Professional Documents
Culture Documents
2015 Asco Edbook
2015 Asco Edbook
American Society of
Clinical Oncology
Educational Book
Editor: Don S. Dizon, MD
Associate Editor: Nathan Pennell, MD, PhD
Managing Editor: Lindsay Pickell, MFA
Editorial Administrator: Devon Carter
Editorial Assistant: Hilary Adams
Production Manager: Donna Dottellis
Contents
2015 ASCO Annual Meeting Disclosure
xiv
xv
xvi
xx
INVITED ARTICLES
The Changing Landscape of Phase I Trials in Oncology
Kit Man Wong, Anna Capasso, and S. Gail Eckhardt
17
22
28
Medical Education: Perils and Progress in Educating and Assessing a New Generation of Learners
Jill Gilbert, Helen Chew, Charlene Dewey, and Leora Horn
33
40
44
BREAST CANCER
Challenging Issues in Metastatic Disease
Precision Medicine for Metastatic Breast Cancer
Elise Deluche, Elisa Onesti, and Fabrice Andre
eArticle
eArticle
The 2015 ASCO Educational Book is published online at asco.org/edbook. Articles can also be accessed
from the Attendee Resource Center at am.asco.org/ARC. Articles that are included in this print edition
include a page number reference in the table of contents.
iii
Controversies in Neoadjuvant Therapy for Breast Cancer: Surgery, Radiation, and Therapeutic Trials
Neoadjuvant Therapy for Breast Cancer: Controversies in Clinical Trial Design and Standard of Care
Julia White and Angela DeMichele
eArticle
48
eArticle
Triple-Negative Breast Cancer: Molecular Subtypes and New Targets for Therapy
Brian D. Lehmann, Jennifer A. Pietenpol, and Antoinette R. Tan
eArticle
eArticle
eArticle
Decision Making in the Context of Breast Cancer Chemoprevention: Patient Perceptions and the Meaning of Risk
Christine Holmberg
eArticle
Early Detection of Cancer: Past, Present, and Future
Early Detection of Cancer: Past, Present, and Future
Joshua D. Schiffman, Paul G. Fisher, and Peter Gibbs
57
eArticle
eArticle
eArticle
eArticle
67
Whole-Brain Radiotherapy and Stereotactic Radiosurgery in Brain Metastases: What Is the Evidence?
Minesh P. Mehta and Manmeet S. Ahluwalia
eArticle
Rare Tumors of the Central Nervous System: More Similar than Different
Biology and Clinical Management Challenges in Meningioma
Christian Mawrin, Caroline Chung, and Matthias Preusser
eArticle
eArticle
eArticle
eArticle
eArticle
eArticle
eArticle
eArticle
eArticle
Clinical Trials of Precision Medicine through Molecular Proling: Focus on Breast Cancer
Dimitrios Zardavas and Martine Piccart-Gebhart
eArticle
76
eArticle
eArticle
85
Treatment of Colorectal Cancer Peritoneal Carcinomatosis: The Role of Surgery, Systemic, and Heated Intraperitoneal
Chemotherapy
Treatment of Peritoneal Carcinomatosis of Colorectal Origin
Andrea Cercek, James C. Cusack Jr, and David P. Ryan
eArticle
eArticle
Making Sense of Emerging Therapies in Pancreatic Cancer: Are We Finally on the Right Track?
Making Sense of Current and Emerging Therapies in Pancreatic Cancer: Balancing Benet and Value
Daniel H. Ahn, Andrew H. Ko, Neal J. Meropol, and Tanios S. Bekaii-Saab
eArticle
eArticle
vi
92
GENITOURINARY CANCER
Beyond Tyrosine Kinase Inhibitor Therapy: Incorporating Immunotherapy and Metastasectomy into Renal Cell Carcinoma
Management
Challenging the Treatment Paradigm for Advanced Renal Cell Carcinoma: A Review of Systemic and Localized
Therapies
Axel Bex, James Larkin, and Martin Voss
eArticle
eArticle
eArticle
eArticle
Debate on Chemotherapy and Radium 223 for the Optimal Treatment of Advanced Prostate Cancer
Why Chemotherapy Should be Given Early for Men with Metastatic Prostate Cancer
Leonel F. Hernandez-Aya and Maha Hussain
eArticle
Radium 223: How Can We Optimize This New Tool for Metastatic Castration-Resistant Prostate Cancer?
Tanya Barauskas Dorff and Mitchell E. Gross
eArticle
eArticle
eArticle
Emerging Role for Novel Immunotherapy Agents in Metastatic Renal Cell Carcinoma: From Bench to Bedside
Matthew Weinstock and David F. McDermott
eArticle
105
GYNECOLOGIC CANCER
Cervical Cancer from Diagnosis to Survivorship
Nonsurgical Management of Cervical Cancer: Locally Advanced, Recurrent, and Metastatic Disease, Survivorship,
and Beyond
Helen J. Mackay, Lari Wenzel, and Linda Mileshkin
eArticle
vii
Managing Ovarian Cancer in the Older Woman: How to Best Select and Sequence Surgery and Chemotherapy for
Optimal Outcome
Epithelial Ovarian Cancer in Older Women: Dening the Best Management Approach
Linda R. Duska, William P. Tew, and Kathleen N. Moore
eArticle
114
eArticle
123
eArticle
Let the Sunshine In: Industrys Impact on Oncology Research and Practice
The Impact of Industry on Oncology Research and Practice
Beverly Moy, Reshma Jagsi, Richard B. Gaynor, and Mark J. Ratain
130
eArticle
viii
eArticle
eArticle
eArticle
eArticle
eArticle
eArticle
From Philadelphia-Negative to JAK2-Positive: Effect of Genetic Discovery on Risk Stratication and Management
Naveen Pemmaraju and Alison R. Moliterno
Current Therapies and Their Indications for the Philadelphia-Negative Myeloproliferative Neoplasms
Jean-Jacques Kiladjian
139
eArticle
eArticle
LUNG CANCER
Beyond Second-Line Treatment in NonSmall Cell Lung Cancer and Small Cell Lung Cancer: What to Do When the Data
End?
Beyond Second-Line in NonSmall Cell Lung Cancer: Therapy and Supportive Care
Renato G. Martins, Craig H. Reynolds, and Gregory J. Riely
eArticle
147
eArticle
eArticle
ix
eArticle
eArticle
eArticle
eArticle
eArticle
eArticle
eArticle
164
MELANOMA/SKIN CANCERS
Cutaneous Squamous, Basal, and Merkel Cell Cancers
Prognostic Factors and the Role of Adjuvant Radiation Therapy in Non-Melanoma Skin Cancer of the Head and Neck
Sandro V. Porceddu
eArticle
Merkel Cell Carcinoma: Emerging Biology, Current Approaches, and Future Directions
Richard Tothill, Vanessa Estall, and Danny Rischin
eArticle
eArticle
Neoadjuvant Therapy for Melanoma: A Promising Therapeutic Approach and an Ideal Platform in Drug Development
Ahmad A. Tarhini
eArticle
177
eArticle
Depression, Anxiety, Neuropathy, and Fatigue: An Update on the 2014 ASCO Survivorship Guidelines and How to
Incorporate Them into Practice
Chemotherapy-Induced Peripheral Neurotoxicity in Cancer Survivors: An Underdiagnosed Clinical Entity?
Guido Cavaletti, Paola Alberti, and Paola Marmiroli
eArticle
Challenges to Standardizing the Care for Adult Cancer Survivors: Highlighting ASCOs Fatigue and Anxiety and
Depression Guidelines
Ann H. Partridge, Paul B. Jacobsen, and Barbara L. Andersen
188
eArticle
Bone Health in Adults Treated with Endocrine Therapy for Early Breast or Prostate Cancer
Catherine H. Van Poznak
eArticle
eArticle
eArticle
eArticle
xi
PEDIATRIC ONCOLOGY
Real-Time Molecular Genetic Proling: The Future Is Now (Or Is It?)
State of the Art Discovery with Tumor Proling in Pediatric Oncology
William L. Carroll, Elizabeth Raetz, and Julia Meyer
eArticle
196
PROFESSIONAL DEVELOPMENT
The Challenge to Stay Current: Incorporating Technology into Practice
Advances in Website Information Resources to Aid in Clinical Practice
Matthew J. Rioth, Travis J. Osterman, and Jeremy L. Warner
eArticle
Using Social Media to Learn and Communicate: It Is Not About the Tweet
Michael A. Thompson
206
eArticle
eArticle
SARCOMA
Adjuvant Treatment of Soft Tissue Sarcoma: What, When, and Why
Adjuvant Chemotherapy for Soft Tissue Sarcoma
Paolo G. Casali
eArticle
eArticle
eArticle
The Biology and Management of Cartilaginous Tumors: A Role for Targeting Isocitrate Dehydrogenase
Gabriel Tinoco, Breelyn A. Wilky, Ana Paz-Mejia, Andrew Rosenberg, and Jonathan C. Trent
eArticle
eArticle
213
TUMOR BIOLOGY
Implications of Intratumor Heterogeneity for Personalized Therapy
Clonal Evolution Models of Tumor Heterogeneity
Liran I. Shlush and Dov Hershkovitz
eArticle
eArticle
220
xiii
xiv
BREAST CANCER
Maxine S. Jochelson, MD, Track Leader
Jennifer A. Brown, MD
Angela DeMichele, MD
Charles E. Geyer Jr, MD, FACP
Raquel Nunes, MD
Debra A. Patt, MD, MPH, MBA
Hope S. Rugo, MD
Julia R. White, MD
CLINICAL TRIALS
Sumithra J. Mandrekar, PhD
Janet Dancey, MD
Bhupinder Singh Mann, MBBS
Apostolia Maria Tsimberidou, MD, PhD
ETHICS
Beverly Moy, MD
Jon Charles Tilburt, MD
GASTROINTESTINAL (COLORECTAL)
CANCER
LUNG CANCER
Laura Quan Man Chow, MD, Track Leader
Martin J. Edelman, MD
Craig H. Reynolds, MD
David R. Spigel, MD
Glen J. Weiss, MD
Mauro Zukin, MD
GASTROINTESTINAL (NONCOLORECTAL)
CANCER
Matthew H.G. Katz, MD, FACS, Track Leader
Tanios S. Bekaii-Saab MD
Jimmy J. Hwang, MD
Se Hoon Park, MD
Vincent J. Picozzi, MD
Manish A. Shah, MD
GENITOURINARY CANCER
MELANOMA/SKIN CANCERS
GYNECOLOGIC CANCER
Linda R. Duska, MD
Helen Mackay, MD
Matthew A. Powell, MD
PEDIATRIC ONCOLOGY
Gregory T. Armstrong, MD, MSCE, Track Leader
Najat C. Daw, MD
Stewart Goldman, MD
Joel A. Weinthal, MD
PROFESSIONAL DEVELOPMENT
Anne S. Tsao, MD, Track leader
Kristin Anderson, MD, MPH
Kelly J. Cooke, DO
Laura Williams Goff, MD
Lee M. Krug, MD
Jason Michael Samuelian, MD
SARCOMA
Gary K. Schwartz, MD, Track Leader
L. Johnetta Blakely, MD
Robert Mikael Henshaw, MD
Min S. Park, MD, MS
TUMOR BIOLOGY
Elizabeth A. Maher, MD, PhD, Track Leader
Elise C. Kohn, MD
Kimryn Rathmell, MD, PhD
Eliezer Mendel Van Allen, MD
xv
Lana Bijelic, MD
MedStar Health
Harvey Cohen, MD
Duke University Medical Center
Jeffrey Abrams, MD
National Cancer Institute at the National
Institutes of Health
William Blum, MD
The Ohio State University
Robert Coleman, MD
The University of Texas MD Anderson Cancer
Center
Sia Daneshmand, MD
USC Institute of Urology
Chau Dang, MD
Memorial Sloan Kettering Cancer Center
Daniel Danila, MD
Memorial Sloan Kettering Cancer Center
Jennifer Brown, MD
Dana-Farber Cancer Institute
Nancy Dawson, MD
Georgetown University
Jonas De Souza, MD
The University of Chicago Medicine
Jayanta Debnath, MD
University of California, San Francisco
Barbara Burtness, MD
Yale University School of Medicine
Keith Argenbright, MD
Moncrief Cancer Institute
Lisa Carey, MD
UNC Lineberger Comprehensive Cancer Center
Richard Carvajal, MD
Columbia University Medical Center
Andrea Cercek, MD
Memorial Sloan Kettering Cancer Center
Paul Chapman, MD
Memorial Sloan Kettering Cancer Center
Anthony Back, MD
University of Washington
Alice Chen, MD
National Cancer Institute at the National
Institutes of Health
Darren Feldman, MD
Memorial Sloan Kettering Cancer Center
xvi
Yoon-Jae Cho, MD
Stanford University School of Medicine
Tatyana Feldman, MD
Hackensack University Medical Center
Toni Choueiri, MD
Dana-Farber Cancer Institute
Jessica Clement, MD
University of Connecticut Health Center
Keith Flaherty, MD
Massachusetts General Hospital
Ezra Cohen, MD
University of California, San Diego
James Ford, MD
Stanford University School of Medicine
Monica Fornier, MD
Memorial Sloan Kettering Cancer Center
Robert Henshaw, MD
Georgetown University College of Medicine
Nathan Fowler, MD
The University of Texas MD Anderson Cancer Center
Hedy Kindler, MD
The University of Chicago
Matt Galsky, MD
The Tisch Cancer Institute, Icahn School of
Medicine at Mount Sinai
Theresa Koppie, MD
Oregon Health & Science University
Thomas Krivak, MD
Magee-Womens Hospital of UPMC
Lee Krug, MD
Memorial Sloan Kettering Cancer Center
Geoff Ku, MD
Memorial Sloan Kettering Cancer Center
Kelly Hunt, MD
The University of Texas MD Anderson Cancer Center
Shaji Kumar, MD
Mayo Clinic
Ann LaCasce, MD
Dana-Farber Cancer Institute
Syma Iqbal, MD
USC Norris Comprehensive Cancer Center
S. Percy Ivy, MD
National Cancer Institute at the National
Insitutes of Health
Amol Ghia, MD
The University of Texas MD Anderson Cancer
Center
Jill Gilbert, MD
Vanderbilt-Ingram Cancer Center
Teresa Gilewski, MD
Memorial Sloan Kettering Cancer Center
Mrinal Gounder, MD
Memorial Sloan Kettering Cancer Center
Norbert Graf, MD, PhD
Saarland University
Timothy Graubert, MD
Massachusetts General Hospital Cancer Center
Jhanelle Gray, MD
Moftt Cancer Center
Gordon Hafner, MD
Inova Health System
Hatem Halabi, MD, FACS
Cancer Treatment Centers of America
Paul Haluska, MD, PhD
Mayo Clinic
Peter Hammerman, MD, PhD
Dana-Farber Cancer Institute
Hans Hammers, MD, PhD
Johns Hopkins Medicine
Jay Harris, MD
Dana-Farber Cancer Institute
Michael Hassett, MD, MPH
Dana-Farber Cancer Institute
Tara Henderson, MD, MPH
Pritzker School of Medicine, The University of
Chicago
Bryan Hennessy, MD
The University of Texas MD Anderson Cancer
Center
Dung Le, MD
Johns Hopkins Medicine
Thomas LeBlanc, MD, MA
Duke University
Jonathan Ledermann, MD, FRCP
University College London Cancer Institute
Mario Leitao, MD
Memorial Sloan Kettering Cancer Center
Nancy Lin, MD
Dana-Farber Cancer Institute
Noralane Lindor, MD
Mayo Clinic
Evan Lipson, MD
Johns Hopkins Medicine
David Liu, MD
University of British Columbia
Karen Kelly, MD
UC Davis Health System
Ravi Madan, MD
National Cancer Institute at the National
Institutes of Health
Rami Manochakian, MD
Case Western Reserve University
xvii
Rana McKay, MD
Dana-Farber Cancer Institute
Michael Prados, MD
UCSF Medical Center
Lawrence Shulman, MD
Dana-Farber Cancer Institute
Shannon Puhalla, MD
University of Pittsburgh
Marc Shuman, MD
USCF Helen Diller Comprehensive Cancer Center
Loren Mell, MD
University of California, San Diego
Ana Molina, MD
Weill Cornell
David Raben, MD
University of Colorado Denver
Ian Smith, MD
The Royal Marsden NHS Foundation Trust
Guilherme Rabinowits, MD
Dana-Farber Cancer Institute, Brigham and
Womens Hospital
Thomas Smith, MD
The Sidney Kimmel Comprehensive Cancer
Center at Johns Hopkins
Bettina Mller, MD
Instituto Nacional del Cancer
Sonali Smith, MD
The University of Chicago
Jeffrey Razier, MD
Northwestern University
Patricia Sneed, MD
University of California, San Francisco
Michael Neuss, MD
Vanderbilt-Ingram Cancer Center
Vernon Sondak, MD
H. Lee Moftt Cancer Center & Research
Institute
Susan OBrien, MD
The University of Texas MD Anderson Cancer
Center
Alyssa Rieber, MD
The University of Texas MD Anderson Cancer
Center
Richard Riedel, MD
Duke University
Sumanta Pal, MD
City of Hope
Nicholas Robert, MD
Virginia Cancer Specialists, US Oncology
Research Network
Channing Paller, MD
Johns Hopkins University School of Medicine
Alberto Pappo, MD
St. Jude Childrens Research Hospital
Heather Parsons, MD, MPH
The Sidney Kimmel Comprehensive Cancer
Center at Johns Hopkins
Harvey Pass, MD
NYU Langone Medical Center
Timothy Pawlik, MD, MPH, PhD
Johns Hopkins University School of Medicine
Solange Peters, MD, PhD
University of Lausanne
Matthew Powell, MD
Washington University School of Medicine in St.
Louis
xviii
Deborah Toppmeyer, MD
Rutgers Cancer Institute of New Jersey
David Ryan, MD
Massachusetts General Hospital Cancer Center
Tiffany Traina, MD
Memorial Sloan Kettering Cancer Center
Michael Sabel, MD
University of Michigan
Rafael Santana-Davila, MD
Seattle Cancer Center Alliance
Lidia Schapira, MD
Massachusetts General Hospital
Leonard Sender, MD
UC Irvine Health
Anna Varghese, MD
Memorial Sloan Kettering Cancer Center
Victor Vogel, MD
Geisinger Health System
Heather Wakelee, MD
Stanford University
Rona Yaeger, MD
Memorial Sloan Kettering Cancer Center
William William, MD
The University of Texas MD Anderson Cancer
Center
Patrick Wen, MD
Dana-Farber Cancer Institute
Thomas Witzig, MD
Mayo Clinic
Howard West, MD
Swedish Medical Center
xix
EDUCATIONAL SUPPORT
Amgen
Clinical Trials Track
Gastrointestinal (Colorectal) Cancers Track
Astellas
Medivation
Genitourinary Cancers Track
AstraZeneca
Breast Cancer Track
Gynecologic Cancers Track
Lung Cancer Track
Bayer HealthCare Pharmaceuticals Inc.
Gastrointestinal (Noncolorectal) Cancers Track
Boehringer Ingelheim Pharmaceuticals, Inc.
Lung Cancer Track
xx
Celgene Corporation
Best of ASCO Meetings
Breast Cancer Track
Gastrointestinal (Noncolorectal) Cancers Track
Leukemia, Myelodysplasia, and Transplantation
Track
Lung Cancer Track
Lymphoma and Plasma Cell Disorders Track
Genentech BioOncology
Annual Meeting Proceedings and Educational
Book Bundle
Breast Cancer Track
Gynecologic Cancer Track
Melanoma/Skin Cancers Track
Genomic Health, Inc.
Breast Cancer Track
HELSINN
Health Services Research
and Quality of Care Track
Patient and Survivor Care Track
BABETTE
Corporate Allies Conquering Cancer
Incyte Corporation
Gastrointestinal (Noncolorectal) Cancers Track
Teva Ongology
Pre-Annual Meeting Seminar: Hematology for
the Oncologist
GENERAL SUPPORT
Bloomingdales
Corporate Allies Conquering Cancer
Lilly
Breast Cancer Track
Gastrointestinal (Colorectal) Cancers Track
Lung Cancer Track
Pre-Annual Meeting Seminar: New Drugs in
Oncology
Ludwig Cancer Research
Cancer Prevention, Genetics, and Epidemiology
Track
Merck Oncology
Annual Meeting Proceedings and Educational
Book Bundle
Breast Cancer Track
Clinical Trials Track
Gastrointestinal (Noncolorectal) Cancers Track
Genitourinary Cancers Track
Lung Cancer Track
Anonymous
Young Investigator Award (2)
Novartis Oncology
Best of ASCO Meetings
Breast Cancer Track
Gastrointestinal (Noncolorectal) Cancers Track
Onyx Pharmaceuticals
Leukemia, Myelodysplasia, and Transplantation
Track
Lymphoma and Plasma Cell Disorders Track
Pzer Oncology
Gastrointestinal (Noncolorectal) Cancers Track
Genitourinary Cancers Track
Leukemia, Myelodysplasia, and Transplantation
Track
Lymphoma and Plasma Cell Disorders Track
Pharmacyclics, Inc.
Leukemia, Myelodysplasia, and Transplantation
Track
AbbVie, Inc.
Young Investigator Award
Amgen
Career Development Award
Merit Awards
Young Investigator Award
Brooks Brothers
Corporate Allies Conquering Cancer
Celgene Corporation
ASCO Virtual Meeting
The Cholangiocarcinoma Foundation
Young Investigator Award in
Cholangiocarcinoma
Coalition of Cancer Cooperative Groups
Clinical Trials Participation Award
ASCO International
International Innovation Grant
xxi
David Yurman
Corporate Allies Conquering Cancer
Sano Oncology
Drug Development Research Professorship
Eisai Inc.
Medical Student Rotation for Underrepresented
Populations
Onsite Connectivity Resources Bundle
Young Investigator Award
Ethicon
Young Investigator Award
Fashion Outlets of Chicago
Corporate Allies Conquering Cancer
Florida Society of Clinical Oncology
Young Investigator Award
Genentech BioOncology
Career Development Award (3)
Medical Student Rotation for Underrepresented
Populations
Young Investigator Award (6)
Gilead Sciences, Inc.
Long-Term International Fellowship
Merit Awards
Young Investigator Award
GlaxoSmithKline Oncology
Career Development Award
Gianni Bonadonna Breast Cancer Award and
Fellowship
Go Airport Express
Corporate Allies Conquering Cancer
HELSINN
General Mission Support
iPlanner Mobile Application and Website Bundle
Incyte Corporation
Merit Awards
Young Investigator Award
Innity Pharmaceuticals Inc.
Onsite Connectivity Resources Bundle
Ipsen Biopharmaceuticals Inc.
Onsite Connectivity Resources Bundle
Janssen Biotech, Inc.
Resident Travel Award for Underrepresented
Populations
Young Investigator Award (2)
The John and Elizabeth Leonard Family
Foundation
Young Investigator Award
xxii
Lilly
Career Development Award
Medical Student Rotation for Underrepresented
Populations
Merit Awards
Patient Advocate Scholarship Program Bundle
Special Attendees Lounge Bundle
Young Investigator Award
Merck Oncology
Annual Meeting Program Publications Bundle
Young Investigator Award (4)
Michaels Mission
Michaels Mission/Conquer Cancer Foundation
of ASCO
Career Development Award
Novartis Oncology
Merit Awards
Resident Travel Award for Underrepresented
Populations
Young Investigator Award
Onyx Pharmaceuticals
Merit Awards
Patient Advocate Scholarship Program Bundle
Young Investigator Award
Palo Alto Medical Foundation
Leaders in PracticeSilver Supporter
Susan K. Parsons, MD, and Walter Armstrong
Young Investigator Award
Patient Access Network Foundation
Patient Advocate Scholarship Program
Pzer Oncology
Young Investigator Award
The Reid R. Sacco Adolescent and Young
Adult Alliance
Young Investigator Award
Roche
Career Development Award
International Development and Education Award
International Innovation Grant
Long-Term International Fellowship
Young Investigator Award
Seattle Genetics
General Mission Support
iPlanner Mobile Application and Website Bundle
Special Attendees Lounge Bundle
Jackson G. Simpson
Merit Awards
Young A. Sohn and Mark Armenante
Young Investigator Award
Strike 3 Foundation
Young Investigator Award in Pediatric
Oncology (2)
TAIHO Oncology, Inc.
iPlanner Mobile Application and Website Bundle
Takeda Oncology
Abstracts on ASCO.org
Career Development Award
International Development and Education Award
Merit Awards
Oncology Trainee Travel Award
Patient Advocate Scholarship Program Bundle
ASCO Virtual Meeting
Young Investigator Award (2)
TESARO
Merit Awards
Teva Oncology
iPlanner Mobile Application and Website Bundle
Onsite Connectivity Resources Bundle
Patient Advocate Scholarship Program Bundle
Tourneau, LLC
Corporate Allies Conquering Cancer
The WWWW Foundation, Inc. (QuadW) and
The Sarcoma Fund of the QuadW Foundation
of Communities Foundation of Texas
Young Investigator Award in Sarcoma, in
Memory of Willie Tichenor
n behalf of my Associate Editor, Dr. Nate Pennell, I welcome you to the 2015 American Society of Clinical Oncology
(ASCO) Annual Meeting. It is my heartfelt privilege as well to present to you the 35th volume of the NLM-indexed ASCO
Educational Book. The theme of the 2015 Annual Meeting is Illumination and Innovation: Transforming Data into Learning.
The Cancer Education Committee, helmed by Dr. John Vernon Cox, has assembled a comprehensive education program that
illustrates how creative transformation of data into knowledge, and knowledge into learning, can change the lives of our patients
in a sustainable and scalable manner.
Long after the halls of McCormick Place have emptied and the echoes of our colleagues lectures have faded from our ears, the
2015 ASCO Educational Book will remain as an enduring source of this shared knowledge. We are indebted to the over 100
authors who generously took the time to write and, in some cases, revise, the articles in this volume. In addition, I want to
recognize our truly remarkable volunteer peer reviewers who dedicated their time and effort to careful, thorough, and thoughtful
reviews. I strongly believe this collaborative effort has resulted in articles that are not only highly informative, but worthy of
indexing in the National Library of Medicine. Thank you for your efforts and for your commitment to education and ASCOs
mission. Special thanks also go out to Lindsay Pickell at ASCO, for whom none of this could ever have been put together.
In the spirit of this years theme, Nate and I have included in this printed volume a curated selection of articles that most
embody the transformative power of data into learning. As with the 2014 ASCO Educational Book, this edition includes invited
articles from thought leaders who played leadership roles in ASCOs many thematic and specially focused meetings. Each invited
author was tasked with bringing forward an article that represented their area of oncology and also spoke to one of the major
themes of the 2015 Annual Meeting. I am proud to say each author delivered high-caliber work that will stand as a major
contribution to the feld of oncology.
It is our honor to invite you to read through the exceptional contributions that comprise the 2015 volume, only a selection of
which are found in the print edition. For access to all of the 2015 ASCO Educational Book articles, as well as access to past
volumes, please visit www.asco.org/edbook.
Nate and I welcome your feedback and suggestions on how we can improve the content, so please contact us at edbook@asco.org
with your comments.
Don S. Dizon, MD
Editor
INVITED ARTICLES
This years invited articles come from a few of the many oncology thought leaders who played leadership
roles in ASCOs thematic and specially focused meetings during 2014 and early 2015. These articles
represent each authors oncology specialty as it relates to one or more of the major themes of the 2015
ASCO Annual Meeting. Articles cover topics such as big data, clinical trials, value from the perspective of
the patient, value from the perspective of the institute/national policy, geriatrics, and quality, and ethics.
AUTHORS
Ezra E.W. Cohen, MD, FRCPC
University of California, San Diego
Robert S. DiPaola, MD, and Maha Hussain, MD, FASCO
Rutgers Cancer Institute of New Jersey and the
University of Michigan Cancer Center
S. Gail Eckhardt, MD, FASCO
University of Colorado, Denver
Cathy Eng, MD, FACP, and George A. Fisher, MD, PhD
The University of Texas MD Anderson Cancer Center and
Stanford University
Jill Gilbert, MD
Vanderbilt University Medical Center
Edward Kim, MD, FACP
Levine Cancer Institute, Carolinas HealthCare System
William M. Sikov, MD, FACP
Women & Infants Hospital of Rhode Island
Stephen T. Sonis, DMSc, DDS
Brigham and Womens Hospital
INVITED ARTICLES
METHODS
TRIAL DESIGN
The conventional goals of phase I trials are to characterize the
safety, tolerability, and maximum tolerated dose (MTD) of a
novel agent by enrolling patients with a wide range of advanced cancers refractory to standard therapy. With the
emergence of MTAs, new approaches related to dose escalation, patient selection, and study endpoints are making their
way into current phase I studies.
Dose Escalation
The classic 3 3 design is a simple algorithmic method consisting of a set of predefned dose escalation rules based on
the observed rate of dose-limiting toxicities (DLTs) within a
specifed window of assessment, typically 28 to 30 days. This
approach enrolls cohorts of three patients at each dose level
based on an algorithm (Table 1). The MTD is defned as the
dose level at which the DLT rate is less than 33% and is usually the recommended phase II dose (RP2D) for further
study. This design is well suited for cytotoxic agents, which
are characterized by a positive correlation between dose, toxicity, and effcacy, and the highest dose with acceptable toxicity is desired.5
Although the 3 3 design is simple to implement, it may
lead to suboptimal treatment in a large number of patients.6
The estimated MTD may be imprecise because of the small
cohort size and the nature of a rule-based approach.7 Furthermore, MTAs may demonstrate delayed or cumulative
mechanism-based toxicities that are not captured within the
DLT assessment window. In these cases, the maximally administered dose is determined instead of the MTD.6 In a systematic review of more than 450 phase I trials, the MTD was
identifed for 64% of MTAs compared with 99% of cytotoxic
agents.8 It is estimated that 20% of dose reductions with
MTAs occur beyond cycle 1, the usual DLT assessment period.9 Indeed, there is great heterogeneity in the DLT definition across published phase I trials of MTAs,
particularly with respect to the window of assessment and
severity.10 In fact, the RP2D of MTAs should incorporate
toxicity data from all cycles of therapy and symptomatic
grade 2 toxicities.9,11
New strategies for dose escalation were developed to address these issues, including accelerated titration and modelbased designs (Table 1). The accelerated titration design
(ATD) as originally proposed consists of an accelerated
phase of 100% dose escalation steps in successive singlepatient cohorts, until DLT or substantial toxicity occurs during any cycle, at which point the trial reverts to the standard
From the Developmental Therapeutics Program, Division of Medical Oncology, Department of Medicine, University of Colorado, Aurora, CO.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: S. Gail Eckhardt, MD, Anschutz Medical Campus, University of Colorado Cancer Center, 12801 E. 17th Ave., L18-8111, Campus Box 8117, Aurora, CO 80045;
email: gail.eckhardt@ucdenver.edu.
2015 by American Society of Clinical Oncology.
KEY POINTS
Several aspects of phase I trials have evolved in the
current era of molecular targeted agents to adapt to the
changing nature of anticancer therapy and to increase the
efciency of drug development.
Current phase I designs are increasingly integrating novel
dose-escalation approaches and biomarker-driven selection
of patients, as well as expanding study objectives to
include the evaluation of efcacy and pharmacodynamics/
pharmacokinetics in addition to safety.
Changes to the regulatory approval process have helped to
expedite drug development, particularly for novel agents
with a strong biologic rationale and proof of concept,
validated predictive biomarker, and clear evidence of
efcacy in early trials.
As a result of the substantial changes in phase I trial goals
and conduct, there is a parallel shift toward multiinstitutional trials and central study management by
clinical research organizations.
The use of multi-institutional trials has a signicant impact
on the structure of phase I programs and the experience
of investigators, particularly because of limited patient
enrollment at each site.
Patient Selection
Rather than a single dominant gene, it is now recognized that
most cancers arise from multiple somatically mutated oncogenes, each contributing a small effect, which accumulate
during tumor progression. Thus, even within the same cancer type, individual tumors are driven by distinct sets of genes
and pathways.20 It is this genetic heterogeneity that underlies
the observed variable responses to MTAs.
In most cases, an MTA is active only in a subgroup of patients who may be identifed using predictive biomarkers,
such as the expression level of a gene or protein, or the presence of a gene mutation, amplifcation, or translocation.
Phase I trials increasingly are used as a platform to explore
biomarkers and enrich molecular subsets of patients most
likely to respond to specifc MTAs. When used appropriately,
this can improve the effciency and safety of drug development.21 For instance, the successful use of biomarker-driven
patient selection was exemplifed by the phase I trials of crizotinib (PF-02341066) in EML4-ALK rearranged non-small
cell lung cancer22 and vemurafenib (PLX4032) in BRAF
V600E mutant melanoma,23 in which the remarkable responses in these patient subsets helped to accelerate their
approval.
However, challenges are inherent in incorporating biomarkers in early drug development.5 As most cancers have
multiple genetic aberrations, sensitivity to an MTA is likely
modulated by many factors. Also, identifying a reliable biomarker may be less feasible when an agent has several targets,
as is the case with most tyrosine kinase inhibitors. Since the
misapplication of predictive biomarkers can potentially be
over-restrictive and exclude patients who might beneft from
an MTA, establishing a very strong scientifc basis for the biomarker with preclinical validation is a prerequisite, as is
acceptable sample collection, assay performance, reproducibility, and standardization.24-28 For these reasons, biomarkers typically are investigated as exploratory objectives.
The increasing use of biomarker-based patient selection
has transformed the enrollment process of phase I trials.
First, patients must be molecularly screened to determine
their eligibility. Where the biomarker of interest has a low
prevalence, many patients must be screened to identify a few
potential candidates, and more studies have to open at a single center to accommodate all patients wishing to enter a
trial. Phase I teams must be highly organized to obtain archival tissue or fresh biopsies in a timely manner and be prepared to manage patient anxiety from invasive screening
procedures and negative results. Furthermore, since many
Dose levels
Number of patients
per cohort
DE scheme
MTD
Advantages
biomarkers are disease-specifc, centers must be able to rapidly screen large numbers of patients for disease-specifc expansion cohorts, which may pose a challenge when the phase
I program is not well integrated with subspecialty clinics. Finally, each patient in need of an experimental therapy has to
be considered for multiple studies at the same time to avoid
delays in entering a trial in the event of a screen fail. Strategies
to facilitate the inclusion of molecularly selected patients are
needed, such as molecular prescreening programs for all
metastatic patients to ease the transition to a phase I trial on
disease progression.29
Endpoints
The conventional primary endpoint of phase I trials has been
toxicity, with effcacy as only a secondary outcome. However,
with the new breakthrough therapy designation created by
the U.S. Food and Drug Administration (FDA) to expedite
drug development, obtaining early evidence of effcacy is
now an important component of phase I studies. This has
increased the use of tumor-specifc expansion cohorts to further characterize both safety and clinical response at the
RP2D,30 which is associated with a higher success rate of
phase II trials and faster drug approval.31 As mentioned
above, the organization of some phase I centers also has
been restructured around disease-specifc investigators
and clinics.
REGULATORY CHANGES
The development of a successful drug from frst-in-human
study to approval normally takes about 7 years, during which
its safety and effcacy are thoroughly and rigorously assessed.42 However, in the case of MTAs with a clearly established biologic mechanism backed by proof of concept,
unprecedented clinical responses with minimal toxicity, and
availability of a strong predictive biomarker, many argue that
the approval process should be shortened, especially when
promising results are observed in early phase. Strategies to
expedite drug development were proposed in the FDA Safety
and Innovation Act of 2012. Thus, the new breakthrough
therapy designation for investigational drugs was added to
FDAs armamentarium of programs that also include the
fast-track designation, accelerated approval pathway, and
priority-review designation (Table 2).43
The opportunity to exploit such pathways has a substantial
effect on phase I trial conduct. Not only are effcacy end-
points emphasized in the design, the quality of data is increasingly scrutinized because it may be used for a new drug
application. In fact, trials frequently are now managed by
large clinical research organizations (CROs) to standardize
trial conduct and data collection.
PRACTICAL IMPLICATIONS
Over the past decade, phase I trials have evolved from single-/
oligo-site studies to increasingly large multi-institutional efforts with the goal of expediting patient accrual. In the latter,
three or more institutions typically enroll patients, and slots
in each cohort are assigned by the sponsor or flled on a competitive frst-come frst-served basis.
Multi-institutional trials have several implications, including limited slot availability per site, thus requiring more trials
to be opened at a center to accommodate the same number of
patients. Moreover, additional staff, resources, and frequent
conference calls among participating sites are needed to enable real-time notifcation of adverse events and DLTs. These
factors have led to greater reliance on CROs for study management. Further, the desire to accelerate patient recruitment results in the selection of sites based on their ability
to enroll rather than on the experience and quality of the
phase I program.
Similarly, the experience of phase I investigators has been
influenced by multi-institutional trials. An individual investigator at one site can only gain limited clinical experience
with a novel agent and its spectrum of toxicities.8 Moreover,
since sponsors and/or CROs are usually responsible for overseeing the operations of current phase I trials, it is a challenge
for trainees and junior faculty to obtain comprehensive training in early drug development. Consequently, many years
Table 2. Main Features of the FDAs Expedited Programs for Serious Conditions
Qualifying Criteria
Features
- Rolling review
- Organizational commitment
- Rolling review
- Other actions to expedite review
Abbreviations: FDA, U.S. Food and Drug Administration; IMM, irreversible morbidity or mortality.
Adapted from: U.S. Department of Health and Human Services, Food and Drug Administration. Guidance for industry: expedited programs for serious conditions-drugs and biologics. May 2014.
www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. Accessed December 27, 2014.
of experience may be required before they are fully competent in designing and carrying out phase I studies, highlighting the importance of strong mentorship in this setting.
At the same time, it has become more diffcult for junior faculty to be truly independent investigators of phase I trials and
advance their academic careers. This is especially true at
smaller centers that lack the capacity to compete for enrollment. Therefore, although multisite trials have the advantage
of improving effciency, these issues have led some to suggest
that no more than three centers participate.5
CONCLUSION
Phase I trials are the cornerstone of developmental therapeutics, and they are playing an expanding role in the changing
landscape of cancer drug development. In the era of MTAs,
they have evolved into complex studies that provide much
more information than merely safety. With different dose es-
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: S. Gail Eckhardt, Entremed. Honoraria: S. Gail Eckhardt,
Kyowa-Hakko Kirin, Lilly/ImClone, Janssen Oncology, Boehringer Ingelheim. Consulting or Advisory Role: S. Gail Eckhardt, Sano, Onconova Therapeutics,
Taiho Pharmaceutical. Speakers Bureau: None. Research Funding: S. Gail Eckhardt, Genentech (Inst), AstraZeneca (Inst), Rexahn Pharmaceuticals (Inst),
OncoMed (Inst), Cleave Biosciences (Inst). Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations,
Expenses: S. Gail Eckhardt, Boehringer Ingelheim, Kyowa-Hakko Kirin, Sano, Lilly/ImClone, Genentech. Other Relationships: None.
References
1. The Pharmaceutical Research and Manufacturers of America. Medicines in Development: Cancer. September 2014. http://www.phrma.
org/. Accessed December 30, 2014.
2. Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates?
Nat Rev Drug Discov. 2004;3:711-715.
3. The Pharmaceutical Research and Manufacturers of America. Researching Cancer Medicines: Setbacks and Stepping Stones. September
2014. http://www.phrma.org/. Accessed December 30, 2014.
4. DiMasi JA, Grabowski HG. Economics of new oncology drug development. J Clin Oncol. 2007;25:209-216.
5. Ivy SP, Siu LL, Garrett-Mayer E, et al. Approaches to phase 1 clinical
trial design focused on safety, effciency, and selected patient populations: a report from the clinical trial design task force of the national
cancer institute investigational drug steering committee. Clin Cancer
Res. 2010;16:1726-1736.
6. LoRusso PM, Boerner SA, Seymour L. An overview of the optimal planning, design, and conduct of phase I studies of new therapeutics. Clin
Cancer Res. 2010;16:1710-1718.
7. Mick R, Ratain MJ. Model-guided determination of maximum tolerated
dose in phase I clinical trials: evidence for increased precision. J Natl
Cancer Inst. 1993;85:217-223.
8. Dowlati A, Manda S, Gibbons J, et al. Multi-institutional phase I trials of
anticancer agents. J Clin Oncol. 2008;26:1926-1931.
9. Postel-Vinay S, Collette L, Paoletti X, et al. Towards new methods for
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31. Bugano D, Hess K, Siu LL, et al. Impact of phase 1 expansion cohorts on
probability of success in phase 2 and time-to-drug-approval: analysis of 385
new drugs in oncology. Eur J Cancer. 2014;50:79-80 (suppl; abstr 237).
32. Parulekar WR, Eisenhauer EA. Phase I trial design for solid tumor studies of targeted, non-cytotoxic agents: theory and practice. J Natl Cancer
Inst. 2004;96:990-997.
33. Dienstmann R, Brana I, Rodon J, et al. Toxicity as a biomarker of effcacy
of molecular targeted therapies: focus on EGFR and VEGF inhibiting
anticancer drugs. Oncologist. 2011;16:1729-1740.
34. Dy GK, Adjei AA. Understanding, recognizing, and managing toxicities of targeted anticancer therapies. CA Cancer J Clin. 2013;63:
249-279.
35. Lynch TJ Jr, Kim ES, Eaby B, et al. Epidermal growth factor receptor
inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12:610-621.
36. Eaby B, Culkin A, Lacouture ME. An interdisciplinary consensus on
managing skin reactions associated with human epidermal growth factor receptor inhibitors. Clin J Oncol Nurs. 2008;12:283-290.
37. Grothey A. Recognizing and managing toxicities of molecular targeted
therapies for colorectal cancer. Oncology (Williston Park). 2006;20:
21-28 (14 suppl 10).
38. Workman P, Aboagye EO, Chung YL, et al. Minimally invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-testing
clinical trials of innovative therapies. J Natl Cancer Inst. 2006;98:580598.
39. Lorente D, Mateo J, de Bono JS. Molecular characterization and clinical
utility of circulating tumor cells in the treatment of prostate cancer. Am
Soc Clin Oncol Educ Book. 2014;34:e197-e203.
40. Diaz LA Jr, Bardelli A. Liquid biopsies: genotyping circulating tumor
DNA. J Clin Oncol. 2014;32:579-586.
41. Comets E, Zohar S. A survey of the way pharmacokinetics are reported
in published phase I clinical trials, with an emphasis on oncology. Clin
Pharmacokinet. 2009;48:387-395.
42. Sherman RE, Li J, Shapley S, et al. Expediting drug developmentthe
FDAs new breakthrough therapy designation. N Engl J Med. 2013;
369:1877-1880.
43. Food and Drug Administration. Guidance for industry expedited
programs for serious conditions drugs and biologics. www.fda.
gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
default.htm. Accessed December 26, 2014.
INVITED ARTICLES
PALLIATIVE CARE
BACKGROUND
The application of genomics as a tool to personalize cancer
care is not new. Headlines about individualizing oncology
treatment have been heralded in both the lay and scientifc
press. The use of Oncotype DX to predict the course and
guide treatment of early estrogen-receptor positive breast
cancers has made its way into both the American Society of
Clinical Oncology and National Comprehensive Cancer
Network guidelines.1,2 However, individualized cancer care
based on genomics is still only having a marginal effect on the
vast majority of oncology patients. Although the emphasis of
oncologic-associated genomics primarily has focused on defning tumor risk, biology, and response, the potential opportunities associated with the application of genomics to
supportive cancer care are just evolving.
Few patients avoid toxicities and side effects of cytotoxic
and targeted anticancer regimens. The list of complications is
extensive and diverse. Treatment can result in specifc tissue
injury (e.g., mucositis, pneumonitis, dermatitis, diarrhea,
nausea and vomiting, and neuropathy) or more generalized
consequences (e.g., fatigue, cognitive dysfunction, and cachexia). As every oncologist has observed, not all patients are
equally threatened for specifc treatment-related side effects.
Although overall risk is, to some degree, associated with regimen selection, drug or radiation dose, and route of admin-
From the Dana-Farber Cancer Institute, Brigham and Womens Hospital, Boston, MA.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Stephen Sonis, DMD, DMSc, Division of Oral Medicine, Brigham and Womens Hospital, 75 Francis Street, Boston, MA 02115; email: ssonis@partners.org.
