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Cancer DeVita, Hellman, and Rosenberg’s

Principles & Practice of Oncology

9th edition

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EDITORS

Vincent T. DeVita, Jr., MD Amy & Joseph Perella Professor of Medicine, Yale Comprehensive Cancer Center and Smilow Cancer Hospital at Yale-New Haven, Yale University School of Medicine, Professor of Epidemiology and Public Health, Yale University School of Public Health, New Haven, Connecticut

Theodore S. Lawrence, MD, PhD Isadore Lampe Professor and Chair, Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan

Steven A. Rosenberg, MD, PhD Chief of Surgery, National Cancer Institute, National Institutes of Health; Professor of Surgery, Uniformed Services University of the Health Sciences School of Medicine, Bethesda, Maryland; Professor of Surgery, George Washington University School of Medicine, Washington, DC

ASSOCIATE SCIENTIFIC ADVISORS Robert A. Weinberg, PhD Member, Whitehead Institute for Biomedical Research, Daniel K. Ludwig Professor of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts

Ronald A. DePinho, MD Director, Center for Applied Cancer Science, Belfer Institute for Innovative Cancer Science, Dana-Farber Cancer Institute; American Cancer Society Research Professor; Professor of Medicine and Genetics, Harvard Medical School, Boston, Massachusetts

With 431 Contributing Authors

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Cancer DeVita, Hellman, and Rosenberg’s

Principles & Practice of Oncology

9th edition

LWBK812-FM_pi-xlviii.indd iii

3/10/11 6:17:27 AM


Executive Editor: Jonathan W. Pine, Jr. Senior Managing Editor: Emilie Moyer Vendor Manager: Alicia Jackson Senior Manufacturing Manager: Benjamin Rivera Senior Marketing Manager: Angela Panetta Senior Designer: Stephen Druding Cover Designer: Stephen Druding Production Service: Aptara, Inc. Š 2011 by LIPPINCOTT WILLIAMS & WILKINS, a WOLTERS KLUWER business Two Commerce Square 2001 Market Street Philadelphia, PA 19103 USA LWW.com First Edition: J.B. Lippincott Company, 1982, Second Edition: J.B. Lippincott Company, 1985. Third Edition: J.B. Lippincott Company, 1989. Fourth Edition: J.B. Lippincott Company, 1993. Fifth Edition: Lippincott-Raven, 1997. Sixth Edition: Lippincott Williams & Wilkins, 2001. Seventh Edition: Lippincott Williams & Wilkins, 2005. Eighth Edition: Lippincott Williams & Wilkins, 2008. All rights reserved. This book is protected by copyright. No part of this book may be reproduced in any form by any means, including photocopying, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Materials appearing in this book prepared by individuals as part of their official duties as U.S. government employees are not covered by the above-mentioned copyright. Printed in the USA

Library of Congress Cataloging-in-Publication Data

Care has been taken to confirm the accuracy of the information presented and to describe generally accepted practices. However, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, expressed or implied, with respect to the currency, completeness, or accuracy of the contents of the publication. Application of the information in a particular situation remains the professional responsibility of the practitioner. The authors, editors, and publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accordance with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new or infrequently employed drug. Some drugs and medical devices presented in the publication have Food and Drug Administration (FDA) clearance for limited use in restricted research settings. It is the responsibility of the health care provider to ascertain the FDA status of each drug or device planned for use in their clinical practice. To purchase additional copies of this book, call our customer service department at (800) 6383030 or fax orders to (301) 223-2320. International customers should call (301) 223-2300. Visit Lippincott Williams & Wilkins on the Internet: at LWW.com. Lippincott Williams & Wilkins customer service representatives are available from 8:30 am to 6 pm, EST. 10 9 8 7 6 5 4 3 2 1

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To Mary Kay Wendy Alice

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CONTRIBUTING AUTHORS

Sumaira Z. Aasi, MD

Jaffer Ajani, MD

Matthew L. Anderson, MD, PhD

Yale Surgical Dermatology Yale New Haven Hospital New Haven, Connecticut

Professor of Medicine Department of Gastrointestinal Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

Assistant Professor Division of Gynecologic Oncology Baylor College of Medicine Attending Surgeon Texas Cancer Institute Saint Luke’s Episcopal Hospital Houston, Texas

Amy P. Abernathy, MD Associate Professor of Medicine Division of Medical Oncology Department of Medicine Associate Director Duke Comprehensive Cancer Center Duke University Durham, North Carolina

Janet L. Abrahm, MD Associate Professor of Medicine Harvard Medical School Staff Physician Department of Medicine Psychosocial Oncology and Palliative Care Dana-Farber Cancer Institute Brigham and Women’s Hospital Boston, Massachusetts

Maysa M. Abu-Khalaf, MD, MBBS Assistant Professor Division of Medical Oncology Yale University School of Medicine Yale Comprehensive Cancer Center New Haven, Connecticut

Gregory P. Adams, PhD Associate Professor Developmental Therapeutics Program Fox Chase Cancer Center Philadelphia, Pennsylvania

Anupriya Agarwal, PhD Postdoctoral Fellow Department of Hematology/Oncology Center for Hematologic Malignancies Oregon Health & Science University Portland, Oregon

Nishant Agrawal, MD Department of Otolaryngology-Head and Neck Surgery Johns Hopkins Medical Institutions Baltimore, Maryland

Daniel M. Albert, MD, MS RRF Emmett A. Humble Distinguished Director of the University of Wisconsin Eye Research Institute F. A. Davis Professor Department of Ophthamology and Visual Sciences University of Wisconsin, Madison Madison, Wisconsin

Peter C. Albertson, MD, MS Professor Department of Surgery University of Connecticut Health Center Farmington, Connecticut

H. Richard Alexander, Jr., MD Professor and Associate Chair for Clinical Research Department of Surgery University of Maryland School of Medicine Baltimore, Maryland

James M. Allan, DPhil Faculty of Medical Sciences Newcastle University Newcastle-Upon-Tyne, United Kingdom

Kenneth C. Anderson, MD Kraft Family Professor of Medicine Department of Medicine Harvard Medical School Chief Division of Hematologic Neoplasms Department of Medical Oncology Dana-Farber Cancer Institute Boston, Massachusetts

Smith Apisarnthanarax, MD Assistant Professor Department of Radiation Oncology University of Pennsylvania Philadelphia, Pennsylvania

Alicia Y. Armstrong, MD, MHSCR Professor Department of Obstetrics and Gyneology Uniformed Services University Chief, Clinical Services Program in Reproductive and Adult Endocrinology National Institue of Child Health and Human Development National Institutes of Health Bethesda, Maryland

Vivek K. Arora, MD, PhD Fellow Human Oncology & Pathogenesis Program Memorial Sloan-Kettering Cancer Center New York, New York

Alan Ashworth, PhD, FRS Chief Executive Institute of Cancer Research London, United Kingdom

Cristina R. Antonescu, MD Department of Pathology Memorial Sloan-Kettering Cancer Center New York, New York

vii

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viii

Contributing Authors

Itzhak Avital, MD

Susan Elaine Bates, MD

Andrew Berchuck, MD

Senior Investigator and Staff Clinician, Assistant Professor of Surgery Surgery Branch National Cancer Institute/National Institute of Health Uniformed University of the Health Sciences Bethesda, Maryland

Senior Investigator Medical Oncology Branch National Cancer Institute Bethesda, Maryland

Director Division of Gynecological Oncology Duke University Medical Center Durham, North Carolina

Steven B. Baylin, MD

Jonathan S. Berek, MD, MMS

Virginia and D.K. Ludwig Professor for Cancer Research Professor of Oncology and Medicine Deputy Director The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Johns Hopkins School of Medicine Baltimore, Maryland

Professor and Director Women’s Cancer Center Stanford Cancer Center Chair, Department of Obstetrics and Gynecology Stanford University School of Medicine Stanford, California

J. Robert Beck, MD

Alice Hawley Berger, BS

Professor and Senior Vice President Chief Academic and Medical Officer Fox Chase Cancer Center Philadelphia, Pennsylvania

Graduate Student Department of Cancer Biology Weill Graduate School of Medical Sciences of Cornell University Cancer Center Genetics Program Beth Israel Deaconess Cancer Center Boston, Massachusetts

Joachim M. Baehring, MD Associate Professor Attending Physician Department of Neurology, Medicine, and Neurosurgery Yale University School of Medicine Yale-New Haven Hospital New Haven, Connecticut

Dean F. Bajorin, MD, FACP Attending Physician and Member Department of Medicine Memorial Sloan-Kettering Cancer Center Professor Department of Medicine Weill Cornell Medical College New York, New York

Igor J. Barani, MD Assistant Professor in Residence Attending Physician Department of Radiation Oncology University of California, San Francisco San Francisco, California

David A. Barbie, MD Department of Medical Oncology Massachusetts General Hospital Boston, Massachusetts

Alberto Bardelli, PhD Laboratory of Molecular Genetics Institute for Cancer Research and Treatment University of Torino Medical School Candiolo, Italy

David L. Bartlett, MD Bernard Fisher Professor of Surgery Department of Surgery University of Pittsburgh Chief Department of Surgery University of Pittsburgh Medical Center Pittsburgh, Pennsylvania

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Jürgen C. Becker, MD, PhD Professor Department of General Dermatology Medical University of Graz (MUG) Chief Department of Dermatology University Hospital-Graz Graz, Austria

Kevin P. Becker, MD, PhD Clinical Instructor Department of Neurology Yale University School of Medicine New Haven, Connecticut

David J. Beddy, MD, FRCS Fellow Division of Colon and Rectal Surgery Mayo Clinic Rochester, Minnesota

Claudio Belluco, MD Attending Surgeon Department of Surgical Oncology Centro di Riferimento Oncologico, National Cancer Institue Aviano (PN), Italy

Edgar Ben-Josef, MD

Ann M. Berger MSN, MD Bethesda, Maryland

Ross S. Berkowitz, MD William H. Baker Professor of Gynecology Department of Obstetrics and Gyncology Harvard Medical School Director of Gynecologic Oncology and Gynecology Department of Obstetrics and Gynecology Brigham and Women’s Hospital and Dana-Farber Cancer Institute Boston, Massachusetts

Jordan D. Berlin, MD Associate Professor of Medicine Clinical Director, GI Oncology Program Director, Phase I Program Medical Director, Clinical Trials Shared Resources Member Vanderbilt Ingram Cancer Center Medical Oncologist Nashville, Tennessee

Professor Department of Radiation Oncology University of Michigan University of Michigan Hospital Ann Arbor, Michigan

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ix

Contributing Authors

Leslie Bernstein, PhD

Danielle Campfield Bonadies, MS

Harold J. Burstein, MD, PhD

Professor and Director Division of Cancer Etiology, Department of Population Sciences Beckman Research Institute of the City of Hope Dean for Faculty Affairs City of Hope Medical Center and Beckman Research Institute Duarte, California

Genetic Counselor Yale Cancer Center Yale School of Medicine New Haven, Connecticut

Associate Professor of Medicine Harvard Medical School Breat Oncology Center Dana-Farber Cancer Institute Boston, Massachusetts

Ravi Bhatia, MD Director Hematopoietic Stem Cell & Leukemia Research Co-Director Hematological Malignancies Program City of Hope Duarte, California

Smita Bhatia, MD, MPH Professor and Chair Department of Population Sciences City of Hope Professor Department of Pediatrics City of Hope National Medical Center Duarte, California

Adrian M. Di Bisceglie, MD, FACP Professor and Chair Department of Internal Medicine St. Louis University St. Louis, Missouri

Dale Bixby, MD, PhD Clinical Assistant Professor Department of Internal Medicine University of Michigan Ann Arbor, Michigan

Elizabeth M. Blanchard, MD Medical Oncologist Southcoast Center for Cancer Care Southcoast Hospital Group North Dartmouth, Massachusetts

Sharon L. Bober, PhD Clinical Instructor Department of Psychology Harvard Medical School Director Sexual Health Program Dana-Farber Cancer Institute Boston, Massachusetts

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Hossein Borghaei, DO, MS Assistant Professor Department of Medical Oncology Fox Chase Cancer Center Philadelphia, Pennsylvania

Tim E. Byers, MD, MPH

George J. Bosl, MD

John C. Byrd, MD

Professor of Medicine Department of Medicine Weill Cornell Medical College Chair Department of Medicine The Patrick M Byrne Chair in Clinical Oncology Memorial Sloan-Keetering Cancer Center New York, New York

Division of Hematology and Comprehensive Cancer Center The Ohio State University Columbus, Ohio

Michael Boyiadzis, MD Division of Hematology/Oncology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania

Dean E. Brenner, MD Kutsche Family Professor of Internal Medicine Professor of Pharmacology University of Michigan and VA Medical Center Ann Arbor, Michigan

Paul D. Brown, MD Professor Department of Radiation Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

Gary L. Buchschacher, Jr., MD, PhD Assistant Clinical Professor of Medicine David Geffen School of Medicine University of California, Los Angeles Staff Physician Department of Hematology/Oncology Los Angeles Medical Center, Kaiser Foundation/SCPMG Los Angeles, California

Associate Dean Colorado School of Public Health Aurora, Colorado

Joseph Califano, MD Department of Otolaryngology-Head and Neck Surgery Johns Hopkins Medical Institutions Milton J. Dance Head and Neck Center Greater Baltimore Medical Center Baltimore, Maryland

Robert B. Cameron, MD Professor of Cardiothoracic Surgery and Surgical Oncology Department of Surgery David Geffen School of Medicine at University of California Los Angeles, California

Stephen A. Cannistra, MD Professor of Medicine Department of Medicine Harvard Medical School Director Department of Gynecological Medical Oncology Beth Israel Deaconess Medical Center Boston, Massachusetts

Lewis C. Cantley, PhD Clinical Oncology Merck Research Laboratories Upper Gwynned, Pennsylvania

David P. Carbone, MD, PhD Professor of Medicine & Cancer Biology Department of Medicine/ Hematology & Oncology Vanderbilt University Nashville, Tennessee

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x

Contributing Authors

Michele Carbone, MD, PhD

Jan Cerny, MD, PhD

Professor and Chair Department of Pathology John A. Burns School of Medicine Director Cancer Research Center of Hawaii University of Hawaii Honolulu, Hawaii

Assistant Professor of Medicine Department of Medicine Division of Hematology and Oncology University of Massachusetts University of Massachusetts Memorial Medical Center Worchester, Massachusetts

Tobias Carling, MD, PhD

Raju S. K. Chaganti, PhD

Assistant Professor of Surgery Attending Surgeon Department of Surgery Yale University School of Medicine Yale New Haven Hospital New Haven, Connecticut

Member and Professor Cell Biology Program Member and Attending Department of Medicine Memorial Sloan-Kettering Cancer Center New York, New York

Chris L. Carpenter, PhD Division of Signal Transduction Department of Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts

Darryl Carter, MD Professor of Pathology, Emeritus Yale University New Haven, Connecticut

Eric J. Cassell, MD, MACP Emeritus Professor of Public Medicine Weill Cornell Medical College New York, New York Adjunt Professor of Medicine Faculty of Medicine McGill University Montreal, Canada Attending Physician Department of Medicine New York Presbyterian Hospital Cornell Medical Center New York, New York

Webster K. Cavenee, PhD Director and Distinguished Professor Ludwig Institute for Cancer Research University of California, San Diego La Jolla, California

Keith A. Cengel, MD, PhD Assistant Professor Department of Radiation Oncology University of Pennsylvania Director, Photodynamic Therapy Program Hospital of the University of Pennsylvania Philadelphia, Pennsylvania

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Richard Champlin, MD Departments of Leukemia and Stem Cell Transplantation and Cellular Therapy The University of Texas MD Anderson Cancer Center Houston, Texas

Susan M. Chang, MD Professor Attending Physician Department of Neurological Surgery University of California, San Francisco San Francisco, California

Cindy H. Chau, PharmD, PhD Scientist Medical Oncology Branch National Cancer Institute Bethesda, Maryland

Yu Chen, MD, PhD Fellow Human Oncology & Pathogenesis Program Fellow Department of Medicine Memorial Sloan-Kettering Cancer Center New York, New York

Douglas Brian Chepeha, MD, MSPH, FRCS(C) Associate Professor Otolaryngology–Head and Neck Surgery University of Michigan Director, Microvascular Reconstructive Surgery Otolaryngology–Head and Neck Surgery University of Michigan Ann Arbor, Michigan

Nathan I. Cherny MBBS, FRACP, FRCP Cancer Pain and Palliative Medicine Service Department of Oncology Shaare Zedek Medical Center Jerusalem, Israel

Richard W. Childs, MD Senior Investigator Hematology Branch National Heart, Lung, and Blood Institute National Institutes of Health Bethesda, Maryland

Lynda Chin, MD Professor of Dermatology Department of Medical Oncology Dana-Farber Cancer Institute Boston, Massachusetts

Murali Chintagumpala, MD Professor of Pediatrics Department of Pediatrics Baylor College of Medicine Professor of Pediatrics Department of Hematology/ Oncology, Pediatrics Texas Children’s Hospital Houston, Texas

Edward Chow, MD Professor Department of Radiation Oncology University of Toronto Radiation Oncologist Department of Radiation Oncology Sunnybrook Health Sciences Centre Toronto, Canada

Edward Chu, MD Professor of Medicine Chief, Division of HematologyOncology Department of Medicine University of Pittsburgh Cancer Institute University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania

Gina G. Chung, MD Assistant Professor Department of Internal Medicine Yale Cancer Center Yale University School of Medicine Smilow Cancer Hospital Yale-New Haven Hospital New Haven, Connecticut

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Contributing Authors

Timothy R. Church, PhD, MS

Craig M. Crews, PhD

Michael W. Deininger, MD, PhD

Professor Division of Environmental Health Sciences University of Minnesota School of Public Health Minneapolis, Minnesota

Lewis B. Cullman Professor Department of Molecular, Cellular, and Developmental Biology Yale University New Haven, Connecticut

Lorenzo Cohen, PhD

Associate Professor of Surgery Harvard Medical School Chief, Division of Urologic Oncology Department of Urology Massachusetts General Hospital Boston, Massachuesetts

Maxwell M. Wintrobe, MD Presidential Endowed Chair in Internal Medicine Chief, Division of Hematology and Hematologic Malignancies Department of Internal Medicine University of Utah/Huntsman Cancer Institute Salt Lake City, Utah

Professor Department of Behavioral Science, Cancer Prevention and Population Sciences The University of Texas MD Anderson Cancer Center Houston, Texas

Robert E. Coleman, MD, FRCP, FRCPE Yorkshire Cancer Research Professor of Medical Oncology Academic Unit of Clinical Oncology University of Sheffield Honorary Consultant Academic Unit of Clinical Oncology Weston Park Hospital Sheffield, United Kingdom

Louis S. Constine, MD, FASTRO Professor of Radiation Oncology and Pediatrics Vice Chair Department of Radiation Oncology James P. Wilmot Cancer Center University of Rochester Medical Center Attending Physician Department of Radiation Oncology Strong Memorial Hospital Rochester, New York

M. Sitki Copur MD, FACP Associate Professor Department of Internal Medicine University of Nebraska Medical Center Medical Director Department of Oncology Saint Francis Cancer Center Omaha, Nebraska

Christopher Crane, MD Professor Program Director and Section Chief, Gastrointestinal Section Department of Radiation Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

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Douglas M. Dahl, MD, FACS

Riccardo Dalla-Favera, MD Professor and Director Institute for Cancer Genetics Columbia University New York, New York

Mary B. Daly, MD, PhD Chairperson Department of Clinical Genetics Fox Chase Cancer Center Philadelphia, Pennsylvania

Alan D. D’Andrea, MD Dana-Farber Cancer Institute Boston, Massachusetts

Laura A. Dawson, FRCPC, MD Radiation Medicine Program Princess Margaret Hospital Toronto, Ontario, Canada

Lisa M. DeAngelis, MD Professor of Neurology Weill Cornell Medical College Chair Department of Neurology Memorial Sloan-Kettering Cancer Center New York, New York

Alan H. DeCherney, MD Head Program in Reproductive and Adult Endocrinology National Institute of Child Health and Human Development National Institutes of Health Bethesda, Maryland

Marcos De Lima, MD Departments of Leukemia and Stem Cell Transplantation and Cellular Therapy The University of Texas MD Anderson Cancer Center Houston, Texas

George D. Demetri, MD Senior Vice President for Experimental Therapeutics Ludwig Center Medical Oncology Dana-Farber Cancer Institute Harvard Medical School Boston, Massachusetts

Ronald A. DePinho, MD Director Belfer Institute for Applied Cancer Science Dana-Farber Cancer Institute Harvard Medical School Professor Department of Medicine Brigham & Women’s Hospital Boston, Massachusetts

