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Series Editor: Charles R. Thomas, Jr., MD Current Multidisciplinary Oncology

Cancers of the Colon and Rectum

Series Editor: Charles R. Thomas, Jr., MD Current Multidisciplinary Oncology

A Multidisciplinary Approach to Diagnosis and ManagementAl B. Benson III, MD • A. Bapsi Chakravarthy, MDStanley R. Hamilton, MD • Elin R. Sigurdson, MD, PhD

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Oncology

11 W. 42nd Street New York, NY 10036www.demosmedpub.com

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The treatment of colorectal cancer has become increasingly complex, requiring the comprehensive

review and assessment of multiple issues including genetics, radiology, surgery, molecular diagnos-

tics, chemotherapy, and more. As a result the collaboration among these specialties facilitated by a

multidisciplinary team approach are crucial in providing the best care to patients and ensuring

successful treatment. Cancers of the Colon and Rectum, written by a team of authors represent-

ing a range of disciplines, is a valuable resource for physicians, fellows, nurses, physician assistants,

physical therapists, and all health care providers involved in the treatment of colorectal cancer.

Cancers of the Colon and Rectum summarizes the state-of-the-art issues related to the treatment

of colorectal cancer and describes an approach for optimal multidisciplinary care for individuals who

have been diagnosed with or who are at higher risk to develop colorectal cancer.

All Current Multidisciplinary Oncology Titles Provide:

w Consolidation and integration of the varied aspects of multidisciplinary care for major topics in oncology

w Coverage of all related topic areas, including medical and surgical oncology, radiation oncology, pain, pathology, imaging, psychological support, and the primary disease

w A chapter focusing on special populations and the disease’s differing impact on them

w Discussion of quality-of-life issues

Cancers of the Colon and RectumA Multidisciplinary Approach to Diagnosis and Management

Al B. Benson III

A. Bapsi Chakravarthy

Stanley R. Hamilton

Elin R. SigurdsonC

ancers of the

Colon

and R

ectum

A M

ultidisciplinary Approach to

Diagnosis and M

anagement

Current Multidisciplinary

Oncology

Benson • Chakravarthy • Hamilton • Sigurdson

© Demos Medical Publishing, LLC.


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Current Multidisciplinary Oncology SeriesCharles R. Thomas, Jr., MD

Series Editor

Breast CancerA Multidisciplinary Approach to Diagnosis and Management

Alphonse G. Taghian, Barbara L. Smith, and John K. Erban

Lung CancerA Multidisciplinary Approach to Diagnosis and Management

Kemp H. Kernstine and Karen L. Reckamp


Al B. Benson III, A. Bapsi Chakravarthy, Stanley R. Hamilton, and Elin R. Sigurdson

Gynecologic CancersA Multidisciplinary Approach to Diagnosis and Management

Kunle Odunsi and Tanja Pejovic

Prostate CancerA Multidisciplinary Approach to Diagnosis and Management

Adam P. Dicker, Wm. Kevin Kelly, and Edouard J. Trabulsi

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New York

Current Multidisciplinary Oncology


Edited by Al B. Benson III, MD Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center Northwestern University Chicago, Illinois

A. Bapsi Chakravarthy, MD Associate Professor Program Director Department of Radiation Oncology Vanderbilt-Ingram Cancer Center Vanderbilt University Nashville, Tennessee

Stanley R. Hamilton, MD Division Head Department of Pathology MD Anderson Cancer Center University of Texas Houston, Texas

Elin R. Sigurdson, MD, PhD Chief, Division of General Surgery Director, Department of Surgical Oncology Fox Chase Cancer Center Philadelphia, Pennsylvania

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Acquisitions Editor: Rich WintersCompositor: NewGen ImagingPrinter: Courier

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© 2014 Demos Medical Publishing, LLC. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or oth-erwise, without the prior written permission of the publisher.

Medicine is an ever-changing science. Research and clinical experience are continually expanding our knowledge, in particular our understanding of proper treatment and drug therapy. The authors, editors, and publisher have made every effort to ensure that all information in this book is in accordance with the state of knowledge at the time of production of the book. Nevertheless, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the informa-tion in this book and make no warranty, expressed or implied, with respect to the contents of the publication. Every reader should examine carefully the package inserts accompanying each drug and should carefully check whether the dosage schedules mentioned therein or the contraindications stated by the manufacturer differ from the statements made in this book. Such examination is par-ticularly important with drugs that are either rarely used or have been newly released on the market.