2015 by American Society of Clinical Oncology.
STEPHEN T. SONIS
portantly, patients were able to make treatment preference decisions based on their understanding of toxicity risk within the
context of cancer therapy treatment outcomes.
From the standpoint of integrating genomics into a comprehensive management paradigm that includes supportive care, a
genomic test that addresses the inclusive risks of toxicities has
most value when it is interpreted in the context of a specifc anticancer regimen. For example, if a patient with breast cancer
can be effectively treated for her disease with either Regimen A
or Regimen B and the risk of the toxicity profle associated with
each regimen can be defned, the patient and the oncologist can
choose one over the other based on patient preference. If, on the
other hand, Regimen A is not as effective as Regimen B, but the
toxicity risk profle is more tolerable to the patient, there may be
a trade-off point at which the patient determines that the risk
and scope of side effects outweigh the selection of the potentially
more effective cancer treatment.
A second value in understanding a patients toxicity risk focuses on the chance to individualize and target the use of medications that prevent or treat specifc side effects. For example,
approximately 40% of patients treated with certain conditioning
regimens for hematopoietic stem cell transplant develop severe
oral mucositis with all of its consequent comorbidities. Palifermin, keratinocyte growth factor-1, is approved to prevent its development.8 To be effective, palifermin must be administered
for 3 days before the infusion of the conditioning regimen, a
time in which there is no evidence of mucosal injury. Not only
does this schedule add days to care, it also incurs substantial fnancial costs. Both are well worth the price for the individual at
risk of mucositis, but there is more to be lost than gained for the
remaining 60% of patients. Thus to administer palifermin to everyone does not make sense at multiple levels. However, if one
could predict with reasonable certainty which patients were at
risk for developing mucositis, the agent could be given selectively and more economically.
In addition to risk prediction, at least two other potential applications for genomics as it relates to personalization of supportive cancer care are available. In the current paradigm of
drug development, success or failure is defned as an assessment
of the mean.9 Criteria for effcacy are set around a one-size-ftsall vision in which it is presumed that all patients have an equivalent response to a drug. Since the response rate for drugs ranges
dramatically (90% of drugs work in only 30% to 50% of patients),10 we know this is not the case. There is clearly individuality in how any population with cancer responds to a drug.
Clinicians often deal with this variance by adjusting dose or
through trial and error. However, genomic differences often defne response/nonresponse and the ability to dichotomize patients prospectively offers a great opportunity to personalize
their care and create hierarchies for toxicity intervention.
For example, if multiple agents to treat chemotherapyinduced nausea and vomiting are available, knowing
which one was most active in a prospective patient makes
prescribing more effcient and cost-effective.
Finally, genomics provides an important tool in drug development discovery through clinical trials. Both radiation
and chemotherapy stimulate changes in gene expression that
10
trigger the pathobiologic events that produce toxicities. Identifying and defning the sequence of gene activation that underlies regimen-related injury provides specifc targets for
intervention. In addition, by mapping the inter-relationships
between cooperative groups of genes and organizing these
into networks, the hubs at the center of the network can be
targeted and disrupted. This approach mimics what happens
to the United Airlines flight schedule when theres a snowstorm in Chicago.
11
STEPHEN T. SONIS
elements of a cluster of polymorphisms is greater than the contribution of any of the contributing parts. This principle was
demonstrated by Tucker et al in studies of radiation-induced
pneumonitis.34 Their evaluation of 16 polymorphisms associated with 10 genes demonstrated the increasing predictive value
of multiple SNPs over fewer numbers. Additionally, although
SNPs occurring outside of genes were mockingly referred to as
junk DNA, it has now become evident that such polymorphisms have value, not only as effective genetic markers,
but as functional modifers.35
Whereas the single SNP approach suffers from its inability
to identify associations because of the simultaneous presence
of multiple variants in different DNA regions,36 GWAS often
identify too many associations (false positives) as a result of
dependencies between SNPs in contiguous regions (linkage
disequilibrium) and the dependency between SNPs on different chromosomes.37
Amalgamating these fndings leads to the conclusion that the
optimal way to identify genomic risk predictors should provide
for a learned outcome in which (1) the genomic results dictate
the genes or SNPs of interest, (2) there is a mechanism to flter
those genes or SNPs that are extraneous without diluting the ultimate prognostic signifcance or pool, (3) there is a way to identify and defne those polymorphisms and genes that function
synergistically to contribute to risk in as precise a way as possible, and (4) there is a high degree of sensitivity and specifcity.
Multivariate statistical models circumvent many of the limitations noted above by examining the overall dependency structure between genotypes, phenotype, and nongenetic variables.
There is now a growing list of other analytic options that
seem to meet the above criteria and seek to identify groups of
SNPs or genes that are defned probabilistically by their combined ability to predict risk. We have used two analytic approaches to identify predictive gene networks or clusters. In
one method, we used a Bayesian approach to identify SNPbased gene networks that were predictive of oral mucositis in
autologous stem cell recipients.38
The frst step is to whittle down the total output from a typical
SNP microarray (1 to 4 million depending on the size of the array) by fltering out those SNPs that are highly unlikely to contribute to the predictive value of the Bayesian network. This is
done using a simple chi-square statistic to identify the top
200,000 SNPs associated with the phenotype of interest (mucositis, in our case). Using another heuristic, the number of
SNPs likely to contribute to risk differential is further fltered to
identify the 4,000 SNPs from which a Bayesian network can be
discovered. Unlike classical methods of identifying the important genes or SNPs based on an expression threshold, the Bayesian approach does not conduct signifcance tests, but ranks
alternative models of association on the basis of posterior probability (to provide for inference). As such, no threshold is
needed to select the most probable network. The predictive
strength of the network is learned so it becomes stronger as
more data are entered. As with any study of this type, a key component is testing the predictive validity of the network using an
independent group of patients.
12
Major roles for TNF-alpha have been suggested in pathoetiology of radiation-induced toxicities, including mucositis and fatigue. The formation of a network based on differentially
expressed genes in patients who developed mucositis conrms a central role for TNF, illustrates its effect on connected nodes, and provides a potential target for pharmacologicallybased intervention.40
mitigated regimen-related toxicities could be selectively administered to the most appropriate patients, favorably affecting the
physiological and fnancial costs of treating nonresponders.
13
STEPHEN T. SONIS
CONCLUSION
The application of genomics to cancer supportive care holds
multiple opportunities to improve our understanding of the biology of regimen-related toxicities, to develop effective interventions, and, most importantly, to guide treatment decisions.
A critical challenge to clinical implementation of this data will be
ensuring that providers and patients understand what the data
mean and how they can be used. Organizing and presenting
data in such a way that results are actionable will be key. Provider education has been identifed as a priority as genomics
moves from the laboratory to the clinic.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: Stephen Sonis, Tenera, LLC, Theramech, Inform Genomics,
Biomodels, LLC. Honoraria: None. Consulting or Advisory Role: Stephen Sonis, Inform Genomics, Quintiles, Clinical Assistance Programs, LLC. Speakers
Bureau: None. Research Funding: None. Patents, Royalties, or Other Intellectual Property: Stephen Sonis, Raman spectropscopy. Expert Testimony:
None. Travel, Accommodations, Expenses: None. Other Relationships: None.
14
References
1. Harris L, Fritsche H, Mennel R, et al. American Society of Clinical
Oncology 2007 update of recommendations for the use of tumor
markers in breast cancer. J Clin Oncol. 2007;25:5287-5312.
2. Gradishar WJ, Anderson BO, Blair SL, et al. Breast cancer version 3.
2014. J Natl Compr Canc Netw. 2014;12:542-590.
3. daCosta DiBonaventura M, Copher R, Basurto E, et al. Patient preferences and treatment adherence among women diagnosed with
metastatic breast cancer. Am Health Drug Benefts. 2014;7:386-395.
4. Health Quality Ontario. Gene expression profling for guiding adjuvant
chemotherapy decisions in women with early breast cancer: an
evidence-based and economic analysis. Ont Health Technol Assess Ser.
2010;10:1-57.
5. Cuffe S, Hon H, Qiu X, et al. Cancer patients acceptance, understanding,
and willingness-to-pay for pharmacogenomic testing. Pharmacogenet
Genomics. 2014;24:348-355.
6. Kuchuk N, Bouganim N, Beusterien K, et al. Preference weights for chemotherapy side effects from the perspective of women with breast cancer. Breast Cancer Res Treat. 2013;142:101-107.
7. Sun CC, Bodurka DC, Weaver CB, et al. Rankings and symptom assessments of side effects from chemotherapy: insights from experienced patients with ovarian cancer. Support Care Cancer. 2005;13:219-227.
8. Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis
after intensive therapy for hematologic cancers. N Engl J Med. 2004;351:
2590-2598.
9. Shah RR. Pharmacogenetics in drug regulation: promise, potential and
pitfalls. Philos Trans R Soc Lond B Biol Sci. 2005;360:1617-1638.
10. Pirmohamed M. Personalized pharmacogenomics: predicting effcacy
and adverse drug reactions. Annu Rev Genomics Hum Genet. 2014;15:
349-370.
11. Papanastasopoulos P, Stebbing J. Molecular basis of 5-fluorouracilrelated toxicity: lessons from clinical practice. Anticancer Res. 2014;34:
1531-1535.
12. Lee AM, Shi Q, Pavey E, et al. DPYD variants as predictors of
5-fluorouracil toxicity in adjuvant colon cancer treatment (NCCTG
N0147). J Natl Cancer Inst. 2014;106:298.
13. Saif MW, Lee AM, Offer SM, et al. A DPYD variant (Y186C) specifc to
individuals of African descent in a patient with life-threatening 5-FU
toxic effects: potential for individualized medicine approach. Mayo Clin
Proc. 2014;89:131-136.
14. Beier MT, Panchapagesan M, Carmen LE. Pharmacogenetics: has the
time come for pharmacists to embrace and implement the science. Consult Pharm. 2013;28:696-711.
15. van Staveren MC, Guchelaar HJ, van Kuilenburg ABP, et al. Evaluation
of predictive tests for screening for dihydropyrimidine dehydrogenase
defciency. Pharmacogenomics J. 2013;13:389-395.
16. Hertz DL, Rae J. Pharmacogenetics of cancer drugs. Annu Rev Med.
2015;66:65-81.
17. Boso V, Herrero MJ, Santaballa A, et al. SNPs and taxane toxicity in
breast cancer patients. Pharmacogenomics. 2014;15:1845-1858.
18. Roco A, Cayun J, Contreras S, et al. Can pharmacogenetics explain effcacy and safety of cisplatin pharmacotherapy? Front Genet. Epub 2014
Nov 14.
19. Gervasini G, Vagace JM. Impact of genetic polymorphisms on chemotherapy toxicity in childhood acute lymphoblastic leukemia. Front
Genet. Epub 2012 Nov 22.
20. den Hoed MA, Lopez-Lopez E, Te Winkel ML, et al. Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric
acute lymphoblastic leukemia. Pharmacogenomics J. Epub 2014 Nov 4.
21. Csordas K, Lautner-Csorba O, Semsei AF, et al. Associations of novel
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
genetic variations in the folate-related and ARID5B genes with the pharmacokinetics and toxicity of high-dose methotrexate in paediatric acute
lymphoblastic leukemia. Br J Haematol. 2014;166:410-420.
Russi EG, Raber-Durlacher JE, Sonis ST. Local and systemic pathogenesis and consequences of regimen-induced inflammatory responses in
patients with head and neck cancer receiving chemoradiation. Mediators Inflamm. 2014;518261.
Wardill HR, Van Sebille YZ, Mander KA, et al. Toll-like receptor 4 signaling: a common biological mechanism of regimen-related toxicities:
an emerging hypothesis for neuropathy and gastrointestinal toxicity.
Cancer Treat Rev. 2015;41:122-128.
Sonis ST, Schwartzberg LS, Weidner SM, et al. From Bayesian modeling
to genomic mapping: biologic validity of predictive single nucleotide
polymorphism networks for chemotherapy-related side effects. J Clin
Oncol. 2013;31 (suppl; abstr 9535).
Alsbeih G, El-Sebaie M, Al-Harbi N, et al. SNPs in genes implicated in
radiation response are associated with radiotoxicity and evoke roles as
predictive and prognostic biomarkers. Radiat Oncol. 2013;8:125.
Gustafson HL, Yao S, Goldman BH, et al. Genetic polymorphisms in
oxidative stress-related genes are associated with outcomes following
treatment for aggressive B-cell non-Hodgkin lymphoma. Am J Hematol.
2014;89:639-645.
Bogunia-Kubik K, Polak M, Lange A. TNF polymorphisms are associated with toxic but not with aGVHD complications in the recipients of
allogeneic sibling hematopoietic stem cell transplantation. Bone Marrow Transplant. 2003;32:617-622.
Schirmer MA, Mergler CP, Rave-Frank M, et al. Acute toxicity of radiochemotherapy in rectal cancer patients: a risk particularly for carriers of the TGFB1 Pro25 variant. Int J Radiat Oncol Biol Phys. 2012;83:
149-157.
Werbrouck J, De Ruyck K, Duprez F, et al. Acute normal tissue reactions
in head-and-neck cancer patients treated with IMRT: influence of dose
and association with genetic polymorphisms in DNA DSB repair genes.
Int J Radiat Oncol Biol Phys. 2009;73:1187-1195.
Della-Morte D, Riondino S, Ferroni P, et al. Impact of VEGF gene polymorphisms in elderly cancer patients: clinical outcome and toxicity.
Pharmacogenomics. 2015;16:61-78.
Barnett GC, Coles CE, Elliott RM, et al. Independent validation of genes
and polymorphisms reported to be associated with radiation toxicity: a
prospective analysis study. Lancet Oncol. 2012;13:65-77.
Corvin A, Craddock N, Sullivan PF. Genome-wide association studies: a
primer. Psychol Med. 2010;40:1063-1077.
Jewell NP. Statistics for Epidemiology. Boca Raton: CRC Press; 2004.
Tucker SL, Li M, Xu T, et al. Incorporating single-nucleotide polymorphisms into the Lyman model to improve prediction of radiation pneumonitis. Int J Radiat Oncol Biol Phys. 2013;85:251-257.
Tragante V, Moore JH, Asselbergs FW. The ENCODE project and perspectives on pathways. Genet Epidemiol. 2014;38:275-280.
Hoh J, Ott J. Mathematical multi-locus approaches to localizing complex human trait genes. Nat Rev Genet. 2003;4:701-709.
Gabriel SB, Salomon R, Pelet A, et al. Segregating at three loci explains
familial and population risk in Hirschsprung disease. Nat Genet. 2002;
31:89-93.
Saligan LN, Fernandez-Martinez JL, deAndres-Galiana EJ, et al. Supervised classifcation by flter methods and recursive feature elimination
predicts risk of radiotherapy-related fatigue in patients with prostate
cancer. Cancer Inform. 2014;13:141-152.
Sonis S, Antin J, Tedaldi M, et al. SNP-based Bayesian networks can
15
STEPHEN T. SONIS
40.
41.
42.
43.
44.
16
45. Carlotto A, Hogsett VL, Maiorini EM, et al. The economic burden of
toxicities associated with cancer treatment: review of the literature and
analysis of nausea and vomiting, diarrhea, oral mucositis and fatigue.
Pharmacoeconomics. 2013;31:753-766.
46. Di Maio M, Gallo C, Leighl NB, et al. Symptomatic toxicities experienced during anticancer treatment: agreement between patient and
physician reporting in three randomized trials. J Clin Oncol. Epub 2015
Jan 26.
47. Hurvitz S, Guerin A, Brammer M, et al. Investigation of adverse-eventrelated costs for patients with metastatic breast cancer in a real-world
setting. Oncologist. 2014;19:901-908.
48. Nonzee NJ, Dandade NA, Patel U, et al. Evaluating the supportive care
costs of severe radiochemotherapy-induced mucositis and pharyngitis: results from a Northwestern University Costs of Cancer Program pilot study with head and neck and nonsmall cell lung cancer
patients who received care at a county hospital, a Veterans Administration hospital, or a comprehensive cancer care center. Cancer.
2008;113:1446-1452.
INVITED ARTICLES
GENITOURINARY CANCER
partly an adaptive process. Furthermore, despite clear evidence to support AR-independent mechanisms, unlike prior
dogmas, AR-dependent signaling continues to be relevant.8
Biologic data on the importance of AR signaling was the basis
for developing several agents targeting AR or relevant enzymatic pathways. The principle was validated by results
from phase III trials with abiraterone and enzalutamide that
demonstrated survival improvements in patients with
mCRPC.9,10 The biologic discoveries regarding progression
to castration resistance led to studies of several other experimental agents targeting additional pathways.8,11-13 Efforts to
target the immune system and bone have led to survival improvement with sipuleucel-T and radium 223 dichloride.7
Therefore, in 2015, oncologists have several standard treatment
options with proven clinical benefts to offer patients, both
docetaxel-naive (sipuleucel-T, abiraterone/prednisone, radium
223 dichloride, enzalutamide) and docetaxel-treated patients
(cabazitaxel/prednisone, abiraterone, enzalutamide, radium
223 dichloride), as well as an array of additional opportunities
for clinical trials.
From the University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Maha Hussain, MD, FACP, FASCO, University of Michigan Comprehensive Cancer Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109; email: mahahuss@umich.edu.
2015 by American Society of Clinical Oncology.
17
Docetaxel GVAX
Sipuleucel-T
Satraplatin
Cabazitaxel
Docetaxel DN101
Abiraterone*
TAK700
Enzalutamide*
Radium 223 dichloride
Pain
Skeletal-related events
GVAX
Docetaxel
Ipilimumab
Bone
Docetaxel dasatinib
Mitoxantrone
Atrasentan
Strontium
Docetaxel atrasentan
Samarium
Zibotenan
Zoledronic acid
Docetaxel zibotenan
Denusomab
VEGF/Angiogenesis
Docetaxel bevacizumab
Docetaxel aibercept
Docetaxel lenalidomide
KEY POINTS
Several therapies targeting the androgen receptor and
other pathways have improved survival and quality of life
for patients with metastatic prostate cancer.
Many costly therapeutic clinical trial efforts have failed to
improve outcomes.
Prostate cancer is a complex disease. Its biologic
heterogeneity warrants that future clinical trials be
carefully designed to achieve higher levels of clinical
impact by attention to targeting more critical pathways;
integrating improved diagnostics; well-designed and
powered clinical trials using multi-targeted strategies; and
optimized timing of therapy.
18
Sunitinib
Dose/Route
Docetaxel
Number of Cycles
Survival
Median: 6
Yes
Cabazitaxel
50 mg IV (25 mg/m 2 m )
$10,797.68
Median: 6
Yes
Abiraterone
1,000 mg PO (30-d)
$8,852.02
Median: 8 ms
Yes
Enzalutamide
160 mg PO (30-d)
$10,026.04
Median: 8 ms
Yes
Sipuleucel-T
IV
$44,162.40
3 cycles
Yes
IV
$22,126.80
6 cycles
Yes
Denusomab
120 mg SC
$2,115.72
Monthly
No
Zoledronic acid
4 mg IV
$838.29
Monthly
No
Abbreviations: AWP, average wholesale price; IV, intravenously; PO, orally; ms, months; SC, subcutaneously.
a language comprehensible to everyone. As a simple fundamental rule, therefore, our next efforts in clinical research
must maximize clinical value and effect on patients, perhaps
by simply using new technology to identify, critically evaluate, and target multiple critical pathways/targets simultaneously (or sequentially).
In the last 2 decades, the course of metastatic prostate
cancer has evolved with improved management of ageassociated comorbidities, PSA-driven stage migration, improved imaging, and the expansion of novel therapies.
Therefore, the focus of therapy also must evolve and, much
like other cancers, a cure should be the overarching objective.
Short of a cure, there is a clear need for greater sustained therapeutic beneft. The latter necessitates substantially more investment in high-quality research and a critical review of our
drug approval standards in this country, which currently do
not incorporate major impact and value or cost of therapy
relative to beneft. The latter, coupled with the cost of
conducting clinical trials, does not necessarily encourage
multitargeted combination therapy strategies; comparative
effectiveness trials, with obvious clinical questions such as a
comparison of competitor drug (e.g., abiraterone vs. enzalutamide effcacy in the same disease setting); nor moving therapeutics into earlier stages of the disease in which the
therapeutic beneft is likely to be much greater.
The optimal development of studies with a higher effect
must consider targeting multiple critical targets; utilization
of improved technology, such as next generation sequencing;
and new preclinical models with the potential to develop
drug combinations and predictive biomarkers with analytic
validity and greater clinical utility. Although the chromosomal translocation of BCR and ABL in chronic myeloid leukemia has served as an effective biomarker for a molecularly
targeted therapy, it has become apparent that most other cancers have multiple driver alterations and adaptations thus requiring combinations of therapies for greater effectiveness.
As additional potential driver mutations are now identifed
in prostate cancer through enhanced diagnostic technologies, such as next generation sequencing, we have new opportunities to design multitargeted approaches, perhaps aided
by preclinical models to select best therapeutic combinations
for clinical trials.30-32 New models include the development
of patient-derived tumor xenograft (PDX) models that allow testing of targeted agents, resistance mechanisms, and
combinations in the preclinical setting in parallel with
clinical trials in patients.33 Recently, organoids have been
created from patients with prostate cancer, allowing the
potential for a novel preclinical model to test combination
therapy.34-36
Taken together, an overall paradigm to create higher effect
for value should include attention to (1) strong science that
identifes critical targets and combinations in preclinical
models; (2) optimization of combinations to target multiple
critical pathways preclinically and clinically, with more precise selection of patients most likely to beneft using improved diagnostics; and (3) consideration to timing of
therapy, with a rationale that therapy in earlier stages of disease may have more effect on outcome. A possible clue to the
potential success of using both a multitargeted strategy and
earlier introduction of therapy may be exemplifed by the recently reported National Cooperative Group study, which
study demonstrated improved survival by the concomitant
use of docetaxel chemotherapy and ADT as compared to
ADT only in patients with newly diagnosed metastatic prostate cancer.38 The magnitude of survival improvement with
early combination therapy (all patients, 57.6 vs. 44 months;
high-volume disease patients, 49.2 vs. 32.2 months, as initially reported at the American Society of Clinical Oncology
Plenary Session, 2014) represents multiples of those observed
with current approved therapies in mCRPC.
CONCLUSION
The landscape of therapy and biologic understanding of metastatic prostate cancer is infnitely better compared to a decade
ago, and it continues to evolve exponentially. However, the long
list of negative trials clearly underscores the need that therapy
development must focus on the totality of disease biology, including comprehensive molecular understanding of disease
states; thorough validation of candidate targets/pathways/biomarkers of response and resistance; and multitargeted approaches to maximize therapeutic effects.
As oncologists, we owe it to our patients to raise the bar for
future trials by requiring greater therapeutic effcacy; miniasco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
19
ACKNOWLEDGMENT
We thank Nina Bobowski, MPH, for assistance with manuscript writing, and Michael P. Kane, RPh.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Maha
Hussain, J&J, Synthon Biopharmaceuticals. Speakers Bureau: None. Research Funding: Maha Hussain, Astellas Pharma (Inst), Bayer (Inst), Genentech
(Inst), Medivation (Inst), Millennium (Inst), Pzer (Inst). Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel,
Accommodations, Expenses: None. Other Relationships: None.
References
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin.
2015;65:5-29.
2. Huggins C, Hodges CV. Studies on prostatic cancer I: the effect of castration, of estrogen and of androgen injection on serum phosphatases in
metastatic carcinoma of the prostate. Cancer Res. 1941;293-297.
3. Huggins C, Stevens RE, Hodges CV. Studies on prostate cancer II: the
effects of castration on advanced carcinoma of the prostate gland. Arch
Surg. 1941;209-223.
4. Alva A, Hussain M. The changing natural history of metastatic prostate
cancer. Cancer J. 2013;19:19-24.
5. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513-1520.
6. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or
mitoxantrone plus prednisone for advanced prostate cancer. N Engl
J Med. 2004;351:1502-1512.
7. Basch E, Loblaw DA, Oliver TK, et al. Systemic therapy in men with
metastatic castration-resistant prostate cancer: American Society of
Clinical Oncology and Cancer Care Ontario clinical practice guideline.
J Clin Oncol. 2014;32:3436-3448.
8. Debes JD, Tindall DJ. Mechanisms of androgen-refractory prostate cancer. N Engl J Med. 2004;351:1488-1490.
9. de Bono JS, Logothetis CJ, Molina A. Abiraterone and increased survival
in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005.
10. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in
prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197.
11. Choudhury Y, Yang Z, Ahmad I, et al. AMP-activated protein kinase
(AMPK) as a potential therapeutic target independent of PI3K/Akt signaling in prostate cancer. Oncoscience. 2014;1:446-456.
12. Goodwin JF, Schiewer MJ, Dean JL, et al. A hormone-DNA repair circuit governs the response to genotoxic insult. Cancer Discov. 2013;3:
1254-1271.
13. Humphrey PA, Zhu X, Zarnegar R, et al. Hepatocyte growth factor
20
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28. Azad AA, Eigl BJ, Murray RN, et al. Effcacy of enzalutamide following
abiraterone acetate in chemotherapy-naive metastatic castrationresistant prostate cancer patients. Eur Urol. 2015;67:23-29.
29. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371:10281038.
30. Tereshchenko IV, Zhong H, Chekmareva MA, et al. ERG and CHD1
heterogeneity in prostate cancer: use of confocal microscopy in assessment of microscopic foci. Prostate. 2014;74:1551-1559.
31. Brenner C, Ateeq B, Li Y, et al. Mechanistic rationale for inhibition of
poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell. 2011;19:664-678.
32. Beltran H, Rubin MA. New strategies in prostate cancer: translating
genomics into the clinic. Clin Cancer Res. 2013;19:517-523.
33. Risbridger GP, Taylor RA, Clouston D, et al. Patient-derived xenografts
reveal that intraductal carcinoma of the prostate is a prominent pathology in BRCA2 mutation carriers with prostate cancer and correlates
with poor prognosis. Eur Urol. Epub 2014 Aug 21.
34. Gao D, Vela I, Sboner A, et al. Organoid cultures derived from patients
with advanced prostate cancer. Cell. 2014;159:176-187.
35. Phillips R. Innovation: organoidsa better model for prostate cancer.
Nat Rev Urol. 2014;11:604.
36. Vela I, Chen Y. Prostate cancer organoids: a potential new tool for testing drug sensitivity. Expert Rev Anticancer Ther. 2015;15:261-263.
37. Sweeney C, Chen YH, Carducci MA, et al. Impact on overall survival (OS)
with chemohormonal therapy versus hormonal therapy for hormonesensitive newly metastatic prostate cancer (mPrCa): an ECOG-led phase III
randomized trial. J Clin Oncol. 2014;32:5s (suppl; abstr LBA2).
38. Truven Health Analytics. Red Book. http://micromedex.com/products/
product-suites/clinical-knowledge/redbook. Accessed December 4, 2014.
21
INVITED ARTICLES
DIAGNOSTICS
BIOMARKERS
The principle of identifying biomarkers to help guide patient
treatment has been a longstanding research initiative. Early
biomarkers and panels were largely classifed as prognostic or
predictive. They were not associated with a specifc biologic
therapy but rather defned the tumor characteristics, including response to therapy. Examples include Ki-67, carcinoembryonic antigen (CEA), and prostate-specifc antigen (PSA).
Breast cancer markers, such as hormone receptor status and
HER2, were some of the earliest markers related directly to
therapy. In lung cancer, validated markers associated with
therapy began with elucidating that EGFR mutations were
more prevalent in patients with adenocarcinoma, Asian ethnicity, and nonsmoking status and were correlated with high
activity of EGFR TKIs (geftinib, erlotinib, afatinib). However, more information was desired by researchers and treating physicians, and, more importantly, correlation with
specifc treatments was sought. Tumor registries were created to collect tissue and test utilizing evolving molecular
From the Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Edward S. Kim, MD, FACP, Levine Cancer Institute, Carolinas HealthCare System, 1021 Morehead Medical Dr., Charlotte, NC 28204; email: edward.kim@carolinashealthcare.org.
2015 by American Society of Clinical Oncology.
22
UMBRELLA TRIALS
DIRECTORS CHALLENGE CONSORTIUM
The Directors Challenge Lung Study comprises gene expression profles acquired on Affymetrix microarray chips from
more than 400 specimens of early-stage lung cancer, with associated clinical and pathologic annotation available to the
public for analysis.10 The investigators reported a large,
training-testing, multisite, blinded validation study to characterize the performance of several prognostic models based
on gene expression for 442 lung adenocarcinomas. The hypotheses proposed examined whether microarray measurements of gene expression, either alone or combined with
basic clinical covariates (stage, age, sex), could be used to predict overall survival in lung cancer subjects. Several models
examined produced risk scores that substantially correlated
with actual subject outcome. Most methods performed better
with clinical data, supporting the combined use of clinical
and molecular information when building prognostic models for early-stage lung cancer.10 This has not yet translated
into clinical practice, but highlighted that clinical information is still very important. This study also provides the largest available set of microarray data with extensive pathologic
and clinical annotation for lung adenocarcinomas.
BATTLE
My colleagues and I initiated the BATTLE trial (BiomarkerBased Approaches of Targeted Therapy for Lung Cancer
Elimination) in 2005. In the study, patients with previously
diagnosed and treated lung cancer underwent a new realtime biopsy to assess biomarkers. These biomarkers were
utilized in an adaptive manner to select treatment recommendations with one of several biologic agents. BATTLE was
conducted before any drugs were approved with companion
diagnostic biomarkers. The trial provided an important
proof of principle that repeat biopsies could be performed
safely and expeditiously in patients who were previously
treated for lung cancer.11 Subsequent BATTLE trials have
been initiated based on our initial trial.
23
EDWARD S. KIM
Title
Cancer Types
Treatment
Biomarkers
Biomarker-Integrated
Approaches of Targeted
Therapy for Lung Cancer
Elimination
BATTLE
250
Non-small cell
lung
BATTLE-2 Program: A
Biomarker-Integrated
Targeted Therapy Study
BATTLE-2
450
Non-small cell
lung
Lung-MAP
Southwest Oncology
Group
2014-2022
Up to 10,000
screened
Squamous cell
lung
I-SPY1
National Cancer
Institute
2002-2010
356
I-SPY2
QuantumLeap
Healthcare
Collaborative
2010-2015
800
NCI MATCH
National Cancer
Institute
Opening early
2015
Up to 3,000
screened for
biomarkers,
approximately
1,000 treated
Advanced solid
tumors,
lymphoma
Advanced
cancers
None
Approximately
5,000
Molecular Proling-Based
Assignment of Cancer
Therapeutics
NCI MPACT
National Cancer
Institute
2014-2017
Temozolomide, everolimus,
carboplatin, trametinib
DMSO, ABT-888, MK-1775
ALCHEMIST
National Cancer
Institute
2014-2020
Up to 8,000
screened
Erlotinib hydrochloride,
crizotinib
EGFR, ALK
Early-stage
non-small
cell lung
screening trial and two treatment trials (EGFR-targeted therapies and ALK-targeted therapies). Approximately 6,000 to
8,000 patients will be enrolled in the screening trial over the
next 5 to 6 years with the goal of determining if selection of
therapy based on these molecular markers leads to improved
survival. Tumor biopsies from these patients will be evaluated
for EGFR and ALK abnormalities. Patients whose tumors harbor one of these mutations will be directed into the appropriate
biologic treatment trial (erlotinib if EGFR is mutated and crizotinib if ALK is abnormal vs. placebo). Each treatment trial is expected to enroll approximately 400 patients.13
ALCHEMIST
The NCI has launched initiatives to study patients with
unique biomarkers and targeted therapy in both early- and
advanced-stage cancer settings. The Adjuvant Lung Cancer
Enrichment Marker Identifcation and Sequencing Trial
(ALCHEMIST) series is focused on patients diagnosed with
early-stage lung cancer. The series of trials consists of a
24
MASTER STUDIES
NCI MATCH
Another NCI-sponsored study, NCI MATCH (The NCI Molecular Analysis for Therapy Choice Trial), will enroll patients with advanced solid tumors (gastrointestinal stromal
tumor, NSCLC, breast, gastric, melanoma, thyroid) and lym-
phomas. Biopsies from approximately 3,000 patients will undergo testing for abnormalities that may respond to targeted
drug therapies. Of these patients, up to 1,000 will then participate in phase II clinical trials of targeted drug therapies.
The patients will be matched to the drug based solely on the genetic abnormality, not on the type of cancer. NCI MATCH is a
master trial, meaning that new drugs can be added to the trial at
any time. The primary endpoint for this trial is response, however, progression-free survival will also be assessed.14
A new public/private cooperative effort is Lung-MAP
(Lung Master Protocol). This study will enroll 500 to 1,000
patients diagnosed with advanced, previously treated squamous cell lung cancer each year. The molecular profling is
done with a central commercial panel and places patients
into different arms with biologic therapies. One feature of
this study is that patients who do not meet the criteria for
treatment with a targeted therapy are placed into a trial involving a nontargeted investigational treatment. The primary objective of this trial is to determine if the effcacy of
targeted therapy is better than that of standard therapy.15
M-PACT
In the NCI-sponsored M-PACT (Molecular ProflingBased
Assignment of Cancer Therapeutics trial), patients with advanced tumors that have progressed on at least one line of
standard therapy undergo tumor biopsy to determine if a
mutation is present. Those who do not have an identifable
mutation are removed from the trial. Those who do have
a mutation are randomly assigned to receive either treatment
with a drug known to target their mutation or treatment with
a drug not known to target their mutation. Cross-over is allowed for those who experience disease progression after receiving treatment with a drug not known to target their
mutation. Tumor response and 4-month progression-free
survival are the endpoints in this trial. Accrual to this trial
began in 2014 and approximately 700 patients are expected to
be screened, with over 150 to be enrolled in a treatment arm.
The goal is to determine whether therapies targeting a mutation can work in the metastatic setting.16
There is a need to test the approach in different settings,
leading to many umbrella and master studies required to answer the overarching question of whether therapies targeting
molecular aberrations lead to better outcomes for patients over
standard chemotherapy, and in what types of patients, tumors,
or aberrations these treatments work (or do not work). The importance of these efforts is not only the testing of the specifc
targeted therapies, but the collection and storage of centralized
tissue and molecular data. These collections will allow large
amounts of data to be analyzed with the hope of someday developing predictive treatment models for patients.
BIG DATA
Big data is defned as any voluminous amount of structured,
semi-structured, and unstructured data that has the potential
to be mined for information. More specifcally, big data is any
data whose scale, diversity, and complexity require new architecture, techniques, algorithms, and analytics to manage it
as well as to extract value and hidden knowledge from it. Big
data expands across four fronts: velocity, variety, volume,
and veracity (Table 2).17,18
Capturing big data in databases may help formulate hypotheses for testing. Statistical testing can be performed on preexisting data to facilitate this process. However, big data
collection can be compromised by bias in medical records, lack
of data validity and reliability, and technology challenges. The
potential for misinterpretation of the data is paramount. Additionally, the structure of electronic medical records may be
poorly suited for adequate data abstraction and are certainly not
suited for numerous secondary analyses. Many institutions also
have different platforms, which can impede data integration.
Attention to privacy, sharing, transparency, and stewardship are
all guiding principles for big data collection and analysis.
Medicine, specifcally cancer medicine, is encountering
this dilemma. As the amount of information exponentially
increases (patient clinical information, pathology, biomarkers, treatment outcomes, and patient questionnaires), the
prospect of harnessing and processing this data is daunting.
However, the potential rewards make it worth the effort. Numerous companies and researchers are working to integrate
and interrogate these data sets with expectations that they
will identify new opportunities for treatment, diagnosis,
prognosis, and prevention. Nontraditional groups are joining the foray into this area, including Google and fnancial
institutions, because of their ability to collect a variety of data
on inordinately large numbers of individuals and variables
(e.g., search, purchasing, and other behaviors).
ASCO CANCERLINQ
The American Society of Clinical Oncology (ASCO) has
established an important initiative called CancerLinQTM
(www.CancerLinQ.org), a health information technology
Description
Velocity
Variety
Volume
Veracity
25
EDWARD S. KIM
platform that plans to collect information from the experiences of patients with cancer. The goal of this big data collection will be to improve the quality and value of cancer care.
Data will be collected from the electronic health records of
patients across the United States and will be restructured and
stored into one single database that will be able to provide
clinical decision-making support for health care providers.
The information from patients and providers will be continuously collected, thus enabling further refnement of the
decision-making algorithm. ASCO has currently created a
prototype platform and has initiated 15 practice sites to collect data from over 500,000 patient experiences.19
Big data projects like CancerLinQ include strategic, technical, and regulatory challenges, but ASCO has established a
robust external advisory structure to guide its development.
An example of clinical utility could be in immunotherapy
treatment. As melanoma, renal cell, and lung cancer have immunotherapy as treatment options, harnessing numerous
patient encounters and clinical data could create guidance for
clinicians in managing not only the disease process, but also
side effects from the treatment. This type of data would be
valuable in helping predict responders and nonresponders,
perhaps predict who will experience side effects, and more
importantly, help keep patients on treatment longer, which
may translate into better survival and quality of life.
CONCLUSION
The era of personalized medicine continues at a rapid pace.
The practice of medicine now requires not only a clinical
examination, but also molecular testing, novel therapeutics, research trial awareness, and perhaps utilization of
information obtained from big data in the near future. Integration of these tools will enable providers to deliver better, more comprehensive care. Much work still needs to be
performed, and more tools needs to be developed and refned, to help providers and clinicians achieve the best
results.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Edward Kim, Myriad Genetics, Eli Lilly, Celgene.
Consulting or Advisory Role: Edward Kim, Myriad Genetics, Eli Lilly, Celgene. Speakers Bureau: None. Research Funding: Edward Kim, Lilly. Patents,
Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl
J Med. 2002;346:92-98.
2. Masters GA, Krilov L, Bailey HH, et al. Clinical Cancer Advances 2015:
Annual Report on Progress Against Cancer from the American Society
of Clinical Oncology. J Clin Oncol. 2015;33:786-809.
3. Mok TS, Wu YL, Thongprasert S, et al. Geftinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947957.
4. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as frst-line treatment for European patients with advanced EGFR
mutation-positive non-small-cell lung cancer (EURTAC): a multicentre,
open-label, randomised phase 3 trial. Lancet Oncol. 2012;13:239-246.
5. Yang JC, Shih JY, Su WC, et al. Afatinib for patients with lung ade-
26
6.
7.
8.
9.
10. Shedden K, Taylor JM, et al. Directors Challenge Consortium for the
Molecular Classifcation of Lung Adenocarcinoma. Gene expressionbased survival prediction in lung adenocarcinoma: a multi-site, blinded
validation study. Nat Med. 2008;14:822-827.
11. Kim ES, Herbst RS, Wistuba II, et al. The BATTLE trial: personalizing
therapy for lung cancer. Cancer Discov. 2011;1:44-53.
12. I-SPY 2 Trial. http://www.ispy2trial.org. Accessed February 2,
2015.
13. National Cancer Institute. ALCHEMIST (The Adjuvant Lung Cancer
Enrichment Marker Identifcation and Sequencing Trials): Question
and Answers. http://www.cancer.gov/newscenter/newsfromnci/2014/
ALCHEMISTlaunchQandA. Accessed February 2, 2015.
14. National Cancer Institute. NCI Molecular Analysis for Therapy Choice
Program (MATCH) & Pediatric MATCH. http://www.cancer.gov/
clinicaltrials/noteworthy-trials/match. Accessed February 2, 2015.
15. Lung-MAP. http://www.lung-map.org.Accessed February 2, 2015.
16. NCI launches trial to assess the utility of genetic sequencing to improve
patient outcomes. Retrieved February 2, 2015 from http://www.nih.gov/
news/health/jan2014/nci-30.htm.
17. Bellazzi R. Big data and biomedical informatics: a challenging opportunity. Yearb Med Inform. 2014;9:8-13.
18. Wigmore I, Rouse M. 3Vs (volume, variety, and velocity). http://
whatis.techtarget.com/defnition/3Vs. Accessed February 19, 2015.
19. American Society of Clinical Oncology. ASCO CancerLinQ: Learning
Intelligence Network for Quality. http://cancerlinq.org. Accessed February 2, 2015.
20. Collins FS, Varmus H. A new initiative on precision medicine. N Engl
J Med. 2015;372:793-795.
21. Offce of the Press Secretary. The White House. Fact Sheet: President
Obamas Precision Medicine Initiative. http://www.whitehouse.gov/
the-press-offce/2015/01/30/fact-sheet-president-obama-s-precisionmedicine-initiative. Accessed February 19, 2015.
27
INVITED ARTICLES
From the Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, CA; Moores Cancer Center, University of California San Diego, La Jolla, CA.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Ezra E.W. Cohen, MD, Moores Cancer Center, University of California San Diego, 3855 Health Sciences Drive, #0658, La Jolla, CA 92093; email: ecohen@ucsd.edu.
2015 by American Society of Clinical Oncology.
28
negative counterparts.11 Underlying these differences in clinical phenotypes are distinct molecular characteristics of
HPV-positive and HPV-negative tumors.12 Gene expression
studies have pointed to subtypes of the disease with different
clinical and molecular characteristics. A recent analysis
based on four discovery cohorts and two independent validation datasets classifed HNSCC into three super groups
called inflamed/mesenchymal (IMS), basal (BA), and classical (CL) based on previously used nomenclature.12 Interestingly, HPV-positive tumors fell into only two of these groups
(IMS and CL), whereas the BA group consisted exclusively of
HPV-negative cancers. Furthermore, the classifcation appears to be prognostic for overall survival even within the
HPV-positive tumors where the IMS HPV-positive group,
enriched for immune-related genes, had the best outcome.
TP53 mutations were shown to be exclusive to HPV-negative
tumors, presumably as a result of the phenocopying effect of E6
viral protein-mediated TP53 degradation. Similarly, whereas
CDKN2A has been shown to be affected by copy number losses
or mutations to the coding sequences of the gene, this was not
seen in HPV-positive tumors as a result of its inactivation by the
E7 viral protein. Other notable differences are seen in kinases
that could be potential targets for therapy including more frequent mutation of PIK3CA and FGFR 2/3 in HPV-positive tumors contrasted with amplifcation of EGFR, FGFR1, and
CCDN1 seen exclusively in HPV-negative tumors.12-13
In tumors lacking HPV infection, long-term studies of
TP53 mutation have shown that its presence is associated
with poor outcomes, an effect that seems to be accentuated by
the functional effect of the mutation. Recent work by Gross et
al looking across multiple data-layers has refned the interpretation of TP53 mutations by showing that they usually cooccur with loss of the 3p chromosomal region and that the
adverse prognostic effect coincides with the combinations of
the two events.14 The putative gene(s) on 3p have yet to be
fully elucidated but one candidate is FHIT, which functions
as a tumor suppressor and has been linked with radiosensitivity, perhaps explaining its key role in HNSCC.15
FIGURE 1. Schematic of the Precision Medicine Paradigm on the (A) Population and (B) Individual Patient Levels
A
Population Level
Data Warehouses
Diagnostics
- gene mutation panels
- whole-exome sequencing
- gene/mirna expression panels
- tumor grade/stage
- tumor location
- HPV status/strain
- risk behaviors
- genetic susceptibility
- alcohol/tobacco use
- HPV vaccination status
- molecular heterogeneity
Synthesizing Platforms
- Flatiron Health
- NexBio
- IBM Watson Oncology
Clinical
Phenotype
+ treatment
Disease Understanding
Outcome
Re-evaluate at disease persistance
or recurrence
29
treatments are poor, such large numbers of patients will facilitate better development and deployment of the next generation
of cancer drugs, and provide patients and their physicians with a
much more precise diagnosis of their disease.
SMARTER OUTCOMES
It remains unclear whether a tumors molecular characteristics
will remain static throughout treatment or alter throughout
therapy. The relative accessibility of HNSCC tumors should allow for exquisite tracking of the characteristics of a patients tumor but has been underutilized thus far. Small studies have been
able to demonstrate target inhibition or pharmacodynamic effects of a drug, but exploration of new models and protocols for
adaptive treatment regimens has yet to be assessed.