Marcello Deraco, MD Professor Department of Postgraduation on Digestive Surgery Tor Vergata University Rome, Italy Responsible for Perotineal Surface Malignancies Department of Surgery IRCCS National Insutute of Tumors Foundation Milan, Italy

Vincent T. DeVita, Jr., MD Amy & Joseph Perella Professor of Medicine Yale Comprehensive Cancer Center and Smilow Cancer Hospital at Yale-New Haven Yale University School of Medicine Professor of Epidemiology and Public Health Yale University School of Public Health New Haven, Connecticut

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xii

Contributing Authors

John E. Dick, PhD

Richard L. Edelson, MD

Virginia Espina, MS

Professor Department of Molecular Biology University of Toronto Canada Research Chair in Stem Cell Biology, Senior Scientist Department of Cellular and Molecular Biology University Health Network Toronto, Ontario, Canada

Professor and Chairman Department of Dermatology Yale School of Medicine Chief, Dermatology Service Department of Dermatology Yale-New Haven Hospital New Haven, Connecticut

Research Assistant Professor George Mason University Center for Applied Proteomics and Molecular Medicine Manassas, Virginia

Laura J. Esserman, MD, MBA

University Hospital of Cologne Cologne, Germany

Resident, Department of Internal Medicine University Hospital of Cologne Cologne, Germany

Director Carol Franc Buck Breast Care Center Department of Surgery University of California, San Francisco San Francisco, California

Gerard M. Doherty, MD

Patricia J. Eifel, MD

Eli Estey, MD

N. W. Thompson Professor and Vice Chair Department of Surgery University of Michigan Chief, General Surgery University of Michigan Hospitals and Health Centers Ann Arbor, Michigan

Professor Department of Radiation Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

Division of Hematology University of Washington and Fred Hutchinson Cancer Research Center Seattle, Washington

Dominique Elias, MD, PhD

Douglas B. Evans, MD

Chief Department of Surgical Oncology Gustave Roussy Institute Villejuif, France

Department of Surgery Medical College of Wisconsin Milwaukee, Wisconsin

Anthony El-Khoueiry, MD

Associate Professor Department of Leukemia The University of Texas MD Anderson Cancer Center Houston, Texas

Volker Diehl, MD

Brian J. Druker, MD Professor Department of Medicine Division of Hematolgy and Medical Oncology Oregon Health & Science University Investigator Howard Hughes Medical Institute Director Oregon Health & Sciences University Knight Cancer Institute Portland, Oregon

Craig C. Earle, MD Associate Professor Department of Medicine University of Toronto Medical Oncologist Odette Cancer Centre Sunnybrook Health Sciences Centre Toronto, Ontario, Canada

James A. Eastham, MD Professor of Urology Department of Surgery Chief, Urology Service Department of Surgery Memorial Sloan-Kettering Cancer Center New York, New York

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Dennis A. Eichenauer, MD

Assistant Professor of Medicine Department of Medicine/Medical Oncology University of Southern California, Norris Comprehensive Cancer Center Los Angeles, California

Lee M. Ellis, MD Professor of Surgery and Cancer Biology Department of Surgical Oncology and Cancer Biology The University of Texas MD Anderson Cancer Center Houston, Texas

Andreas Engert, MD

Stefan Faderl, MD

Jane M. Fall-Dickson, PhD, RN, AOCN National Institute of Nursing Research Bethesda, Maryland

Ann Theresa Farrell, MD Deputy Division Director Division of Drug Oncology Products Office of Oncology Drug Products Center for Drug Evaluation and Research Silver Spring, Maryland

Department of Internal Medicine University Hospital of Cologne Cologne, Germany

Eve C. Feinberg, MD

Charles Erlichman, MD

Darren R. Feldman, MD

Consultant, Professor of Oncology Department of Oncology, Division of Medical Oncology Mayo Clinic College of Medicine Rochester, Minnesota

Instructor Department of Medicine Weill Medical College of Cornell University Assistant Attending Department of Medicine Memorial Sloan-Kettering Cancer Center New York, New York

Fertility Centers of Illinois Highland Park, Illinois

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Contributing Authors

James L. M. Ferrara, MD, ScD

Antonio Tito Fojo, MD, PhD

Craig J. Galbรกn, PhD

Professor Department of Pediatrics and Internal Medicine University of Michigan Medical School Director, Blood and Marrow Transplant Program Department of Pediatrics, Hematology/Oncology University of Michigan Comprehensive Cancer Center Ann Arbor, Michigan

Senior Investigator Medical Oncology Branch National Cancer Institute Bethesda, Maryland

Professor Department of Radiology and Biomedical Engineering University of Michigan Ann Arbor, Michigan

William D. Figg, PharmD, MBA Senior Investigator Medical Oncology Branch National Cancer Institute National Institute of Health Bethesda, Maryland

Michelle Cororve Fingeret, PhD Assistant Professor Department of Behavioral Science The University of Texas MD Anderson Cancer Center Houston, Texas

Joel Finkelstein, MSc, MD, FRCS(C) Associate Professor Department of Surgery University of Toronto Consultant Orthopaedic Surgeon Division of Orthopaedics Sunnybrook Health Sciences Center Toronto, Ontario

Richard I. Fisher, MD Senior Associate Dean for Clinical Affairs Department of HematologyOncology Director James P. Wilmot Cancer Center Strong Memorial Hospital Rochester, New York

Keith Thomas Flaherty, MD Associate Professor Harvard School of Medicine Director of Developmental Therapeutics Department of Medicine Massachusetts General Hospital Boston, Massachusetts

Chris I. Flowers, MBBS, FRCR Associate Professor Department of Radiology and Biomedical Imaging University of California, San Francisco San Francisco, California

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Kathleen M. Foley, MD Professor of Nuerology, Neuroscience & Clinical Pharmacology School of Medicine and Public Health Department of Neurology Weill Medical College of Cornell University Attending Neurologist Memorial Sloan-Kettering Cancer Center New York, New York

xiii

Don Ganem, MD Departments of Medicine and of Microbiology and Immunology University of California, San Francisco School of Medicine San Francisco, California

Patricia A. Ganz, MD

Chief Department of Hematologic Malignance Nevada Cancer Institute Las Vegas, Nevada

Professor School of Medicine and Public Health Director Division of Cancer Prevention and Control Research Jonsson Comprehensive Cancer Center University of California Los Angeles, California

Francine Foss, MD

Levi A. Garraway, MD, PhD

Professor of Medicine Department of Medical Oncology and and Bone Marrow Transplantion Yale University School of Medicine New Haven, Connecticut

Assistant Professor of Medicine, Harvard Medical School Department of Medical Oncology Dana-Farber Cancer Institute Boston, Massachusetts Senior Associate Member, The Broad Institute of Harvard and MIT Cambridge, Massachusetts

Kenneth A. Foon, MD

Harold P. Freeman, MD Professor Emeritus Department of Surgery Columbia University Attending Surgeon Department of Surgery Memorial Hospital for Cancer and Allied Diseases New York, New York

Jonathan W. Friedberg, MD, MMSc Professor, Department of Medicine Chief, Hematology/Oncology Division James P. Wilmot Cancer Center Rochester University Medical Center Rochester, New York

Sheryl G. A. Gabram, MD, MBA Professor Department of Surgery Emory University Director Avon Comprehensive Breast Center Grady Memorial Hospital Atlanta, Georgia

Juan C. Gea-Banacloche, MD Chief Infectious Diseases Consultation Service Experimental Transplantation and Immunology Branch National Cancer Institute National Institutes of Health Bethesda, Maryland

Christos S. Georgiades, PhD, MD, FSIR Associate Professor Department of Radiology Johns Hopkins University Clinical Director Department of Vascular and Interventional Radiology Johns Hopkins Hospital Baltimore, Maryland

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Contributing Authors

David M. Gershenson, MD

Matthew P. Goetz, MD

Ellen R. Gritz, PhD

J. Taylor Wharton, MD Distinguished Chair in Gynecological Oncology Professor & Chairman Department of Gynecologic Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

Consultant, Associate Professor of Oncology Department of Oncology, Division of Medical Oncology Mayo Clinic College of Medicine Rochester, Minnesota

Professor and Chair Department of Behavioral Science The University of Texas MD Anderson Cancer Center Houston, Texas

Donald P. Goldstein, MD

Jean-Francois H. Geschwind, MD Professor Department of Radiology Johns Hopkins University Chief Department of Vascular and Interventional Radiology Johns Hopkins Hospital Baltimore, Maryland

Professor Department of Obstetrics, Gyncology, and Reproductive Biology Harvard Medical School Attending Gynecologist Department of Obstetrics and Gynecology Brigham and Women’s Hospital Boston, Massachusetts

Department of Surgery Memorial Sloan-Kettering Cancer Center New York, New York

Larisa J. Geskin, MD

Leonard G. Gomella, MD, FACS

Director, Cutaneous Oncology Center Department of Dermatology University of Pittsburgh Medical Center Pittsburgh, Pennsylvania

Chairman Department of Urology Kimmel Cancer Center, Thomas Jefferson University Hospital Philadelphia, Pennsylvania

Scott Gettinger, MD

David J. Gordon, MD, PhD

Assistant Professor of Medicine Yale University School of Medicine Yale Cancer Center New Haven, Connecticut

Instructor Department of Pediatrics Harvard Medical School Department of Hematology/Oncology Dana-Farber Cancer Institute Boston, Massachusetts

Giuseppe Giaccone, MD, PhD Chief Medical Oncology Branch National Cancer Institute Bethesda, Maryland

Edward L. Giovannucci, MD, ScD Professor Department of Nutrition and Epidemiology Harvard School of Public Health Associate Professor Department of Medicine Brigham and Women’s Hospital Havard Medical School Boston, Massachusetts

Olivier Glehen, MD, PhD Professor Equipe Accueil Université Claude Bernard Lyon 1 Oullins, France Professor Department of Surgical Oncology Centre Hospitalier Lyon Sud Pierre Bénite, France

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Steven D. Gore, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland

F. Anthony Greco, MD Director Sarah Cannon Cancer Center Centennial Medical Center Nashville, Tennessee

Jan Grimm, MD, PhD Department of Radiology Memorial Sloan-Kettering Cancer Center New York, New York

Joe W. Grisham, MD Senior Scientist Laboratory of Experimental Carcinogenesis Center for Cancer Research, NCI, National Institutes of Health Bethesda, Maryland

José G. Guillem, MD

Patrick K. Ha, MD Department of Otolaryngology-Head and Neck Surgery Johns Hopkins Medical Institutions Milton J. Dance Head and Neck Center Greater Baltimore Medical Center Baltimore, Maryland

Stephen M. Hahn, MD Professor and Chair Department of Radiation Oncology University of Pennsylvania School of Medicine Philadelphia, Pennsylvania

William C. Hahn, MD, PhD Associate Professor Department of Medicine Harvard Medical School Division Chief Department of Molecular and Cellular Oncology Dana-Farber Cancer Institute Boston, Massachusetts

John D. Hainsworth, MD Chief Scientific Officer Sarah Cannon Cancer Center Centennial Medical Center Nashville, Tennessee

Lyndsay N. Harris, MD Associate Professor Yale Cancer Center, Section of Medical Oncology Co-Director Breast Disease Unit Smilow Cancer Hospital Yale-New Haven Hospital New Haven, Connecticut

Jay R. Harris, MD Professor Department of Radiation Oncology Harvard Medical School Chair Department of Radiation Oncology Dana-Farber Cancer Institute Brigham and Women’s Hospital Boston, Massachusetts

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Contributing Authors

Nancy Lee Harris, MD

C. William Helm, MB, BChir

Peter M. Howley, MD

Austin L. Vickery Professor Department of Pathology Harvard Medical School Pathologist; Editor, Case Records of the Massachusetts General Hospital Department of Pathology Massachusetts General Hospital Boston, Massachusetts

Professor Division of Gynecologic Oncology Department of Obstetrics, Gynecology and Women’s Health Division of Gynecologic Oncology, Cancer Center St. Louis University Hospital St. Louis, Missouri

Professor Department of Pathology Harvard Medical School Boston, Massachusetts

Axel Hauschild, MD

Katherine D. Henderson, PhD

Professor of Dermatology Department of Dermatology, Campus Kiel University Hospital (UKSH) Kiel, Germany

Assistant Research Professor Division of Cancer Etiology, Department of Population Sciences Beckman Research Institute of the City of Hope Duarte, California

Melissa M. Hudson, MD

James G. Herman, MD

David H. Ilson, MD, PhD

Department of Hematology/Medical Oncology Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center Baltimore, Maryland

Professor Department of Medicine Weill Medical College of Cornell University Attending Physician Department of Medicine Memorial Sloan-Kettering Cancer Center New York, New York

Marc J. Haxer, MA, CCC-SLP Speech–Language Pathologist Departments of Speech–Pathology and Otolaryngology—Head and Neck Surgery University of Michigan Ann Arbor, Michigan

Daniel F. Hayes, MD Professor Department of Internal Medicine University of Michgan School of Medicine Co- Director Breast Oncology Program University of Michigan Comprehensive Cancer Center Ann Arbor, Michigan

Stephen S. Hecht, PhD Wallin Professor of Cancer Prevention Masonic Cancer Center University of Minnesota Minneapolis, Minnesota

Matthew T. Heller, MD Assistant Professor of Radiology Division of Abdominal Imaging University of Pittsburgh Medical Center Pittsburgh, Pennsylvania

Lee J. Helman, MD Scientific Director for Clinical Research Center for Cancer Research National Cancer Institute Bethesda, Maryland

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Paul J. Hesketh, MD Professor Department of Medicine Tufts University School of Medicine Boston, Massachusetts Director Thoracic Oncology Division of Hematology/Oncology Lahey Clinic Medical Center Burlington, Massachusetts

Erin W. Hofstatter, MD Assistant Professor Yale Cancer Center, Section of Medical Oncology Yale University Smilow Cancer Hospital Yale-New Haven Hospital New Haven, Connecticut

Leora Horn, MD, MS Assistant Professor Department of Internal Medicine Vanderbilt University Nashville, Tennessee

Yoshinori Hosoya, MD, PhD Associate Professor Department of Surgery Jichi Medical University Tochigi, Japan

xv

Ralph H. Hruban, MD Department of Pathology Johns Hopkins University Baltimore, Maryland

Director, Cancer Survivorship Division Department of Oncology St. Jude Children’s Research Hospital Memphis, Tennessee

Bonnie A. Indeck, MSW, LCSW Clinical Instructor Department of Internal Medicine Yale Cancer Center Manager, Oncology Social Worker Department of Social Work Yale-New Haven Hospital New Haven, Connecticut

C. David James, PhD Professor Department of Neurological Surgery University of California, San Francisco San Francisco, California

Ahmedin Jemal American Cancer Society Atlanta, Georgia

James R. Jett, MD Professor of Medicine Staff Physician Department of Pulmonary Medicine Mayo Clinic Rochester, Minnesota

Yixing Jiang, MD Assitant Professor Department of Medicine Penn State College of Medicine Hershey, Pennsylvania

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Contributing Authors

Peter A. Jones, MD

Donald S. Kaufman, MD

Scott E. Kern, MD

Distinguished Professor Department of Urology, Biochemistry and Molecular Biology Keck School of Medicine of University of Southern California Director, Cancer Center University of Southern California/ Norris Comprehensive Cancer Center Los Angeles, California

Clinical Professor of Medicine Department of Medicine Harvard Medical School Director of Education, The John and Claire Bertucci Center for Genitourinary Cancers Division of Hematology/Oncology Massachusetts General Hospital Boston, Massachusetts

Professor Department of Oncology Johns Hopkins University Baltimore, Maryland

Lisa A. Kachnic, MD

Vanderbilt University Medical Center Nashville, Tennessee

Associate Professor Chief Department of Radiation Oncology Boston Medical Center Boston, Massachusetts

Madhuri Kakarala, MD, PhD Clinical Lecturer University of Michigan and VA Medical Center Ann Arbor, Michigan

Udai S. Kammula, MD Senior Investigator Surgery Branch National Cancer Institute National Institutes of Health Bethesda, Maryland

Hagop M. Kantarjian, MD Department of Leukemia The University of Texas MD Anderson Cancer Center Houston, Texas

Joyson J. Karakunnel, MD, FACP Bethesda, MD

Vassiliki Karantza, MD, PhD Assistant Professor Department of Medicine-Medical Oncology Cancer Institute of New Jersey Attending Physician Robert Wood Johnson University Hospital New Brunswick, New Jersey

Michael G. Kauffman, MD, PhD Onyx Pharmaceuticals

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Jacob Kaufman

Electron Kebebew, MD Senior Investigator, Head of Endocrine Oncology Surgery Branch National Cancer Institute Bethesda, Maryland

Partow Kebriaei, MD Associate Professor Department of Stem Cell Transplant and Cellular Therapy The University of Texas MD Anderson Cancer Center Houston, Texas

David P. Kelsen, MD Chief, Gastrointestinal Oncology Department of Medicine Memorial Sloan Kettering Cancer Center Edward S. Gordon Chair in Medical Oncology Professor of Medicine Weill School of Medicine of Cornell University New York, New York

Alok Anand Khorana, MD, FACP Associate Professor of Medicine and Oncology Division of Hematology/Oncology Department of Medicine James P. Wilmot Cancer Center University of Rochester Medical Center Rochester, New York

Elliott Kieff, MD, PhD Departments of Medicine and of Microbiology and Molecular Genetics Harvard Medical School Boston, Massachusetts

Christopher J. Kirk, PhD Onyx Pharmaceuticals

Mio Kitano, MD Surgery Branch National Cancer Institute, Center for Cancer Research National Institutes of Health, Bethesda, Maryland

Margaret A. Knowles, PhD Professor of Experimental Cancer Research Section of Experimental Oncology Leeds Institute of Molecular Medicine St. James’s University Hospital University of Leeds Leeds, United Kingdom

Christopher R. Kelsey, MD

Manish Kohli, MD

Assistant Professor Department of Radiation Oncology Duke Cancer Institute Duke University Medical Center Durham, North Carolina

Associate Professor of Oncology Department of Oncology Mayo Clinic, College of Medicine Chief, Genitourinary Medical Oncology Department of Oncology Mayo Clinic Rochester, Minnesota

Robert S. Kerbel, PhD Professor Department of Biophysics Senior Scientist Department of Molecular & Cellular Biology Research Sunnybrook Health Sciences Centre Toronto, Ontario, Canada

Marisa A. Kollmeier, MD Assistant Professor and Assistant Attending Department of Radiation Oncology Memorial Sloan-Kettering Cancer Center New York, New York

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Contributing Authors

Mark G. Kris, MD

Cho Lam, PhD

Richard Lee, MD

Professor of Medicine Department of Medicine Weill Medical College of Cornell University Chief Department of Thoracic Medicine Memorial Sloan-Kettering Cancer Center New York, New York

Assistant Professor Department of Behavioral Science The University of Texas MD Anderson Cancer Center Houston, Texas

Assistant Professor Department of General Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

Wendy Landier, RN, MSN

David J. Leffell, MD

Clinical Director Center for Cancer Survivorship Department of Population Sciences City of Hope Duarte, California

Section Director Department of Dermatology Yale University New Haven, Connecticut

David A. Larson, MD, PhD

Professor Department of Surgery Jichi Medical University Tochigi, Japan

Lee M. Krug, MD Associate Member Associate Attending Physician Department of Medicine Memorial Sloan-Kettering Cancer Center New York, New York

Raju Kucherlapati, PhD Paul C. Cabot Professor of Genetics Department of Genetics Havard Medical School Professor of Medicine Departments of Medicine and Genetics Brigham and Women’s Hospital Boston, Massachusetts

Professor Department of Radiation Oncology University of California, San Francisco San Francisco, California

Steven M. Larson, MD, FACNP, FACR Chief of Nuclear Medicine Department of Nuclear Medicine Memorial Sloan-Kettering Cancer Center New York, New York

Amol D. Kulkarni, MD

Alessandro Laviano, MD

Resident Physician Department of Ophthamology University of Wisconsin, Madison Madison, Wisconsin

Associate Professor Department of Clinical Medicine Sapienza University of Rome Dirigente Medico I Livello Department of Internal Medicine, Clinical Immunology, Clinical Nutrition and Endocrinology Umberto I, Policlinico di Roma Rome, Italy

Carla Kurkjian, MD Assistant Professor Section of Hematology/Oncology Department of Medicine University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma

King F. Kwong, MD Principle Investigator Department of Thoracic Oncology, Surgery Branch Attending Thoracic Surgeon Surgery Branch, Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda, Maryland

Nadia N. Issa Laack, MD, MS Assistant Professor Department of Radiation Oncology Mayo Clinic Rochester, Minnesota

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Theodore S. Lawrence, MD, PhD Isadore Lampe Professor and Chair Department of Radiation Oncology University of Michigan Ann Arbor, Michigan