Library of Congress Cataloging-in-Publication Data

Cancers of the colon and rectum : a multidisciplinary approach to diagnosis and management / [edited by] Al B. Benson III, A. Bapsi Chakravarthy, Stanley R. Hamilton, Elin R. Sigurdson. p. ; cm.—(Current multidisciplinary oncology) Includes bibliographical references and index. ISBN 978-1-936287-58-1 (hbk.)—ISBN 978-1-61705-105-0 (eISBN) I. Benson, Al B., III, editor of compilation. II. Chakravarthy, A. Bapsi (Anuradha Bapsi), editor of compilation. III. Hamilton, Stanley R., editor of compilation. IV. Sigurdson, Elin R., editor of compilation. V. Series: Current multidisciplinary oncology. [DNLM: 1. Colorectal Neoplasms—diagnosis. 2. Colorectal Neoplasms—therapy. WI 529] RC280.C6 616.99’4347—dc23

2013020938

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Contents

Series Foreword vii Preface ix Contributors xi

1. Importance of Multidisciplinary Approach to Colorectal Cancer 1

Al B. Benson III

2. Prevention and Screening 5 Karen Colbert Maresso, Sherri Patterson, Eduardo

Vilar, Ernest Hawk, Faraz Bishehsari, Barbara H. Jung, Henry T. Lynch, Kristen Drescher, Poonam Sharma, Carrie Snyder, Jane F. Lynch, Joseph Knezetic, Megan Hitchins, Peter Silberstein, Stephen Lanspa, Hiliary Bownik, Michael V. Chiorean, and Laura Yun

3. Navigation Programs in Colorectal Cancer 67 Margaret A. O’Grady and Elaine Sein

4. Assessment and Management of Colorectal Polyps and Cancer Precursor Lesions 79

Reid M. Ness

5. Preoperative Staging: Imaging and Endoscopic Approaches 93

Rohit Walia, Kiran Bidari, and Srinadh Komanduri

6. Pathology and Molecular Diagnostics 115 Stanley R. Hamilton

7. Management of Nonmetastatic Colon Cancer 129 Allison Goldberg, Adam C. Berger,

and Rebecca A. Moss

8. Nonmetastatic Rectal Cancer: Early and Locally Advanced 147

William A. Hall, Roshan S. Prabhu, Jerome C. Landry, Emily Chan, and Charles Staley

9. Management of Synchronous Metastases 161 Jeffrey M. Farma, Elin R. Sigurdson, Laura Goff,

Monique J. Youl, and Laura A. Dawson

10. Management of Potentially Resectable Recurrent Disease 175

E. Gabriela Chiorean, Patrick J. Loehrer, Yun Shin Chun, Prashant Shah, Julio Garcia-Aguilar, Julian Sanchez, and Lisa A. Kachnic

11. Systemic Therapy 197 Jaykumar Thumar, Howard S. Hochster, Neeta K.

Venepalli, and Jordan Berlin

12. Phase I/II Clinical Trials in Metastatic Colorectal Cancer 217

Davendra P. S. Sohal, Rodolfo F. Perini, and Peter J. O’Dwyer

13. Management of Systemic Treatment-Induced Toxicities 223

Maxwell T. Vergo, Axel Grothey, Julia Minocha, and Jonathan Cotliar

14. Radiation Palliative Care 241 Hannah Yoon, William Small, Jr., and Stephen Lutz

15. Multidisciplinary Approach to Quality of Life 247 John M. Salsman, David Cella, Maxwell T. Vergo,

and Susan E. Yount

16. Racial Disparities in Colorectal Cancer 263 Edith Mitchell

17. Models of Care Delivery 273 Julia Trosman and Christine Weldon

18. Future Directions: Gene Expression Profiling 281

Richard C. Turkington, Sandra Van Schaeybroeck, and Patrick G. Johnston

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21. Colon Cancer Survivorship 307 John Kauh and Fadlo R. Khuri

22. Patient Advocacy: What Does That Mean, and Why Should I Care? 319

Nancy Roach

Index 323

19. Development of Targeted Therapies 293 Christopher H. Lieu, S. Gail Eckhardt, and Wells

A. Messersmith

20. Future Directions in the Treatment of Colorectal Cancers: Designs for Biomarker-Driven Clinical Trials 301

Qian Shi, Sumithra J. Mandrekar, and Daniel J. Sargent

vi Contents

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Series Foreword

This volume of the series Current Multidisciplinary Oncology, devoted to colorectal cancer, brings me great pleasure to introduce the practicing clinician to a valuable resource that will aid in the multidisciplinary approach of these common solid tumors.