The incorporation of targeted therapy will change how we
approach initial therapy and assess drug resistance. Combinations of drugs may be developed to preemptively silence
resistance pathways.25 Although the use of single targeted
drugs may attack a key feature or vulnerability of the tumor, it
is likely that a more detailed understanding of a patients tumor
and the specifc pathways being altered will be necessary for effective combinatorial targeting. Even if a patient is likely to develop resistance, if it is predictable and its manifestation has its
own treatment strategy, multistage treatment plans with careful
planning and monitoring may be in order. Making these alternative treatment paradigms a reality will require a wide range of
advancements such as better tissue biopsies or noninvasive
measurements of tumor DNA from blood to track the molecular makeup of the tumor, as well as faster experimental and analytic pipelines for ensure timely treatment.
Alongside genomic advancements, the digitization of medical records will also allow for rich recording of patient outcomes past the standard metrics of progression-free interval
and overall survival. Alternative metrics such as patient heart
rate, activity levels, and sleep quality will be measured by specialized and/or consumer sensors, bands, and watches. Such
rich measurements will be aggregated and used to inform
treatment by allowing for unbiased understanding of the effects of a treatment on quality of life.26
the war on cancer. However, signifcant hurdles remain before big data can be translated into better outcomes for patients with cancer. Determining which elements of big data
are biologically and clinically relevant will require the development of new analysis methods, changes in clinical trial design, new infrastructure for data sharing, and, perhaps most
importantly, close collaboration between bioinformaticists,
oncologists, and the pharmaceutical industry.
ACKNOWLEDGMENTS
We would like to thank John Paul Shen for thoughtful review.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Ezra Cohen,
Eisai, AstraZeneca, Bristol-Myers Squibb, Merck, VentiRx, Novartis, Bayer. Speakers Bureau: Ezra Cohen, Bayer, Blodesix. Research Funding: None.
Patents, Royalties, or Other Intellectual Property: Andrew Gross, Patents, etc. (Provisional patient, Iterative Feature Selection for the Development
of Prognostic Models)(Inst). Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Halevy A, Norvig P, Pereira F. The unreasonable effectiveness of data.
IEEE Intelligent Systems. 2009;24:8-12.
2. Carneiro HA, Mylonakis E. Google trends: a web-based tool for realtime surveillance of disease outbreaks. Clinical Infectious Diseases. 2009;
49:1557-1564.
3. Lazer D, Kennedy R, King G, Vespignani A. Big data. The parable of
Google Flu: traps in big data analysis. Science. 2014;343:1203-1205.
4. Ogden GR, Kiddie RA, Lunny DP, Lane DP. Assessment of p53 protein
expression in normal, benign, and malignant oral mucosa. J Pathol.
1992;166:389-394.
5. Califano J, van der Riet P, Westra W, et al. Genetic progression model
for head and neck cancer: implications for feld cancerization. Cancer
Res. 1996;56:2488-2492.
6. Grandis JR, Tweardy DJ. Elevated levels of transforming growth factor
alpha and epidermal growth factor receptor messenger RNA are early
markers of carcinogenesis in head and neck cancer. Cancer Res. 1993;
53:3579-3584.
7. Stransky N, Egloff AM, Tward AD, et al. The mutational landscape of
head and neck squamous cell carcinoma. Science. 2011;333:1157-1160.
8. Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517:576582.
9. Sepiashvili L, Bruce JP, Huang SH, et al. Novel insights into head and
neck cancer using next-generation omic technologies. Cancer Res.
2015;75:480-486.
10. Hammerman PS, Hayes DN, Grandis JR. Therapeutic insights from
genomic studies of head and neck squamous cell carcinomas. Cancer
Discovery. (2015). doi:10.1158/2159-8290.CD-14-1205.
11. DSouza G, Kreimer AR, Viscidi R, et al. Case-control study of human
papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356:
1944-1956.
12. Seiwert TY, Zuo Z, Keck MK, et al. Integrative and comparative
13.
14.
15.
16.
17.
18.
19.
20.
21.
31
22. Ratner M. Pharma partners with efforts to pool patient genotype and
phenotype data. Nature Biotechnology. 2014;32:967.
23. Genomics England. NHS Genomic Medicine Centres announced for
100,000 Genomes Project. Press release, December 22, 2014. http://
www.genomicsengland.co.uk/genomic-medicine-centres/.
24. Global Alliance. Creating a global alliance to enable responsible
sharing of genomic and clinical data. White paper, June 3, 2013.
32
http://genomicsandhealth.org/about-the-global-alliance/keyabout-the-global-alliance/key
25. Sawyers CL. Perspective: combined forces. Nature. 2013;498:
S7-S7.
26. Abernethy A, Abrahams E, Barker A, et al. Turning the tide against cancer through sustained medical innovation: the pathway to progress. Clin
Cancer Res. 2014;20:1081-1086.
INVITED ARTICLES
PROFESSIONAL DEVELOPMENT
From the Vanderbilt University School of Medicine, Nashville, TN; University of California Davis School of Medicine, Sacramento, CA; Vanderbilt University School of Medicine, Nashville, TN.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Jill Gilbert, MD, Vanderbilt University School of Medicine 2220 Pierce Ave., 777PRB, Nashville, TN 37232; email: jill.gilbert@vanderbilt.edu.
2015 by American Society of Clinical Oncology.
33
GILBERT ET AL
Outputs
Mentorship
Faculty time
Networking community
Educators in leadership
development
Funding
tural/ethnic background, trainee discussing informed consent with a patient with low literacy level, etc. The trainee is
then judged based on an entrustment scale that describes the
level of trust that the trainee can carry out the given activity
competently and independently. For example, the trainee
can perform the skill with distant supervision, the trainee can
perform the skill with direct supervision, the trainee is aspirational and can teach this skill to others. This gives the faculty a more grounded view of how to evaluate trainees to
ascertain clinical competence in an area of emphasis in
modern-day medicine/health care. However, activities need
to be prescribed that allow observable behaviors to ensue.
Trainees will be evaluated on a trajectory of competence
and should demonstrate progress, not perfection, as they
advance toward independent practice. However, the question remains how is the behavior measured or observed to
accurately place the trainee on a milestone trajectory? Additionally, what activities meet the millennial learner
right where they are and, thus, provide a meaningful educational experience? To meet these challenges, educators
need to cultivate and employ new assessment strategies.
Some of these new processes are described below and
placed in context of the aforementioned milestone.
In order to ground milestones in observable behavior, programs are encouraged to develop entrustable professional activities (EPAs) for each rotation. EPAs are units of
professional practice that can be performed (and observed by
faculty) with increasing autonomy and decreasing supervision over time.26,27 Think of EPAs as essential goals to achieve
over training. For instance, on the ward service, a trainee
should know how to manage febrile neutropenia and conduct a family meeting; on the hematology consult rotation, a
trainee should accurately interpret a peripheral blood smear;
in their continuity clinic, a trainee should recognize and
manage the toxicities associated with chemotherapy. EPAs
can inform multiple competencies as noted in Table 2. The
ASSESSMENT STRATEGIES
Direct Observation
Direct observation provides the most accurate assessment of
a learner and provides the opportunity for immediate feedback. Direct observation removes the biases of hearsay, selective recall, or forgetting details that are common in global
end-of-rotation ratings. One of the limitations of direct observation is that the rater may observe the learner in only a
fraction of their working hours. Direct observation should be
made by multiple observers on many occasions, and these
should be reviewed by the training programs competency
committee.
ACGME Competencies
PC
MK
PBL
SBP
ICS
35
GILBERT ET AL
TEACHING STRATEGIES
Lets return to the milestone mentioned previously: Responds to each patients unique characteristics and needs.
Although the faculty member might globally note that a
trainee is professional, has the evaluator actually witnessed
the trainee communicating with the patient in a culturally
competent manner and is the trainee able to involve the patient in his or her own care? Although this may occur in the
course of clinic or ward duties, it is recognized that such opportunity may not regularly occur. Educators could use simulation/standardization training to inform this milestone in a
structured encounter where the trainee discusses end-of-life
issues with a patient from a different ethnic or socioeconomic
backgrounds. Although this may occur in the course of training, this structured activity allows trained evaluators to observe these behaviors, and provide direct feedback (from
both patient and evaluator) immediately at the point of interaction. Examples of such SP/simulation examples to teach
this skill can be seen in Table 3.
Trainees would rotate through each example in a half-day
session devoted to development of these communication
skills. On a resource level, several items will be required including space, funding, faculty who are trained and willing to
develop scripts for SP, training for the SP, faculty trained in
communication skills and observation to observe and provide direct feedback (ideally several faculty members), and
faculty and trainee time to perform these activities. The
ACGME now mandates all programs to participate in training using simulation. Thus, the onus remains on the medical
educator to plan and perform activities that meet the needs of
the learners at each institution.
Standardized
Patient 2:
Standardized
Patient 3:
E-Learning
E-learning is a unique pedagogy in which Internet technology is used to enhance learner knowledge and performance.36 Educational content delivered via e-learning is
rapidly revolutionizing medical education and health care
delivery. Educational websites, virtual patient simulations,
online problem-based learning, podcasts, and interactive
multimedia tutorials are all forms of e-learning.36,37 Alur et al
describe a blueprint for educating health professionals
through e-learning that necessitates the development of an
educational website that acts as a medium for sharing information while encouraging active learning, critical thinking,
and independent and evidence-based learning by the
learner.38 A study evaluating 112 teaching websites in North
America, the United Kingdom, and Australia found only
17% of websites ascribed to these principles.38
When used appropriately e-learning applications can enhance the effciency and effcacy of educational interventions,39 and basic science and clinical educators have begun
using e-learning as adjuncts or replacements to traditional
in-person courses. E-learning has the capability to result in effective learning, but also offers benefts that a traditional classroom may not offer. These benefts include effciency,40,41
flexible scheduling,40,41 and customized feedback.42 In addition, e-learning programs can be designed with hyperlinks
that allow learners to independently research information
and broaden their search to related topics. These attributes
are particularly useful in the self-directed, problem-based
learning environment, which is valued by practicing physicians. In addition, e-learning is able to overcome barriers of
physical distance, allows unlimited viewers and viewing, is
easily updated, and allows retention and transfer to new
settings.40-42 Barriers to the use of e-learning include lack of
time for the user, dissatisfaction with speed of the medium,
technology problems, student support issues, and instructional design.43,44
A prior meta-analysis demonstrated that e-learning leads
to greater learning than no learning.45 E-learning also has
similar levels of participant satisfaction and equal or greater
improvement in knowledge and skills acquisition compared
with traditional in-person learning methods.45,46 Prior studies regarding learning have shown that integration of new
material into the learners previous subject knowledge may
be advantageous and result in effective learning.47,48 Cook
and Dupras49 identifed key elements required to develop an
effective educational website including performing a needs
analysis and specifying goals and objectives, determining
technical resources and needs, evaluating and using preexisting software, securing commitment from participants to
identify potential barriers to implementation, developing
content in close coordination with Web design, encouraging
active learning, self-reflection and use by the learner, evaluating the learner and the course, piloting the site, and monitoring the site. Harden and Laidlaw describe the CRISIS
model for developing effective continuing medical education. In their model they describe convenience, relevance, individualization, self-assessment, independent learning, and
systematic.50 These frameworks are being used in the development of e-learning modules to ensure best practice.50
Social Media
Social media has changed the way information is communicated and disseminated. Examples include podcasts, Twitter,
and networking communities such as LinkedIn. Podcasting
is a form of asynchronous learning where the learner can
tune in at their own convenience and listen to talks or discussions. The American Society of Clinical Oncology (ASCO),
as an example, uses podcasts where key Journal of Clinical
Oncology articles are discussed, allowing the reader not only a
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
37
GILBERT ET AL
greater understanding of the study results, but how these results can be applied in their daily practice. Training programs
can incorporate podcasts into their curriculum in a similar
fashion. Twitter allows subscribers to send brief updates on topics they believe are important to their followers. An example of a
recent tweet is What are the treatment paradigms for prostate
cancer? that serves as a notice for an upcoming tumor board on
ASCO University. ASCO members can tweet on interesting
fndings that are published or presented at meetings. Networking communities such as LinkedIn or Doximity allow health
care professionals to connect with one another and industry
partners, view new job postings or promotions, or connect with
communities of liked-minded individuals online.
CONCLUSION
With all these changes, this is an exciting time in medical education. With new teaching and assessment strategies and all
the technology available to the educator, we can now only ask
How could Tinsley Harrison do it differently? We are
teaching a new generation of students who have the Internet
at their fngertips and an application for every indication. In
our changing health care environment, with limited duty
hours, busy clinics, and overflowing hospitals, adaptation of
new assessment strategies and novel teaching strategies will
allow for a generation of physicians who may not think like
Harrison, but will continue to deliver outstanding patient
care.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Leora Horn,
Xcovery, Bayer, Merck, PUMA, Clovis, Helix Bio, Bristol-Myers Squibb. Speakers Bureau: None. Research Funding: Leora Horn, Astellas. Patents, Royalties,
or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: Leora Horn, Boehringer Ingelheim. Other
Relationships: None.
References
1. Pittman JA. Tinsley Harrison, M.D.: Teacher of Medicine. Montgomery,
AL: New South Books; 2015.
2. Ludmerer KM. Time to Heal: American Medical Education from the
Turn of the Century to the Turn Era of Managed Care. New York: Oxford
University Press; 1999.
3. Anderson KT. Tinsley Randolph Harrison, MD: a legacy of medical education. Pharos Alpha Omega Alpha Honor Med Soc. 2010;73:4-10.
4. Nasca TJ, Heard JK, Philibert I, Brigham, et al. Commentary: the
ACGME: public advocacy before resident advocacy. Acad Med. 2009;84:
293-295.
5. McLean M, Cilliers F, Van Wyk JM. Faculty development: yesterday,
today and tomorrow. Med Teach. 2008;30:555-584.
6. Steinert Y, Mann K, Centeno A, et al. A systematic review of faculty
development initiatives designed to improve teaching effectiveness in
medical education: BEME Guide No. 8. Med Teach. 2006;28:497-526.
7. Wilkerson L, Irby DM. Strategies for improving teaching practices: a
comprehensive approach to faculty development. Acad Med. 1998;73:
387-396.
8. Searle NS, Hatem CJ, Perkowski L, et al. Why invest in an educational
fellowship program? Acad Med. 2006;81:936-940.
9. Cooke M, Irby DM, Debas HT. The UCSF Academy of Medical Educators. Acad Med. 2003;78:666-672.
10. Frohna AZ, Hamstra SJ, Mullan PB, et al. Teaching medical education
principles and methods to faculty using an active learning approach: the
University of Michigan Medical Education Scholars Program. Acad
Med. 2006;81:975-978.
11. Gruppen LD, Simpson D, Searle NS, et al. Educational fellowship programs: common themes and overarching issues. Acad Med. 2006;81:
990-994.
12. Hitchcock MA, Stritter FT, Bland CJ. Faculty development in health
38
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40. Cook DA, Dupras DM. Teaching on the web: automated online instruction and assessment of residents in an acute care clinic. Med Teach.
2004;26:599-603.
41. Campbell M, Gibson W, Hall A, et al. Online vs. face-to-face discussion
in a Web-based research methods course for postgraduate nursing students: a quasi-experimental study. Int J Nurs Stud. 2008;45:750-759.
42. Cook DA. Web-based learning: pros, cons and controversies. Clin Med.
2007;7:37-42.
43. Casebeer L, Bennett N, Kristofco R, et al. Physician Internet medical
information seeking and on-line continuing education use patterns.
J Contin Educ Health Prof. 2002;22:33-42.
44. Mills ME, Fisher C, Stair N. Web-based courses. More than curriculum.
Nurs Health Care Perspect. 2001;22:235-239.
45. Cook DA, Levinson AJ, Garside S, et al. Internet-based learning in the
health professions: a meta-analysis. JAMA. 2008;300:1181-1196.
46. Fordis M, King JE, Ballantyne CM, et al. Comparison of the instructional effcacy of Internet-based CME with live interactive CME workshops: a randomized controlled trial. JAMA. 2005;294:1043-1051.
47. Cook DA. The failure of e-learning research to inform educational practice, and what we can do about it. Med Teach. 2009;31:158-162.
48. Clark D. Psychological myths in e-learning. Med Teach. 2002;24:598604.
49. Cook DA, Dupras DM. A practical guide to developing effective webbased learning. J Gen Intern Med. 2004;19:698-707.
50. Harden RM, Laidlaw JM. Effective continuing education: the CRISIS
criteria. Med Educ. 1992;26:408-422.
51. Prober CG, Heath C. Lecture halls without lectures-a proposal for medical education. N Engl J Med. 2012;366:1657-1659.
52. Belf LM, Bartolotta RJ, Giambrone AE, et al. Flipping the introductory clerkship in radiology: impact on medical student performance and
perceptions. Acad Radiol. Epub 2015 Jan 13.
53. Morgan H, Marzano D, Lanham M, et al. Preparing medical students for
obstetrics and gynecology milestone level one: a description of a pilot
curriculum. Med Educ Online. 2014;19:25746.
54. Young TP, Bailey CJ, Guptill M, et al. The flipped classroom: a modality
for mixed asynchronous and synchronous learning in a residency program. West J Emerg Med. 2014;15:938-944.
39
INVITED ARTICLES
GASTROINTESTINAL CANCER
From The University of Texas MD Anderson Cancer Center, Houston, TX; Stanford University School of Medicine, Stanford, CA.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Cathy Eng, MD, FACP, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; email: ceng@mdanderson.org.
2015 by American Society of Clinical Oncology.
40
41
ENG ET AL
colorectal cancer. Indeed there are plans to open an NCIsponsored ASSIGN trial to test targeted agents in molecular
subsets as second-line therapy of metastatic colon cancer. Although critically important to fnding and validating new targeted agents for colorectal cancer, the diffculty in getting
such a trial activated is daunting and would still leave the
many other GI sites lacking this level of trial access.
Although studies have shown that the cost of care for patients in cancer clinical trials is not substantially greater than
the costs of routine care, insurance16 companies have not
universally embraced clinical trials as a component of standard care for patients with cancer. Legislative efforts such as
SB37 in California have mandated that insurers pay for the
routine care costs for patients to participate in a clinical trial
and cannot deny access to a trial. However, loopholes exist.
Nearly 30% of California adults are uninsured, which makes
us hopeful that ACA will provide coverage for and access to
clinical trials for those who were previously uninsured.
In the 2014 ASCO Educational Book, the use of social media
to improve clinical trial accrual was discussed.17 Another creative use of the Internet is crowd sourcing for feedback on
how to improve the design and accrual of a particular clinical
trial. Leiter et al18 used a Web-based platform that allowed
participants to comment on the design of a clinical trial using
metformin in prostate cancer. Hyperlinks were posted to social networking sites. The platform was available for 6 weeks,
and this crowd-sourcing exercise resulted in 9 changes to the
protocol, 4 of which were major changes. Certainly the potential of the Internet and social media to improve awareness
of and accrual to trials remains relatively untapped.
Patient advocacy groups may positively influence clinical trial
accrual. The Pancreatic Cancer Action Network (PANCAN)
has reported that although only 3% of patients with pancreatic cancer in the United States enroll in trials, 16% of those
patients have called a help line to participate in clinical trials.
Although an obvious selection bias favors patients and families who want more information, we would contend that the
effect is real and that PANCANs advocacy for trials has an
effect, even if not fve-fold in magnitude. Sadly there are relatively few support groups for other GI sites and none of the
size and fnancial power of those for breast and prostate cancer. However, if there could be a coalition of GI-minded advocacy groups to make clinical trial accrual a priority, we
CONCLUSION
As academic oncologists, we know how rigorous the scientifc methodology must be to prove a treatment is benefcial.
As a community of providers, patients and families, we know
all too well the emotional and physical toll a cancer diagnosis
takes. The price of neglect is too high. Together we must fnd
ways to increase access, improve design, and speed completion of clinical trialsfor the good of all.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: George Fisher, Seattle Genetics (I). Honoraria: Cathy Eng, Sano,
Roche, Lilly. Consulting or Advisory Role: George Fisher, Genentech. Cathy Eng, Roche/Genentech, Bayer Schering Pharma. Nancy Roach, Genentech.
Speakers Bureau: None. Research Funding: George Fisher, Celgene (Inst), Novartis Pharmaceutical Group (Inst), Tercica (Inst), Bristol-Meyers Squibb
(Inst), Newlink Genetics (Inst), Medivation (Inst), Pharmaceutical Research Associates (Inst), Polaris Group (Inst), Eli Lilly (Inst), PRA International (Inst),
XBiotech (Inst), Bristol-Meyers Squibb (Inst), Tercica (Inst), Novartis, Celgene. Cathy Eng, Keryx, ArQule. Patents, Royalties, or Other Intellectual
42
Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: George Fisher, Genentech/Roche. Nancy Roach, Millenium, Genentech.
Other Relationships: None.
References
1. Murthy VH, Krumholz HM, Gross CP. Participation in cancer clinical trials: race-, sex-, and age-based disparities. JAMA. 2004;291:
2720-2726.
2. Ries LAG, Harkins D, Krapcho M, et al (eds). SEER Cancer Statistics
Review, 1975-2003. http://seer.cancer.gov/archive/csr/1975_2003/.
Accessed March 1, 2015.
3. Al-Refaie WB, Vickers SM, Zhong W, et al. Cancer trials versus the real
world in the United States. Ann Surg. 2011;254:438-442.
4. Lavarreda SA, Brown ER, Cabezas L, et al. Number of uninsured jumped
to more than eight million from 2007 to 2009. Policy Brief UCLA Cent
Health Policy Res. 2010;(PB2010-4):1-6.
5. Sinha G. United Kingdom becomes the cancer clinical trials recruitment
capital of the world. J Natl Cancer Inst. 2007;99:420-422.
6. Cancer Research UK. Over 60,000 cancer patients enrolled on clinical
trials in the UK last year. http://www.cancerresearchuk.org/content/
over-60000-cancer-patients-enrolled-on-clinical-trials-in-the-uk-lastyear. Accessed March 11, 2015.
7. American Society of Clinical Onoclogy. Insurance Coverage for Clinical
Trial Participants. http://www.asco.org/insurance-coverage-clinicaltrial-participants. Accessed March 2015.
8. Tepper JE. Gastrointestinal Cancers and the Cooperative Groups - 2011.
Gastrointest Cancer Res. 2012;5(3 suppl 1):S1-S3.
9. Doroshow JH, Friedman S. National Cancer Institute. Clinical Trial Activation Timelines: Update on Implementation of the Operational Effciency Working Group Recommendations. http://deainfo.nci.nih.gov/
advisory/ctac/1210/presentations/OEWG.pdf. Accessed March 8, 2015.
10. National Institutes of Health. Fact sheet: Impact of Sequestration on the
11.
12.
13.
14.
15.
16.
17.
18.
19.
43
INVITED ARTICLES
BREAST CANCER
ou have completed your examination and have left the patients room to let her get dressed while preparing to sit
down with her and her partner to discuss her diagnosis, stage,
prognosis, and treatment recommendations. With the patients permission, a second-year medical resident will sit in on
this discussion. As you wait, you run through what you are
planning to say, especially about her standard treatment options and about a clinical trial for which she appears to be eligiblea randomized study that could answer important
questions about the treatment of her disease. You tell the resident that the doctors role in suggesting and explaining a study
to a patient is vital, even though the research staff will do much
of the work if the patient agrees to consider the study. But you
can only succeed if you try. Albrecht et al, studying interactions
between oncologists and patients and their families at two
comprehensive cancer centers, found that clinical trials were
offered to patients only 20% of the time, but, when offered, 75%
of patients agreed to participate.1 In a telephone survey of
1,000 adults, 32% of responders said they would be very willing
to participate in a cancer clinical trial if asked and another
38% indicated that they would be inclined to do so.2
Unfortunately, scenes like this could well become much
less common for many medical oncologists, especially those
who work at smaller academic cancer centers, community
hospitals, and private practices, where the vast majority of
Americans receive their oncologic care. Many sites that have
been involved in clinical research for decades are fnding it
increasingly diffcult to gain access to clinical trials that they
can offer to more than a minute fraction of their patients.
Why is this? Certainly there is no dearth of important questions to address regarding the management of many common cancers. In the past, many of the larger trials in which
patients participated originated with the sites cooperative
group; the creation of the Clinical Trials Study Unit (CTSU)
offered the opportunity to enroll patients on phase II and III
studies conducted by other groups. Many institutions and
practices have supported their staffs participation in the
groups, covering the costs of membership and travel to at-
tend group meetings and accepting a reduction in productivity so that the site can contribute to the research effort.
You know that this part of the conversation can be disconcerting for the patient; she was referred to you because of your
knowledge and experience, not to have such an important decision made by a computer, by a flip of a virtual coin. Why open
this can of worms? You are already 40 minutes behind schedule, and the study discussion is bound to add at least 30 minutes to this visit. It is certainly not for the money; with the
exception of a few well-funded pharmaceutical company
sponsored trials, your protocol offce actually loses money on a
per-accrual basis. It is not for the glorythere is no way your
site will enroll enough patients on this large study to be given
authorship credit, and, in the academic scheme of things, clinical research is a poor relation. You know the statistics, which
you share with the resident how few patients are candidates
for available trials despite efforts to liberalize eligibility criteria, how few are offered the chance to be part of a trial, how few
agree to participate (less than 5% of adult patients with cancer
enroll in clinical trials, in comparison to more than 60% of
children with cancer), and how many studies fail to meet accrual goals or take years longer than planned to answer the
important questions they address. How many axillae were unnecessarily dissected because it took so long to complete
ACOSOG Z0011?
The accomplishments of the U.S. cooperative groups in advancing the understanding of and improving outcomes for
many different types of cancer should not be underestimated
(see summary by Schilsky3); if you scan the lists of plenary
and oral abstract presentations at the American Society of
Clinical Oncologys Annual Meetings, or any other major national meeting over the past 2 decades, you will see ample
evidence of their effect, despite being level-funded since 2003
(which has the effect of reducing available funding by a few
percent every year, given inflation), and over the past few
years, many presenters have reminded us of this origin for
their practice-changing trials. Still, there is no doubt that they
could have been more productive and effcient and that there
were costs associated with their conduct that could be re-
From the Program in Womens Oncology, Women and Infants Hospital of Rhode Island and Warren Alpert Medical School of Brown University, Providence, Rhode Island.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: William M. Sikov, MD, Women and Infants Hospital of Rhode Island, Breast Health Center, 101 Dudley St., Providence, RI 02905: email: wsikov@wihri.org.
2015 by American Society of Clinical Oncology.
44
duced, and thus it was no surprise when the Institute of Medicine report A National Cancer Clinical Trials System for the
21st Century: Reinvigorating the NCI Cooperative Group
Program produced at the request of the National Cancer Institute (NCI), recommended major changes designed to improve the cooperative group system.4 Many in the
cooperative groups applauded the recommendations,
which included providing additional funds to help the
groups modernize systems and increase patient and physician incentives.
You know that the patient and those closest to her simply
want to know what is best for her, not for some faceless stranger
in the future, and admitting that we do not know what is best
is diffcult. You know that random selection, fear of receiving a
placebo, and fear of developing any of the long list of potential
side effects listed in the consent form (even if the list of side
effects for the standard treatment is just as long) are among the
greatest barriers to clinical trial participation.5 As you explain
to the resident, it is a delicate balance. If you come across as too
enthusiastic about the experimental approach, it may seem
that you are trying to sell the study and could lead the patient
to believe that she would be getting inferior treatment if she is
randomized to the control arm, so why do not you just give her
the better treatment? You remind yourself of how often what
some experts were sure was a major advancesuch as bone
marrow transplants for breast cancer and MACOP-B instead
of CHOP for diffuse large cell B-cell lymphomasproved to be
no better and only more toxic when the randomized trials were
fnally completed.
Instead of using the Institute of Medicine report to support
their efforts to lobby Congress for additional funds for the
clinical trials program, the NCI leadership chose a different
direction. While announcing plans to support upgrades in
information technology, centralized laboratories, and biospecimen tracking, they compelled the existing cooperative
groups to consolidate and announced reductions in overall
accrual, achieved in part by eliminating sponsorship of studies with an accrual goal over 1,000. The NCIs decision essentially leaves the feld of larger, randomized clinical trials to
the pharmaceutical companies, which suggests that the only
studies done will be those designed to support the approval of
costly new therapies. The NCIs stated intent is to use its limited funds to sponsor early phase trials designed to test
biomarker-driven hypotheses,6 which by defnition will be
limited to the small subset of patients whose tumors test positive for a potentially targetable mutation. This strategy is designed to look for large differences in outcomes instead of
incremental improvements rendered statistically signifcant
by sheer size. While not questioning the value of this approach for hypothesis-testing in biologically defned patient
subsets, it leaves scant resources to answer clinical questions
that will not beneft a pharmaceutical sponsor, such as comparing two regimens comprised of generic drugs or determining if a biologically defned patient subgroup might do
better without or with briefer exposure to a costly and/or
toxic treatment that is the current standard of care.
You dread hearing I do not want to be a guinea pig, because it makes you want to scream that none of your patients
are guinea pigs and that giving a patient an investigational
treatmentno matter how promising before it has been
proven to be more effective and/or less toxic in with a welldesigned and well-conducted clinical trial would be inappropriate. Instead, you calmly tell them that it is only because
patients like her agreed to participate in past studies that we
have been able to defne our current, yet admittedly imperfect,
standard treatment. And when they ask you, What would you
do if she were your wife or partner? you can honestly answer
that you would support participating in the study. You can
also say, to patients who are members of an ethnic minority,
that it is important that a variety of ethnic groups take part in
the study, to make sure that its results are broadly applicable
and to identify any differences in disease biology and treatment effect; close to 90% of patients who enroll in NCIsponsored clinical trials are white, of whom less than 6% are
Hispanics/Latinos.7 There may be the added challenge of overcoming suspicions as to the benefcence of the clinical trials process based on a few infamous historic precedents, such as the
Tuskegee syphilis study.
In addition, except for the 30 Lead Academic Participating
Sites (LAPS), which under the new system receive additional
funding to support their clinical trials program, fnancial
support for participating in NCI-sponsored studies remains
inadequate. After spending the last 20 to 30 years training the
next generation of medical oncologists, radiation oncologists, surgeons, etc., to revere the randomized clinical trial
and encouraging cancer programs to hire research staff, the
rug is being pulled out from under their feet. To maintain
these research programs will require even greater dependence on pharmaceutical companysponsored studies. To
expand and diversify their study portfolios, cooperative
groups have established or expanded affliated foundations, which hope to compete with contract research organizations with the promise of improving the science
associated with these trials; it is too early to know how successful these efforts will be. And although many of the pharmaceutical companies have been generous in supporting
investigator-initiated studies that may never lead to drug approval or label expansion, to what extent this will continue is
unclear.
You will have to explain that participating in a study may
require additional offce visits, blood tests, scans, questionnaires, blood and/or tissue samples, in some cases even additional biopsies, for correlative research studies. New ways of
analyzing patients and their cancers promise to revolutionize
our understanding of and, hopefully, treatment for her cancer,
offering the hope of truly personalized oncology, but only if
studies are completed that demonstrate a correlation between
these fndings and patient outcomes. You comment to the resident that maybe we should make it easier to enroll in studies,
or harder to refuse them. In some countries the only way to get
a standard treatment is to participate in a study, but fortunately that is not often the case in the United States. Of course
it is easier to accrue if the only way to get a promising investiasco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
45
WILLIAM M. SIKOV
gational treatment is on trial, such as in the adjuvant trastuzumab studies. Would it not be easier if consent forms were not
20 or more pages long, with interminable lists of potential (if
rare) side effects? Do we really expect our patients to read and
comprehend such a lengthy document, even if (supposedly)
written at an eighth-grade level?
So what can or should we do about the direction of the U.S.
clinical trials system? I agree with those who have spoken in
favor of a publicly funded clinical trials system,3,8 and I do not
expect or want the NCI leadership to reverse direction on the
value of precision medicine trials. Although that initiative is
important, I would like to believe that we can walk and chew
gum at the same time; that is, conduct those smaller-focused
studies without relinquishing the ability to pose pertinent
questions that require much larger trials to answer. So we
should lobby our congresspeople and senators to increase
funding to the National Institutes of Health that is earmarked
to the cancer clinical trials program, perhaps even specifed
to go toward larger trials, some of which may be designed to
determine if we can reduce the toxicity and cost of treatment
without reducing its effcacy. We could make the argument
that a relatively small investment in such studies could potentially save the system a great deal more. As an alternative
to government spending, we should encourage philanthropies like the Conquer Cancer Foundation to consider trying
to enlarge their donor base by offering individuals and foundations the opportunity to step into this gap and help fund
large, simple trials that address important questions. Such
trials could be run on, relatively speaking, a shoestring budget, with sites making up for low per-case funding with
higher accrual, and reducing costs by collecting only key outcomes and toxicity data and minimizing costs by holding
study group meetings via the Web.
We could even explore creating a virtual tissue bank, where
samples are held at the treating institutions and sent to a designated research facility only when requested.
It boils down to understanding the importance of your role
as the patients physician and advocate, even if it is the frst
time you have met. If you truly believe that participating in the
study could be her best option, you can also acknowledge that
an important reason why you take the time to do this is so that
when you, or another physician, perhaps even that resident, sit
down with a patient like her in 5, 10, or 20 years you will be
able to say whether treatment A is better, equivalent to, inferior to, or less or more toxic, than treatment B. In the end,
when the results of this study have been presented and published, you can both be proud to have been part of the process.
That is, assuming you still have suffcient access to trials to
offer to her and your other patients.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: William Sikov, Bristol-Myers Squibb. Consulting
or Advisory Role: William Sikov, Celgene, AbbVie. Speakers Bureau: None. Research Funding: None. Patents, Royalties, or Other Intellectual
Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Albrecht TL, Eggly SS, Gleason ME, et al. Influence of clinical communication on patients decision making on participation in clinical trials.
J Clin Oncol. 2008;26:2666-2673.
2. Comis RL, Miller JD, Aldige C, et al. Public attitudes toward participation in cancer clinical trials. J Clin Oncol. 2003;21:830-835.
3. Schilsky RL. Wither the cooperative groups? J Clin Oncol. 2014;32:251254.
4. National Research Council. A National Cancer Clinical Trials System for
the 21st Century: Reinvigorating the NCI Cooperative Group Program.
Washington, DC: The National Academies Press; 2010.
46
5. Meropol NJ, Buzaglo JS, Millard J, et al. Barriers to clinical trial participation as perceived by oncologists and patients. J Natl Compr Canc
Netw. 2007;5:655-664.
6. Abrams J, Kramer B, Doroshow JH, et al. National Cancer Institutesupported clinical trials networks. J Clin Oncol. Epub 2014 Dec 1.
7. Greenwood A. Taking action to diversify clinical cancer research. NCI
Cancer Bulletin. 2010;7(10). http://www.cancer.gov/ncicancerbulletin/
051810/page7. Accessed April 7, 2015.
8. Tempero M. A publicly funded clinical trials network: Do we need it?
J Natl Compr Canc Netw. 2014;12:953.
BREAST CANCER
SPEAKERS
Maxine S. Jochelson, MD
Memorial Sloan Kettering Cancer Center
New York, NY
Joseph K. Salama, MD
Duke University Medical Center
Durham, NC
olecular studies have shown that breast cancer includes a large number of subgroups defned by the
presence of a specifc genomic or protein alteration. ER expression was the frst validated target in breast cancer, leading to the optimal development of endocrine therapy.1 In the
late 1990s, HER2 overexpression was validated as a target and
was shown to be a predictive biomarker for the effcacy of
trastuzumab.2 During the 2000s, genomic analyses based on
gene expression arrays suggested that breast cancer could be
divided into four different subgroups: luminal A, luminal B,
HER2-enriched, and basal-like.3-5 Further studies have suggested that basal-like cancers can be subdivided into six subgroups.6 More recently, studies on NGS have suggested that
approximately 40 genomic alterations can be found in primary breast cancers.7,8 Overall, this introduction emphasizes
that each single breast cancer presents a specifc molecular
profle and specifc molecular mechanisms of cancer progression. Parallel to the advances in the understanding of disease
biology, several advances in technology could dramatically
change patient care. Indeed, it has been shown that highthroughput DNA sequencing together with comparative
genomic hybridization (CGH; copy number analyses) can be
performed robustly in the clinical practice.9,10 This has led to
the development of precision medicine that involves multiplex molecular analyses to identify molecular mechanisms of
e2
Molecular alterations can be divided between drivers, mechanisms of resistance, mutational process and DNA-repair defects, immune alterations, cell death, angiogenesis, and
metabolism. These latter three systems will not be discussed
in the present article. The list of the most investigated molecular alterations and their level of evidence are reported in
Table 1.
Oncogenic drivers can be defned as molecular alterations
involved in malignant transformation and cancer progression. Targeting a driver is expected to lead to tumor shrinkage (known as oncogene deaddiction). As mentioned in the
introduction, the two historic drivers include ER expression
KEY POINTS
Only a few molecular alterations are validated as targets in
breast cancer (specically ER and HER2 expression).
Driver identication in breast cancers includes DNA-based
analyses but also detection of pathway activation and
dependency (e.g., ER, mTOR, and CDK4).
Driver identication is not the sole application of genomics
to personalize therapy for metastatic breast cancer.
There is no evidence that using multiplex genomic testing
for metastatic breast cancer improves outcomes.
Ongoing trials are evaluating the medical usefulness of nextgeneration sequencing in metastatic breast cancers.
Application
of Genomics
Optimal
Technology
Drivers (DNA)
Next-generation
sequencing if
multiple genes
validated
Drivers (RNA/
proteins)
Gene expression
Phosphoprotein
assays
Targets
Level of Evidence
Associated with
the Target11
ERBB2
amplication
PIK3CA mutations
II
AKT1 mutations
III
ERBB2 mutations
III
ER expression
mTOR activation
ND
CDK4/6 activation
ND
Lethal
subclone
Ultra-deep
sequencing
Circulating DNA
ESR1 mutations
III
DNA repair
Targeted
sequencing
Whole-exome
sequencing
SNP arrays
BRCA1/2 mutations
I/II
Immune
system
Whole-exome
sequencing
RNA sequencing
PD-L1
overexpression
ND
Neoantigen
Abbreviations: ER, estrogen receptor; mTOR, mammalian target of rapamycin; ND, not
determined; PD-L1, programmed death ligand 1.
e3
that high-dose fulvestrant could present some antitumor activity in this subset of patients. Several new ER degraders like
GDC-0810 are being developed in this setting (NCT01823835).
Until now, this target is classifed level III. There are several
questions surrounding this genomic alteration that could have
some clinical influence. First, as opposed to T790M, this mutation has not yet been reported in a minority subclone in a primary tumor. Finding the ESR1 mutation in a minority clone in a
primary tumor would open the path for the development of
ultra-deep sequencing to detect them and potentially treating
them very early during the disease course. Second, the use of
circulating DNA could help detect these mutations during the
disease course and treat them early. Finally, one study has suggested that ESR1 mutations could be associated with very poor
outcome. If validated, this fnding would suggest that this
genomic segment would deserve some fast-track approvals
based on phase II data.
The third application for genomic tests is the identifcation of
DNA repair defects and mutational processes at the individual
level. Identifying DNA repair defects could lead to administration of personalized synthetic lethality strategies or specifc
genotoxic agents. The best example in breast cancer is provided
by BRCA1 and BRCA2 mutations. When biallelic, BRCA1 and
BRCA2 mutations and/or loss lead to homologous recombination defciency and genomic instability. BRCA1/2 mutations
have been associated with sensitivity to PARP1 inhibitors (synthetic lethality) and DNA alkylating agents (genotoxic).25 Interestingly in these trials, patients without BRCA1/2 alterations did
not present a similar degree of antitumor activity as compared
with patients with mutations. Based on these consistent data
from phase III and large phase II programs, BRCA1/2 mutations
as drug targets have a level I evidence.11 The controversy in this
area is more about how to position each therapeutic strategy
(PARP1 inhibition and DNA alkylating agents) and to show
medical usefulness over standard of care, rather than whether
BRCA1/2 mutations constitute a target per se. The second controversy is about whether some functional tests evaluating homologous recombination defciency (HRD) could have better
performance than detecting BRCA1/2 mutations. HRD tests
could have better performance either by selecting the right patient with the BRCA1/2 mutation or by identifying patients with
BRCA1/2 wild-type who present with HRD. When assessed retrospectively, the HRD test developed by Myriad was not associated with a differential sensitivity between platinum and
docetaxel. The HRD test developed by Clovis has been associated with sensitivity to the PARP inhibitor rucaparib, even in the
absence of BRCA mutation.26 An ongoing phase II trial (RUBY)
is testing whether rucaparib could present antitumor activity in
patients with BRCA1/2 wild-type who present a high HRD. Beyond HRD and BRCA, assessing other DNA repair genes or
pathways could allow expanding the array of patients who could
be eligible for synthetic lethality strategies. ATM and ATR mutations are observed in approximately 2% of breast cancers and
could defne a subset of patients eligible for synthetic lethality
approaches. In terms of pathways, several studies have suggested that the mutational pattern detected by whole-exome sequencing could allow for defning which DNA repair pathway is
e5
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Fabrice Andre, AstraZeneca, Novartis. Consulting
or Advisory Role: Fabrice Andre, Astellas Pharma, AstraZeneca, Novartis. Speakers Bureau: None. Research Funding: Fabrice Andre, AstraZeneca (Inst),
Novartis (Inst), Roche/Genentech (Inst). Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations,
Expenses: Fabrice Andre, GSK, Novartis, Roche. Other Relationships: None.
References
1. Early Breast Cancer Trialists Collaborative Group (EBCTCG). Effects
of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overviewof the randomised trials.
Lancet. 2005;365:1687-1717.
2. Vogel CL, Cobleigh MA, Tripathy D, et al. Effcacy and safety of trastuzumab as a single agent in frst-line treatment of HER2-overexpressing
metastatic breast cancer. J Clin Oncol. 2002;20:719-726.
3. Perou CM, Srlie T, Eisen MB, et al. Molecular portraits of human
breast tumours. Nature. 2000;406:747-752.
4. Srlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of
breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98:10869-10874.
5. Sotiriou C, Neo SY, McShane LM, et al. Breast cancer classifcation and
prognosis based on gene expression profles from a population-based
study. Proc Natl Acad Sci U S A. 2003;100:10393-10398.
6. Lehmann BD, Bauer JA, Chen X, et al. Identifcation of human
triple-negative breast cancer subtypes and preclinical models
e6
7.
8.
9.
10.
11.
12.
e7
From the Department of Radiation Oncology, Duke University Medical Center, Durham, NC; The University of Chicago, Chicago, IL.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Joseph K. Salama, MD, Box 3085, Duke University Medical Center, Durham, NC 27710; email: joseph.salama@duke.edu.
2015 by American Society of Clinical Oncology.
e8
KEY POINTS
Oligometastases are a common presentation in many
cancer types and are frequently represented in patients
with breast cancer who are enrolled in clinical trials.
Patients with oligometastases have a favorable prognosis
compared to patients with more widespread metastases.
Surgical complete resection of breast cancer metastases to
the lung and liver in patients with oligometastases and
long disease-free intervals have been associated with
favorable survival compared with historical controls. Recent
improvements in radiotherapy planning and delivery have
allowed for the precise targeting of breast cancer
metastases to any organ in the body with tumor control
approaching that of surgical series.
Data supporting use of surgery and/or ablative radiation
are limited and primarily retrospective.
Enrollment into ongoing prospective controlled studies is
critical to determine if there is truly a benet to either
ablative radiation or surgical resection of all known
metastases.
e9
TABLE 1. Frequency of Patients Enrolled in First-Line Metastatic Breast Cancer Trials with Limited Number of
Metastatic Sites Who Appear Potentially Eligible for Ablative Therapy
Author/Study
Phase
No. of Patients
ER/PR (%)
HER2 Status
Arms
PFS (Months)
Albain 2008
II
599
32
57
91
1. Gem/Paclitaxel
9.89
2. Paclitaxel
8.4
Bergh 2012
III
593
72
Pos
52
1. Sunitinib/Docetaxel
8.6
2. Docetaxel
8.3
Tawk 2013
II
30
77
Neg
50
1. Vinorelbine/Capecitabine
8.6*
Hurvitz 2013
IIR
137
54
Pos
49.3
1. Trastuz/Docetaxel
9.2
2. T-DM1
14.2
Gianni 2013
AVEREL
III
Sledge 2003
E1193
III
424
739
51
45
Pos
-
50
49
1. Docetaxel/Trastuz
13.7
2. Docetaxel/Trastuz/Bev
16.5
1. Doxorubicin
6*
2. Paclitaxel
6.3*
3. Doxorubicin/Paclitaxel
8.2*
Abbreviations: ER, estrogen receptor; PR, progesterone receptor; met, metastases; PFS, progression-free survival; gem, gemcitabine; pos, positive; neg, negative; trastuz, trastuzumab; Bev,
bevacizumab.