Agnes Yuet Ying Lee, MD, MSc, FRCPC Associate Professor Department of Medicine University of British Columbia Medical Director, Thrombosis Program Department of Medicine, Division of Hematology Vancouver Acute, Vancouver Coastal Health Vancouver, British Columbia, Canada

xvii

Alan T. Lefor, MD, MPH

Heinz-Josef Lenz, MD Professor of Medicine Department of Medicine/Medical Oncology University of Southern California, Norris Comprehensive Cancer Center Los Angeles, California

Steven K. Libutti, MD Professor Department of Surgery and Genetics Albert Einstein College of Medicine Vice Chairman Department of Surgery Montefiore Medical Center Bronx, New York

Frank S. Lieberman, MD Director, Adult Neurooncology Program Department of Neurology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania

W. Marston Linehan, MD Chief Urologic Oncology Branch National Cancer Institute National Institutes of Health Bethesda, Maryland

Lance A. Liotta, MD Professor, Life Science George Mason University Center for Applied Proteomics and Molecular Medicine Manassas, Virginia

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xviii

Contributing Authors

Scott M. Lippman, MD

Chrystal Louis, MD, MPH

Martin M. Malawer, MD

Professor Chairman Department of Thoracic Head & Neck Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

Assistant Professor Department of Pediatrics Baylor College of Medicine Houston, Texas

Professor (Clinical Scholar) Professor of Pediatrics (Hematology and Oncology) Department of Orthopedic Surgery and Pediatrics Professor of Orthopedic Surgery Director of Othopedic Oncology Department of Orthopedic Surgery George Washington University School of Medicine Washington, DC

Richard F. Little, MD, MPH Head, Blood and AIDS-related Cancers and Hematopoietic Stem Cell Transplant Clinical Investigations Branch, Cancer Therapy Evaluation Program Division of Cancer Therapy and Diagnosis National Cancer Institute Bethesda, Maryland

Mats Ljungman, PhD Associate Professor Department of Radiation Oncology University of Michigan Ann Arbor, Michigan

Patrick J. Loehrer, Sr., MD H. H. Gregg Professor of Medicine Department of Medicine Indiana University Director Indiana University School of Medicine Indiana University Melvin and Bren Simon Cancer Center Indianapolis, Indiana

Carlos López-Otín Departamento de Bioquímica y Biología Molecular Instituto Universitario de Oncología (IUOPA) Universidad de Oviedo Oviedo, Spain

Charles L. Loprinzi, MD Regis Professor of Breast Cancer Research Department of Oncology Mayo Clinic Rochester, Minnesota

David N. Louis, MD James Homer Wright Pathology Laboratories Massachusetts General Hospital and Harvard Medical School Pathology Massachusetts General Hospital Boston, Massachusetts

Douglas R. Lowy, MD Deputy Director, National Cancer Institute Chief, Laboratory of Cellular Oncology National Cancer Institute National Institutes of Health Bethesda, Maryland

Yani Lu, MD, PhD Postdoctoral Fellow Department of Population Sciences City of Hope National Medical Center Beckman Research Institute Duarte, California

Teresa H. Lyden, MA, CCC-SLP Speech–Language Pathologist Departments of Speech–Pathology and Otolaryngology—Head and Neck Surgery University of Michigan Ann Arbor, Michigan

Xiaomei Ma, PhD Associate Professor Department of Epidemiology and Public Health Yale University New Haven, Connecticut

John M. Magenau, MD Department of Hematology/Oncology University of Michigan Ann Arbor, Michigan

Michael T. Lotze, MD

Robert G. Maki, MD

Vice Chair Research Department of Surgery University of Pittsburgh School of Medicine Pittsburg, Pennsylvania

Departments of Medicine and Pediatrics Mount Sinai School of Medicine New York, New York

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David Malkin, MD, FRCPC Professor Department of Pediatrics Universtiy of Toronto Senior Staff Oncologist Division of Hematology/Oncology The Hospital for Sick Children Toronto, Ontario, Canada

Jack S. Mandel, PhD, MPH Chief Science Officer Exponent, Inc Menlo Park, California

Judith F. Margolin, MD Associate Professor of Pediatrics Department of Pediatrics Baylor College of Medicine Attending Physician Texas Children’s Cancer Center Texas Children’s Hospital Houston, Texas

Maurie A. Markman, MD Vice President Department of Clinical Research Chairman Department of Gynecological Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

Lawrence B. Marks, MD Professor and Chair Department of Radiation Oncology University of North Carolina at Chapel Hill School of Medicine North Carolina Cancer Hospital Chapel Hill, North Carolina

Joan Massagué, PhD Member and Chair Cancer Biology and Genetics Program Memorial Sloan-Kettering Cancer Center New York, New York

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Contributing Authors

xix

Ellen T. Matloff, MS

Minesh P. Mehta, MD

Andy J. Minn, MD, PhD

Research Scientist Department of Genetics Director, Cancer Genetic Counseling Yale Cancer Center Yale School of Medicine New Haven, Connecticut

Professor of Human Oncology Department of Human Oncology University of Wisconsin School of Medicine and Public Health Physician Department of Radiation Therapy Wisconsin Hospitals and Clinics Madison, Wisconsin

Assistant Professor, Assistant Investigator Department of Radiation Oncology Abramson Family Cancer Research Institute University of Pennsylvania Philadelphia, Pennsylvania

William M. Mendenhall, MD

Associate Dean and Professor of Radiation and Cellular Oncology Division of Biological Sciences University of Chicago Chief Quality Officer University of Chicago Medical Center Chicago, Illinois

Peter M. Mauch, MD Professor Department of Radiation Oncology Harvard Medical School Brigham and Women’s Hospital Boston, Massachusetts

Susan T. Mayne, PhD Professor of Epidemiology Department of Epidemiology and Public Health Yale School of Medicine New Haven, Connecticut

Michael W. McDermott, MD, FRCSC Professor Department of Neurosurgery University of California, San Francisco Robert & Ruth Halperin Chair Department of Neurosurgery Moffitt Hospital San Francisco, California

Professor Department of Radiation Oncology University of Florida Physician Department of Radiation Oncology Shands Hospital at University of Florida Gainesville, Florida

Matthew Meyerson, PhD Departeent of Medical Oncology and Center for Genome Discovery Dana-Farber Cancer Institute Boston, Massachusetts Broad Institute of Cambridge, Massachusetts Broad Institute of Harvard and M.I.T. Cambridge, Massachusetts

M. Dror Michaelson, MD, PhD

Professor of Urology Harvard Medical School Chief of Urology Department of Urology Massachusetts General Hospital Boston, Massachusetts

Assistant Professor of Medicine Department of Medicine Harvard Medical School Assistant in Medicine Massachusetts General Hospital Cancer Center Massachusetts General Hospital Boston, Massachusetts

Michael M. Meguid, MD

Karin B. Michels, ScD, PhD

Surgical Metabolism and Nutrition Laboratory Neurosciences Program Department of Surgery University Hospital SUNY Upstate Medical University Syracuse, New York

Associate Professor Harvard Medical School Co-Director Obstetrics and Gynecology Epidemiology Center Brigham and Women’s Hospital Boston, Massachusetts

Robert A. Meguid, MD, MPH

David E. Midthun, MD

Chief Resident Department of Surgery Johns Hopkins University, School of Medicine House Staff Department of Surgery Johns Hopkins Hospital Baltimore, Maryland

Professor of Medicine Division of Pulmonary and Critical Care Medicine College of Medicine, Mayo Clinic Rochester, Minnesota

W. Scott McDougal, MD

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Bruce D. Minsky, MD

Sandra A. Mitchell, PhD, CRNP, AOCN Research Scientist, Program Director Outcomes Research Branch National Camcer Institute Bethesda, Maryland

Fred Moeslein, MD, PhD Assistant Professor Division of Vascular and Interventional Radiology University of Maryland School of Medicine Baltimore, Maryland

Jeffrey F. Moley, MD Professor of Surgery Department of Surgery Washington University Surgeon Department of Surgery Barnes Jewish Hospital St. Louis, Missouri

Christopher J. Molineaux, PhD CJM Consulting

Meredith A. Morgan, PhD Research Assistant Professor Department of Radiation Oncology University of Michigan Ann Arbor, Michigan

Monica Morrow, MD Professor Department of Surgery Weill Medical College of Cornell University Chief, Breast Service Anne Burnett Windfohr Chair of Clinical Oncology Department of Surgery Memorial Sloan-Kettering Cancer Center New York, New York

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xx

Contributing Authors

Robert J. Motzer, MD

Chee M. Ng, PharmD, PhD

Susan O’Brien, MD

Professor of Medicine Weill Cornell Medical College Attending Physician Department of Medicine Memorial Sloan-Keetering Cancer Center New York, New York

Research Assistant Professor Department of Pediatrics Department of Pharmacology and Therapeutics Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Professor of Medicine Department of Leukemia The University of Texas MD Anderson Cancer Center Houston, Texas

Dao Minh Nguyen, MD

Franco Muggia, MD

Professor Department of Surgery University of Miami Chief Section of Thoracic Surgery Jackson Memorial Hospital Miami, Florida

Professor and Chairman Department of Gynecologic Oncology Roswell Park Cancer Institute Buffalo, New York

Professor of Medicine Division of Medical Oncology New York University New York University Langone Medical Center New York, New York

Arno J. Mundt, MD Department of Radiology and Cellular Oncology University of Chicago Hospitals Chicago, Illinois

Nikhil C. Munshi, MD Associate Professor of Medicine Harvard Medical School Associate Director/Jerome Lipper Multiple Myeloma Center Department of Medical Oncology VA Boston Healthcare Systems Dana-Farber Cancer Institute Boston, Massachusetts

Torsten O. Nielsen, MD, PhD, FRCPC Associate Professor Department of Pathology and Laboratory Medicine University of British Columbia Pathologist Provincial Pathology Program British Columbia Cancer Agency Vancouver, Canada

John M. Norian, MD

Professor of Surgery Division of Colon and Rectal Surgery Mayo Clinic Rochester, Minnesota

Clinical Instructor Department of Gynecology and Obstetrics Loma Linda University Divsion of Reproductive Endocrinology and Infertility Department Gynecology and Obstetrics Loma Linda University Health Care Loma Linda, California

Christian J. Nelson, PhD

Jeffrey Norton, MD

Assistant Attending Psychologist Psychiatry and Behavioral Sciences Memorial Sloan-Kettering Cancer Center New York, New York

Department of Surgery Stanford University School of Medicine Stanford, California

Andrea K. Ng, MD, PhD

Research Scientist Institute for Cancer Genetics Columbia University New York, New York Klinik und Poliklinik für Medizinische Onkologie INSELSPITAL, Universitätsspital Bern Freiburgstrasse Switzerland

Heidi Nelson, MD

Associate Professor Department of Radiation Oncology Harvard Medical School Attending Physician Department of Radiation Oncology Dana-Farber Cancer Institute Brigham and Women’s Hospital Boston, Massachusetts

Urban Novak, MD

Kunle Odunsi, MD, PhD

Kevin C. Oeffinger, MD Attending and Member Director, MSKCC Adult LTFU Program Departments of Pediatrics and Medicine Memorial Sloan-Kettering Cancer Center New York, New York

Brian O’Sullivan, MD, FRCPI, FRCPC, FFRRCS (Hon) Professor Department of Radiation Oncology University of Toronto Associate Director Radiation Medicine Program Princess Margaret Hospital Toronto, Ontario, Canada

Howard Ozer, MD, PhD Heidrick Professor of Medicine Chief Department of Hematology and Oncology Associate Director University of Illinois at Chicago Cancer Center University of Illinois at Chicago Chicago, Illinois

Pier Paolo Pandolfi, MD, PhD George C. Reisman Professor of Medicine Department of Pathology Harvard Medical School Director, Cancer Genetics Program Beth Israel Deaconess Cancer Center Associate Director of Research Chief, Division of Genetics Department of Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts

Jed G. Nuchtern, MD, FACS, FAAP Pediatric Surgery Baylor College of Medicine Houston, Texas

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Contributing Authors

Alberto S. Pappo, MD Professor Division of Pediatrics University of Tennesee Health Science Center Member Department of Hematology and Oncology St. Jude Children’s Research Hospital Memphis, Tennessee

Laura Pasqualucci, MD Associate Professor Department of Pathology and Cell Biology Institute for Caner Genetics Columbia University New York, New York

Harvey I. Pass, MD Professor of Surgery and Cardiothoracic Surgery Director, Division of Thoracic Surgery and Thoracic Oncology Department of Cardiothoracic Surgery NYU Langone Medical Center New York, New York

Neha J. Patel, MD Assistant Professor Division of Pediatric Hematology and Oncology University of Wisconsin Director, Neurocutaneous Clinic Department of Pediatrics American Family Children’s Hospital Madison, Wisconsin

Erin Patterson, PhD Surgery Branch National Cancer Institute, Center for Cancer Research National Institutes of Health Bethesda, Maryland

Arnold C. Paulino, MD Professor Vice Chair for Education Department of Radiation Oncology Weill-Cornell Medical College/The Methodist Hospital Houston, Texas

Richard Pazdur, MD Director Office of Oncology Drug Products United States Food and Drug Administration Silver Spring, Maryland

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Tanja B. Pejovic, MD, PhD, FACOG

xxi

David G. Poplack, MD

Assistant Professor, Division Chief Gynecological Oncologist Department of Obstetrics and Gynecology Kinght Cancer Institute Oregon Health & Science University Portland, Oregon

Elise C. Young Professor of Pediatric Oncology Head, Hematology-Oncology Section Baylor College of Medicine Director, Texas Children’s Cancer Center Texas Children’s Hospital Houston, Texas

David Pellman, MD

Carol S. Portlock, MD

Massachusetts General Hospital Boston, Massachusetts

Professor of Clinical Medicine Department of Medicine Weill Medical College of Cornell University Attending Physician Department of Medicine/Lymphoma Service Memorial Sloan-Kettering Medical Center New York, New York

Emanuel F. Petricoin, III, PhD Professor, Life Science George Mason University Center for Applied Proteomics and Molecular Medicine Manassas, Virginia

David G. Pfister, MD Attending Physician and Member Chief, Head and Neck Oncology Service Division of Solid Tumor Oncology Department of Medicine Co-Leader, Head and Neck Cancer Disease Management Team Memorial Sloan-Kettering Cancer Center New York, New York

Maria Catherine Pietanza, MD Assistant Member, Level I Department of Medicine Memorial Sloan-Kettering Cancer Center Assistant Attending Physician Department of Medicine Memorial Hospital for Cancer & Allied Diseases New York, New York

James F. Pingpank, MD Division of Surgical Oncology University of Pittsburgh Medical Center Pittsburgh, Pennsylvania

Peter W. T. Pisters, MD, FACS Professor of Surgery Department of Surgical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

Mitchell C. Posner, MD Thomas D. Jones Professor of Surgery Chief, Section of General Surgery Chief, Surgical Oncology University of Chicago Medical Center Chicago, Illinois

Thomas A. Puchalski, PharmD Director, Oncology PK/PD Department of Biological Clinical Pharmacology Malvern, Pennsylvania

Karen R. Rabin, MD, PhD Assistant Professor Department of Pediatric Hematolog/ Oncology Baylor College of Medicine Attending Physician Department of Pediatrics Texas Children’s Hospital Houston, Texas

Janet S. Rader, MD Professor Department of Obstetrics and Gynecology Medical College of Wisconsin Chairman Department of Obstetrics and Gynecology Froedtert Hospital Milwaukee, Wisconsin

Sherri L. Place, MSLIS Fox Chase Cancer Center Philadelphia, Pennsylvania

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Contributing Authors

Glen D. Raffel, MD, PhD

Steven I. Reed, PhD

Lisa M. Rimsza, MD

Assistant Professor of Medicine Department of Medicine Division of Hematology and Oncology University of Massachusetts Medical School Worchester, Massachusetts

Professor Department of Molecular Biology The Scripps Research Institute La Jolla, California

Professor of Pathology The Arizona Cancer Center Tucson, Arizona

Eddie Reed, MD

Professor Institute of Anatomic Pathology UniversitĂ Cattolica del Sacro Cuore Chief Histopathology and Cytodiagnosis Service Policlinico A. Gemelli Rome, Italy

Reza Rahbari, MD Clinical Fellow Surgery Branch National Cancer Institute Bethesda, Maryland House Officer Department of Surgery Universtiy of California San Francisco East Bay Oakland, California

Ramesh K. Ramanathan, MD Clinical Professor of Medicine College of Medicine, Phoenix Campus University of Arizona Medical Director TGen Clinical Research Service Virginia G. Piper Cancer Center Scottsdale Health Care Scottsdale, Arizona

Professor Department of Oncologic Sciences University of South Alabama Clinical Director Point Clear Charities Chair Abraham Mitchell Distinguished Investigator Mitchell Cancer Institute Mobile, Alabama

Alnawaz Rehemtulla, PhD Professor Department of Radiation Oncology and Radiology University of Michigan Ann Arbor, Michigan

Nicholas P. Restifo, MD Principal Investigator Surgery Branch National Cancer Institute Bethesda, Maryland

Pedro T. Ramirez, MD

Anetta Reszko, MD, PhD

Associate Professor Director of Minimally Invasive Surgical Research & Education Department of Gynecological Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

Clinical Instructor Department of Dermatology Yale University New Haven, Connecticut

Victor E. Reuter, MD

Fellow Department of Medical Oncology Johns Hopkins University School of Medicine Baltimore, Maryland

Professor Department of Pathology Weill Medical College of Cornell University Vice Chairman Department of Pathology Memorial Sloan-Kettering Cancer Center New York, New York

Paul W. Read, MD, PhD

Michelle B. Riba, MD, MS

Associate Professor Vice Chairman Department of Radiation Oncology University of Virginia Medical Center Charlottesville, Virginia

Professor of Psychiatry Associate Chair for Integrated Medicine and Psychiatric Services Department of Psychiatry University of Michigan Ann Arbor, Michigan

Zeshaan Rasheed, MD, PhD

Abram Recht, MD Professor Department of Radiation Oncology Harvard Medical School Deputy Chief Department of Radiation Oncology Beth Israel Deaconess Medical Center Boston, Massachusetts

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Nora C. Rightmer, MSW, LCSW Oncology Social Worker Department of Social Work Smilow Cancer Hospital at Yale-New Haven New Haven, Connecticut

Guido Rindi, MD, PhD

Brian I. Rini, MD, FACP Associate Professor Department of Medicine CCF/Lerner College of Medicine Case Western Reserve University Staff Department of Solid Tumor Oncology/Urology Cleveland Clinic, Taussig Cancer Institute Cleveland, Ohio

Paul F. Robbins, PhD Staff Scientist Surgery Branch National Cancer Institute National Institutes of Health Bethesda, Maryland

Matthew K. Robinson, MD Assistant Professor Department of Developmental Therapeutics Fox Chase Cancer Center Philadelphia, Pennsylvania

Michal G. Rose, MD Associate Professor Department of Medicine Yale University School of Medicine New Haven, Connecticut Director, Cancer Center VA Connecticut Healthcare System West Haven, Connecticut

Steven A. Rosenberg, MD, PhD Chief of Surgery National Cancer Institute National Institutes of Health Professor of Surgery Uniformed Services University of the Health Sciences School of Medicine Bethesda, Maryland Professor of Surgery George Washington University School of Medicine Washington, DC

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Contributing Authors

Kenneth Rosenzweig, MD

M. Wasif Saif, MD, MBBS

Laura S. Schmidt, PhD

Professor Chairman Department of Radiation Oncology Mount Sinai Medical Center New York, New York

Professor of Clinical Medicine Director, Section of Gastrointestinal Cancers Medical Director, Pancreas Center Columbia University College of Physicians and Surgeons & New York Presbyterian Hospital New York, New York

Principal Scientist SAIC-Frederick, Inc. NCI-Frederick National Cancer Institute National Institutes of Health Bethesda, Maryland

Brian D. Ross, PhD Professor Department of Radiology and Biological Chemistry University of Michigan Ann Arbor, Michigan

Richard E. Royal, MD Associate Professor Department of Surgical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

James Louis Rubenstein, MD, PhD Associate Professor of Medicine Attending Physician Department of Medicine University of California, San Francisco San Francisco, California

Eric H. Rubin, MD

Leonard B. Saltz, MD Head, Colorectal Oncology Section Department of Medicine Memorial-Sloan Kettering Cancer Center Professor Department of Medicine Cornell University Medical College New York, New York

Yardena Samuels, PhD Assistant Professor Cancer Genetics Branch National Human Genome Research Institute National Institutes of Health Bethesda, Maryland

Alton Oliver Sartor, MD

Therapeutic Area Head, Vice-President Merck Research Labratories North Wales, Pennsylvania