Drs. Al B. Benson III, A. Bapsi Chakravarthy, Stanley R. Hamilton, and Elin R. Sigurdson have put together a cadre of leading-edge investigators as contributors on the multidisciplinary approach to colorectal cancer.

Over the past decade, a myriad of advances in the diag-nosis and treatment of colorectal cancer have occurred. Some of the advances include, but are not limited to, diagnostic molecular tools that may aid in predicting a response to certain treatment approaches and/or in provid-ing a guide of a prognostic outcomes for certain patients.

Colorectal neoplasms comprise some of the most common malignancies in the world and hence warrant intense efforts to find a cure. In recent years, investment of resources to help further understand the nature of this malignancy have increased.

Drs. Benson, Chakravarthy, Hamilton, and Sigurdson represent the current generation of academic, forward-thinking oncologists who have committed their careers to eradicating colorectal cancer using multidisciplinary approaches. Their collective vision and ability to assem-ble an outstanding group of investigators in the field have provided a very high quality product that will be a use-ful resource to the busy clinician as well as those along various stages of the learning spectrum. I’m sure that you will enjoy this innovative and easy-to-read volume as you look for guidance in the multidisciplinary approach of your patients with colorectal cancer.

Charles R. Thomas, Jr., MDSeries Editor

Department of Radiation MedicineOregon Health and Science University

Knight Cancer InstitutePortland, Oregon

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Preface

Colorectal cancer (CRC) is the third most common can-cer worldwide. Although largely preventable, this disease continues to engender significant morbidity and mortality. Advances in understanding the genetics of CRC (includ-ing inherited and sporadic cases), screening and preven-tion strategies, and treatment have resulted in improved outcomes even for patients with advanced cancer. This is the third book in the series Current Multidisciplinary Oncology, edited by Dr. Charles R. Thomas, Jr., with the intent to provide a comprehensive textbook that encom-passes the entire spectrum of multidisciplinary manage-ment considerations and a significant body of evidence with references to support the decision strategies and recommendations.

The chapters in this book are arranged in a logical progression from screening and prevention to diagnosis, treatment and surveillance, which is similar to the other books in this series. Chapter 2 is composed of four in-depth sections that serve as a critical introduction to principles of screening with extensive discussion of inher-ited CRC, details of other risk factors including diet and inflammatory bowel disease, and review of advances in chemoprevention. Chapters that address polyps and pre-cursor lesions and preoperative staging and endoscopic approaches such as endoscopic mucosal resection (EMR) and colonic stenting are included. Multimodality CRC imaging is reviewed in Chapter 5 revealing the utility of CT colonography, PET-CT, and MRI in rectal cancer. Principles of pathology including staging criteria and advances in molecular pathology are integrated in sev-eral chapters outlining the importance of MSI and K-ras mutation status as two examples.

The management of colon cancer and rectal cancer has been separated in a series of distinct chapters for each of the two disease locations since the strategies vary particularly for locally advanced disease (nonmetastatic). Neoadjuvant chemoradiation for rectal cancer and adjuvant therapy for both colon and rectal cancer are extensively reviewed. The care of patients with potentially resectable metastatic disease also is highlighted. The evolving complexity of

the continuum of care for patients with advanced disease receiving systemic therapy incorporates chemotherapy regimens and the most recent evidence that guides the use of anti-VEGF and anti-EGFR agents. There are two chap-ters devoted to management of systemic toxicities includ-ing diarrhea, skin and neurologic toxicities, as well as a section on the use of radiation as a palliative care option for patients. In addition, Chapter 15 reviews health-related quality of life both for locally advanced and advanced disease with a discussion of the instruments to measure quality of life.

There are also unique chapters that address special topics. These include chapters with an emphasis on clini-cal trials encompassing phase I/II clinical trials in meta-static CRC and future directions integrating concepts of the development of targeted therapies for CRC patients, biomarker clinical trial designs, and the potential of gene profiling both as a prognostic and predictive tool. Models of care delivery, including a community practice case study and patient navigation as it supports multidisci-plinary care models, are innovative chapters emphasizing some of the complexities of offering comprehensive can-cer care using CRC as an example. The concluding chap-ters speak to the growing emphasis on health disparities, surveillance and survivorship, and patient advocacy.

This book is truly multidisciplinary in scope and is designed as a management text for the gamut of health professionals who provide care for CRC patients includ-ing medical oncologists, radiation oncologists, surgeons, gastroenterologists, radiologists, pathologists, palliative care experts, nurses and other allied health profession-als, students, residents and fellows in training, as well as patients, families and advocates. The CRC thought lead-ers who have contributed to this volume have offered their considerable expertise to provide the most current evidence-based approach, including extensive references, to provide a valuable tool designed to enhance evaluation and management of CRC patients.