*Time to failure.
e11
PET was able to detect responses in those with nonmeasureable lesions by standard RECIST, particularly useful in patients with breast cancer who often present with osseousonly metastases. Another potential biomarker to evaluate
response to ablative therapy is via enumeration of circulating
tumor cells (CTCs). Already established as a prognostic tool
for patients with MBC as well as a predictive tool evaluating
response to systemic therapy,55 the presence of less than fve
CTCs per 7.5 mL whole blood at baseline may also serve as a
way to identify those patients with truly oligometastatic disease from the cohort of patients with few clinically apparent
metastases. Furthermore, the ability of surgery or ablative radiotherapy to reduce the number of CTCs to less than fve
may predict good responses to therapy. Furthermore, the
eradication of previously detectable CTCs after metastasectomy or ablative radiation may indicate that the primary
sources of CTCs were the known and treated metastases and
not from the occult sites reseeding after ablative therapy preventing durable long-term control.
In conclusion, from available data many if not most patients with MBC present with a limited number of metastases, which portents improved outcomes. Ablation of
imaging-detected metastases, with either surgery or radiation, has been associated with long disease-free intervals for
patients with breast cancer. Although ablative therapies are
gaining in popularity, only now are prospective trials open to
identify the role of ablative therapy in oligometastatic breast
cancer. Patients should be enrolled in these studies to identify
the true effect of ablative therapy. Although early data are
beginning to elucidate the biologic underpinnings of patients
with oligometastatic disease, more work is needed, and biomarkers need to be validated in this patient population to
better identify responses to treatment. All of this work is
needed to truly determine if there is potentially a subset of
patients with MBC that can achieve long-term survival. With
better identifcation of which patients belong in this subset
and what the utility is of the ablative therapy options, a new
treatment paradigm may become the cure for a subset of patients with MBC.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: None.
Speakers Bureau: None. Research Funding: Joseph K. Salama, Merk (I), BMS (I), GSK (I), Abbvie. Patents, Royalties, or Other Intellectual Property:
None. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Macdermed DM, Weichselbaum RR, Salama JK. A rationale for the targeted treatment of oligometastases with radiotherapy. J Surg Oncol.
2008;98:202-206.
2. Pockaj BA, Wasif N, Dueck AC, et al. Metastasectomy and surgical resec-
tion of the primary tumor in patients with stage IV breast cancer: time for a
second look? Ann Surg Oncol. 2010;17:2419-2426.
3. Halstead W. The results of radical operations for the cure of carcinoma
of the breast. Ann Surg. 1907;46:1-19.
e13
e14
26. Abbott DE, Brouquet A, Mittendorf EA, et al. Resection of liver metastases from breast cancer: estrogen receptor status and response to chemotherapy before metastasectomy defne outcome. Surgery. 2012;151:
710-716.
27. Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival beneft
with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: fnal results from the EGF104900 Study. J Clin Oncol. 2012;30:25852592.
28. Salama JK, Hasselle MD, Chmura SJ, et al. Stereotactic body radiotherapy for multisite extracranial oligometastases: fnal report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease. Cancer.
2012;118:2962-2970.
29. Milano MT, Zhang H, Metcalfe SK, et al. Oligometastatic breast cancer
treated with curative-intent stereotactic body radiation therapy. Breast
Cancer Res Treat. 2009;115:601-608.
30. Mehta N, Mauer AM, Hellman S, et al. Analysis of further disease progression in metastatic non-small cell lung cancer: implications for locoregional treatment. Int J Oncol. 2004;25:1677-1683.
31. Kirkpatrick JP, Kelsey CR, Palta M, et al. Stereotactic body radiotherapy:
A critical review for non-radiation oncologists. Cancer. 2014;120:942954.
32. Fuks Z, Kolesnick R. Engaging the vascular component of the tumor
response. Cancer Cell. 2005;8:89-91.
33. Garcia-Barros M, Paris F, Cordon-Cardo C, et al. Tumor response to
radiotherapy regulated by endothelial cell apoptosis. Science. 2003;300:
1155-1159.
34. Lee Y, Auh SL, Wang Y, et al. Therapeutic effects of ablative radiation on
local tumor require CD8 T cells: changing strategies for cancer treatment. Blood. 2009;114:589-595.
35. Liang H, Deng L, Chmura S, et al. Radiation-induced equilibrium is a
balance between tumor cell proliferation and T cell-mediated killing.
J Immunol. 2013;190:5874-5881.
36. McCammon R, Schefter TE, Gaspar LE, et al. Observation of a dosecontrol relationship for lung and liver tumors after stereotactic body
radiation therapy. Int J Radiat Oncol Biol Phys. 2009;73:112-118.
37. Corbin KS, Ranck MC, Hasselle MD, et al. Feasibility and toxicity of
hypofractionated image-guided radiotherapy for large volume limited
metastatic disease. Pract Radiat Oncol. 2013;3:316-322.
38. de Vin T, Engels B, Gevaert T, et al. Stereotactic radiotherapy for oligometastatic cancer: a prognostic model for survival. Ann Oncol. 2014;25:
467-471.
39. Lee J, Milano MT, Kao J, et al. A multi-institution pooled analysis of
oligometastatic patients treated with SBRT. Int J Radiat Oncol Biol Phys.
2014;90:S699.
40. Sahgal A, Larson DA, Chang EL. Stereotactic body radiosurgery for spinal metastases: a critical review. Int J Radiat Oncol Biol Phys. 2008;71:
652-665.
41. Forquer JA, Fakiris AJ, Timmerman RD, et al. Brachial plexopathy from
stereotactic body radiotherapy in early-stage NSCLC: dose-limiting toxicity in apical tumor sites. Radiother Oncol. 2009;93:408-413.
42. Hoppe BS, Laser B, Kowalski AV, et al. Acute skin toxicity following
stereotactic body radiation therapy for stage I non-small-cell lung cancer: whos at risk? Int J Radiat Oncol Biol Phys. 2008;72:1283-1286.
43. Sahgal A, Weinberg V, Ma L, et al. Probabilities of radiation myelopathy
specifc to stereotactic body radiation therapy to guide safe practice. Int
J Radiat Oncol Biol Phys. 2013;85:341-347.
44. Sahgal A, Atenafu EG, Chao S, et al. Vertebral compression fracture
after spine stereotactic body radiotherapy: a multi-institutional analysis
with a focus on radiation dose and the spinal instability neoplastic score.
J Clin Oncol. 2013;31:3426-3431.
45. Formenti SC, Friedman K, Chao K, et al. Abscopal response in irradi-
46.
47.
48.
49.
50.
ated patients: results of a proof of priniciple trial. Int J Radiat Oncol Biol
Phys. 2008;72:S6-S7.
Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of
the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366:
925-931.
Treasure T. Oligometastatic cancer: an entity, a useful concept, or a
therapeutic opportunity? J R Soc Med. 2012;105:242-246.
Berry DA, Ueno NT, Johnson MM, et al. High-dose chemotherapy with
autologous hematopoietic stem-cell transplantation in metastatic breast
cancer: overview of six randomized trials. J Clin Oncol. 2011;29:3224-3231.
Lewis SL, Porceddu S, Nakamura N, et al. Defnitive stereotactic
body radiotherapy (SBRT) for extracranial oligometastases: an international survey of 1000 radiation oncologists. Am J Clin Oncol.
Epub 2015 Feb 2.
Tree AC, Khoo VS, Eeles RA, et al. Stereotactic body radiotherapy for
oligometastases. Lancet Oncol. 2013;14:e28-e37.
51. Palma DA, Haasbeek CJ, Rodrigues GB, et al. Stereotactic ablative radiotherapy for comprehensive treatment of oligometastatic tumors
(SABR-COMET): study protocol for a randomized phase II trial. BMC
Cancer. 2012;12:305.
52. Lussier YA, Xing HR, Salama JK, et al. MicroRNA expression characterizes oligometastasis(es). PLoS One. 2011;6:e28650.
53. Lussier YA, Khodarev NN, Regan K, et al. Oligo- and polymetastatic
progression in lung metastasis(es) patients is associated with specifc
microRNAs. PLoS One. 2012;7:e50141.
54. Solanki AA, Weichselbaum RR, Appelbaum D, et al. The utility of FDGPET for assessing outcomes in oligometastatic cancer patients treated
with stereotactic body radiotherapy: a cohort study. Radiat Oncol. 2012;
7:216.
55. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease
progression, and survival in metastatic breast cancer. N Engl J Med.
2004;351:781-791.
e15
BREAST CANCER
Controversies in Neoadjuvant
Therapy for Breast Cancer:
Surgery, Radiation, and
Therapeutic Trials
CHAIR
Angela DeMichele, MD, MSCE
Abramson Cancer Center of the University of Pennsylvania
Philadelphia, PA
SPEAKERS
Julia White, MD
NRG Oncology/RTOG, The Ohio State University
Columbus, OH
Tari A. King, MD
Memorial Sloan Kettering Cancer Center
New York, NY
eoadjuvant therapy for breast cancer has gained traction in recent years as both a management strategy
and research tool. In addition to the established benefts of
downstaging inoperable cancers and improving breastconservation rates,1,2 investigators have recognized this approachs potential advantages for developing new therapies.
Preoperative therapy provides the opportunity for in vivo assessment of pharmacodynamics markers to assess biologic
effects and allows new compounds to be tested in a more responsive, treatment-naive population. In addition, early surrogates of response, such as pCR and residual cancer burden,
provide proximate measures that correlate with long-term
outcomes, thus potentially shortening the time needed to
identify effective adjuvant therapies. But with these advantages, come challenges, both in optimizing the research data
that is obtained and integrating this approach into the standard of care. What are the appropriate endpoints for neoadjuvant clinical trials? When do we integrate fndings from
these clinical trials into standard systemic therapy approaches? And fnally, what are the implications of neoadjuvant therapy and trials on locoregional surgical and radiation
therapy outcomes and approaches? These controversies continue to evolve as our understanding of the biology and natural history of breast cancer subtypes and use of preoperative
therapy grows.
From the University of Pennsylvania, Philadelphia, PA; The Ohio State University Comprehensive Cancer Center, Columbus, OH.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Angela DeMichele, MD, MSCE, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104; email: angela.demichele@uphs.upenn.edu.
2015 by American Society of Clinical Oncology.
e17
KEY POINTS
Neoadjuvant systemic therapy improves surgical outcomes
and is a platform for translational research and clinical
trials.
New therapeutic approaches that result from neoadjuvant
trials ideally demonstrate benets in terms of pathologic
complete response and event-free and overall survival.
Downstaging with neoadjuvant therapy enables more
women to undergo breast conservation with lumpectomy
and breast radiotherapy.
Locoregional cancer outcomes comparable to mastectomy
are expected from breast conservation in appropriately
selected patients after neoadjuvant therapy.
Postmastectomy radiotherapy appears to be of most
benet after neoadjuvant therapy in those with extensive
clinical stage III breast cancer (T3 4, N23).
The extent of locoregional therapy necessary for those
who downstage to pathologically node negative after
neoadjuvant therapy is evolving and clinical trials are
ongoing.
e18
select the most promising agents to take forward to confrmatory trials. First, all chemotherapy should be given before
surgery. Second, pathologic assessment of residual diseae at
surgery must use the FDA-recommended defnition of elimination of all invasive cancer in the breast and axillary lymph
nodes. Third, the neoadjuvant trial and subsequent adjuvant
trial must have identical chemotherapy treatment plans and
minimal differences in variability in postoperative treatments such as radiation. Finally, the subsequent confrmatory phase III trial should be suffciently powered for the EFS
HR that would be predicted by the improvement in pCR.
The FDA has proposed such a strategy in its guidance allowing
pCR to be considered an endpoint for accelerated approval of
drugs before completion of confrmatory trials.13
increased the pCR rate (breast and axilla) from 41% to 54%
(p 0.0029). Several additional proximate outcomes showed
improvement as well, with carboplatin increasing the proportion of patients who converted from clinical nodepositive to pathologically node-negative status and the
proportion who became eligible for breast-conserving
therapy.
But these benefts did come with a price. The overall number of serious adverse events, defned as any unexpected
grade 3 or higher toxicity or toxicity that required hospitalization or surgical intervention, was higher in the carboplatin
arm, including higher rates of febrile neutropenia and severe
nausea, vomiting, and dehydration. Patients assigned to carboplatin were more likely to miss two or more doses of paclitaxel and required more dose reductions of paclitaxel, and
20% were unable to complete all planned doses of doxorubicin/cyclophosphamide. Thus, the risk/beneft equation of
adding carboplatin to standard neoadjuvant chemotherapy
for triple-negative breast cancer is complicated. In the absence of EFS/OS data, the most appropriate candidates are
those who would beneft most from surgical downstaging;
those with conditions that increase intolerance to standard
therapy could have that therapy compromised with the addition of carboplatin. The treatment decision requires individualization of therapy and extensive discussion with the
patient about possible implications before embarking on this
new treatment approach.
e19
growing body of literature now supports that when appropriately selected by downstaging, breast conservation can yield
comparable locoregional cancer outcomes in comparison to
mastectomy after neoadjuvant therapy irrespective of age,
subtype, and whether mastectomy was initially intended.17-20
As newer neoadjuvant agents are utilized resulting in even
higher rates of pathologic response in some breast cancers,5
women with more locally advanced breast cancer are even
better poised to feasibly and safely achieve breast conservation when desired. In contrast, the increasing use of neoadjuvant systemic therapy has created considerable controversy
and debate regarding the optimal use of postmastectomy radiotherapy in this setting.
No. of Patients
676
Follow-up (Months)
RT, 73
No RT, 66
Path Response
RT, 14%
No RT, 8%
Clinical Stage
II, 30%
III, 70%
PMRT
Yes/No
Yes
No
LRR %
11*
22
OS %
54*
47
McGuire24 19822002
106
62
100% pCR
II, 30%
III, 70%
Yes
No
5
10
LeScodan25 19902004
134
91
100% ypN0
II, 63%
III, 37%
Yes
No
4
12
88
94
Shim26 19982009
151
57
100% ypN0
II, 60%
III, 40%
Yes
No
2
8
93
90
Abbreviations: PMRT, postmastectomy radiotherapy; LRR, locoregional recurrence; OS, overall survival; RT, radiotherapy; ypN0, pathologically node-negative.
*Signicant statistical difference in comparison with no PMRT.
e20
independent predictors of LRR after neoadjuvant chemotherapy and mastectomy. The 10-year cumulative incidence
of LRR was 12.3% for patients who underwent mastectomy
(local, 8.9%; regional, 3.4%). Independent predictors of LRR
postmastectomy, were clinical tumor size, clinical node status, and pathologic node status/pathologic breast response.
In particular, those with clinically involved nodes before chemotherapy who had pathologically node-negative disease
(ypN0) at surgery (with or without pCR in the breast) had a
lower LRR than those who were found to have persistent
nodal metastases pathologically. In a small subset of 102 patients undergoing mastectomy with clinically positive nodes
before neoadjuvant chemotherapy who were downstaged to
ypN0 afterwards, the risk of chest wall and regional nodal
recurrence was between 0% and 10.8% at 10 years. These LRR
rates ft into a low-risk category of patients who may not experience a signifcant beneft from postmastectomy radiotherapy,
particularly in terms of improved survival, and could be spared
the associated toxicity. It is important to emphasize that the results of the combined analysis of NSABP B-18 and B-27 are primarily applicable to patients with clinical stage I to II disease;
55% of the patients presented with cT12N0 disease, 20% with
cT12N1 disease, and 6% with cT3N0 disease. Only 9% of the
patients presented with cT3N1 disease.
The combined analysis of NSABP B-18 and B-27 supports
that for patients who have positive nodes before neoadjuvant
chemotherapy, the rate of LRR can be modifed downward if
the nodes become pathologically node-negative after neoadjuvant chemotherapy (particularly if there is also pCR in the
breast). These fndings are supported by the outcomes reported in the retrospective studies in those downstaged to
ypN0 after neoadjuvant therapy as described above.27,28
However, prospective data are needed to ensure omission of
postmastectomy is safe given the extensive data supporting
its beneft in improving survival for the treatment of nodepositive breast cancer.21,22 The NSABP B-51/Radiation Therapy Oncology Group (RTOG) 1304 phase III clinical trial
(NCT01872975)30 is designed to answer whether regional radiotherapy improves the invasive breast cancer recurrencefree interval rate (local, regional, and distant recurrences and
deaths resulting from breast cancer) in women who present
with clinical N1 axillary node disease (documented pathologically by needle biopsy) before neoadjuvant chemotherapy and then become pathologically node-negative at time of
surgery. After mastectomy, patients are randomly assigned
to no radiotherapy or chest wall and regional nodal radiotherapy, and after lumpectomy, random assignment is to
breast radiotherapy alone or breast and regional lymph node
radiotherapy.
CONCLUSION
In summary, the neoadjuvant setting provides a wealth of opportunities to identify better treatment strategies through
clinical trials, evaluate new drugs for effcacy, and improve
locoregional outcomes for individual patients. However, to
fully realize these opportunities, clinical trials must be deasco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e21
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Angela DeMichele, Pzer Oncology. Julia R. White,
Bayer Healthcare, Genomic Health, Qx, Varian. Consulting or Advisory Role: None. Speakers Bureau: None. Research Funding: Angela DeMichele, Bayer
(Inst), Calithera (Inst), Genentech (Inst), GlaxoSmithKline (Inst), Incyte (Inst), Millenium (Inst), Pzer (Inst), Veridex (Inst), Wyeth-Ayerst (Inst). Patents,
Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: Angela DeMichele, Pzer Oncology.
Other Relationships: None.
References
1. Fisher B, Bryant J, Wolmark N, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol.
1998;16:2672-2685.
2. Bear HD, Anderson S, Smith RE, et al. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast
and Bowel Project Protocol B-27. J Clin Oncol. 2006;24:2019-2027.
3. von Minckwitz G, Untch M, Blohmer JU, et al. Defnition and impact of
pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012;
30:1796-1804.
4. Esserman LJ, Berry DA, DeMichele A, et al. Pathologic complete response predicts recurrence-free survival more effectively by cancer subset: results from the I-SPY 1 TRIAL-CALGB 150007/150012. ACRIN
6657. J Clin Oncol. 2012;30:3242-3249.
5. Cortazar P, Zhang L, Untch M, et al. Pathological complete response
and long-term clinical beneft in breast cancer: the CTNeoBC pooled
analysis. Lancet. Epub 2014 Feb 14.
6. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy
with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled
superiority trial with a parallel HER2-negative cohort. Lancet. 2010;375:
377-384.
7. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med.
2005;353:1673-1684.
8. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for
HER2-positive early breast cancer (NeoALTTO): a randomised, openlabel, multicentre, phase 3 trial. Lancet. 2012;379:633-640.
9. Piccart-Gebhart MJ, Holmes AP, Baselga J, et al. First results from the
phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab
alone (T), their sequence (T3 L), or their combination (TL) in the
adjuvant treatment of HER2-positive early breast cancer (EBC). J Clin
Oncol. 2014;32:5s (suppl; abstr LBA4).
e22
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
proves local-regional control and survival for selected patients with locally advanced breast cancer treated with neoadjuvant chemotherapy
and mastectomy. J Clin Oncol. 2004;22:4691-4699.
McGuire SE, Gonzalez-Angulo AM, Huang EH, et al. Postmastectomy
radiation improves the outcome of patients with locally advanced breast
cancer who achieve a pathologic complete response to neoadjuvant chemotherapy. Int J Radiat Oncol Biol Phys. 2007;68:1004-1009.
Le Scodan R, Selz J, Stevens D, et al. Radiotherapy for stage II and stage III
breast cancer patients with negative lymph nodes after preoperative chemotherapy and mastectomy. Int J Radiat Oncol Biol Phys. 2012:82:1-7.
Shim SJ, Park W, Huh SJ, et al. The role of postmastectomy radiation
therapy after neoadjuvant chemotherapy in clinical stage II-III breast
cancer patients with pN0: a multicenter retrospective study (KROG 1205). Int J Radiat Oncol Biol Phys. 2014;88:65-72.
Mamounas EP, Anderson SJ, Dignam JJ, et al. Predictors of locoregional
recurrence after neoadjuvant chemotherapy: results from combined
analysis of National Surgical Adjuvant Breast and Bowel Project B-18
and B-27. J Clin Oncol. 2012;30:3960-3966.
NCT01872975. Standard or Comprehensive Radiation Therapy in
Treating Patients With Early-Stage Breast Cancer Previously Treated
With Chemotherapy and Surgery. https://clinicaltrials.gov/ct2/show/
NCT01872975. Accessed March 8, 2015.
e23
BREAST CANCER
SPEAKERS
Rinaa S. Punglia, MD, MPH
Dana-Farber Cancer Institute
Boston, MA
Kevin S. Hughes, MD, FACS
Massachusetts General Hospital
Boston, MA
SURGICAL MANAGEMENT
In the 1980s, the question regarding surgery in older patients
was, Can we? Herbman et al showed that older women
could tolerate mastectomy and had a substantial long-term
survival and concluded the standard treatmentmastec-
tomy at that timeshould not be withheld from these patients.5 Today the question is different: Should we? In many
ways, early-stage breast cancer in older, healthy women
should be considered more of an inconvenience than a threat
to their lives. The treatment should minimize not only the
inconvenience but also the morbidity produced. Although
radiation to the breast is well tolerated, it does increase breast
pain, fbrosis, and retraction for at least a limited amount of
time, as shown in Cancer and Leukemia Group B (CALGB)
9343.6 In many older women with comorbidities, the effect of
breast cancer on their quality of life is less than in younger
patients because of their limited life expectancy. In these
older women especially, the major goal should be limiting
treatment to the minimum amount necessary to prevent
locoregional recurrence during the patients remaining
lifetime.
When the older woman presents with early-stage breast
cancer, the surgeon must evaluate the size and location of the
cancer by physical exam and imaging and then determine the
patients general health status and life expectancy. For those
with severe comorbidities and limited life expectancy, it may
be best to avoid surgery all together. If the cancer is hormonereceptor positive, the use of an aromatase inhibitor (AI) or
tamoxifen can often control the cancer for the duration of the
patients life.7 For healthier older women, the decision is be-
From Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA; Avon Comprehensive Breast Evaluation Center, Harvard Medical School and Bermuda Cancer Genetics and Risk
Assessment Clinic, Massachusetts General Hospital, Boston, MA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Hyman B. Muss, MD, Lineberger Comprehensive Cancer Center, Campus Box 7305, 170 Manning Dr., Chapel Hill, NC 27514; email: muss@med.unc.edu.
2015 by American Society of Clinical Oncology.
48
KEY POINTS
The goals of treatment of older patients are typically
different than for younger patients and should be clearly
dened when making treatment recommendations.
Life expectancy and comorbidities are key factors in
treatment decisions.
Surgical and radiation oncology decisions should focus on
optimizing local control while minimizing a negative effect
on quality of life.
Adjuvant chemotherapy should only be considered if it will
improve survival more than several percentage points.
We believe that caring for older patients is best done by a
team of experts including oncologists, geriatricians, and
other support staff.
RADIATION THERAPY
After lumpectomy, the decision to add radiation therapy for
older women needs to be carefully considered. The Early
Breast Cancer Trialists Collaborative Group (EBCTCG)
published an updated analysis using individual patient data
from 10,801 patients included in 17 randomized trials of radiation after breast-conserving surgery.15 This publication
revealed that the addition of radiation therapy was associated
with a highly signifcant absolute beneft of 15.7% in any frst
recurrence (local, regional, or distant recurrence) at 10 years
(2p 0.00001). The benefts of radiation therapy varied
when adjusted for estrogen receptor status, grade, and age.
The potential benefts of radiation among age groups in the
EBCTCG analysis revealed that the absolute beneft of radiation therapy depended on the baseline risk of recurrence: a
function of age. With increasing age, the baseline risk of recurrence was lower, leading to a smaller but still signifcant
absolute beneft of radiation overall. In women older than
age 70, the baseline risk of recurrence and therefore the
beneft derived from radiation was about halfan 8.9%
absolute reduction in a 10-year risk of a locoregional or
distant recurrence. This analysis was based on chronologic
age and included healthy older women as well as those
with comorbidities.
This concept of proportional beneftsthat the absolute
beneft of radiation therapy varies with the underlying risk of
recurrenceraises the question of whether radiation therapy
following breast-conserving surgery can be safely omitted if
the absolute risk is low. This question was directly addressed
by four randomized trials of endocrine therapy with radiation therapy or endocrine therapy alone in older women with
estrogen receptorpositive breast cancer (Table 1). Each of
these trials showed that the addition of radiation therapy to
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
49
TABLE 1. Randomized Trials of Hormonal Therapy and Breast-Conserving Surgery with or without Radiation
Therapy in Older Women
Trial (No. of Patients)
Inclusion Criteria
Locoregional
Recurrence without RT
Locoregional
Recurrence with RT
p Value
Overall Survival
Difference
CALGB9 (636)
10% at 10 yr
2% at 10 yr
0.001
Not signicant
0.001
Not signicant
T1, HR/unknown
Negative nodes
Princess Margaret (749)
17.6% at 8 yr
3.5% at 8 yr
2.7% at 5 yr
0.6% at 5 yr
0.004
Not signicant
ABCSG61 (869)
5.1% at 5 yr
0.4% at 5 yr
0.001
Not signicant
59
Abbreviations: RT, radiation therapy; CALGB, Cancer and Leukemia Group B; HR, hormone receptor.
dian follow-up of 9.9 years, there was no signifcant difference in the likelihood of local recurrence between the two
treatment arms. Indeed, the absolute rate of local recurrence
was slightly lower (by 1%, p 0.21) and freedom from
marked or moderate cosmetic change improved (hazard ratio [HR] 0.77; 95% CI, 0.66 to 0.89) in the hypofractionated
arm. Unlike partial breast radiation and intraoperative radiation, which also reduce treatment length, boost omission
and hypofractionation do not require additional equipment
or training, potentially enabling patients to have fewer radiation visits in all radiation treatment centers.
A question that remains unanswered is whether tumor biology may be more relevant than patient age in determining
the risk of local recurrence. A retrospective study of 1,434
patients treated with breast-conserving surgery and radiation therapy at three hospitals used immunohistochemistry
and grade to divide the cancers into fve tumor subtypes: Luminal A, Luminal B, Luminal-HER2, HER2, and triple negative.25 The overall risk of local recurrence at 5 years was only
1.6%. However, in addition to patient age, tumor subtype was
a highly signifcant predictor for local recurrence. Among patients older than age 64, the crude risk of local recurrence was
under 0.5% for all subtypes, except those with triple-negative
cancers where it jumped to 6.9%. An initial report of a randomized study of 769 women older than age 50 with earlystage breast cancer treated with endocrine therapy with or
without radiation therapy reported a reduction in the risk of
local recurrence with radiation therapy from 13.8% to 5% at a
median follow-up of 10 years (p 0.0001).26 However, interestingly, among a subset of 304 patients in whom molecular
subtyping was performed, those with Luminal A cancers did
not derive beneft from radiation therapy as the risk of local
recurrence was low even without radiation therapy. In these
patients with Luminal A disease, there was a 5.5% risk without and 4.9% risk with radiation (p 0.9). In contrast, those
patients with Luminal B cancers had a higher baseline risk of
local recurrence and a striking improvement in this risk with
the addition of radiation therapy: 16.1% with tamoxifen
alone and 3.9% with both tamoxifen and radiation (p 0.05).
It is likely that the lower likelihood of local recurrence in
older patients is not because of age itself but that older patients are more likely to have cancers with more favorable
subtypes.27 Prospective trials that omit radiation in women
with low-risk tumor subtypes are currently underway.
Estimation of the individuals risk of recurrence will improve with further molecular characterization of cancers and
life expectancy, and functional age calculations can be used to
put this risk into context for an individual patient. In addition, a careful assessment of comorbidity and other potential
impediments to receiving radiation therapy, such as being a
great distance from a radiation treatment facility, is necessary
to balance these burdens associated with treatment with its
potential benefts. Although radiation therapy is associated
with increased treatment time, it may reduce the likelihood
of mastectomy at a later date, when an older patients functional status may become further compromised.28 Therefore,
the choice regarding radiation therapy needs to be made by
51
TABLE 2. Recommendations for Adjuvant Systemic Therapy for Patients with Life Expectancies Longer Than 5
Years
Tumor Phenotype
Extent of Disease
Recommendation
Hormone receptorpositive
and HER2 negative
All
Node-negative
13 nodes positive
Triple negative
HER2 positive
All
For patients who present with large primary lesions or extensive locoregional disease but without distant metastases,
neoadjuvant therapy can improve chances for breast conservation. For patients with hormone receptorpositive, HER2negative tumors, neoadjuvant endocrine therapy can be
extremely effective, possibly as effective as chemotherapy.53
For those with triple-negative breast cancer and good life expectancy, anthracycline and taxane regimens can be used.
For patients with HER2-positive disease, neoadjuvant therapy that includes pertuzumab in addition to trastuzumab
provides the best chances for tumor reduction.54,55 A summary of our recommendations for adjuvant systemic therapy
is shown in Table 2.
CONCLUSION
Caring for older patients with cancer takes time and in our
opinion is best done using a team of interested and informed
specialists including surgical radiation and medical oncologists. In addition, other support staff such as counseling, palliative care, nutritional, and physical and occupational
therapy are frequently integral to optimizing outcomes.
Geriatric assessment can be learned and performed in a
short period of time and can identify problems that, if addressed, may improve a patients tolerance for treatment,
quality of life, and perhaps survival.56,57 The goals of therapy for seriously ill patients age 60 and older suggests that
loss of physical or cognitive function is a major treatmentrelated concern.58 This would likely be of even greater
concern for 70- and 80-year-old patients. We believe that
estimating life expectancy, performing the geriatric assessment to separate vulnerable from healthy older patients, and then using this information to optimize
treatment based on the evidence of randomized trials will
result in the best outcomes.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: Kevin S. Hughes, Hughes RiskApps, LLC. Honoraria: Kevin S.
Hughes, Myriad Genetics. Consulting or Advisory Role: Hyman B. Muss, Eisai, Pzer. Speakers Bureau: None. Research Funding: Hyman B. Muss,
numerous at UNC (Inst). Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: None.
Other Relationships: None.
References
1. Smith BD, Jiang J, McLaughlin SS, et al. Improvement in breast cancer
outcomes over time: are older women missing out? J Clin Oncol. 2011;
29:4647-4653.
2. Biganzoli L, Wildiers H, Oakman C, et al. Management of elderly patients
with breast cancer: updated recommendations of the International Society
of Geriatric Oncology (SIOG) and European Society of Breast Cancer Specialists (EUSOMA). Lancet Oncol. 2012;13:e148-e160.
3. Tew WP, Muss HB, Kimmick GG, et al. Breast and ovarian cancer in the
older woman. J Clin Oncol. 2014;32:2553-2561.
4. Jones EL, Leak A, Muss HB. Adjuvant therapy of breast cancer in
women 70 years of age and older: tough decisions, high stakes. Oncology
(Williston Park). 2012;26:793-801.
5. Herbsman H, Feldman J, Seldera J, et al. Survival following breast cancer
surgery in the elderly. Cancer. 1981;47:2358-2363.
53
54
23. Whelan TJ, Pignol JP, Levine MN, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med. 2010;362:513-520.
24. Haviland JS, Owen JR, Dewar JA, et al. The UK Standardisation of
Breast Radiotherapy (START) trials of radiotherapy hypofractionation
for treatment of early breast cancer: 10-year follow-up results of two
randomised controlled trials. Lancet Oncol. 2013;14:1086-1094.
25. Arvold ND, Taghian AG, Niemierko A, et al. Age, breast cancer subtype
approximation, and local recurrence after breast-conserving therapy.
J Clin Oncol. 2011;29:3885-3891.
26. Shi W, Fyles A, Pintilie M, et al. Abstract 1032: Post-menopausal women
with luminal A subtype might not require breast radiotherapy: Preliminary results from a randomized clinical trial of tamoxifen radiation.
Cancer Res. 2012;72:1032.
27. Jenkins EO, Deal AM, Anders CK, et al. Age-specifc changes in intrinsic
breast cancer subtypes: a focus on older women. Oncologist. 2014;19:
1076-1083.
28. Albert JM, Pan IW, Shih YC, et al. Effectiveness of radiation for prevention of mastectomy in older breast cancer patients treated with conservative surgery. Cancer. 2012;118:4642-4651.
29. Muss HB. Adjuvant chemotherapy in older women with breast cancer:
who and what? J Clin Oncol. 2014;32:1996-2000.
30. Dowsett M, Cuzick J, Ingle J, et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin
Oncol. 2010;28:509-518.
31. Muss HB, Tu D, Ingle JN, et al. The benefts of letrozole in postmenopausal women with early stage breast cancer who have had fve years of
tamoxifen are independent of age. Breast Cancer Res and Treatment.
2006;S23.
32. Owusu C, Buist DS, Field TS, et al. Predictors of tamoxifen discontinuation among older women with estrogen receptor-positive breast cancer. J Clin Oncol. 2008;26:549-555.
33. Paik S, Tang G, Shak S, et al. Gene expression and beneft of chemotherapy in women with node-negative, estrogen receptor-positive breast
cancer. J Clin Oncol. 2006;24:3726-3734.
34. Dowsett M, Sestak I, Lopez-Knowles E, et al. Comparison of PAM50
risk of recurrence score with Oncotype DX and IHC4 for predicting risk
of distant recurrence after endocrine therapy. J Clin Oncol. 2013;31:
2783-2790.
35. Goldhirsch A, Winer EP, Coates AS, et al. Personalizing the treatment of
women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer
2013. Ann Oncol. 2013;24:2206-2223.
36. Dowsett M, Cuzick J, Wale C, et al. Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and nodepositive postmenopausal patients with breast cancer treated with
anastrozole or tamoxifen: a TransATAC study. J Clin Oncol. 2010;28:
1829-1834.
37. Albain KS, Barlow WE, Shak S, et al. Prognostic and predictive value of
the 21-gene recurrence score assay in postmenopausal women with
node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol.
2010;11:55-65.
38. Early Breast Cancer Trialists Collaborative Group, Peto R, Davies C, et
al. Comparisons between different polychemotherapy regimens for
early breast cancer: Meta-analyses of long-term outcome among 100
000 women in 123 randomised trials. Lancet. 2012;379:432-444.
39. de Glas NA, van de Water W, Engelhardt EG, et al. Validity of Adjuvant!
Online program in older patients with breast cancer: a population-based
study. Lancet Oncol. 2014;15:722-729.
40. Muss HB, Berry DA, Cirrincione CT, et al. Adjuvant chemotherapy in
older women with early-stage breast cancer. N Engl J Med. 2009;360:
2055-2065.
41. Jones S, Holmes FA, OShaughnessy J, et al. Docetaxel with cyclophosphamide is associated with an overall survival beneft compared with
doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology
Research Trial 9735. J Clin Oncol. 2009;27:1177-1183.
42. Muss HB, Woolf S, Berry D, et al. Adjuvant chemotherapy in older and
younger women with lymph node-positive breast cancer. JAMA. 2005;
293:1073-1081.
43. Muss HB, Berry DA, Cirrincione C, et al. Toxicity of older and younger
patients treated with adjuvant chemotherapy for node-positive breast
cancer: the Cancer and Leukemia Group B Experience. J Clin Oncol.
2007;25:3699-3704.
44. Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the adjuvant
treatment of breast cancer. N Engl J Med. 2008;358:1663-1671.
45. Extermann M, Boler I, Reich RR, et al. Predicting the risk of chemotherapy toxicity in older patients: the Chemotherapy Risk Assessment Scale
for High-Age Patients (CRASH) score. Cancer. 2012;118:3377-3386.
46. Hurria A, Togawa K, Mohile SG, et al. Predicting chemotherapy toxicity
in older adults with cancer: a prospective multicenter study. J Clin Oncol. 2011;29:3457-3465.
47. Versteeg KS, Konings IR, Lagaay AM, et al. Prediction of treatmentrelated toxicity and outcome with geriatric assessment in elderly patients with solid malignancies treated with chemotherapy: a systematic
review. Ann Oncol. 2014;25:1914-1918.
48. Tolaney SM, Barry WT, Dang CT, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med.
2015;372:134-141.
49. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in
HER2-positive breast cancer. N Engl J Med. 2011;365:1273-1283.
50. Vaz-Luis I, Keating NL, Lin NU, et al. Duration and toxicity of adjuvant
trastuzumab in older patients with early-stage breast cancer: a
population-based study. J Clin Oncol. 2014;32:927-934.
51. Kalam K, Marwick TH. Role of cardioprotective therapy for prevention
of cardiotoxicity with chemotherapy: a systematic review and metaanalysis. Eur J Cancer. 2013;49:2900-2909.
52. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2positive advanced breast cancer. N Engl J Med. 2012;367:1783-1791.
53. Semiglazov VF, Semiglazov VV, Dashyan GA, et al. Phase 2 randomized
trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. Cancer.
2007;110:244-254.
54. Gianni L, Pienkowski T, Im YH, et al. Effcacy and safety of neoadjuvant
pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25-32.
55. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in
combination with standard neoadjuvant anthracycline-containing and
anthracycline-free chemotherapy regimens in patients with HER2positive early breast cancer: a randomized phase II cardiac safety study
(TRYPHAENA). Ann Oncol. 2013;24:2278-2284.
56. Wildiers H, Heeren P, Puts M, et al. International Society of Geriatric
Oncology consensus on geriatric assessment in older patients with cancer. J Clin Oncol. 2014;32:2595-2603.
57. Sattar S, Alibhai SM, Wildiers H, et al. How to implement a geriatric
assessment in your clinical practice. Oncologist. 2014;19:1056-1068.
58. Fried TR, Bradley EH, Towle VR, et al. Understanding the treatment
preferences of seriously ill patients. N Engl J Med. 2002;346:10611066.
59. Fyles AW, McCready DR, Manchul LA, et al. Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast
cancer. N Engl J Med. 2004;351:963-970.
60. Kunkler IH, Williams LW, Jack W, et al. The PRIME II trial: Wide local
excision and adjuvant hormonal therapy postoperative whole
breast irradiation in women 65 years with early breast cancer managed by breast conservation. San Antonio Breast Cancer Symposium. 2013;S2-S01.
61. Potter R, Gnant M, Kwasny W, et al. Lumpectomy plus tamoxifen or anastrozole with or without whole breast irradiation in women with favorable
early breast cancer. Int J Radiat Oncol Biol Phys. 2007;68:334-340.
55
BREAST CANCER
SPEAKERS
Brian D. Lehmann, PhD
Vanderbilt-Ingram Cancer Center
Nashville, TN
Mary L. Disis, MD
University of Washington
Seattle, WA
From the Tumor Vaccine Group, Center for Translational Medicine in Womens Health, University of Washington, Seattle, WA.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Mary L. Disis, MD, Center for Translational Medicine in Womens Health, 850 Republican St., Box 358050, University of Washington, Seattle, WA 98109; email: ndisis@uw.edu.
2015 by American Society of Clinical Oncology.
e25
KEY POINTS
In triple-negative breast cancer (TNBC), robust levels of
tumor inltrating lymphocytes (TIL) are associated with
improved disease-free and overall survival as well as
pathologic complete response in the neoadjuvant setting.
Only a minority of TNBC express robust TIL; most tumors
show low to no levels of inltrating lymphocytes.
Increased incidence of robust TIL in TNBC, as compared
with other breast cancer subtypes, could be caused by
increased mutations creating a neoepitope signature, as
well as increased B cells augmenting adaptive immunity via
antibody-dependent cell-mediated cytotoxicity.
The immune checkpoint inhibitor protein programmed cell
death protein 1 (PD-1) is commonly expressed in TNBC, with
70% of patients demonstrating PD-1 upregulation on T cells
and approximately 50% of triple-negative tumors expressing
coreceptor programmed death ligand 1 receptor (PD-L1).
In metastatic TNBC, clinical trials of monoclonal antibodies
blocking immune checkpoint proteins PD-1 and PD-L1 show
similar overall response rates (approximately 20%), as has
been observed for metastatic melanoma where immune
checkpoint inhibitors are now a U.S. Food and Drug
Administrationapproved therapy.
e26
e27
Rational
T cells proliferate and divide in response to antigen and immunomodulation. T cells need time
to expand to the numbers required for an inuence on tumor growth.
Trafcking T cells can inltrate the tumor in high enough numbers to cause inammation and
swellingknown as pseudoprogression.
General immune stimulators, such as checkpoint inhibitors, can induce immunity reactive to
normal tissues that are immunologically active (e.g., skin, gut).
T cells and tumor cells can exist in an immunologic equilibrium in which T cells control tumor
growth but do not eradicate cancer.
This represents the development of immunologic remodeling where some metastatic deposits
have developed mechanisms of immune resistance.
CONCLUSION
Population-based studies of TIL in breast cancer have underscored that the disease is immunologically active, with TNBC
showing the greatest beneft from an endogenous immune
response. Initial studies of immune modulation clearly indicate that TNBC is responsive to newly developed immunooncology agents that have been clinically effective in classic
immunologic tumors such as melanoma. This observation
furthermore may allow immune-based therapies to move
rapidly from clinical development to standard of care in
TNBC. Rational combinations to further enhance immunity
should be tested in all subtypes of breast cancer. Identifying
the components of the tumor immune environment that improve prognosis in breast cancer may also identify methods
Adverse Event
Skin
Liver
Endocrine
Gut
Diarrhea, colitis
in clinical beneft. A better understanding of the immune microenvironment and why certain subtypes of breast cancer
are more, or less, immunogenic will speed the clinical application of immune modulatory therapies to the beneft
of all patients with breast cancer. Lessons learned in triplenegative disease is a great start to improved outcomes for
all.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: Mary L. Disis, Epithany, VentiRx. Honoraria: None. Consulting or
Advisory Role: Mary L. Disis, Celgene, EMD Seronon, Emergent BioSolutions, VentiRx. Speakers Bureau: None. Research Funding: Mary L. Disis, Seattle
Genetics, Ventrx. Patents, Royalties, or Other Intellectual Property: Mary L. Disis, I am an inventor on patents held by the University of Washington.
Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Denkert C, Loibl S, Noske A, et al. Tumor-associated lymphocytes as an
independent predictor of response to neoadjuvant chemotherapy in
breast cancer. J Clin Oncol. 2010;28:105-113.
2. Loi S, Sirtaine N, Piette F, et al. Prognostic and predictive value of
tumor-infltrating lymphocytes in a phase III randomized adjuvant
breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013;31:860-867.
3. Issa-Nummer Y, Darb-Esfahani S, Loibl S, et al. Prospective validation
of immunological infltrate for prediction of response to neoadjuvant
chemotherapy in HER2-negative breast cancer-a substudy of the neoadjuvant GeparQuinto trial. PLoS One. 2013;8:e79775.
4. Pedroza-Gonzalez A, Xu K, Wu TC, et al. Thymic stromal lymphopoietin fosters human breast tumor growth by promoting type 2 inflammation. J Exp Med. 2011;208:479-490.
5. Cecil DL, Holt GE, Park KH, et al. Elimination of IL-10-inducing
T-helper epitopes from an IGFBP-2 vaccine ensures potent antitumor
activity. Cancer Res. 2014;74:2710-2718.
6. Wimberly H, Brown JR, Schalper KA, et al. PD-L1 expression correlates with tumor-infltrating lymphocytes and response to neoadjuvant chemotherapy in breast cancer. Cancer Immunol Res. Epub
2014 December 19.
7. Arnould L, Gelly M, Penault-Llorca F, et al. Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular
cytotoxicity mechanism? Br J Cancer. 2006;94:259-267.
8. Dieci MV, Criscitiello C, Goubar A, et al. Prognostic value of tumorinfltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study.
Ann Oncol. 2014;25:611-618.
9. Ono M, Tsuda H, Shimizu C, et al. Tumor-infltrating lymphocytes are
correlated with response to neoadjuvant chemotherapy in triplenegative breast cancer. Breast Cancer Res Treat. 2012;132:793-805.