Plitz Professor for Cancer Research Departments of Medicine and Urology Tulane Medical School Tulane University Hospital New Orleans, Louisiana

Heidi V. Russell, MD

Charles L. Sawyers, MD

Texas Children’s Cancer Center Baylor College of Medicine Houston, Texas

Investigator Howard Hughes Medical Institute Chairman Human Oncology & Pathogenesis Program Memorial Sloan-Kettering Cancer Center New York, New York

Anil K. Rustgi, MD T. Grier Miller Professor of Medicine and Genetics Chief of Gastroenterology University of Pennsylvania Philadelphia, Pennsylvania

Arjun Sahgal, MD Assistant Professor Department of Radiation Oncology University of Toronto Radiation Oncologist Department of Radiation Oncology Sunnybrook Health Sciences Centre Toronto, Canada

Kristen G. Schaefer, MD Instructor Department of Psychosocial Oncology and Palliative Care Harvard Medical School Attending Department of Psychosocial Oncology and Palliative Care Dana-Farber Cancer Institute Boston, Massachusetts

xxiii

Heiko Schöder, MD Department of Radiology Memorial Sloan-Kettering Cancer Center New York, New York

Deborah Schrag, MD, MPH Associate Professor Department of Medicine/Oncology Harvard Medical School Oncologist Department of GI/Medical Oncology Dana-Farber Cancer Institute Boston, Massachusetts

David S. Schrump, MD Head, Thoracic Oncology Section Surgery Branch National Cancer Institute Bethesda, Maryland

Brahm H. Segal, MD Professor Department of Medicine University of Buffalo School of Medicine Chief, Division of Infectious Diseases Department of Medicine Roswell Park Cancer Institute Buffalo, New York

Kathy J. Selvaggi, MD Associate Professor of Medicine Harvard Medical School Staff Physician Medicine: Psychosocial Oncology and Palliative Care Dana-Farber Cancer Institute Brigham and Women’s Hospital Boston, Massachusetts

Norman E. Sharpless, MD Associate Professor Department of Medicine and Genetics The University of North Carolina Chapel Hill, North Carolina

John T. Schiller, PhD Laboratory of Cellular Oncology Center for Cancer Research, National Cancer Institute National Institutes of Health Bethesda, Maryland

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Contributing Authors

Joel Sheinfeld, MD

Craig L. Slingluff, MD

Diane E. Stover, MD

Professor of Urology Weill Medical College of Cornell University Deputy Chief Department of Urology Memorial Sloan-Kettering Cancer Center New York, New York

Associate Professor Department of Radiation Oncology University of Virginia Vice Chairman Department of Radiation Oncology University of Virginia Medical Center Charlottesville, Virginia

Peter G. Shields, MD

Director – Cancer Screening American Cancer Society Atlanta, Georgia

Professor of Clinical Medicine Department of Medicine Weill Medical College of Cornell University Head of General Medicine Chief Pulmonary Service Department of Medicine Memorial Sloan-Kettering Medical Center New York, New York

Carcinogenesis, Biomarkers, and Epidemiology Program Lombardi Comprehensive Cancer Center Georgetown University Medical Center Washington, DC

Robert A. Smith, PhD

Harris S. Soifer, PhD Assistant Professor of Medicine Albert Einstein College of Medicine Bronx, New York

Michael D. Stubblefield, MD Assistant Professor of Rehabilitation Medicine Department of Physical Medicine and Rehabilitation Weill Medical College of Cornell University Assistant Attending Psychiatrist Rehabilitation Medicine Service Department of Neurology Memorial Sloan-Kettering Cancer Center New York, New York

William U. Shipley, MD

Vernon K. Sondak, MD

Soriano Professor of Radiaiton Oncology Department of Radiation Oncology Harvard Medical School Head, Radiation Therapy Oncology Group Research Department of Radiation Oncology Masschusetts General Hospital Boston, Massachusetts

Professor Department of Surgery and Oncologic Sciences University of Southern Florida Chair Department of Cutaneous Oncology H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida

Ramesh A. Shivdasani, MD, PhD

Eliezer Soto, MD

Associate Professor Department of Medicine Harvard Medical School Associate Professor Department of Medical Oncology Dana-Farber Cancer Institute Boston, Massachusetts

Pain and Palliative Care Service Bethesda, Maryland

Director of Programs Peritoneal Surface Oncology Cancer Institute Washington Hospital Center Washington, DC

David Spiegel, MD

Chris H. Takimoto, MD, PhD

Willson Professor and Associate Chair Department of Psychiatry and Behavioral Sciences Stanford University School of Medicine Medical Director Center for Integrative Medicine Stanford Hospital and Clinics Stanford, California

Vice President Department of Translational Medicine Janssen Research and Development Radnor, Pennsylvania

Richard M. Simon, DSc Chief Biometric Research Branch National Cancer Institute Bethesda, Maryland

Samuel Singer, MD Professor of Surgery Department of Surgery Weill Cornell Medical College Member with Tenure-of-Title Chief, Gastric and Mixed Tumor Service Department of Surgery Memorial Sloan-Kettering Cancer Center New York, New York

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Cy A. Stein, MD, PhD Professor Department of Medicine and Molecular Pharmacology Albert Einstein College of Medicine Director, Medical Genitourinary Oncology Department of Medicine Montefiore Medical Center Bronx, New York

Paul H. Sugarbaker, MD, FACS, FRCS

Randall K. Ten Haken, PhD Professor of Radiation Oncology Co-Director, Radiation Physics Division Department of Radiation Oncology University of Michigan Ann Arbor, Michigan

Kenneth D. Tew, PhD, DSc Professor and Chairman Department of Cell and Molecular Pharmacology Medical University of South Carolina Charleston, South Carolina

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Contributing Authors

xxv

Charles R. Thomas, Jr., MD

Giorgio Trinchieri, MD

Michael Vogelbaum, MD, PhD

Professor and Chair Department of Radiation Medicine Knight Cancer Institute, Oregon Health and Sciences University Service Chief Department of Radiation Medicine Oregon Health and Sciences University Hospitals and Clinics Portland, Oregon

Director Cancer and Inflammation Program Center for Cancer Research National Cancer Institute - Frederick Frederick, Maryland

Associate Director Brain Tumor and Neuro-Oncology Center Cleveland Clinic Cleveland, Ohio

Robert Udelsman, MD, MBA

Nicholas J. Vogelzang, MD

William H. Carmalt Professor and Chairman Department of Surgery Yale University School of Medicine New Haven, Connecticut

Chair and Medical Director Developmental Therapeutics Member GU Committee US Oncology Research Vice chair SWOG GU Committee Professor of Medicine University of Nevada School of Medicine Comprehensive Cancer Centers NV Las Vegas, Nevada

Snorri S. Thorgeirsson, MD, PhD Chief Laboratory of Experimental Carcinogenesis Center for Cancer Research National Cancer Institute Bethesda, Maryland

Michael J. Thun, MD American Cancer Society Atlanta, Georgia

Robert Timmerman, MD Professor of Radiation Oncology and Neurosurgery Department of Radiation Oncology University of Texas Southwestern Medical Center Director Annette Simmons Stereotactic Radiation Center Zale Lipshy University Hospital Dallas, Texas

Edouard J. Trabulsi, MD Associate Professor Department of Urology Kimmel Cancer, Thomas Jefferson University Hospital Philadelphia, Pennsylvania

William D. Travis, MD Professor of Pathology Attanding Thoracic Pathologist Department of Pathology Weill Medical College of Cornell Univeristy Memorial Sloan-Kettering Cancer Center New York, New York

Lois B. Travis, MD, ScD Director Ruben Center for Cancer Survivorship Professor Department of Radiation Oncology James P. Wilmot Cancer Center University of Rochester Medical Center Rochester, New York

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Catherine E. Ulbricht, PharmD, MBA(c) Founder, Editor in Chief Natural Standard Research Collaboration Sommerville, Massachusetts Senior Attending Pharmacist Massachusetts General Hospital Boston, Massachusetts

Thomas S. Uldrick, MD, MS Staff Clinician HIV and AIDS Malignancy Branch Center for Cancer Research, National Cancer Institutes Bethesda, Maryland

Matthew G. Vander Heiden, MD Koch Institute for Integrative Cancer Research at M.I.T. Dana-Farber Cancer Institute Boston, Massachusetts

Veronic Sanchez Varela, PhD

Jean C.Y. Wang, MD, PhD Assistant Professor Department of Medicine University of Toronto Affiliate Scientist Division of Stem Cell and Developmental Biology Ontario Cancer Institute Toronto, Ontario, Canada

Lisa L. Wang, MD Assistant Professor Department of Pediatrics Baylor College of Medicine Houston, Texas

Elizabeth Ward, PhD American Cancer Society Atlanta, Georgia

Research Fellow Department of Psychosocial Oncology and Palliative Care Harvard Medical School Dana-Farber Cancer Institute Boston, Massachusetts

Jeffrey S. Wefel, PhD

Vic J. Verwaal, MD

Louis M. Weiner, MD

Surgeon Department of Surgery The Netherlands Cancer Institute Amsterdam, the Netherlands

Director Lombardt Comprehensive Cancer Center Georgetown University Washington, DC

Damon J. Vidrine, PhD Assistant Professor Department of Behavioral Science The University of Texas MD Anderson Cancer Center Houston, Texas

Assistant Professor Department of Neuro-oncology The University of Texas MD Anderson Cancer Center Houston, Texas

Samuel A. Wells, Jr., MD Senior Clinician Medical Oncology Branch National Cancer Institute Center for Cancer Research National Institutes of Health Bethesda, Maryland

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xxvi

Contributing Authors

John W. Werning, MD

Kwok-Kin Wong, MD, PhD

Stuart H. Yuspa, MD

Associate Professor Department of Otolaryngology University of Florida Head and Neck Surgical Oncologist Department of Otolaryngology Shands Hospital at University of Florida Gainesville, Florida

Associate Professor Department of Medical Oncology Dana-Farber Cancer Institute Harvard Medical School Attending Physician Department of Medicine Brigham & Women’s Hospital Boston, Massachusetts

Labroratory Chief Laboratory of Cancer Biology and Genetics National Institutes of Health Bethesda, Maryland

Eileen White, PhD

Flossie Wong-Staal, PhD

Professor Department of Molecular Biology and Biochemistry Rutgers University Associate Director for Basic Science Cancer Institute of New Jersey New Brunswick, New Jersey

Professor Emeritus Department of Medicine University of California, San Diego La Jolla, California

William Wierda, MD, PhD Associate Professor Department of Leukemia The University of Texas MD Anderson Cancer Center Houston, Texas

Walter C. Willett, MD, PhD Professor and Chair Department of Nutrition Harvard School of Public Health Associate Physician Department of Medicine Brigham and Women’s Hospital Boston, Massachusetts

Christopher G. Willett, MD Professor and Chair Department of Radiation Oncology Duke University Medical Center Durham, North Carolina

Grant A. Williams, MD Division of Oncology Drug Products Center for Drug Evaluation and Research United States Food and Drug Administration Rockville, Maryland

Lynn D. Wilson, MD, MPH Professor Department of Therapeutic Radiology Yale School of Medicine New Haven, Connecticut

Robert A. Wolff, MD Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

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Joachim Yahalom, MD, FACR Professor of Radiation Oncology Department of Radiation Weill Medical College of Cornell University Attending and Member Department of Radiation Oncology Memorial Sloan-Kettering Cancer Center New York, New York

James C. Yang, MD Surgery Branch Center for Cancer Research National Cancer Institute Bethesda, Maryland

James C. Yao, MD Associate Professor Department of Gastrointestinal Medical Oncology University of Texas Deputy Chairman Department of Gastrointestinal Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

Robert Yarchoan, MD

Jason Todd Yustein, MD, PhD Assistant Professor Department of Pediatrics, Hematology/Oncology Baylor College of Medicine Houston, Texas

Herbert J. Zeh, III, MD Assistant Professor of Surgery Department of Surgical Oncology University of Pittsburgh Medical Center Pittsburgh, Pennsylvania

Michael J. Zelefsky, MD Member, Chief of Brachytherapy Service Department of Radiation Oncology Memorial Sloan-Kettering Cancer Center Professor of Radiation Oncology Department of Radiation Oncology New York Cornell Hospital New York, New York

Anthony L. Zietman, MD Jenot and William Shipley Professor of Radiation Oncology Department of Radiation Oncology Harvard Medical School Massachusetts General Hospital Boston, Massachusetts

Amer H. Zureikat, MD Assistant Professor of Surgery, Department of Surgical Oncology University of Pittsburgh Medical Center Pittsburgh, Pennsylvania

Branch Chief HIV and AIDS Malignancy Branch Center for Cancer Research Attending Physician National Cancer Institute NIH Clinical Center Bethesda, Maryland

Herbert Yu, MD, PhD Associate Professor Department of Epidemiology and Public Health Yale University New Haven, Connecticut

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PREFACE

It seems that we are now overloaded every day with new information suggesting that we should be changing our treatments to a new (and, by definition, better?) drug or device. We all want to practice with the best and newest data. Yet which of the new studies we read about each day will actually change practice and which will turn out to be no better, or possibly worse, than current standard practice? Going to the Internet simply produces a list of references, without any ability to distinguish the trustworthy study from the one that my lead us down the wrong path. Where can the general practitioner or oncologist turn to find information that is reliable, practical, and comprehensive? We feel that the 9th edition of Cancer: Principles & Practice of Oncology is that place. As with the 8th edition, we wanted to maintain a 3-year cycle so that the printed book fulfills the needs of the oncologist. In addition, beginning with this 9th edition, the electronic version of the book will be continuously revised to incorporate the most recent practice-changing information. We will be searching the literature for substantiated improvements in treatment while avoiding the speculative and unproven. These changes will be highlighted in the electronic text to permit easy identification. We are excited that this combination of accelerated print editions with a continuously updated electronic version revised by experts should meet the needs of both the specialist and the generalist in oncology. This new edition also builds on many of the changes we made in the 8th edition. We have continued to work with Drs. Ronald DePinho and Robert Weinberg of Harvard and MIT, respectively, to substantially revise and improve the first section of the book that focuses on the Molecular Biology of Cancer.

This section of the book (and the chapters on the molecular biology of specific cancers) has become more and more important in understanding the recent explosion of targeted therapies. Several new chapters, particularly those on personalized medicine and on tyrosine kinase inhibitors, bridge the science of the first section directly to the clinic. The parts covering the principles and the practice of oncology have also been extensively revised so that each chapter reflects the most recent clinical findings. In addition to these improvements in the book, we have also continued to use The Cancer Journal: Journal of the Principles & Practice of Oncology to carry out in-depth multimodality analyses of topical subjects. Each issue contains a set of papers that approach a topic (such as Hepatocellular Cancer or Sexuality and the Cancer Patient) from multiple viewpoints that complements and updates the material found in the book. Principles & Practice of Oncology Updates cover more focused topics in detail. We have attempted to make Cancer: Principles and Practice of Oncology and its companions the antidote for information overload. Taken together, the printed and electronic book, the journal and the updates provide a complete package of printed and electronic media that will be permit the busy practitioner to have a suite of materials that is both a comprehensive and usable resource for their patients. Vincent T. DeVita, Jr., MD Theodore S. Lawrence, MD, PhD Steven A. Rosenberg, MD, PhD

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ACKNOWLEDGMENTS

The Editors would like to acknowledge the extraordinary contributions of Zia Raven, who played a vital role in the preparation of this edition. Ms. Raven assumed responsibility for the organization and compilation of all of the chapters in this text. We are also grateful to Jonathan W. Pine, Jr., Senior

Executive Editor at Lippincott Williams & Wilkins, for his excellent help in the production of this text. VTD TSL SAR

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CONTENTS

6. Cell Cycle. . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Contributing Authors vii Preface xxvii Acknowledgments xxix

Steven I. Reed

PART ONE MOLECULAR BIOLOGY OF CANCER 1. The Cancer Genome . . . . . . . . . . . . . . . . . . . 2 Yardena Samuels, Alberto Bardelli, and Carlos López-Otín Cancer Genes and Their Mutations 2 Identification of Cancer Genes 2 Cancer Genome Investigation: Tools and Quality Controls 2 Somatic Alteration Classes Detected by Cancer Genome Analysis Pathway-Oriented Models of Cancer Genome Analysis 14 Networks of Cancer Genome Projects 16 The Genomic Landscape of Cancers 18 The Cancer Genome and the New Taxonomy of Tumors 18 Cancer Genomics and Drug Resistance 20 Perspectives of Cancer Genome Analysis 20

12

David J. Gordon, David A. Barbie, Alan D. D’Andrea, and David Pellman Basic Defenses Against Genomic Instability 23 Barriers to Genomic Instability 23 Mutations in Cancer 26 Mechanisms of Genome Destabilization in Human Tumors 29 What Causes Chromosomal Instability and Whole-Chromosome Aneuploidy? 35 Does Whole-Chromosome Aneuploidy Cause Cancer? 37 Perspectives and Implications for Cancer Therapeutics 38

3. Epigenetics of Cancer . . . . . . . . . . . . . . . . . . 41 Peter A. Jones and Karin B. Michels

44

4. Telomeres, Telomerase, and Cancer . . . . . . . 48 Kwok-Kin Wong, Norman E. Sharpless, and Ronald A. DePinho Telomeres and Telomerase 48 Senescence 50 Telomere Maintenance and Cancer

7. Mechanisms of Cell Death . . . . . . . . . . . . . . 82 Vassiliki Karantza and Eileen White

2. Mechanisms of Genomic Instability . . . . . . . 23

Epigenetic Processes 41 Epigenomic Changes in Cancer 43 The Timing of Epigenetic Alterations 44 Epigenetic Biomarkers for Early Detection of Cancer Epigenetic Therapies 45 Problems with Epigenetic Therapies 46

Cell-Cycle Engine 68 Induction of Cell-Cycle Phase Transitions 71 Ubiquitin-Mediated Proteolysis 71 Regulation of the Cell Cycle 72 Cell Cycle and Cancer 76 MicroRNAs, the Cell Cycle, and Cancer 79 The Cell Cycle and Cancer Therapy 80

Apoptosis 82 Autophagy 87 Necrosis 89

8. Cancer Metabolism . . . . . . . . . . . . . . . . . . . 91 Matthew G. Vander Heiden Altered Metabolism in Cancer Cells 91 Energetics of Cell Proliferation 93 Imaging Cancer Metabolism in Patients 94 Genetic Events Important for Cancer Influence Metabolism Targeting Metabolism to Treat Cancer 99

95

9. Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . 101 Robert S. Kerbel and Lee M. Ellis Introduction: Origins of the Concept of Antiangiogenic Therapy for Cancer 101 Sequential Steps Involved in the Formation of Blood Vessel Capillaries in Tumors 101 Pericytes 102 Dysfunctional Nature of the Tumor Vasculature 102 Molecular Mediators of Tumor Angiogenesis: Angiogenic Stimulators and Their Receptors 103 Endogenous Inhibitors of Tumor Angiogenesis 105 A Cooperative Regulator of Tumor Angiogenesis: The Notch ReceptorDLL4 Signaling Pathway in Endothelial Cells 106 Strategies for Development of Antiangiogenic Drugs 106 Enhancement of Chemotherapy Efficacy and Other Therapeutic Modalities by Antiangiogenic Drugs 107 Resistance to Antiangiogenic Drugs or Treatments 108 Biomarkers for Tumor Angiogenesis and Antiangiogenic Therapy 109 Antiangiogenic/Anti-VEGF Drug-Based Clinical Trials 109 Looking Ahead: New Targets, New Drugs, and New Strategies for Antiangiogenic Therapy 111

10. Invasion and Metastasis . . . . . . . . . . . . . . . 113 Andy J. Minn and Joan Massagué

53

5. Cell Signaling Growth Factors and Their

Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 Lewis C. Cantley, Chris L. Carpenter, William C. Hahn, and Matthew Meyerson Signal Transduction Systems 57 Sensory Machinery: Ligands and Receptors 57 Regulation of Protein Kinases 60 Small-Molecule Second Messengers 63 Efficiency and Specificity: Formation of Multiprotein Signaling Complexes 64 Signaling Networks 66

The Evolution and Pathogenesis of Metastasis 113 An Integrated Model for Metastasis 115 Selective Pressures at the Primary Tumor Driving Acquisition of Metastasis Functions 117 Coupling Tumorigenesis with Metastasis Initiation 119 Coupling Tumorigenesis with Metastasis Progression 121 From Metastasis Progression to Macrometastatic Colonization 122 Micro-RNAs and Metastasis 126

11. Cancer Stem Cells . . . . . . . . . . . . . . . . . . . 128 Jean C. Y. Wang and John E. Dick Tumor Heterogeneity 128 Leukemia Stem Cells 129

