pharmacokinetics of cisplatin and methotrexate in a patient suffering from advanced ureteral tumor accompanied by chronic renal failure, undergoing combined hemodialysis and systemic M-VAC chemotherapy. Gan To Kagaku Ryoho 2000;27:2079– 2085. Cho H, Imada T, Masudo K, et al. Combined 5-FU and CDDP in a gastric cancer patient undergoing hemodialysispharmacokinetics of 5-FU and CDDP. Gan To Kagaku Ryoho 2000;27:2135–2138 Obana T, Tanio Y, Takenaka M, et al. Chemotherapy for smallcell lung cancer (SCLC) patients with renal failure. Gan To Kagaku Ryoho 2002;29:435–438. Chan KK, Chlebowski RT, Tong M, et al. Clinical Pharmacokinetics of Adriamycin in Hepatoma Patients with Cirrhosis. Cancer Res 1980;40:1263–1268. Johnson PJ, Dobbs N, Kalayci C, et al. Clinical efficacy and toxicity of standard dose Adriamycin in hyperbilirubinemic patients with hepatocellular carcinoma—relation to liver tests and pharmacokinetic parameters. Br J Cancer 1992;65:751–755. Hong R-L, Tseng Y-L, Chang F-H. Pegylated liposomal doxorubicin in treating a case of advanced hepatocellular carcinoma with severe hepatic dysfunction and pharmacokinetic study. Ann Oncol 2000;22:349–353. Daniele B, De Vivo R, Perrone F, et al. Phase I Clinical Trial of Liposomal Daunorubicin in Hepatocellular Carcinoma Complicating Liver Cirrhosis. Anticancer Research. 2000;20:1249–1252.

9 9

Management of the Pregnant Cancer Patient Deepjot Singh and Paula Silverman

O

ne in every 1,000 pregnant women will be diagnosed with cancer.1 Despite this fact, the level of evidencebased medicine2 available in the field of cancer during pregnancy is low. Randomized controlled trials in this area do not exist. Instead, retrospective collections of patients treated with varying treatment regimens and strategies, collected case reports, studies based on events, such as the Japanese atomic bomb experience, and, for rare malignancies, isolated case reports generally constitute the medical literature on pregnancy and cancer. Nonetheless, this chapter may guide oncologists facing patients in this relatively uncommon, but serious position. We discuss the use of the major diagnostic and treatment modalities in oncology during pregnancy: surgery, diagnostic imaging and therapeutic radiation, and antineoplastic agents. Therapeutic strategies for malignancies seen most frequently during pregnancy are addressed: these include breast cancer, cancer of the uterine cervix, Hodgkin’s disease, and non-Hodgkin’s lymphoma. Medical management of symptoms of malignancy and its treatment that are unique to the pregnant patient are discussed. Cancer is the second leading cause of death in women between the ages of 20 and 39, following closely behind accidents.3 The most frequent cancer deaths in this age group are cancers of the breast, lung, colon, and rectum, leukemia, and nervous system cancers. Because of differences between incidence and mortality, the malignancies seen most often in conjunction with pregnancy are lymphoma, leukemia, melanoma, and cancers of the breast, cervix, ovary, thyroid, and colon.1 Evidence does not support an increased incidence of cancer during pregnancy. The coincidence of pregnancy and cancer does not influence the biology of cancer, nor does it worsen the prognosis of cancer, except when it delays diagnosis or alters therapy. No firm data exist supporting a greater likelihood of a previously treated cancer relapsing during pregnancy. Cancer itself rarely affects the fetus, with only rare reports of placental metastases or fetal malignancy.4 The impact on mother and fetus may, however, be profound. Diagnostic and therapeutic interventions that are selected may affect the fetus and may even include terminating the pregnancy. Delays in diagnosis or alterations in treatment based on the coincidence of cancer and pregnancy may affect maternal outcome. The optimal management of a cancer associated with pregnancy requires cooperation and collaboration with a multidisciplinary team that may include obstetricians, gynecologists, medical and radiation oncologists, surgeons, neonatologists, psychologists, nurses, and social workers.

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It demands intensive interaction between the patient and her care team, and increases the burden of education of the patient and her family members. Ideally, a desired pregnancy will continue without fetal injury or interruption, with delivery of a normal infant at term. Ideally, the mother will receive optimal cancer treatment without delay. Balancing these ideals and making reasonable compromises constitute the crux of medical decision making when cancer is diagnosed during pregnancy. The management of malignancy in the pregnant woman depends on factors including the type of cancer, its stage, maternal and fetal prognosis, and the week of gestation.5 The need for therapy may be deemed “relative” or “absolute” depending on the urgency of treatment with regard to maternal well-being. Figure 99.1 illustrates one author’s overview of potential therapeutic choices.5 With some malignancies (e.g., low-grade lymphoma), treatment may be delayed until week 24 of gestation or longer, when early cesarean section or cancer therapy can be more safely performed. In other cases (e.g., acute leukemia), delay will endanger the mother’s life. Diagnosis early in pregnancy of a life-threatening malignancy requires consideration of therapeutic abortion and careful assessment of treatment-related risks to the fetus. Diagnosis in late trimesters may allow treatment during pregnancy with less fetal risk.

Use of Specific Treatment Modalities in Pregnant Patients Surgery During Pregnancy Surgical interventions and procedures may be indicated for cancer diagnosis, staging, or treatment. For the most part, uncomplicated surgery or anesthetic procedures do not increase the risk of an adverse pregnancy outcome. Although primarily nononcologic, the largest report and analysis of surgical and anesthetic risk to pregnancy is from the Swedish Birth Registry.6 The authors found increases in perinatal morbidity associated with nonobstetric surgery during pregnancy. The significant adverse outcomes were low birth weight and increased early infant mortality. The authors concluded that the morbidity was most likely attributable to the disease prompting surgery, rather than the adverse effects of surgery or anesthesia. An updated report by the same group7 linked three Swedish healthcare registries and reviewed outcomes after surgery during pregnancy. They

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Diagnosis Cancer in Pregnancy

2nd/3rd trimester

1st trimester

relative treatment indication

waiting until week 24 of gestation and later for early cesarean section FIGURE 99.1. Potential treatment options during different stages of pregnancy. For Oduncu et al.,5 the distinction between the terms absolute and relative treatment indication refers to the therapeutic necessity with regards to the mother’s well-being. (From Oduncu et al.,5 by permission of Journal of Cancer Research and Clinical Oncology.)

absolute treatment indication

decision for abortion

starting tumor therapy

found that offspring of mothers who had undergone surgery in the first trimester had increased neural tube defects (6 versus expected number, 2.5). The significance of this finding is greater because five of the six mothers with affected offspring had surgery during the fourth or fifth week of gestation, the period of neural tube formation. However, the association between neural tube defects and maternal surgery during the period of neural tube formation was thought by the authors to be unclear and hypothetical. Based on these findings, Sylvester et al.8 used the Atlanta Birth Defects Registry to do a population-based case control study that evaluated whether general anesthesia exposure during the first trimester of pregnancy is associated with increased central nervous system defects (Table 99.1). They

relative treatment indication

absolute treatment indication

waiting until abortion week 24 of not gestation and primarily later for early cesarean section indicated

decision against abortion

omitting tumor therapy

starting tumor therapy

found a strong association between exposure and the combination of hydrocephalus and eye defects. The limitation of this study is the self-reporting of anesthesia exposure, which is subject to recall bias. Laparotomy during pregnancy has become safer in recent years. In 1987, Kort et al.9 reported a fetal death rate of 3.8% after major intraabdominal or extraabdominal surgery, with no postoperative fetal deaths after 60 laparotomies. This result was comparable to a fetal death rate of 2% in pregnancy controls not undergoing surgery, and superior to studies from the 1960s and 1970s, where the fetal wastage after surgery was four to six times higher.10 However, in Kort’s study, premature deliveries were 21.8% after major surgery, twice the rate seen in controls.9 Another series, reported by Duncan and

TABLE 99.1. Association between multiple central nervous system defects and first-trimester exposure to general anesthesia: Atlanta Birth Defects Case-Control Study, 1968–1990.

Mothers of control infants Mothers of infants with central nervous system defects Neural tube defects Microcephaly Hydrocephalus All Eye defects Cataracts

abortion in exeptional cases

N

Exposed number (%)

Odds ratio

2,846 204

32 (1.1) 7 (3.4)

1.0 2.9

Reference 1.2, 6.8

70 41

0 (0.0) 0 (0.0)

0.0 0.0

0.0, 4.0 0.0, 7.0

70 8 2

7 (10.0) 3 (37.5) 2 (100.0)

Source: From Sylvester et al.,8 by permission of American Journal of Public Health.

9.6 39.6 Infinity

95% confidence interval (CI)

3.8, 24.6 7.5, 209.2 1,329, infinity

1740 colleagues in 1986,11 compared 2,565 pregnant women who underwent surgery with pregnant controls who did not. No increase in congenital anomalies was observed. The greatest risk of spontaneous preterm birth or pregnancy occurred with intraabdominal surgery, especially in the presence of infection. Laparoscopy is a safe surgical option during pregnancy. It has been used for the exploration and treatment of adnexal masses, cholecystectomy, and appendectomy. Reedy et al.12 used the Swedish Birth Registry to study the impact of laparoscopy on pregnancy. They compared the outcomes of more than 2 million pregnancies, of whom 2,181 had laparoscopy and 1,522 had laparotomy. Nearly all the laparoscopic procedures were in the first trimester, whereas the laparotomies were evenly distributed throughout, with fewer in weeks 32 to 40. The authors found an increased risk of low birth weight infants, preterm delivery, and fetal growth retardation in the operative group compared to pregnancies without surgery. However, there was no increased risk when laparoscopy was compared with laparotomy. Fine-needle aspiration, core needle, or excisional biopsy under local anesthesia pose essentially no risk to the fetus.5,13 Modified radical mastectomies have been performed during pregnancy without fetal compromise or preterm labor.14 Mastectomy with axillary dissection is considered the treatment of choice for operable breast cancer in the pregnant woman.14,15 Breast reconstruction should be delayed until after delivery.

Antineoplastic Agents During Pregnancy Drug metabolism is altered by several mechanisms during pregnancy.4,16 Delayed gastric emptying during late pregnancy may alter the rate of oral drug absorption. Plasma volume increases by approximately 50%, allowing a greater space for drug dilution. Plasma unbound drug concentration is altered as albumin concentration decreases and plasma protein levels increase. Both the hepatic drug metabolism and glomerular filtration rate increase during pregnancy. It is unknown whether the amniotic fluid acts as a functional third space. These changes may alter the narrow therapeutic window of cancer chemotherapy and potentially have an impact on its efficacy. Before the thalidomide disaster of the early 1960s, the placenta was believed to be an effective barrier, protecting the fetus from drugs given to the mother.17 Placental transfer is now understood to depend on maternal metabolism, protein binding and storage, molecular size, electrical charge, and lipid solubility.18 Many antineoplastic agents share properties that permit placental transfer. Because of immaturity of the fetal metabolic and excretory processes, drugs that do cross the placenta may cause severe toxicity in the fetus. A brief review of fetal development18 underscores the potential effects of chemotherapy on the fetus. The first phase of gestation is preimplantation, occurring in the first 2 weeks following conception. Administration of chemotherapy during this time period may cause spontaneous abortion. All major organs and organ systems are formed during the period of organogenesis in the second to eighth week of gestation (first trimester). Most congenital malformations caused by drugs occur because of injury during this critical period. Although the development of many organ systems is com-

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pleted during this period, the nervous system, eye, respiratory, and hematopoietic systems continue to develop throughout gestation. These systems may continue to be susceptible to damage from antineoplastic agents. The final phase of fetal development is characterized by growth and maturation of tissues, beginning with the third month of pregnancy. Growth retardation and low birth weight are the major effects of insults from drugs or disease during this period. A birth defect is defined as a major deviation from normal morphology or function that is congenital in origin. Birth defects are common, and 3% of children born in the United States have a birth defect.18 A teratogen is any agent that acts during embryonic or fetal development to produce a permanent alteration of form or function. Only 10% of malformations identified at birth are caused by teratogens. The U.S. Food and Drug Administration (FDA) developed a rating system to provide guidance to drug use during pregnancy. In this system, drugs are divided into five categories depending on the fetal risk demonstrated in animal or human studies. A summary of these categories is provided in Table 99.2. Most antineoplastic drugs are classified as category D, drugs that have fetal risk, but benefit is thought to outweigh these risks. Updates to the FDA ratings are somewhat slow, and information that is more current may be obtained through online services, such as reprotox (http://reprotox.org). Much of the medical literature on chemotherapy during pregnancy consists of retrospective series of patients with varying diseases treated with different multidrug regimens at times throughout pregnancy. Only limited information exists on outcomes of children exposed to chemotherapy in utero. For example, one of the larger series is that of Aviles et al.19 The authors reported a series from Mexico, examining the growth and development of 43 children of mothers treated with chemotherapy during pregnancy. The mothers had hematologic malignancies and were treated with a variety of antineoplastic agents. Drug exposure for the leukemia patients included combinations of vincristine, prednisone, doxorubicin, 6-mercaptopurine, methotrexate, cyclophosphamide, busulfan, and cytosine arabinoside. Lymphoma patients were given cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or CHOP with bleomycin, some with the addition of etoposide and methotrexate. Hodgkin’s disease patients were given mechlorethamine

TABLE 99.2. U.S. Food and Drug Administration (FDA) classification of therapeutic agents based on fetal risk. Category A Category B

Category C

Category D Category X

Drugs have shown no fetal risks in controlled studies in humans Drugs do not show fetal risks in animal studies but human studies do not exist; or adverse effects have been demonstrated in animals but not in wellcontrolled human studies No adequate animal or human studies, or there are adverse fetal effects in animal studies but no available human data Fetal risk present, but benefits are thought to outweigh these risks Drugs for which the proven fetal risks clearly outweigh any benefits

Source: From Briggs et al.,15 by permission of Lippincott, Wilkins & Williams, 2002.

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(nitrogen mustard), vincristine, prednisone, and procarbazine (MOPP), or doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or a combination of both. Nineteen of the 43 mothers received treatment during the first trimester. Children were examined from ages 3 to 19 for physical, neurologic, psychologic, hematologic, and immune functions and cytogenetics. All children were found to be normal, leading the authors to conclude that chemotherapy during pregnancy, including the first trimester, is safe. In another report, Reynoso and colleagues reported the effects of intrapartum combination chemotherapy for acute leukemia in seven children.20 The drugs used included vincristine, cytarabine, prednisone, cyclophosphamide, 6-thioguanine, and daunorubicin. With a follow-up interval ranging from 1 to 17 years, growth and development were reported as normal. No evidence of malignancy was found in any of the seven children. Other authors do not concur with Aviles or Reynoso, and chemotherapy is generally avoided during the first trimester of pregnancy to reduce the risk of fetal loss and teratogenesis. In a retrospective review of 217 pregnant women treated with a variety of systemic therapies, there were 2 spontaneous abortions, 1 stillbirth, and 3 infants born with congenital anomalies. The majority of complications occurred when the chemotherapy was administered during the first trimester.21 During the second or third trimester, there does not appear to be an increased risk of teratogenesis. However, there is a risk of central nervous system or other major organ toxicity and intrauterine growth retardation, and the potential for premature labor.22 The timing of chemotherapy given late in pregnancy should be coordinated to avoid delivery during the nadir in the mother’s blood count. This practice reduces the fetal risk of myelosuppression with resultant infectious complications or hemorrhage from thrombocytopenia.

Specific Antineoplastic Agents in Pregnancy CYCLOPHOSPHAMIDE AND OTHER ALKYLATING AGENTS The alkylating agents, such as busulfan, chlorambucil, cyclophosphamide, and nitrogen mustard, show a rate of fetal malformation of approximately 13% with first-trimester exposure, compared with 4% with exposure in the later trimesters.16 Cyclophosphamide may inflict a chemical insult on developing fetal tissues, resulting in cell death and heritable DNA alterations in surviving cells.18 Anomalies of the extremities, including absent toes and fingers, palatal grooves and other facial abnormalities, microcephaly, and hernias have been attributed to cyclophosphamide exposure in early pregnancy.23 Later in pregnancy, the drug is without significant reported fetal abnormalities and can therefore be given during the second and third trimester.15,18 Growth retardation has been reported with cyclophosphamide late in pregnancy.24 The use of busulfan in pregnancy has been linked to a variety of fetal abnormalities.15 The use of chlorambucil during pregnancy has been associated with both normal and abnormal outcomes.15 METHOTREXATE AND OTHER ANTIMETABOLITES Methotrexate is a folic acid antagonist; exposure to this drug during pregnancy is associated with fetal loss and a distinct pattern of fetal abnormalities. The principal features of the

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abnormalities include growth restriction, failure of calvarial ossification, craniosynostosis, hypoplastic supraorbital ridges, micrognathia, and external ear and severe limb abnormalities.18 Methotrexate crosses the placenta15and has been found in cord serum and fetal red cells. Inhibition of dihydrofolate reductase in fetal tissues is thought to be responsible for methotrexate-induced embryopathy.25 Feldcamp and Carey stress that in cases of inadvertent methotrexate exposure during unanticipated pregnancy, it is important to define the period of drug exposure and the dose to avoid an unnecessary recommendation for abortion of a potentially healthy fetus.26 The critical period of exposure to this drug appears to be weeks 6 through 8 from conception, with a teratogenic dose probably above 10 mg per week.26 Other antimetabolites, such as 5-fluoruracil and cytosine arabinoside are less frequently associated with malformations.16 Although hydroxyurea is teratogenic in animals, no fetal abnormalities have been observed in 13 human pregnancies that resulted in live infants when the drug was used to treat maternal disease.15 DOXORUBICIN AND OTHER ANTITUMOR ANTIBIOTICS Bleomycin, doxorubicin, dactinomycin, and daunorubicin infrequently cause fetal abnormalities. Doxorubicin has been used in breast cancer patients during second and third trimesters with infrequent adverse outcome.14,27 A number of reports support the use of anthracycline-based chemotherapy in pregnancy, but patients should be informed that long-term follow-up data on large numbers of children exposed to chemotherapy in utero are not available.28 No reports have linked bleomycin use with congenital defects in humans.15 In six pregnancies, dactinomycin was administered in the second and third trimesters with delivery of normal infants.15 OTHER CHEMOTHERAPEUTIC AGENTS Cisplatin use has been reported infrequently in pregnancy, but no fetal abnormalities have been identified.15 Vinca alkaloids (vincristine, vinorelbine, and vinblastine) have been associated with fetal abnormalities, spontaneous abortions, and low birth weight.15 Asparaginase use during pregnancy is limited, but it has been reported in combination with other agents.15 In six cases of exposure during the second trimester, no fetal abnormalities were noted.15 Two infants did suffer drug-induced bone marrow suppression. The safety of the taxanes in pregnancy is unknown. The use of paclitaxel and docetaxel during pregnancy is limited to isolated case reports and case series.29–31 In rats, the use of paclitaxel in early pregnancy has been associated with craniofacial malformations, diaphragmatic hernias, and kidney and cardiovascular defects.29 The taxanes have been used mainly as part of combination chemotherapy regimens in the treatment of breast cancer and gynecologic cancers. Gaducci et al.32 used sequential epirubicin with paclitaxel from the 14th to 32nd weeks of gestation with no reported side effects in the patients or the fetus and normal development and growth at 36 months of follow-up. De Santis et al.30 reported the use of docetaxel in the treatment of metastatic breast cancer in a pregnant patient during the second trimester. No adverse effects were noted in either the patient or the infant. Sood et al.29 used cisplatin and paclitaxel in the case of a pregnant woman with advanced ovarian epithelial cancer with resultant maternal neutropenia. Similarly, Méndez et al.31

1742 reported the use of combined paclitaxel and carboplatin in a woman with Stage IIIc ovarian cancer without any adverse effects on the infant.