10. Ibrahim EM, Al-Foheidi ME, Al-Mansour MM, et al. The prognostic
value of tumor-infltrating lymphocytes in triple-negative breast cancer:
a meta-analysis. Breast Cancer Res Treat. 2014;148:467-476.
11. Mao Y, Qu Q, Zhang Y, et al. The value of tumor infltrating lymphocytes (TILs) for predicting response to neoadjuvant chemotherapy in
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
e29
e30
(MK-3475) in patients with advanced triple-negative breast cancer. Presented at San Antonio Breast Cancer Symposium. December 9-13, 2014.
San Antonio, TX. Abstract S1-09.
27. Emens LA, Braiteh FS, Cassier P, et al. Inhibition of PD-L1 by
MPDL3280A leads to clinical activity in patients with metastatic triplenegative breast cancer. Presented at San Antonio Breast Cancer Symposium. December 9-13, 2014. San Antonio, TX.
NBC is a heterogeneous collection of breast cancers lacking expression of estrogen receptor (ER), progesterone
receptor (PR), and HER2 amplifcation. Together these tumors represent approximately 15% of all breast cancers, preferentially affect young women, and are more frequent in
women of African and Hispanic descent.1,2 Patients with
TNBC have a higher risk of both local and distant recurrence,
and metastasis is more likely to occur in the brain and lungs
rather than bone compared to other subtypes. The overwhelming majority of metastases of TNBC occur within the
frst 3 years following diagnosis, and patients who have not
recurred during this time have similar survival rates as do
patients with ER-positive breast cancers.3
There is a well-established association between deleterious
BRCA1 mutations and the risk of developing TNBC, with
lifetime risks reaching as high as 50% to 85%. BRCA1 encodes an E3 ubiquitin protein ligase essential for homologous
recombination mediated-repair of DNA double-stand
breaks. Retrospective analysis and previous trials have shown
striking pathologic complete response (pCR) rates in BRCA1
mutation carriers (72% to 90%) with single-agent neoadjuvant DNA-crosslinking platinum salts (e.g., cisplatin).4,5 In
the metastatic TNBC setting, a phase III study (Triple Negative Breast Cancer Trial, TNT) of carboplatin area under the
curve (AUC) 6 every 3 weeks compared with docetaxel 100
mg/m2 every 3 weeks as frst-line treatment was conducted in
376 women with assessment of BRCA status.6 In the overall
From the Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN; Levine Cancer Institute, Carolinas Healthcare System, Charlotte, NC.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Antoinette R. Tan, MD, MHSc, Levine Cancer Institute, Carolinas Healthcare System, 1021 Morehead Medical Drive, Charlotte, NC 28204;
email: antoinette.tan@carolinashealthcare.org.
2015 by American Society of Clinical Oncology.
e31
KEY POINTS
Triple-negative breast cancer (TNBC) is a histologically and
transcriptionally diverse collection of breast cancers.
Chemotherapy is the current mainstay of therapy for TNBC
in the adjuvant, neoadjuvant, and metastatic settings.
Poly(ADP-ribose) polymerase (PARP) inhibitors show
promise as a single-agent in BRCA 1/2-associated TNBC, but
for sporadic TNBC, PARP inhibitors likely need to be
combined with DNA-damaging agents or other targeted
agents to be an effective therapeutic approach.
Antiandrogen therapy shows clinical benet in the luminal
androgen receptor (AR) subtype of TNBC, which is enriched
with luminal genes and expression of the AR.
Targeting low frequency specic alterations in broblast
growth factor receptor (FGFR) and NOTCH proteins merits
further investigation and will require multicenter and
collaborative clinical trials to evaluate the efcacy of FGFR
and gamma-secretase inhibitors in these small subsets of
TNBC.
e32
SUBTYPES OF TNBC
Using gene expression analyses from 386 tumors, we recently
identifed six distinct TNBC subtypes, each displaying
unique biologies.20 The TNBC molecular subtypes include
two basal-like (BL1 and BL2), an immunomodulatory (IM), a
mesenchymal (M), a mesenchymal stem-like (MSL), and a
luminal AR (LAR) subtype. The BL1 subtype is characterized
by elevated cell cycle and DNA damage response gene expression, while the BL2 subtype is enriched in growth factor signaling and myoepithelial markers. Both M and MSL
share elevated expression of genes involved in epithelialmesenchymal-transition (EMT) and growth factor pathways, but the MSL subtype has decreased expression of
genes involved in proliferation. Consistent with the dedifferentiated mesenchymal gene expression pattern is the
recent analysis of metaplastic breast cancers showing the majority of chondroid and spindle cell carcinomas to be of the
MSL subtype.17 The IM subtype is composed of immune antigens and genes involved in cytokine and core immune signal transduction pathways. The LAR subtype is characterized
by luminal gene expression and is driven by the AR. Comparison with the intrinsic subtypes demonstrated that BL1,
BL2, IM, and M are largely composed of basal-like subtype,
while MSL has a large fraction of normal-like and LAR
mostly composed of luminal and HER2 subtypes.19 In addition to the intrinsic subtypes, a claudin-low subtype has recently been described and is enriched for EMT markers,
immune response, and cancer stem celllike genes.22 This
claudin-low subtype is mostly composed of M and MSL
TNBC subtypes.19
In addition, we identifed representative cell lines and demonstrated differential sensitivity to chemotherapy and targeted agents. BL1 cell lines are sensitive to genotoxic agents,
LAR cell lines have differential sensitivity to the LAR antagonist bicalutamide and PI3K inhibitors, mesenchymal cell
lines are more sensitive to the multifamily tyrosine kinase inhibitor dasatinib, and M cell lines display some sensitivity to
PI3K/mTOR inhibitors. Subtyping of breast tumors from
The Cancer Genome Atlas (TCGA) resulted in identifcation
of 163 tumors and analysis of the clinical data associated with
TNBC tumors demonstrated that the median OS and DFS of
patients with BL1, IM, and MSL subtype tumors were nearly
double that of patients with BL2, LAR, and M tumors.23 Further, patients with tumors of the IM subtype had the best outcome. Analysis of the gene expression data from the IM
subtype and identifcation of transcripts associated with lymphocytes suggests that the IM tumor samples may contain
tumor-infltrating lymphocytes (TILs). The favorable outcome of patients with TNBC with higher levels of TILs associated with their tumors has recently been demonstrated in
two adjuvant phase III trials.24
A similar transcriptional analysis was recently performed
on a smaller cohort of 84 patients, and investigators identifed four stable TNBC subgroups associated with distinct
clinical outcomes.21 They defned these subtypes as luminal/
androgen receptor (LAR), mesenchymal (MES), basallike/immune-suppressed (BLIS), and basal-like/immune
activated (BLIA) groups. Similar to the previous study,
TNBC patients with tumors expressing immune component
features had the best outcome. Between the two studies there
is clearly evident overlap between MSL and MES, IM and BL1
with BLIA, M with BLIS, and the two LAR subtypes. In summary, these data show that reproducible and distinct transcriptional subtypes can be unmasked when TNBC samples
are analyzed in the absence of ER- and HER2-expressing tumors and as sample size is increased there will likely be additional unique subtypes revealed.
Despite the rather aggressive clinical behavior of TNBC,
approximately 30% of patients with TNBC beneft from chemotherapy. In a retrospective reanalysis of pretreatment
biopsies, TNBC molecular subtypes were predictive of response to neoadjuvant anthracycline and cyclophosphamide
followed by taxane.25 This study showed BL1 had the highest
pCR rate (50%) at time of surgery and BL2 and LAR had the
lowest (0% and 10%, respectively). Similar to the initial classifcation, patients with LAR subtype were signifcantly older
at diagnosis, and recent preclinical data suggest that these patients may beneft from antiandrogen or PI3K inhibitors.26
We recently demonstrated that PIK3CA kinase domain mutations are a frequent event in AR-positive TNBC tumors relative to the other subtypes (40% vs. 4%), and targeting of AR
in LAR cells increases sensitivity to PI3K inhibitors. These
data suggest that although there are few genomic alterations
shared by TNBC as a whole, individual subtypes may be enriched in select somatic alterations, several of which may afford opportunities for preclinical discovery and translation
to clinical investigation.
e33
Ipatasertib (GDC-0068) is a novel, selective, ATPcompetitive small molecule inhibitor of all three isoforms of
the serine/threonine kinase AKT.44 It shows single-agent activity in several xenograft models with AKT pathway activation via PTEN loss and/or PIK3CA mutation, including
breast. In a phase Ib study of ipatasertib and paclitaxel in patients with MBC, the most commonly reported side effects
were diarrhea, nausea, fatigue, vomiting, anorexia, and
rash.45 LOTUS (NCT02162719) is a randomized, doubleblind, placebo-controlled international phase II study to
evaluate the effcacy of ipatasertib combined with paclitaxel
compared with placebo with paclitaxel in approximately 120
patients with previously untreated locally advanced or
MBC.46 The primary endpoint is PFS in all patients with
TNBC and patients with TNBC with PTEN-low tumors.
Randomization is 1:1 to either paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 of each 28-day cycle and ipatasertib 400 mg orally daily on days 1 through 21 of each cycle or
paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 of
each 28-day cycle and placebo. The trial is currently accruing.
The combination of weekly paclitaxel and ipatasertib is also
being evaluated in the neoadjuvant setting. FAIRLANE
(NCT02301988) is a randomized, double-blind, placebocontrolled, multicenter, preoperative phase II study designed
to estimate the effcacy of ipatasertib combined with paclitaxel compared with placebo combined with paclitaxel in
women with stage IA-IIIA (primary tumors 1.5 cm)
TNBC.47 The primary endpoint is pCR in the breast and
lymph nodes. Approximately 150 patients will be enrolled at
approximately 30 centers. Patients will be randomly assigned
in a 1:1 ratio, stratifed by the following three factors: PTEN
status (null, low, medium), prior adjuvant/neoadjuvant
treatment including chemotherapy with or without radiation, and disease-free interval from last dose of chemotherapy. Following surgical resection of primary tumor, patients
are expected to continue postoperative treatment with a standard adjuvant anthracycline-based chemotherapy regimen.
The trial is being conducted in collaboration with the SOLTI
Breast Cancer Research Group and is ongoing.
OTHER STRATEGIES
Other notable targets have led to additional clinical trial efforts to evaluate more tailored therapies for specifc subpopulations within TNBC.
Blockade of the AR
Approximately 10% to 15% of TNBC express the AR.59 The
LAR subclass of TNBC is characterized by luminal gene expression and enriched for AR and AR gene targets.20 This is
the basis for targeting this subset of TNBC with antiandrogen
therapy. In a multicenter phase II study by Gucalp et al, 150
mg of bicalutamide, an oral nonsteroidal antiandrogen, was
administered daily to 26 patients with AR-positive, ERnegative, and PR-negative MBC, who were determined to be
evaluable for the primary endpoint of clinical beneft rate
(CBR; complete response partial response stable disease 6 months).60 A CBR of 18% (95% CI, 6% to 37%),
consisting of all stable disease, and a median PFS of 12 weeks
(95% CI, 11 to 22 weeks) was reported. The most common
treatment-related toxicities were fatigue (21%), hot flashes
(21%), limb edema (21%), aspartate aminotransferase elevation (25%), and alanine aminotransferase elevation (21%). Of
note, 452 patients with ER-negative and PR-negative breast
cancer were screened for AR expression, and 12% tested ARpositive, consistent with an earlier report.59 The activity of a
next-generation antiandrogen, enzalutamide, was evaluated
in advanced AR-positive TNBC. In this multicenter trial, 26
patients evaluable for the primary endpoint of CBR (complete response partial response stable disease at 16
weeks) received enzalutamide 160 mg orally daily.61 The
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e35
Targeting Trop-2
Trop-2, also referred to as M1S1, TACSTD2, EGP-1, is a cell
surface protein overexpressed in several epithelial cancers,
but not in corresponding normal tissues.73 Trop-2 is a transmembrane calcium signal transducer and is involved in the
regulation of cell-cell adhesion.74 Membrane-associated
Trop-2 was found to be associated with poor prognosis in
breast cancer.75 There is a growing interest in targeting
Trop-2 in TNBC. IMMU-132 (isactuzumab govitecan) is an
antibody-drug conjugate containing the humanized mono-
ing of 7 partial responses, and a CBR (partial response stable disease 6 months) of 40%.77 Immunohistochemical
data on Trop-2 scoring is being collected. A phase II trial will
treat 80 patients with metastatic TNBC who have received
two or more prior regimens with IMMU-132 alone or in
combination with carboplatin (NCT02161679).78 Further research is necessary to evaluate the strategy of using antitrop-2
therapeutics for breast cancer and the relationship of Trop-2
expression to response.
CONCLUSION
TNBC is a heterogeneous disease. The identifcation of several specifc subtypes characterized by different biologic
pathways and various sensitivities to chemotherapy is instrumental in delivering more personalized therapy for TNBC.
Ongoing and future clinical research in selected subsets of
TNBC will validate the effcacy of such novel treatment
strategies.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: None.
Speakers Bureau: None. Research Funding: Antoinette R. Tan, Abbvie (Inst), Bayer/Onyx (Inst), Eisai (Inst), Genentech (Inst), GlaxoSmithKline (Inst),
ImClone Systems (Inst), Merck (Inst), Nektar Therapeutics (Inst). Patents, Royalties, or Other Intellectual Property: Brian D. Lehmann, Intellectual
property for TNBCtype licensed by Insight Genetics LLC. (Inst). Jennifer Pietenpol, Insight Genetics. Expert Testimony: None. Travel, Accommodations,
Expenses: Jennifer Pietenpol, Roche. Other Relationships: None.
References
1. Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and
survival in the Carolina Breast Cancer Study. JAMA. 2006;295:24922502.
2. Amirikia KC, Mills P, Bush J, et al. Higher population-based incidence
rates of triple-negative breast cancer among young African-American
women: implications for breast cancer screening recommendations.
Cancer. 2011;117:2747-2753.
3. Dent R, Trudeau M, Pritchard KI, et al. Triple-negative breast cancer:
clinical features and patterns of recurrence. Clin Cancer Res. 2007;13:
4429-4434.
4. Silver DP, Richardson AL, Eklund AC, et al. Effcacy of neoadjuvant cisplatin in triple-negative breast cancer. J Clin Oncol. 2010;28:1145-1153.
5. Byrski T, Gronwald J, Huzarski T, et al. Pathologic complete response
rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol. 2010;28:375-379.
6. Tutt A, Ellis P, Kilburn L, et al. TNT: a randomized phase III trial of carboplatin compared with docetaxel for patients with metastatic or recurrent
locally advanced triple-negative or BRCA1/2 breast cancer. 37th Annual
San Antonio Breast Cancer Symposium. December 2014. Abstract S3-01.
7. Gonzalez-Angulo AM, Timms KM, Liu S, et al. Incidence and outcome
of BRCA mutations in unselected patients with triple receptor-negative
breast cancer. Clin Cancer Res. 2011;17:1082-1089.
8. Shah SP, Roth A, Goya R, et al. The clonal and mutational evolution
9.
10.
11.
12.
13.
14.
15.
16.
e37
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
e38
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
e39
BREAST CANCER
Optimizing Treatment of
HER2-Positive Breast Cancer
CHAIR
Stephen K. Chia, MD, FRCP(C)
BC Cancer Agency
Vancouver, BC, Canada
SPEAKERS
Sunil Verma, MD, MSEd, FRCP(C)
Sunnybrook Odette Cancer Centre
Toronto, ON, Canada
Michelle E. Melisko, MD
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, CA
e41
STEPHEN K. CHIA
NSABP B-313
Trastuzumab
Duration
Median Follow-up
(Months)
Treatment Arms
No. of Patients
1 yr
24
Chemotherapy
1,698
Chemotherapy 3 H
1,703
AC 3 P
1,679
1 yr
24
1 yr
36
NCCTG N9831
BCIRG 0065
HR for DFS
(95% CI)
2-3 yr DFS
0.64 (0.540.76)
85.8%
HR for OS
(95% CI)
2-yr OS
0.66 (0.470.91)
96.0%
77.4%
95.1%
75.4%
0.48 (0.390.59)
87.1%
91.7%
AC 3 P 3 H
1,672
AC 3 T
1,073
0.67 (0.480.93)
AC 3 TH
1,074
0.61 (0.480.76)
88%
0.59 (0.420.85)
N/A
TcarboH
1,075
0.67 (0.540.83)
87%
0.66 (0.470.93)
N/A
81%
94.3%
N/A
Abbreviations: HR, hazard ratio; DFS, disease-free survival; OS, overall survival; H, trastuzumab; NSABP, National Surgical Adjuvant Breast and Bowel Project; A, doxorubicin; C, cyclophosphamide;
P, paclitaxel; NCCTG, National Central Cancer Treatment Group; BCIRG, Breast Cancer International Research Group; T, docetaxel; carbo, carboplatin.
New York Heart Association class I or class II cardiac dysfunction with a left ventricular ejection fraction (LVEF) drop
of 10% or more below baseline and to an absolute LVEF of
50% or less. Furthermore, it is felt that the majority of cardiac
events secondary to trastuzumab are reversible in nature.
Perhaps the remaining limited questions at hand specifc to
clinical practice in relation to these landmark trials are (1)
treatment of HER2-positive T1a-bN0 breast cancers, (2) anthracycline or no anthracycline-based regimen, and (3) concurrent compared with sequential trastuzumab therapy. A
small minority of patients in these four pivotal trials had
T1a-bN0 breast cancers. Several retrospective prognostic
studies demonstrate a signifcantly worse prognosis in HER2positive T1a-bN0 breast cancers compared with HER2-negative
T1a-bN0 breast cancers.9,10 In a recent analysis from the National Comprehensive Cancer Network (NCCN) database
examining this exact question, 4,113 patients with T1a-bN0
breast cancers treated between 2000 and 2009 were assessed
by biologic subtype and receipt of chemotherapy (or not) and
trastuzumab (or not).11 Within this subgroup not treated
KEY POINTS
The treatment of HER2-positive early-stage breast cancer
should incorporate 12 months of adjuvant trastuzumab,
preferably concurrent with a taxane backbone.
Neoadjuvant systemic therapies are now routinely delivered
in both primary operable and locally advanced breast
cancer in the research domain and in clinical practice.
The combination of lapatinib and trastuzumab
inconsistently improved pathologic complete response
(pCR) rates across its neoadjuvant trials and ultimately did
not improve disease-free survival (DFS) in the large
adjuvant ALTTO trial.
In a large pooled analysis, pCR (with or without the
presence of in situ disease) in the breast and nodes most
closely correlates with DFS and overall survival.
Well-designed, randomized, neoadjuvant trials with tissue
acquisition are essential to more precisely plan adjuvant
trials, assess for predictive biomarkers, and accelerate
drug development for early-stage disease.
e42
Treatment Arms
HERA7
8 yr
Chemotherapy
NSABP B-316
8.4 yr
AC 3 P
Chemotherapy 3 H
NCCTG N9831
BCIRG 006
AC 3 P 3 H
5.5 yr
DFS
76.0%
0.76 (0.670.86)
OS
N/A
0.76 (0.650.88)
62.2%
N/A
75.2%
0.60 (0.530.68)
73.7%
AC 3 TH
0.64 (0.530.78)
84%
0.63 (0.480.81)
92%
TCarboH
0.75 (0.630.90)
81%
0.77 (0.600.99)
91%
AC 3 T
0.63 (0.540.73)
75%
84.0%
87%
Abbreviations: HR, hazard ratio; DFS, disease-free survival; OS, overall survival; H, trastuzumab; NSABP, National Surgical Adjuvant Breast and Bowel Project; A, doxorubicin; C, cyclophosphamide;
P, paclitaxel; NCCTG, National Central Cancer Treatment Group; BCIRG, Breast Cancer International Research Group; T, docetaxel; carbo, carboplatin.
taxane. In the NCCTG N9831 study, one arm delivered paclitaxel (weekly) concurrent with trastuzumab (arm C),
whereas in another arm, the trastuzumab was delivered sequential (arm B).14 Alhtough there was a numerical increase
in DFS in favor of the concurrent arm (84.4% vs. 80.1%), it
did not meet statistical signifcance based on the interim
analysis criteria (arm C/arm B HR 0.77; 95% CI, 0.53 to 1.11).
However, as there was no difference in toxicity between these
two arms, and for convenience and earlier completion of
therapy, it would be overall advantageous to deliver the trastuzumab concurrent with the taxane.
trial.16 NOAH randomly selected 228 patients with HER2positive disease to receive a neoadjuvant regimen consisting
of doxorubicin, paclitaxel, cyclophosphamide, methotrexate,
and 5-fluorouracil (CMF) with or without concurrent trastuzumab (throughout the entire chemotherapeutic regimen).
This is the largest randomized trial of a true locally advanced
and inflammatory population to date. The trastuzumabtreated cohort demonstrated a signifcantly superior rate of
pCR in breast and nodes (total pCR [tpCR]; 38% vs. 19%; p
0.001), which ultimately translated to an improved 3-year
event-free survival (EFS; 71% vs. 56%, HR 0.59; 95% CI, 0.38
to 0.90).17 Not only was a doubling of the tpCR rate impressive, but also the magnitude of improvement in EFS of a similar degree (HR 0.59) as the landmark adjuvant trastuzumab
trials is an interesting observation. Although the use of the
specifc chemotherapy regimen from NOAH is not likely to
be common, the concept of neoadjuvant trastuzumab concurrent with chemotherapy now is.
e43
STEPHEN K. CHIA
with either weekly trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly) or lapatinib (1,250 mg daily) given
concurrently with chemotherapy.18 This study also examined
the effcacy of a trastuzumab-lapatinib doublet with doseadjusted lapatinib (750 mg/day). Dual HER2 targeting
substantially improved pCR (breast and nodes) over either
trastuzumab or lapatinib alone. pCR rates were 46% (90%
CI, 34.4% to 58.9%), 25% (90% CI, 13.1% to 36.9%), and
26.3% (90% CI, 14.5% to 38.1%), respectively. As was seen
in the GeparQuinto trial, gastrointestinal toxicity with
lapatinib was a signifcant adverse event. More than 50%
of those receiving lapatinib experienced diarrhea of grade
1 or higher, even after a protocol amendment directing a
dose reduction from 1,500 mg/day to 1,250 mg/day in the
single-agent arm, and from 1,000 mg/day to 750 mg/day in
the doublet arm.
The NeoAdjuvant Lapatinib and/or Trastuzumab Optimization (NeoALTTO) trial was a three-armed study addressing the comparative effcacy of single compared with dual
HER2 blockade using trastuzumab (4 mg/kg loading dose
followed by 2 mg/kg weekly), lapatinib (1,500 mg daily), or a
combination (trastuzumab standard dose and lapatinib 1,000
mg daily), alongside weekly paclitaxel (80 mg/m2) chemotherapy.19 This trial scheduled a 6-week lead in period of targeted therapy alone before introduction of paclitaxel for a
further 12 weeks of therapy. Dual HER2 targeting induced
tpCR (breast and nodes) rates in 46.8% of patients compared
No. of Patients
309
Treatment Arms
ECH 3 TH
ECL 3 TL
21.7%
149
H 3 HP
27.6%
154
L 3 LP
20.0%
p 0.13
78%
152
HL 3 HLP
46.9%
p 0.001
84%
36
HP 3 FECH
25%
N/A
39
LP 3 FECL
26.3%
N/A
46
HLP 3 FECHL
46.7%
N/A
177
AC 3 HP
52.5% (breast)
171
AC 3 LP
53.2% (breast)
p 0.9852
p 0.095
311
NeoALTTO
19
CHER-LOB
18
NSABP B-41
20
CALGB 4060121
NeoSphere22
TRYPHENA23
171
AC 3 HLP
62.0% (breast)
120
HP
40% (breast)
p
p 0.05
3-yr EFS
N/A
N/A
76%
N/A
N/A
N/A
N/A
67
LP
32% (breast)
118
HLP
51% (breast)
N/A
107
TH
29.0% (breast)
107
PerHT
45.8% (breast)
107
PerH
24.0% (breast)
N/A
96
PerT
16.8% (breast)
N/A
p 0.11
N/A
N/A
p 0.0141
N/A
73
PerHFEC 3 PerTH
61.6% (breast)
N/A
75
FEC 3 PerTH
57.3% (breast)
N/A
77
TcarboHPer
66.2% (breast)
N/A
Abbreviations: pCR, pathologic complete response; EFS, event-free survival; E, epirubicin; C, cyclophosphamide; H, trastuzumab; T, docetaxel; L, lapatinib; P, paclitaxel; F, 5-uorouracil; NSABP,
National Surgical Adjuvant Breast and Bowel Project; A, doxorubicin; CALGB, Cancer and Leukemia Group B; Per, pertuzumab; carbo, carboplatin.
e44
timal use of anti-HER2 targeted therapy in early-stage disease. We eagerly wait to see if dual adjuvant anti-HER2
antibody inhibition with trastuzumab and pertuzumab produces clinically signifcant improvements in outcome. Results from both the metastatic setting and the neoadjuvant
trials (in particular NeoSphere) would predict that the large
adjuvant trial APHINITY (NCT01358877) will likely be signifcant. The question will then be how signifcant will the
result need to be to alter standard clinical practice and be
cost-effective. The following are other remaining questions.
e45
STEPHEN K. CHIA
trend was seen, there was no signifcant difference in EFS between the combination arm and the trastuzumab arm (HR
0.78; 95% CI, 0.47 to 1.28; p 0.33).27
The ALTTO trial randomly assigned 8,381 patients, of
whom 40% had node-negative disease and 57% had hormone
receptorpositive disease.28 The four arms of the study were
trastuzumab for 12 months (T), lapatinib for 12 months (L),
trastuzumab for 12 weeks followed sequentially by lapatinib
for 34 weeks (T3 L), and the combination of trastuzumab
and lapatinib for 12 months (TL). Although the study was
powered for 850 DFS events, the study was analyzed at 4.5
years (median) of follow-up as per protocol stipulation but
with only 555 DFS events. At the frst effcacy interim analysis, the comparison of L to T crossed the futility boundary,
and as such, the L arm was crossed over to a recommended
course of trastuzumab for 12 months. At the time of reporting of the effcacy of the primary endpoint at the 2014 ASCO
Annual Meeting, the 4-year DFS for the T, T3 L, and TL
arms were 86%, 87%, and 88%, respectively. The HR comparing TL and T was 0.84 (0.70 1.02; p 0.048), which was not
signifcant, for a p 0.025 was required for statistical significance. The interaction test for hormone receptor status and
for schedule of anti-HER2 therapy was not signifcant. However, numerically, the sequential administration of antiHER2 therapy arms had some difference (T vs. TL 4-year
DFS of 83% vs. 86%, respectively), whereas the combination
arms did not (T vs. TL 4-year DFS of 90% vs. 90%, respectively). Lapatinib was also associated with a greater rate of
adverse events, which subsequently led to only 60% to 78% of
patients in the lapatinib treatment arms receiving at least 85%
of the intended dose intensity of L. These factors, in addition
to a time-driven analysis (rather than the initial powering of
the study for an event-driven analysis) may have affected the
true effcacy of the dual anti-HER2 combination arm.
Neratinib has been studied in a neoadjuvant manner as
part of the I-SPY 2 program, as well as in an extended manner
in a placebo-controlled trial in a population of patients following 1 year of standard adjuvant trastuzumab-based therapy. In the I-SPY 2 trial, neratinib was given in combination
with weekly paclitaxel (80 mg/m2 for 12 weeks) in both the
HER2-positive and HER2-negative cohorts.29 All patients
subsequently received sequential doxorubicin (60 mg/m2)
and cyclophosphamide (600 mg/m2) for four cycles without
neratinib or trastuzumab before proceeding to defnitive surgery. In the HER2-positive signature cohort, the pCR rate
was 39% in the neratinib plus paclitaxel arm, compared to
23% in the trastuzumab plus paclitaxel arm. The magnitude
of improvement in pCR was similar regardless of the hormone receptor status in the HER2-positive cohort. No significant difference in pCR rates was seen in the HER2-negative
signature cohort. A signifcant rate of grade 23 diarrhea was
seen, however, in the neratinib arms resulting in dose reductions/holds in 65% of cases for neratinib (vs. 15% in the control arm).
ExteNET is a double-blind phase III trial of neratinib (240
mg orally once daily) versus placebo in 2,821 women with
early-stage HER2-positive (local confrmation) breast cancer
e46
CONCLUSION
In conclusion, in the post-adjuvant trastuzumab era, the outcome of HER2-positive breast cancer has now evolved from a
subtype with the worse prognosis to one with arguably the
best long-term outcomes. Current standard of care should
incorporate 12 months of adjuvant trastuzumab and preferably be concurrent with a taxane backbone. Moving forward
we must continue embracing the neoadjuvant model as both
standard of care and an important strategy to test new ther-
apeutic agents and accelerate drug development. Welldesigned, randomized, neoadjuvant studies importantly
allow us to more intelligently guide and support the trial design of adjuvant studies and, by doing so, will minimize overall timelines for drug development in early-stage disease.
Although an adequate signal from preoperative trials may
not necessarily predict the outcome in a confrmatory adjuvant trial, the lack of a signal should halt further development
in a more resource-intensive adjuvant trial.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Stephen K. Chia, Genomic Health, Hoffmann
LaRoche, Novartis. Consulting or Advisory Role: Stephen K. Chia, Hoffmann LaRoche, Novartis. Speakers Bureau: Stephen K. Chia, Genomic Health.
Research Funding: Stephen K. Chia, Hoffmann LaRoche (Inst), Novartis (Inst). Patents, Royalties, or Other Intellectual Property: None. Expert
Testimony: None. Travel, Accommodations, Expenses: Stephen K. Chia, Hoffmann LaRoche. Other Relationships: None.
References
1. Goldhirsch A, Winer EP, Coates AS, et al. Personalizing the treatment of
women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer
2013. Ann Oncol. 2013;24:2206-2223.
2. Gradishar WJ, Anderson BO, et al. NCCN clinical practice guidelines in
oncology: Breast Cancer Version 3.2014. http://nccn.org. Accessed February 7, 2015.
3. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med.
2005;353:1673-1684.
4. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl
J Med. 2005;353:1659-1672.
5. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in
HER-2 positive breast cancer. N Engl J Med. 2011;365:1273-1283.
6. Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant
chemotherapy for human epidermal growth factor receptor 2 positive
breast cancer: planned joint analysis of overall survival from NSABP
B-31 and NCCTG N9831. J Clin Oncol. 2014;32:3744-3752.
7. Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 year versus 1 year
of adjuvant trastuzumab for HER2 positive breast cancer (HERA): an
open label randomised controlled trial. Lancet. 2013;382:1021-1028.
8. Slamon DJ, Eiermann W, Robert N, et al. BCIRG 006 phase III trial
comparing AC T with AC H and with TCH in the adjuvant treatment of
HER2-amplifed early breast cancer patients: third planned effcacy
analysis. 32nd Annual San Antonio Breast Cancer Symposium. December 2009. San Antonio, TX.
9. Chia S, Norris B, Speers C, et al. Human epidermal growth factor receptor 2 overexpression as a prognostic factor in a large tissue microarray
series of node-negative breast cancers. J Clin Oncol. 2008;26:5697-5704.
10. Gonzalez-Angulo AM, Litton JK, Broglio KR, et al. High risk of recurrence for patients with breast cancer who have human epidermal
growth factor receptor 2-positive, node-negative tumors 1 cm or
smaller. J Clin Oncol. 2009;27:5700-5706.
11. Vas-Luis I, Ottesen RA, Hughes ME, et al. Outcomes by tumor subtype
12.
13.
14.
15.
16.
17.
18.
19.
20.
and treatment pattern in women with small node negative breast cancer:
a multi-institutional study. J Clin Oncol. 2014;32:2142-2150.
Tolaney SM, Barry WT, Dang CT, et al. Adjuvant paclitaxel and trastuzumab for node negative HER2 positive breast cancer. N Engl J Med.
2015;372:134-141.
Jones SE, Collea R, Paul D, et al. Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplifed early stage
breast cancer: a single group, open label, phase 2 study. Lancet Oncol.
2013;14:1121-1128.
Perez EA, Suman VJ, Davidson NE, et al. Sequential versus concurrent
trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol.
20111;29:4491-4497.
Rastogi P, Anderson SJ, Bear HD, et al. Pre-operative chemotherapy:
updates of National Surgical Adjuvant Breast and Bowel Project Protocol B-18 and B-27. J Clin Oncol. 2008;26:778-785.
Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy
with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled
superiority trial with a parallel HER2-negative cohort. Lancet. 2010;375:
377-384.
Untch M, Loibl S, Bischoff J, et al. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy
(GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol. 2012;
13:135-144.
Guarneri V, Frassoldati A, Bottini A, et al. Preoperative chemotherapy
plus trastuzumab, lapatinib, or both in human epidermal growth factor
receptor 2-positive operable breast cancer: results of the randomized
phase II CHER-LOB study. J Clin Oncol. 2012;30:1989-1995.
Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for
HER2-positive early breast cancer (NeoALTTO): a randomised, openlabel, multicentre, phase 3 trial. Lancet. 2012;379:633-640.
Robidoux A, Tang G, Rastogi P, et al. Lapatinib as a component of neoadjuvant therapy for HER2 operable breast cancer: NSABP protocol
e47
STEPHEN K. CHIA
21.
22.
23.
24.
25.
26.
e48
SPEAKERS
Katherine D. Crew, MD, MS
Columbia University Medical Center
New York, NY
Christine Holmberg, PhD, MPH
Charite Universittsmedizin Berlin, Berlin School of Public Health
Berlin, Germany
KATHERINE D. CREW
nlike cardiovascular disease, limited pharmacologic options exist for the primary prevention of cancer. Antiestrogens, such as SERMs and AIs, have been shown to
reduce breast cancer incidence by up to 50% to 65% among
women at high risk.1-5 Based on this evidence, the U.S. Preventive Services Task Force (USPSTF) and other professional
organizations recommend that clinicians discuss chemoprevention with women at high risk.6-8 An estimated 15% of
women age 35 to 79 in the United States may be eligible for
chemoprevention,9 but less than 5% of women at high risk
who are offered an antiestrogen for primary prevention agree
to take it.10 Compounding this underutilization is the large
proportion of women who may be unaware of their high-risk
status because of an inability to routinely screen for high risk
in the primary care setting. Other reasons for low chemoprevention uptake include insuffcient knowledge about antiestrogens on the part of clinicians and patients, multiple
competing demands for PCPs, and concerns about side effects.10,11 Even the term chemoprevention has negative
connotations, because it sounds like chemotherapy. The
perception among patients and PCPs is that medications
used to treat cancer and prescribed by oncologists may have
From the Department of Medicine, College of Physicians and Surgeons, Department of Epidemiology, Mailman School of Public Health, and Herbert Irving Comprehensive Cancer Center, Columbia
University, New York, NY.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Katherine D. Crew, MD, MS, Herbert Irving Comprehensive Cancer Center, Columbia University, 161 Fort Washington Ave., 10-1072, New York, NY 10032; email:
kd59@cumc.columbia.edu.
2015 by American Society of Clinical Oncology.
e50
into account a womans age, race, reproductive history, frstdegree family history of breast cancer, and benign breast disease including atypia, is the most commonly used model in
the United States and has been well validated at the population level.14 It can be administered to women age 35 or older
and provides an individuals absolute 5-year and lifetime risk
of invasive breast cancer compared to women of the same age
and race in the general population. High-risk criteria used to
determine eligibility in chemoprevention trials are at least a
1.67% 5-year risk or 20% or greater lifetime risk of invasive
breast cancer. To account for differences in breast cancer risk
by race and ethnicity, the Gail model incorporated data from
the Womens Contraceptive and Reproductive Experiences15
and Asian American Breast Cancer Study16 to provide more
sensitive estimates for African American and Asian women,
respectively. Few studies have used this model in Hispanic
populations.17,18 Hispanic women have signifcantly lower
breast cancer risk compared to non-Hispanic white women;
however, risk differs among Hispanic subgroups in the
United States: according to the Gail model, Cubans have a
higher 5-year risk (p 0.05) and Dominicans have a higher
lifetime risk than Mexicans (p 0.001).19 Interestingly, eligibility for chemoprevention among U.S. women varies dramatically by race and ethnicity, with 18.7% of whites, 5.7% of
blacks, and 2.9% of Hispanics meeting high-risk criteria according to the Gail model.9
In women with a strong family history of breast cancer (i.e.,
two or more affected family members, particularly those with
early-age onset), the Tyrer-Cuzick model is useful because it
also accounts for second- and third-degree family history of
KEY POINTS
Breast cancer chemoprevention with antiestrogens is
underutilized despite several randomized controlled trials
demonstrating up to a 50% to 65% relative risk reduction
of breast cancer incidence among women at high risk.
Approximately 10 million women in the United States may
be eligible for breast cancer chemoprevention, but less
than 5% of women at high risk who are offered an
antiestrogen for primary prevention agree to take it.
Reasons for low chemoprevention uptake include lack of
routine breast cancer risk assessment in the primary care
setting, insufcient knowledge about antiestrogens on the
part of clinicians and patients, and concerns about side
effects.
Interventions designed to increase identication of women
at high risk and chemoprevention uptake, including written
materials, decision aids, and incorporating breast cancer
risk assessment tools into clinical practice, have met with
limited success.
Because of the proven efcacy of breast cancer
chemopreventive agents, widespread use of antiestrogens
for primary prevention among women at high risk has the
potential to signicantly improve the public health burden
of this disease.
Tyrer-Cuzick Model
Age
Age at menarche
Age at menarche
e51
KATHERINE D. CREW
Aromatase Inhibitors
TABLE 2. Updated Results from Major Randomized Controlled Trials of Selective Estrogen Receptor Modulators
and Aromatase Inhibitors for Breast Cancer Chemoprevention
Median
Follow-up
(Months)
Breast Cancer
Incidence
84
0.57 (0.460.70)
192
0.71 (0.600.83)
19,747
81
1.24 (1.051.47)
MAP.3, 20114
4,560
35
0.35 (0.180.70)
IBIS-II, 20135
3,864
60
2% versus 4%b
0.47 (0.320.68)
No. of
Participants
BCPT, 2005
13,388
IBIS-I, 20142
7,154
STAR, 20103
Trial
Intervention
Abbreviations: SERM, selective receptor estrogen modulators; AI, aromatase inhibitor; AH, atypical hyperplasia; BCPT, Breast Cancer Prevention Trial; CI, condence interval; DCIS, ductal
carcinoma-in-situ; HR, hazard ratio; IBIS, International Breast cancer Intervention Study; LCIS, lobular carcinoma in situ; MAP, Mammary Prevention Trial; RR, relative risk; STAR, Study of
Tamoxifen and Raloxifene.
a
Invasive breast cancer incidence rate/1,000 women.
b
All breast cancers, invasive and noninvasive.
c
Annual incidence of invasive breast cancers.
e52
anastrozole arm compared to 85 in the placebo group (hazard ratio 0.47; 95% confdence interval 0.32 0.68; p
0.0001). In the anastrozole group compared to placebo, more
arthralgia (51% vs. 46%), vasomotor symptoms (57% vs.
49%), vaginal dryness (19% vs. 16%), and hypertension (5%
vs. 3%) occurred. In general, there appear to be fewer serious
side effects with AIs compared to tamoxifen.
To date, there are no head-to-head trials comparing
SERMs to AIs or evaluating extended hormone therapy for
up to 10 years in the primary prevention setting. Also, these
antiestrogens have no effect on the incidence of ER tumors,
which are associated with a poorer prognosis compared to
ER breast cancer and are more common in younger
women, black women, and BRCA1 mutation carriers. In addition, limited data exist on the effcacy of antiestrogens for
breast cancer risk reduction in women with hereditary breast
cancer syndromes, such as BRCA1 and BRCA2 mutation carriers.43,44 Of note, none of these chemoprevention trials were
adequately powered to detect a difference in breast cancer
specifc or overall mortality.
Chemoprevention Guidelines
Based on this evidence, the USPSTF, American Society of
Clinical Oncology, and the National Comprehensive Cancer
Network published consensus guidelines on breast cancer
chemoprevention.6-8 Premenopausal and postmenopausal
women at high risk, defned as a 5-year Gail risk 1.67% or
greater or LCIS, may take tamoxifen for 5 years for the primary prevention of breast cancer. Younger women (age 35
50), those without a uterus, and those at higher risk for breast
cancer derive the greatest clinical beneft from tamoxifen.
Postmenopausal women at high risk also have the options of
raloxifene, exemestane, and anastrozole for breast cancer risk
reduction. Because of the increased risk of uterine cancer,
follow-up for women on tamoxifen should include annual
gynecologic examinations with a timely work-up of abnormal vaginal bleeding, but routine endometrial biopsies in the
absence of vaginal symptoms is not recommended. SERMs
are contraindicated in women with a history of thromboembolism, such as deep vein thrombosis, pulmonary embolus,
stoke, or transient ischemic attack. In addition, the STAR
trial excluded women with uncontrolled diabetes or hypertension, those with atrial fbrillation, and those on hormone
replacement therapy.45
Figure 1 depicts a potential algorithm for clinical decision
making about antiestrogens for breast cancer chemoprevention based on menopausal status, history of thromboembolism, risk of osteoporosis, and prior hysterectomy. For
premenopausal women at high risk, tamoxifen is currently
the only FDA-approved drug for the primary prevention of
breast cancer. Younger women (age 3550) at high risk derive the greatest clinical beneft from tamoxifen because the
risk of serious side effects, such as thromboembolism and
uterine cancer, is negligible compared to placebo. For postmenopausal women at high risk with an intact uterus, raloxifene may be favored over tamoxifen, whereas tamoxifen may
be preferable in women with a prior hysterectomy because of
e53
KATHERINE D. CREW
assessment varied by medical specialty (37% internal medicine, 33% family medicine, 60% gynecology), as well as ever
recommending or prescribing breast cancer chemoprevention (9% internal medicine, 8% family medicine, 30% gynecology).51 Barriers to routine breast cancer risk assessment in
the primary care setting include time constraints during
clinic visits and lack of familiarity with risk assessment tools
and chemoprevention.52 There may also be concerns about
the accuracy of breast cancer risk prediction models.
CONCLUSION
Breast cancer chemoprevention with antiestrogens has
proven effcacy in high-risk populations, but uptake remains
low. Preventive therapy for cancer is currently less well established compared to other chronic conditions, such as cardiovascular disease, and could beneft from lessons learned.101
Health care providers can do more in the area of cancer prevention by identifying high-risk populations in the primary
care setting. Chemoprevention needs to be integrated into
broader strategies of preventive care, which may include
nonpharmacologic interventions such as lifestyle modifcation. Given the high compliance rates for breast cancer
screening, incorporating formal risk assessments at the time
of screening mammography may represent a teachable
moment when women are already engaging in a health behavior related to breast cancer. Novel health information
technologies such as electronic health records and patient
health portals may be a method for integrating information
about breast cancer risk and chemoprevention into clinic
workflow.
No. of
Participants
Eligibility
Intervention
Outcomes
Fagerlin et al
201179
1,197
Owens et al 201180
868
Kaplan et al 201481
1,235
e55
KATHERINE D. CREW
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
e56
Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 2005;97:
1652-1662.
Cuzick J, Sestak I, Cawthorn S, et al. Tamoxifen for prevention of
breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncol. 2015;16:67-75.
Vogel VG, Costantino JP, Wickerham DL, et al. Update of the National
Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and
Raloxifene (STAR) P-2 Trial: preventing breast cancer. Cancer Prev
Res (Phila). 2010;3:696-706.
Goss PE, Ingle JN, Ales-Martinez JE, et al. Exemestane for breastcancer prevention in postmenopausal women. N Engl J Med. 2011;364:
2381-2391.
Cuzick J, Sestak I, Forbes JF, et al. Anastrozole for prevention of breast
cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet.
2013;383:1041-1048.
Nelson HD, Smith ME, Griffn JC, et al. Use of medications to reduce
risk for primary breast cancer: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2013;158:604-614.
Visvanathan K, Chlebowski RT, Hurley P, et al. American society of
clinical oncology clinical practice guideline update on the use of pharmacologic interventions including tamoxifen, raloxifene, and aromatase inhibition for breast cancer risk reduction. J Clin Oncol. 2009;27:
3235-3258.
Bevers TB. NCCN Clinical Practice Guidelines in Oncology: Breast
Cancer Risk Reduction. 2012. http://www.nccn.org/professionals/
physician_gls/pdf/breast_risk.pdf. Accessed February 15, 2015.
