THE ROLE OF
OBESITY

IN CANCER SURVIVAL AND RECURRENCE
WORKSHOP SUMMARY

 

 

 

 

National Cancer Policy Forum
Board on Health Care Services
Margie Patlak and Sharyl J. Nass, Rapporteurs

INSTITUTE OF MEDICINE

             OF THE NATIONAL ACADEMIES

 

 

THE NATIONAL ACADEMIES PRESS
Washington, D.C.
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National Cancer Policy Forum Board on Health Care Services Margie Patlak and Sharyl J. Nass, Rapporteurs

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. This study was supported by Contract Nos. HHSN261200900003C and 200-2005- 13434 TO #1 between the National Academy of Sciences and the National Cancer Insti- tute and the Centers for Disease Control and Prevention, respectively. In addition, the National Cancer Policy Forum is also supported by the American Association for Cancer Research, the American Cancer Society, the American Society of Clinical Oncology, the Association of American Cancer Institutes, Bristol-Myers Squibb, C-Change, the CEO Roundtable on Cancer, Novartis Oncology, and the Oncology Nursing Society. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-25333-8 International Standard Book Number-10: 0-309-25333-0 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334- 3313; http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2012 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Cover credit: Design by Casey Weeks. The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. Suggested citation: IOM (Institute of Medicine). 2012. The role of obesity in cancer survival and recurrence: Workshop summary. Washington, DC: The National Academies Press.

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a man- date that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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WORKSHOP PLANNING COMMITTEE1 WENDY DEMARK-WAHNEFRIED (Chair), Professor and Webb Endowed Chair of Nutrition Sciences, Associate Director, University of Alabama at Birmingham Comprehensive Cancer Center RACHEL M. BALLARD-BARBASH, Associate Director, Applied Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD THOMAS G. BURISH, Provost, Notre Dame University, South Bend, IN PATRICIA A. GANZ, Professor, University of California, Los Angeles, School of Medicine & Public Health, Division of Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Center PAMELA J. GOODWIN, Senior Scientist, Samuel Lunenfeld Research Institute, Marvelle Koffler Chair in Breast Research, Professor of Medicine, University of Toronto Mount Sinai Hospital, Ontario, Canada STEPHEN D. HURSTING, Professor and McKean Love Chair, Department of Nutritional Sciences, University of Texas at Austin MARTIN J. MURPHY, Chief Executive Officer, CEO Roundtable on Cancer, Durham, NC LISA C. RICHARDSON, Associate Director for Science, Division of Cancer Prevention and Control, Centers for Disease Control and Prevention, Atlanta, GA Project Staff SHARYL J. NASS, Director, National Cancer Policy Forum ERIN BALOGH, Associate Program Officer NIHARIKA SATHE, Research Assistant (until March 2012) PAMELA LIGHTER, Research Assistant (from March 2012) MICHAEL PARK, Senior Program Assistant ROGER HERDMAN, Director, Board on Health Care Services 1 Institute of Medicine planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. v

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NATIONAL CANCER POLICY FORUM1 JOHN MENDELSOHN (Chair), Codirector, Khalifa Institute for Personalized Cancer Therapy, MD Anderson Cancer Center, Houston, TX PATRICIA A. GANZ (Vice Chair), Professor, University of California, Los Angeles, School of Medicine & Public Health, Division of Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Center AMY ABERNETHY, Associate Professor of Medicine, Duke University School of Medicine, and Director, Duke Cancer Care Research Program, Durham, NC FRED APPELBAUM, Director, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA PETER B. BACH, Attending Physician, Memorial Sloan-Kettering Cancer Center, New York EDWARD BENZ, JR., President, Dana-Farber Cancer Institute and Director, Harvard Cancer Center, Harvard School of Medicine, Boston, MA MONICA BERTAGNOLLI, Professor of Surgery, Harvard University Medical School, Boston, MA OTIS BRAWLEY, Chief Medical Officer and Executive Vice President, American Cancer Society, Atlanta, GA MICHAEL A. CALIGIURI, Director, Ohio State Comprehensive Cancer Center, Columbus, OH, and President, Association of American Cancer Institutes RENZO CANETTA, Vice President, Oncology Global Clinical Research, Bristol-Myers Squibb, Wallingford, CT MICHAELE CHAMBLEE CHRISTIAN, Retired, Washington, DC WILLIAM DALTON, President, CEO, and Center Director, Moffitt Cancer Center, Tampa, FL, and Chair, AACR Committee on Science Policy and Legislative Affairs 1Institute of Medicine forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. vii

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WENDY DEMARK-WAHNEFRIED, Associate Director for Cancer Prevention and Control, University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL ROBERT ERWIN, President, Marti Nelson Cancer Foundation, Davis, CA ROY S. HERBST, Chief of Medical Oncology, Yale Cancer Center, New Haven, CT THOMAS J. KEAN, President and CEO, C-Change, Washington, DC DOUGLAS R. LOWY, Deputy Director, National Cancer Institute, Bethesda, MD DANIEL R. MASYS, Affiliate Professor, Biomedical Informatics, University of Washington, Seattle, WA MARTIN J. MURPHY, Chief Executive Officer, CEO Roundtable on Cancer, Durham, NC BRENDA NEVIDJON, Clinical Professor and Specialty Director, Nursing & Healthcare Leadership, Duke University School of Nursing, Durham, NC, and Past President, Oncology Nursing Society STEVEN PIANTADOSI, Director, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA LISA C. RICHARDSON, Associate Director for Science, Division of Cancer Prevention and Control, Centers for Disease Control and Prevention, Atlanta, GA YA-CHEN TINA SHIH, Director, Program in the Economics of Cancer, University of Chicago, Chicago, IL ELLEN SIGAL, Chairperson and Founder, Friends of Cancer Research, Washington, DC STEVEN STEIN, Senior Vice President, US Clinical Development and Medical Affairs, Novartis Oncology, East Hanover, NJ JOHN A. WAGNER, Vice President, Clinical Pharmacology, Merck and Company, Inc., Rahway, NJ RALPH R. WEICHSELBAUM, Chair, Radiation and Cellular Oncology, and Director, Ludwig Center for Metastasis Research, The University of Chicago Medical Center, Chicago, IL JANET WOODCOCK, Director, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, MD viii