Immunomodulating Agents INTERFERON ALPHA Interferon alpha is a family of similar subtypes of immunomodulating human proteins and glycoproteins. Interferon alpha does not appear to transfer across the placenta to the fetus. There are reports describing the use of interferon alpha in all phases of pregnancy without adverse fetal outcome.15 This agent is not thought to pose a significant risk when used during pregnancy. Interferon alpha is a class C agent. THALIDOMIDE The evidence implicating thalidomide as a teratogen is overwhelming. In pregnant women, exposure to even a single dose, from the 20th to the 35th day after conception, produced a unique syndrome characterized principally by deformities of the arms, legs and face, often with other more widespread abnormalities.17 Thalidomide was unavailable until recently, when applications for it were found in the immunomodulation of patients with neoplastic and immunologic diseases.33,34 Thalidomide has shown activity in the treatment of multiple myeloma and other lymphoproliferative and myeloproliferative disorders, malignant melanoma, glioblastoma multiforme, and renal cell carcinoma. Thalidomide is contraindicated throughout pregnancy. Its use is additionally prohibited by the manufacturer in women of childbearing age who are not using two reliable methods of contraception for 1 month before starting therapy, during therapy, and 1 month after stopping therapy.35 Special precautions are taken in labeling and distribution to be sure no women of childbearing potential are exposed to thalidomide.36 MONOCLONAL ANTIBODIES Limited information exists regarding the use of monoclonal antibodies, such as trastuzumab or rituximab in malignancy associated with pregnancy. However, immunoglobulins appear safe and several are indicated for conditions occurring in pregnancy.15 Intramuscular immunoglobulin is recommended for postexposure prophylaxis for hepatitis A and measles.37 Intravenous immunoglobulin is indicated in pregnancy for common variable immunodeficiency and in autoimmune diseases, such as immune thrombocytopenia and alloimmune diseases, such as severe Rh immunization.38 Immunoglobulin crosses the human placenta if the gestational age is greater than 32 weeks. Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody that selectively binds to the extracellular domain of the human epidermal growth factor receptor 2 protein, HER2. Trastuzumab has proven efficacy in HER-2overexpressing metastatic breast cancer both as a single agent and in combination with chemotherapeutic agents.39 Trastuzumab is classified as a category B drug, having shown no adverse effects when tested in monkeys during pregnancy.40 However, the HER2 protein expression is high in many embryonic tissues in early gestation.41 Placental transfer of trastuzumab has been observed in monkeys.40 There are no adequate or well-controlled studies in pregnant women.

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Rituximab is a genetically engineered chimeric murine/ human antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes.42 Rituximab is indicated for the treatment of patients with CD20positive, B-cell non-Hodgkin’s lymphoma, and is used as a single agent and in conjunction with chemotherapy. Rituximab has efficacy in both indolent and aggressive lymphomas. Recent studies have demonstrated efficacy in a variety of other B-cell-mediated disorders.43 Rituximab is classified as a category C drug because animal studies in pregnancy have not been performed.42 It is not known whether rituximab can cause fetal harm when administered to a pregnant woman or whether it can affect reproductive capacity. A concern is that because human immunoglobulin is known to pass the placental barrier, rituximab could potentially cause fetal B-cell depletion. HORMONAL AGENTS Tamoxifen is a selective estrogen receptor-modulating agent that acts primarily as an antiestrogen but has some estrogenic properties. There are limited data pertaining to human fetal exposure. In a reported case in which tamoxifen was inadvertently used in all three trimesters, the fetus was born with a syndrome of ambiguous genitalia.15,21 Because of its long half-life, women should be informed that a pregnancy occurring within 8 weeks of stopping the drug could expose the fetus to tamoxifen. Other hormonal agents primarily used to treat breast cancer include gonadotropin-releasing hormone agonists, aromatase inhibitors (e.g., letrozole, anastrazole, and exemestane), and progestins, primarily megestrol acetate. The gonadotropin-releasing hormone agonist leuprolide may theoretically cause spontaneous abortions because it suppresses endometrial proliferation. Its manufacturer maintains a registry of inadvertent human exposures during pregnancy and, with more than 100 cases reported, has found no congenital defects attributable to the drug.15 However, the numbers of cases are too few to draw conclusions regarding safety or risk. Aromatase inhibitors are recommended only for postmenopausal women, as they act by preventing the peripheral conversion of circulating androgens to estrogen. No information is available regarding their use in pregnancy. All progestins have had an FDA-mandated deletion of pregnancy-related indications because of a possible association with congenital abnormalities.15 Cases of ambiguous genitalia have been reported to the FDA, and a paired analysis of first-trimester fetal exposure has shown an increase in cardiovascular defects and hypospadias.15 Prednisone and other corticosteroids are widely used in treatment regimens for leukemia, lymphoma, and Hodgkin’s disease. They appear to pose only small risks to the fetus, but may increase the incidence of orofacial clefts.15 The risk is greatest in the first trimester.

Ionizing Radiation and Diagnostic Imaging During Pregnancy Ionizing radiation techniques are used during pregnancy both for diagnosis and staging of cancer and as a treatment modality. Ionizing radiation refers to waves or particles of sufficient energy to break chemical bonds, such as those in DNA, or

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Pecentage of Severe Mental Retardation

60 8-15 weeks

50

All gestational ages

40 30

ciation, with the estimated risk per unit absorbed dose to be about 200 to 250 excess cancer deaths per 10,000 person-Gy in the first 10 years of life.49 Animal studies suggest that there are late-occurring cancers following prenatal exposure, but long-term studies of atomic bomb survivors are not available.44 Retardation of growth has also been shown over a broad range of gestational ages in animal models and in humans.49

Diagnostic Imaging

20 18-25 weeks 10 0

1743

0 0.10 0.20 0.30

0.50 1.00 1.50 Fetal Dose (Gy) FIGURE 99.2. Effects of ionizing radiation on severe mental retardation in fetuses exposed at various gestational ages to the atomic bomb in Hiroshima and Nagasaki (1 Gy = 100 rad). The bar lines represent 90%. (From Sacher and King,38 by permission of Obstetrical & Gynecological Survey.)

create free radicals that can cause tissue damage. The potential harmful effects on a fetus from ionizing radiation exposure are (1) cell death, affecting embryogenesis, (2) growth restriction, (3) congenital malformation, (4) carcinogenesis, (5) microcephaly and neonatal mental retardation, and (6) sterility.44 Much of the pertinent research has been performed in animals. Human data have been obtained largely from studies of atomic bomb survivors from Hiroshima and Nagasaki. Significant radiation exposure during preimplantation, the period in human development corresponding to the first 9 or 10 days after conception, results in prenatal death.45 Preimplantation is the most sensitive time with respect to fetal death from radiation. Mouse and rat studies constitute the bulk of evidence for prenatal or neonatal death caused by ionizing radiation.46,47 The consequences of radiation of the fetus during the period of major organogenesis may include teratogenic effects on various organs, as shown in many experimental animal studies.45 In humans, effects on the central nervous system are the best documented. Japanese atomic bomb survivors irradiated in utero show an increased risk of microcephaly and severe mental retardation with high prenatal exposure. The risk is greatest at 8 to 15 weeks of gestation, with even very low doses causing a slight increase in the risk of mental retardation. As shown in Figure 99.2, this risk is probably a nonthreshold linear function of dose, with the risk of severe mental retardation being as low as 4% for 10 cGy and as high as 60% 150 cGy.44,48 After 16 weeks, the risk is less, and there is no proven risk between 0 to 8 weeks or after 25 weeks. Fortunately, 10 cGy is many times higher than exposure seen from diagnostic radiation. It is controversial whether there is an association between in utero diagnostic radiation exposure and an increased risk of childhood cancers. Some investigators have found an increased risk of leukemia and other cancers; others have not.18 A major positive study used concordance data on twins exposed to diagnostic X-rays in utero; this led to a finding by the National Research Council Committee on Biological Effects of Ionizing Radiation to conclude that there is an asso-

How then, do the doses of radiation delivered during a single exam or series of diagnostic X-rays compare with those doses that increase the risk of the effects discussed previously? Which of our diagnostic procedures involves exposure to ionizing radiation? Imaging modalities, including ultrasound, magnetic resonance imaging (MRI), and X-rays, are all used as adjuncts to the diagnosis and staging of cancer in pregnancy. Most diagnostic imaging procedures, even those involving X-rays, are associated with little or no known fetal risks. Fetal anomalies, growth restriction, or abortions are not increased with radiation exposure of less than 5 cGy, which is above the range of exposure for diagnostic procedures.50 The estimated fetal exposure from common radiologic procedures that involve ionizing radiation is summarized in Table 99.3. The uterus should be shielded for nonpelvic procedures during pregnancy. Nuclear studies are performed by tagging a chemical agent with a radioisotope for tests, such as pulmonary ventilation-perfusion, thyroid, and bone scans. Bone scans that use technetium (99 mTc) result in a fetal exposure of less than 0.5 cGy.51 One of the more common nuclear medicine studies performed during pregnancy is the ventilation-perfusion scan for suspected pulmonary embolism. Both intravenous 99 mTc and inhaled xenon gas are used. Nonetheless, in total, the fetal exposure is approximately 0.05 cGy.51 Radioactive iodine readily crosses the placenta and can adversely affect the fetal thyroid, especially after 10 to 12 weeks of gestation. If a diagnostic scan of the thyroid is essential, 123I or 99 mTc should be used instead of 131I.51 Ultrasound uses sound waves and is not a form of ionizing radiation. Ultrasound appears to present minimal or no

TABLE 99.3. Estimated fetal exposure from common radiologic procedures. Procedure

Chest X-ray (two views) Abdominal film (single view) Intravenous pyelogram Hip film (single view) Mammography Barium enema or small bowel series CT scan of head or chest CT scan of abdomen and lumbar spine CT pelvimetry

Fetal exposure (cGy)

0.00002–0.00007 0.1 ≥1a 0.2 0.007–0.02 2–4 60 years old or after MRM. chapter

Cohort of 5-year survivors

Cohort q 6 mo for up to 3 years

Clinic population over a 6-month window

Retrospective review

Study population and follow-up (years)

TABLE 106.1. Arm symptoms in treatment for breast cancer. (continued)

1840 106

To identify risk factors for decline in upper body function

Assess postoperative morbidity of the operated arm

Assess the effect of patient characteristics and therapy on selfreported upper-body function and discomfort Characterize the incidence and predictors of upper body function decline and recovery

Silliman et al. 199917

Schrenk et al. 20004

Lash et al. 200016

Cohort for 5 years

Prospective cohort 5 and 21 months postoperative

Cross-sectional observational study 3–5 months postoperative Prospective cohort 15–17 months F/U

Prospective randomized trial 3, 12, 24, and 36 months after surgery

303 women

388 invited, 303 interviewed

35 women

300 women

381 women

BCS ± XRT or MRM

MRM or BCS ± XRT

BCS or MRM ± XRT with ALND or SN dissection

BCS or MRM ± XRT

Sector resection and ALND ± XRT

• Review of medical records • Telephone interviews • SF-36

• Physical exam: arm circumference (15 cm above and 10 cm below the lateral epicondyle), numbness, mobility, strength, stiffness • Interview • Review of medical records • Computerassisted telephone interviews

• Review of medical records • Telephone interview

• Subjective arm symptoms (graded as none, moderate, or severe)

• Arm circumference 10 cm above and below the elbow on both arms

82 met case definition for upper-body function decline. 32 met the definition for recovery.

35 patients (100%)

213 women (71%)

Arm circumference: 273 pts at 3–12 mo., 270 pts at 13–36 mo., 36 mo. Arm symptoms: 368 pts at 3–12 mo., 335 pts at 13–36 mo., 115 pts >36 mo.

The incidence of decline in the first year was substantially higher than in the subsequent 4 years. Women with less than a high school education had an increased risk of decline (HR 2.3). Recovery was higher for women followed by breast cancer specialist.

Cardiopulmonary comorbidity associated with decline at 5-month interview (OR 2.8, 95% CI 1.3–5.7). ALND associated with axillary numbness, pain.

SN associated with negligible morbidity compared with ALND.

Extent and type of primary therapy and cardiopulmonary comorbidity associated with a decline in upper body function.

Extent of surgical procedure and young age are determinants of arm morbidity. Arm symptoms are most common during the first year.

BCS, breast-conserving surgery; XRT, radiation therapy; HR, hazard ratio; OR, odds ratio; ALND, axillary lymph node dissection; SN, sentinel node dissection; AE, arm edema; F/U, follow-up; TAL, total axillary lymphadenectomy; EPESE, Established Populations for the Epidemiological Study of the Elderly; GHQ, General Health Questionnaire; STAI, State Trait Anxiety Inventory; SF-36, Medical Outcomes Study Short Form—36 Items.

Lash et al. 2002140

Assess arm morbidity after sector resection and ALND ± XRT

Liljegren et al. 199712

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morbidity was an independent predictor of upper body function decline (P = 0.006) in a second study17; mastectomy and XRT were also associated with significant declines in upper body function. Women treated with an ALND were more likely to report numbness or pain in the axilla (OR, 6.4; 95% CI, 0.2–33).16 In a prospective cohort study, Segerstrom et al.18 reported 35 of 93 (37.6%) patients had restricted shoulder range of motion during the first 2 years after surgery; this increased to 49.5% up to 2 years later. Paci et al.8 reported that 18.9% of patients experienced shoulder deficit as assessed by physical examination performed 5 or more years after diagnosis. Lin et al.19 reported 15° or greater loss of ROM in 17% of the patients and 30° or more loss in 4% at 1 or more years after ALND. In contrast, Gerber et al.5 found no significant loss in functional ROM (assessed using goniometry) 1 year postoperatively; however, patients undergoing MRM reached their preoperative ROM more slowly than those undergoing BCS.5 Pain and chest wall tenderness have been reported following breast surgery.5,7,11 Pain was more frequent after BCS in one study7 and after mastectomy in another.11 Arm symptoms have been associated with psychologic, social, sexual, and functional morbidity.20 In two case-control studies, women experiencing AE after treatment for breast cancer showed greater psychologic morbidity and greater impact of illness measured using the Psychosocial Adjustment to Illness Scale (PAIS), effects that remained stable over a 6-month period, even if AE was being treated.21,22 Maunsell et al. also reported the proportion of women experiencing psychological distress as measured by the Psychiatric Symptom Index (PSI) increased significantly with an increased number of problems in the affected arm.23 In summary, significant physical and functional sequelae in the arm and upper body may occur as a result of local therapy, especially ALND and axillary XRT. Prospective, population-based studies that include an assessment of patient demographics, risk factors, stage, and treatment coupled with outcome evaluation that involves standardized, blinded assessment of arm symptoms and function preoperatively and during long-term follow-up would expand available information; intervention research to identify effective management approaches is urgently needed.