Al B. Benson III, MD

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Contributors

Al B. Benson III, MD

Professor of MedicineAssociate Director for Clinical InvestigationsRobert H. Lurie Comprehensive Cancer CenterNorthwestern UniversityChicago, IL

Adam C. Berger, MD, FACS

Department of SurgeryKimmel Cancer CenterThomas Jefferson UniversityPhiladelphia, PA

Jordan Berlin, MD

Ingram Professor of Cancer ResearchDivision of Hematology-OncologyVanderbilt-Ingram Cancer CenterNashville, TN

Kiran Bidari, MD

FellowDivision of Gastroenterology and HepatologyFeinberg School of MedicineNorthwestern UniversityChicago, IL

Faraz Bishehasri, MD, PhD

FellowDivision of GastroenterologyDepartment of Medicine Feinberg School of MedicineNorthwestern UniversityChicago, IL

Hiliary Bownik, MD

Gastroenterology Fellow Feinberg School of MedicineNorthwestern University Chicago, IL

David Cella, MD

Department of Medical Social SciencesFeinberg School of Medicine Northwestern UniversityRobhert H. Lurie Comprehensive Cancer Center of

Northwestern UniversityChicago, IL

Emily Chan, MD, PhD

Assistant ProfessorDepartment of Medical OncologyVanderbilt-Ingram Cancer CenterNashville, TN

E. Gabriela Chiorean, MD

Associate ProfessorDepartment of MedicineDivision of Hematology/OncologyUniversity of WashingtonSeattle, WA

Michael V. Chiorean, MD, AGAF

Director IBD Center of ExcellenceDigestive Disease Institute Virginia Mason Medical Center Division of Gastroenterology and HepatologySeattle, WA

Yun Shin Chun, MD

Assistant ProfessorDepartment of Surgical OncologyFox Chase Cancer CenterPhiladelphia, PA

Jonathan Cotliar, MD

Assistant ProfessorDepartments of Dermatology and MedicineRobert H. Lurie Comprehensive Cancer CenterNorthwestern University Feinberg School of MedicineChicago, IL

Laura A. Dawson, MD

Department of Radiation OncologyUniversity of TorontoRadiation Medicine ProgramPrincess Margaret Hospital/University Health NetworkToronto, Ontario, Canada

Kristen Drescher, PhD

ProfessorDepartment of Microbiology and ImmunologyCreighton University School of MedicineOmaha, NE

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Howard S. Hochster, MD

Associate DirectorYale Cancer Center DirectorGI OncologyProfessor of MedicineYale School of MedicineNew Haven, CT

Patrick G. Johnston

Professor, Dean of the School of MedicineDentistry and Biomedical SciencesDrug Resistance GroupCentre for Cancer Research and Cell BiologyQueen’s University Belfast, BelfastNorthern Ireland

Barbara H. Jung, MD

Assistant ProfessorDepartment of MedicineFeinberg School of MedicineNorthwestern University GastroenterologistNorthwestern Memorial HospitalChicago, IL

Lisa A. Kachnic, MD

Department of Radiation OncologyBoston Medical CenterBoston University School of MedicineBoston, MA

John Kauh, MD, FACP

Associate Professor of Hematology and OncologyDepartment of Hematology and OncologyWinship Cancer InstituteEmory University School of MedicineAtlanta, GA

Fadlo R. Khuri, MD, FACP

Professor and Chair of Hematology and Medical OncologyWinship Cancer InstituteEmory University School of MedicineAtlanta, GA

Joseph Knezetic, PhD

Associate Professor of Pathology and Biomedical Sciences Director of the Laboratory of Molecular PathologyCreighton UniversityOmaha, NE

Srinadh Komanduri, MD, MS

Director of Interventional EndoscopyAssociate ProfessorDivision of Gastroenterology and HepatologyFeinberg School of MedicineNorthwestern UniversityChicago, IL

S. Gail Eckhardt, MD

Professor and Co-Division Head Medical OncologyUniversity of ColoradoAurora, CO

Jeffrey M. Farma, MD, FACS

Assistant Professor of Surgical Oncology Fox Chase Cancer CenterPhiladelphia, PA

Julio Garcia-Aguilar, MD, PhD

Colorectal ServiceDepartment of SurgeryMemorial Sloan-Kettering Cancer CenterNew York, NY