Freedman AN, Graubard BI, Rao SR, et al. Estimates of the number of
US women who could beneft from tamoxifen for breast cancer chemoprevention. J Natl Cancer Inst. 2003;95:526-532.
Ropka ME, Keim J, Philbrick JT. Patient decisions about breast cancer
chemoprevention: a systematic review and meta-analysis. J Clin Oncol.
2010;28:3090-3095.
Ravdin PM. The lack, need, and opportunities for decision-making
and informational tools to educate primary-care physicians and
women about breast cancer chemoprevention. Cancer Prev Res (Phila).
2010;3:686-688.
Singletary SE. Rating the risk factors for breast cancer. Ann Surg. 2003;
237:474-482.
Dupont WD, Page DL. Risk factors for breast cancer in women with
proliferative breast disease. N Engl J Med. 1985;312:146-151.
Costantino JP, Gail MH, Pee D, et al. Validation studies for models
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
projecting the risk of invasive and total breast cancer incidence. J Natl
Cancer Inst. 1999;91:1541-1548.
Gail MH, Costantino JP, Pee D, et al. Projecting individualized absolute invasive breast cancer risk in African American women. J Natl
Cancer Inst. 2007;99:1782-1792.
Matsuno RK, Costantino JP, Ziegler RG, et al. Projecting individualized absolute invasive breast cancer risk in Asian and Pacifc Islander
American women. J Natl Cancer Inst. 2011;103:951-961.
Abu-Rustum NR, Herbolsheimer H. Breast cancer risk assessment in
indigent women at a public hospital. Gynecol Oncol. 2001;81:287-290.
Grann VR, Jacobson JS, Troxel AB, et al. Barriers to minority participation in breast carcinoma prevention trials. Cancer. 2005;104:374379.
Banegas MP, Leng M, Graubard BI, et al. The risk of developing invasive breast cancer in Hispanic women: a look across Hispanic subgroups. Cancer. 2013;119:1373-1380.
Tyrer J, Duffy SW, Cuzick J. A breast cancer prediction model incorporating familial and personal risk factors. Stat Med. 2004;23:11111130.
Hartmann LC, Degnim AC, Santen RJ, et al. Atypical hyperplasia of the
breast-risk assessment and management options. N Engl J Med. 2015;
372:78-89.
Gutwein LG, Ang DN, Liu H, et al. Utilization of minimally invasive
breast biopsy for the evaluation of suspicious breast lesions. Am J Surg.
2011;202:127-132.
Simpson JF. Update on atypical epithelial hyperplasia and ductal carcinoma in situ. Pathology. 2009;41:36-39.
Coopey SB, Mazzola E, Buckley JM, et al. The role of chemoprevention
in modifying the risk of breast cancer in women with atypical breast
lesions. Breast Cancer Res Treat. 2012;136:627-633.
Hartmann LC, Radisky DC, Frost MH, et al. Understanding the premalignant potential of atypical hyperplasia through its natural history:
a longitudinal cohort study. Cancer Prev Res (Phila). 2014;7:211-217.
London SJ, Connolly JL, Schnitt SJ, et al. A prospective study of benign
breast disease and the risk of breast cancer. JAMA. 1992;267:941-944.
Degnim AC, Visscher DW, Berman HK, et al. Stratifcation of breast
cancer risk in women with atypia: a Mayo cohort study. J Clin Oncol.
2007;25:2671-2677.
Page DL, Schuyler PA, Dupont WD, et al. Atypical lobular hyperplasia
as a unilateral predictor of breast cancer risk: a retrospective cohort
study. Lancet. 2003;361:125-129.
Pankratz VS, Hartmann LC, Degnim AC, et al. Assessment of the accuracy of the Gail model in women with atypical hyperplasia. J Clin
Oncol. 2008;26:5374-5379.
Boughey JC, Hartmann LC, Anderson SS, et al. Evaluation of the
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
e57
KATHERINE D. CREW
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
e58
reast cancer is the leading cancer in females and is responsible for the greatest number of cancer deaths among
women worldwide,1 including the United States.2 According to
data for 2008 to 2010 collected in the Surveillance, Epidemiology, and End Results (SEER) program, 12.3% of women in the
United States will be diagnosed with breast cancer during their
lifetime. There is conflicting evidence as to whether changing
behavioral factors such as a sedentary lifestyle, smoking, or regular alcohol consumption can reduce the risk of breast cancer.3-6
Risk reduction efforts for breast cancer therefore pose a challenge, especially as the most effective options (young age at frst
live birth and having multiple children) conflict with other public health messages and efforts.7 In this context, chemoprevention with selective estrogen receptor modulators (SERMs) is
considered one of the most promising risk reduction options to
date in the United States. At the present time two SERMstamoxifen and raloxifeneare approved by the U.S. FDA for
breast cancer risk reduction, although other medications are under investigation.8 Leading oncologic organizations such as the
American Society for Clinical Oncology and the National Comprehensive Cancer Network recommend the use of these medications for prevention of breast cancer. Uptake, however, has
lagged behind expectations.9
Tamoxifen was the frst medication to be approved for breast
cancer risk reduction. The Breast Cancer Prevention Trial
e59
CHRISTINE HOLMBERG
KEY POINTS
Decision making in the context of breast cancer
chemoprevention includes complex risk benet trade-offs.
The decision should be based on individual preferences.
Increased knowledge on chemoprevention may deter
women from taking drugs for breast cancer prevention.
Perceptions of low efcacy, worries about side effects, and
the notion of tamoxifen as a cancer drug have all been
suggested as factors inuencing womens decision making
regarding chemoprevention for breast cancer risk
reduction.
Understandings of risk differ between health care providers
and laywomen.
e60
benefts.22 However, to truly understand, evaluate, and predict the uptake of SERM drugs, it may be crucial to understand womens perceptions of chemoprevention, as these are
likely to influence decision making.
PERCEPTIONS OF CHEMOPREVENTION
Below are presented some of the prevailing perceptions, assumptions, and beliefs about chemoprevention, as revealed
by research to date. However, most of this research has
looked only at tamoxifen. The study of Fagerlin et al23 provides one of the few exceptions, from which we may also
learn about perceptions of raloxifene.
Side Effects
Several studies have shown that women are concerned about
the side effects of SERM use.18,29 Moreover, these concerns
are not only related to the severe side effects such as endometrial cancers, but also to the more common but less serious effects of taking the drugs, such as hot flashes. For
example, one nested qualitative study reported that participants in focus group discussions were reluctant to end
hormone replacement therapy in favor of chemoprevention.29 SERMs may induce hot flashes, which are reduced
by hormone replacement therapy. Although hot flashes
may not be considered serious from a medical point of
view, they can impair a womans day-to-day activities and
reduce quality of life.
Risk Perception
Many womens perception of their breast cancer risk differs
from the objective risk estimates derived from personalized
risk assessments such as the Gail score or Claus model.
Indeed, when objective breast cancer risk estimates are compared to womens own estimates, women regularly overestimate their personal risk level.30 This generally high level of
risk perception may influence a womans decision making
about chemoprevention. When women receive their objective personalized risk estimate they may be surprised by the
relatively low values, and this may deter them from taking
preventive action that could increase the risk of other
diseases.23,24,31-33
On the other hand, there is evidence that women may not
necessarily believe the risk levels provided through personal-
ized risk estimates.34 Furthermore, womens personal assessments of their risk have been shown to be extremely
persistent and may not change through counseling. In one
study, for example, among women attending a high-risk
clinic in the United States to discuss their breast cancer
risk and treatment options the womens preferences regarding chemoprevention were shown to be stable over
time. The women were surveyed before and after the consultation, and their level of breast cancer risk that would
indicate chemoprevention uptake was similar at both
points.27 In this study, 75% of the women indicated that
they would take chemoprevention for breast cancer risk
reduction if their lifetime risk of developing breast cancer
was estimated at 60%. In comparison, the actual average
risk in this sample of high-risk women was 18.5% (as determined by the Gail score).
Efcacy
It has been suggested that women might not believe that taking a chemopreventive agent will substantially reduce their
breast cancer risk.18,23 Such assumptions may be related to
the low absolute risk scores of most of the women whose decision making patterns regarding chemoprevention have
been studied. An accurate understanding of ones risk of developing breast cancer may therefore lead to the belief that
the risk is too small to warrant action, particularly if such
action in itself involves risks.
Taking Medicines
The idea of taking medication on a daily basis over a period of
5 years may be seen by some women as a constant reminder
of their breast cancer risk and the potential of developing the
disease.20 This has been shown to be considered a drawback
by some women when considering chemoprevention. Other
studies have found that women are reluctant to take medicine
in general because it is seen as unnatural.28 A general aversion to taking medicines has also been described in other
contexts. This reluctance might be heightened for medicines
that are not perceived as necessary. Such generalized attitudes toward medications are likely to influence the perception of chemoprevention drugs and thus affect the overall
acceptance of their use. This example also highlights the importance of viewing something (such as a medicine) as necessary in order to consider taking it.
e61
CHRISTINE HOLMBERG
bers of women interested in and willing to take chemoprevention drugs compared to studies that have assessed actual
behavior.16,31,35,36 Kaplan et al35 and Salant et al37 present
studies that may be illuminating in this regard. To study potential acceptance of chemoprevention in a sample of women
with diverse ethnic and racial backgrounds, Kaplan et al surveyed women through their primary care networks. The authors developed a generic information guide on tamoxifen
that included information on who is at high risk for breast
cancer, the ability of tamoxifen to reduce breast cancer risk,
and the drugs side effects. These facts were all presented as
probabilities using an easy to understand visual format. In
this study, more than 40% of women indicated that they
would be likely or very likely to take tamoxifen if they were
determined to be at high risk of breast cancer. When reading
these study results, however, one must take into account the
fact that the women sampled were not high risk, but women
in the general population, and thus they merely hypothesized
that if they were at high risk, they would be likely to take the
drug. Given this fact, and in the light of some of the previously presented studies, one may ask what to be at risk of
developing breast cancer actually means to laywomen,
health professionals, and researchers.
The study of Salant et al37 found that risk meant different
things to the medical staff and to the women deemed to be at
risk by the medical staff. Although the women were aware of
their objective risk estimate level, they were more concerned
about their personal feelings regarding being at risk, which
were influenced by bodily signs and symptoms and not by
population-derived probabilities. Feeling at risk is thus likely
to be very different from being told that one is at risk.38
The term risk means very different things in epidemiology and medical care compared to everyday language. In everyday language, risk is typically associated with danger.39 A
probability of 1.66% may therefore not feel like much of a risk
at all. When women answer that they would take action if
determined to be at risk, it is thus very likely that they have
other constructs in mind than the probabilistic concepts of
the Gail model. For example, Dillard et al40 found an association between anxiety and womens intention to
gather additional information about tamoxifen and take
the drug in the next few months. The psychological construct of anxiety may be more similar to individuals connotations of risk than probabilistic concepts of risk and
risk perception.
DECISION MAKING
As discussed above, decision making about whether or not to
take chemoprevention to reduce breast cancer risk involves
complex risks and trade-offs and should be based on an individuals preferences rather than on population-based standards. The prerequisite to enable such decision making is
presentation of the involved risks and benefts in a way that is
understandable, even to low-numerate populations.41 Nevertheless, even when risks and benefts appear to be understood, willingness to take chemoprevention remains low
among women who are eligible on the basis of their Gail
score. Other research has shown that health decision making
may not be based on an accurate understanding of risk information, but perhaps more on heuristics and feelings.42,43
Feelings, assumptions, and experiences influence how risk
information is perceived. As such, individuals may not always use the risk information presented to them in the ways
that health care providers intend.44
The accumulating evidence that personalized risk information may not be as successful as previously thought in initiating particular health behaviors may also point to an
increasing gap between approaches to treatment decision
making using personalized risk information as advocated
in health care, and the approaches of the individuals,
which rely on feelings and heuristics. Various perceptions
surrounding chemopreventionthat tamoxifen is a cancer drug, fear of medication side effects, differences in the
understanding of risk between laywomen and health care
providers, a lack of knowledge about chemoprevention,
and societal opinions of medication intakeprovide the
framework within which decision making takes place.
Health care providers should be aware that counseling
may be neither as effective nor as influential in terms of
decision making as they assume,27 since decisions may be
based on perceptions that are influenced by an individuals
family history, societal assumptions, and culture as much
as, or even more than, the information and guidance offered by individual health care providers.45
IMPLICATIONS
There are several avenues through which women may be diagnosed as being at an increased risk for developing breast
cancer and offered SERM treatment for risk reduction. For
example, a family history of the disease, positive genetic evaluation, a history of LCIS or AH, or a Gail score higher than
1.66% are all indications for offering women SERMs as a
treatment option. The risk beneft trade-offs vary depending on the avenue through which a woman comes to be at risk
for breast cancer. These different reasons for being or becoming at risk may also be important for decision making in this
context since they may influence how an individual perceives
the risk and, perhaps more importantly, to what degree she
feels at risk.
References
1. WHO. Breast cancer: prevention and control. http://www.who.int/cancer/detection/breastcancer/en. Accessed July 25, 2014.
2. National Cancer Institute. SEER stat fact sheets: breast cancer. http://
seer.cancer.gov/statfacts/html/breast.html. Accessed July 25, 2014.
3. Kruk J. Association between vegetable, fruit and carbohydrate intake
and breast cancer risk in relation to physical activity. Asian Pac J Cancer
Prev. 2014;15:4429-4436.
4. Gaudet MM, Britton JA, Kabat GC, et al. Fruits, vegetables, and micronutrients in relation to breast cancer modifed by menopause and hormone receptor status. Cancer Epidemiol Biomarkers Prev. 2004;13:14851494.
5. Jung S, Spiegelman D, Baglietto L, et al. Fruit and vegetable intake and
risk of breast cancer by hormone receptor status. J Natl Cancer Inst.
2013;105:219-236.
6. Aune D, Chan DS, Vieira AR, et al. Fruits, vegetables and breast cancer
risk: a systematic review and meta-analysis of prospective studies. Breast
Cancer Res Treat. 2012;134:479-493.
7. Rockhill B, Kawachi I, Colditz GA. Individual risk prediction and
population-wide disease prevention. Epidemiol Rev. 2000;22:176-180.
8. Cuzick J, DeCensi A, Arun B, et al. Preventive therapy for breast cancer:
a consensus statement. Lancet Oncol. 2011;12:496-503.
9. Brewster AM, Davidson NE, McCaskill-Stevens W. Chemoprevention
for breast cancer: overcoming barriers to treatment. Am Soc Clin Oncol
Educ Book. 2012;85-90.
10. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 2005;97:
1652-1662.
11. Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs
raloxifene on the risk of developing invasive breast cancer and other
disease outcomes: the NSABP Study of Tamoxifen and Raloxifene
(STAR) P-2 trial. JAMA. 2006;295:2727-2741.
12. Vogel VG, Costantino JP, Wickerham DL, et al. Update of the National
Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and
Raloxifene (STAR) P-2 Trial: preventing breast cancer. Cancer Prev Res
(Phila). 2010;3:696-706.
13. Waters EA, Cronin KA, Graubard BI, et al. Prevalence of tamoxifen use
for breast cancer chemoprevention among U.S. women. Cancer Epidemiol Biomarkers Prev. 2010;19:443-446.
14. Waters EA, McNeel TS, Stevens WM, et al. Use of tamoxifen and raloxifene for breast cancer chemoprevention in 2010. Breast Cancer Res
Treat. 2012;134:875-880.
15. Freedman AN, Graubard BI, Rao SR, et al. Estimates of the number of
US women who could beneft from tamoxifen for breast cancer chemoprevention. J Natl Cancer Inst. 2003;95:526-532.
16. Ropka ME, Keim J, Philbrick JT. Patient decisions about breast cancer
chemoprevention: a systematic review and meta-analysis. J Clin Oncol.
2010;28:3090-3095.
17. Tchou J, Hou N, Rademaker A, et al. Acceptance of tamoxifen chemoprevention by physicians and women at risk. Cancer. 2004;100:18001806.
18. McKay A, Martin W, Latosinsky S. How should we inform women at
higher risk of breast cancer about tamoxifen? An approach with a decision guide. Breast Cancer Res Treat. 2005;94:153-159.
19. McKay A, Latosinsky S, Martin W. Acceptance of tamoxifen chemoprevention by physicians and women at risk. Cancer. 2005;103:209210.
20. Donnelly LS, Evans DG, Wiseman J, et al. Uptake of tamoxifen in con-
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
e63
CHRISTINE HOLMBERG
40. Dillard AJ, Scherer L, Ubel PA, et al. Breast cancer anxietys associations
with responses to a chemoprevention decision aid. Soc Sci Med. 2013;
77:13-19.
41. Zikmund-Fisher BJ, Ubel PA, Smith DM, et al. Communicating side
effect risks in a tamoxifen prophylaxis decision aid: the debiasing
influence of pictographs. Patient Educ Couns. 2008;73:209-214.
42. Slovic P, Peters E, Finucane ML, et al. Affect, risk, and decision making.
Health Psychol. 2005;24:S35-S40.
e64
43. Zikmund-Fisher BJ, Fagerlin A, Ubel PA. Risky feelings: why a 6% risk
of cancer does not always feel like 6%. Patient Educ Couns. 2010; 81
Suppl:S87-S93.
44. Schwartz PH, Meslin EM. The ethics of information: absolute risk reduction and patient understanding of screening. J Gen Intern Med. 2008;
23:867-870.
45. Rapley T. Distributed decision making: the anatomy of decisions-inaction. Sociol Health Illn. 2008;30:429-444.
SPEAKERS
Paul G. Fisher, MD
Stanford University
Palo Alto, CA
Peter Gibbs, MBBS, FRACP, MD
Walter and Eliza Hall Institute of Medical Research
Melbourne, Australia
From the Department of Pediatrics and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Stanford Cancer Center, Stanford University, Palo Alto, CA; Walter and Eliza Hall
Institute, Ludwig Cancer Research, Royal Melbourne and Western Hospital, Melbourne, Australia.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Joshua D. Schiffman, MD, Department of Pediatrics and Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Room 4245, Salt Lake City, UT 84112;
email: joshua.schiffman@hci.utah.edu.
2015 by American Society of Clinical Oncology.
57
58
PSA (kallikrein-3 [KLK3]) is a glycoprotein secreted by epithelial cells of the prostate gland, and is elevated in prostate
cancer as well as benign prostatic hypertrophy and prostatitis. Although prostate cancer is an important cause of morbidity and mortality, the PSA test, which is both safe and
acceptable, has led to the diagnosis of more cancers at an
Cancers
Alpha-fetoprotein
Beta-human chorionic
gonadotropin
Beta-2 microglobulin
CA-125
Ovarian
CA-15.3, CA2-7.29
Breast
CA-19.9
CD20
Non-Hodgkin lymphoma
Calcitonin
Medullary thyroid
Carcinoembryonic antigen
Lactate dehydrogenase
Prostate-specic antigen
Prostate
demonstrated its effcacy in specifc instances. Despite the evidence for the role of imaging as part of an early cancer
screening and surveillance program, debate continues about
the specifc timing and imaging modalities that provide the
most beneft with least harm to general and high-risk populations. The three cancers with the best consensus for beneft
from early cancer detection using imaging include breast
cancer, colorectal cancer (CRC), and most recently, lung
cancer.
59
High-risk populations (hereditary breast and/or ovarian cancer). Lifetime risk for breast cancer for women with hereditary breast and/or ovarian cancer (HBOC) syndrome
(BRCA1/BRCA2 germ-line mutations) approaches 40% to
65%, and some women are diagnosed as early as in their 20s.
Recommended screening includes mammography plus
breast MRI.19,20 Compared with mammography, breast MRI
offers better visualization of denser breast tissue often found
in younger women.21-24 In addition, exposure to mammography before the age 30 has been associated with increased
risk for breast cancer in women with BRCA1/BRCA2 mutations.25 Mammography plus breast MRI in women who are
BRCA1/BRCA2 carriers offers comparable survival beneft
with prophylactic bilateral mastectomy at age 25 and prophylactic bilateral salpingo-oophorectomy at age 40.26 Sensitivity, metastasis-free survival, and overall survival was higher
in patients with familial breast cancer treated with MRI compared with mammography-based screening for invasive cancer, but not ductal carcinoma in situ.27 Many guidelines now
suggest performing an annual MRI at age 25 and then alternating with digital mammography beginning at age 30 so that
imaging of the breasts occurs every 6 months.16,28
colonoscopy, then rescreening with any modality is recommended in 10 years. If sigmoidoscopy is negative, then rescreening with any modality is recommended in 5 years. If
adenoma/SSP is detected, then depending on number, size,
and completeness of resection, repeat colonoscopy may be
required every 2 to 6 months, 3 years, or 5 years. Results from
the frst two CRC screening examinations predict future CRC
risks.43 Despite the widespread adoption of colonoscopy for
CRC screening, Samadder et al recently described in a
population-based study that 6% of all patients with CRC still
developed interval tumors within 6 to 60 months of colonoscopy (associated with higher rate of adenomas and CRC
family history).44 Three current randomized clinical trials in
Europe and the United States are now investigating screening
for CRC using colonoscopy and comparing colonoscopy
with fecal immunochemical testing (or no screen) with 10- to
15-year CRC mortality. The reader is referred to the following consensus update by the U.S. Multi-Society Task Force
on CRC41 and in-depth review article32 for excellent summaries of recent trials and discussions of CRC surveillance.
High-risk population (hereditary CRC syndromes). Patients at
risk for hereditary CRC beneft the most from a rigorous
screening program for early detection and polyp removal. Samadder et al offer an in-depth discussion about the evidence
for screening for CRC in patients at high risk.45 Specifc recommendations are based on the CRC lifetime risk and earliest age of presentation unique to each syndrome. The NCCN
offers excellent guidance on this topic organized by specifc
mutations.42,46 For MLH1 or MSH2 mutations (Lynch syndrome/hereditary nonpolyposis colorectal cancer [HNPCC]), colonoscopy is recommended every 1 to 2 years
beginning at age 20 to 25, or 2 to 5 years before the earliest
colon cancer diagnosis before age 25. For MSH6 or PMS2
mutations (Lynch syndrome/HNPCC), colonoscopy is recommended every 1 to 2 years beginning at age 25 to 30, or 2 to
5 years before earliest colon cancer diagnosis before age 30.
For an APC mutation resulting in familial adenomatous polyposis (FAP), if no symptoms are present, flexible sigmoidoscopy or colonoscopy every 12 months beginning at age 10
to 15 with consideration of prophylactic colectomy once the
patient reaches an adult age. For an APC mutation resulting
in attenuated FAP, colonoscopy is recommended during the
late teen years, then every 2 to 3 years (Samadder et al suggest
starting later at age 20 to 25). For MUTYH mutation
(MUTYH-associated polyposis [MAP]), colonoscopy and
polypectomy is recommended every 1 to 2 years, starting at
younger than age 21 if there is a small adenoma burden. For
STK11 mutations (Peutz-Jeghers syndrome), colonoscopy
and upper endoscopy is recommended every 2 to 3 years
starting in the late teens (risk for stomach cancer is nearly
30%). For SMAD4 mutations (juvenile polyposis syndrome),
colonoscopy starting at approximately age 15 is recommended and should be continued annually if polyps are detected or every 2 to 3 years if no polyps are identifed, with the
same strategy for upper endoscopy (risk for stomach cancer
is over 20% if multiple polyps are present).
61
rithms for further investigation of any positive test, and the patient populations that will beneft most from screening.
ACKNOWLEDGEMENTS
Joshua D. Schiffman holds the Edward B. Clark MD Endowed
Chair in Pediatric Research at the University of Utah and is
supported through the Primary Childrens Hospital Pediatric
Cancer Program, funded by the Intermountain Healthcare
Foundation and the Primary Childrens Hospital Foundation.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Joshua D. Schiffman, Affymetrix, Inc. Consulting
or Advisory Role: None. Speakers Bureau: None. Research Funding: None. Patents, Royalties, or Other Intellectual Property: None. Expert
Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin.
2014;64:9-29.
2. Porta MA. A Dictionary of Epidemiology (6th ed). New York: Oxford
University Press; 2014.
3. Catalona WJ, Richie JP, Ahmann FR, et al. Comparison of digital rectal
examination and serum prostate specifc antigen in the early detection
of prostate cancer: results of a multicenter clinical trial of 6,630 men.
J Urol. 1994;151:1283-1290.
4. Moyer VA, U.S. Preventative Services Task Force. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;157:120-134.
5. Basch E, Oliver TK, Vickers A, et al. Screening for prostate cancer with
prostate-specifc antigen testing: American Society of Clinical Oncology
Provisional Clinical Opinion. J Clin Oncol. 2012;30:3020-3025.
6. Smith RA, Manassaram-Baptiste D, Brooks D, et al. Cancer screening in
the United States, 2015: a review of current American Cancer Society
guidelines and current issues in cancer screening. CA Cancer J Clin.
2015;65:30-54.
7. Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in
breast cancer. J Clin Oncol. 2007;25:5287-5312.
8. Ramsey SD, Henry NL, Gralow JR, et al. Tumor marker usage and medical care costs among older early-stage breast cancer survivors. J Clin
Oncol. 2015;33:149-155.
9. Han PK, Klabunde CN, Noone AM, et al. Physicians beliefs about
breast cancer surveillance testing are consistent with test overuse. Med
Care. 2013;51:315-323.
10. Pace LE, Keating NL. A systematic assessment of benefts and risks to
guide breast cancer screening decisions. JAMA. 2014;311:1327-1335.
11. Elmore JG, Kramer BS. Breast cancer screening: toward informed decisions. JAMA. 2014;311:1298-1299.
12. Elmore JG, Harris RP. The harms and benefts of modern screening
mammography. BMJ. 2014;348:g3824.
13. Weedon-Fekjaer H, Romundstad PR, Vatten LJ. Modern mammogra-
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
phy screening and breast cancer mortality: population study. BMJ. 2014;
348:g3701.
Nelson HD, Tyne K, Naik A, et al. Screening for Breast Cancer: Systematic Evidence Review Update for the US Preventive Services Task Force.
Evidence Review Update No. 74. AHRQ Publication No. 10-05142EF-1. Rockville: Agency for Healthcare Research and Quality; 2009.
U.S. Preventative Services Task Force. Screening for breast cancer: U.S.
Preventive Services Task Force recommendation statement. Ann Intern
Med. 2009;151:716-726:W-236.
Bevers TB, Helvie M, Bonaccio E, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Breast Cancer Screening and Diagnosis. Version I.2014. http://www.nccn.org/professionals/physician_
gls/pdf/breast-screening.pdf. Accessed March 10, 2015.
Cancer Registry of Norway, Institute of Population-Based Cancer
Research. Norwegian Breast Cancer Screening Programme. http://
www.kreftregisteret.no/en/Cancerprevention/Breast-CancerScreening-Programme/. Accessed March 10, 2015.
Public Health England. National Health Service (NHS) Breast Screening
Programme. http://www.cancerscreening.nhs.uk/breastscreen/. Accessed March 10, 2015.
John EM, Miron A, Gong G, et al. Prevalence of pathogenic BRCA1
mutation carriers in 5 US racial/ethnic groups. JAMA. 2007;298:28692876.
Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and
ovarian cancer associated with BRCA1 or BRCA2 mutations detected in
case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72:1117-1130.
Zuley ML, Bandos AI, Ganott MA, et al. Digital breast tomosynthesis
versus supplemental diagnostic mammographic views for evaluation of
noncalcifed breast lesions. Radiology. 2013;266:89-95.
Gilbert FJ, Warren RM, Kwan-Lim G, et al. Cancers in BRCA1 and
BRCA2 carriers and in women at high risk for breast cancer: MR imaging and mammographic features. Radiology. 2009;252:358-368.
Robson M. Breast cancer surveillance in women with hereditary risk
63
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
64
due to BRCA1 or BRCA2 mutations. Clin Breast Cancer. 2004;5:260268; discussion 269-271.
Warner E, Plewes DB, Shumak RS, et al. Comparison of breast magnetic
resonance imaging, mammography, and ultrasound for surveillance of
women at high risk for hereditary breast cancer. J Clin Oncol. 2001;19:
3524-3531.
Pijpe A, Andrieu N, Easton DF, et al. Exposure to diagnostic radiation
and risk of breast cancer among carriers of BRCA1/2 mutations: retrospective cohort study (GENE-RAD-RISK). BMJ. 2012;345:e5660.
Kurian AW, Sigal BM, Plevritis SK. Survival analysis of cancer risk reduction strategies for BRCA1/2 mutation carriers. J Clin Oncol. 2010;28:
222-231.
Rijnsburger AJ, Obdeijn IM, Kaas R, et al. BRCA1-associated breast
cancers present differently from BRCA2-associated and familial cases:
long-term follow-up of the Dutch MRISC Screening Study. J Clin Oncol.
2010;28:5265-5273.
Lowry KP, Lee JM, Kong CY, et al. Annual screening strategies in
BRCA1 and BRCA2 gene mutation carriers: a comparative effectiveness
analysis. Cancer. 2012;118:2021-2030.
Winawer SJ, Zauber AG, OBrien MJ, et al. Randomized comparison of
surveillance intervals after colonoscopic removal of newly diagnosed
adenomatous polyps. The National Polyp Study Workgroup. N Engl
J Med. 1993;328:901-906.
Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal cancer
by colonoscopic polypectomy. The National Polyp Study Workgroup.
N Engl J Med. 1993;329:1977-1981.
Winawer SJ, Zauber AG, OBrien MJ, et al. The National Polyp Study.
Design, methods, and characteristics of patients with newly diagnosed
polyps. The National Polyp Study Workgroup. Cancer. 1992;70:12361245.
Kahi CJ, Anderson JC, Rex DK. Screening and surveillance for colorectal cancer: state of the art. Gastrointest Endosc. 2013;77:335-350.
Baxter NN, Goldwasser MA, Paszat LF, et al. Association of colonoscopy and death from colorectal cancer. Ann Intern Med. 2009;150:1-8.
Mulder SA, van Soest EM, Dieleman JP, et al. Exposure to colorectal
examinations before a colorectal cancer diagnosis: a case-control study.
Eur J Gastroenterol Hepatol. 2010;22:437-443.
Brenner H, Haug U, Arndt V, et al. Low risk of colorectal cancer and
advanced adenomas more than 10 years after negative colonoscopy.
Gastroenterology. 2010;138:870-876.
Singh H, Nugent Z, Demers AA, et al. The reduction in colorectal cancer
mortality after colonoscopy varies by site of the cancer. Gastroenterology.
2010;139:1128-1137.
Brenner H, Chang-Claude J, Seiler CM, et al. Long-term risk of colorectal cancer after negative colonoscopy. J Clin Oncol. 2011;29:3761-3767.
Baxter NN, Warren JL, Barrett MJ, et al. Association between colonoscopy and colorectal cancer mortality in a US cohort according to site of
cancer and colonoscopist specialty. J Clin Oncol. 2012;30:2664-2669.
Brenner H, Chang-Claude J, Seiler CM, et al. Protection from colorectal
cancer after colonoscopy: a population-based, case-control study. Ann
Intern Med. 2011;154:22-30.
Knudsen AB, Hur C, Gazelle GS, et al. Rescreening of persons with a
negative colonoscopy result: results from a microsimulation model.
Ann Intern Med. 2012;157:611-620.
Lieberman DA, Rex DK, Winawer SJ, et al. Guidelines for colonoscopy
surveillance after screening and polypectomy: a consensus update by the
US Multi-Society Task Force on Colorectal Cancer. Gastroenterology.
2012;143:844-857.
Provenzale D, Jasperson K, Ahnen DJ, et al. NCCNNCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Colorectal Cancer
Screening. Version I.2014. http://www.nccn.org/professionals/physician_
gls/pdf/colorectal_screening.pdf. Accessed March 10, 2015.
43. U.S. Preventative Services Task Force. Screening for colorectal cancer:
U.S. Preventive Services Task Force recommendation statement. Ann
Intern Med. 2008;149:627-637.
44. Samadder NJ, Curtin K, Tuohy TM, et al. Characteristics of missed or
interval colorectal cancer and patient survival: a population-based
study. Gastroenterology. 2014;146:950-960.
45. Samadder NJ, Jasperson K, Burt RW. Hereditary and common familial
colorectal cancer: evidence for colorectal screening. Dig Dis Sci. Epub
2014 Dec 12.
46. Burt RW, Cannon JA, David DS, et al. Colorectal cancer screening.
J Natl Compr Canc Netw. 2013;11:1538-1575.
47. Aberle DR, Abtin F, Brown K. Computed tomography screening for
lung cancer: has it fnally arrived? Implications of the national lung
screening trial. J Clin Oncol. 2013;31:1002-1008.
48. National Lung Screening Trial Research Team, Aberle DR, Adams AM,
et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395-409.
49. Aberle DR, DeMello S, Berg CD, et al. Results of the two incidence
screenings in the National Lung Screening Trial. N Engl J Med. 2013;
369:920-931.
50. Infante M, Cavuto S, Lutman FR, et al. A randomized study of lung
cancer screening with spiral computed tomography: three-year results
from the DANTE trial. Am J Respir Crit Care Med. 2009;180:445-453.
51. Saghir Z, Dirksen A, Ashraf H, et al. CT screening for lung cancer brings
forward early disease. The randomised Danish Lung Cancer Screening
Trial: status after fve annual screening rounds with low-dose CT.
Thorax. 2012;67:296-301.
52. Lopes Pegna A, Picozzi G, Falaschi F, et al. Four-year results of low-dose
CT screening and nodule management in the ITALUNG trial. J Thorac
Oncol. 2013;8:866-875.
53. Pastorino U, Rossi M, Rosato V, et al. Annual or biennial CT screening
versus observation in heavy smokers: 5-year results of the MILD trial.
Eur J Cancer Prev. 2012;21:308-315.
54. Horeweg N, Scholten ET, de Jong PA, et al. Detection of lung cancer
through low-dose CT screening (NELSON): a prespecifed analysis of
screening test performance and interval cancers. Lancet Oncol. 2014;15:
1342-1350.
55. Becker N, Motsch E, Gross ML, et al. Randomized study on early detection of lung cancer with MSCT in Germany: study design and results of
the frst screening round. J Cancer Res Clin Oncol. 2012;138:1475-1486.
56. McWilliams A, Tammemagi MC, Mayo JR, et al. Probability of cancer in
pulmonary nodules detected on frst screening CT. N Engl J Med. 2013;
369:910-919.
57. Bach PB, Mirkin JN, Oliver TK, et al. Benefts and harms of CT screening for lung cancer: a systematic review. JAMA. 2012;307:2418-2429.
58. Gould MK. Clinical practice. Lung-cancer screening with low-dose
computed tomography. N Engl J Med. 2014;371:1813-1820.
59. Kanodra NM, Silvestri GA, Tanner NT. Screening and early detection
efforts in lung cancer. Cancer. Epub 2015 Jan 13.
60. OConnor GT, Hatabu H. Lung cancer screening, radiation, risks, benefts, and uncertainty. JAMA. 2012;307:2434-2435.
61. Moyer VA, U.S. Preventative Services Task Force. Screening for lung
cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014;160:330-338.
62. Detterbeck FC, Mazzone PJ, Naidich DP, et al. Screening for lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.
Chest. 2013;143:e78S-92S.
63. Jaklitsch MT, Jacobson FL, Austin JH, et al. The American Association
for Thoracic Surgery guidelines for lung cancer screening using lowdose computed tomography scans for lung cancer survivors and other
high-risk groups. J Thorac Cardiovasc Surg. 2012;144:33-38.
64. Wood DE, Kazerooni E, Baum SL, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Lung Cancer Screening. Version
I.2015. http://www.nccn.org/professionals/physician_gls/pdf/lung_
screening.pdf. Accessed March 10, 2015.
65. Wender R, Fontham ET, Barrera E Jr, et al. American Cancer Society
lung cancer screening guidelines. CA Cancer J Clin. 2013;63:107-117.
66. American Lung Association. American Lung Association Provides
GuidanceonLungCancerScreening.http://www.lung.org/lung-disease/
lung-cancer/lung-cancer-screening-guidelines/. Accessed March 10,
2015.
67. Goulart BH, Bensink ME, Mummy DG, et al. Lung cancer screening
with low-dose computed tomography: costs, national expenditures, and
cost-effectiveness. J Natl Compr Canc Netw. 2012;10:267-275.
68. Black WC, Gareen IF, Soneji SS, et al. Cost-effectiveness of CT screening
in the National Lung Screening Trial. N Engl J Med. 2014;371:17931802.
69. Croswell JM, Baker SG, Marcus PM, et al. Cumulative incidence of falsepositive test results in lung cancer screening: a randomized trial. Ann
Intern Med. 2010;152:505-512, W176-180.
70. Ilie M, Hofman V, Long E, et al. Current challenges for detection of
circulating tumor cells and cell-free circulating nucleic acids, and their
characterization in non-small cell lung carcinoma patients. What is the
best blood substrate for personalized medicine? Ann Transl Med. 2014;
2:107.
71. Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor
DNA in early- and late-stage human malignancies. Sci Transl Med.
2014;6:224ra24.
72. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease
progression, and survival in metastatic breast cancer. N Engl J Med.
2004;351:781-791.
73. Miyamoto DT, Sequist LV, Lee RJ. Circulating tumour cells-monitoring
treatment response in prostate cancer. Nat Rev Clin Oncol. 2014;11:401412.
65
SPEAKERS
Michelle Harvie, PhD
University Hospital of South Manchester NHS Foundation Trust
Manchester, United Kingdom
Heather Greenlee, ND, PhD
Columbia University Medical Center
New York, NY
From the Genesis Breast Cancer Prevention Centre, University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Michelle Harvie, PhD, Genesis Prevention Centre, University Hospital of South Manchester NHS Foundation Trust, Southmoor Rd., Manchester, M23 9LT, United Kingdom;
email: michelle.harvie@manchester.ac.,uk.
2015 by American Society of Clinical Oncology.
e66
style factors and breast cancer risk. We will present the sum
of evidence of any specifc links with pre- and postmenopausal breast cancer, ER-positive and ER-negative disease,
and among women with familial risk, including those with
the high-risk BRCA1 and BRCA2 breast cancer susceptibility
genes.
KEY POINTS
Breast cancer is the most common cancer in women in
both developed and less-developed countries. Rates of
breast cancer are increasing worldwide, with particular
increases in postmenopausal breast cancer and estrogen
receptor-positive disease.
Overweight, obesity, and weight gain are linked to
postmenopausal breast cancer, whereas alcohol
consumption and lack of exercise increase the risk for both
pre- and postmenopausal breast cancer.
Rapid height growth or exposure to smoking and alcohol in
the period between menarche and rst pregnancy may
increase risk because the rapidly developing breast is
particularly susceptible to carcinogenesis.
Adherence to a healthy dietary pattern does not have
specic effects on breast cancer risk but remains
important for women because it reduces the risk of other
common diseases, such as cardiovascular disease, diabetes,
and dementia.
Excess weight, alcohol, and lack of exercise increase risk
among women with a family history, but their specic
associations with carriers of BRCA1 and BRCA2 mutations
requires further study.
ALCOHOL
Consumption of an additional 10 g of alcohol (1 unit; e.g., 284
mL of 4% strength beer or cider, 25 mL of 40% strength spirits, or 80 mL of 12% strength wine) on a daily basis is estimated to increase risk by 2% to 12%,20 with no further
increase beyond 60 g of alcohol per day.21 The increased risk
is thought to be related to acetaldehyde-induced DNA strand
deletions, chromosomal aberrations, and DNA adducts,
downregulation of the tumor suppressor gene BRCA1, and
increased estrogen and prolactin receptor activity. Data sugasco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e67
TABLE 1. World Cancer Research Fund Prevention Guidelines for Breast Cancer and Cardiovascular Disease
Breast Cancer Risk Reduction
No effect
6. Limit red meats (i.e., beef, pork, and lamb) and avoid processed meats
7. Limit alcoholic drinks to 2 for men and 1 for women per day
No effect
PHYSICAL ACTIVITY
The American College of Sports Medicine recommends a total of 150 minutes per week of moderate intensity cardiorespiratory exercise to reduce all-cause mortality and improve
quality of life.25 The optimal level of physical activity for
breast cancer risk reduction appears to be greater than these
recommendations, with an estimated 3% reduction in risk
for every additional 180 minutes of moderate intensity exercise per week.26 Physical activity is associated with reduced
risk among pre- and postmenopausal women and among
women with a family history, albeit with an apparent smaller
effect than for the general population, and reduced risk of
both ER-positive and ER-negative cancers.27 Potential anticancer effects of physical activity include reductions in endogenous sex hormone concentrations, insulin resistance,
and chronic low-grade inflammation. In addition, other
pathways are emerging as potentially important, including
those involving oxidative stress and telomere length,
global DNA hypomethylation, immune function,28 and
e68
Vitamin Supplements
One in three adults in the United States take vitamin supplements in the hope of protecting themselves against ill health
and cancer. Large-scale randomized trials of supplement use
have mainly yielded negative fndings, with some notable adverse and benefcial effects. For example, beta-carotene increases the risk of lung and stomach cancer, vitamin E
increases the risk of prostate cancer and colorectal adenoma,
and selenium reduces the rates of gastric and lung cancer in
populations with low selenium levels but increases rates in
those with higher levels. Both beta-carotene and vitamin E
supplementation increase overall mortality.46 Supplementation with vitamin D,47 calcium,48 folic acid,49 or multivitamins50 neither decrease or increase the risk of breast cancer.
The best advice is to avoid nutritional supplements unless
indicated for a specifc reason.
SMOKING
The 2004 Surgeon General Report concluded, It would be
false to tell women they will prevent breast cancer if they quit
smoking. Accumulating evidence from the better-designed
epidemiologic studies suggests an increased breast cancer
risk among women with the highest exposure, i.e., the longest
duration and highest pack years of smoking. The updated
2014 Surgeon General Report concluded that current evidence was suggestive, but not suffcient, to infer a causal relationship between active or passive smoking and breast
cancer.51 Smoking appears to have adverse effects if initiated
during adolescence or early adulthood before the frst pregnancy because of heightened susceptibility to chemical carcinogens before full differentiation of the breast. Smoking
appears to have more consistent links with premenopausal
breast cancer but has also been linked to postmenopausal
breast cancer.52,53 Multivariate adjusted relative risks between the highest exposure category and never active smokasco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e69
Before Menarche
Premenopausal
Years
Postmenopausal Years
Pre
Post
Pre
Post
Pre
Post
Post
Greater adiposity
or 2
or 2
or 2
or 2
NA
NA
NA
NA
NA
Sedentary lifestyle
NA
NA
Smoking
Abbreviations: NA, not applicable; Pre, premenopausal breast cancer; Post, postmenopausal breast cancer.
No effect.
2Decreased risk.
1Increased risk.
ers in positive cohort studies are between 1.1 and 1.4. The
effect of smoking appears to be mainly linked to ER-positive
cancers and among individuals with polymorphisms in genes
involved in the metabolism of tobacco products, such as
NAT2, although the current evidence is equivocal.52
TABLE 3. What Causes Breast Cancer? The Mismatch between Expert Opinion and Lay Perception
Expert Opinion (Estimated Attributable Risk [U.K])63
Non-modiable
% of cases
Non-modiable*
Genetic factors**
47
Genetic factors
77.6
Environmental pollutants
31.7
Stress
27.9
11
4.6
% of cases
Food additives
18.4
Obesity
9.0
Pesticides
10.0
Alcohol consumption
6.4
Food additives
18.4
Physical activity
3.4
Reproductive
7.2
Use of HRT
3.2
Breast injury
6.6
6.5
e70
Diet
23.2
Alcohol
12.6
Physical activity
11.6
Smoking
11.6
Use of HRT
7.2
Premenopausal
Postmenopausal
ER-positive
ER-negative
Family History
BRCA1
BRCA2
Mixed effects
* Mixed effects
* Mixed effects
Lack of exercise
Reduced effect
cf non family
history
* Mixed effects
* Mixed effects
Alcohol intake
* No links found
* No links found
Smoking during
adolescence/early
adulthood/lifelong
smoking
Lack of data
No data
No data
No data
reduced with physical activity (especially if undertaken during adolescence and early adulthood), with consistent null
effects of alcohol.55,56 The limitations of these studies are well
recognized and large-scale prospective studies are required.