Menopause Women with breast cancer may experience early menopause as a result of their treatment. They report a higher frequency of menopausal symptoms than women in the general population.24 The high frequency of menopausal symptoms in breast cancer survivors is caused by several factors25: (1) age at diagnosis (frequently over 50 years), (2) abrupt discontinuation of hormone replacement therapy (HRT) at the time of breast cancer diagnosis, (3) induction of premature menopause by therapy (i.e., chemotherapy and ovarian ablation), and (4) induction of estrogen deficiency symptoms by therapy (e.g., tamoxifen and aromatase inhibitors) (Table 106.2). Chemotherapy is frequently associated with either temporary or permanent amenorrhea. The incidence of amenorrhea is related to the type of chemotherapy regimen, the cumulative dose (particularly cyclophosphamide), and the age of the patient.26,27 Surgically induced menopause and premature menopause have been associated with more severe symp-

106

toms than natural menopause.28,29 The health consequences of menopause can be divided into four categories: vasomotor symptoms, genitourinary signs and symptoms, skeletal effects, and cardiovascular effects.30 In a survey of 190 breast cancer survivors, the most common symptoms experienced were hot flashes (65%), night sweats (44%), vaginal dryness (44%), difficulty sleeping (44%), depression (44%), and dyspareunia (26%).31 Hot flashes (HF) are more frequent, severe, distressing, and of greater duration in breast cancer survivors compared with controls without breast cancer.32 Before 2002, HRT was frequently prescribed to healthy women for the control of menopausal symptoms and primary prevention of disease (i.e., cardiovascular disease and osteoporosis). In 2002, the Women’s Health Initiative (WHI), a large randomized trial of HRT versus placebo in healthy women, was stopped early because overall health risks of combined estrogen plus progesterone exceeded benefits at an average 5.2-year follow-up.33 Risks of coronary heart disease, stroke, pulmonary embolism, and invasive breast cancer were increased, whereas risks of colon cancer and hip fracture were minimally decreased. Results for estrogen alone versus placebo are pending. The use of HRT in breast cancer survivors has been controversial.34,35 Four case series,36–39 three case-control studies,40–43 and one cohort study44 failed to identify an increased risk in women who chose to take HRT; two additional studies reported a lower risk of recurrence and death when HRT was used.42,43 The studies are susceptible to selection bias, particularly in view of the reluctance of many breast cancer survivors to accept HRT.45,46 One randomized clinical trial of HRT in 434 breast cancer survivors was recently stopped for safety reasons because of an unacceptably high risk of breast cancer events [hazard ratio (HR), 3.5; 95% CI, 1.5–8.1] in women receiving HRT.47 Women on HRT were advised to discontinue the treatment. Current guidelines34,48 that recommend postmenopausal breast cancer survivors be encouraged to consider alternatives to HRT but state that minimal HRT use may be considered in a well-informed patient with severe symptoms will likely be modified in view of these results, with a greater focus on recommending nonhormonal approaches to symptom management. Vasomotor symptoms are the most common complaint of perimenopausal and postmenopausal women. More than 60% of postmenopausal women experience hot flashes, and onethird of those find them nearly intolerable.49 HRT relieves HF in 80% to 90% of women who initiate treatment.50–52 Progestational agents (e.g., megestrol acetate, medroxyprogesterone acetate, and depo-Provera) decrease HF by 85%.53–57 Herbal remedies, including soy products and black cohosh, have been reported to minimally decrease HF or have no effect. Vitamin E (800 IU/day) minimally decreases HF (i.e., one fewer HF/day). Clonidine is modestly active in reducing hot flashes. Selective serotonin reuptake inhibitors (SSRIs) such as venlafaxine and paroxetine have also been shown to significantly reduce HF. Possible interactions between SSRIs and selective estrogen receptor modulators (SERMS) are being evaluated. Gabapentin (widely used in neurologic disorders) has been recently reported to reduce HF scores.58 Most of these trials have evaluated the short-term effect (e.g., 4–12 weeks); long-term effects have not been addressed. Severe symptoms of urogenital atrophy occur in nearly half of postmenopausal women surviving breast cancer.

m e d i c a l , p s yc h o s o c i a l , a n d h r q o l i s s u e s i n b r e a s t c a n c e r s u rv i vo r s

Lubricants and moisturizers have been shown to be helpful but do not completely relieve symptoms. Very low dose vaginal estrogen creams can reverse atrophy but systemic absorption of estrogen may occur. Newer methods of estrogen delivery include a ring device (Estring; Pfizer, New York, NY). This device provides almost complete relief of symptoms and minimal systemic absorption48; however, recent evidence that lipid levels may be altered59 raises concerns about its use. One randomized trial60 evaluated the use of a comprehensive menopause assessment program in breast cancer survivors; the intervention (which did not involve use of estrogen but permitted megestrol acetate and nonhormonal agents such as clonidine) reduced menopausal symptoms and improved sexual functioning when compared with a control arm. Bone loss occurs at a rate of 1% to 5% per year and is greatest during the first 5 years after natural menopause.61 Chemotherapy-induced ovarian failure causes more rapid and significant bone loss.62 Tamoxifen in premenopausal, but not postmenopausal, women and aromatase inhibitors have also been associated with increased bone loss. Bone density should be monitored in survivors.63 Preventive measures such as proper intake of vitamin D and calcium, regular exercise, and counseling about the relationship between cigarette smoking, alcohol, and bone loss should be initiated in all patients. Pharmacologic approaches currently recommended for survivors include (1) bisphosphonates (alendronate, risedronate), (2) SERMs (raloxifene), and (3) calcitonin. The risk of coronary heart disease increases with increasing age.64,65 HRT in the primary and secondary prevention of coronary heart disease has not been shown to reduce cardiac events in four large randomized clinical trials.33,66,67 Management of known risk factors and encouragement of lifestyle modification are warranted.68

Pregnancy Limited data exist on the effect of pregnancy on breast cancer outcome. Based on the experience at major institutions68–71 and population-based registries,68,72,73 women who become pregnant after a diagnosis of breast cancer appear to have similar breast cancer outcomes to those who do not. Selection biases may be responsible for these results. Prior chemotherapy does not appear to have teratogenic effects in future pregnancies74,75; however, local breast cancer treatment (i.e., surgery and XRT) may affect the ability to lactate after BCS.68,76,77 Breast cancer and pregnancy have been recently reviewed (see Chapter 99).78,79

Fatigue Fatigue is often experienced during, and shortly after, cancer treatment. The level of fatigue in a large survey of breast cancer survivors (1–5 years after initial diagnosis) was comparable with that of age-matched controls using the RAND36 questionnaire.80,81 However, severe and persistent fatigue was experienced in a subgroup of survivors and was related to depression and pain. In a second smaller cohort study, fatigue (measured using a number of fatigue questionnaires including the RAND-36) was more common in breast cancer survivors than in age-matched controls.81,82

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Second Malignancies Second malignancies (e.g., angiosarcoma, sarcoma, and skin cancer) at the site of previous local treatment for breast cancer occur in less than 1% of survivors (see Chapter 111).68

Cardiac Toxicity The most common form of anthracycline-induced cardiotoxicity is chronic cardiomyopathy.83 The risk of cardiomyopathy is principally dependent on the cumulative anthracycline dose and may occur years after therapy.84 Prospective monitoring of signs and symptoms of congestive heart failure (CHF) revealed a 9% risk of CHF after 450 mg/m2 doxorubicin and 25% after 500 mg/m2 85; this risk may be higher when doxorubicin is used in combination with paclitaxel.86 Prospective cardiac monitoring using MUGA scans has been included in more recent clinical trials of breast cancer treatment including anthracyclines, taxanes, and herceptin. Based on a recent randomized trial,87 cardiotoxicity is particularly pronounced when herceptin is combined with either adriamycin or epirubicin plus cyclophosphamide (any cardiotoxicity = 27%, grade 3–4 cardiotoxicity = 10%). Bradycardia has been reported with the use of paclitaxel alone.

Surveillance Evidence-based surveillance strategies for breast cancer survivors have been established.63 There are sufficient data to recommend monthly breast self-examination, annual mammography of the preserved and contralateral breast, as well as a careful history and physical examination every 3 to 6 months for 3 years, then every 6 to 12 months for 2 years, then annually. Data are not sufficient to recommend routine radiologic investigations or blood work (including tumor markers). Primary care of breast cancer survivors has also been reviewed.68 Grunfeld et al.88 conducted a large randomized trial of specialist versus general practitioner care in Great Britain; patients were more satisfied with care provided by the latter, with no differences in medical outcomes being observed, although only a small number of medical events were reported.

Psychosocial Status and HRQOL Breast cancer is a stressful event that can perturb psychologic equilibrium and reduce HRQOL in the short-term89–92; recent survivorship research has evaluated long-term sequelae. Early studies involved mainly small convenience samples (maximum, 61 survivors), descriptive designs, and interviewbased measurements.93–97 Key results of these studies include observations that the majority of survivors are fairly to very satisfied with their lives 8 years after diagnosis despite thoughts of recurrence reported by 50%93; that survivors have a positive perception of life and attach less importance to trivial stressors even though fear of recurrence is a major concern94; and that the majority of survivors thrive despite experiencing problems related to breast cancer and its treatment.95 Several ongoing issues were identified in a focus group of 10-year survivors: integration of disease into current life, change in relationship with others, restructuring life perspective, and unresolved issues.96

141

Determine whether ERT alters the development of new or recurrent breast cancer Assess willingness to undergo HRT in survivors

Assess the efficacy of a comprehensive menopausal assessment (CMA) intervention program in achieving relief of symptoms, improvement in QOL, and sexual functioning in survivors Define the prevalence of ERT usage, identify risks

Vassilopoulou-Sellin et al. 199944

Ganz et al. 200060

Cohort of survivors (ER+ in 74%), median disease-free 46.7 months (range, 0–448 months), followed for ≥60 months, treated with ERT

Randomized controlled design of postmenopausal breast cancer survivors (8 months to 5 years after diagnosis)

Sample of survivors from a previous survey an average of 3.1 years postdiagnosis

Convenience sample treated with oral continuous ERT for at least 3 months starting 41 months (range 0–401 months) postdiagnosis; median F/U 30 months Prospective randomized study of ERT, cohort of nonparticipants

Prospective descriptive study of women 8–91 months postdiagnosis treated with oral continuous opposed ERT observed for 24–44 months

Study population and follow-up (years)

56

72

39

319

145

24

No. of patients

• Decision analysis interview. • Menopausal symptom scale score adapted from the Breast Cancer Prevention Trial Symptom Checklist • Vitality Scale from the RAND Health Survey 1.0 • Sexual Summary Scale from the Cancer Rehabilitation Evaluation System. • Review of medical records Routine surveillance by an oncologist including history and physical examinations every 3–6 months, annual mammograms and CXR, and evaluation of liver chemistries at each visit.

• Interview • Standardized health-related instruments including the RAND Health Survey

• Monitor clinical outcome for new or recurrent cancer

• History and physical exam 3¥/year • Mammogram yearly. • BSE taught to the patient. • Appointment with surgeon annually. • Routine surveillance by an oncologist

Instruments

56/607 interviewed

72/197

319/331

145/168

Response rate

Use of ERT was not associated with increased events.

A clinical assessment and intervention program for menopausal symptom management is feasible and acceptable to patients, leading to reduction in symptoms and improvement in sexual functioning.

Older survivors are reluctant to take estrogen. Increased willingness to consider therapy if multiple symptoms coexisted and the risk of recurrence was small.

ERT does not seem to increase events. Events during follow-up: 20/280 in controls vs. 1/39 in ERT group.

13 recurrences (9%).

No recurrences.

Results and conclusions

chapter

Peters et al. 2001143

Ganz et al. 199945

Evaluate the outcome of patients who elected ERT

Determine whether ERT adversely affects outcome of survivors

Primary objective(s)

Brewster et al. 1999142

Guidozzi et al. 1999

Reference

TABLE 106.2. Menopause in breast cancer survivors.

1844 106

Assess the burden of menopausal symptoms, HRT use, and alternative treatments in recent survivors Compare the QOL of survivors who received HRT and those who did not

Harris et al. 200224

Determine the prevalence of menopausal symptoms, explore attitudes toward HRT or other treatments and the willingness to take estrogen To examine impact of HRT on events in survivors

Biglia et al. 200346

RCT of HRT vs. no therapy in survivors

Convenience sample (early breast cancer) Mean F/U not stated

Nonrandomized qualitative study of women from a cancer registry. QOL was compared for 3 groups based on the time since diagnosis: 8 years Descriptive, cross-sectional, comparative study of survivors (mean of 39 months postdiagnosis) and age-matched healthy female volunteers

Population-based, case-control study of survivors (8–11 months postdiagnosis) and age-matched controls

Record-based study of women 35–74 years identified in the SEER records (1977–1994) (1 user matched to 4 nonusers) (48% of users/59% of nonusers ER+)

434

250

69 survivors/ 63 agematched

123

183

2,755

• Clinical examination, mammography

Data obtained from: • The Cancer Surveillance System • Group Health Cooperative pharmacy • Medical records • Standardized telephone questionnaire • F/U 10-minute telephone questionnaire on HRT and menopause Questionnaires including: • Demographic data • QOL Breast Cancer version Questionnaire • QOL Self Evaluation Questionnaire Questionnaires: • Demographic and disease/ treatment information • Gynecologic and reproductive history form • Hot flash questionnaire and diary • POMS-SF • PANAS • HFRDIS • 35-item questionnaire formulated for this study

345 had ≥1 follow-up

Not stated

69/207 survivors

123/190 (64.8%)

93% cases, 95% controls

RCT stopped early because of excess events in survivors treated with HRT (relative hazard 3.5, 95% CI 1.5–8.1).

Survivors are interested in treatments that may improve their QOL, but fear of HRT persists among survivors and their doctors.

Hot flashes are a significant problem for survivors. Survivors with severe hot flashes reported significantly greater mood disturbance, higher negative affect, more interference with daily activities (sleep, concentration, and sexuality), and decreased QOL.

Cases more likely to experience menopausal symptoms, less likely to use HRT, more likely to use alternative therapies (soy, vitamin E, and herbal remedies). No significant difference between users and nonusers. Near-normal QOL after a 4-year adjustment period.

Lower risks of recurrence and mortality observed with HRT.

HRT, hormone replacement therapy; ERT, estrogen replacement therapy; RCT, randomized clinical trial; F/U, follow-up; POMS-SF, Profile of Mood States-Short Form; PANAS, Positive and Negative Affect Scale; HFRDIS, Hot Flash-Related Daily Interference Scale; BSE, breast self-examination; QOL, quality of life.

Holmberg 200447

Compare the HF symptom experience and related outcomes between survivors and healthy women

Carpenter et al. 200232

Durna et al. 2002144

Evaluate the impact of HRT on recurrence and mortality

O’Meara et al. 200143

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Second-generation studies used stronger designs, more standardized measurement approaches, and larger sample sizes. They were more often population based and/or used control groups of women without breast cancer. They frequently used generic instruments (applicable to healthy and medically ill individuals) for which normative data are available. One generic instrument that has been widely used in survivorship research is the Medical Outcomes Study Short Form—36 (MOS SF-36), a reliable and valid measure of HRQOL. It has 36 items rated on a 5-point Likert scale. There are eight subscales grouped in two composite scales: Physical Component Summary (PCS) and Mental Component Summary (MCS). Cancer-specific instruments, which measure attributes that are specific or unique to cancer patients, were also used in a large number of studies. Due to their nature, normative data for the general population are not available for these instruments. Nonetheless, they provide data that can be used to describe groups of survivors, evaluate change in their status over time, or compare different groups of survivors. Specific examples of these instruments are discussed.

Psychologic Status and Overall HRQOL Many studies have examined psychosocial status and HRQOL in breast cancer survivors as a single group. Results of these studies are reviewed first, followed by a discussion of the status of defined subgroups of survivors. Several cross-sectional, case-control, and cohort studies using the MOS SF-36 have reported scores on the Mental Component Summary scale or one of its subscales in breast cancer survivors 2 to 8 years postdiagnosis to be comparable with, or better than, scores obtained from either the general population or individuals with other chronic illnesses80,98–102 (Table 106.3). Dorval et al.103 used the Psychiatric Symptom Index (PSI), another generic instrument that measures the presence and intensity of four psychologic dimensions (depression, anxiety, cognitive impairment, and irritability) in a case-control study; no difference was found between 8-year survivors and controls randomly matched for age and residence. Studies using the generic measure of mood, the Profile of Mood States (POMS), reported women with breast cancer who were 2 years postdiagnosis to have scores comparable to published norms80 or to a control group.104 Taken together, these observations using generic instruments provide little evidence of impaired long-term HRQOL or psychologic status in breast cancer survivors compared to the general population. A cancer-specific instrument, the QOL Cancer Survivors Tool (QOL-CS), yielded psychologic subscale scores that were worse than those for the social, spiritual well-being, and physical subscales 5.7 years postdiagnosis.105 The inclusion of specific questions related to fear of recurrence of the cancer, which are not explicitly evaluated in generic questionnaires, and the specific population studied (members of the National Coalition for Cancer Survivorship) may have contributed to this result. Mosconi et al.102 used the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30), a multidimensional cancer-specific questionnaire, to study Italian breast and colon cancer survivors. Overall HRQOL was reported to be

106

good, and scores for emotional functioning did not differ between the two groups of survivors.

Physical Functioning Earlier, we discussed specific physical symptoms in breast cancer survivors. The MOS SF-36 has been employed to measure general physical functioning. Physical functioning scores in survivors have been reported to be similar to,102 or better than, published norms for individuals with other chronic illnesses80,106 or the general population.106 However, some studies98,99,101 reported physical functioning scores in survivors that were lower than norms for the general population. A modest decline in physical functioning over time (mean, 6.3 years) has been reported by Ganz et al.99; the magnitude of the decline was small and was thought to be related to aging. Dow et al.105 studied members of the National Coalition for Cancer Survivorship, a group that may not be representative of all cancer survivors. Overall physical well-being scores were good compared with other domains (e.g. psychologic); however, problems with components of physical wellbeing (i.e., pain, energy) were identified. Thus, evaluation of general physical functioning in breast cancer survivors has yielded inconsistent results in comparison with published norms for the general population. However, differences from general population norms are small and may be due to effects of age.

Sexual Functioning Breast cancer diagnosis and treatment can adversely affect sexuality. Surgical treatment of the primary tumor can affect body image, while systemic therapy can cause premature menopause or vaginal dryness. Measurement of the impact of breast cancer and its treatment on sexual functioning is challenging because few instruments specifically address this aspect of HRQOL. These measurement challenges may be compounded by a reporting bias if survivors are reluctant to respond to questions about sexual functioning. The use of specific questionnaires (e.g., the Sexual Activity Questionnaire, SAQ) in recent studies permits a more detailed assessment than is possible using more general multidimensional questionnaires. Matthews et al.98 administered the Satisfaction with Life Domains Scale for Cancer (SLDS-C) to breast cancer survivors (American Cancer Society Reach to Recovery volunteers) a mean of 8.6 years postdiagnosis. Scores for sexual functioning were worse than for other aspects of functioning. Dow et al.105 also reported that satisfaction with sex life was the worst of all domains on the Functional Assessment of Cancer Therapy—General (FACT-G) in 294 survivors taking part in a peer-support group 5.7 years postdiagnosis. In contrast, Kurtz et al.107 reported 5- to 10-year breast cancer survivors had high levels of sexual satisfaction on the Long Term Quality of Life Instrument. Ganz et al.99,106 used questionnaires that specifically address sexual functioning in two recent studies. In a crosssectional study of 864 women,106 use of the Watts Sexual Functioning Questionnaire identified modest increases in sexual dysfunction with aging but use of the Cancer

1847

To assess the effect of age, time since diagnosis and disease severity

To measure anxiety and depression

To explore six aspects of QOL

To describe psychosocial concerns and QOL among survivors

To describe QOL in survivors including positive and negative outcomes

To compare emotional status of survivors to screening population

To compare mood and QOL of survivors to screening population To examine social support, type of surgery, geographic location, and QOL To describe survivorship in relation to age, menopausal status, treatment

Vinokur et al. 1989120

Ellman et al. 1995145

Kurtz et al. 1995107

Ganz et al. 199680

Dow et al. 1996105

Saleeba et al. 1996146

Weitzner et al. 1997147

Ganz et al. 1998106

Lee 1997148

Primary objective(s)

Reference

Case-control, clinic samples >5 years Convenience sample (Reach for Recovery volunteers) 14.1 years Cross-sectional (random selection from two large metropolitan areas; tumor registry, clinics, hospitals) 3.1 years

Convenience sample (mailed questionnaire to national coalition for cancer survivorship-peer support) 5.7 years Case-control (MDACC, screening clinic) >5 years

Participants in rehabilitation RCT 2–3 years

Hospital based tumor registry >5 years

Case-control (screening clinic registry) 13 years

Case-control (population-based screening program) 53% > 5 years

Study population and follow-up (years)

864

100

Survivors = 60 Controls = 93

Survivors = 52 Control = 88

294 BCS (56 had recurrence)

139 (12 had recurrence)

191

331 survivors 584 controls

178 survivors 176 controls

No. of subjects

HSC PM SE ICO PQOL PREF SC Others

FLIC CARES SF-36 POMS

• • • • • •

• • • •

SF-36 CES-D DAS CARES WSFQ Others

BDI STAI FPQLI FPQLI

• BDI • STAI

• QOL-CS • FACT-G

• • • •

• LTQL • CARES

• HADS

• • • • • • • •

Instrument(s)

39%

88%

Not stated

Not stated

56%

77%

55%

76% (survivors) 75% (controls)

91%

Response rate

TABLE 106.3. Psychosocial status and health-related quality of life (HRQOL) overall associations in breast cancer survivors.