Laura Goff, MD

Assistant ProfessorDepartment of Medical OncologyVanderbilt-Ingram Cancer CenterNashville, TN

Allison Goldberg, MD

Department of SurgeryKimmel Cancer CenterThomas Jefferson UniversityPhiladelphia, PA

Axel Grothey, MD

Professor of OncologyMayo Clinic RochesterRochester, MN

William A. Hall, MD

Department of Radiation OncologyEmory University Winship Cancer CenterAtlanta, GA

Stanley R. Hamilton, MD

Division HeadDepartment of PathologyMD Anderson Cancer CenterUniversity of TexasHouston, TX

Ernest Hawk, MD, MPH

Vice PresidentDivision of OVPCancer Prevention and Population SciencesMD Anderson Cancer CenterUniversity of Texas Houston, TX

Megan Hitchins, PhD

Associate Professor Stanford Cancer CenterDepartment of MedicineDivision of OncologyStanford UniversityStanford, CA

xi i Con t r ibu to rs

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Julia Minocha, MD

ResidentDepartment of DermatologyFeinberg School of MedicineNorthwestern University Chicago, IL

Edith Mitchell, MD, FACP

Clinical ProfessorDirectorCenter to Eliminate Cancer DisparitiesProgram LeaderGastrointestinal OncologyJefferson University HospitalsPhiladelphia, PA

Rebecca A. Moss, MD

Assistant ProfessorDepartment of Medical OncologyThe Cancer Institute of New JerseyNew Brunswick, NJ

Reid M. Ness, MD, MPH

Assistant Professor of MedicineVanderbilt Digestive Disease CenterVanderbilt University Medical CenterNashville, TN

Peter J. O’Dwyer, MD

Professor of MedicineAbramson Cancer CenterPerelman School of MedicineUniversity of PennsylvaniaPhiladelphia, PA

Margaret A. O’Grady, RN, MSN, OCN, FAAMA

Senior DirectorFox Chase Cancer Center PartnersPhiladelphia, PA

Sherri Patterson, MD

DirectorDivision of Cancer Prevention and Population Science Research Planning and Development MD Anderson Cancer Center Houston, TX

Rodolfo F. Perini, MD

Clinical Instructor in RadiologyUniversity of PennsylvaniaPhiladelphia, PA

Roshan S. Prabhu, MD

Department of Radiation OncologyEmory University Winship Cancer CenterAtlanta, GA

Jerome C. Landry, MD

Chief of ServiceGrady Memorial HospitalProfessorDepartment of Radiation OncologyEmory University Winship Cancer CenterAtlanta, GA

Stephen J. Lanspa, MD

Senior Associate Dean of MedicineDivision of GastroenterologyCreighton University School of MedicineOmaha, NE

Christopher H. Lieu, MD

Assistant ProfessorDivision of Medical OncologyUniversity of ColoradoAurora, CO

Patrick J. Loehrer, MD

ProfessorDepartment of MedicineDivision of Hematology/OncologyIndiana University—Purdue University of IndianapolisIndianapolis, IN

Stephen Lutz, MD

Blanchard Valley Regional Cancer CenterFindlay, OH

Henry T. Lynch, MD

Chair of Preventive Medicine and Professor of Medicine

Hereditary Cancer CenterCreighton Univeristy School of MedicineOmaha, NE

Jane F. Lynch, BSN

Creighton UniversityDepartment of Preventive MedicineOmaha, NE

Sumithra J. Mandrekar, PhD

Department of Health Science ResearchMayo ClinicRochester, MN

Karen Colbert Maresso, MPH

Cancer Prevention and Population SciencesUniversity of TexasMD Anderson Cancer CenterHouston, TX

Wells A. Messersmith, MD

Professor and Co-Division Head Medical OncologyUniversity of ColoradoAurora, CO

Cont r ibu to r s xi i i

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William Small, Jr., MD

Professor, Department of Radiation OncologyFeinberg School of MedicineNorthwestern University Chicago, IL

Carrie Snyder, MSN, RN, APNG, AOCNS

Cancer Genetics Nurse SpecialistCreighton UniversityDepartment of Preventive MedicineHereditary Cancer Prevention ClinicOmaha, NE

Davendra P. S. Sohal, MD, MPH

Assistant Professor of MedicineTaussig Cancer InstituteLerner College of MedicineCleveland ClinicCleveland, OH

Charles Staley, MD

Professor of SurgeryHolland M. Ware Professor of Surgery and ChiefDivision of Surgical OncologyDepartment of SurgeryEmory University School of MedicineAtlanta, GA