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xxxii

Contents Cancer Stem Cells in Solid Tumors 130 Genetic Diversity and Clonal Evolution in Cancer The Origins of Cancer Stem Cells 134 Epithelial-Mesenchymal Transition 137 Cancer Stem Cells: Targeted Therapy 137

Mechanisms of Cell Transformation and Cancer Initiation in the Inflammatory Environment 196 Inflammatory Cells and Stromal Cells in the Initiation of Neoplasia and in the Tumor Microenvironment 198

133

12. Biology of Personalized Cancer Medicine . . .141 Raju Kucherlapati Cancer Predisposition 141 Familial Adenomatous Polyposis 141 Lynch Syndrome 142 Other Polyposis Syndromes 142 Association Studies 142 Breast Cancer 142 Early Detection 143 Tumor Classification and Patient Stratification 143 Treatment 144 Development of Resistance to Tyrosine Kinase Inhibitors Alternative Mechanisms of Resistance 145 BRAF Inhibitors 146 The Future 146 Changing Face of Personalized Medicine 146 Summary 146

18. Chemical Factors . . . . . . . . . . . . . . . . . . . . 203 Stuart H. Yuspa and Peter G. Shields The Nature of Chemical Carcinogens: Chemistry and Metabolism 203 Animal Model Systems and Chemical Carcinogenesis 205 DNA Repair Protects the Host from Chemical Carcinogens 205 Genetic Susceptibility to Chemical Carcinogenesis 205 Molecular Epidemiology, Chemical Carcinogenesis, and Cancer Risk in Human Populations 206 Polyclic Aromatic Hydrocarbons as a Model for Gene-Environment Interaction 207

145

PART TWO ETIOLOGY AND EPIDEMIOLOGY OF CANCER Section 1: Etiology of Cancer 13. Tobacco . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 Stephen S. Hecht Epidemiology of Tobacco and Cancer 150 Tumor Induction in Laboratory Animals by Tobacco Products 152 Carcinogens in Tobacco Products 153 Overview of Mechanisms of Tumor Induction by Tobacco Products 156 Tobacco Carcinogen and Toxicant Biomarkers 157

14. Cancer Susceptibility Syndromes . . . . . . . . 161 Alice Hawley Berger and Pier Paolo Pandolfi Principles of Cancer Susceptibility 161 Genetic Testing 163 Cancer Susceptibility Syndromes 164 Future Directions 170

15. DNA Viruses . . . . . . . . . . . . . . . . . . . . . . . 173 Peter M. Howley, Don Ganem, and Elliott Kieff History of Viral Oncology 173 Hepadnaviruses and Hepatocellular Carcinoma 174 Papillomaviruses 176 Epstein-Barr Virus 180 Kaposi’s Sarcoma–Associated Herpesvirus 182 Human Polyomaviruses 184

16. RNA Viruses . . . . . . . . . . . . . . . . . . . . . . . 186

19. Physical Factors . . . . . . . . . . . . . . . . . . . . . 209 Mats Ljungman Ionizing Radiation 209 Ultraviolet Light 212 Radiofrequency and Microwave Radiation Electromagnetic Fields 214 Asbestos 214 Nanoparticles 215

20. Dietary Factors . . . . . . . . . . . . . . . . . . . . . 217 Karin B. Michels and Walter C. Willett Methodologic Challenges 217 The Role of Individual Food and Nutrients in Cancer Etiology 218 Other Foods and Nutrients 222 Dietary Patterns 224 Diet During Early Phases of Life 224 Summary 224 Limitations 224 Future Directions 225 Recommendations 225

21. Obesity and Physical Activity . . . . . . . . . . . 227 Katherine D. Henderson, Yani Lu, and Leslie Bernstein Breast Cancer 227 Colon and Rectal Cancer 228 Endometrial Cancer 229 Adenocarcinoma of the Esophagus Kidney/Renal Cell Cancer 230 Pancreatic Cancer 230 Gallbladder Cancer 230 Non-Hodgkin Lymphoma 230 Prostate Cancer 231 Lung Cancer 231 Ovarian Cancer 231 Overview 231

229

Section 2: Epidemiology of Cancer 22. Epidemiologic Methods . . . . . . . . . . . . . . . 233

Gary L. Buchschacher, Jr. and Flossie Wong-Staal

Xiaomei Ma and Herbert Yu

Retroviruses: Background, Replication Cycle, and Molecular Genetics 186 Human T-Lymphotropic Virus Type 1 189 Human T-Lymphotropic Virus Type 2 190 Human Immunodeficiency Virus 190 Hepatitis C Virus 190

Analytical Studies 233 Interpretation of Epidemiologic Findings Molecular Epidemiology 237

17. Inflammation . . . . . . . . . . . . . . . . . . . . . . . 193 Giorgio Trinchieri Tumor Immune Surveillance 193 Inflammation and Tumorigenesis 194

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214

236

23. Global Cancer Incidence and Mortality . . . 241 Michael J. Thun, Ahmedin Jemal, and Elizabeth Ward Data Sources and Measurements 241 Overall Cancer Risk 243 Incidence and Mortality Patterns for Common Cancers Issues in Interpreting Temporal Trends 258 Conclusion 259

251

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Contents

24. Trends in Cancer Mortality . . . . . . . . . . . . 261 Tim E. Byers Cancer Surveillance Systems 261 Making Sense of Cancer Trends 261 Trends in Cancer Risk Factors 261 Cancer Trends 263 Predicting Future Cancer Trends 265

Categories of Tumor Antigens Can Be Defined by Expression Patterns 334 Cancer Immunotherapies 337

31. Health Services Research and Economics

of Cancer Care . . . . . . . . . . . . . . . . . . . . . . 345 Craig C. Earle and Deborah Schrag

PART THREE PRINCIPLES OF CANCER TREATMENT

Studies of Health Service Delivery in Cancer Medicine Patient-Reported Outcomes Assessment 350 The Economics of Cancer Care 353 Comparative Effectiveness Research 356

PART FOUR

25. Surgical Oncology: General Issues . . . . . . . 268 Steven A. Rosenberg

345

PHARMACOLOGY OF CANCER THERAPEUTICS

Historical Perspective 268 Anesthesia for Oncologic Surgery 268 Determination of Operative Risk 270 Roles for Surgery 272 Surgical Oncologist 274

Section 1: Chemotherapy Agents 32. Pharmacokinetics and Pharmacodynamics . . . .360

26. Surgical Oncology: Laparoscopic

Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . 277

Chris H. Takimoto, Chee M. Ng, and Thomas Puchalski

Yoshinori Hosoya and Alan T. Lefor

Why Study Pharmacokinetics and Pharmacodynamics? 360 Cancer Patients Present Unique Challenges 361 Pharmacokinetic Concepts 361 Pharmacodynamic Concepts 365 Special Topics in Pharmacokinetics and Pharmacodynamics 365 Population Pharmacokinetics/Pharmacodynamics 366 Pharmacokinetics and Pharmacodynamics in Oncology Drug Development 366

New Technology 277 Physiology of Laparoscopy 278 Laparoscopy in the Diagnosis of Malignancy 279 Laparoscopy in the Staging of Malignancy 279 Laparoscopy in the Treatment of Malignancy 281 Laparoscopy in the Palliation of Malignancy 287

27. Radiation Oncology . . . . . . . . . . . . . . . . . . 289 Meredith A. Morgan, Randall K. Ten Haken, and Theodore S. Lawrence Biologic Aspects of Radiation Oncology 289 Factors that Affect Radiation Response 294 Drugs that Affect Radiation Sensitivity 296 Radiation Physics 297 Treatment Planning 301 Other Treatment Modalities 303 Clinical Applications of Radiation Therapy 304 Treatment Intent 305 Fractionation 306 Adverse Effects 307 Principles of Combining Anticancer Agents with Radiation Therapy 308

28. Medical Oncology . . . . . . . . . . . . . . . . . . . 312 Vincent T. DeVita, Jr. and Edward Chu Introduction 312 Biology of Drug Resistance

316

29. Assessment of Clinical Response . . . . . . . . 322 Antonio Tito Fojo and Susan Elaine Bates Overall Response Rate and Stable Disease 322 Alternate Response Criteria 323 Waterfall Plots 326 Progression Free Survival and Time to Progression Overall Survival 327 Kaplan-Meier Plots 328 Hazard Ratios 329 Forest Plots 329 Meta-Analyses 329 Quality of Life 329 Novel End Points 329

33. Pharmacogenomics . . . . . . . . . . . . . . . . . . 369 Anthony El-Khoueiry and Heinz Josef Lenz Definitions: Terms and Concepts 369 Pharmacogenomics and Predictive Molecular Markers Pharmacogenomics and Prognostic Markers 372 Current Challenges and Future Directions 373

369

34. Alkylating Agents . . . . . . . . . . . . . . . . . . . . 375 Kenneth D. Tew Perspectives 375 Chemistry 375 Classification 375 Clinical Pharmacokinetics/Pharmacodynamics 380 Therapeutic Uses 381 Toxicities 381 Complications with High-Dose Alkylating Agent Therapy 383 Alkylating Agent–Steroid Conjugates 383 Drug Resistance and Modulation 383 Recent Developments 383

35. Platinum Analogs . . . . . . . . . . . . . . . . . . . . 386 Eddie Reed 326

Common Features of Platinum Chemistry 387 Clinical Pharmacology 388 Determinants of Cellular Sensitivity and Resistance to Platinum Agents 389 Cellular Accumulation and Cytosolic Inactivation of Drug 390 DNA Damage and Repair 390

36. Antimetabolites . . . . . . . . . . . . . . . . . . . . . 393 M. Wasif Saif and Edward Chu

30. Cancer Immunotherapy . . . . . . . . . . . . . . . 332 Steven A. Rosenberg, Paul F. Robbins, and Nicholas P. Restifo Approaches to the Identification of Human Tumor Antigens 332

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Antifolates 393 5-Fluoropyrimidines Capecitabine 396 Cytarabine 397

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Contents

Gemcitabine 397 6-Thiopurines 398 Fludarabine 399 Cladribine 399 Clofarabine 400

l-Asparaginase 456 Bleomycin 456 Procarbazine 457 Thalidomide 458 Lenalidomide 458

37. Topoisomerase-Interacting Agents . . . . . . . 402

Section 2: Biotherapeutics

Zeshaan A. Rasheed and Eric H. Rubin

44. Interferons . . . . . . . . . . . . . . . . . . . . . . . . . 461

Topoisomerase Biology 402 Camptothecins 402 Anthracyclines 404 Anthracenediones 409 Epipodophyllotoxins 410

Vernon K. Sondak, Jürgen C. Becker, and Axel Hauschild

38. Antimicrotubule Agents . . . . . . . . . . . . . . . 413 Maysa M. Abu-Khalaf and Lyndsay N. Harris Microtubules 413 Taxanes 413 New Taxane Formulations 416 Vinca Alkaloids 417 Estramustine Phosphate 420 Epothilones 420 Novel Compounds Targeting Microtubules and Mitotic Motor Proteins 420

Michael T. Lotze

Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . 422 Charles L. Sawyers

Interleukins as Therapeutics 469 Interleukin-1 Family 469 Interleukin 3, Interleukin 11, and Interleukin 34 Interleukin-2 Family 470 Interleukin 6 Family 477 Interleukin 10 Family 480

470

46. Antisense Agents . . . . . . . . . . . . . . . . . . . . 482

Early Successes: Targeting Cancers with Well-Known Kinase Mutations 422 Targeting the PI3K Pathway Directly 431 Combinations of Kinase Inhibitors 431 Speculations on the Future Role of Kinase Inhibitors in Cancer Medicine 432

40. Histone Deacetylase Inhibitors and

Demethylating Agents . . . . . . . . . . . . . . . . 434 Steven D. Gore, Stephen B. Baylin, and James G. Herman Epigenetics and Gene Silencing 434 Changes in DNA Methylation 434 Histone Deacetylase Inhibitors 437 Pharmacodynamic Observations 439

41. Proteasome Inhibitors . . . . . . . . . . . . . . . . 441 Michael G. Kauffman, Christopher J. Molineaux, Christopher J. Kirk, and Craig M. Crews Biochemistry of the Ubiquitin-Proteasome Pathway Proteasome Inhibitors 441 Preclinical Pharmacology of PIs 445 Proteasome Inhibitors in Cancer 445

441

42. Poly(ADP-Ribose) Polymerase

Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . 450 Alan Ashworth Cellular DNA Repair Pathways 450 The Development of PARP Inhibitors 450 BRCA1 and BRCA2 Mutations and DNA Repair 451 PARP1 Inhibition as a Synthetic Lethal Therapeutic Strategy for the Treatment of BRCA-Deficient Cancers 451 Mechanisms of Resistance to PARP Inhibitors 452 Initial Clinical Results Testing Synthetic Lethality 452 The Use of PARP Inhibitors in Sporadic Cancers with “BRCAness” 452 Prospects 453

43. Miscellaneous Chemotherapeutic Agents . . . 455 M. Sitki Copur, Michal Rose, and Scott Gettinger

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464

45. Interleukin Therapy . . . . . . . . . . . . . . . . . . 469

39. Targeted Therapy with Small Molecule Kinase

Sirolimus and Temsirolimus Everolimus 455

Interferon Signaling Pathways 461 Immunologic Effects of Interferon 463 Nonimmunologic Antiangiogenic Effects of Interferon Direct Antitumor Effects of Interferons 464 Clinical Toxicity of Interferon Administration 464 Potential Drug Interactions 466 Oncologic Applications of Interferons 466

455

Cy A. Stein and Harris S. Soifer Oligonucleotide Stability and Efficacy: The Role of Phosphorothioates 482 Clinical Trials of G3139 (Oblimersen) in Chronic Lymphocytic Leukemia 483 Clinical Trials in Advanced Melanoma 484

47. Antiangiogenesis Agents . . . . . . . . . . . . . . . 489 Cindy H. Chau and William D. Figg Understanding the Angiogenic Process 489 Drug Development of Angiogenesis Inhibitors 490 Clinical Utility of Approved Antiangiogenic Agents in Cancer Therapy 494 Combination Therapies 496 Surrogate Markers of Antiangiogenic Therapy 497 Resistance to Antiangiogenic Therapy 497

48. Monoclonal Antibodies . . . . . . . . . . . . . . . 499 Matthew K. Robinson, Hossein Borghaei, Gregory P. Adams, and Louis M. Weiner Immunoglobulin Structure 499 Modified Antibody-Based Molecules 499 Factors Regulating Antibody-Based Tumor Targeting 500 Unconjugated Antibodies 502 Altering Signal Transduction 503 Immunoconjugates 504 Unconjugated Antibodies Approved for Use Against Solid Tumors 505 Antibodies Used in Hematologic Malignancies 506

49. Endocrine Manipulation . . . . . . . . . . . . . . 508 Matthew P. Goetz, Charles Erlichman, Manish Kohli, and Charles L. Loprinzi Selective Estrogen Receptor Modulators 508 Aromatase Inhibitors 513 Gonadotropin-Releasing Hormone Analogues 514 Gonadotropin-Releasing Hormone Antagonists 515 Antiandrogens 515 Novel Antiandrogens 516 Other Sex Steroid Therapies 516 Other Hormonal Therapies 518

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Contents

PART FIVE

PART SIX

CANCER PREVENTION

CANCER SCREENING

50. Preventive Cancer Vaccines. . . . . . . . . . . . . 522

56. Principles of Cancer Screening . . . . . . . . . . 582

Douglas R. Lowy and John T. Schiller

Jack S. Mandel and Robert Smith

Background 522 Infectious Agents and Cancer 522 Prophylactic Versus Therapeutic Vaccination Hepatitis B Virus 524 Human Papillomavirus 525 Helicobacter Pylori 527

Principles of Screening 582 Evaluating Screening Tests 583 Developing and Evaluating a Cancer Screening Program 585

524

57. Early Detection Using Proteomics . . . . . . . . 587

51. Tobacco Dependence and Its Treatment . . . 529 Ellen R. Gritz, Cho Y. Lam, Damon J. Vidrine, and Michelle Cororve Fingeret Nicotine and the Neurobiological Basis of Smoking 529 Smoking Prevalence and Quit Rates 529 Effects of Continued Smoking on Cancer Treatment Outcomes Cessation Treatment and Research 532 Future Research and Clinical Opportunities 540

xxxv

Virginia Espina, Claudio Belluco, Emanuel F. Petricoin III, and Lance A. Liotta Cellular Proteomics 587 Biomarker Proteomics 592

530

52. Role of Surgery in Cancer Prevention . . . . . 543 JosĂŠ G. Guillem, Andrew Berchuck, Jeffrey F. Moley, Jeffrey Norton, and Sheryl G. A. Gabram Patients at High Risk for Breast Cancer 543 Hereditary Diffuse Gastric Cancer 545 Surgical Prophylaxis of Hereditary Ovarian and Endometrial Cancer 547 Hereditary Endometrial Cancer (Lynch Syndrome) 548 Multiple Endocrine Neoplasia Type 2 549 Familial Adenomatous Polyposis, MYH-Associated Polyposis, and Lynch Syndrome 552

53. Principles of Cancer Risk Reduction

58. Screening for Gastrointestinal Cancers . . . . 596 Timothy R. Church and Jack S. Mandel History of Colorectal Cancer Screening 596 Polyp Removal and Colorectal Cancer Prevention 597 Methods of Screening for Colorectal Cancer 597 Colorectal Cancer Screening for High-Risk Patients 600 Other Gastrointestinal Cancers 600 Screening 601

59. Screening for Gynecologic Cancers . . . . . . 603 Mary B. Daly and Janet S. Rader Cervical Cancer 603 Ovarian Cancer 606 Endometrial Cancer 607

60. Screening for Breast Cancer . . . . . . . . . . . . 610

Intervention . . . . . . . . . . . . . . . . . . . . . . . . 558

Laura J. Esserman and Chris I. Flowers

Dean E. Brenner

The Evidence of Mortality Benefit from Randomized Trials of Mammography Screening 610 Changes in Systemic Therapies and Impact on Screening 610 Optimizing the Organization of Screening 611 Optimizing the Interpretation of Mammography 611 Addressing the Potential Harms and Limitations of Screening 612 High-Risk Screening 614 What has Biology Taught Us? 614 Conclusion and Considerations for Screening 615

Why Cancer Prevention as a Clinical Oncology Discipline? 558 Defining Cancer Risk Reductive Intervention (Chemoprevention) 558 Identifying Potential Cancer Risk Reductive Interventions 558 Preclinical Development of Cancer Risk Reductive Interventions 559 Clinical Development of Cancer Risk Reductive Interventions 561 Implementation of Cancer Risk Reductive Interventions in the Community 562

54. Retinoids, Carotenoids, and Other

61. Screening for Prostate Cancer . . . . . . . . . . 617

Micronutrients in Cancer Prevention . . . . . 564

Peter C. Albertsen

Susan T. Mayne, Edward Giovannucci, and Scott M. Lippman

Is Prostate Cancer a Suitable Disease for Screening? 617 Is Treatment for Prostate Cancer Effective? 618 Is Prostate-Specific Antigen an Effective Screening Test? 620 Recent Evidence from Randomized Trials 621 Are there Substantial Risks Associated with Prostate-Specific Antigen Screening? 622 How Should Physicians Advise their Patients? 622

Head and Neck Cancer Chemoprevention 564 Lung Cancer Chemoprevention 565 Breast Cancer Chemoprevention 567 Skin Cancer Chemoprevention 567 Bladder Cancer Chemoprevention 568 Cervical Cancer Chemoprevention 568 Esophageal/Gastric Cancer Chemoprevention 569 Colorectal Cancer Chemoprevention 569 Prostate Cancer Chemoprevention 570 Conclusions 571

55. Drugs and Nutritional Extracts for Cancer Risk

Reduction (Chemoprevention) . . . . . . . . . . 573 Madhuri Kakarala and Dean E. Brenner Anti-Inflammatory Drugs 573 Signal Transduction Modifiers 578 Anti-Infectives 579

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62. Screening for Lung Cancer . . . . . . . . . . . . . 625 David E. Midthun and James R. Jett The Opportunity 625 Chest Radiography and Sputum Cytology CT Screening 626 The Problems with CT Screening 627 Other Methods of Screening 629 Future Directions 629

625

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Contents

63. Genetic Counseling . . . . . . . . . . . . . . . . . . 631

PART EIGHT

Ellen T. Matloff and Danielle Campfield Bonadies Who is a Candidate for Cancer Genetic Counseling? 631 Components of the Cancer Genetic Counseling Session 632 Issues in Cancer Genetic Counseling 635 Future Directions 637

PRACTICE OF ONCOLOGY 70. Design and Analysis of Clinical Trials . . . . 704 Richard Simon

PART SEVEN SPECIALIZED TECHNIQUES IN CANCER MANAGEMENT 64. Vascular Access and Specialized