(continued)

Survivors had more frequent physical symptoms. Worse sexual functioning in survivors with chemo, menopause. and age 5.5 years

Convenience sample (outpatient)

Survivors cohort assembled from seven hospitals, random digit dialing agematched control, random digit dialing age-matched control 8.8 years Survivors cohort assembled from seven hospitals 3 months–8 years Inception cohort (from a RCT on chemo) 9.6 years Members of the three support groups 1–5 years (54%)

Cross-sectional (mailed survey, tumor registry, clinics, hospitals) 2.7–3.1 years

Primary objective(s)

Reference

Study population and follow-up (years)

BCS = 164 Control = 164

586

87

56

119

366

124 survivors (26 had new events) 427 controls

1,098

No. of subjects

PSI LWMAT MOS SSS Others

SF36 CES-D CARES LLS Others

• • • • •

WAS SWBS FACI SF-36 PANAS

• SF-36 • SLDS-C

• EORTC QLQ-C30 • FACT-B

• EORTC QLQ-C30 • Others • HADS

• SLES • LWMA • Others

• • • •

• • • • •

Instrument(s)

61%

63%

Not stated

100%

68%

89%–95%

96% (survivors) 61% (controls)

35%

Response rate

Overall HRQOL similar in survivors and controls; no-intervention survivors had worse physical functioning. Poor QOL associated with beliefs of lasting harmful effect of treatment, low level of personal control, lack of sense of purpose in life.

Survivors reported higher emotional well-being, social functioning, and vitality but lower physical functioning compared to population-based norms. Worse sexual satisfaction, body image, physical strength for survivors. Younger women had better physical functioning but lower emotional well-being and vitality.

Worse emotional, cognitive, sexual functioning, global QOL >5 years vs. 2–5 years posttreatment. Better global QOL, social, emotional functioning >5 years vs. 1–2 years post Rx. Highest QOL in the period between 2–5 year post Rx.

No difference in functioning scales, body image, sex life, breast symptoms, social or professional life; trend for poorer cognitive functioning in CMF. 29% and 14% scored above “case” cutpoint for anxiety and depression at baseline; significant improvement at 1 year.

Marital breakdown similar in survivors and controls. Marital satisfaction: predictor of marital breakdown in both groups.

No difference in QOL. Arm problems and sexual satisfaction worse in survivors.

No difference in mental-psychologic (SF-36, CES-D) and global QOL according to treatment. Physical and sexual: worse functioning in adjuvant therapy. Small adverse impact of adjuvant treatment on physical functioning but no impact on overall QOL.

Results and conclusions

TABLE 106.3. Psychosocial status and health-related quality of life (HRQOL) overall associations in breast cancer survivors. (continued)

1849

To assess long-term HRQOL of survivors

To assess age, duration of survival, and QOL

To evaluate long-term survivorship

To evaluate QOL and reproductive health in younger survivors

To examine HRQOL in older survivors

Mosconi et al. 2002102

Cimprich et al. 2002121

Ganz et al. 200299

Ganz et al. 2003122

Ganz et al. 2003123

Cohort (identified through pathology reports, tumor registries) 3–5, 6–8, and 15–17 months

Cohort (two hospitals tumor registries) 5.9 years

Tumor registry of Midwestern comprehensive cancer center 11.5 years 5- to 10-year F/U of earlier cohort (population-based tumor registries, clinics, and hospitals) 6.3 years.

Convenience sample (ACS Reach for Recovery program) Mean 3.5 years (10 years) Survivors in a RCT of F/U testing (colon cancer survivors also studied) 8.3 years

691

577

817 (*54 had recurrence and were excluded)

105

433

148 (23 had metastasis)

• • • • •

• • • • • •

• • • • • • • • •

PF10 MHI-5 CARES-SF-36 MOS-SSS Others

SF-36 LLS CES-D PANAS SAQ Others

SF-36 LLS CES-D$ PANAS RDAS SAQ CARES MOS-SSS Others

• QOL-CS

• PANAS • QOLM (Selby and Boyd) • Others • SF-36 • EORTC QLQ-C30

43%

56%

61%

54%

52%

71%

Physical and mental health score decreased significantly at 15 months (SF-36). Improvement at 15 months in CARES.

High level of physical functioning. Youngest: Decrement in vitality, lowest score in social and emotional functioning, more depressive symptomatology, lower positive affect, and more negative affect. Amenorrhea frequent in women age ≥40 and associated with poorer health perception.

Excellent physical and emotional well-being (minimal declines reflected expected age-related changes). No change in sexual interest but sexual activities declined. Stable energy level and social functioning. Some symptoms improved; others worsened. Survivors not receiving chemo had better overall QOL, physical functioning, less sexual discomfort.

Lower QOL on physical domain in older survivors. Lower QOL on social domain in younger survivors. Best QOL (overall and physical) in middle-aged survivors.

Long-term survivors have HRQOL comparable to age/sex-matched norms. HRQOL lower with comorbidities or chemo. Physical functioning lower in breast vs. colon survivors.

QOL improved with increasing time from diagnosis and less extensive disease. More positive and less negative affect associated with better QOL.

QOL, quality of life; BC, breast cancer; F/U, follow-up; Rx, treatment; ACS, American Cancer Society; HSC, Hopkins Symptom Checklist*; PM, positive morale, based from Bradburn’s positive affect scale; SE, self-esteem: based on Rosenberg’s scale of self esteem; ICO, internal control orientation, based on Rotter’s scale; PQOL, perceived QOL, based on scale developed by Andrews and Withey; PREF, perceived role and emotional functioning; SC, social contacts, from Berkman’s Social Network Index; HADS, Hospital Anxiety and Depression Scale*; LTQL, long-term quality of life*; CARES, Cancer Rehabilitation Evaluation System*; FLIC, Functional Living Index–Cancer*; SF-36, RAND or MOS Short-Form-36*; POMS, Profile of Mood States*; QOL-CS, Quality of Life–Cancer Survivors*; FACT, Functional Assessment of Cancer Therapy*; BDI, Beck Depression Inventory*; STAI, State-Trait Anxiety Inventory*; FPQLI, Ferrans and Powers Quality of Life Index*; CES-D, Center of Epidemiologic Studies–Depression Scale*; DAS, Dyadic Adjustment Scale*; WSFQ, Watts Sexual Function Questionnaire*; PSI, Psychiatric Symptom Index*; LWMAT, Locke–Wallace Marital Adjustment Test*; MOS SSS, MOS Social Support Survey*; SLES, Stressful Life Event Scale*; EORTC-QLQ C-30, European Organization for Research and Treatment of Cancer–Quality of Life Questionnaire C-30*; SLDS-C, Satisfaction with Life Domains Scales for Cancer; WAS, Words Assumption Scale; SWBS, Spiritual Well-Being Scale of FACI (Functional Assessment of Chronic Illness therapy); PANAS, Positive and Negative Affect Schedule*; QOLM, WOL Measurement, Selby and Boyd*; RDAS, Revised Dyadic Adjustment Scale*; SAQ, Sexual Activity Questionnaire*; LLS, Ladder of Life scale*; PF-10, 10-item functioning scale from SF-36; MHI-5, Mental Health Inventory, from the SF-36.

*, Valid and reliable instruments.

Response rate: as stated in the paper or if not, the percentage of eligible patients who completed the study.

To assess HRQOL

Kessler et al. 2002137

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chapter

Rehabilitation Evaluation System (CARES) identified no impairment in sexual satisfaction. Sexual functioning was significantly worse in those who received chemotherapy (but not tamoxifen), particularly in women who were menopausal (either naturally or secondary to treatment) and in women under 50 years of age. Using the SAQ in their cohort study of 763 long-term breast cancer survivors, this group also reported sexual discomfort to be greatest in women who received chemotherapy but identified no differences in sexual pleasure or sexual habits.99 In summary, sexual functioning appears to be adversely impacted in breast cancer survivors, particularly in younger women who receive adjuvant chemotherapy.

Social Functioning and Marital Status Studies evaluating social functioning in breast cancer survivors have usually shown little evidence of impairment. The social functioning subscale of the MOS SF-36 has yielded similar scores in breast cancer survivors and in the general population in the majority of studies.80,98–102 Use of the EORTC QLQ-C30 has also demonstrated high level of social functioning in breast cancer survivors.102 Use of the MOS Social Support Measure also showed no difference between breast cancer patients with a control population99,103 and no change according to time elapsed since diagnosis.99 In a cohort of 763 survivors, there was no significant change in marital status over 5 years of follow-up.99 In another cohort followed for 8 years, no difference in divorce or separation rates at 12 months, 18 months, and 8 years after diagnosis was identified in survivors compared to age-/residence-matched women.108 In survivors, low marital satisfaction at 3 months predicted future marital difficulties (16.7% divorced at 1 year versus 2.1% in those with high marital satisfaction; P = 0.02). Women not in a partnered relationship expressed concerns about dating, telling about cancer, and fear of initiating sexual relationship.80,106 Finally, in their follow-up of 817 long-term breast cancer survivors, Ganz et al. reported more than two-thirds had stable household income and 20% had increased income (versus 12% who had decreased income) since diagnosis.99 Eighty percent reported no change in employment status; a minority moved from full- to part-time work or retired. Marital status did not change. In a separate study, this group reported that 90% of survivors had health insurance 2 or 3 years postdiagnosis, although some had their premiums increased or had switched to a spouse’s plan.80 Most (65%) were working or doing volunteer work. Thus, there is little evidence that social or marital functioning or employment is adversely affected in survivors. Specific concerns about dating have been reported, especially in young, unpartnered women.

106

Sensitivity Cognitive Screen,104 a valid reliable instrument that predicts overall qualitative results of formal neuropsychologic testing. All four studies identified significantly lower cognitive functioning in women receiving adjuvant chemotherapy (with or without anthracyclines) compared with those not receiving chemotherapy or to a control group without breast cancer. Cognitive dysfunction was more prevalent in women who received high-dose chemotherapy in one study.111 Interestingly, there appears to be little correlation between cognitive functioning as assessed by the test battery and self-reported by the patient.110,111 Studies evaluating cognitive dysfunction beyond 2 years have yielded conflicting results. Schagen et al.112 reported improvement in performance in all chemotherapy groups between 2 and 4 years posttreatment. Ahles et al.113 reported patients who had been diagnosed at least 5 years earlier had greater cognitive impairment on a battery of neuropsychologic tests and were more likely to report memory problems on the Squire Memory Self-Rating Questionnaire if they had received adjuvant chemotherapy. Cognitive dysfunction in women receiving adjuvant chemotherapy is an emerging area of interest in survivorship research. Future research should identify risk factors for this complication and evaluate potential interventions to minimize its impact.

Spirituality Spirituality is often poorly addressed in multidimensional questionnaires. Based on the holistic Ferrell114 model of QOL in breast cancer survivors (physical, psychologic, social, spiritual), Wyatt et al. developed the Long-Term Quality of Life (LTQL) instrument, which includes a philosophical/spiritual view dimension.115 Kurtz et al.,107 using this instrument in long-term (more than 5 years) survivors, reported a positive spiritual outlook to be associated with good health habits and an increased likelihood of being supportive of others. In their cohort of long-term survivors (6.3 years), Ganz et al.99 reported a positive impact of breast cancer on religious beliefs and activities, an effect that tended to be more pronounced in young survivors. Dow et al.105 used the QOL-CS to evaluate spiritual well-being in members of the National Coalition for Cancer Survivorship. Although fears about future cancer and uncertainty about the future were identified as important concerns, beneficial spiritual outcomes including hopefulness and having a purpose in life as well as positive and spiritual change were also reported. Further research is needed to confirm these early observations, using population-based controls as a comparison group.

Diet and Complementary and Alternative Medicine

Cognitive Functioning 109

In 1995, Wieneke and Dienst published the first report of cognitive dysfunction in women with breast cancer (Table 106.4). To date, four reports have evaluated cognitive functioning during and within the first 2 years postchemotherapy using a battery of neuropsychologic tests109–111 or the High

Maunsell et al.116 evaluated diet during the first year after breast cancer diagnosis in a group of 250 women who were surveyed with a standardized interview about diet changes. Forty-one percent of women reported a change in their diet; these changes were positive (i.e., healthy) in over 90%. Women under 50 years and those who were more distressed

To evaluate cognitive functioning after adjuvant chemo

To assess the prevalence of cognitive deficit after adjuvant chemo

To assess neuropsychologic functioning following CMF vs. no chemo

To assess cognitive function in chemo vs. control patients

To assess long-term neuropsychologic sequelae following chemo

To compare neuropsychologic functioning of longterm survivors

Wieneke et al. 1995109

van Dam et al. 1998111

Schagen et al. 1999110

Brezden et al. 2000104

Schagen et al. 2002112

Ahles et al. 2002113

Tumor registry 9.7 years for BC

Follow-up of earlier cohort120,121 4 years

Convenience sample (two academic hospitals) 2.1 years for the group post chemo

Consecutive series 2 years

RCT of high-dose vs. standard dose chemo Control group were BCS who did not received chemo 2 years

Convenience sample (clinic) 6.6 months post chemo

Study population and follow-up (years)

BC = 70 Lymphoma = 58

103

Chemo: 31 Postchemo: 40 Controls: 36

39 chemo 34 control

34 high dose 36 standard dose 34 no chemo

28

No. of subjects

• Neuropsychologic tests • SMSRQ • CES-D • STAI • FSI

• Neuropsychologic tests • EORTC QLQ-C30 • HSCL

• HSCS • POMS

• Neuropsychologic test • Semistructured interview • EORTC QLQ-C30 • HSCL-25

• Neuropsychologic tests • Semistructured interview for selfreported cognitive functioning • EORTC QLQ-C30 • HSCL-25

• Neuropsychologic tests

Instruments

75%

84%–96%

Not stated

78% (chemo) 68% (control)

84%–85% (chemo treated) 68% (controls)

84%

Response rate

Neuropsychologic test and SMSRQ: chemo group score lower than local therapy group (adjusted for age and education). No other differences.

Improvement in performance in all chemo group (FEC, high-dose, CMF) and a slight deterioration in controls. Cognitive dysfunction following adjuvant chemo may be transient.

More patients with cognitive impairment during or after chemo vs. controls. No difference in mood status in the three groups.

Higher IQ at baseline in CMF group. Neuropsychologic tests: 28% of patients in chemo cognitively impaired vs. 12% in control. Self-reported problems: in chemo group, more problems with concentration and memory. No relation between reported complaints and neuropsychologic testing. Chemo: lower QOL (physical, cognitive), greater depression.

Lower global QOL and higher score on depression subscale with high dose. Cognitive impairment: 32% high dose, 17% standard dose, 9% no chemo (P = 0.043).

Cognitive deficit related to tests norms (adjusted for age, education, gender) in 5 of 7 domains assessed. 75% had moderate impairment on at least 1 test. Level of impairment unrelated to depression, type of chemo, time since treatment; positively related to the length of chemo.

Results and conclusions

CMF, cyclophosphamide, methotrexate, 5-fluouracil; Chemo, chemotherapy; RCT, randomized controlled trial; FEC, 5-fluouracil, epirubicin, cyclophosphamide; BC, breast cancer; neuropsychologic tests, a battery of tests were used; Cf., see reference for more details; EORTC-QLQC-30, European Organization for Research and Treatment of Cancer–Quality of Life Questionnaire C-30*; HSCL, Hopkins Symptom Checklist-25; HSCS, High Sensitivity Cognitive Screen*; POMS, Profile of Mood States*; SMSRQ, Squire Memory Self-Rating Questionnaire; CES-D, Center for Epidemiological Study-Depression*; STAI, State-Trait Anxiety Inventory*; FSI, Fatigue Symptom Inventory*.

*, Valid and reliable instruments.

Response rate: as stated in the paper or if not, the percentage of eligible patients who completed the study.

Primary objective(s)

Reference

TABLE 106.4. QOL and cognitive dysfunction in breast cancer survivors.

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chapter

at diagnosis were most likely to change their diets (P = 0.0001). Burstein et al.117 evaluated complementary and alternative medicine (CAM) use during the first 12 months after breast cancer diagnosis (see Chapter 15). Twenty-eight percent of 480 women began an alternative therapy after diagnosis; these women tended to be younger and more educated. Ganz et al.99 reported vitamins and herbal preparations were used by 86.6% and 49.3% of breast cancer survivors, respectively. More than half (60.7%) altered diet or used dietary supplements. Few women were using psychosocial or counseling therapies (13%) or attending a cancer support group (5.5%). More than one-third reported enhanced physical activity postdiagnosis. Lee et al.118 conducted telephone interviews in 379 women (black, Chinese, Latino, white) 3 to 6 years after breast cancer diagnosis. At least one alternative therapy was used by 48.3%. Most common approaches therapies were dietary change (26.6%), herbal/homeopathic medication (13.5%), psychologic or spiritual healing (30.1%), and physical approaches such as yoga or acupuncture (14.2%). Therapies were used for brief periods, usually for 3 to 6 months. Women who used alternative therapies were younger and more educated. Thus, more than one-third of breast cancer survivors use at least one kind of alternative therapy. Nonpharmacologic supplements appear to be most commonly used. Further research is needed to evaluate duration of use and changes over time in use of CAMS, comparing survivors to healthy controls.