Recent prospective data from a New York cohort showed that
adherence to cancer prevention guidelines for a healthy
weight, reduced alcohol, and high physical activity reduced
breast cancer mortality by 61% (hazard ratio 0.39; 95% CI,
0.16 to 0.97) among BRCA1 and BRCA2 carriers.57
e71
References
1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN
2012. Int J Cancer. 2015;136:E359-E386.
2. Ghiasvand R, Adami HO, Harirchi I, et al. Higher incidence of premenopausal breast cancer in less developed countries; myth or truth?
BMC Cancer. 2014;14:343.
3. Anderson WF, Rosenberg PS, Petito L, et al. Divergent estrogen
receptor-positive and -negative breast cancer trends and etiologic heterogeneity in Denmark. Int J Cancer. 2013;133:2201-2206.
4. Hou N, Huo D. A trend analysis of breast cancer incidence rates in the
United States from 2000 to 2009 shows a recent increase. Breast Cancer
Res Treat. 2013;138:633-641.
5. Sestak I. Preventative therapies for healthy women at high risk of breast
cancer. Cancer Manag Res. 2014;6:423-430.
6. Donnelly LS, Evans DG, Wiseman J, et al. Uptake of tamoxifen in consecutive premenopausal women under surveillance in a high-risk breast
cancer clinic. Br J Cancer. 2014;110:1681-1687.
7. Litzenburger BC, Brown PH. Advances in preventive therapy for
estrogen-receptor-negative breast cancer. Curr Breast Cancer Rep. 2014;
6:96-109.
8. Hastert TA, Beresford SA, Patterson RE, et al. Adherence to WCRF/
AICR cancer prevention recommendations and risk of postmenopausal
breast cancer. Cancer Epidemiol Biomarkers Prev. 2013;22:1498-1508.
9. Thomson CA, McCullough ML, Wertheim BC, et al. Nutrition and
physical activity cancer prevention guidelines, cancer risk, and mortality in the womens health initiative. Cancer Prev Res (Phila). 2014;
7:42-53.
10. Makarem N, Lin Y, Bandera EV, et al. Concordance with World Cancer
Res Fund/American Institute for Cancer Res (WCRF/AICR) guidelines
for cancer prevention and obesity-related cancer risk in the Framingham Offspring cohort (1991-2008). Cancer Causes Control. 2015;26:
277-286.
11. McKenzie F, Ferrari P, Freisling H, et al. Healthy lifestyle and risk of
breast cancer among postmenopausal women in the European Prospective Investigation into Cancer and Nutrition cohort study. Int J Cancer.
2014.
12. Catsburg C, Miller AB, Rohan TE. Adherence to cancer prevention
guidelines and risk of breast cancer. Int J Cancer. 2014.
13. Gramling R, Lash TL, Rothman KJ, et al. Family history of later-onset
breast cancer, breast healthy behavior and invasive breast cancer among
postmenopausal women: a cohort study. Breast Cancer Res. 2010;12:
R82.
14. Vrieling A, Buck K, Kaaks R, et al. Adult weight gain in relation to breast
cancer risk by estrogen and progesterone receptor status: a metaanalysis. Breast Cancer Res Treat. 2010;123:641-649.
15. Colditz GA, Willett WC, Rotnitzky A, et al. Weight gain as a risk factor
for clinical diabetes mellitus in women. Ann Intern Med. 1995;122:481486.
16. Willett WC, Manson JE, Stampfer MJ, et al. Weight, weight change, and
coronary heart disease in women. Risk within the normal weight range.
JAMA. 1995;273:461-465.
17. Aleksandrova K, Pischon T, Buijsse B, et al. Adult weight change and
e72
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53. Glantz SA, Johnson KC. The surgeon general report on smoking and
health 50 years later: breast cancer and the cost of increasing caution.
Cancer Epidemiol Biomarkers Prev. 2014;23:37-46.
54. Tryggvadottir L, Sigvaldason H, Olafsdottir GH, et al. Population-based
study of changing breast cancer risk in Icelandic BRCA2 mutation carriers, 1920-2000. J Natl Cancer Inst. 2006;98:116-122.
55. Friebel TM, Domchek SM, Rebbeck TR. Modifers of cancer risk in
BRCA1 and BRCA2 mutation carriers: systematic review and metaanalysis. J Natl Cancer Inst. 2014;106:dju091.
56. Pettapiece-Phillips R, Narod SA, Kotsopoulos J. The role of body size
and physical activity on the risk of breast cancer in BRCA mutation carriers. Cancer Causes Control. 2015;26:333-344.
57. Cloud AJ, Thai A, Liao Y, et al. The impact of cancer prevention guideline adherence on overall mortality in a high-risk cohort of women from
the New York site of the Breast Cancer Family Registry. Breast Cancer
Res Treat. 2015;149:537-546.
58. Orr N, Dudbridge F, Dryden N, et al. Fine-mapping identifes two additional breast cancer susceptibility loci at 9q31.2. Hum Mol Genet.
Epub 2015 Feb 4.
59. Fletcher O, Dudbridge F. Candidate gene-environment interactions in
breast cancer. BMC Med. 2014;12:195.
60. Vrieling A, Kampman E. The role of body mass index, physical activity,
and diet in colorectal cancer recurrence and survival: a review of the
literature. Am J Clin Nutr. 2010;92:471-490.
61. Emaus MJ, van Gils CH, Bakker MF, et al. Weight change in middle
adulthood and breast cancer risk in the EPIC-PANACEA study. Int J
Cancer. 2014;135:2887-2899.
62. Dowsett M, Folkerd E. Reduced progesterone levels explain the reduced
risk of breast cancer in obese premenopausal women: a new hypothesis.
Breast Cancer Res Treat. 2015;149:1-4.
63. Parkin DM, Boyd L, Walker LC. The fraction of cancer attributable to
lifestyle and environmental factors in the UK in 2010. Br J Cancer. 2011;
105 Suppl 2:S77-S81.
64. Wright CE, Harvie M, Howell A, et al. Beliefs about weight and breast
cancer: an interview study with high risk women following a 12 month
weight loss intervention. Hered Cancer Clin Pract. 2015;13:1.
65. Anderson AS, Mackison D, Boath C, et al. Promoting changes in diet
and physical activity in breast and colorectal cancer screening settings:
an unexplored opportunity for endorsing healthy behaviors. Cancer
Prev Res (Phila). 2013;6:165-172.
66. Colditz GA, Bohlke K, Berkey CS. Breast cancer risk accumulation starts
early: prevention must also. Breast Cancer Res Treat. 2014;145:567-579.
67. Bjerkaas E, Parajuli R, Weiderpass E, et al. Smoking duration before frst
childbirth: an emerging risk factor for breast cancer? Results from
302,865 Norwegian women. Cancer Causes Control. 2013;24:1347-1356.
68. Thomson AK, Heyworth JS, Girschik J, et al. Beliefs and perceptions
about the causes of breast cancer: a case-control study. BMC Res Notes.
2014;7:558.
69. Breast cancer and breastfeeding: collaborative reanalysis of individual
data from 47 epidemiological studies in 30 countries, including 50302
women with breast cancer and 96973 women without the disease.
Lancet. 2002;360:187-195.
e73
Alternatives to ASP-Plus-Six:
What Are the Options?
CHAIR
Jeffery C. Ward, MD
Swedish Cancer Institute
Edmonds, WA
SPEAKERS
Blase Polite, MD, MPP
The University of Chicago
Chicago, IL
Rena M. Conti, PhD
The University of Chicago
Chicago, IL
THE ECONOMIST
Treating patients with cancer with infused or injected anticancer prescription drugs (oncolytics) is a central component of an outpatient oncology practice. Practices purchase
these drugs and then bill insurers for their use to treat specifc
patients, a system known as buy and bill. Spending on these
drugs by third-party payers is also increasingly important
Medicare spent approximately 5% ($125 billion) of the 2013
federal budget on the use of these drugs.1
From an economic perspective, reform of the buy-and-bill
system is inevitable for two reasons. First, these purchases
have had a substantial effect on practices fnancial health and
have created signifcant practice risk, jeopardizing many
From the Section of Hematology and Oncology, Department of Medicine, The University of Chicago, Chicago, IL; Departments of Pediatrics and Public Health Science, The University of Chicago,
Chicago, IL; Department of Medical Oncology, Swedish Cancer Institute, Seattle, WA.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Jeffrey C. Ward, MD, Department of Medical Oncology, Swedish Cancer Institute, 21632 Highway 99, Edmonds, WA 98026; email: jeffery.ward@swedish.org.
2015 by American Society of Clinical Oncology.
e75
and Drug Administration approval and authoritative compendia to determine what uses of physician-administered
drugs to reimburse, including off-label uses determined by
expert assessments of available supportive evidence.4,5
Currently, Medicare pays for Part B covered drugs using
an ASP of cancer drugs plus the 6% facilities/operations services fee reimbursement system, implemented in 2006 after
the passage of the Medical Modernization Act (MMA) in
2003. ASPs for each Part B covered drug are calculated and
reported by pharmaceutical companies to CMS.6 The MMA
sets CMS reimbursement for these drugs at ASP plus 6%,
which preserved the buy-and-bill system while reducing
the potentially substantial spread between Part B covered
drugs acquisition costs and reimbursement rates. Medicare benefciaries treated with these drugs are subject to a
20% coinsurance requirement, which is covered under
secondary insurance plans for the majority of FFS Medicare benefciaries.
KEY POINTS
Reform of buy-and-bill chemotherapy is inevitable due to
the nancial risks it poses on practices and the widespread
perception that it incentivizes increased utilization of the
most expensive oncolytics.
Challenges imposed by ASP-based reimbursement include
underwater drugs, generic drug shortages, direction of
underinsured and uninsured patients from private practice
to more expensive hospital outpatient departments, and
consolidation of oncologists into mega-practices and
hospital employment.
Although the U.S. Congress has not yet heeded regular
calls for reductions in ASP plus 6% by presidential budgets
and MedPAC, neither has it succeeded in removing prompt
pay discounts from its calculation after 10 years of
lobbying, and calls to x the disproportionate impact of
sequestration on oncology have been given only lip service
by legislators.
Though the failings of the buy-and-bill system impact all
oncologists, small independent practices shoulder the
greater burden, and their very existence, and with it
access to care for many of our most vulnerable patients, is
threatened.
Oncologists are encouraged to be engaged and innovative
in seeking alternative payment systems for buy-and-bill
chemotherapy that will complement reforms of fee-forservice medicine. Possibilities include bundled payments,
least costly alternative reimbursement, shifting Medicare
Part B drugs into Medicare Part D, invoice pricing with
management fees, government/payer-negotiated drug
pricing, value-based payment formulas, and revamping the
Competitive Acquisition Program.
e76
history, several flaws in the methodology have become apparent to practitioners and policy makers.
First, CMS posts a new ASP every quarter based on information submitted by drug manufacturers 6 months earlier.
As a consequence, drug prices commonly increase, whereas
physician reimbursement remains stagnant because of the
lag in ASP reimbursement policy.7 This mismatch between
acquisition costs and Medicare reimbursement for a particular drug can result in it being underwater (meaning the buy
costs more than the bill) among providersprice increases
are borne by outpatient practices until Medicare reimbursements catch up two quarters later.
Second, the lag in ASP-based reimbursement may have some
perverse effects on the supply of generic oncolytics that commonly act as the backbones of chemotherapy with more novel
agents. Once multiple manufacturers produce a given generic
drug, competitive market forces drive their acquisition costs to
levels that leave manufacturers very thin margins. If a generic
drug manufacturer faces increases in the prices of raw material
acquisition or costs of manufacturing and/or distribution, they
may wish to pass these cost increases in whole or in part to drug
purchasers. The lag in ASP reimbursement, however, forces generic manufacturers to assume all or some of the fnancial consequences of increased production costs for a defned period of
time. Facing this option, generic manufacturers may opt to cease
production of these drugs or outsource them to contract manufacturers. This may have contributed to ongoing generic cancer drug shortages.8
Third, reliance on ASP as the basis of outpatient oncology
practice drug reimbursement has had heterogeneous and unequal effects across providers. On the bill side, practices can
have substantially different payer mixes because of socioeconomic characteristics of their location. Commercial payers
were slow to adopt ASP pricing and generally continue to
reimburse more generously than Medicare, making practices
that have richer, commercially insured patients less vulnerable to ASP and its changes.
On the buy side, ASP rewards practices enjoying substantial purchasing advantages that others do not immediately
enjoy. For example, institutions that are eligible for 340B
drug discounts access drugs at relatively low costs, insulating
them from many of the fnancial pressures independent practices face.9 When calculating ASP for purposes of Medicare
reimbursement, regulations instruct manufacturers to exclude sales to 340B providers. Hence, Medicare reimbursement rates are not affected by growth in the 340B discount
program, although providers acquisition costs are reduced.
Large group and institutional practices with lower drugacquisition costs have a competitive advantage compared
with smaller practices. Large practices typically have better
access to capital and favorable commercial contracts compared with smaller practices, allowing them to more easily
beneft from any spread between insurer reimbursements
and the acquisition costs of drugs.
The risks and inequities in the ASP system have become
exacerbated in recent years as the acquisition costs for newly
launched Part B covered oncolytics have increased expo-
zation 2013) predicts that the volume of drug sales under the
340B program will increase from $6 billion in 2010 to $12
billion in 2016. This fgure includes anticancer and noncancer drugs. Industry sources indicate that the two therapeutic classes having the largest 340B sales are anticancer
drugs and anti-infectives. These decisions influence the
number of available oncology practices in a community, and
places upward pressure on the prices paid for the provision of
similar services.21,22,23
Finally, ASP-based reimbursement does not appear to curb
the initial pricing of a branded cancer drug, most of which
now meet or exceed $10,000 per month of treatment.
Howard and colleagues24 reported that the launch prices of
cancer drugs increased 9% to 17% between 1995 and 2012,
after controlling for inflation. Because many rebates and discounts are based on a drugs average price, the expansion of
rebate and/or discount availability presents pharmaceutical
companies with an incentive to set higher list prices to offset
discounts. In this way, increases in the number of 340Beliglble providers may have led to upward pressure in the
prices paid by noneligible providers.24 This incentive likely
acts to inflate the launch prices of new drugs, in part because
manufacturers understand that practices may face substantial fnancial risk if drug prices increase after launch because
of the lag in ASP-based reimbursement.
THE REALPOLITIK
It is an open secret in Washington, D.C., that when the Congress
or the President are looking for substantial savings to pay for tax
cuts or other spending priorities, they go to the Medicare program for the same reason that Willie Sutton robbed banks: that
is where the money is. In an ideal world, savings would be
achieved through careful consideration of the intended and unintended consequences of the proposed policy reform, but that
is not how the process usually works. Typically, a savings target
(the amount of money needed to pay for other policy priorities)
is established, and the policies that are most likely to be scored by
the Congressional Budget Offce to achieve this target are chosen. Formulas such as ASP and ASP plus are an ideal target for
this type of approach because the math is straightforward. Combine simple math with a strong feeling by many health policy
analysts and economists that ASP plusbased reimbursement
creates perverse incentives for oncologists to preferentially
choose drugs with the highest ASP to maximize revenue, and
you have an irresistible target.
Although there are certainly members of Congress who are
sympathetic to the havoc that would be created to the fnancial viability of oncology practices if ASP were to be eliminated, this sympathy has not led to a strong defense of cuts
that have already gone into effect. As part of the 2012 budget
sequester, Congress mandated CMS to cut Part B drug reimbursement by 2%the result of which is that drugs are now
paid at ASP plus 4.3%. Congress has had two subsequent opportunities to fx this problem with bipartisan budget agreements in November 2013 and November 2014, but not only
did the problem go unfxed, Congress extended the cuts to
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e77
THE ONCOLOGIST
At the core of cancer medicine is the delivery of oncolytic
therapies and supportive care. For the medical oncologist
this means pharmaceuticals, the majority of which are administered in hospitals and clinics. In contrast to oral
medications, where direct physician ownership of pharmacy is largely prohibited, oncologists in private practice
buy and bill the drugs that they then prescribe and administer. These drugs represent the largest single item expenditure and the largest source of gross revenue for these
practices, and, until recently, the margin between purchase price and sale price was the fnancial driver of oncology infusion suites and oncologist incomes.25 Similarly,
e78
hospitals for infusion.28 Brown bagging, the practice of having patients acquire chemotherapy through their pharmacy
beneft and bringing it to the clinic to have it infused, or white
bagging, the outsourcing of chemotherapy to a specialty
pharmacy that delivers it to the practice for infusion, has become increasingly attractive for small practices, some of
whom have had diffculty obtaining credit.29
Larger practices, particularly those in mid-size metropolitan communities with a large community presence, have survived and may continue to thrive in this environment. They
have greater buying power and may be able to buy drugs at
less than ASP, though the average in ASP requires that their
largess be to the detriment of the smaller practice who will
fnd that they then buy at more than ASP. The mega-practice
may also have an upper hand in negotiations with commercial payers and beneft from diversifcation of revenues,
capturing downstream revenues such as imaging and pharmacy.30 Likewise, hospitals with 340B discounts, facility fees,
inpatient and outpatient downstream revenue, and commercial contracting leverage do not feel the same pain wrought
by the decreasing margins in buy-and-bill chemotherapy.31
Given the history, it should be no surprise that the oncologists sentiment is shaped by personal circumstances.
Stereotypical as it may be, it appears that there are four
popular responses to the notion of reforming the way we
pay for chemotherapy: (1) discouraged and resigned, (2)
embittered and angry, (3) removed and aloof, and (4) engaged and innovative.
Discouraged and resigned oncologists have seen and are
dismayed by an inexorable increase in the price of oncolytics.
The only response they see from policy makers and payers is
to decrease the margins available to physicians. They take
note that every White House budget proposes paying a lower
margin on ASP and they fully anticipate that there will eventually be no margin. Many of them practice in small groups of
less than fve medical oncologists. They already shift as much
risk as possible to hospitals, are acutely aware that they cannot administer the drugs that are underwater this month,
brown bag when necessary and are arranging for white bagging, and have a tenuous, at best, line of credit with their distributors. They have or plan to cut staff to bare bones and are
actively exploring retirement or negotiating a new employment arrangement. They are too busy generating Evaluation
and Management Services to participate in ASCO or state societies. They just wish buy and bill would go away.
To be embittered and angry, physicians have to have practiced long enough to remember buy and bill the way it used to
be. Many of the most successful and largest private practices
are populated by the embittered and angry. Proud of their
independence and the good care that they give their patients,
community oncology is a way of life to be defended and
fought for. To criticize buy and bill is to criticize their culture,
and they feel that ASCO has failed to adequately defend and
fght for it. As hospitals grow through acquisition of independent oncologists, they feel further threatened by the relative
wealth afforded by facility fees and 340B and angrily seek to
level the playing feld.
Removed and aloof could be used to characterize many of
our young oncologists, indifferent because they do not know
better and are content with avoiding the fray through employment. These terms could also be used to describe some
oncologists who have left independent practices for the refuge of hospitals, but these should be lumped in with the discouraged and resigned; instead, think of the oncologist who
has always been employed and has felt above the fray because
of it. They can be found among new hospital partners and in
academic institutions. They are proud that their salaries are not
tied to how much chemotherapy they prescribe or how expensive the drugs they use are, and they are convinced that their
private practice brothers and sisters have succumbed to practice
by the margins. They seem oblivious to the fact that the administrators who negotiate their institutional contracts are very
much aware of the margins on the drugs they order, or that,
should the proft center they work in become a cost center, it
may well turn their well-ordered world upside down.
Many oncologists are engaged and innovative. They are
growing medical oncology homes, communicating with their
local accountable care organizations, engaging with payers to
explore payment reform pilots, and building relationships
with their representatives in Congress. Many have recovered
from discouragement and resignation or evolved beyond bitter and angry, and the lines between community and institution have been blurred. Work is being done by the Clinical
Practice Committees Payment Reform Workgroup to explore alternatives to ASP-based reimbursement to include
bundled payments, least costly alternative, shifting Medicare
Part B drugs into Medicare Part D, invoice pricing with oncolytics management fees, government/payer negotiation of
drug prices, value-based payment, and revamping the Competitive Acquisition Program.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Blase N. Polite, Sirtex Medical. Jeffery C. Ward,
Bayer Healthcare, Celgene, Genentech, Prometheus. Consulting or Advisory Role: None. Speakers Bureau: Blase N. Polite, Bayer/Onyx. Research
Funding: Blase N. Polite, Merck. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations,
Expenses: None. Other Relationships: Blase N. Polite, Gerson Lehrman Group.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e79
References
1. Government Accountability Offce. GAO-13-739T. Medicare: Information on Highest Expenditure Part B Drugs. http://www.gao.gov/assets/
660/655608.pdf. Accessed March 4, 2015.
2. Towle EL, Barr TR, Senese JL. The national practice benchmark for oncology, 2013 report on 2012 data. J Oncol Pract. 2013;9:20s-38s.
3. Neumann PJ. Using Cost-Effectiveness Analysis to Improve Health Care.
Oxford, United Kingdom: Oxford University Press; 2005.
4. American Society of Clinical Oncology. Reimbursement for cancer
treatment: coverage of off-label drug indications. J Clin Oncol. 2006;24:
3206-3208.
5. Laetz T, Silberman G. Reimbursement policies constrain the practice of
oncology [erratum in: 1992;267:3287]. JAMA. 1991;266:2996-2999.
6. Medicare Prescription Drug, Improvement, and Modernization Act of
2003, Pub. L. No. 108-173, 117 Stat 2066 (codifed in scattered sections
of 42 USC and 26 USC).
7. Conti RM, Berndt ER. Winners and Losers of the Zaltrap Price Discount: Unintended Consequences? Health Affairs Blog, February 20,
2013. http://healthaffairs.org/blog/2013/02/.
8. U.S. Department of Health and Human Services. ASPE Issue Brief: Economic Analysis of the Causes of Drug Shortages. http://aspe.hhs.gov/
sp/reports/2011/drugshortages/ib.shtml. Accessed March 4, 2015.
9. Conti RM, Bach PB. Cost consequences of the 340B drug discount program. JAMA. 2013;309:1995-1996.
10. Malin JL, Weeks JC, Potosky AL, et al. Medical oncologists perceptions
of fnancial incentives in cancer care. J Clin Oncol. 2013;31:530-535.
Epub 2012 Dec 26.
11. Jacobson M, Earle CC, Price M, et al. How Medicares payment cuts for
cancer chemotherapy drugs changed patterns of treatment. Health Aff
(Millwood). 2010;29:1391-1399.
12. Conti RM, Rosenthal MB, Polite BN, et al. Infused chemotherapy use in
the elderly after patent expiration. Am J Manag Care. 2012;18:e173e178.
13. Mayer RJ. Targeted therapy for advanced colorectal cancer-more is not
always better. N Engl J Med. 2009;360:623-625.
14. Nadler E, Eckert B, Neumann PJ. Do oncologists believe new cancer
drugs offer good value? Oncologist. 2006;11:90-95.
15. Bach PB. Limits on Medicares ability to control rising spending on cancer drugs. N Engl J Med. 2009;360:626-633.
16. Malin JL, Schneider EC, Epstein AM, et al. Results of the National Initiative for Cancer Care Quality: how can we improve the quality of cancer care in the United States? J Clin Oncol. 2006;24:626-634.
17. Shrank WH, Asch SM, Adams J, et al. The quality of pharmacologic care
for adults in the United States. Med Care. 2006;44:936-945.
e80
18. Chassin MR, Galvin RW. The urgent need to improve health care quality. Institute of Medicine National Roundtable on Health Care Quality.
JAMA. 1998;280:1000-1005.
19. Conti RM, Bernstein AC, Villaflor VM, et al. Prevalence of off-label use and
spending in 2010 among patent-protected chemotherapies in a populationbased cohort of medical oncologists. J Clin Oncol. 2013;31:1134-1139.
20. The Moran Company. Results of Analyses for Chemotherapy Administration
Utilization and Chemotherapy Drug Utilization, 2005-2011 for Medicare Feefor-Service Benefciaries. http://www.communityoncology.org/UserFiles/
Moran_Site_Shift_Study_P1.pdf. Accessed June 20, 2013.
21. Baker LC, Bundorf MK, Kessler DP. Vertical integration: hospital ownership of physician practices is associated with higher prices and spending. Health Aff (Millwood). 2014;33:756-763.
22. Cutler DM, Scott Morton F. Hospitals, market share, and consolidation.
JAMA. 2013;310:1964-1970.
23. Welch WP, Cuellar AE, Stearns SC, et al. Proportion of physicians in
large group practices continued to grow in 2009-11. Health Aff (Millwood). 2013;32:1659-1666.
24. Howard DH, Bach PB, Berndt ER, et al. Pricing in the market for anticancer drugs. J Econ Perspect. 2015;29:139-162.
25. Towle EL, Barr TR, Senese JL. The national practice benchmark for oncology, 2014 report on 2013 data. J Oncol Pract. 2014;10:385-407.
26. Medicare Payment Advisory Commission. Medicare Payments for Outpatient Drugs Under Part B. In: Report to the Congress: Variation and
Innovation in Medicare. Washington, DC: June 2003.
27. Polite BN, Ward JC, Cox JV, et al. Payment for oncolytics in the United
States: a history of buy and bill and proposals for reform. J Oncol Pract.
2014;10:357-362.
28. Hanley A, Hagerty K, Towle EL, et al. Results of the 2013 American
Society of Clinical Oncology National Oncology Census. J Oncol Pract.
2014;10:143-148.
29. Boekell DD. The Evolving Use of White Bagging in Oncology. http://
www.onclive.com/publications/oncology-business-news/2014/June-2013/
The-Evolving-Use-of-White-Bagging-in-Oncology. Accessed March 4, 2015.
30. HemOnc Today. In big medicine era, innovation essential to sustainability of
independent practices. Helio, October 10, 2014. http://www.healio.com/
hematology-oncology/practice-management/news/print/hemonc-today/
%7B599ebed3-382f-491f-a866-074855b58c0c%7D/in-big-medicine-erainnovation-essential-to-sustainability-of-independent-practices.
31. Guidi TU. Medicares Hospital Outpatient Prospective Payment System: OPPS 101 (part 2 of 2). J Oncol Pract. 2011;7:57-60.
SPEAKERS
John D. Sprandio, MD
Consultants in Medical Oncology and Hematology
Drexel Hill, PA
Lee N. Newcomer, MD
UnitedHealthCare
Minnetonka, MN
Barbara L. McAneny, MD
New Mexico Cancer Center
Albuquerque, NM
PAGE ET AL
nder our current health care system, the care and management of patients with cancer comes with exponentially increasing costs along with compromises in quality of
care. Today there are several payment reform models that are
being designed and piloted intended to address the desire for
evidence-based, value-driven cancer care. One element of
this is the OMH concept, which is rooted in the National
Commission on Quality Assurance (NCQA) standards originally created for primary care and expanded into specialty
medicine. In 2010, Sprandio established an oncology patientcentered medical home (OPCMH) model that showed
the ability to control cancer care costs by improving overall
management of patients with cancer throughout their treatment.1 Consultants in Medical Oncology and Hematology
(CMOH) became the frst oncology practice to be recognized
by the NCQA as a level III PCMH, with their OPCMH
model. Through NCQA standards, CMOH implemented efforts and aspects of care to target costs, quality, and patient
care processes. Results showed that ED visits decreased by
68%, hospital admissions per patient treated with chemotherapy per year decreased by 51%, and the length of stay for
admitted patients decreased by 21%. CMOH has shown substantial overall cost savings estimated at $1 million per physician annually. The OPCMH emphasizes the importance of
delivery reform in oncology.2 However, the improved total
From The Center for Cancer and Blood Disorders, Fort Worth, TX; UnitedHealthcare, Minnetonka, MN; Consultants in Medical Oncology and Hematology, Drexel Hill, PA; New Mexico Cancer Center,
Albuquerque, NM.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Ray D. Page, DO, PhD, The Center for Cancer and Blood Disorders, 800 W. Magnolia Ave., Fort Worth, TX 76104; email: rpage@txcc.com.
2015 by American Society of Clinical Oncology.
e82
KEY POINTS
As we look at fee-for-service (FFS) alternatives, several
performance-based payment options exist with ranges of
nancial risk, reward, and accountability.
Oncology medical homes (OMHs) have been shown to
improve patient care, patient outcomes (less emergency
department and hospital admissions), patient satisfaction,
and with substantial cost savings to the payers.
The OMH practice infrastructure required to create cost
savings is not covered under traditional FFS. Rewards for
OMH performance should be based on a small number of
meaningful quality performance measures.
To cover practice costs of an OMH, practices will need to
enter payer contracts that recognize the value of all
services provided.
An OMH infrastructure gives the best opportunity for
sustaining contracted bundled payments with risk sharing/
shared savings, which are anticipated in the near future.
Shared Risk
Shared Savings
Bundled/Episode
Payments
Centers of Excellence
Performance-Based
Contracts (PBC)
Primary Care
Performance-Based Programs
Incentives
Fee-for-Service
Degree of Provider Integration and Accountability
e83
PAGE ET AL
FIGURE 2. Triage System Utilization by (A) Outcome and (B) Time of Triage Call
B
911 Call
80.00%
STAT
Appointment
Same Day
Appointment
Other
Appointment
Follow Up Phone
Call
60.00%
20.00%
0.00%
Oce Hours Evening Hours Weekends
home, the COME HOME program practices will need to enter into contracts with payers that recognize the value of the
services provided. These services generate savings through
reduced ED and inpatient use, but these savings only accrue
to the payer. We see bundled payments, with options for risk
sharing/shared savings as the best contracting option for sustaining the medical home infrastructure.
Oncology bundled payments and other risk-sharing arrangements are highly innovative, untested, and fnancially
risky to physician practices. COME HOME is now beginning
to develop the necessary knowledge base to support bundled
payments/shared savings in this arena. Together with the
COME HOME practices, the team at IOBS has launched two
related efforts to support future oncology bundled payments
with shared savings. First, they are developing a data analytics infrastructure that will allow for the participating practices to track improved outcomes, understand their costs for
treating common cancer types (breast, lung, and colon) and
be familiar with sources of savings from the medical home
model to set bundled price targets/shared savings in a transparent and data-driven way. Second, IOBS is conducting a
series of limited bundled payment pilots with small patient
pools. These pilots allow the participating practices to become familiar with bundled payment mechanisms while limiting overall risk. Both of these activities are ongoing at the
moment, and they often inform each other.
0%
1
triage, evening/weekend clinic hours, electronic health record [EHR] access through patient portals and on-call clinicians), on-site or near-site imaging and laboratory testing,
and admitting physicians who shepherd patients through inpatient encounters, avoiding handoffs and readmissions, to
ensure seamless, safe, and effcient care. Further, the COME
HOME program offers physicians and administrators from
community oncology practices unprecedented access to realtime quality, pathway adherence, and utilization data, including provider-level measures and benchmarking within
each practice and within the COME HOME Program.
The medical home infrastructure creates four sets of costs
that are not covered under traditional FFS and must be addressed using an alternative payment model.
1. Medical homes need triage nurses, patient care coordinators, data analysts, lab technicians, and other staff to
meet the goal of providing the right care at the right time
in the right place. However, most of the services provided by these staff are not billable under a FFS contract.
2. The medical home relies on leaving daytime physician
time available, thus, running the risk that a valuable
commodity (physician time) will go unused and, therefore, generate no revenue (opportunity cost).
3. Treating patients with the hydration and symptom control treatments instead of using the infusion center
overhead for chemotherapy replaces better paying services with services given at a loss.
4. Offering evening and weekend clinic hours for the infusion of antibiotics, symptom control medications, and
hydration will keep patients out of the ED and hospital,
but does not generate suffcient evaluation and management and infusion codes to cover the salaries of personnel.
During these after-hours clinics, at least two nurses and
associated support staff must be present, but the services
provided, such as hydration and intravenous antibiotics
administration, generate very low reimbursements.
Under the medical home infrastructure as described above,
participating practice sites have shown a 23% to 28% reduction in the percent of patients with ED visits (Figs. 3 and 4).
Treating patients in a physicians offce after hours rather
than sending them to the ED saves payers money, but it actually costs physicians more money to provide the care than
they are reimbursed. To cover practice costs of a medical
40.00%
Outcome
The COME HOME beta site shows a 23% reduction in the percent of patients with
emergency department visits.
e85
PAGE ET AL
60%
50%
Baseline
30%
20%
Health care reform is focused on value and the demonstration of results. Value is commonly defned as some variation
of the equation quality/cost. Lets review the Institute of
Medicines (IOM) defnition of quality in health care as it relates to cancer care (Fig. 5).
Quality is: The degree to which health services [center
column on diagram] delivered to individuals or populations increase the likelihood of desired health outcomes
[left column] and are consistent with current professional knowledge [right column].
Value can be defned using the IOM defnition of quality
care delivered with the proper allocation of resources
(cost).
It has become recognized by patients and payers that the
utilization of unnecessary resources often, a result of the
execution of even the most artfully constructed treatment
planis poor quality care, no matter the degree of adherence
to the evidence base. Transformation of a practice to a
PCMH-related model is related to improving the consistency
of the activities of a coordinated care team.
The effectiveness and effciency of the physician-led care
teams activities (primary driver, center column) drive the
desired payer- and patient-centric outcomes (left column).
In cancer care, the desired outcomes are self-evident:
guideline-based multidisciplinary care, improved patient experience, prompt palliation of symptoms, reduction in unnecessary resources, coordinated survivorship care, rational
care at the end of life, and control of cost by focusing on the
reduction of unnecessary resource utilization.
There are well-recognized quality performance metrics in
the domain of secondary drivers, the evidence base (right column). Oncology is rich in externally recommended treatment standards from which all cancer care providers beneft:
National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), and Commission
on Cancer (COC) all have created guidelines. In the OPCMH
model, validated process standards (NCQA, American College of Physicians, National Coalition of Cancer Survivors)
are equally important secondary drivers of quality, cost, service, and practice effciency.
Value and quality metrics are embedded within all three
columns of the driver diagram (Fig. 5). As we study and understand which specifc process-related activities drive outcomes, we can better defne future quality measures (i.e.,
turnaround time, content and dissemination of documentation). Quality measures (based on the IOM defnition) will
not be limited to well-recognized evidence-based standards
or even outcomes; rather, the emergence of practice-level
performance-based metrics that are proven to drive desired
outcomes.
10%
0%
The COME HOME beta site shows a 28% reduction in the percent of patients with
emergency department visits.
PAYER SUPPORT
The last of the seven Joint Principles of PCMH, a collaborative
effort to standardize the PCMH model for primary care, calls
for appropriate payment recognizing the added value of the
model.8 Payer recognition of the variability of cost and quality, and the willingness to align appropriately motivated
changes in care delivery was critical to the adoption of the
model by primary care providers. The same holds true for
specialty care providers, most notably oncology. As outlined
in the OPCMH payer-provider collaboration diagram
(Fig. 6), several synergistic activities and commitments
between providers (right column) and payers (left column) drive performance enhancement within the care
team (center column).
By focusing on the essential demand for improved quality
and value regardless of the payment model or organizational
structure of the parties adopting it, transformed practices
can become providers of choice by driving consistency of
the execution of care and being flexible enough to accommodate whatever payment changes may come in the future:
e87
PAGE ET AL
standards within a Patient-Centered Outcomes Research Institutefunded project in southeastern Pennsylvania. This
project is studying practice transformation in fve practices in
community- and institutional-based settings. Process standardization is encouraged, with each practice having the freedom to develop specifc processes most appropriate to their
individual sites. The use and optimization of technology is
encouraged, but not mandated, as one of the participating
practices does not even use an EHR. It is anticipated that the
NCQA PCOC standards will be fnalized during the course of
the project. The PCSP and PCOC standards are complementary to the CMS OCM, reinforcing the common processes
and service components required for the creation and demonstration of value by the oncology care team.
It is anticipated that additional nongovernmental organizations will be providing certifcation or recognition of cancer programs and practices including ASCO, the COC, and
The Joint Commission.
CONCLUDING REMARKS
Innovative payment models in cancer care are getting increased attention from all oncology stakeholders, including
CMS, private payers, providers, drug manufacturers and distributors, hospitals, professional societies, and, importantly,
the patients. Faced with spiraling costs, regulatory burdens,
impaired access to treatment, and ineffciencies of care there
has been a driven focus on delivering cancer care with greater
value to all the stakeholders. The OPCMH concept has now
been shown to be a viable foundation for carrying out
quality-driven, cost-effective comprehensive management of
patients with cancer. Much of the value gained from the
OMH infrastructures comes through refnement of day-today patient care processes resulting in superior outcomes.
Practices should be held accountable to quality practice standards through established and developing accreditation standards through entities such as NCQA and COC, as well as
adherence to recognized treatment guidelines and pathways.
The further development of these quality metrics should be
evidence-based, succinct (clinically relevant), advocate the
patients best interests, and with expert consensus from all
stakeholders.
As it becomes acutely apparent that a major element of
health care reform is to move away from FFS to varieties of
bundled payment options, we believe that the PCMH models
in oncology can provide the stable infrastructure required to
mitigate the inherent fnancial risks of bundled payment, episodes of care, and share savings payment options. However,
without payer support, further attrition of community-based
practices can be anticipated, resulting in escalating costs
and a decline in the value of cancer care. It is important for
payers and policymakers to understand that for providers
to implement substantive practice management changes
that provide higher quality care at lower costs under a system other than FFS, it is mandatory that the fnancial value
of uncompensated comprehensive services provided
through an OMH program be recognized to be sustainable
and scalable.
Employment: Barbara L. McAneny, NMOHC. Lee N. Newcomer, UnitedHealth Group. Leadership Position: Barbara L. McAneny, AMA. Stock or Other
Ownership Interests: Lee N. Newcomer, UnitedHealth Group, UnitedHealth Group. Ray D. Page, Oncology Metrics. Honoraria: None. Consulting or Advisory
Role: Barbara L. McAneny, Genentech, Lilly Oncology. Ray D. Page, International Oncology Network, Via Oncology. Speakers Bureau: Ray D. Page, Biodesix,
Celgene. Research Funding: Ray D. Page, Bristol-Myers Squibb, Celgene, Genentech/Roche, Gilead Sciences, Pzer. Patents, Royalties, or Other
Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: Barbara L. McAneny, ASCO, COA. Ray D. Page, RainTree.
Other Relationships: None.
References
1. Sprandio JD. Oncology patient-centered medical home and accountable cancer care. Commun Oncol. 2010;7:565-572.
2. Sprandio JD. Oncology patient-centered medical home. J Oncol Pract.
2012;8:47s-49s.
3. McAneny BL. The future of oncology? Come home, the oncology medical home. J Manag Care. 2013;19:cover, SP41-SP42.
4. Kuntz G, Tozer JM, Snegosky J, et al. Michigan Oncology Medical Home
Demonstration Project: frst-year results. J Oncol Pract. 2014;10:294-297.
5. Newcomer LN, Gould B, Page RD, et al. Changing physician incentives
for affordable, quality cancer care: results of an episode payment model.
J Oncol Pract. 2014;10:322-326.
e89
SPEAKERS
Stuart Staggs, MSIE
McKesson Specialty Health
The Woodlands, TX
Sue Bowman, MJ, RHIA, CCS, FAHIMA
American Health Information Management Association
Chicago, IL
nless there is another delay, the United States will transition from ICD-9 to ICD-10 in all health care settings
on October 1, 2015. This will not be a gradual transition as
there will be no grace period. Still, the replacement of ICD-9
with ICD-10 as the Health Insurance Portability and Accountability Act (HIPAA)-named code set did not come
without plenty of notice. Before we get into the practical elements of ICD-10 implementation and the opportunities associated with the implementation of ICD-10, let us step back
and take a brief look at the history of the ICD.
The frst international classifcation edition was adopted in
1893 by the International Statistical Institute and was called
the International List of Causes of Death. The ICD has been
revised over the years and is now the standard diagnostic tool
for epidemiology, health management, and clinical purposes.
It is used globally as the foundation for the identifcation of
health trends and statistics.1
The World Health Organization (WHO) has been maintaining and publishing the ICD since 1948, with periodic revisions. To date, there have been 10 revisions of the ICD; the
most current edition is ICD-10. The United States has used
ICD to classify the causes of death since 1900 and is currently
using ICD-10 to report causes of death.
In 1979, the WHO adopted ICD-9, and, with the approval
of WHO, the United States adopted a modifed version of
ICD-9, the International Classifcation of Diseases Clinical
Modifcation (ICD-9-CM), to assign codes to diagnoses associated with inpatient, outpatient, and physician offce utilization, and the International Classifcation of Diseases
Procedure Coding System (ICD-9-PCS) to assign codes associated with inpatient procedures.2
From the American Health Information Management Association, Chicago, IL; Washington State Medical Oncology Society and Oplinc, Inc., Vancouver, WA; McKesson Specialty Health, The
Woodlands, TX.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Rise Marie Cleland, BS, Oplinc, Inc., 300 W. 8th St., Unit 419, Vancouver, WA 98660; email: rise@wsmos.org.
2015 by American Society of Clinical Oncology.
e91
Abbreviations: ICD, International Classication of Disease; CMS, Centers for Medicare & Medicaid Services; CM, clinical modication; CPT/HCPCS, Current Procedural Terminology/Healthcare
Common Procedure Coding System; PCS, procedural coding system.
has not been paid for at least 90 days; at least 25% of their
patients are on Medicare; or at least 25% of their reimbursements are from Medicare.
The Protecting Access to Medicare Act of 2014, implemented
on April 1, 2014, includes a provision that the Secretary of the
U.S. Department of Health and Human Services may not
adopt ICD-10 before October 1, 2015.3 Nevertheless, not everyone was in favor of another delay in ICD-10 implementation. The American Hospital Association, most of the
national payers, and the American Academy of Professional
Coders lobbied against another delay.
Absent another delay, effective October 1, 2015, ICD10-CM will replace ICD-9 as a HIPAA-named code set to be
used on electronic, paper, fax, and phone transactions by
HIPAA-covered entities, which include providers, payers,
health care clearinghouses, software vendors, and thirdparty billing services. Furthermore, ICD-9-CM will not be
maintained after implementation of ICD-10-CM, thus noncovered entities will also likely transition to ICD-10.
KEY POINTS
The International Classication of Disease (ICD) is used
globally to identify health trends and statistics.
In 1994, the World Health Organization adopted the 10th
revision of the ICD, ICD-10.
Despite the advantage of more precise coding under ICD10, the United States has delayed adoption of the code set
several times.
The transition from the current ICD-9 code set to ICD-10 is
a major undertaking that will require signicant resources.
Careful systematic planning is necessary to minimize costly
disruptions and errors during the transition.
e92
e93
e95
Quality measurement
Better data for evaluating and improving quality of
care
Reduction in complications and improved patient
safety
Improved patient outcomes
Greater ability to measure outcomes, effcacy, and
costs of new medical technology
Greater ability to ascertain disease severity for risk and
severity adjustment
Greater ability to manage chronic diseases
Public health
Enhanced public health surveillance
Greater ability to track and respond to global health
threats
Facilitate international comparisons of quality of care
and global sharing of best practices
Research
Code analysis is essential to research when direct access to patient records is not possible
Data could be used in more meaningful ways to enable
better understanding of complications, better design
of clinically robust algorithms, and better tracking of
the outcomes of care
Greater detail offers the ability to discover previously
unrecognized relationships or uncover phenomenon
such as an incipient epidemic early
Expanded injury research and successful injury prevention strategies
Organizational monitoring and performance
Administrative effciencies
Cost containment
More accurate trend and cost analysis
Improved ability to analyze trend and cost data
More effective monitoring of resource and service utilization
Reduced submission of medical record documentation to support reimbursement claims
Reduced reliance on manual medical review
Improved coding accuracy and productivity
Reimbursement
More accurate and fair reimbursement
Better justifcation of medical necessity
Fewer erroneous and rejected claims
Increased sensitivity when making refnements in applications, such as grouping and reimbursement
methodologies
Reduced opportunities for fraud and improved fraud
detection capabilities
Health information technology
Realize benefts of SNOMED-Clinical Terms and interoperable health data exchange
Facilitate electronic data retrieval
Expanded computer-assisted coding technologies
Health policy and strategy
Improved information for setting health policy
Better data for operational and strategic planning
e96
ICD-10 recognizes distinctions in clinical conditions and severity that can help segment patient populations within a disease category. ICD-10 offers opportunities for improved,
automated identifcation, stratifcation, and segmentation of
patient populations. With greater code specifcity, better algorithms can be developed to identify and target-specifc
patient populations and subpopulations for disease management programs and customize programs for patients with
differences in severity or risk. Target groups progress toward
goals and effectiveness of treatment can be monitored
through the clinical and severity distinctions in ICD-10
codes. As more ICD-10 data is collected and additional
ICD-10 experience is gained, prediction models can be
greatly enhanced to more accurately predict risk within populations by a number of refned parameters. Superior data
will improve the ability to evaluate the effectiveness of disease
management programs in improving patient outcomes, reducing the incidence of acute episodes, and decreasing health
care costs.