Techniques . . . . . . . . . . . . . . . . . . . . . . . . . 640 James F. Pingpank, Jr. Catheter Types 640 Catheter Selection 643 Pediatric Patients 643 Insertion Techniques 643 Catheter-Related Complications

Section 1: Cancer of the Head and Neck 71. Molecular Biology of Head and

Neck Cancers . . . . . . . . . . . . . . . . . . . . . . . 723 Nishant Agrawal, Joseph Califano, and Patrick Ha

645

65. Interventional Radiology . . . . . . . . . . . . . . 648 Christos S. Georgiades and Jean-Francois H. Geschwind Pulmonary 648 Hepaticobiliary 649 Cholangiocarcinoma 652 Liver Metastases 655 Genitourinary 657 Musculoskeletal Cancer 659 Special Topic: Inferior Vena Cava/Portal Vein Occlusion 661

66. Functional Imaging . . . . . . . . . . . . . . . . . . 666 Brian D. Ross, Craig J. Galbรกn, and Alnawaz Rehemtulla Diffusion Magnetic Resonance Imaging 666 Perfusion Magnetic Resonance Imaging 670 Magnetic Resonance Spectroscopy 672

67. Molecular Imaging . . . . . . . . . . . . . . . . . . . 676 Steven M. Larson, Heiko Schรถder, and Jan Grimm Characterizing the Cancer Cell Phenotype Clinical Applications 680 Optical Imaging 683

676

68. Photodynamic Therapy . . . . . . . . . . . . . . . 686 Keith A. Cengel, Smith Apisarnthanarax, and Stephen M. Hahn Components of Photodynamic Therapy: Photosensitizers, Light, and Oxygen 686 Mechanisms of Photodynamic Therapy Cytotoxicity 688 Clinical Indications for Photodynamic Therapy for Early Stage Cancers in the Definitive Setting 689 Clinical Indications for Photodynamic Therapy in the Locally Advanced and Palliative Settings 690 Molecularly Targeted Photodynamic Therapy 692

69. Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . 694 Daniel F. Hayes What is a Biomarker Used for? 694 What are the Criteria to Incorporate a Tumor Marker into Clinical Practice? 695 Prognosis Versus Prediction 698 Pharmacogenomics: A Special Circumstance 698 Markers that are Accepted for Routine Clinical Utility 700

LWBK812-FM_pi-xlviii.indd xxxvi

Phase 1 Clinical Trials 704 Phase 2 Clinical Trials 706 Design of Phase 3 Clinical Trials 711 Factorial Designs 713 Analysis of Phase 3 Clinical Trials 716 Reporting Results of Clinical Trials 719 False-Positive Reports in the Literature 720 Meta-Analysis 720

Genetic Susceptibility 723 Molecular Networks Altered in HNSCC 724 Epigenetics 727 Loss of Heterozygosity and Risk of Malignant Progression

727

72. Treatment of Head and Neck Cancer . . . . . 729 William M. Mendenhall, John W. Werning, and David G. Pfister Epidemiology of Head and Neck Cancer 729 Anatomy 729 Pathology 729 Natural History of Squamous Cell Carcinoma 729 Diagnostic Evaluation 730 Staging 731 Principles of Treatment for Squamous Cell Carcinoma 731 Management 731 NECK 732 Chemotherapy 734 General Principles of Combining Modalities 738 Chemotherapy as Part of Curative Treatment 738 Follow-Up 744 ORAL CAVITY 744 Lip 744 Floor of the Mouth 745 Oral Tongue 747 Buccal Mucosa 749 Gingiva and Hard Palate (Including Retromolar Trigone) 750 OROPHARYNX 752 Anatomy 752 LARYNX 756 Anatomy 756 Pathology 756 Hypopharynx: Pharyngeal Walls, Pyriform Sinus, and Postcricoid Pharynx 761 NASOPHARYNX 764 Anatomy 764 Pathology 764 Patterns of Spread 765 Clinical Picture 765 Staging 765 Treatment 766 Nasal Vestibule, Nasal Cavity, and Paranasal Sinuses 766 Paragangliomas 772 Major Salivary Glands 774 Minor Salivary Glands 777

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Contents

73. Rehabilitation after Treatment of Head and

Neck Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . .781 Douglas B. Chepeha, Mark J. Haxer, and Teresa H. Lyden Pretreatment Counseling 781 Support During Treatment and Rehabilitation of the Chemoradiation Patient 781 Resources for Rehabilitation of Head and Neck Cancer Patients

Stomach . . . . . . . . . . . . . . . . . . . . . . . . . . . 882 Anil K. Rustgi 787

74. Molecular Biology of Lung Cancer . . . . . . 789 Jacob Kaufman, Leora Horn, and David Carbone Susceptibility to Lung Cancer: Genetic Susceptibility and Carcinogens in Tobacco Smoke 789 Molecular Changes in Preneoplasia 789 Genetic and Epigenetic Alterations in Lung Cancers 791 Protooncogenes, Growth Factor Signaling, and Growth Factor Targeted Therapies 791 Tumor Suppressor Genes and Growth Suppression 793 Cyclins and Cell Cycle Regulatory Pathways 794 Other Biologic Abnormalities in Lung Cancer 795 Cancer Stem Cell Hypothesis 796 Genomic Analysis of Lung Cancer 797 Molecular Tools in the Lung Cancer Clinic 797

75. Non–Small Cell Lung Cancer . . . . . . . . . . . 799 David S. Schrump, Darryl Carter, Christopher R. Kelsey, Lawrence B. Marks, and Giuseppe Giaccone

843

863

77. Neoplasms of the Mediastinum . . . . . . . . . 871

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Mitchell C. Posner, Bruce D. Minsky, and David H. Ilson Epidemiology 887 Etiologic Factors and Predisposing Conditions 887 Applied Anatomy and Histology 891 Natural History and Patterns of Failure 892 Clinical Presentation 892 Diagnostic Studies and Pretreatment Staging 893 Pathologic Staging 894 Treatment 895 Stage-Directed Treatment Recommendations 921

80. Cancer of the Stomach . . . . . . . . . . . . . . . . 924 Itzhak Avital, Peter W.T. Pisters, David P. Kelsen, and Christopher G. Willett Epidemiology and Etiology 924 Anatomic Considerations 926 Pathology and Tumor Biology 927 Histopathology 927 Patterns of Spread 927 Clinical Presentation and Pretreatment Evaluation 928 Pretreatment Staging 929 Staging, Classification, and Prognosis 930 Gastric Cancer Nomograms: Predicting Individual Patient Prognosis After Potentially Curative Resection 933 Treatment of Localized Disease 934 Technical Treatment-Related Issues 944 Treatment of Advanced Disease (Stage IV) 945 Surgery in Treatment of Metastatic Gastric Cancer 952 Radiation for Palliation 952

Common Molecular Changes 955 Low-Frequency Genetic Changes 958

82. Cancer of the Pancreas . . . . . . . . . . . . . . . . 961

the Lung. . . . . . . . . . . . . . . . . . . . . . . . . . . 848

Thymic Neoplasms 871 Thymoma 871 Thymic Carcinoma 872 Thymic Carcinoid 878 Thymolipoma 878 Germ Cell Tumors 878

79. Cancer of the Esophagus . . . . . . . . . . . . . . 887

Scott E. Kern and Ralph H. Hruban

Lee M. Krug, M. Catherine Pietanza, Mark G. Kris, Kenneth Rosenzweig, and William D. Travis

Robert B. Cameron, Patrick J. Loehrer, and Charles R. Thomas, Jr.

Molecular Biology of Esophageal Cancer 882 Molecular Biology of Gastric Cancer 884

81. Molecular Biology of Pancreas Cancer . . . . 955

76. Small Cell and Neuroendocrine Tumors of

Small Cell Lung Cancer 848 Typical Carcinoid and Atypical Carcinoid Tumors Large Cell Neuroendocrine Carcinoma 867

Section 3: Cancers of the Gastrointestinal Tract 78. Molecular Biology of the Esophagus and

Section 2: Cancer of the Thoracic Cavity

Incidence 799 Etiology 799 Pathology 802 Molecular Markers of Prognosis 805 Modes of Metastasis 806 Clinical Manifestations 806 Staging and Diagnosis 807 Methods to Establish Tissue Diagnosis 811 Overview of Invasive Lung Cancer Management: Treatment Modalities 813 Specifics of Lung Cancer Management 820 Superior Sulcus Tumors 829 Unresectable or Medically Inoperable 829 Locally Advanced 830 Advanced Disease 833 Investigational Agents in Development for NSCLC Personalized Medicine in NSCLC 843 Local Therapies and Palliation 844

xxxvii

Richard E. Royal, Robert A. Wolff, and Christopher H. Crane Incidence and Etiology 961 Anatomy and Pathology 964 Screening 964 Diagnosis and Staging 965 Staging 967 Treatment of Potentially Resectable Disease: American Joint Committee on Cancer Stage I and II 967 Treatment of Locally Advanced Disease: American Joint Committee on Cancer Stage III 975 Treatment of Metastatic Disease: American Joint Committee on Cancer Stage IV 980 Other Exocrine Neoplasms 986

83. Molecular Biology of Liver Cancer . . . . . . 990 Snorri S. Thorgeirsson and Joe W. Grisham Allelic Imbalance in Liver Cancer 990 Classification and Prognostic Prediction of Hepatocellular Carcinoma 991 Comparative Functional Genomics 995 Conclusion and Perspective 995

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xxxviii

Contents

84. Cancer of the Liver . . . . . . . . . . . . . . . . . . 997 David L. Bartlett, Adrian M. Di Bisceglie, and Laura A. Dawson Epidemiology 997 Etiologic Factors 997 Pathology 1001 Staging 1002 Clinical Features 1002 Clinical Evaluation 1004 Clinical Management 1008 Adjuvant Therapy 1012 Treatment of Other Primary Liver Tumors

1016

85. Cancer of the Biliary Tree . . . . . . . . . . . . 1019 David L. Bartlett, Ramesh K. Ramanathan, and Edgar Ben-Josef Cholangiocarcinomas 1019 Tumors of the Gallbladder 1035

86. Cancer of the Small Intestine . . . . . . . . . . 1048 Amer H. Zureikat, Matthew T. Heller, and Herbert J Zeh, III Small Bowel Cancer 1048 Adenocarcinoma 1052 Carcinoid Tumors 1053 Intestinal Lymphoma 1055 Gastrointestinal Stromal Tumors 1056 Other Mesenchymal Tumors 1057

87. Gastrointestinal Stromal Tumor . . . . . . . . 1060 George D. Demetri GIST as a Unique Clinicopathologic Subset of Sarcoma 1060 GIST Cells are Related to the Mesenchymal Precursor Cells that Give Rise to Normal Interstitial Cells of Cajal: Aberrant Developmental Biology 1061 The Development of a Molecular Understanding of GIST 1061 Clinical Considerations 1062 Prognostic Features of Gastrointestinal Stromal Tumor 1064 Diagnostic Imaging of Patients with Gastrointestinal Stromal Tumors 1064 Treatment Options and Management Decisions in the Era of Molecularly Targeted Therapies for GIST 1065 Extrapolation of Emerging Management Paradigms to Early-Stage GIST 1070 Adjuvant Therapy to Improve Outcomes for Patients with Resected Early-Stage GIST 1070 Special Considerations in GIST 1071 New Challenges and Alternative Approaches 1071

88. Molecular Biology of Colorectal Cancer . 1074 Ramesh A. Shivdasani The Adenoma–Carcinoma Sequence and Multistep Models of Colorectal Tumorigenesis 1074 Early Events and Critical Pathways in Colorectal Tumorigenesis Highlighted by Inherited Syndromes of Increased Cancer Risk 1075 Oncogene and Tumor Suppressor Gene Mutations in Colorectal Cancer Progression 1079 Infrequent Changes and Current Views of the Mutational Landscape of Colorectal Cancer 1082

89. Cancer of the Colon . . . . . . . . . . . . . . . . . 1084 Steven K. Libutti, Leonard B. Saltz, and Christopher G. Willett Epidemiology 1084 Etiology: Genetic and Environmental Risk Factors 1085 Familial Colorectal Cancer 1086 Anatomy of the Colon 1088 Diagnosis of Colorectal Cancer 1089 Screening for Colorectal Cancer 1089 Staging and Prognosis of Colorectal Cancer 1090

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Approaches to Surgical Resection of Colon Cancer 1096 Surgical Management of Complications from Primary Colon Cancer 1098 Polyps and Stage I Colon Cancer 1099 Stage II and Stage III Colon Cancer 1099 Treatment of Stage II Patients 1102 Treatment Options for Stage III Patients 1104 Radiation Therapy of Colon Cancer 1104 Follow-Up After Management of Colon Cancer with Curative Intent 1106 Surgical Management of Stage IV Disease 1108 Management of Unresectable Metastatic Disease 1108 Gene Therapy 1123 Molecular Predictive Markers 1123 Management of Synchronous Primary and Metastatic Disease 1123 Unusual Colorectal Tumors 1124

90. Cancer of the Rectum . . . . . . . . . . . . . . . 1127 Steven K. Libutti, Christopher G. Willett, and Leonard B. Saltz Anatomy 1127 Staging 1128 Surgery 1130 Does Adjuvant Radiation Therapy Impact Survival? 1134 Preoperative Radiation Therapy 1135 Which Patients Should Receive Adjuvant Therapy? 1136 Concurrent Chemotherapy 1137 Synchronous Rectal Primary and Metastases 1138 Management of Unresectable Primary and Locally Advanced Disease (T4) 1138 Radiation Therapy Technique 1139

91. Cancer of the Anal Region . . . . . . . . . . . . 1142 Yixing Jiang, David J. Beddy, Heidi Nelson, Lisa A. Kachnic, and Jaffer A. Ajani Epidemiology and Etiology 1142 Pathology 1143 Clinical Presentation and Staging 1144 Prognostic Factors 1144 Treatment of Localized Squamous Cell Carcinoma of the Anal Canal 1145 Treatment of Other Sites and Pathologies 1151

Section 4: Cancers of the Genitourinary System 92. Molecular Biology of Kidney Cancer . . . . 1154 W. Marston Linehan and Laura S. Schmidt Von Hippel-Lindau 1154 Hereditary Papillary Renal Carcinoma Type 1 1155 XP11.2 Translocation Renal Cell Cancer 1156 Birt-Hogg-DubĂŠ Syndrome 1156 Hereditary Leiomyomatosis and Renal Cell Carcinoma 1157 Familial Renal Cancer: Succinate Dehydrogenase Gene 1158 Tuberous Sclerosis Complex 1159 Conclusion 1159

93. Cancer of the Kidney . . . . . . . . . . . . . . . . 1161 W. Marston Linehan, Brian I. Rini, and James C. Yang Histologic Types of Renal Carcinoma 1161 Hereditary Forms of Kidney Cancer 1161 Transcription Factors and Kidney Cancer 1164 Localized Renal Carcinoma 1169 Metastatic Renal Carcinoma 1170

94. Molecular Biology of Bladder Cancer . . . 1183 Margaret A. Knowles Molecular Alterations in Superficial Urothelial Carcinoma 1183 Carcinoma in Situ 1186 Molecular Alterations in Invasive Urothelial Carcinoma 1186

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Contents Information from Expression and Genomic Microarray Profiling 1188 Signaling Pathways in Urothelial Carcinoma 1189 Urothelial Tumor-Initiating Cells 1189 Molecular Pathogenesis and Tumor Clonality 1189

95. Cancer of the Bladder, Ureter, and

Renal Pelvis . . . . . . . . . . . . . . . . . . . . . . . 1192 W. Scott McDougal, William U. Shipley, Donald S. Kaufman, Douglas M. Dahl, M. Dror Michaelson, and Anthony L. Zietman Urothelial Cancers 1192 Cancer of the Bladder 1194 Cancers of the Renal Pelvis and Ureter

xxxix

Section 5: Gynecologic Cancers 100. Molecular Biology of Gynecologic

Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . 1302 Kunle Odunsi, Tanja Pejovic, and Matthew L. Anderson Ovarian Cancer 1302 Endometrial Cancer 1306 Cervix, Vaginal, and Vulvar Cancers 1307 Gestational Trophoblastic Disease 1309

101. Cancer of the Cervix, Vagina, and 1205

Vulva . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1311 Patricia J. Eifel, Jonathan S. Berek, and Maurie A. Markman

96. Molecular Biology of Prostate Cancer . . . 1212 Yu Chen, Vivek K. Arora, and Charles L. Sawyers Genetic Predisposition 1212 Genetic Landscape of Prostate Cancer ETS Transcription Factors 1216

1212

Carcinoma of the Cervix 1311 Carcinoma of the Vagina 1330 Carcinoma of the Vulva 1335

102. Cancers of the Uterine Body . . . . . . . . . . 1345 Pedro T. Ramirez, Arno J. Mundt, and Franco M. Muggia

97. Cancer of the Prostate . . . . . . . . . . . . . . . 1220 Michael J. Zelefsky, James A. Eastham, and A. Oliver Sartor Anatomy of the Prostate 1220 Prostate Zonal Anatomy 1220 Histopathology 1220 Gleason Score 1222 Incidence, Epidemiology, and Risk Factors 1222 Incidence and Mortality of Prostate Cancer 1223 Clinical Risk Factors for Prostate Cancer 1223 Genetic Alterations and Risk 1224 Prostate Cancer Prevention 1224 Disease Presentation and Diagnosis 1227 Staging Workup 1228 Prognostic Factors and the Assessment of Risk 1230 Treating Clinically Localized Prostate Cancer 1231 External-Beam Radiotherapy 1238 Androgen Deprivation and Radiation Therapy 1249 Adjuvant Radiation Therapy for High-Risk Patients After Radical Prostatectomy 1252 Management of the Rising PSA After Definitive Local Therapy 1253 Management of Metastatic Prostate Cancer 1258 Castration-Resistant Prostate Cancer 1262

98. Cancer of the Urethra and Penis. . . . . . . . 1272 Edouard J. Trabulsi and Leonard G. Gomella Cancer of the Male Urethra 1272 Carcinoma of the Female Urethra 1273 Cancer of the Penis 1274

99. Cancer of the Testis . . . . . . . . . . . . . . . . . 1280 George J. Bosl, Darren R. Feldman, Dean F. Bajorin, Joel Sheinfeld, Robert J. Motzer, Victor E. Reuter, Marisa A. Kollmeier, and Raju S. K. Chaganti Background: Incidence 1280 Epidemiology 1280 Risk Factors 1280 Initial Presentation and Management 1280 Histology 1281 Biology 1282 Immunohistochemical Markers 1284 Staging 1284 Management of Clinical Stage I Disease 1286 Management of Clinical Stage II (Low Tumor Burden) 1290 Management of Stage II and Stage III Disease (High Tumor Burden) 1291 Management of Relapse and Refractory Disease 1296 Treatment Sequelae 1298 Long-Term Follow-Up 1299 Midline Tumors of Uncertain Histogenesis 1299 Other Testicular Tumors 1299

LWBK812-FM_pi-xlviii.indd xxxix

Endometrial Carcinoma 1345 Uterine Sarcomas 1356

103. Gestational Trophoblastic Neoplasms . . . 1363 Donald P. Goldstein and Ross S. Berkowitz Epidemiology 1363 Pathology and Natural History 1363 Indications for Treatment 1363 Measurement of hCG 1364 Phantom hCG 1364 Pretreatment Evaluation 1364 Staging and Prognostic Score 1364 Treatment 1364 Placental Site Trophoblastic Tumors 1366 Subsequent Pregnancy 1366 Psychosocial Issues 1366

104. Ovarian Cancer, Fallopian Tube Carcinoma, and

Peritoneal Carcinoma. . . . . . . . . . . . . . . . . . .1368 Stephen A. Cannistra, David M. Gershenson, and Abram Recht Epithelial Ovarian Cancer 1368 Borderline Tumors 1385 Germ Cell Tumors of the Ovary 1386 Sex Cord–Stromal Tumors 1387 Primary Peritoneal Serous Carcinoma 1389 Fallopian Tube Cancer 1389

Section 6: Cancer of the Breast 105. Molecular Biology of Breast Cancer . . . . 1392 Erin Wysong Hofstatter, Gina G. Chung, and Lyndsay N. Harris Genetics of Breast Cancer 1392 Hereditary Breast Cancer 1392 Somatic Changes in Breast Cancer 1393 Gene Expression Patterns in Breast Cancer Epigenetics of Breast Cancer 1396 Protein/Pathway Alterations 1397

1395

106. Malignant Tumors of the Breast . . . . . . . 1401 Harold J. Burstein, Jay R. Harris, and Monica Morrow Anatomy of the Breast 1401 Risk Factors for Breast Cancer 1401 Benign Breast Disease 1404 Breast Density 1404 Environmental Factors 1404 Management of the High-Risk Patient 1404