106

In the first of these, a cohort of 577 patients diagnosed at age 50 or younger was assembled for the Cancer and Menopause Study a mean of 5.9 years postdiagnosis.122 Most had received adjuvant chemotherapy. Physical functioning was good. The youngest women reported poor mental health, less vitality, and poorer social and emotional functioning (MOS SF36). In the second study, 691 women aged 65 years of age or more at diagnosis were evaluated 3, 6, and 15 months after surgery.123 Physical and mental functioning (MOS SF-36) showed significant declines during the year of follow-up. Declines in the former were associated with greater comorbidity and receipt of adjuvant chemotherapy. In contrast, the CARES Psychosocial Summary and Medical Interaction Scales showed significant improvement over time. Social support was lowest in women over 75 years. The discrepant results obtained with the MOS SF-36 Mental Health Inventory and the CARES Psychosocial Summary Scale were explored: the former appeared to be influenced to a greater extent by declines in physical functioning and the latter appeared to reflect adaptation and adjustment to cancer-specific concerns. In summary, younger age is associated with lower mental and emotional wellbeing. Older women experience more physical problems, partly the result of aging.

Ethnicity

Consideration of breast cancer survivors as a group may mask important differences in subgroups and over time. In this section we summarize research examining subgroups defined by age, ethnicity, and treatment (surgery, adjuvant therapy) and according to time elapsed since diagnosis.

The impact of ethnicity on survivorship has been poorly studied. Ashing-Giwa et al.124 investigated HRQOL in white and African-American survivors. Response rate among African-Americans was significantly lower than among whites (44% versus 65%). The former were more often single, had a lower income, and lower HRQOL. Multivariate analyses revealed that 45% of the variance in HRQOL was accounted for by general health perception, life stress, partnership status, and income; ethnicity was not a significant contributor. The authors concluded that African-American and white report favorable overall QOL; differences are secondary to life burden and socioeconomic factors but not to ethnicity per se.

Age at Diagnosis

Primary Surgical Procedure

Age at diagnosis appears to be an important determinant of survivorship. This may be due, in part, to treatment: women who receive chemotherapy, many of whom are younger, experience greater long-term physical and sexual sequelae (see following discussion); psychosocial effects of mastectomy may also differ with age, especially in the short term.119 However, Ganz et al.106 reported poorer sexual functioning in younger survivors who became menopausal, regardless of whether they received chemotherapy. Vinokur et al.120 compared survivors (50% of whom were followed more than 5 years) to controls participating in a breast cancer screening program; younger survivors had more problems in psychosocial adjustment while older survivors had more physical difficulties. Cimprich et al.121 reported similar findings in 105 survivors using the QOL-CS. Women over 65 at diagnosis had worse scores in the physical domain while those diagnosed before 44 years of age had poorer scores in the social domain. Women diagnosed between 45 and 65 years of age had the best overall HRQOL. Two pivotal studies examining survivorship issues in younger122 and older women123 have been reported recently.

The primary surgical procedure performed also appears to impact survivorship (Table 106.5). Maunsell et al.119 reported that psychologic distress (measured using the PSI) at 3 months was worse in women undergoing BCS; this difference was not present at 18 months. Age modified this effect; the greater psychologic distress at 3 months was not present in women under 40 years. Follow-up 8 years after diagnosis found that psychologic distress declined over time and was similar to that in the general population.125 Ganz et al.,126 using a battery of general questionnaires, reported few differences in HRQOL with respect to type of surgery; however, women undergoing mastectomy had more problems with clothing and body image than those undergoing BCS. Mosconi et al.102 found none of the EORTC QLQ C-30 domains to be affected by the type of surgery. Janni et al.127 studied 76 pairs of patients who had undergone either a mastectomy or BCS a mean of 3.8 years earlier; women undergoing mastectomy were significantly less satisfied with their cosmetic result and change in appearance and were twice as likely to be stressed by their physical appearance secondary to the surgery. No

Psychosocial Status and HRQOL in Defined Subgroups

To compare longterm psychosocial and sexual adaptation after MRM vs. BCS To describe psychologic distress after MRM vs. BCS To evaluate QOL and psychologic adjustment after MRM vs. BCS

Meyer et al. 1989131

To compare QOL after BCS, MRM, MRM ± R

Nissen et al. 2001134

198

152 pairmatched patients

1,957

278

235 at 3 months 211 at 18 months 124 at 8 years

66

257

109

227 at 3 months and 205 at 18 months

58

38

No. of subjects

PSI LES (modified) DSI Others FLIC CARES Karnofsky (PS) POMS GAIS BIS TSCS BIVAS

SF-36 MOS SSS CES-D RDAS WSFQ CARES

PSI MOS-SSS LES LWMAT Newly constructed questionnaire

• MUIS • POMS • FACT-B

• EORTC QLQ C-30 • Other

• • • • • •

• • • • •

• Interview • Others

• • • • • • • • • • • •

• Interview

• Others

Instruments

94%

Not stated

14%–64% (between different countries) 54%

97% 3 months 97% 18 months 96% 8 years

80% (of the first study)

57%

44%

97%

68%

97%

Response rate

At 8 years no difference in QOL. BCS protected women against distress if they were 4 years Pain group: 33% had constant pain, 43% numbness, 23% shoulder pain Pain interfered with daily lives (44%) Five used medication, 3 had undergone nerve block NS differences in demographic or disease/ treatment variables in groups with or without pain Patients with no pain reported functional limitations, numbness Dyspnea peaked at 3-months (34%), but continued for 10% at 6 and 9 months Patients with cancer had 2¥ decrease in QOL at 1, 3 months postop ADL returned to baseline at 6, 9 months QOL scores similar for all groups preop, patients with cancer had significantly greater deterioration postop Extent of resection and cancer dx associated with deterioration in QOL in SIP Older age associated with poorer scores on QL-Index

Lobectomy: 20% reduction in exercise capacity Pneumonectomy: 28% reduction in exercise capacity due to dyspnea Leg discomfort contributed to decreased exercise capacity postop; none were limited by thoracic pain Decrease in PF is a poor predictor of exercise capacity

Good QOL among 5-year survivors: most capable of full-time work Initial preop QOL highest for long-term survivors Noncurative resection associated with lower QOL Specific information about symptoms not provided

chapter

Histology: ND Stage: ND Surgery: 73% Lobectomy, 20% Pneumonectomy Follow-up: up to 9 months

Histology: ND Stage: ND Surgery: 43% pneumonectomy, 57% lobectomy Follow-up: approximately 3 months (mean 73 days postlobectomy, 62 days postpneumonectomy, range 29–200 days) Histology: ND Stage: ND Surgery: lateral thoracotomy by 1 surgeon; 13% received postoperative radiation Rx Follow-up: median 19.5 months (range 2 months–5 years), disease free at time of interview

Histology: bronchial carcinoma (1967 WHO classification) Stage: mixed Surgery: 27% pneumonectomy, 62% lobectomy, 13% nonresectional thoracotomies Follow up: 3–8 years Disease-free status not clear

Disease characteristics/treatment/ follow-up period

TABLE 108.1. Studies documenting symptoms, functional status, and quality of life of lung cancer survivors since 1980 (in chronologic order).

1872 108

N = 64, >2 years in remission Age: 61 (median) Sex: 51% male Ethnicity: Scottish Education: 19% > HS Health status: ND

N = 142 VATS, N = 97 thoracotomy (1 year postoperative) Age: 60 (VATS), 59 (thoracotomy) Sex: 56% men (VATS), 42% men (thoracotomy) Health status: ND N = 100, N = 31 with QOL data (48%) response ND for QOL subset

Cull et al.48

Landreneau et al.39

Hendriks et al.23

N = 57 Mean age: 62 Sex: 56% male Ethnicity: 93% white Education: 68% ≥ HS Marital status: 61% married Health status: 41% hypertension, 32% heart disease, 11% diabetes, 7% skin cancer, 11% alcohol use

Schag et al.9

ND for subset

Histology: malignant group: 66% of thoracotomy patients, 42% VATS Stage: ND Surgery: VATS, thoracotomy Follow-up: 1 year postop

Histology: SCLC Stage: 95% limited-stage disease Treatment: 80% PCI (50% with concurrent chemo) Follow-up: 2 to >8 years

Histology: ND Stage: disease-free Surgery: 84% had surgery (details not described) Follow up: Mean 3.4 years since diagnosis, n = 33 short-term (>2–5 years), n = 24 long-term (>5 years) survivors

Purpose: describe QOL 2.5 months postthoracotomy Methods: mailed questionnaire Instruments: EORTC QLQ = 30 Comparison: none

Purpose: compare prevalence and severity of chronic pain post-VATS vs. lateral thoracotomy Method: cross-sectional Instruments: Visual analogue scale to assess presence and intensity of discomfort, and shoulder limitations on the side of the operation Use of medication: Comparison: None

Purpose: describe QOL and prevalence of neuropsychologic disturbances in longterm survivors Method: Instruments: clinical and neurologic examination, CT scan, neuropsychologic testing, QOL (RSC, HADS)

Purpose: describe and compare QOL among lung, colon, and prostate cancer survivors Method: cross-sectional, self-report Instruments: Cancer Rehabilitation Evaluation System (CARES), QOL–LASA Comparison: survivors of colon (n = 117) and prostate cancer (n = 104)

Good/excellent global QOL (56%) Poor/very poor QOL (26%) Higher percent of patients with pneumonectomy had lower scores Dyspnea (29%), pain (29%) no clear relationship of sx to extent of resection (continued)

Lung cancer survivors had more problems than other cancer survivors Disruptions in physical function and pain were frequent and severe problems (46% chronic pain from scars) Short-term survivors noted depression (51%) and anxiety (63%), and distress with body changes (35%), 28% report feeling overwhelmed by cancer 17%–45% report difficulties with partners (e.g., communication, expressions of affection), 79% decreased sexual contact and problems, 7%–27% difficulty in dating, 63% difficulty with memory, 25%–32% with difficulty with thinking clearly Of the 1/4 working at the time of diagnosis, 96% of short-term survivors quit work due to disease and treatment Abnormal neuro exams (24% of n = 37), 16% with ataxia, 11% cognitive deficits; no association with abnormalities found on neuropsych testing: 81% (of 59) impaired on ≥1 exam, 54% ≥ 2 Most common QOL disruptions: fatigue (64%), lack of energy (59%), difficulty sleeping (54%), problems with concentration (54%); >1/3 had dryness of mouth, tingling hands/feet, pain/ burning in eyes; psychologic distress similar to normative data for cancer survivors HADS (borderline/case level): 19% anxiety, 15% depression 1 year postop

p h y s i c a l a n d p s yc h o s o c i a l i s s u e s i n l u n g c a n c e r s u rv i vo r s

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34

N = 68 Age: 61 Sex: 84% males Ethnicity: Swiss Health status: Preoperative FEV1 = 2.38 (lobectomy), 2.50 (pneumonectomy)

N = 57 with pre and post assessments Age: 59 (pneumonectomy); 67 (lobectomy) Sex: 72% male Ethnicity: Danish Health status: ND

N = 123 with lung cancer Age: 64 Sex: 54% male Ethnicity: 97% white Health status: 94% with at least 1 comorbid condition, 49% with >3

Larsen et al.28

Mangione et al.42

N = 52 (12 months postoperative), n = 20 (preand postoperative data) Age: 61 years Sex: 73% male Ethnicity: German Marital status: 12% partnered Health status: ND

Bolliger et al.30

Zieren et al.

Author

Samplea characteristics: mean ageb, sex, ethnicityc, education, marital status, health status

Histology: NSCLC Stage: ND Surgery: thoracotomy Follow-up: 6 and 12 months postsurgery

Purpose: examine QOL changes over time and compare QOL of patients undergoing elective surgery Method: prospective, pre- and postsurgery Instruments: SF-36, Specific Activity Scale, health transition questions and rating of general health Comparison: n = 236, with total hip arthroplasty, n = 95, repair of abdominal aortic aneurysm

Purpose: describe postop changes in cardiopulmonary function Methods Instruments: exercise testing, pulmonary function, arterial blood gas

Purpose: compare effect of lobectomy and pneumonectomy on PFT, exercise capacity, and perception of symptoms Method: prospective, pre, 3, 6 months postsurgery Instruments: PFT Comparison group: none

Purpose: describe QOL post surgery Method: mix of cross-sectional and prospective Instruments: EORTC QOL, Psychologistrated Spitzer QOL Index Comparison: none

Purpose/method Comparison group

Dyspnea at exertion and pain continued at 12 months Physical dysfunction returned to preoperative level at 12 months postsurgery Emotional, social, and financial dysfunction was less severe, but continued postop Pneumonectomy was associated with more symptom distress and limitations in physical function, but not with greater emotional, social, or financial dysfunction NS differences based upon adjuvant treatment. QOL rated as higher by the external rater as compared to the patient. 12% employed full time Recurrence negatively impacted postop QOL Lobectomy: no change in exercise capacity; PFT significant decreased at 3 months and significant increased at 6 months (10% permanent loss) Exercise capacity limited by leg muscle fatigue and deconditioning Pneumonectomy: 20% reduction in exercise capacity; PFT significant lower at 3 months and did not recover at 6 months (30% permanent loss); significantly lower than lobectomy, exercise capacity limited by Dyspnea Lobectomy: minimal change in lung function or exercise capacity Pneumonectomy: decrease in PF, but compensation due to better oxygen uptake; decrease in exercise values less than expected Change in FEV1 was a poor predictor of change in exercise capacity Variable changes in PF and exercise capacity with some patient improving postop, some worsening, and some with little change Significant declines in health perceptions, physical function, role-physical, bodily pain, vitality, social function at 6 and 12 months after surgery Improvement in mental health and role-mental function over time By 12 months, physical function, bodily pain, health perceptions were lower than preop levels, but similar to population-based norms Compared to other groups, lung cancer patients continued to have the lowest health perceptions, lower role-physical and social function ratings

Findings related to survivorship

chapter

Histology: NSCLC Stage: ND Surgery: 28% pneumonectomy, 72% lobectomy

Histology: ND Stage: ND Surgery: 74% lobectomy, 26% pneumonectomy Follow-up: 3 and 6 months postop

Histology: NSCLC Stage: ND Treatment Surgery: 81% Lobectomy, 10% pneumonectomy Adjuvant treatment: 25% radiation therapy Follow-up period: 1 year, 19% with recurrence

Disease characteristics/treatment/ follow-up period

TABLE 108.1. Studies documenting symptoms, functional status, and quality of life of lung cancer survivors since 1980 (in chronologic order). (continued)

1874 108

Uchitomi et al.14

Sugiura et al.41

Miyazawa et al.27

Nugent et al.36

Nezu et al.26

N = 223 with successful surgical resection Age: 63 years Ethnicity: Japanese Marital status: 82% married Education: 21% ≥ HS Health status: 23% < 70% predicted FEV1 6% history of depression Tobacco use: 41% current smokers, 24% former smokers

N = 82 (including n = 10 undergoing lobectomy with hemodynamic data) Lobectomy: Age: 64 Sex: 84% male Ethnicity: Japanese Pneumonectomy: Age: 62 Sex: 90% male Ethnicity: Japanese Health status: FEV1% predicted: 86 (lobectomy) n = 6 hypertension, n = 2 chronic bronchitis N = 106, n = 53 with follow-up data Age: 61–64 (by surgical procedure) Ethnicity: Irish sample Health status: Preoperative FEV1 % predicted ranged from 71% to 82% N=8 Age: 67 Health status: FEV1% predicted = 67.2, VC = 3.47 Tobacco use: all had quit smoking after surgery (never smokers were excluded); smoking “piece-years” range 600–1,600 N = 22 VATS, N = 22 thoracotomy Age: 62 (VATS), 61 (thoracotomy) Sex: 83% men (VATS), 38% thoracotomy Health status: ND Histology: 68% adenocarcinoma, 21% squamous carcinoma; Stage: 92% stage I or II Treatment: 96% lobectomy, 5% pneumonectomy Follow-up: 1 and 3 months postresection

Histology: NSCLC Stage: stage I Surgery: VATS, thoracotomy Follow-up: mean 21 months (VATS), 30 months (thoracotomy)

Histology: ND Stage: potentially resectable Surgery: lobectomy Follow-up: 4–6 months, 42–48 months

Histology: not reported Stage: ND Surgery: n = 13, pneumonectomy, n = 26, lobectomy/wedge resection, n = 13 thoracotomy (inoperable tumor) Follow-up: 3 and 6 months

Histology: ND Stage: “operable” Surgery: n = 20 pneumonectomy, n = 62 lobectomy Follow-up: 3, >6 months postop

Purpose: describe and compare QOL postVAT with thoracotomy Method: prospective; Instruments: self-report questionnaire regarding chest pain, arm/shoulder limitations, time to return to preop activity, satisfaction Comparison: none Purpose: to describe depression at 1, 3 months post curative resection Method: prospective; Instruments: Psychiatric interview at baseline using criteria from the DSMMD, Profile of Mood States

Purpose: to examine postop changes in cardiopulmonary function Method: prospective Instruments: PF, exercise testing, hemodynamic monitoring, Fletcher, Hugh–Jones’ dyspnea index Comparison: none

Purpose: describe and compare the effects of different types of lung resections and thoracotomy alone (inoperable tumor) on exercise capacity Method: prospective, pre-, postsurgery Instruments: PF, exercise testing, Borg dyspnea scale Comparison:

Purpose: assess effects of resection on exercise limitation Method: prospective, pre- and postop Instruments: exercise testing, spirometry, Borg scale (dyspnea) Comparison: none

(continued)

Major or minor depressions: at 1 month (9.0%), at 2 months (9.4%), at 3 months (5.8%) Education level related to depression in the perioperative phase Depression preop was related to subsequent depression Lack of confidence in confidants (social support), pain and diminished performance status significantly associated with depression at 3 months

NS differences in patient characteristics Significantly decreased in chronic pain, return to ADL, and improved satisfaction with VATS At 12 months, no patient who received the VATS reported postthoracotomy pain; 4 patients in thoracotomy group required narcotics at 12 months

None had any symptoms before surgery 63% had increased dyspnea scores at 4–6 months; at 42–48 months, all had decreased to preop levels except for 1 patient Symptoms not directly related to physiologic outcomes FEV1% predicted increased postop (77% at 4–6 months; at 72% 42–48 months); airway resistance at preop levels over time Long-term decrease in cardiopulmonary function

Thoracotomy alone did not significantly affect exercise capacity Pneumonectomy: exercise capacity reduced by 28% Lobectomy: exercise capacity unchanged No significant difference in Borg dyspnea rating pre and post any procedures

Improvement in exercise capacity 3–6 months postop for lobectomy but not pneumonectomy patients Mean loss of exercise capacity (VO2 max) after 6 months: 28% pneumonectomy, 13% lobectomy Changes in PF did not correlate with exercise capacity Dyspnea was a limiting factor in exercise testing for pneumonectomy (65% at 3 months, 60% after 6 months), leg discomfort continued as the limiting factor for the lobectomy group (58% at 3 months, 64% after 6 months)

p h y s i c a l a n d p s yc h o s o c i a l i s s u e s i n l u n g c a n c e r s u rv i vo r s