Jaykumar Thumar, MD, MBBS

Yale School of MedicineYale Cancer CenterNew Haven, CT

Julia Trosman, PhD, MBA

DirectorCenter for Business Models in HealthcareAssistant Adjunct ProfessorNorthwestern University Feinberg School of MedicineChicago, ILAssistant Adjunct ProfessorDepartment of Clinical PharmacyUniversity of CaliforniaSan Francisco, CA

Richard C. Turkington

Academic Clinical Lecturer (Medical Oncology)Drug Resistance GroupCentre for Cancer Research and Cell BiologyQueen’s University BelfastBelfast, Northern Ireland

Nancy Roach

Board MemberFight Colorectal CancerAlexandria, VA

John M. Salsman, PhD

Department of Medical Social SciencesFeinberg School of MedicineNorthwestern University Robhert H. Lurie Comprehensive Cancer Center of


Julian Sanchez, MD

Assistant Professor of SurgeryColorectal Surgery SectionDivision of Surgical OncologyDepartment of SurgeryCity of HopeDuarte, CA

Daniel J. Sargent, PhD


Elaine Sein, RN, BSN, OCN, CBCN

Senior Project ManagerFox Chase Cancer Center PartnersPhiladelphia, PA

Prashant Shah, MD

Assistant ProfessorDepartment of Surgical OncologyDivision of Thoracic and Esophageal SurgeryFox Chase Cancer CenterPhiladelphia, PA

Poonam Sharma, MBBS

Associate ProfessorDepartment of PathologyCreighton University School of MedicineOmaha, NE

Qian Shi, PhD


Elin R. Sigurdson, MD, PhD

Chief, Division of General Surgery Director, Department of Surgical OncologyFox Chase Cancer CenterPhiladelphia, PA

Peter Silberstein, MD

Department of Internal Medicine-HematologyAlegent Creighton Medical CenterOmaha, NE

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Christine Weldon, MBA

DirectorCenter for Business Models in Healthcare Adjunct FacultyFeinberg School of MedicineNorthwestern University Chicago, IL

Hannah Yoon, MD

Department of Radiation OncologyThe Robert H. Lurie Comprehensive Cancer CenterNorthwestern UniversityChicago, IL

Monique J. Youl, MBBS

Department of Radiation OncologyPeter MacCallum Cancer CentreMelbourne, Victoria, Australia

Susan E. Yount, PhD

Department of Medical Social SciencesFeinberg School of MedicineNorthwestern University Robert H. Lurie Comprehensive Cancer Center of


Laura Yun, MD

Assistant Professor of MedicineFeinberg School of MedicineNorthwestern University Chicago, IL

Sandra Van Schaeybroeck

Cancer Research UK Clinician Scientist Drug Resistance GroupCentre for Cancer Research and Cell BiologyQueen’s University BelfastBelfast, Northern Ireland

Neeta K. Venepalli, MD

Assistant ProfessorDivision of Hematology-OncologyDepartment of MedicineUniversity of IllinoisChicago, IL

Maxwell T. Vergo, MD

Assistant Professor in MedicineGeisel School of Medicine, Attending PhysicianDepartment of MedicineSection of Palliative CareDartmouth Hitchcock Medical CenterLebanon, NH

Eduardo Vilar, MD, PhD

Assistant ProfessorDepartment of Clinical Cancer PreventionDivision of Cancer Prevention and Population SciencesThe University of Texas MD Anderson Cancer CenterHouston, TX

Rohit Walia, MD

Assistant ProfessorDepartment of RadiologyFox Chase Cancer CenterPhiladelphia, PA

Cont r ibu to r s xv

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© Demos Medical Publishing, LLC. 1

1 Importance of the Multidisciplinary Approach to Colorectal Cancer

becomes of paramount importance to educate the popula-tion and provide access to the required services.