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xl

Contents Diagnosis and Biopsy 1407 Lobular Carcinoma In Situ 1408 Ductal Carcinoma In Situ 1409 Treatment of the Breast 1409 Treatment of the Axilla 1411 Endocrine Therapy 1411 Staging 1411 Pathology of Breast Cancer 1413 Local Management of Invasive Cancer 1414 Breast-Conserving Therapy 1414 Mastectomy 1422 Management of the Axilla 1423 Local-Regional Therapy and Survival 1425 Prognostic and Predictive Factors 1426 Other Factors 1427 Molecular and Genomic Factors 1427 Adjuvant Systemic Therapy 1428 Integration of Multimodality Primary Therapy 1434 Follow-Up for Breast Cancer Survivors 1435 Special Therapeutic Problems 1436 Metastatic Disease 1439

Additional Clinical Considerations 1499 Surgery Pitfalls 1500 Emerging Therapeutic Options 1501

112. Neuroendocrine (Carcinoid) Tumors and the

Carcinoid Syndrome . . . . . . . . . . . . . . . . 1503 Gerard M. Doherty Pathology and Tumor Histology 1503 Molecular Pathogenesis 1506 Clinical Features of Carcinoid Tumors 1506 Carcinoid Syndrome 1506 Treatment of the Carcinoid Tumor 1512

113. Multiple Endocrine Neoplasias . . . . . . . . 1516 Gerard M. Doherty Multiple Endocrine Neoplasia Type 1 1516 Familial Medullary Thyroid Carcinoma and Multiple Endocrine Neoplasia Types 2A and 2B 1519

Section 7: Cancer of the Endocrine System 107. Molecular Biology of Endocrine Tumors . 1447 Samuel A. Wells, Jr. The Multiple Endocrine Neoplasia Syndromes 1447 Application of Molecular Genetics to Clinical Medicine Sporadic Thyroid Cancers 1453 Future Directions 1455

1452

108. Thyroid Tumors . . . . . . . . . . . . . . . . . . . . . . .1457 Tobias Carling and Robert Udelsman Thyroid Tumor Classification and Staging Systems 1457 Epidemiology and Demographics 1458 Etiology and Risk Factors 1458 Evaluation of the Thyroid Nodule 1460 Well-Differentiated Thyroid Carcinoma 1462 Treatment of Well and Intermediately Differentiated Thyroid Carcinoma 1464 Poorly Differentiated Thyroid Carcinoma 1468 Medullary Thyroid Carcinoma 1469 Treatment of Familial Medullary Thyroid Carcinoma 1470 Thyroid Lymphoma 1470 Metastatic Disease of the Thyroid 1471 Children with Thyroid Carcinoma 1471

109. Parathyroid Tumors . . . . . . . . . . . . . . . . . 1473 Reza Rahbari and Electron Kebebew Epidemiology 1473 Pathology 1474 Molecular Genetics 1475 Clinical Manifestations 1475 Diagnosis 1475 Management of Parathyroid Cancer 1476 Follow-Up and Natural History 1477 Prognosis 1478

110. Adrenal Tumors . . . . . . . . . . . . . . . . . . . . 1480 Mio Kitano, Erin Patterson, and Electron Kebebew Adrenocortical Cancer 1480 Pediatric Adrenocortical Carcinoma Pheochromocytoma 1484 Adrenal Incidentaloma 1487

1484

111. Pancreatic Neuroendocrine Tumors . . . . . 1489 James C. Yao, Guido Rindi, and Douglas B. Evans Epidemiology 1489 Classification, Histopathology, and Molecular Genetics 1489 Diagnosis and Management of Pancreatic Endocrine Tumors 1492

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Section 8: Sarcomas of Soft Tissue and Bone 114. Molecular Biology of Soft Tissue Sarcoma 1522 Samuel Singer, Torsten Nielsen, and Cristina R. Antonescu Translocation-Associated Sarcomas 1522 Simple Karyotype Tumors Associated with Mutations 1528 Complex Sarcoma Types 1528 Future Directions: Functional Screens and Next-Generation Sequencing 1531

115. Soft Tissue Sarcoma . . . . . . . . . . . . . . . . . 1533 Samuel Singer, Robert G. Maki, and Brian O’Sullivan Incidence and Etiology 1533 Anatomic and Age Distribution and Pathology 1535 Diagnosis and Staging 1547 Management by Presentation Status, Extent of Disease, and Anatomic Location 1552 Palliative Care 1574 Future Directions 1576

116. Sarcomas of Bone . . . . . . . . . . . . . . . . . . 1578 Martin M. Malawer, Lee J. Helman, and Brian O’Sullivan Classification and Types of Bone Tumor 1578 Radiographic Evaluation and Diagnosis 1578 Natural History 1579 Staging Bone Tumors 1581 Preoperative Radiographic Evaluation 1581 Biopsy Technique and Timing 1585 Restaging After Induction (Preoperative) Chemotherapy 1585 Guidelines for Limb-Sparing Resection 1586 Types of Skeletal Reconstruction 1586 Limb-Sparing Surgery and Perioperative Pain Management 1587 Amputations 1588 Chemotherapy for Bone Sarcomas 1589 Radiotherapy for Osteosarcoma 1594 Malignant Bone Tumors 1595

Section 9: Cancers of the Skin 117. Cancer of the Skin . . . . . . . . . . . . . . . . . . 1610 Anetta Reszko, Sumaira Z. Aasi, Lynn D. Wilson, and David J. Leffell NONMELANOMA SKIN CANCER 1610 Diagnosis 1610 General Approach to Management of Skin Cancer Topical Therapy for Skin Cancer 1613 Radiation Therapy for Skin Cancer 1614 ACTINIC KERATOSES 1614

1610

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xli

Contents Pathogenesis of AK 1615 Clinical Features of AK 1615 Treatment of AK 1615 BASAL CELL CARCINOMA 1616 Clinical Behavior of BCC 1617 BCC Subtypes 1617 Histology 1618 Treatment 1619 SQUAMOUS CELL CARCINOMA 1620 Pathogenesis of SCC 1620 Biologic Behavior of SCC 1620 Clinical Features of SCC 1621 Histology 1621 Recurrence and Metastatic Risk 1621 Treatment 1622 Follow Up 1623 Immunosuppression and Nonmelanoma Skin Cancer 1623 ANGIOSARCOMA 1624 Pathogenesis 1624 Clinical Presentation and Prognosis 1624 Histology 1625 Treatment 1625 DERMATOFIBROSARCOMA PROTUBERANS 1625 Pathogenesis 1625 Histology 1625 Treatment 1625 Recurrence and Metastatic Potential 1626 MERKEL CELL CARCINOMA 1626 Pathogenesis 1626 Clinical Presentation 1626 Histology 1626 Treatment 1627 Staging 1627 Recurrence and Metastatic Risk 1627 Prognosis 1628 MICROCYSTIC ADNEXAL CARCINOMA 1628 Pathogenesis 1629 Clinical Presentation 1629 Histology 1629 Treatment 1629 SEBACEOUS CARCINOMA 1629 Histology 1630 Treatment 1630 ATYPICAL FIBROXANTHOMA AND MALIGNANT FIBROUS HISTIOCYTOMA 1630 ATYPICAL FIBROXANTHOMA 1630 Pathogenesis 1630 Clinical Presentation 1630 Histology 1631 Treatment 1631 MALIGNANT FIBROUS HISTIOCYTOMA 1631 Clinical Presentation 1631 Histology 1631 Treatment and Prognosis 1631 CARCINOMA METASTATIC TO SKIN 1631

118. Molecular Biology of Cutaneous

Melanoma . . . . . . . . . . . . . . . . . . . . . . . . 1634 Levi A. Garraway and Lynda Chin The CDKN2A Locus 1634 The Retinoblastoma Pathway 1634 The p53 Pathway 1635 The MAP Kinase Pathway 1636 The RAS Family: H-, N-, and K-RAS 1636 The Phosphatidylinositol 3-Kinase Pathway 1638 Receptor Tyrosine Kinases 1638 Epidermal Growth Factor Receptor Family 1639 The MITF Pathway 1639 The WNT Pathway 1639 The MC1R Pathway 1640 The FAK Pathway 1640 Cancer Stem Cells and Melanoma 1640 Cancer Genomics and Translation 1640 Looking Ahead 1641

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119. Cutaneous Melanoma . . . . . . . . . . . . . . . 1643 Craig L. Slingluff Jr., Keith Flaherty, Steven A. Rosenberg, and Paul W. Read Cutaneous Melanoma Biology 1643 Epidemiology 1644 Changes in Incidence 1645 Gender and Age Distribution 1645 Melanoma in Children, Infants, and Neonates 1645 Anatomic Distribution 1646 Etiology and Risk Factors 1646 Pregnancy and Estrogen Use 1646 Prevention and Screening 1647 Diagnosis of Primary Melanoma 1648 General Considerations in Clinical Management of a Newly Diagnosed Cutaneous Melanoma (Stage I窶的I) 1652 Wide Local Excision for Clinical Stage I窶的I Melanoma: General Considerations 1653 Clinical Trials to Define Margins of Excision for Primary Cutaneous Melanomas 1653 Surgical Staging of Regional Nodes 1655 Management of Clinically Localized Melanoma 1658 Management of Thin Primary Melanoma (Clinical T1a) 1658 Management of Clinical T2a, T2b Melanomas 1660 Management of Clinical T3a Melanomas (Clinical Stage IIA) 1660 Management of Clinical T3b Melanomas (Clinical Stage IIB) 1660 Management of Thick Melanomas (T4a, T4b, Greater than 4 mm Thick) 1660 Special Considerations in Management of Primary Melanomas 1661 The Role of Radiation Therapy in the Management of Primary Melanoma Lesions 1662 Clinical Follow-Up for Intermediate-Thickness and Thick Melanomas (Stage IB窶的IC) 1662 Regionally Metastatic Melanoma (Stage III): Lymph Node Metastasis, Satellite Lesions, and In-Transit Metastases 1662 Management of Regional Metastases in Patients with Visceral or Other Distant Disease 1666 Adjuvant Systemic Therapy (Stages IIB, IIC, and III) 1667 Management of Distant Metastases of Melanoma (Stage IV) 1672 Combination Chemotherapy 1678 Experimental and Developing Immunologic Therapies for Stage IV Melanoma 1682 Rationale for Targeted Therapy in Melanoma 1684 Radiation Therapy for Metastatic Melanoma (Stage IV) 1687

Section 10: Neoplasms of the Central Nervous System 120. Molecular Biology of Central Nervous

System Tumors. . . . . . . . . . . . . . . . . . . . . 1692 C. David James, David N. Louis, and Webster K. Cavenee Neurologic Tumor Syndromes 1692 CNS Tumor Histopathology and Molecular Correlates Current Basis of CNS Tumor Treatment and Response to Therapy 1698

1692

121. Neoplasms of the Central Nervous System 1700 Minesh Mehta, Michael A. Vogelbaum, Susan Chang, and Neha Patel Epidemiology of Brain Tumors 1700 Anatomic Location and Clinical Considerations 1702 Neurodiagnostic Tests 1705 Surgery 1706 Radiation Therapy 1708 Chemotherapy and Targeted Agents 1710 Specific Central Nervous System Neoplasms 1712 Gliomatosis Cerebri 1720 Optic, Chiasmal, and Hypothalamic Gliomas 1720 Brainstem Gliomas 1722 Cerebellar Astrocytomas 1723 Gangliogliomas 1723 Ependymoma 1724

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xlii

Contents Meningiomas 1727 Primitive Neuroectodermal or Embryonal Central Nervous System Neoplasms 1730 Pineal Region Tumors and Germ Cell Tumors 1733 Pituitary Adenomas 1735 Craniopharyngiomas 1737 Vestibular Schwannomas 1738 Glomus Jugulare Tumors 1740 Hemangioblastomas 1741 Chordomas and Chondrosarcomas 1742 Choroid Plexus Tumors 1744 Spinal Axis Tumors 1745

Diagnosis and Staging of Hodgkin Lymphomas 1825 Clinical Presentation of Hodgkin Lymphomas 1827 Treatment Methods for Hodgkin Lymphoma 1827 Choice of Treatment 1829 Treatment for Early Favorable Hodgkin Lymphoma 1832 Early Unfavorable Hodgkin Lymphoma 1834 Advanced Stages of Hodgkin Lymphoma 1836 Progressive and Relapsed Disease 1840 Lymphocyte-Predominant Hodgkin Lymphoma 1844 Special Populations 1846 Treatment-Related Late Side Effects 1848 Quality of Life 1850 New Drugs in Hodgkin Lymphoma 1851

Section 11: Cancers of Childhood

127. Non-Hodgkin Lymphomas . . . . . . . . . . . 1855

122. Molecular Biology of Childhood Cancers . . .1750 Lee J. Helman and David Malkin Tumor Suppressor Genes 1750 Retinoblastoma: The Paradigm 1752 Wilms Tumor: Three Distinct Loci 1753 Neurofibromatoses 1753 Neuroblastoma 1754 Ewing Sarcoma Family of Tumors 1755 Rhabdomyosarcoma 1755 Hereditary Syndromes Associated with Tumors of Childhood Malignant Rhabdoid Tumors 1757 Predictive Testing for Germ Line Mutations and Childhood Cancers 1757 Molecular Therapeutics 1758

1756

123. Solid Tumors of Childhood . . . . . . . . . . . 1760 Lisa L. Wang, Jason Yustein, Chrystal Louis, Heidi V. Russell, Alberto S. Pappo, Arnold Paulino, Jed G. Nuchtern, and Murali Chintagumpala The Importance of Multidisciplinary Management Teams in Pediatric Solid Tumors 1760 Neuroblastoma 1760 Wilms’ Tumor 1766 Retinoblastoma 1769 Pediatric Bone Sarcomas: Osteosarcoma and Ewing’s Sarcoma 1771 Rhabdomyosarcoma 1780 Liver Tumors 1784 Germ Cell Tumors 1786

124. Leukemias and Lymphomas of

Jonathan W. Friedberg, Peter M. Mauch, Lisa Rimsza, and Richard I. Fisher Epidemiology 1855 Etiology 1855 Biologic Background for Classification of Lymphoid Neoplasms B- and T-Cell Differentiation 1857 Immunophenotyping of Lymphoid Cells 1862 Chromosomal Translocations and Oncogene Rearrangements 1863 Use of Immunophenotyping and Genetic Studies in the Diagnosis of Lymphoid Neoplasms 1864 Principles of the World Health Organization Classification of Lymphoid Neoplasms 1864 Principles of Management of Non-Hodgkin Lymphoma 1867 Specific Disease Entities 1869 Mature T-Cell and NK Cell Neoplasms 1884 Special Clinical Situations 1889

1857

128. Cutaneous Lymphomas . . . . . . . . . . . . . . 1894 Francine M. Foss, Richard L. Edelson, and Lynn D. Wilson Mycosis Fungoides and the Sézary Syndrome 1894 Diagnosis and Staging 1896 Clinical Evaluation of Patients with Cutaneous Lymphoma 1898 Principles of Therapy of Mycosis Fungoides and the Sézary Syndrome 1899 Systemic Therapy for Mycosis Fungoides and the Sézary Syndrome 1902 Other Cutaneous Lymphomas 1905

129. Primary Central Nervous System

Childhood . . . . . . . . . . . . . . . . . . . . . . . . 1793

Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . 1908

Judith F. Margolin, Karen R. Rabin, and David G. Poplack

Lisa M. DeAngelis and Joachim Yahalom

Leukemias 1793 Lymphomas 1801 Supportive Care 1804 Long-Term, Palliative, and Hospice Care in Pediatric Oncology

Clinical Features 1908 Diagnostic Tests 1909 Pathology 1909 Management and Therapy

1804

Section 12: Lymphomas in Adults

1910

Section 13: Leukemias and Plasma Cell Tumors

125. Molecular Biology of Lymphomas . . . . . . 1806

130. Molecular Biology of Acute

Urban Novak, Laura Pasqualucci, and Riccardo Dalla-Favera

Leukemias . . . . . . . . . . . . . . . . . . . . . . . . 1916

The Cell of Origin of Lymphoma 1806 General Mechanisms of Genetic Lesion in Lymphoma 1807 Molecular Pathogenesis of B-Cell Non-Hodgkin’s Lymphoma Molecular Pathogenesis of T-Cell NHL 1816 Molecular Pathogenesis of HL 1817

Glen D. Raffel and Jan Cerny 1810

126. Hodgkin Lymphoma . . . . . . . . . . . . . . . . 1819 Andreas Engert, Dennis A. Eichenauer, Nancy Lee Harris, Peter M. Mauch, and Volker Diehl History of Hodgkin Lymphoma 1819 Etiology and Epidemiology 1819 Biology and Cell of Origin 1820 Immunology of Hodgkin Lymphoma 1820

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Leukemic Stem Cell 1916 Elucidation of Genetic Events in Acute Leukemia 1916 Recurring Chromosomal Abnormalities in Acute Leukemia 1917 Chromosomal Translocations that Target CoreBinding Factor 1917 Chromosomal Translocations that Target the Retinoic Acid Receptor Alpha Gene 1919 Chromosomal Translocations that Target HOX Family Members 1920 Chromosomal Translocations that Target the MLL Gene 1920 Chromosomal Translocations that Involve Transcriptional Coactivators and Chromatin Remodeling Proteins 1921

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Contents t(1;22) Translocation Associated with Infant Acute Megakaryoblastic Leukemia 1921 Deletions and Numeric Abnormalities in Acute Leukemias 1921 Chromosomal Translocations that Result in Overexpression of Otherwise Normal Genes 1922 Chromosomal Translocations Involving the T-Cell Receptor 1922 Point Mutations in Acute Leukemia 1922 Mutation in Tumor Suppressor Genes 1924 Activating Mutations of NOTCH 1924 Mutations Altering Localization of NPM1 1925 Loss-of-Function Point Mutations in AML1,C/EBP␣, and GATA-1 1925 Mutation of Lymphoid Development Genes in ALL 1925 Mutational Complementation Groups in Acute Leukemias 1925 Conclusion 1926

131. Management of Acute Leukemias . . . . . . 1928 Partow Kebriaei, Richard Champlin, Marcos de Lima, and Elihu Estey Acute Myelogenous Leukemia 1929 Acute Lymphoblastic Leukemia 1946

132. Molecular Biology of Chronic

Leukemias . . . . . . . . . . . . . . . . . . . . . . . . 1955 Anupriya Agarwal, John C. Byrd, and Michael W. Deininger Chronic Myeloid Leukemia 1955 Chronic Lymphocytic Leukemia 1958

133. Chronic Myelogenous Leukemia . . . . . . . 1962 Brian J. Druker and Stephanie J. Lee Epidemiology 1962 Pathogenesis 1962 Diagnosis 1963 Clinical Course and Prognosis 1964 Treatment of Chronic Phase Disease 1965 Tyrosine Kinase Inhibitors 1965 Hematopoietic Cell Transplantation 1968 Advanced Phase Disease 1970 Future Directions 1971

Molecular Biology 1973 Immune Abnormalities 1975 Diagnosis 1975 Clinical Manifestations 1975 Treatment and Response Criteria 1977 New and Novel Agents for Treatment of Chronic Lymphocytic Leukemia 1984 Second Malignancies and Transformation 1985 Prolymphocytic Leukemia 1985 Large Granular Lymphocyte Leukemia 1985 Hairy Cell Leukemia 1986

138. Benign and Malignant Mesothelioma . . . 2052 Harvey I. Pass, Nicholas T. Vogelzang, Steven M. Hahn, and Michele Carbone Mechanism of Asbestos-Carcinogenesis 2052 Overview of Molecular Mechanisms in Mesothelioma 2054 Alterations of Oncogenesin Mesothelioma 2054 Pathology of Mesothelioma 2056 Epidemiology and Clinical Presentation 2058 Diagnostic Approach for Presumed Mesothelioma 2062 Natural History 2064 Treatment 2066 Pleurectomy 2068 Radiotherapy for Mesothelioma 2069 Multimodality Treatment 2071 Novel Intrapleural Approaches: New Techniques with New/Old Agents 2072 Chemotherapy and Newer Agents 2074 Novel Treatment Approaches 2076 Other Agents 2077

Rationale for a Combined Treatment for Peritoneal Surface Malignancy 2081 Validated Quantitative Prognostic Indicators 2081 Appendiceal Malignancy 2083 Colorectal Carcinomatosis: Curative Treatment and Prevention Diffuse Malignant Peritoneal Mesothelioma 2085 Gastric Cancer 2086 Peritoneal Carcinomatosis in Ovarian Cancer 2087 Sarcomatosis 2087