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N = 226 patients with curative disease Age: 62 years Sex: 61% male Ethnicity: Japanese Education: 66% > JHS Marital status: 82% married Health status: 22% < 70 & FEV1% predicted 31% with prior history of depression, 43% with moderate/severe dyspnea

N = 139, n = 103 with 6-month data Age: 62 years Sex: 59% male Health status: Respiratory function: mean predicted FEV1 76% Comorbid conditions: 30%, cardiac, 16% diabetes, 15% peripheral vascular disease Tobacco use: 40% smoking within 8 weeks of surgery

N = 51 Age: 63 years (VATS), 67 years (thoracotomy) Sex: 74% male Ethnicity: Chinese Marital status: 71% married

N = 142 (5-year minimum disease-free survivors of NSCLC) Age: 71 years Sex: 46% male Ethnicity: 83% Caucasian Marital status: 47% married Education: 28% ≥ HS Health status: 50% FEV1 < 70% 60% had at least 1 comorbid condition, 50% reported 2 conditions (heart disease, 29% and cataracts, 35%, most

Uchitomi et al.60

Handy et al.29

Li et al.44

Sarna et al.10

Author

Samplea characteristics: mean ageb, sex, ethnicityc, education, marital status, health status Purpose/method Comparison group

Purpose: describe QOL Method: cross-sectional Instruments: QOL-Survivor, SF-36, CES-D, spirometry Comparison group: population-based norms

Purpose: compare QOL and symptoms between VATS and thoracotomy Design: cross-sectional Instruments: EORTC-C30 core questionnaire, EORTC QLQ-LC13 (Chinese versions) Investigator developed additional surgery-related questions

Purpose: compare functional status and QOL preop and 6-month post lung resection. Design: prospective Methods: prospective; Instruments: Short-Form 36, Ferrans and Powers Quality of Life Index Control: Age-matched healthy controls

Purpose: describe impact of physician support on psychologic responses post curative surgery Method: prospective; Instruments: Structured interviews 1 and 3 months after surgery using DSM-III-R, Profile of Mood States, Mental Adjustment to Cancer

Findings related to survivorship

Depression: 9% at 1 month, 6% at 3 months postop; 26% had hx of depression History of depression was related to psychologic distress postsurgery Dyspnea, FEV1, and PS related to psychologic distress at 3 months 24% used the physician and 4% used nurses for social support Physician support related to decreased psychologic distress, helplessness/ hopelessness, and increased fighting spirit, not related to depression Physician support was the sole factor in a multivariate regression related to increased fighting spirit for females and patients with no hx of depression Functional health status impaired Preop pain, impaired physical status, role function, social functioning, and mental health were present 6 months postsurgery Dyspnea significantly worse postop General health status, energy level unchanged Postthoracotomy/neuropathic pain was an issue for 8 subjects No age or gender differences Pre-operative DLCO (HS Health status: FEV1 % predicted, 59.8% Average of 1.75 comorbid conditions Tobacco use: 10% current smoking, 79% former smokers

N = 112, NSCLC Age 67 Sex: 57% male Ethnicity: Swedish Health status: Preoperative pulmonary function: 33% < 60% FEV1 Tobacco use: 70% former, 11% current smokers

N = 77 Age: ND Sex: ND Ethnicity: Belgian Health status: ND

Evangelista et al.13

Maliski et al.12

Myrdal et al.35

De Leyn et al.20

common); 9% with second primary lung cancer, 17% with history of other cancers Tobacco use: 76% former smokers, 13% current smokers

Histology: bronchogenic ca Stage: Surgery: sleeve-lobectomy Follow-up: early postop recovery, 45.6% at 5 years

Histology: ND Stage: 67% stage I, 17% stage II. Surgery: 22% pneumonectomy, 76% lobectomy Follow-up: mean 48 months, range, 4–48 months

Histology: 48% adenocarcinoma, 48% squamous cell, Stage: 72% stage I, 10% stage II Surgery: 79%, lobectomy/ wedge resection Follow-up period: mean 11 years

As described above

Purpose: to describe postop complications Instruments: medical record Comparison: none

Purpose: describe symptoms and QOL postsurgery Method: cross-sectional, mailed survey. Instruments SF-36, HADS, assessment of pulmonary symptoms Comparison group: N = 121 post-CABG

Purpose: describe the survivorship experience in long-term survivors Method: cross-sectional, qualitative interviews, self-report questionnaires, pulmonary function Instruments: Interview questions about survivorship experience CES-D Spirometry Comparison group: none

Purpose: describe health perceptions and risk behaviors of survivors Method: cross-sectional Instruments: Perceived health status item (from Short-Form 36), self-report and biochemical verification of tobacco use, self-reported alcohol use, spirometry, BMI Comparison group: none

(continued)

Bodily pain was the only SF-36 subscale similar to a normative cohort QOL scores comparable to patients who underwent CABG except for physical function, which was significantly lower Social and mental health scores similar to normative standards Dyspnea on exertion higher among those with lung cancer. 20% of patients had possible depression Compared to never and former smokers, smokers had lower mental health (SF-36) and higher ratings of depression and anxiety Exercise tolerance and QOL acceptable and better than that reported for pneumonectomy Five developed an anastomotic suture and required subsequent pneumonectomy

Most survivors had healthy lifestyles. Good/ excellent health (37%), fair/poor health (30%) NS difference based upon clinical or demographic characteristics. 67% of smokers quit after diagnosis; 16% never smokers Current smokers (13%) more likely to be male (32%) and single (60%), 28% exposed to secondhand smoke, 58% used alcohol (16% quit after diagnosis), 51% overweight (BMI ≥ 25); 16% obese (BMI ≥ 30) Current smoking, exposure to second-hand smoke, current drinking, and BMI ≥ 25 were significant predictors of poor health perceptions Themes related to physical and emotional well-being: (1) appreciation for life and a changed outlook, (2) taking control and appreciation of health, (3) overcoming and rationalizing changes in physical ability, (4) changed lifestyle, (5) giving and receiving support. 31% met CES-D criteria for potential depression and those in that group had more negative views of survivorship

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135

As described above10

Histology: 9 adenocarcinoma, 5 squamous, 2 large cell Stage: 11 (T1N)M0, 5, T2N0M0 Surgery: VATS (n = 5 LVR, n = 3 wedge resections, n = 2 segmentectomy), open thoracotomy (n = 6 lobectomy) Follow-up: 46 months

Histology: NSCLC Stage: surgery for surgical intent Surgery: variety of surgical procedures (n = 2 pneumonectomy, n = 36 lobectomy) Follow-up: 1+ year postsurgery Histology Stage: 65% stage I, 10% stage II Surgery: VATS, ALT, AAT, PLT Follow-up: pre-, 1, 2, 4, 12, 24 weeks postsurgery for PF; 1

Purpose: describe respiratory symptoms and PF of long-term survivors Method: cross-sectional Instruments: self-report of respiratory symptoms, spirometry, SF-36 Control: none

Purpose: describe QOL in lung cancer patients with emphysema who underwent resection plus lung volume reduction Method: prospective assessments: preop, 6 (n = 16), 12 (n = 15), 24 (n = 13), 36 months (n = 9) Instruments: SF-36, Medical Research Council Dyspnea Index, 6-minute walk test, self-report postthoracotomy pain Spirometry Control: n = 16 healthy adults

Purpose: compare differences in functional impairment by type of surgery Methods: retrospective Instruments: PFT, 6MW Comparison:

Purpose: to examine cost and quality of life after thoracic surgery Methods: retrospective, cross-sectional, mailed survey Instruments: SF-36, cost indicators, Qualys Comparison: none

Purpose/method Comparison group

Patients with end-stage emphysema and stage 1 lung cancer benefited from surgical resection Significant improvement QOL domains and dyspnea at 6 months, continuing through 36 months Some differences based upon type of resection No differences between lobectomy and VATS patients Pain peaked at 6 months and continued for a small subset throughout the assessment period 68% 5-year survival Analysis includes patients with recurrence and metastasis 2/3 of survivors reported respiratory symptoms: 39% dyspnea, 31% wheezing, 28% phlegm, 25% cough; 21% reported that they stayed most of the day in bed because of symptoms % predicted FEV1 68%; 21% % predicted 100,000/mL

Diagnosis/stage of disease Survival statistics

47% survival at 5 years with prednisone plus azathioprine, 61% with prednisone plus placebo (P = 0.03)

No statistically significant difference in transplantrelated mortality

Incidence of partial or complete response at 2, 6, and 12 months = 83%, 88% and 85% with thalidomide, 89%, 84%, and 73% without thalidomide

49% survival at 4 years with thalidomide, 47% without thalidomide (P = 0.87)

66% at 2 years with thalidomide, 54% without thalidomide (P = 0.85)

Incidence of 67% survival at 5 years nonrelapse with prednisone plus mortality at 5 cyclosporine, 72% with years = 17% with prednisone; hazard ratio prednisone plus = 1.35 (P = 0.13) cyclosporine, 61% survival without 13% with recurrent malignancy at prednisone; 5 years with prednisone hazard ratio = plus cyclosporine, 71% 1.55 (P = 0.11) with prednisone; hazard ratio = 1.51 (P = 0.03)

Not stated

Relative risk/ outcomes

Conclusions/comments

Thalidomide caused intolerable side effects, leading to premature discontinuation of administration in 92% of patients; the duration of thalidomide administration was not sufficient to allow assessment of efficacy

High response rate was observed in both groups; study was terminated early due to low accrual rate

Subset analysis suggested increased mortality among patients with chronic GVHD that evolved directly from acute GVHD Incidence of avascular necrosis was lower with prednisone plus cyclosporine than with prednisone alone

Results demonstrate inferior outcomes when azathioprine was used to treat chronic GVHD

chapter

2000

2001

2002

1988

Year

TABLE 110.2. Clinical trials of chronic graft-versus-host disease.

1906 110

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Phase 2 studies have been carried out to evaluate the use of many immunosuppressive agents for treatment of steroidrefractory chronic GVHD. The small number of enrolled patients, the widely divergent enrollment criteria and poorly defined efficacy criteria, and the lack of controls hamper the interpretation of these studies. Efficacy is generally reported as improvement in symptoms or signs of chronic GVHD at any time after introduction of the additional immunosuppressive treatment. The duration of clinical improvement is typically not taken into account, and survival data are difficult to interpret because of variable follow-up and possible selection biases in enrollment. In the absence of pharmacokinetic evaluation, studies of this type typically do not add useful information to the available safety profile of approved immunosuppressive agents. Trial designs with prior specification of criteria for judging efficacy according to robust and meaningful endpoints would help to make the results of Phase 2 studies more informative.

Emerging Challenges in Chronic GVHD Advances in supportive care have reduced morbidity, but survival for patients with newly diagnosed chronic GVHD has not changed since the mid-1980s.3,5 In the past, investigators have taken the highly empirical approach of testing virtually any available immunosuppressive agent for treatment of chronic GVHD, because the pathophysiology of chronic GVHD is complex and poorly understood. Development of a more-direct approach will require an improved understanding of the pathophysiologic mechanisms leading to chronic GVHD.

Infections A susceptibility to late infectious complications persists because of residual immunodeficiency that is observed in all HCT recipients, not only those with allogeneic donors,29 although infection risk is increased with the additional immunosuppression associated with chronic GVHD and its treatment (Table 110.3).

Bacterial There is a significant risk for severe infection with encapsulating bacteria (Streptococcus pneumoniae, Haemophilus influenzae) after HCT in the setting of chronic GVHD.30 Patients may develop rapidly progressive disease, which is often fatal. The presumed explanation for bacteremic pneumococcal infections is that HCT patients lose and do not subsequently make opsonizing antibody to encapsulated gram-positive organisms, even after recovery from infection.30 Patients also respond poorly to immunization with prototype pneumococcal vaccines for the first 1 to 2 years after transplant, although response again improves with time.31,32 Immunization with the available pneumococcal vaccines provides incomplete protection for those most in need, that is, patients with chronic GVHD.33 Antibacterial prophylaxis is recommended in patients with chronic GVHD to prevent both bacteremic pneumococcal and other infection, although no randomized placebocontrolled trials have been performed.34 The 23-valent

1907

pneumococcal polysaccharide vaccine (12 and 24 months after transplantation) and the Haemophilus influenzae B conjugate vaccine (12, 14, and 24 months after transplantation) are recommended in standard guidelines.34 However, these vaccinations are not 100% protective; the 7-valent conjugated pneumococcal vaccine has not been evaluated in transplant recipients. Althouogh penicillin appears to work for this indication, the recent emergence of penicillin-resistant pneumococci make it a less preferable choice.35 Rather, trimethoprimsulfamethoxazole (TMP-SMX) given once daily (80 mg TMP component) provides protection both against Pneumocystis jiroveci pneumonia (PCP), encapsulated bacteria, and possibly also against toxoplasmosis. Controlled trial data are not available to evaluate the efficacy of such prophylaxis, but retrospective study of nonrandomized treatment groups indicates that patients with chronic GVHD who receive TMP-SMX prophylaxis have a significantly lower incidence of infection.29 Oral penicillins should be reserved for patients who are unable to tolerate daily TMP-SMX. No reports exist about new quinolones or macrolides for this indication. Because infection with other organisms including both Staphylococcus species and gram-negative aerobic bacteria also occurs, empirical antibiotic treatment of HCT patients admitted with clinical sepsis should include broad-spectrum coverage until the identity of the infecting organisms is known.

Viral Varicella-zoster virus (VZV) disease is the most common viral infection late after HCT.36–40 Median time of onset is 5 months after transplant, and most cases occur within the first year. However, VZV disease can occur up to several years after transplantation, especially in the setting of chronic GVHD. A subgroup at particularly high risk for VZV infection is VZVseropositive allogeneic transplant recipients of age greater than 10 years who received total-body irradiation (TBI). In one study, the risk of VZV disease was 44% during the first 3 years after transplant among these patients.41 Abdominal infections without skin manifestations are observed occasionally. These manifestations carry a high mortality, and the clinical hallmark is rapidly rising transaminases. In an unpublished randomized double-blind trial, oral acyclovir at a dose of 800 mg twice daily for 1 year prevented VZV infection after HCT without rebound disease after discontinuation of prophylaxis. This treatment may be particularly useful in patients with continued chronic GVHD.37 Strategies that used lower doses for a shorter duration resulted in a high number of infections after discontinuation of prophylaxis.42 Cytomegalovirus (CMV) seropositive transplant recipients and recipients of stem cell products from a seropositive donor continue to be at risk for late CMV disease if they have chronic GVHD and/or have reactivated CMV during the first 100 days after transplantation.43–46 The majority of late disease occurs during the first year after transplantation, but there may be cases until 3 years after transplant if immunosuppression continues. Clinical manifestation of late CMV disease may differ from the typical pneumonia and gastrointestinal disease seen earlier. Cases of retinitis, late marrow failure, and encephalitis have been described.47 Outcome of late CMV disease is poor, with pneumonia having the highest

36

37

46

48

49

50

Locksley et al.

Han et al.

Boeckh et al.

Peggs et al.

Marr et al.

Fukuda et al.

Year

2003

2002

2000

2003

1994

1985

1986

163

1,682

81

146

1,186

1,394

42

N

N

N

N

N

N

Y

Randomized (Y/N)

Retrospective cohort study

Prospective cohort study

Cohort study

Cohort study

Cohort study

Intervention/design RCT

Nonmyeloma Cohort study blative conditioning

Allogeneic, CMV seropositive Allogeneic, CMV seropositive All types of transplants

Various

Various

Various

Diagnosis/ stage of disease

23 months

NR

13.5 months

NR

NR

NR

Median follow-up 12 months Relative risk/hazard ratio

2.8 (acute GVHD) 3.7 (chronic GVHD) 13.3 (CMV disease)

6.7 (GVHD) 6.6 (CMV disease)

Not reported

3.3 (CMV reactivation 6 months

Late CMV disease common Late viremia associated with poor survival

VZV seropositive + age > 10 years + radiation pretransplant: 44% VZV infection

Risk factors for dissemination of VZV or death: GVHD (all deaths within 9 months after transplantation)

Acyclovir prophylaxis given for 6 months leads to prevention of HSV and VZV infection during prophylaxis but frequent recurrence of VZV after discontinuation

chapter

HSV, herpes simplex virus; VZV, varicella-zoster virus; CMV, cytomegalovirus; PCR, polymerase chain reaction; NR, not reported.

42

Reference

Ljungman et al.

Author

No. of patients

TABLE 110.3. Infections after hematopoietic cell transplantation (HCT).

1908 110

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mortality.46 About one-third of patients who survive the first episode of late disease will suffer a relapse after a median of 3 months.46 Continued monitoring [pp65 antigenemia, polymerase chain reaction (PCR) for CMV DNA] and use of preemptive therapy in high-risk patients is useful in the management of patients at risk for late CMV disease.46,48 HCT recipients with chronic GVHD continue to be at risk for acquisition of respiratory virus infections such as respiratory syncytial virus, influenza viruses, and parainfluenza viruses. Seasonal vaccination of close contacts with the inactivated vaccine is recommended.34 Recipient vaccination starting at 6 months after transplantation is also recommended.34 Less commonly, late impaired graft function has been described in association with human herpes virus (HHV)-6 and human parvovirus B 19.

Fungal Late invasive aspergillosis is an increasingly frequent event in allogeneic graft recipients with chronic GVHD and preceding viral infections (i.e., CMV, respiratory viruses), possibly due to an immunosuppressive effect of these viruses.49 Recipients of lower-dose conditioning regimens who have GVHD are also at risk for late mold infections.50 In contrast, invasive candidiasis occurs infrequently after day 100.50,51 The outcomes of both mold and candidal infections in this setting remain poor. Mold-active drugs are now available (itraconazole, voriconazole). However, the efficacy and toxicity of long-term prophylaxis have not been tested in randomized fashion in this setting. Sensitive diagnostic tests (aspergillus galactomannan assay, PCR) can be used for early diagnosis of disease.