The unmasking of critical components of the biol-ogy of CRC, beginning with the understanding of the adenoma-to-carcinoma sequence leading to the current advances in the understanding of the molecular pathogen-esis of CRC, has crystallized the importance of integrating laboratory science in the construct of the multidisciplinary team. Chapter 2 of this text, for example, highlights The identification of three major molecular pathways, which has led to refinement in genetic counseling, risk assess-ment, prognosis determination, and screening programs. The chromosomal instability pathway is characterized by the initial alteration of the APC gene, followed by genetic and epigenetic events, including the mutation of K-ras, the presence of global hypomethylation, and allelic deletions of other tumor suppression genes. The DNA mismatch repair pathway (mutator phenotype pathway) is characterized by the presence of microsatellite instability and contrib-utes to approximately 15% of all CRCs. The third critical pathway includes inflammatory bowel disease resulting in increased risk for development of CRC with defined genetic and epigenetic events. In addition, there is also perhaps a fourth pathway, the serrated pathway, involv-ing mutations including BRAF and hypermethylation of CpG islands generally evolving from hyperplastic polyps through serrated adenomas. These pathways further sup-port the concept of tumor heterogeneity, reinforcing the observation that CRC does not represent a single disease entity but a growing assortment of subsets of tumors. Tumor heterogeneity also is a potentially confounding factor for individual patients, further complicated by observed biological differences comparing primary versus metastatic disease. The identification of the accumulation of molecular events within an individual patient will man-date novel clinical trial designs to incorporate molecular pathology, multiple pathway-driven drug development strategies, and sequential biopsies over time for patients with metastatic disease to determine a more optimal bio-logically driven treatment strategy.

Identifying individuals at risk for CRC is a respon-sibility across health care disciplines, particularly shared by the primary care physician and gastroenterologist. The

1

The concept of personalized or precision medicine by definition embraces the integration of a multidisciplinary approach for the care of an individual patient. Although many would emphasize the link between tumor biologic constructs and treatment selection (admittedly an impor-tant goal if not yet a realization), precision medicine should encompass the entire spectrum of not only an indi-vidual clinical situation but also the social, psychological, and physical factors that affect the individual patient. The colon and rectal cancer patient may routinely require the expertise of the surgeon, medical oncologist, patholo-gist, gastroenterologist, radiologist, radiation oncologist, and primary care physician to provide the most coher-ent, informed, comprehensive, and effective strategy for diagnosis, treatment, and in many cases, long-term sur-veillance. To truly personalize the individual patient’s experience, the comprehensive cancer care program must also offer critical services including psychiatry/psychology, social work, physical and occupational therapy, and nutri-tion counseling as needed. Access to additional health care personnel in surgery, other medical disciplines, nursing and genetic counseling is also critical based on symptoms, potential complications, and long-term risks both for the patient and potentially for other family members who may also be at risk for an eventual cancer diagnosis.

Over the past 2 decades, and particularly during the last 10 years, there have emerged profound advances in the treatment of colon and rectal cancer, including public recognition of the importance of colorectal cancer (CRC), and the rise of advocacy groups, which focus on education and patient support, research, and significant advances in laboratory science and treatment opportunities. The end result has been fewer patients dying from CRC, more than doubling the survivorship for those with metastatic dis-ease, enhanced potential for a cure for those with isolated metastatic disease, particularly in the liver and lung, and increases in the numbers of individuals screened for CRC. Since CRC is a preventable disease and one that can be cured when diagnosed at early stages, the involvement of multiple health professionals and patient organizations

AL B. BENSON I I I

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2 Cancers of the Colon and Rectum

procurement of a detailed family history and the attribu-tion of other important risk factors linked to CRC with integration of appropriate screening methodologies and risk reduction are of paramount importance given the high incidence rate of CRC. Rising rates of obesity and diabetes linked to both poor dietary habits and lack of exercise are noteworthy because of the potential acceleration in risk for development of CRC and other comorbid conditions in the future. Rise in risk also will provide opportunities to develop chemoprevention strategies which depend on the understanding of carcinogenesis and identification of molecular derangements that can serve as targets to develop interventions that may inhibit, reverse, or delay an eventual cancer transformation.

The initial diagnosis and assessment of colon or rec-tal cancer is particularly dependent on the assessments of the gastroenterologist, radiologist, surgeon, pathologist, and in the case of rectal cancer, the radiation oncologist. Advances in transrectal endoscopic ultrasound (TEUS) and MRI have improved the accuracy of clinical staging for rectal cancer. Endoscopic mucosal resection has enhanced the polyp assessment and resection rate. The placement of self-expandable metal stents has evolved into the most widely used nonsurgical option for colonic decompression secondary to malignancy. Sphincter sparing rectal cancer surgeries have reduced the colostomy rate, particularly because of the emergence of neoadjuvant chemoradiation, a treatment of choice compared to the past standard of postoperative chemoradiation. Improved outcomes with total mesorectal excision (TME) have defined surgical practice for rectal cancer and the use of laparoscopically assisted colectomy for colon cancer has also emerged as a standard of care.