2084

Daniel M. Albert and Amol D. Kulkarni

Stefan Faderl and Hagop M. Kantarjian

1990

136. Plasma Cell Neoplasms . . . . . . . . . . . . . . 1997

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Pathologic Evaluation 2033 Clinical Features and Evaluation 2038 Treatment 2040 Special Issues in Carcinoma of Unknown Primary Site 2048 Unknown Primary Cancer in Children 2049 Future Directions and Changing Treatment Paradigm 2050

140. Intraocular Melanoma . . . . . . . . . . . . . . . 2090

135. Myelodysplastic Syndromes . . . . . . . . . . . 1988

History 1997 Epidemiology 1998 Etiology 1998 Pathogenesis 1999 Drug Resistance 2004 Clinical Manifestations 2005 Treatment 2015

F. Anthony Greco and John D. Hainsworth

Marcello Deraco, Dominique Elias, Olivier Glehen, Cyril W. Helm, Paul H. Sugarbaker, and Vic J. Verwaal

William G. Wierda and Susan O’Brien

Nikhil C. Munshi and Kenneth C. Anderson

137. Cancer of Unknown Primary Site. . . . . . . 2033

139. Peritoneal Surface Malignancy . . . . . . . . . 2081

134. Chronic Lymphocytic Leukemias . . . . . . . 1973

Epidemiology and Etiology 1988 Presentation and Diagnosis 1988 Cytogenetic-Molecular Abnormalities and MDS Pathogenesis Classification 1991 Therapy 1992 Outlook 1995

Section 14: Other Cancers

Incidence and Etiology 2090 Anatomy and Pathology 2090 Diagnosis 2091 Metastatic Workup 2093 Staging 2093 Management 2093 Prognostic and Predictive Factors 2096 Posttreatment Quality of Life 2097

Section 15: Immunosuppression-Related Malignancies 141. AIDS-Related Malignancies . . . . . . . . . . . 2099 Robert Yarchoan, Thomas S. Uldrick, and Richard F. Little Cancer and HIV: Incidence and Etiology 2099 Kaposi Sarcoma 2101 KSHV-Associated Multicentric Castleman Disease AIDS-Associated Lymphomas 2104 Hodgkin’s Lymphoma 2110 HPV-Associated Cancer in HIV Infection 2110 Cervical Cancer 2110 Anal Cancer 2110 Future Directions 2111

2104

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Contents

142. Transplantation-Related Malignancies . . . 2113 Smita Bhatia and Ravi Bhatia Myelodysplasia and Acute Myeloid Leukemia Lymphomas 2119 Solid Tumors 2120

H. Richard Alexander Jr., Jordan Berlin, and Fred Moeslein 2113

Section 16: Oncologic Emergencies 143. Superior Vena Cava Syndrome . . . . . . . . . 2123 Joachim Yahalom Anatomy and Pathophysiology 2123 Etiology and Natural History 2123 Diagnostic Procedures 2124 Management 2125 Small Cell Lung Cancer 2125 Non–Small Cell Lung Cancer 2125 Non−Hodgkin’s Lymphoma 2125 Nonmalignant Causes 2126 Catheter-Induced Obstruction 2126 Treatment 2126 Areas of Uncertainty 2127 Recommendations 2128

2183

Edward Chow, Joel A. Finkelstein, Arjun Sahgal, and Robert E. Coleman

Kevin P. Becker and Joachim M. Baehring Pathophysiological Considerations 2130 Epidemiology and Pathogenesis 2131 Clinical Presentation 2131 Diagnosis 2133 Treatment 2134

Presentation 2192 Pathophysiology 2192 Diagnostic Evaluation 2192 Therapeutic Modalities 2193 New Targeted Therapies in the Treatment of Metastatic Bone Disease 2194 External-Beam Radiation Therapy 2195 Systemic Radionuclides 2197 Radiotherapy for Complications of Bone Metastases: Localized External Beam Radiotherapy for Pathological Fractures and Spinal Cord Compression 2198 Mechanical Stability and Fracture Risk 2199

151. Malignant Effusions of the Pleura and

145. Spinal Cord Compression . . . . . . . . . . . . 2136 Kevin P. Becker and Joachim M. Baehring

the Pericardium . . . . . . . . . . . . . . . . . . . . 2205 King F. Kwong and Dao M. Nguyen Malignant Pleural Effusion 2205 Malignant Pericardial Effusion 2209

Epidemiology 2136 Pathophysiology 2136 Clinical Presentation 2138 Differential Diagnosis 2138 Diagnosis 2139 Treatment 2139 Prognosis 2140

152. Malignant Ascites . . . . . . . . . . . . . . . . . . 2214 Udai S. Kammula

146. Metabolic Emergencies . . . . . . . . . . . . . . 2142

Pathophysiology 2214 Diagnosis and Workup 2215 Treatment of Malignant Ascites

2216

153. Paraneoplastic Syndromes . . . . . . . . . . . . 2220

Antonio Tito Fojo Tumor Lysis Syndrome 2142 Hyperuricemia 2144 Cancer and Hyponatremia 2147 Lactic Acidosis and Cancer 2148 Hypercalcemia and Cancer 2148 Cancer-Related Hemolytic Uremic Syndrome

Michael Boyiadzis, Frank S. Lieberman, Larisa J. Geskin, and Kenneth A. Foon

2150

Section 17: Treatment of Metastatic Cancer 147. Metastatic Cancer to the Brain . . . . . . . . 2153 David A. Larson, James L. Rubenstein, Michael W. McDermott, and Igor Barani 2162

148. Metastatic Cancer to the Lung. . . . . . . . . . . .2165 King F. Kwong and Robert Timmerman Rationale for Local Therapies for Lung Metastases 2165 Modes of Metastatic Spread 2165 Diagnosis 2165

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Natural History of Liver Metastases 2177 Imaging of Liver Metastases 2179 Resection of Liver Metastases 2179 Results of Hepatic Resection for CRC 2180 Results of Resection for Noncolorectal Cancers 2181 Adjuvant Therapy for Resectable CRC Liver Metastases 2181 Neoadjuvant Chemotherapy for CRC Liver Metastases Regional Therapies for Unresectable Isolated Liver Metastases 2184 Radiation Therapy for Liver Metastases 2188 Conclusions 2190

150. Metastatic Cancer to the Bone . . . . . . . . . 2192

144. Increased Intracranial Pressure . . . . . . . . . 2130

Brain Metastasis 2153 Carcinomatous Meningitis

149. Metastatic Cancer to the Liver . . . . . . . . . 2177

Endocrinologic Manifestations of Cancer 2220 Hematologic Manifestations of Cancer 2222 Renal Manifestations 2223 Cutaneous Manifestations of Cancer 2224 Disorders of Epidermal Proliferation and Keratinization (Papulosquamous Disorders) 2224 Disorders of Cutaneous Discoloration and Deposition 2225 Neutrophilic Dermatoses 2226 Vascular Abnormalities 2226 Endocrine and Metabolic Disorders 2226 Bullous Disorders 2226 Collagen-Vascular Diseases 2227 Disorders of Hair 2227 Skin Neoplasms Associated with Internal Malignancy 2227 Miscellaneous Lesions 2229 Neurologic Manifestations of Cancer 2229 Limbic Encephalitis 2229 Autonomic Neuropathy 2231 Progressive Cerebellar Degeneration 2231 Paraneoplastic Visual Loss 2231 Opsoclonus-Myoclonus 2232 Paraneoplastic Motor Neuron Disorders 2232 Paraneoplastic Peripheral Neuropathies 2233 Neuromuscular Junction Disorders 2233

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Contents Paraneoplastic Syndromes with Muscle Rigidity Dermatomyositis 2234 Movement Disorders 2234 Approach to the Patient with Paraneoplastic Neurologic Disease 2234

158. Cancer-Associated Thrombosis . . . . . . . . . . .2314

2234

Agnes Y. Y. Lee and Alok A. Khorana Mechanisms of Cancer-Associated Thrombosis 2314 Epidemiology of Cancer-Associated Thrombosis 2314 Prevention of Cancer-Associated Thrombosis 2316 Treatment of Cancer-Associated Thrombosis 2317

Section 18: Stem Cell Transplantation 154. Autologous Stem Cell Transplantation . . . 2236 John Magenau, Dale Bixby, and James Ferrara

Elizabeth M. Blanchard and Paul J. Hesketh

160. Diarrhea and Constipation . . . . . . . . . . . . 2329 Nathan I. Cherny Diarrhea 2329 Constipation 2333

155. Allogeneic Stem Cell Transplantation . . . . 2244 Richard W. Childs

161. Oral Complications . . . . . . . . . . . . . . . . . 2337 Eliezer Soto, Jane M. Fall-Dickson, and Ann M. Berger Oral Mucositis 2337 Chemotherapy-Induced Stomatitis 2337 Radiation-Induced Stomatitis 2337 Radiation Therapy-Related Complications 2338 Pathogenesis of Chemotherapy- and Radiation-Induced Oral Mucositis 2338 Chronic Graft-Versus-Host Disease Oral Manifestations 2339 Sequelae of Oral Complications 2339 Strategies for Prevention and Treatment of Oral Complications 2340 Treatment Strategies 2340 Radioprotectors 2342 Biological Response Modifiers 2343 Treatment for Oral Chronic Graft-Versus-Host Disease 2344 Symptom Management 2345

Conditioning Regimens 2244 Graft-Versus-Leukemia Effect 2245 Mechanisms of Graft-Versus-Leukemia Effect 2246 Complications of Allogeneic Hematopoietic Stem Cell Transplantation 2247 Veno-Occlusive Disease 2247 Epstein-Barr Virus Lymphoproliferative Disorder 2248 Sources of Allogeneic Hematopoietic Stem Cells 2251 Results of Conventional Allogeneic Transplantation for Hematologic Malignancies 2254 Future Prospects 2260

Section 19: Management of Adverse Effects of Treatment

162. Pulmonary Toxicity . . . . . . . . . . . . . . . . . 2348

156. Infections in the Cancer Patient . . . . . . . . 2262 Juan Gea-Banacloche and Brahm H. Segal RISK FACTORS FOR INFECTIONS IN PATIENTS WITH CANCER AND ANTIMICROBIAL PROPHYLAXIS 2262 Risk Factors for Infection 2262 Prevention of Infections 2266 DIAGNOSIS AND MANAGEMENT OF INFECTIOUS DISEASES SYNDROMES 2272 Fever and Neutropenia 2272 SELECTED PATHOGENS OF INTEREST IN ONCOLOGY 2291 Selected Bacterial Infections in Patients with Cancer 2291

157. Leukopenia and Thrombocytopenia . . . . . 2300 Carla Kurkjian and Howard Ozer

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159. Nausea and Vomiting . . . . . . . . . . . . . . . . 2321 Nausea and Vomiting Syndromes 2321 Pathophysiology of Treatment-Induced Nausea and Vomiting 2321 Defining the Risk of Nausea and Vomiting 2322 Antiemetic Agents 2323 Antiemetic Treatment by Clinical Setting 2326 Special Chemotherapy-Induced Nausea and Vomiting Problems 2326 Radiotherapy-Induced Nausea and Vomiting 2327

History 2236 Stem Cell Mobilization 2236 Inadequate Mobilization of Stem Cells 2237 Tumor Contamination 2237 Indication and Timing of Autologous Hematopoietic Stem Cell Transplantation 2237 Standard Infection Prophylaxis 2238 High-Dose Conditioning Regimens 2239 Complications of Autologous Hematopoietic Stem Cell Transplantation 2239 Recent Developments in Autologous Hematopoietic Stem Cell Transplantation 2241 Future Directions 2241

Overview of Hematopoiesis and Hematopoietic Growth Factors 2300 Erythropoietin 2300 Granulocyte Colony-Stimulating Factor 2301 Granulocyte-Macrophage Colony-Stimulating Factor 2304 Interleukin-11 2304 Thrombopoietin Agents 2305 Clinical Use of Erythropoietin-Stimulating Agents in Cancer Therapy 2305 Clinical Use of Recombinant Granulocyte Colony-Stimulating Factors in Cancer Therapy 2307 Use of Colony-Stimulating Factors in other Oncology Settings Clinical Use of Thrombopoietin Agents 2311

xlv

Diane E. Stover and Robert J. Kaner Radiation-Induced Pulmonary Toxicity 2348 Chemotherapy-Induced Pulmonary Toxicity 2351

163. Cardiac Toxicity . . . . . . . . . . . . . . . . . . . . 2360 Joachim Yahalom and Carol S. Portlock Anthracyclines 2360 Cyclophosphamide 2362 Ifosfamide 2362 Taxanes 2362 Trastuzumab 2363 Fluoropyrimidines 2363 Tyrosine Kinase Inhibitors 2364 Radiation-Induced Heart Disease 2364 Future Directions 2367

164. Hair Loss . . . . . . . . . . . . . . . . . . . . . . . . . . 2368 Joyson J. Karakunnel and Ann M. Berger Anatomy and Physiology Classification 2368 Diagnosis 2369 Treatment 2369

2368

165. Gonadal Dysfunction . . . . . . . . . . . . . . . . 2372 2309

John M. Norian, Eve C. Feinberg, Alan H. DeCherney, and Alicia Y. Armstrong Effects of Cytotoxic Agents on Adult Men 2372 Effects of Cytotoxic Agents on Adult Women 2374

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Contents Effects of Cytotoxic Agents on Children 2378 Gonadal Dysfunction After Cranial Irradiation 2378 Preservation of Fertility, Hormone Levels, and Sexual Function 2378 Pharmacologic Attempts at Preserving Fertility in Men 2382 Pharmacologic Attempts at Preserving Fertility in Women 2382 Fertility Preservation in Women with Cervical Cancer 2384 Evaluation of Fertility After Treatment 2384 Hormone Replacement Therapy 2384 Prevention and Management of Erectile and Ejaculatory Dysfunction 2384 Genetic Concerns 2385

166. Fatigue . . . . . . . . . . . . . . . . . . . . . . . . . . . 2387 Sandra A. Mitchell and Ann M. Berger Definition and Etiology of Cancer-Related Fatigue 2387 Current Theories of Cancer-Related Fatigue 2387 Evaluation of the Patient with Cancer-Related Fatigue 2388 Interventions for Fatigue 2389

167. Second Primary Cancers . . . . . . . . . . . . . . 2393 Lois B. Travis, Smita Bhatia, James M. Allan, Kevin C. Oeffinger, and Andrea Ng Methods to Assess Second Cancer Risk 2393 Carcinogenicity of Individual Treatment Modalities 2394 Genetic Susceptibility to Second Primary Cancers 2396 Risk of Second Malignancy in Patients with Selected Primary Cancers 2398 Pediatric Malignancies 2406 Comment 2409

168. Neurocognitive Effects . . . . . . . . . . . . . . . 2411 Paul D. Brown, Nadia N. I. Laack, and Jeffrey S. Wefel Assessment of Neurocognitive Function 2411 Impact of Treatment 2412 Impact of Tumor 2415 Treatment of Cognitive Dysfunction 2415

169. Cancer Survivorship . . . . . . . . . . . . . . . . . 2418 Wendy Landier, Craig C. Earle, Smita Bhatia, Melissa M. Hudson, Kevin Oeffinger, Patricia A. Ganz, and Louis S. Constine Definition of Survivorship and Scope of the Problem 2418 Goals of Survivorship Health Care 2419 Care Plans 2422 Delivery of Follow-Up Care and Best-Practice Models 2423 Educational Considerations 2423 Enhancing Research 2423 Survivorship Advocacy 2424

Section 20: Supportive Care and Quality of Life 170. Management of Cancer Pain . . . . . . . . . . 2426 Amy Abernathy and Kathleen M. Foley Epidemiology 2426 Definition of Pain 2427 Common Pain Syndromes 2429 Management of Cancer Pain 2432 Psychological Approaches 2442 Anesthetic and Neurosurgical Approaches 2442 Neuropharmacologic Approaches 2445 Neuroablative and Neurostimulatory Procedures for the Relief of Pain 2445 Trigger Point Injection and Acupuncture 2445 Physiatric Approaches 2446 Algorithm for Cancer Pain Management 2446 Future Directions 2446

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171. Nutritional Support . . . . . . . . . . . . . . . . . 2448 Alessandro Laviano, Robert A. Meguid, and Michael M. Meguid Anorexia 2448 Changes in Host Metabolism: Weight Loss and Cachexia 2449 Nutrition Therapy for Cancer Cachexia 2450 Nutrition and Tumor Growth 2450 Nutritional Assessment of the Cancer Patient 2451 Parenteral Versus Enteral Nutrition in Cancer Patients 2451 Ethical and Legal Aspects of Nutrition Therapy 2454

172. Sexual Problems . . . . . . . . . . . . . . . . . . . . 2456 Veronica Sanchez Varela, Christian J. Nelson, and Sharon L. Bober Cancer in Men 2456 Cancers that Affect Men and Women 2458 Cancer in Women 2460 Cancer in Children and Young Adults 2463 Relevant Sociocultural Considerations 2463 Disruption of Intimacy and Relational Considerations 2464

173. Psychological Issues in Cancer . . . . . . . . . 2467 David Spiegel and Michelle B. Riba Understanding Cancer as a Trauma 2467 Common Psychiatric Conditions 2467 Screening for Psychological Problems 2467 Coping 2469 Treatment Interventions 2469 Outcome 2472 Implications for Cancer Progression and Mortality 2472 Survivorship 2472 Psychotropic Medication 2473

174. Communicating News to the Cancer

Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . 2477 Eric J. Cassell Preventing Illness 2477 Communication 2477 Explanations 2478 Uncomfortable Questions 2479 Information 2479 Meaning 2479 Cafeteria Explanations 2480

175. Specialized Care of the Terminally Ill . . . . 2481 Kristen G. Schaefer, Kathy Selvaggi, and Janet L. Abrahm Discussing Prognosis 2481 Discussing End of Life 2481 Hope 2482 Healing Versus Curing 2482 How to Tell the Children 2482 Cultural and Religious Considerations Care without Chemotherapy 2483 Palliative Care Programs 2483 Hospice Programs 2483 Relief of Suffering 2483 The Final Days 2488 After the Death 2488 Grief and Bereavement 2488

2482

176. Community Resources . . . . . . . . . . . . . . . 2491 Bonnie A. Indeck and Nora Rightmer Community Resources for the Cancer Patient and Family The Cancer Patient 2491 Social and Emotional Support 2491 Informational Support 2492

2491

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Contributing Authors Instrumental Support 2493 Common Community Resources 2493 Internet Resources 2496 Language Resources 2498 Legal Resources 2498 Palliative Care 2498 Personal Websites that Facilitate Communication Survivorship 2498 Transportation 2498 Wish Foundations 2499

179. Health Disparities in Cancer . . . . . . . . . . 2532 Harold P. Freeman Race and Cancer 2534 Relationships Between Culture and Cancer 2535 Poverty as a Cause of Cancer Disparities 2535 Patient Navigation 2535 The Harlem Breast Cancer Experience 2536 Discussion 2538 What Must be Done to Diminish Cancer Disparities

2498

177. Rehabilitation of the Cancer Patient . . . . 2500

2538

180. Cancer Information on the Internet . . . . . 2540

Michael D. Stubblefield

Sherri L. Place and J. Robert Beck

The Rehabilitation Team 2500 Complications of Cancer and its Treatment 2501 Neuromuscualr Complications of Cancer and Cancer Treatment Musculoskeletal Complications of Cancer and Cancer Treatment 2510 Radiation Fibrosis Syndrome 2513 Lymphedema 2518 Rehabilittion Interventions 2519 Nonpharmacologic Pain Management 2521

Background 2540 Tools for Finding Information 2540 Evaluating Information 2541 Search Strategies 2543 Useful Tools for Keeping Up 2544

2503

Section 22: Complementary, Alternative, and Integrative Therapies

Section 21: Societal Issues in Oncology

181. Complementary, Alternative, and Integrative

178. Regulatory Issues . . . . . . . . . . . . . . . . . . . 2523

Catherine Ulbricht, Lorenzo Cohen, and Richard Lee

Therapies in Cancer Care . . . . . . . . . . . . . 2550 Ann T. Farrell, Grant A. Williams, and Richard Pazdur The History of Food and Drug Administration Regulation of Drugs and Biologics 2523 Food and Drug Administration Oversight of Clinical Trials for Drugs and Biologics 2523 The Basis for Cancer Drug Approval 2525 Drug Safety Reporting and Evaluation 2527 Expanded Access to Investigational Drugs 2527 Regulation of Devices for Cancer Treatment and Diagnosis 2528

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Background 2550 Establishing an Integrative Oncology Approach with Patients Standardization and Quality 2555 Specific Complementary and Alternative Medicine Therapies 2556

Index

2550

2563

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1_9781451105452  

Principles & Practice of Oncology DeVita, Hellman, and Rosenberg’s edition LWBK812-FM_pi-xlviii.indd iLWBK812-FM_pi-xlviii.inddi 3/10/11...

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