Pneumocystis jiroveci Pneumonia (PCP) With the availability of effective prophylaxis, early cases of Pneumocystis jiroveci pneumonia (PCP) are only rarely seen late after transplant.52 Most cases occur in a setting of poor adherence or in patients who are unable to tolerate TMP-SMX because of side effects or allergy, or who received ineffective alternative prophylaxis regimens.53 Standard guidelines following allogeneic transplantation recommend prophylaxis for the duration of drug-induced immunosuppression.34 However, the optimal duration of prophylaxis after autologous transplant is currently poorly defined, as recent data suggest that there is late PCP in autologous graft recipients as well.54 Approximately 15% to 30% of HCT recipients require alternative prophylaxis regimens at some time after transplantation.55 Reasons for requiring alternative prophylaxis include allergy to TMP-SMX, gastrointestinal intolerance, increased transaminases, and neutropenia. Very few data exist on the efficacy and toxicity of alternative prophylaxis regimens. Daily dapsone appears to be superior to inhaled pentamidine.55 As it has overall superior results, TMP-SMX should be given whenever possible. Desensitization should be attempted in all patients with allergy to TMPSMX.52 Only limited data exist on atovaquone.56 The clinical syndrome of PCP is indistinguishable both clinically and radiologically from other nonbacterial pneumonias. The diagnosis is established either by bronchoalveolar lavage (BAL), induced sputum, or thoracoscopic or open

1909

lung biopsy. The treatment of choice is high-dose intravenous TMP-SMX in combination with a short course of corticosteroids based on results in human immunodeficiency virus (HIV)-infected patients.57 Of the alternative agents used in the HIV setting (intravenous pentamidine, atovaquone, clindamycin/primaquine, dapsone/trimethoprim, and trimetrexate), clindamycin/primaquine appears to be most effective for treatment of disease.58

Distinctions in Adult and Pediatric Presentation, Course, and Treatment Virtually no data exist on differences in infection risk and outcome among survivors of HCT. Whether immune reconstitution is faster in younger individuals has not been studied. However, if chronic GVHD is present, all available data suggest that children have the same infectious risk as adults. The exposure to respiratory viruses may even be higher if children are exposed to group settings. Certain contraindications for use of antimicrobials (e.g., quinolones) should be considered in the management of children.

Emerging Challenges in Infection The major challenge is to design infection prevention strategies for survivors of HCT with persistent severe immunosuppression. These patients are not only at risk for VZV, PCP, and encapsulated bacteria but also for CMV and invasive mold infections. Strategies need to be easy to administer, effective, and well tolerated. With increasing long-term use of antimicrobials, resistance may become a challenge in the future.

Other Medical Complications Pulmonary Chronic pulmonary complications affect at least 15% to 20% of patients after HCT, and pulmonary dysfunction is an important risk factor for delayed mortality. However, current knowledge is based exclusively on retrospective analyses (Table 110.4).

Late-Onset Pneumonitis Late-onset interstitial pneumonitis usually occurs in patients with chronic GVHD.59 Most require therapy with immunosuppressive agents; treatment with bronchodilators is usually ineffective. However, late pneumonias occur also in the absence of GVHD, and even after autologous transplantation in patients who have not previously had pulmonary disease, with an incidence of 31% at 4 years. The prognosis is generally good with bacterial etiology, but mortality reaches 80% with fungal or polymicrobial pneumonia.54

Restrictive Pulmonary Disease Pretransplant and posttransplant abnormal pulmonary function tests (PFTs), in particular decreased diffusing capacity (DLCO) and increased oxygen gradient [P(A-a) O2], are associated with higher posttransplant mortality than seen in

Reference

63

54

Author

Chien et al.

Chen et al.

1,359

1,131

No. of patients

N

N

Randomized (Y/N)

Various

Various

Diagnosis/stage of disease

Retrospective cohort study

Retrospective cohort study

Intervention/ design

0.01–5 years

1–11 years

Follow-up

Disease-free survival (or survival statistics)

Conclusions/results

75% of AFO occurred in patients with chronic GVHD AFO is more frequent than previously reported and has a major negative impact on long-term survival, particularly in patients with chronic GVHD

Risk factors include: Cumulative incidence of Pneumonia is patient age, HLA nonfirst pneumonia at 4 frequent, even late identity, and chronic years was 31% (18% after transGVHD among allogeneic for autologous, 34% for plantation and recipients (none identified HLA-identical poses a significant for autologous) allogeneic, 39% for risk, particularly other allogeneic/ among patients unrelated) more than 40 years Survival rates were best of age, and in with bacterial (71%), patients with and worst with chronic GVHD multimicrobial pneumonias (8%)

AFO associated with AFO attribution to decrease in FEV1 mortality, all patients >5%/year, decreased (those with chronic pretransplant FEV1/FVC, GVHD): 9% (22), 12% acute and chronic GVHD, (27), 18% (40) at 3, 5, respiratory virus infection and 10 years, Among patients with respectively chronic GVHD, those with AFO have a higher risk of mortality (HR 2.3, 95% CI 1.63.3) than patients without AFO Risk increases with increasing age (RR 1.7–2.5) for patients more than 20 to more than 60 years of age and patients with quiescent (RR 1.6) or progressive onset (RR 1.9) of chronic GVHD

Relative risk/outcomes/predictors

chapter

2003

2003

Year

TABLE 110.4. Pulmonary complications after HCT.

1910 110

68

69

Sullivan et al.

Freudenberger et al.

AFO, air flow obstruction.

60

Crawford et al.

2003

1996

1995

49 patients 161 controls

250

906

N

Y

N

Various

Various

Various

Case-control study

IV immunoglobulin (500 mg/ kg/month) between days 90 and days xvs. none; RCT

Retrospective cohort study

No difference in systemic infections; localized infections marginally more frequent in controls (P = 0.07); after 2 years total infections less common in controls (P = 0.03)

5-year survival 31% in patients with BOOP vs. 45% in controls (P = 0.05)

No difference

BOOP is more frequent in patients with acute or chronic GVHD Steroid treatment has no recognizable therapeutic effect

Prophylactic administration of IV immunoglobulin, in the absence of in the absence of hypogammaglobulin emia, has no demonstrable benefit, and in fact may delay endogenous immune recovery

Restrictive lung defect at 3 Death from respiratory Impaired total lung months after transplant or failure occurred in capacity, impaired ≥15% decline in total 1.9% of patients with airflow, and lung capacity from normal or unchanging decreased diffusing baseline was associated total lung capacity, capacity all had a with a twofold increase in compared to 5.3% in negative impact on risk of nonrelapse patients with survival mortality (respiratory restrictive ventilatory failure) defects; chronic GVHD did not appear to influence the rate of death with respiratory failure

Sequentially Risk factors for bronchiolitis obliterans organizing pneumonia (BOOP): acute (P = 0.002) and chronic (P = 0.02) GVHD; progressive onset chronic GVHD (P = 0.001); skin involvement with acute (HR 4.6), and oral (HR 5.9) and gut involvement (HR 6.6)

1–9 years

m e d i c a l a n d p s yc h o s o c i a l i s s u e s i n t r a n s p l a n t s u rv i vo r s

1911

1912

chapter

patients with normal tests.60 Restrictive defects, defined as a decrease in total lung capacity to less than 80% of predicted values, are present in one-third of all patients studied. Changes are not correlated with the type of conditioning regimen or with chronic GVHD and generally do not produce severe symptoms. However, becuase they are associated with an increase in late mortality, routine evaluation of lung function after HCT is warranted.61 Aggressive therapy of any infection of the respiratory tract is indicated.

Obstructive Pulmonary Disease Air flow obstruction (AFO), defined as decreased expiratory airflow, in particular, a decrease in the proportion of air that can be exhaled over the first second of expiration, may represent sequelae to extensive restrictive changes in the small airways or may be related to small airway destruction.62 Both acute and chronic GVHD are important risk factors for AFO, and thereby affect long-term survival, with 75% of AFO cases occurring among patients with chronic GVHD, particularly those with quiescent or progressive onset (see Table 110.4).63 There is generally no response to bronchodilator treatment; 30% to 40% of patients improve on glucocorticoids. Few patients with end-stage disease have been treated successfully with cadaveric lung transplants.64,65

Bronchiolitis Obliterans Progressive bronchiolitis obliterans has been reported in 10% of patients with chronic GVHD.66,67 Chest radiographs may show hyperinflation of the lungs and flattening of the diaphragm, but abnormalities are best identified by highresolution computed tomography (CT) scans (inspiratory and expiratory cuts). PFTs show a reduction in forced midexpiratory flow to 10% or 20% of predicted values and moderate to severe reduction in forced vital capacity. The diffusion capacity is usually normal. Pulmonary ventilation scans show decreased activity patterns corresponding to areas of obliteration of bronchiolar walls along with atelectatic areas. Histologic changes are thought to be due to a graft-versus-host reaction, possibly aggravated by infections. The clinical course of bronchiolitis varies from mild, with slow deterioration, to diffuse necrotizing fatal bronchiolitis. Severe disease may not respond to glucocorticoids, but corticosteroids in combination with calcineurin inhibitors or possibly azathioprine can stabilize PFTs and improve outcome. It is of note that a randomized trial examining the effect of intravenous immunoglobulin on chronic GVHD and bronchiolitis showed a marked decrease in the incidence of obliterative bronchiolitis in all patients such that an effect of intravenous Ig was not apparent.68 Bronchiolitis obliterans organizing pneumonia (BOOP) histologically shows polypoid masses of granulation tissue in the bronchioles and alveolar sacs as well as infiltration of alveolar septa by mononuclear cells. A recent analysis of results in 6,523 patients transplanted at the Fred Hutchinson Cancer Research Center revealed 51 cases of BOOP, all but 2 after allogeneic transplants.69,70 BOOP was diagnosed at 5 to 2,819 (median, 108) days after HCT. The chest radiograph was abnormal in 47 patients. Most patients presented with fever, dyspnea, or cough, but 23% were asymptomatic. Most patients respond to glucocorticosteroids (1–2 mg/kg), which often must be continued for 6 months or longer.

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Osteoporosis Dual-energy X-ray absorptiometry (DEXA), a semiquantitative method to assess bone mineral density (BMD), is a validated method commonly used to detect osteoporosis [as defined by a Z-score of less than or equal to 2.5 standard deviations (SD) below sex- and age-related mean bone mineral density (BMD)] and osteopenia (defined by a Z-score of 1.0 to 2.4 SD below sex- and age-related mean BMD). Reduction of bone mass using DEXA has been reported in approximately 40% of men and women at 1 year after allogeneic HCT, with nontraumatic fractures in 11% by 3 years.71 Risk factors include number of days and dose of glucocorticoids and number of days of cyclosporine or tacrolimus used for treating chronic GVHD. In women, supplementation with estrogens and medroxyprogesterone can increase bone mass after HCT.72 However, there may be increased risks of cardiovascular diseases (venous thrombosis, strokes, pulmonary emboli) and breast cancer in postmenopausal women given conjugated equine estrogen (0.625 mg) with medroxyprogesterone (2.5 mg).73 This possibility is of concern because HCT recipients are at risk for secondary malignancies even without hormone therapy. Thus, the overall risks and benefits of hormone replacement in this situation remain to be determined. Lower doses of estrogen alone (after hysterectomy) or combined with progestin (in women with uterus intact) have been used for the management of bone loss in other patient populations.74 Alternative regimens of bisphosphonates or hormone therapy have not been tested in clinical trials for efficacy or safety in women after HCT either for osteoporosis prevention or for postmenopausal symptoms.

Aseptic Necrosis Avascular necrosis, especially in weight-bearing joints, is a classic side effect of glucocorticoid therapy and has been reported in 4% to 10% of allogeneic HCT survivors as early as 2 months and as late as 10 years posttransplant.75–77 The hip is the joint most frequently affected (two-thirds of all cases). In most patients more than one joint is affected. Onethird of patients with this disease required joint replacement at 2 to 42 months.76 A case-control study of 87 patients with avascular necrosis found that posttransplant glucocorticoid use and TBI given in preparation for HCT were significant risk factors.78 In addition to glucocorticoid therapy, male gender (relative risk, 4.2) and age greater than 15 years (relative risk, 3.8) were risk factors.

Endocrinology Thyroid Overt or compensated hypothyroidism and the “euthyroid sick syndrome” [ETS; low free triiodothyronine, free thyroxine, or both, along with normal or low thyroid-stimulating hormone (TSH)] are the most frequent thyroid abnormalities following transplantation (Table 110.5).79 In one study ETS was associated with a significantly lower survival than observed in patients not affected by ETS (34.5% versus 96.2%; P less than 0.0001).80,81 The risk of hypothyroidism is increased in patients who received pretransplant cranial

182

183

184

83

83

Leung et al.

Thomas et al.

Sanders

Sanders

Sanders

2004

2004

1991

1993

2000

Year

562 498

128/98

145/93

63 (55) (154)

49

43

No. of patients

N

N

N

N

N

Randomized (Y/N) Intervention/design

Various

Various

Various

Retrospective cohort study

Retrospective cohort study

Retrospective cohort study

Various with Retrospective chemotherapy cohort study alone vs. chemo + cranial irradiation vs. chemo +TBI HCT Various Retrospective cohort study

Diagnosis/stage of disease

TBI, total-body irradiation; FSH, follicle-stimulating hormone.

Reference

Author

TABLE 110.5. Endocrine function, and growth and development.

1–14 years

1–12 years

>12 years

1–3 years

Median 13 years

Follow-up

Cyclophosphamide by itself is well tolerated; little if any delay and normal rates of pregnancy Busulfan has intermediate effect TBI results in marked impairment

Irradiation impairs growth; more so as single dose, and even further with cranial irradiation; growth hormone is helpful; should be instituted early (before the growth lag is >1.5 SD); dose should be adjusted for puberty

Importance of irradiation; growth hormone deficiency only with HCT

Conclusions/results

1,000 cGy single or 1,200–1,575 fractionated TBI; 83 women recovered ovarian function at 3–7 years; in men Leydig cell function was generally preserved, but Sertoli cell function was impaired in the majority

TBI has major impact; high frequency of sexual dysfunction, decrease in libido (associated with decreased testosterone in men) Chronic GVHD further impairs function. In women, systemic and topical vaginal hormone application is indicated

Cyclophosphamide alone, 54% Significant impairment of gonadal function of women recover normal with busulfan-containing regimens; less function; among men, 95% so with cyclophosphamide normal Sertoli cellfunction, 61% normal FSH; with busulfan/cyclophosphamide, only 2 of 93 women recovered ovarian function. Among men 65% showed azoospermia

Cyclophosphamide alone leads to little delay; TBI, single dose (71%; 83%) more than fractionated (49%; 58%) delays development

TBI 1,000 cGy single vs. 1,200–1,440 cGy fractionated dose; decrease in height of 0.2–0.9 SD vs. 0.09–0.2 SD; accentuated by cranial irradiation

Decreased height by 0.21 SD with chemo vs. 1.2 with chemo + cranial vs.1.33 with HCT

Relative risk/outcomes/predictors

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irradiation or irradiation to the neck (e.g., for Hodgkin’s disease).82 All patients who have received irradiation to the thyroid should be followed for life with annual physical evaluation and thyroid function studies as indicated.82

Adrenal Glands Many HCT patients receive glucocorticoid therapy. Endogenous cortisol production is suppressed, and any superimposed stress may cause a relative adrenal insufficiency. However, lasting adrenal dysfunction appears to be uncommon. One study in 78 patients showed 24% to have subnormal 11deoxycortisol levels following discontinuation of glucocorticoid therapy at 1 to 8 years posttransplant. No patient was symptomatic, and the proportion of patients affected did not increase with time posttransplant.83,84

Hypothalamic–Pituitary Axis Cranial irradiation, with or without TBI, affects the pituitary gland.85–87 Thyrotropin-releasing hormone (TRH) may be low early posttransplant, and TRH-induced TSH responses may be subnormal and delayed.85 Release of gonadotropin in response to luteinizing hormone-releasing hormone (LHRH) may be elevated.85 Prolactin secretion and the pituitary– adrenal axis are usually intact. Growth hormone levels are decreased after cranial irradiation, and deficiency becomes apparent earlier with younger age at transplant.83,86

Gonadal Function, Puberty, and Fertility Chemotherapy and TBI regimens used before hematopoietic transplantation for malignancies usually cause gonadal failure. Puberty and menarche are markedly delayed or may not occur, and fertility is infrequently regained in either men or women. In men, testosterone levels usually decline as a result of transplant conditioning, but recover by 1 year posttransplant. Decreased libido, reduced bone mineral density, and low testosterone levels after transplant are indications for testosterone replacement unless contraindicated for other reasons. Risk for short stature is increased in males and those who are younger if they also receive TBI.88 Permanent ovarian failure invariably occurs in women who receive busulfan and cyclophosphamide pretransplant, whereas recovery of ovarian function has been observed after transplant in 54% of younger patients less than 26 years conditioned with cyclophosphamide only, and in 10% of younger patients who received more than 1,000 cGy TBI with cyclophosphamide. Pregnancy, although not common, has occurred following high-dose HCT, with increased risk for spontaneous abortion after TBI and preterm delivery of low birth weight babies. However, no increased risk of congenital abnormalities has been observed.89,90 Lack of hormone therapy by 1 year after HCT for women with ovarian failure is a risk factor for sexual dissatisfaction at 3 years after HCT.91 Vasomotor and sexual complaints 6 months after HCT improve after the start of hormone therapy, based on results from a nonrandomized pre–post cohort study.92 Safety of hormone therapy after transplantation has not been reported; thus, hormone replacement for survivors must be individualized. Males treated with testosterone may be at increased risk for prostate hypertrophy and prostate

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carcinoma. A nonrandomized cohort study has reported that hormone therapy in women does not influence chronic GVHD activity between 3 and 24 months after starting the hormone therapy (most of whom were also receiving cyclosporine) after allogeneic HCT.93 Unfortunately, combined estrogen and progestin was recently found to increase the risk of cardiovascular disease and to increase the risk of invasive breast cancer after 3 years of therapy in naturally postmenopausal older women who had not had transplants, but no effect on survival was observed.73 Human pituitary growth hormone replacement has been associated with increased risk of mortality from colorectal and Hodgkin’s disease in a cohort study, a study not conducted in survivors of HCT.94 These relative risks versus the consequences of delayed pubertal development, extremely short stature, attainment of peak bone mass, osteoporosis, and other quality of life factors need to be weighed along with hormone alternatives. If hormone therapy is elected, duration of treatment and a monitoring plan for complications should be part of the treatment plan.

Emerging Challenges in Medical Complications Most treatment strategies for pulmonary, bone, and endocrine complications in transplant survivors are empirical rather than evidence based. Safety and toxicity of hormone therapies and efficacy of treatments for all medical complications need to be examined further, but in general are those that apply to the population at large.