Collaborations between medical oncologists and surgeons, particularly since the recent era of improved response rates with combination chemotherapy, have introduced the concepts of neoadjuvant chemotherapy for patients with potentially resectable metastatic CRC and conversion chemotherapy for those who become resect-able after therapy. Over the past decade, 5-year overall survival rates have improved for patients who are able to undergo R0 resections, particularly for isolated liver or lung disease. The advancements in chemotherapy have not only improved the outcomes for patients with resectable metastatic disease, but also for those with stage III colon cancer who receive adjuvant oxaliplatin with a fluoropy-rimidine. CRC patients with metastatic disease that is not resectable have also experienced a survival benefit with the introduction of the concept of the continuum of care, which encourages the use of all 3 active chemotherapy agents (oxaliplatin, irinotecan, 5FU/capecitabine) over time during the course of the patient’s illness, resulting in a definitive survival advantage. This last decade has intro-duced targeted or biological agents into treatment regi-mens for metastatic CRC patients, including bevacizumab

and cetuximab/panitumumab for those patients with K-ras wild type tumors. In 2012, two additional targeted agents became available for patients, including ziv-aflibercept and regorafenib. There are significant challenges, how-ever, to identify the patients most likely to benefit from the addition of a targeted agent, since defining predictive molecular markers has been elusive, particularly in the case of bevacizumab, ziv-aflibercept, and regorafenib.

Inclusion of experts in quality of life and symptom management has enhanced a multidisciplinary approach for CRC patients. Clinical trials comparing treatment vs best supportive care for patients with refractory CRC, for example, have demonstrated both a survival benefit as well as maintenance of quality of life for irinotecan, cetuximab, panitumumab, and regorafenib. Quality of life measures have been integrated into the design of randomized phase III clinical trials. With the introduction of new agents and the potential toxicity of such, health-related quality of life (HRQL) assessment is an important methodology to incor-porate aspects of function (eg, mood, affect), as well as the patient’s perspective. Treatment related symptom manage-ment strategies have incorporated algorithms to more effectively manage diarrhea as an important example. The development of oxaliplatin has resulted in the recognition of prevention and control of treatment related peripheral neuropathy. The use of anti-EGFR treatments has brought dermatologists into the multidisciplinary team to better control the treatment related rash associated with agents such as cetuximab and panitumumab.

The last decade has heralded a focus on care delivery in the United States, including patient navigation in cancer care, assessment of comprehensive CRC care, and access to care in the community with development of new models for care delivery. Patient navigation is designed to elimi-nate barriers to care as well as to streamline care, ensur-ing timely diagnosis and treatment. Since multidisciplinary CRC disease teams are essential for optimal patient care, navigation programs are increasingly integrated in cancer center programs to achieve the goal of seamless multidis-ciplinary delivery of care. In addition, survivorship has emerged as an integral component of comprehensive cancer care, particularly as increasing numbers of CRC patients are surviving their disease. It is estimated that there are over 11 million patients with a diagnosis of CRC living in the United States. Cancer centers must increasingly address survivorship issues including access to health care and fol-low-up treatment, assessment of late effects of treatment, evaluation of second cancers and quality of life. The 2006 Survivorship Report from the Institute of Medicine (IOM) states that multiple disciplines must be involved in survi-vorship efforts, including health care providers, patient advocates as well as other stakeholders with the intent of raising the awareness of the needs of cancer survivors and embracing the four critical components of comprehen-sive survivorship care, including prevention, surveillance,



CHAPTER 1 • Importance of the Multidisciplinary Approach 3

I/II trials in metastatic CRC with an emphasis on the importance of pharmacokinetics, refinement of phar-macodynamic markers and the integration of genom-ics, including the identification of genetic and epigenetic changes which are potential targets for drug develop-ment. The chapter devoted to future directions discusses gene expression profiling as well as integrative genomics, clinical trials designed to validate prognostic and predic-tive biomarkers and surrogate endpoints, and potential biologic targets for drug development. The future con-tinues to embrace the era of multidisciplinary CRC care and research strategies, signifying a fusion of bench to bedside strategies.

intervention, and coordination of care. In this text, there is also a chapter devoted to racial disparities in the care of patients with CRC, which is particularly relevant since this topic not only applies to providing access to high quality cancer care, but also reflects the importance of risk assess-ment. For example, the incidence and mortality rate for CRC are highest among African Americans.

The chapters in this text have been assembled to pro-vide the current best available evidence to support the standard of care integrating multidisciplinary approaches to CRC, including prevention and screening, diagnos-tics, treatment, and surveillance. In addition, with an eye to the future, there is discussion of the role of phase


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