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National Cancer Policy Forum Staff SHARYL J. NASS, Director, National Cancer Policy Forum LAURA LEVIT, Program Officer ERIN BALOGH, Associate Program Officer NIHARIKA SATHE, Research Assistant (until March 2012) PAMELA LIGHTER, Research Assistant (from March 2012) MICHAEL PARK, Senior Program Assistant PATRICK BURKE, Financial Associate SHARON B. MURPHY, Scholar in Residence ROGER HERDMAN, Director, Board on Health Care Services ix

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Reviewers This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the process. We wish to thank the following individuals for their review of this report: OTIS W. BRADLEY, Chief Medical Officer and Executive Vice President, American Cancer Society, Atlanta, GA ELIZABETH A. PLATZ, Professor and Martin D. Abeloff, MD Scholar in Cancer Prevention, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD THOMAS WADDEN, Director, Center for Weight and Eating Disorders, University of Pennsylvania, Philadelphia, PA RENA WING, Professor and Director, Weight Control and Diabetes Research Center, Brown University, Providence, RI Although the reviewers listed above have provided many constructive comments and suggestions, they did not see the final draft of the report xi

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xii REVIEWERS before its release. The review of this report was overseen by Melvin Worth. Appointed by the Institute of Medicine, he was responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.

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Contents INTRODUCTION, 1 OVERVIEW OF THE OBESITY–CANCER LINK, 3 MOLECULAR MECHANISMS, 7 Estrogen, 11 Insulin, 11 Other Molecular Mechanisms, 13 Inflammation, 15 The Role of Stem Cells, 18 The Role of Diet, 19 CLINICAL EVIDENCE OF THE OBESITY LINK TO CANCER, 21 Breast Cancer, 21 Prostate Cancer, 23 Colon Cancer, 24 CLINICAL STUDY DESIGN ISSUES, 24 Study Measures, 25 Confounders, 27 Generalizability of Study Results, 30 Improper Analyses, 32 Study Design Suggestions, 33 Exercise Interventions, 37 POTENTIAL TREATMENTS TO COUNTER EFFECTS OF OBESITY, 39 Weight Loss/Diet Changes, 39 xiii

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xiv CONTENTS Exercise, 42 Exercise Versus or in Combination with Diet and/or Weight Loss, 46 Surgery for Weight Loss, 48 Dugs Targeting Cancer-Causing or Cancer-Promoting Obesity Mechanisms, 48 Metformin, 49 Rapamycin and Other mTOR Inhibitors, 49 Stem Cell Pathway Inhibitors, 51 Drugs That Target Estrogen or Its Receptor, 52 CHALLENGES IN STUDYING OR INDUCING LIFESTYLE CHANGES IN PATIENTS, 52 Physical Limitations or Time Constraints of Cancer Survivors, 52 Long-Term Adherence to Diet or Exercise Plans, 53 Costs of Frequent Sessions, 54 WHAT TO ADVISE CANCER PATIENTS, 56 Is There Enough Evidence?, 60 Research and Clinical Tools—Needs and Opportunities, 61 POLICY SUGGESTIONS, 62 Research Policies, 62 Public- and Private-Sector Policies, 66 Education and Dissemination, 68 WRAPPING UP, 70 REFERENCES, 71 APPENDIXES A Acronyms, 81 B Workshop Agenda, 85 C Speaker Biographies, 91

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Boxes, Figures, and Tables BOXES 1 Energy Balance and Cancer Risk, 4 2 How Obesity Is Measured, 7 3 Suggestions from Individual Participants on How to Improve Study Designs, 34 4 Lifestyle Modifications to Reduce Weight, 40 5 Colon Health and Life-Long Exercise Change (CHALLENGE) Trial, 44 6 Potential Policy Actions Suggested by Individual Workshop Participants, 63 7 Transdisciplinary Research on Energetics and Cancer (TREC), 64 FIGURES 1 Energy balance, 6 2 An integrative view of obesity, 8 3 Putative factors involved in obesity-related carcinogenesis, 9 4 Converging signaling pathways, 15 5 IGF1, leptin, adiponectin, and IL-6 are prosurvival cytokines for epithelial and mesenchymal cells, 19 6 Mechanism of metformin action in the clinical setting, 50 7 Regulation of stem cell self-renewal and clonal expansion, 51 xv

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xvi BOXES, FIGURES, AND TABLES TABLES 1 Observational Evidence Suggests a Link Between Physical Activity and Breast Cancer Prognosis, 45 2 Weight Loss Interventions in Breast Cancer Survivors, 57