Late Medical Complications As large numbers of survivors live longer, late complications are being recognized. With fractionated TBI, 30% to 47% of HCT recipients have cataracts by 5 to 7 years; without TBI, 10% to 16% have cataracts, most often those who received corticosteroids for longer than 3 months.95,96 Keratoconjunctivitis sicca syndrome is seen in up to 40% of patients with chronic GVHD. Other risk factors include female gender, older age, and methotrexate for GVHD prophylaxis.97 Other than hepatitis, iron overload is the primary identified hepatic late effect; 22% of survivors showed fibrosis at a median follow-up of 5 years.98 After mean follow-up of 7 years for four randomized trials comparing busulfan plus cyclophosphamide regimens with cyclophosphamide plus TBI in 488 survivors, late complications have not been noted to differ, with the exceptions of cataracts (more common after busulfan) and alopecia (more common after TBI).96 Of greatest concern because of their potential lethality are second cancers and cardiovascular effects of transplantation.

Second Cancers Lymphoproliferative disorders after HCT [posttransplant lymphoproliferative disorder (PTLD)], generally of B-cell lineage, occur mostly in allogeneic transplant recipients.99,100 T-cell PTLD, non-Hodgkin’s lymphoma and Hodgkin’s disease have also been reported (Table 110.6). More than 80% of cases of PTLD are diagnosed within 1 year of transplantation, with peak occurrence (120 cases/10,000 patients/year) at 2 to 5 months.101 The incidence is highest in patients

109

110

101

Metayer et al.

Curtis et al.

Curtis et al.

1999

1997

2003

Year

18,014

19,229

56 patients, 168 controls

DS, myelodysplasias; AML, acute myeloid leukemia.

Reference

Author

No. of patients

TABLE 110.6. Malignancies after HCT.

N

N

N

Randomized (Y/N)

Various

Various

Hodgkin’s disease; nonHodgkin’s lymphoma

Diagnosis/ stage of disease

Retrospective multicenter cohort study

Retrospective multicenter cohort study

Multicenter retrospective case-control study

Intervention/ design

10 years

Median 3.5 years

Not reported

Duration of follow-up

Cumulative incidence 1% at 10 years. Unrelated or HLA non-identical transplants, T-cell depletion of donor marrow, use of ATG or anti-CD3 monoclonal antibody, acute GVHD, and conditioning with TBI were risk factors

Ratio of observed/ expected cases was 2.7. The risk was 8.3 fold increased in patients surviving >10 years. Younger age, higher doses of TBI, chronic GVHD, and male sex were risk factors

Pretransplant use of mechlorethamine (P = 0.04) or chlorambucil (P = 0.009) significantly increased the risk of MDS/AML after autologous transplantation; conditioning with TBI ≥1,320 cGy increased risk (P = 0.03)

Relative risk/outcomes/ predictors

Conclusions/results

Most lymphopro-liferative disorders occurred within 5 months of transplantation; late cases rare. Risk factors are cumulative. The use of broadly reactive monoclonal antibodies was associated with a lower risk than narrowly reactive anti-T-cell antibodies

Solid tumors, in particular malignant melanoma, cancers of the buccal cavity, liver, brain, thyroid, bone, and connective tissue were increased. Cancers of the buccal cavity were prominent among male patients and patients with chronic GVHD. Lifelong surveillance is indicated

The risk of MDS/AML after autologous transplants for Hodgkin’s disease or nonHodgkin’s lymphoma is significantly increased with pretransplant use of alkylating agents and highdose TBI in preparation for transplantation

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transplanted for immunodeficiency disorders. Risk factors include the use of ATG or anti-CD3 monoclonal antibody (MAB) for acute GVHD prophylaxis or in the preparative regimen, use of TBI in the conditioning regimen, T-cell depletion of donor marrow, unrelated donor or HLA nonidenticalrelated donor, and primary immunodeficiency disease. The impact of risk factors is additive (or synergistic). Increasing intensity of posttransplant immunosuppression in patients who are otherwise at low risk significantly increases the incidence of PTLD.100 The best approach to prevent Epstein–Barr virus (EBV)-related PTLD currently is close monitoring and preemptive therapy with anti-CD20 monoclonal antibody (325 mg) in patients with rising EBV titers. Additional doses of anti-CD20 antibody can be given if high EBV titers persist. Rare T-cell proliferative disorders with or without EBV association have been reported.102 None was associated with HTLV1, HIV, or HHV-6 infection. Several cases of lateoccurring lymphomas have been reported,103–105 some linked to EBV infection (just as early-onset PTLD), and others associated with T-cell depletion of the graft. “Secondary” myelodysplasias (MDS) and acute myeloid leukemia (AML) occur after conventional chemotherapy with or without radiotherapy for Hodgkin’s disease, nonHodgkin’s lymphoma, and solid tumors,106 as well as after autologous HCT.103,107,108 After autologous HCT, incidence rates of 4% to 18% have been reported. A case-control study analyzed data on 56 patients who developed MDS/leukemia and 168 controls within a cohort of 2,739 patients with Hodgkin’s disease or non-Hodgkin’s lymphoma transplanted at 12 institutions.109 MDS/AML was significantly correlated with the intensity of pretransplant chemotherapy, specifically mechlorethamine [relative risk (RR), 2.0 and 4.3 for doses of less than 50 or 50 mg/m2 or more, respectively], and chlorambucil (RR, 3.8 and 8.4 for duration of less than 10 or 10 months or more; P = 0.0009) compared to cyclophosphamide. Also, higher doses of TBI (more than 1,200 cGy) used for transplant conditioning tended to carry a higher risk (RR, 4.7). A spectrum of tumors including glioblastoma, melanoma, squamous cell carcinoma, adenocarcinoma, hepatoma, and basal cell carcinoma has been reported. A recent study analyzed results in 19,220 patients (97.2% allogeneic, 2.8% syngeneic recipients) transplanted between 1964 and 1992.110 There were 80 solid tumors for an observed/expected (O : E) ratio of 2.7 (P less than 0.001). In 10-year survivors, the risk increased eightfold. The tumor incidence was 2.2% at 10 years and 6.7% at 15 years. The risk increased significantly for melanoma (O : E, 5.0), cancers of the oral cavity (11.1), liver (7.5), central nervous system (CNS) (7.6), thyroid (6.6), bone (13.4), and connective tissue (8.0). The risk was highest for the youngest patients and declined with age. Preliminary data from an ongoing nested case-control study in a cohort of 29,737 patients suggest that duration of chronic GVHD for more than 2 years and prolonged therapy are risk factors, in particular for the development of squamous cell carcinoma.

Cardiovascular Effects Cardiac insufficiency and coronary artery disease are known complications of intensive cytotoxic therapy, in particular, high-dose anthracycline and mediastinal irradiation. Cardiac insufficiency may also be seen in patients conditioned with cyclophosphamide 200 mg/kg, usually early, sometimes

110

before conditioning is completed, although the overall incidence is low and approximately 0.7% are life threatening or fatal.111 Late cardiomyopathy has occasionally been observed and treated successfully by orthotopic cardiac transplantation.112 Coronary artery disease and thrombotic events have been reported at various time intervals after HCT.113,114 Hyperlipidemia and hyperglycemia are common in patients treated with calcineurin inhibitors, rapamycin, and glucocorticosteroids. Although data are lacking, potential risk factors for the development of coronary disease in long-term survivors of HCT include treatment with estrogen/progesterone and inactivity due to fatigue or other causes.

Functional and Quality of Life Outcomes Many cross-sectional cohort studies, and a smaller number of prospective longitudinal cohort or case-control studies, have defined functional and psychosocial outcomes after HCT. These investigations consistently find that 85% to 90% of survivors of HCT do well in their return to “normal” life in the domains of physical, psychologic, social, existential, and overall subjective quality of life, although specific residual problems remain for many.2,115,116 Physical recovery returns to pretransplant levels by 1 year for most survivors. However, return to work and emotional recovery may take longer.117–119 Although physical recovery is more rapid for autologous transplant recipients, results are inconsistent as to whether function continues better for autologous survivors after 1 year.118,120 Risk factors for poorer quality of life include older age, being female, and chronic GVHD.118,121–124 Specifically, females have a more difficult time in the areas of sexuality, fatigue, emotional adaptation, and return to work.116,123–126 After resolution of chronic GVHD, survivor function seems to be equal to those patients who did not have chronic GVHD.118,127 Crosssectional studies of survivors 5 to 18 years after HCT do not suggest deterioration over time in quality of life.124,128,129 Residual symptoms that are most common and remain after 5 years in at least a third of survivors, based on a survey of 125 adults, include sexual dysfunction, emotional reactivity and fears, fatigue, joint and muscle pains, eye problems, sleep disruption, financial and insurance worries, cognitive concerns, and social roles and relationships.128 Only 7% of this cohort was disabled and 74% was employed; the number who considered homemaking their job was not reported, but only 3 survivors were seeking employment. Rates of return to work continue to rise until 5 years after HCT. By 3 or more years after HCT, between 72% and 89% of patients have returned to full-time work or school.96,119,124,127 Survivors who are older, female, have had chronic myeloid leukemia, or have had extensive chronic GVHD are at risk for incomplete resumption of work or school activity after 5 years.124,127 A nonrandomized cohortcontrolled trial found that HCT survivors who received a 3to 4-week inpatient rehabilitation program demonstrated no difference in employment when compared with a group of patients who did not receive this rehabilitation.130 Pediatric survivor quality of life is similar to adults. A cohort study compared 120 survivors who had HCT as children 5 or more years previously, with 114 survivors of childhood leukemia who had received chemotherapy without

m e d i c a l a n d p s yc h o s o c i a l i s s u e s i n t r a n s p l a n t s u rv i vo r s

transplant, and 149 age- and gender-matched nontransplanted comparison subjects.131 The HCT survivors reported more major illness, physician visits, diabetes, second malignancies, and poorer physical health than participants in either of the other two cohorts. Both survivor groups reported more health or life insurance refusals (25% and 33% versus 3% for comparison subjects). Marital status and mental health did not differ between cohorts, and other psychosocial factors also did not differ.131 Other researchers have found comparable results. Investigators who compared adolescents and young adults 2 to 13 years after HCT or bone cancer found that132 the groups did not differ in adjustment or perceived quality of life, with the exception that HCT survivors reported higher anxiety and feelings of sensitivity and vulnerability. Other researchers have reported that pediatric survivors do better than their peers in psychosocial domains.133 The rate of successful return to school (85% to 95%) is similar to rates of return to work in adult survivors.134

Fatigue Fatigue is the one of the most persistent symptoms beyond the first year after HCT. A multicenter longitudinal cohort study of fatigue and sleep disturbance in 172 adult survivors more than 12 months after HCT, followed again 18 months after the first assessment, found that a majority reported at least mild problems at both time points, with 15% to 20% reporting moderate to severe problems.135 Risk factors for sleep but not fatigue included older age, receipt of TBI, and female sex. Problems did not resolve over time, and no specific risk factors for fatigue were identified. Other studies have reported age to be a risk factor for fatigue.128 A cohort study of breast cancer 20-month survivors after autologous HCT found significantly higher levels of fatigue than in a matched noncancer cohort of women,136 and another longitudinal cohort study reported that more than 80% of survivors at both 100 days and 1 year reported “I tire easily”.137 Many biologic mechanisms have been postulated to explain fatigue following HCT or other cancer treatments. Considered among potential causes are effects of interleukins and interferons, anemia, metabolic abnormalities, infection, immunosuppression, gonadal insufficiency, TBI, sleep disruption, lack of physical activity, depression, systemic medications such as corticosteroids, and other medications. However, evidence does not clearly support any of these causes over others in HCT survivors.138 Treatments for fatigue and physical strength have been tested in randomized or nonrandomized trials using exercise, erythropoietin, or coping skills that included relaxation training. Results show improved fatigue and reduced medical complications.139–141 However, these studies have focused on the acute phase of treatment, not fatigue in survivors.

Neurologic and Cognitive Deficits Neurologic complications are numerous during acute treatment and as a consequence of chronic GVHD treatment. Neuroradiologic studies have determined that changes such as cortical atrophy and ventricular enlargement occur in some patients after HCT conditioning chemotherapy or total body irradiation.142 Chronic GVHD-related CNS neurotoxicities

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seem to resolve with discontinuation of the drug causing the problems unless stroke or other permanent brain events occur.143–146 An adult cohort study146 tested 66 patients with neurologic examination, magnetic resonance imaging, and neuropsychologic exams from 8 months to 5 years after transplant. Neuropsychologic deficits did not correlate with pathology seen in neurologic or imaging tests. Pathology on neuroradiologic examination was greater for patients with progressive-onset chronic GVHD or corticosteroid or cyclosporine use. Meanwhile, long-term cyclosporine use and age increased the risk for neuropsychologic impairment. Twenty percent to 56% of patients enter transplant with cognitive deficits that could interfere with function.147–149 Thus, without knowing the pretransplant function of a patient, it is not possible to determine whether long-term problems are a consequence of transplantation, or of treatment predating HCT, or instead are outcomes of depression, anxiety, or fatigue. Patient complaints about cognitive difficulties following transplantation are prevalent. However, complaints do not always match objective neuropsychologic test results150,151 and more likely correlate with subjective anxiety, depression, and fatigue. Mechanisms underlying cognitive impairment related to chemotherapy remain uncertain but include (1) direct neurotoxic injury, (2) secondary inflammatory response, (3) microvascular injury leading to obstruction, and (4) altered neurotransmitter levels.152 Data indicate that TBI has significant diffuse effects on neuropsychologic function in the short term, but toxicities resolve with time if doses are 12 Gy or less.153–156 A study of patients tested pretransplant and at 80 days and 1 year after transplantation found major decrements at 80 days, but recovery of function to pretransplant levels by 1 year, in most neuropsychologic areas tested.149 A crosssectional study reported impairment in 25% of allogeneic transplant recipients 2 or more years posttransplant.151 Among survivors of pediatric transplantation, a prospective longitudinal cohort study of 102 pediatric survivors found no declines at 1- or 3-year follow-up testing of patients over the age of 5 at the time of transplant.157 However, younger patients, particularly those under 3 years of age, do have some risk of IQ decline over time posttransplant.157–159 Testing of children before and at 1 year and 3 years after transplant indicates no difference in performance based on whether the child received TBI.159,160 To date there is no indication that adult cognitive abilities decline more rapidly after HCT when compared with nontransplanted adults.155 By 1 or 2 years posttransplant, approximately 55% to 60% of adult allogeneic HCT survivors and 32% of autologous breast cancer survivors have some evidence of neuropsychologic impairment on objective tests versus 17% of standard-dose chemotherapy recipients.149–151 Surprisingly, few risk factors specific to HCT have been identified as predictors of long-term deficits. Rather, accumulated difficulties in overall health, fatigue, mood, and physical function predict deficits (Table 110.7).

Sexual Function Both men and women report lower rates of sexual activity and satisfaction after HCT than before transplantation and in comparison with either the general population or patients who receive chemotherapy without transplantation (Table 110.8). This result is consistent across time points after

158

151

159

146

154

Harder et al.

Kramer et al.

Padovan et al.

Peper et al.

Reference

Arvidson et al.

Author

No. of patients

Adult acute leukemias, lymphoma

Various adults

Pediatric HCT

Progression-free adult survivors of allogeneic HCT including TBI

Pediatric hematologic malignancies with autologous HCT

Disease/stage

Cohort and casecontrol study

Cohort study

Prospective cohort study

Cohort study

Cohort study

Intervention/ design

32 months and 8.8 years

Mean 34 months postHCT

1 year or 3 years

22–82 months after HCT

8–10 years postHCT

Follow-up

Relative risk/outcomes

Conclusions/results

Brain atrophy increase was associated primarily with pretransplant irradiation or methotrexate No medical factors were associated with cognitive deficits

Risk factors for neuropsychologic impairment were age, long time post-HCT, intrathecal methotrexate, long-term cyclosporine, progressive chronic GVHD

Not reported

Predictors of poor performance included fatigue, global health, educational level, subjective cognitive complaints, physical functioning, social functioning, mood, employment status

Neurologic deficits seen in one new case after HCT All brain atrophy measures were within normal range, but were slightly increased after TBI Cognitive deficit levels were not significant Power may have been inadequate to detect clinically meaningful differences Some tests were associated with ventricle index results No decline in cognitive function seen long term

Mild cognitive deficit, especially impaired memory, seen in more than 1/3 of allogeneic-HCT patients; lower risk of pathologic neurologic exam after auto-HCT

Significant decline in IQ was seen between baseline and 1 year Although IQ was lower at 1 year, no further changes were evident at 3year follow-up

Mild to moderate cognitive impairment found in 60% Compared with healthy population norms, areas most likely to be affected were selective attention and executive function, information processing speed, verbal learning, and verbal and visual memory HCT may lead to cognitive complaints and late cognitive deficits in longterm adult survivors

Risk for impairment increased with Children treated with auto HCT had younger age, longer follow-up time average IQ; however, deficits in memory and attention were seen

chapter

2000 14: before TBI and HCT, 20: after TBI and autologous HCT 11: controls with renal insufficiency

1998 66

1997 67: 1 year after HCT 26: 3 years after HCT

2002 40

1999 26

Year

TABLE 110.7. Neuropsychologic function after HCT.

1918 110

157

160

149

150

155

Phipps et al.

Simms et al.

Syrjala et al.

van Dam et al.

Wenz et al.

1998 34: autologous HCT 36: standard dose 34: controls, stage I, no chemotherapy 2000 58

2004 142

1998 122

2000 102 survivors to 1 year with 54 followed to 3 years

Case-control and cohort study

Prospective cohort study

Prospective cohort study

Prospective cohort study

Adult Prospective hyperfractionated cohort TBI with autologous study HCT

Adult breast cancer

Adults with malignancy receiving first allogeneic HCT

Pediatric HCT recipients with no previous cranial irradiation

Pediatric HCT

Median 27 months

Mean 2 years, minimum 6 months

80 days and 1 year

1 year

3 years

None found

8.2 RR (CI = 1.8–37.7) for HCT vs. control 3.5 RR (CI = 1.1–12.8) for HCT vs. standard chemotherapy

2.76 RR (CI = 1.01–7.55) for impaired motor dexterity in patients actively receiving cyclosporine, tacrolimus or my cophenolate mofetil vs. not 2.99 RR (CI = 1.08–8.30) for impairment on any test pretransplant in patients with no previous chemotherapy, or only hydroxyurea before HCT

None identified

Younger age showed more decline over time;