Ultimately benefting patients, better data will support:
Improvements in patient outcomes and patient safety
through better data for analysis and research
Improved ability to manage chronic diseases by better
capturing patient populations
More accurate reflection of patients clinical complexity
and severity of illness
Improved ability to identify high-risk patients who require more intensive resources
Improved ability to manage population health
Improved information sharing, which can enhance
treatment accuracy and improve care coordination
Improved ability to assess effectiveness and safety of new
medical technology
Improved diagnosis of chronic illness and identifcation
of underlying causes, complications of diseases, and conditions that contribute to disease complexity
More accurate reflection of clinical complexity and severity of illness
Increased patient engagement
Complete and accurate data must be reported to put the
most appropriate picture of the quality of care delivery in
front of increasingly sophisticated and informed potential
patients. With better data will come an expanded ability to
educate consumers on costs and outcomes of treatment options. Increased patient understanding and involvement in
their health care will improve the populations health and decrease the cost of health care.
e97
The transition to ICD-10 presents opportunities for innovations in improving the quality of clinical documentation
while minimizing the burden of documentation capture on
clinicians. For example, technology can be leveraged to facilitate documentation capture at the point of care (such as the
use of prompts or templates in EHRs). Mobile devices can be
used to provide physicians with customized lists of documentation tips.
High-quality documentation is increasingly in demand to
support many emerging health care initiatives aimed at improving care and reducing costs. Growing demands for more
detailed diagnostic data generated from medical record doc-
Many ICD-10 preparation activities can provide value in advance of the transition to ICD-10. Clinical documentation is
necessary for supporting many health care initiatives, including
improving the quality of care, lowering health care costs, measuring mortality risk and severity of illness, analyzing readmission rates, and meeting meaningful use requirements. Also,
high-quality documentation will help improve todays ICD9-CM coding accuracy. Accurate and complete documentation
is important for good patient care regardless of the code set in use.
ICD-10 education has been shown to improve ICD-9-CM coding
accuracy,asbasiccodingprinciplesarereinforcedandfoundational
knowledge in biomedical sciences is strengthened.6
Employment: Stuart Staggs, McKesson Specialty Health. Leadership Position: None. Stock or Other Ownership Interests: Stuart Staggs, McKesson.
Honoraria: Ris M. Cleland, Lilly Oncology. Consulting or Advisory Role: None. Speakers Bureau: Ris M. Cleland, Genentech, Merck, Novartis. Research
Funding: None. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: Stuart Staggs,
McKesson. Other Relationships: None.
References
1. World Health Organization. International Classifcation of Diseases
(ICD) Information Sheet 2015. http://www.who.int/classifcations/icd/
factsheet/en/. Accessed January 2015.
2. Centers for Disease Control and Prevention. International Classifcation of Diseases, Ninth Revision (ICD-9) 2009. http://www.cdc.gov/
nchs/icd/icd9.htm. Accessed January 12, 2015.
3. Protecting Access to Medicare Act of 2014, Pub. L. No. 113-193.
2014. https://www.govtrack.us/congress/bills/113/hr4302/text. Accessed January 2015.
4. Hearings Before the Standards Subcommittee of National Committee
on Vital and Health Statistics (June 2014) (testimony of Susan Bowman,
MJ, RHIA, CCS, FAHIMA on behalf of the American Health Information Management Association).
5. Nichols JC. ICD-10: Advantages to Providers. Looking beyond the isolated patient provider encounter. http://www.legacyhealth.org//media/Files/PDF/
e98
6.
7.
8.
9.
Health%20Professionals/ICD_10/ICD10Advantages012812.pdf. Accessed
March 5, 2015.
Bloomrosen, M, Bowman S, Zender, A. Achieving ICD-10-CM/PCS Compliance in 2015: Staying the Course for Better HealthcareA Report from
the AHIMA 2014 ICD-10/CAC Coding Summit. http://perspectives.
ahima.org/wp-content/uploads/2014/06/AchievingICD10CMCPS
Compliancein2015.pdf. Accessed January 12, 2015.
Mitchell G. Synergizing ICD-10. J AHIMA. 2013;84:34-38.
Scott K. Leveraging CAC to prepare for ICD-10-CM/PCS. J AHIMA.
2013;84:62-64.
Nachimson Advisors, LLC. The cost of Implementing ICD-10 for Physician PracticesUpdating the 2008 Nachimson Advisors Study: A Report to the American Medical Association. February 2014. http://
docs.house.gov/meetings/IF/IF14/20150211/102940/HHRG-114IF14-Wstate-TerryW-20150211-SD001.pdf. Accessed on April 7, 2015.
SPEAKERS
Frank Winkler, MD
University of Heidelberg
Heidelberg, Germany
Minesh P. Mehta, MD
University of Maryland School of Medicine
Baltimore, MD
From the Burkhardt Brain Tumor Neuro-Oncology Center, Neurological Institute, Cleveland Clinic, Cleveland, OH; Neurology Clinic, University of Heidelberg and German Cancer Research Center,
Heidelberg, Germany.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Manmeet S. Ahluwalia, MD, Burkhardt Brain Tumor and Neuro-Oncology Center, Neurological Institute, Cleveland Clinic, 9500 Euclid Ave., S70, Cleveland, OH 44195;
email: ahluwam@ccf.org.
2015 by American Society of Clinical Oncology.
67
TARGETING ANGIOGENESIS
Preclinical data from multiple animal models support the
potential role of antiangiogenic agents for the prevention
and treatment of brain metastases. Elevated vascular endothelial growth factor (VEGF) expression has been
linked to the development of brain metastasis in a murine
model.13 Kim et al14 showed that treatment with a VEGF
receptor tyrosine kinase inhibitor reduced angiogenesis
and restricted the growth of brain metastasis in a murine
breast cancer model.14 In another mouse model, inhibition of VEGF signaling using bevacizumab effciently
inhibited angiogenesis-dependent macrometastases formation of brain-metastasizing lung adenocarcinoma cells,
arresting micrometastases in a chronic dormant state.9
However, the growth pattern of different tumor (sub)types in the brain is highly different; for example, lung
carcinoma is highly angiogenesis dependent, and melanoma is less dependent on angiogenesis (because of the
ability to grow co-optively along pre-existing brain microvessels9). These preclinical observations support the clinical evaluation of antiangiogenic agents in brain metastases
therapy and prevention. Antiangiogenic agents (e.g., those
targeting the VEGF pathway) have to reach only the endothelial cell to inhibit ligand-receptor interactions and may
not need to fully cross the blood-brain barrier. Initial experience with bevacizumab in six patients who had nonsmall
cell lung cancer (NSCLC) with brain metastases was shown
to be safe and resulted in a partial response in two patients,
KEY POINTS
A multidisciplinary approach involving the neurosurgeon,
medical oncologist, neuro-oncologist, and radiation
oncologist is recommended in the management of brain
metastases.
A number of agents that target epidermal growth factor
receptor and anaplastic lymphoma kinase mutations have
been effective in the treatment of brain metastases that
harbor these mutations.
The greatest advances in the systemic treatment of breast
cancer brain metastases have been made in patients who
have HER2-positive disease.
Small-molecule tyrosine kinase BRAF inhibitors that target
BRAFV600-mutant melanoma have demonstrated activity in
active melanoma brain metastases. Ipilimumab is an
immunotherapeutic agent that has demonstrated activity in
a prospective, phase II trial conducted in patients who
have melanoma with asymptomatic brain metastases.
(Patients who did not require corticosteroid therapy had a
better response than those who needed corticosteroids
because of brain edema.)
There is a need for prospective clinical trials to test new
combinations of targeted and immunotherapeutic agents
with local therapies to address the optimal sequencing of
local and systemic therapies in the management of brain
metastases.
68
TABLE 1. Selected Clinical Trials with Targeted Agents and Immunotherapy in Brain Metastasis
Study
Ceresoli et al24
2004 Phase II
41
27
Wu et al69
40
9.0
32
15.0
WBRT SRS
44
8.1
13.4
40
4.6
6.3
Welsh J et al21
2013
Lee et al70
2014
Long et al48
(BREAK-MB)
2012
Kefford et al51*
2015
New NSCLC-BM
New NSCLC-BM
41
4.8
6.1
WBRT erlotinib
40
8.0
86
11.8
WBRT
40
1.6
2.9
WBRT erlotinib
HER2 BCBM
Lapatinib capecitabine
HER2 BCBM
Lapatinib
2009 Phase II
No. of Patients
Median
Median PFS Intracranial OS
(Months)
RR (%)
(Months)
1.6
3.4
Cohort A, V600E
(new): 74
40
4.0
39.2
8.2
Cohort A, V600K
(new): 15
2.0
6.7
4.0
Cohort B, V600E
(recurrent): 65
4.1
30.8
7.8
Cohort B, V600K
(recurrent): 18
4.0
22.2
5.4
18
7.0
Cohort 2 (new): 56
4.3
20
6.9
45
5.5 months
(TTP)
66
17
242
2.4 months
6.4
Abbreviations: PFS, progression-free survival; RR, response rate; OS, overall survival; NSCLC-BM, nonsmall cell lung cancer brain metastases; WBRT, whole-brain radiation therapy; SRS,
stereotactic radiotherapy; MBM, melanoma brain metastases; BCBM, breast cancer brain metastasis; TTP, time to tumor progression.
*Preliminary results.
65%, the intracranial DCR was 62%, and the median intracranial TTP was 13.2 months.
69
TABLE 2. Selected Ongoing Clinical Trials of Targeted and Immunotherapeutic Agents in Brain Metastasis
Intervention
WBRT vs. erlotinib WBRT
Phase
Primary Malignancy
Target
Anticipated Enrollment
(No. of Patients)
CT No.
III
NSCLC
EGFR
224
NCT01887795
II
NSCLC
PARP
307
NCT01657799
Pembrolizumab63
II
PD-1
64
NCT02085070
Radiation ipilimumab74
II
Melanoma
CTLA-4
66
NCT02115139
Vemurafenib
II
Melanoma
BRAF
34
NCT01781026
Dabrafenib49
II
Melanoma
BRAF
39
NCT01721603
II
Melanoma
PD-1/CTLA-4
148
NCT02320058
II
Breast
HER2
35
NCT01305941
II
Breast
HER2/PI3K
72
NCT01132664
WBRT lapatinib41
II
Breast
HER2
143
NCT01622868
HKI-272 (neratinib)42
II
Breast
HER2
105
NCT01494662
Afatinib43
II
Breast
HER2
121
NCT01441596
ARRY-380 trastuzumab44
Breast
HER2
50
NCT01921335
72
75
Nivolumab ipilimumab76
77
Abbreviations: CT, clinical trials; WBRT, whole-brain radiation therapy; NSCLC, nonsmall cell lung cancer; PARP, poly(ADP-ribose) polymerase; PD-1, programmed cell death protein 1; CTLA-4,
cytotoxic T-lymphocyteassociated antigen 4; PI3K, phosphatidylinositol 3-kinase.
70
71
However, the potential of targeted agents (like classical chemotherapy) to prevent metastases, including brain metastases, has rarely been systemically addressed.66,67 In general,
clinical trials are not (yet) designed to prospectively investigate the rate of metastasis formation. Given that the vast majority of patients with cancer die from metastatic disease and
not from the primary tumor, and given that brain metastases
constitute a most serious neurologic complication of cancer,
brain metastasis is an important area for future preclinical
and clinical cancer research.68 Targeted therapies are excellent candidates for such brain metastases prevention studies;
they often can be given to patients over prolonged periods of
time with good tolerability.
CONCLUSION
A multidisciplinary strategy is recommended for the individualized management of brain metastases for every patient. An approach that includes surgery, WBRT, SRS, or
systemic therapy, or a combination of these modalities, often is advocated on the basis of the performance status,
age, tumor type, number of metastases, and extracranial
disease status of patient. There is emerging data that targeted agents and immunotherapeutic approaches have activity in the brain, which is likely to develop a signifcant
impact on the intracranial disease. The optimal timing of
systemic therapies (therapeutic or prophylactic) remains
to be determined.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Manmeet S. Ahluwalia, Elekta, Sigma-Tau. Frank
Winkler, Serono. Consulting or Advisory Role: Manmeet S. Ahluwalia, Genentech/Roche, Monteris Medical, Novocure. Frank Winkler, Roche. Speakers
Bureau: Manmeet S. Ahluwalia, Sigma-Tau. Research Funding: Manmeet S. Ahluwalia, Boehringer Ingelheim, Lilly/ImClone, Novartis, Novocure, Spectrum
Pharmaceuticals, TRACON Pharma. Frank Winkler, Genentech, Roche. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None.
Travel, Accommodations, Expenses: Manmeet S. Ahluwalia, Elekta. Other Relationships: None.
References
1. Ahluwalia MS, Vogelbaum MV, Chao ST, et al. Brain metastasis and
treatment. F1000 Prime Reports. 2014;6:114.
2. Aronson SM, Garcia JH, Aronson BE. Metastatic neoplasms of the
brain: their frequency in relation to age. Cancer. 1964;17:558-563.
3. Fox BD, Cheung VJ, Patel AJ, et al. Epidemiology of metastatic brain
tumors. Neurosurg Clin North Am. 2011;22:1-6, v.
4. Brastianos PK, Curry WT, Oh KS. Clinical discussion and review of the
management of brain metastases. J Natl Compr Canc Netw. 2013;11:
1153-1164.
5. Nayak L, Lee EQ, Wen PY. Epidemiology of brain metastases. Curr Oncol Rep. 2012;14:48-54.
6. Tsao MN, Lloyd N, Wong RK, et al. Whole brain radiotherapy for the
treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev. 2012;4:CD003869.
7. Nguyen DX, Bos PD, Massague J. Metastasis: from dissemination to
organ-specifc colonization. Nat Rev Cancer. 2009;9:274-284.
8. Muldoon LL, Soussain C, Jahnke K, et al. Chemotherapy delivery issues
in central nervous system malignancy: a reality check. J Clin Oncol.
2007;25:2295-2305.
9. Kienast Y, von Baumgarten L, Fuhrmann M, et al. Real-time imaging
reveals the single steps of brain metastasis formation. Nat Med. 2010;16:
116-122.
10. Carbonell WS, Ansorge O, Sibson N, et al. The vascular basement membrane as soil in brain metastasis. PloS One. 2009;4:e5857.
11. Valiente M, Obenauf AC, Jin X, et al. Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell. 2014;156:10021016.
12. Lin Q, Balasubramanian K, Fan D, et al. Reactive astrocytes protect melanoma cells from chemotherapy by sequestering intracellular calcium
72
13.
14.
15.
16.
17.
18.
19.
20.
21.
22. Sperduto PW, Wang M, Robins HI, et al. A phase 3 trial of whole brain
radiation therapy and stereotactic radiosurgery alone versus WBRT and
SRS with temozolomide or erlotinib for non-small cell lung cancer and
1 to 3 brain metastases: Radiation Therapy Oncology Group 0320. Int J
Radiat Oncol Biol Phys. 2013;85:1312-1318.
23. Gerber NK, Yamada Y, Rimner A, et al. Erlotinib versus radiation therapy for brain metastases in patients with EGFR-mutant lung adenocarcinoma. Int J Radiat Oncol Biol Phys. 2014;89:322-329.
24. Ceresoli GL, Cappuzzo F, Gregorc V, et al. Geftinib in patients with
brain metastases from non-small-cell lung cancer: a prospective trial.
Ann Oncol. 2004;15:1042-1047.
25. Park SJ, Kim HT, Lee DH, et al. Effcacy of epidermal growth factor
receptor tyrosine kinase inhibitors for brain metastasis in non-small cell
lung cancer patients harboring either exon 19 or 21 mutation. Lung
Cancer. 2012;77:556-560.
26. Wu YL, Zhou C, Cheng Y, et al. Erlotinib as second-line treatment in
patients with advanced non-small-cell lung cancer and asymptomatic
brain metastases: a phase II study (CTONG-0803). Ann Oncol. 2013;24:
993-999.
27. Fan Y, Xu X, Xie C. EGFR-TKI therapy for patients with brain metastases from non-small-cell lung cancer: a pooled analysis of published data.
Onco Targets Ther. 2014;7:2075-2084.
28. Masuda T, Hattori N, Hamada A, et al. Erlotinib effcacy and cerebrospinal fluid concentration in patients with lung adenocarcinoma developing leptomeningeal metastases during geftinib therapy. Cancer
Chemother Pharmacol. 2011;67:1465-1469.
29. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase
inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:16931703.
30. Costa DB, Shaw AT, Ou SH, et al. Clinical experience with crizotinib in
patients with advanced ALK-rearranged non-small-cell lung cancer and
brain metastases. J Clin Oncol. Epub 2015 Jan 26.
31. Lin NU, Bellon JR, Winer EP. CNS metastases in breast cancer. J Clin
Oncol. 2004;22:3608-3617.
32. Kennecke H, Yerushalmi R, Woods R, et al. Metastatic behavior of
breast cancer subtypes. J Clin Oncol. 2010;28:3271-3277.
33. Kirsch DG, Ledezma CJ, Mathews CS, et al. Survival after brain metastases from breast cancer in the trastuzumab era. J Clin Oncol. 2005;23:
2114-2116; author reply, 2116-2117.
34. Dijkers EC, Oude Munnink TH, Kosterink JG, et al. Biodistribution of
89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clin Pharmacol Ther. 2010;87:586592.
35. Park YH, Park MJ, Ji SH, et al. Trastuzumab treatment improves brain
metastasis outcomes through control and durable prolongation of systemic extracranial disease in HER2-overexpressing breast cancer patients. Br J Cancer. 2009;100:894-900.
36. Bartsch R, Berghoff AS, Preusser M. Breast cancer brain metastases responding to primary systemic therapy with T-DM1. J Neurooncol. 2014;
116:205-206.
37. Torres S, Maralani P, Verma S. Activity of T-DM1 in HER2-positive
central nervous system breast cancer metastases. BMJ Case Rep. 2014;
2014:bcr2014205680.
38. Gril B, Palmieri D, Bronder JL, et al. Effect of lapatinib on the outgrowth
of metastatic breast cancer cells to the brain. J Natl Cancer Inst. 2008;
100:1092-1103.
39. Lin NU, Carey LA, Liu MC, et al. Phase II trial of lapatinib for brain
metastases in patients with human epidermal growth factor receptor
2-positive breast cancer. J Clin Oncol. 2008;26:1993-1999.
40. Bachelot T, Romieu G, Campone M, et al. Lapatinib plus capecitabine in
patients with previously untreated brain metastases from HER2-
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
73
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
74
72.
73.
74.
75.
76.
77.
78.
From the Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD; Burkhardt Brain Tumor Neuro-Oncology Center, Neurological Institute, Cleveland Clinic,
Cleveland, OH.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Minesh M. Mehta, MBChB, FASTRO, Department of Radiation Oncology, University of Maryland School of Medicine, 22 South Greene St., GGK19, Baltimore, MD 21201;
email: mmehta@umm.edu.
2015 by American Society of Clinical Oncology.
e99
of SRS for brain metastases was frst reported in multiple retrospective studies. Sanghavi et al4 showed in a retrospective,
multi-institutional analysis of 502 patients who were stratifed by recursive partitioning analysis (RPA) classes I, II, and
III that patients treated with WBRT and SRS compared with
WBRT alone had a signifcant increase in median survival
times.4 The survival times in classes I, II, and III with the
combination versus alone were 16.1 versus 7.1 months, 10.3
versus 4.3 months, and 8.7 versus 2.1 months, respectively
(p 0.05).4 RTOG 9508 was a randomized, controlled, phase
III trial of 333 patients with one to three brain metastases and
a Karnofsky performance score (KPS) of 70 or greater who
were treated with WBRT and SRS or WBRT alone.5 In patients who had a single brain metastasis, treatment with
WBRT and SRS compared with only WBRT resulted in a decreased rate of local recurrence at 1 year (18% vs. 29%; p
0.01) and superior median survival times (6.5 vs. 4.9
months; p 0.039). In patients who had two or three brain
metastases, local control was signifcantly improved in the
combination arm, but there was no difference in survival
time between the two groups. There was an additional
beneft in outcomes (maintenance or improvement of KPS
and corticosteroid use) in patients who received SRS and
WBRT compared with WBRT alone.
The role of SRS alone, without WBRT, was evaluated in
subsequent studies. Aoyama et al6 published a prospective,
phase III trial, JROSG 99-1, that randomly assigned 132
patients (mostly with lung cancer) who had a KPS score of
70 or greater and four or fewer metastases to SRS with or
without WBRT. The results showed no survival difference
(8.0 months for SRS vs. 7.5 months for SRS with WBRT;
p 0.42); however, the trial was not powered to detect a
signifcant difference in overall survival and, relative to
longer-term survival, there was a nonsignifcant survival
trend in favor of the WBRT arm (1-year survival rates of
38.5% in the group treated with WBRT plus SRS vs. 28.4%
for SRS alone).6 As anticipated, the study demonstrated
that local control rates were improved with the addition of
KEY POINTS
Selection of local therapy for brain metastases requires a
multidisciplinary approach that includes neurosurgery,
radiation oncology, medical oncology, and neuro-oncology.
Treatment with whole-brain radiotherapy (WBRT) after
surgery or radiosurgery improves local and distant brain
failure but does not improve survival.
Stereotactic radiosurgery (SRS) increasingly is employed in
the management of these metastases in combination with
surgery, WBRT, and medical systemic therapies.
Prospective, randomized trials are needed to dene the
role and applications of WBRT and SRS.
Areas of active investigation include techniques (e.g.,
pharmacologic, hippocampal sparing) to preserve
neurocognitive function with radiotherapy.
e100
e101
for patients older than age 55 who were treated with SRS
alone (4.5 vs. 6.5 months). The time to local failure was
superior with the use of WBRT (7.4 vs. 6.6 months). Crucially, it is important to recognize that the recommendation regarding the survival gain in the younger patient
category with SRS alone is based on approximately 35 patients per arm and on a post hoc analysis of a cohort in
which the pre-enrollment balance regarding the extent of
systemic disease could not be assured, because structured
pre-SRS staginga necessary element for assessing overall
survival as an endpoint to avoid systemic burden as a confounderwas not performed.
Therefore, it is reasonable to hypothesize that, in reality,
the survival beneft from WBRT is likely limited primarily
to patients who do not experience extracranial disease
progression. Unless this question is studied in such an enriched cohort, most other studies would likely remain signifcantly underpowered to demonstrate a survival
advantage. In fact, as early as 1998, Pirzkall et al23 reported
on a 236-patient retrospective cohort and found a trend
toward improved longer-term survival in favor of SRS plus
WBRT (actuarial 1- and 2-year survival rates: 30% and
14% vs. 19% and 8%). More importantly, for patients without extracranial disease, the median survival was impressively (but not signifcantly) different at 15.4 vs 8.3 months
(p 0.08) in favor of WBRT.23 More recently, Wang et al24
retrospectively reviewed a 528-patient database (lung cancer,
257 patients; breast cancer, 102 patients; melanoma, 62 patients; renal cell carcinoma, 40 patients) from Columbia University; patients were treated between 1998 and 2013 with
SRS alone (206 patients), with SRS and WBRT (111 patients),
with resection followed by SRS (109 patients), or with all
three modalities (102 patients). The overall median survival
was 16.6 months; for patients who had a single brain metastasis, the median survival times after SRS, SRS plus WBRT,
SRS plus resection, and all three modalities were 9.0, 19.1,
25.5, and 25.0 months, respectively. Even for patients who
had more than one metastasis, the corresponding median
survival times were 8.6, 20.4, 20.7, and 24.5 months, respectively, which demonstrated the survival inferiority of SRS
alone as a modality in this cohort. This inferiority associated
with the use of SRS alone as a modality was validated in a
multivariate analysis.24
The data that call the meta-analysis by Sahgal et al22
most into question, however, come from one of the key
sources used within that analysis, JROSG 99-1. At the
JASTRO 2014 annual meeting, Aoyama et al (personal
communication, March 2015, quoted with permission)
presented their own reanalysis of this study, using the now
widely accepted disease-specifc Graded Prognostic Assessment (ds-GPA), a prognostic stratifcation tool.25 Because
the ds-GPA relies on molecular variables for stratifying patients who have breast cancer, information that was not collected on JROSG 99-1, these patients could not be adequately
categorized and were excluded; 88 (of the 132 total enrolled
patients) patients who had nonsmall cell lung cancer were
grouped into favorable (ds-GPA of 2.5 to 4; 47 patients) and
e102
ical models.28,29 In a prospective human study, a strong association with increasing hippocampal radiation dose and
neurocognitive dysfunction was demonstrated.30 Intensitymodulated radiotherapy can be used to conformally avoid
the hippocampal neural stem cell compartment during
WBRT (HA-WBRT). This hypothesis was tested in a singlearm phase II study of HA-WBRT for brain metastases that
used a prespecifed comparison with a historic control of patients treated with WBRT without hippocampal avoidance
(RTOG 0933).31 The primary endpoint was change in
HVLT-DR measured at 4 months. The historic control
(without hippocampal avoidance) resulted in a 30% mean
relative loss in HVLT-DR from baseline to 4 months. The
actual observed mean relative decline in HVLT-DR from
baseline to 4 months was, in fact, only 7.0%, which was signifcantly lower than the historic control of 30% (p 0.0003).
No decline in quality-of-life scores up to 6 months was
CONCLUSION
The management of brain metastases has evolved over the
years from palliation to an era of exciting active research. Local therapies (WBRT, SRS) are important modalities in the
management of brain metastases. Areas of active investigation include techniques to preserve neurocognitive function
with radiotherapy. The optimal management strategy for
these patients involves a multidisciplinary approach that accounts for individual characteristics of both the patient and
the tumor. A number of ongoing prospective clinical trials
will help further defne the role and application of WBRT and
SRS in the management of brain metastases.
Employment: None. Leadership Position: Minesh P. Mehta, Pharmacyclics. Stock or Other Ownership Interests: Minesh P. Mehta, Pharmacyclics.
Honoraria: Minesh P. Mehta, Ca Progress, Elekta, Research to Practice, Serono Foundation. Manmeet S. Ahluwalia, Elekta, Sigma-Tau. Consulting or
Advisory Role: Minesh P. Mehta, Abbvie, Best Medical Opinion, BMS, Celldex, GLG, MedaCorp, Medical Director Solutions, Novelos, Novocure, Philips
Healthcare, Roche/Genentech, Strategic Edge, US Oncology Ask The Expert. Manmeet S. Ahluwalia, Genentech/Roche, Monteris Medical, Novocure. Speakers
Bureau: Manmeet S. Ahluwalia, Sigma-Tau. Research Funding: Minesh P. Mehta, Novelos (Inst), Novocure (Inst). Manmeet S. Ahluwalia, Boehringer
Ingelheim, Lilly/ImClone, Novartis, Novocure, Spectrum Pharmaceuticals, TRACON Pharma. Patents, Royalties, or Other Intellectual Property: None.
Expert Testimony: None. Travel, Accommodations, Expenses: Manmeet S. Ahluwalia, Elekta. Other Relationships: None.
References
1. Chao JH, Phillips R, Nickson JJ. Roentgen-ray therapy of cerebral metastases. Cancer. 1954;7:682-689.
2. Borgelt B, Gelber R, Larson M, et al. Ultra-rapid high dose irradiation
schedules for the palliation of brain metastases: fnal results of the frst
two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys. 1981;7:1633-1638.
3. Patchell RA, Tibbs PA, Regine WF, et al. Postoperative radiotherapy in
the treatment of single metastases to the brain: a randomized trial.
JAMA. 1998;280:1485-1489.
4. Sanghavi SN, Miranpuri SS, Chappell R, et al. Radiosurgery for patients
with brain metastases: a multi-institutional analysis, stratifed by the
RTOG recursive partitioning analysis method. Int J Radiat Oncol Biol
Phys. 2001;51:426-434.
5. Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation
therapy with or without stereotactic radiosurgery boost for patients with
one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet. 2004;363:1665-1672.
6. Aoyama H, Shirato H, Tago M, et al. Stereotactic radiosurgery plus
whole-brain radiation therapy vs stereotactic radiosurgery alone for
treatment of brain metastases: a randomized controlled trial. JAMA.
2006;295:2483-2491.
7. Kocher M, Soffetti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of
8.
9.
10.
11.
12.
13.
e103
14. Atalar B, Modlin LA, Choi CY, et al. Risk of leptomeningeal disease in
patients treated with stereotactic radiosurgery targeting the postoperative resection cavity for brain metastases. Int J Radiat Oncol Biol Phys.
2013;87:713-718.
15. Asher AL, Burri SH, Wiggins WF, et al. A new treatment paradigm:
neoadjuvant radiosurgery before surgical resection of brain metastases
with analysis of local tumor recurrence. Int J Radiat Oncol Biol Phys.
2014;88:899-906.
16. Bindal AK, Bindal RK, Hess KR, et al. Surgery versus radiosurgery in the
treatment of brain metastasis. J Neurosurg. 1996;84:748-754.
17. Shaw E, Scott C, Souhami L, et al. Single dose radiosurgical treatment of
recurrent previously irradiated primary brain tumors and brain metastases: fnal report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys.
2000;47:291-298.
18. Auchter RM, Lamond JP, Alexander E, et al. A multiinstitutional outcome and prognostic factor analysis of radiosurgery for resectable single
brain metastasis. Int J Radiat Oncol Biol Phys. 1996;35:27-35.
19. Schoggl A, Kitz K, Reddy M, et al. Defning the role of stereotactic radiosurgery versus microsurgery in the treatment of single brain metastases. Acta Neurochir (Wien). 2000;142:621-626.
20. ONeill BP, Iturria NJ, Link MJ, et al. A comparison of surgical resection
and stereotactic radiosurgery in the treatment of solitary brain metastases. Int J Radiat Oncol Biol Phys. 2003;55:1169-1176.
21. Muacevic A, Kreth FW, Horstmann GA, et al. Surgery and radiotherapy
compared with gamma knife radiosurgery in the treatment of solitary
cerebral metastases of small diameter. J Neurosurg. 1999;91:35-43.
22. Sahgal A, Aoyama H, Kocher M, et al. Individual patient data (IPD)
meta-analysis of radomized controlled trials comparing stereotactic radiosurgery (SRS) alone to SRS plus whole brain radiation therapy in
patients with brain metastases. Int J Rad Oncol Biol Phys. 2013;87:1187.
23. Pirzkall A, Debus J, Lohr F, et al. Radiosurgery alone or in combination
e104
24.
25.
26.
27.
28.
29.
30.
31.
SPEAKERS
Scott Randall Plotkin, MD, PhD
Massachusetts General Hospital Cancer Center
Boston, MA
Mark R. Gilbert, MD
The University of Texas MD Anderson Cancer Center
Houston, TX
Matthias Preusser, MD
Medical University of Vienna
Vienna, Austria
From the Department of Neuropathology, Otto-von-Guericke University, Magdeburg, Germany; Department of Radiation Oncology, University of Toronto/Princess Margaret Cancer Centre, Toronto,
Canada; Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Matthias Preusser, MD, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria;
email: matthias.preusser@meduniwien.ac.at.
2015 by American Society of Clinical Oncology.
e106
MENINGIOMA MANAGEMENT
WHO Grade
Molecular Alteration*
Meningothelial meningioma
NF2
Fibroblastic meningioma
NF2
NF2
Psammomatous meningioma
Angiomatous meningioma
Microcystic meningioma
Secretory meningioma
Lymphoplasmacyte-rich meningioma
KLF4/TRAF7
Metaplastic meningioma
Chordoid meningioma
SMARCB1
Atypical meningioma
NF2
Papillary meningioma
Rhabdoid meningioma
Anaplastic meningioma
NF2
*Includes only molecular changes with high frequency and/or association with a specic
tumor location.
KEY POINTS
Meningiomas are the most frequent types of intracranial
tumors.
Surgery and radiotherapy are established treatments.
No standard treatments exist for recurrent/progressive
meningiomas.
Vascular endothelial growth factor pathway inhibitors
sunitinib, vatalinib, and bevacizumab showed potential
activity in small, uncontrolled studies that require
conrmation.
e107
TRAF7/KLF4 mutation characterizes secretory meningiomas39,43 and provides a molecular marker for this grade 1
subtype. Meningiomas with TRAF7/KLF4 mutations are predominantly located at the medial/lateral skull base.
Another nonNF2-associated mutation of skull base meningiomas affects the Smoothened gene, SMO. SMO mutations occur in 4% to 5% of grade 1 meningiomas and are
restricted to the medial anterior skull base near the midline.
SMO mutations are exclusive of NF2 and of AKT1 or TRAF7/
KLF4.29,39
Although all of these mutations are mutually exclusive of
NF2 alterations, other genetic alterations occur in association
with chromosome 22 in meningiomas. One gene located on
chromosome is SMARCB1, and alterations are frequently
found in SMARCB1 in pediatric malignant rhabdoid tumors.
Screening a large group of sporadic meningiomas revealed
that SMARCB1 mutations occur with low frequency and
might be cooperating with NF2 mutations, because tumors
showing both SMACRB1 and NF2 mutations were reported.45,46 SMARCB1-mutated meningiomas are preferentially found at the falx cerebri.47
In families with multiple spinal meningiomas and without
NF2 mutations, a loss-of-function mutation in the SMARCE1
gene was recently identifed.48 SMARCE1 is located on chromosome 17q21 and encodes for a 57-kDa subunit of the SWI/SNF
complex, which is involved in the regulation of chromatin structure by nucleosome remodeling. The mutation occurs selectively in spinal meningiomas with histologic features of clear cell
meningioma, so it providing a potential molecular hallmark for
this rare meningioma subtype.
The merlin protein belongs to the protein 4.1 family, with
members linking the membrane protein to the cytoskeleton.
One gene of the protein 4.1 family relevant for meningioma
biology is DAL1. Reduced expression of the DAL1 gene product protein 4.1B was found in approximately 60% of meningiomas regardless of histologic grade, which suggests that
protein 4.1B loss is another early event in meningioma
pathogenesis.49,50 Nearly all tumors with DAL1 LOH have simultaneous NF2 LOH.51 Mice lacking DAL1 do not develop
tumors,52 which suggests that DAL1 alterations are early progressionassociated steps. In patients with multiple meningiomas, DAL1 mutations were found in both tumor and
paired blood samples, which suggests substantial differences
between patients with sporadic single and multiple meningioma with respect to DAL1.34
MENINGIOMA MANAGEMENT
and 1p and 14q loss especially are associated with meningioma progression.60-62 Interestingly, 1p loss commonly is
found in tumors located at the convexity but is rare in skull
base or spinal meningiomas.13 Moreover, 1p loss is associated
with faster meningioma recurrence.63 Losses of 6q, 9p, 13,
and 14 are found exclusively in highly proliferating meningiomas.64 Radiation-induced aggressive meningiomas show
cytogenetic aberrations on chromosome 1p, 6q, and 22.65
Few specifc genes associated with chromosomal alterations have been identifed. Besides NF2, the tissue inhibitor of
metalloproteinase 3 gene (TIMP3), location on 22q12, is another gene associated with meningioma progression . Hypermethylation of the TIMP3 promoter occurs in 17% of benign,
22% of atypical, and 67% of anaplastic meningiomas and is
associated with allelic loss on 22q12.66 The TIMP3 protein
inhibits matrix metalloproteinases, which suggests that epigenetic inactivation of TIMP3 by promoter hypermethylation might favor aggressive invasive tumor growth. TIMP3
has additional tumor suppressor activity, and in vitro overexpression of TIMP3 reduces tumor growth and induces apoptosis.67 However, TIMP3 hypermethylation does not seem
associated with tumor recurrence or overall survival.63
Alterations on 9p21 have been found to represent losses of
the tumor suppressor genes CDKN2A (p16INK4a), p14ARF,
and CDKN2B (p15INK4b).30,68 In anaplastic grade 3 meningiomas, deletions of CDKN2A/CDKN2B are associated with poorer
survival.69 In mouse models, deletion of CDKN2A, together
with NF2 inactivation, results in increased meningioma frequency and the development of grade 2 or 3 meningiomas,
which proves that loss of CDKN2A and CDKN2B is a feature for
aggressive meningioma development.70
Amplifcation of the S6 kinase gene region on chromosome
17q23 is present in malignant meningiomas,71,72 which suggests that mammalian target of rapamycin (mTOR) signaling
pathway inhibition might be a therapeutic target.73 The
14q32 region has been implicated in meningioma progression because of the maternally expressed gene 3 (MEG3),
which has antiproliferative activity in meningiomas. Aggressive meningiomas show allelic losses, promoter hypermethylation, and reduced expression of MEG3 compared with
normal arachnoidal cells.74,75 The important role of chromosome 14q loss was supported by fndings that showed
NDRG2 as a gene commonly inactivated in meningioma progression. NDRG2 is downregulated in anaplastic meningiomas and in a small subset of lower-grade meningiomas and
atypical meningiomas with aggressive clinical behavior. The
reduced expression of NDRG2 is associated with promoter
hypermethylation.76,77
MANAGEMENT OF MENINGIOMAS
The overall management approach for newly diagnosed
meningiomas is usually dependent on a number of factors
including the patients age, comorbidities, and clinical symptoms as well as the tumor location (proximity to critical
structures or regions of brain), size, and mass effect. For patients who are symptomatic as a result of the mass effect from
the tumor, surgery is typically recommended. For other patients, discussion with the patient and interdisciplinary discussion of all management options, including observation,
surgical resection, and radiotherapy (including radiosurgery
and fractionated radiotherapy) are considered.
OBSERVATION
For patients who have asymptomatic meningiomas that are
not in close proximity to critical structures, an observational
approach may be considered. Most meningiomas are low
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e109
SURGERY
The usual initial treatment is surgical excision of the tumor
and its dural base, particularly for tumors located on the
outer brain surface and surgically easily accessible. After
gross total resection (i.e., complete excision of the tumor and
its dural attachments) of a benign meningioma, the risk of
tumor recurrences are 5%, 10%, and 30% at 5, 10, and 15
years, respectively.100 The extent of surgery is reported by
Simpson grade. Sughrue et al101 reported that, for patients
who have grade 1 meningioma, the extent of resection impacts the risk of recurrence and progression-free survival. After Simpson grade 1, 2, 3, and 4 resections, the respective
5-year progression-free survival rates were 95%, 85%, 88%,
and 81%.101
Not all meningiomas can be totally resected without an unacceptable risk of postoperative neurologic defcits. For skullbased meningiomas, a particular surgical risk is cranial nerve
palsy.102-104 Newer microsurgical and endoscopic techniques
in combination with advances in neuroimaging have improved the outcomes of surgical resection of meningiomas.105,106 Finally, there has been a move toward optimizing
functional preservation by utilizing a combination of the currently available surgical and radiotherapy techniques personalized to the patient and particular clinical situation over
achieving radical resections that results in functional loss.
RADIOTHERAPY
The role of radiotherapy in the management of meningiomas
depends on patient factors, such as their comorbidities and
preference, and on tumor factors, including tumor size, resectability, andparticularly grade. Radiotherapy also is
usually recommended for recurrent meningiomas after initial surgical resection, either as monotherapy or as adjuvant
therapy after reresection.107
In general, radiotherapy is recommended after surgical resection of malignant (WHO grade 3) meningiomas because
of the considerably better 5-year progression-free survival
seen with surgery followed by adjuvant radiotherapy (80%)
compared with surgery alone (15%).108 Radiotherapy was
shown to shrink any remaining tumor burden in addition to
preventing tumor recurrence.109,110
For atypical (WHO grade 2) meningiomas, the optimal
timing of radiotherapy is less clear, particularly after a complete resection. Retrospective studies have demonstrated that
early adjuvant radiotherapy for nonbenign meningiomas improves progression-free survival, but the majority of these
e110
Radiosurgery
Radiosurgery can be delivered with a variety of devices, including the Gamma Knife, Cyberknife, and a linear accelerator (LINAC). A single fraction to a marginal dose of 10 to 15
Gy is usually given.117,118 Because treatment of a larger target
volume results in greater treatment-related toxicity, radiosurgery typically is offered to tumors that are smaller volume
and not in very close proximity to critical structures, such as
the optic chiasm.119 In a multicenter study of 254 patients
treated up front for petroclival meningioma with radiosurgery (140 patients) or with radiosurgery after surgery (144
patients), the actuarial progression-free survival rates were
93% and 84% at 5 and 10 years, respectively.120 Similar tumor
control, with actuarial 5- and 10-year progression-free survival rates of 95% and 92%, respectively, has been reported
for sellar and parasellar meningiomas treated with a singlefraction radiosurgery treatment to a median prescription
dose of 13 Gy (range, 5 to 30 Gy).121
Fractionated Radiotherapy
Fractionated radiotherapy is often delivered with stereotactic
radiotherapy (SRT) or image-guided radiotherapy approaches to optimize the precision of radiotherapy delivery
in combination with intensity-modulated radiotherapy techniques to improve the dose shaping around complex targets
in close vicinity to critical normal structures. For benign meningiomas, fractionated radiotherapy is offered for large volume tumors or those in very close proximity to critical
structures, such as the optic chiasm. The volume that is targeted for benign tumors is typically the enhancing tumor,
with a minimal margin for set-up error. The radiation dose
MENINGIOMA MANAGEMENT
Proton Therapy
Proton therapy provides the potential beneft of a more conformal dose distribution that can cover the tumor with a
higher dose of radiation while minimizing entry, exit, and
overall integral radiation dose. At the present time, the ability
to generate a highly conformal proton radiotherapy plan is
user and center dependent. Using standard fraction sizes of
1.8 Gy and total doses of 50.4 to 66.6 Gy for grade 1 meningiomas and doses of 54.0 to 72.0 Gy for grade 2 meningiomas,
the results from Loma Linda show a 5-year actuarial control
rate of 96%, with better control for grade 1 meningiomas
(99% at 5 years) compared with grade 2 meningiomas (50%
at 5 years). No associations with local control and total dose
were seen in this retrospective review, but increased optic
neuropathy was seen with higher doses delivered to tumors
in close proximity to the optic apparatus.124 Gudjonsson et
al125 reported their outcomes of stereotactic hypofractionated proton radiotherapy using doses between 14 Gy in three
fractions to 24 Gy in four fractions. They reported no signs of
tumor progression after 36 months of follow-up of 19 patients with partially resected grade 1 (15 patients) or unresectable (4 patients) meningiomas. However, two patients
developed clinical signs and radiologic evidence of a radiation reaction with this hypofractionated approach.125
SYSTEMIC THERAPIES
Systemic therapies are usually considered in patients who experience progression after exhaustion of all local treatment
options (surgical resection, radiotherapy) and in the rare
cases of metastatic meningiomas. Unfortunately, the lack of
adequately designed and powered clinical trials on systemic
therapeutics in meningiomas prohibits treatment planning
on a high level of evidence. On the basis of documented
low response rates and progression-free survival times, a
number of drugs, including hydroxyurea, interferon alfa,
octreotide analogs (sandostatin, pasireotide), mifepristone, megestrol acetate, imatinib, erlotinib, and geftinib
are not considered benefcial agents.126 However, some
agents have shown promising signs of effcacy in preclinical investigations and small clinical studies that may
translate into clinically relevant activity if confrmed in
larger, prospective clinical trials.
e111
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: Christian Mawrin, Merck Germany (I). Honoraria: Matthias Preusser,
GSK, Roche. Christian Mawrin, Bayer Schering Pharma. Consulting or Advisory Role: None. Speakers Bureau: None. Research Funding: Matthias Preusser,
Bhringer Ingelheim (Inst), GSK (Inst), Roche (Inst). Caroline Chung, Pzer. Christian Mawrin, Bayer Schering Pharma. Patents, Royalties, or Other
Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: Matthias Preusser, GSK, Roche. Other Relationships:
Christian Mawrin, Bayer Schering Pharma, Medac.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
e112
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
omas: a clinicopathologic study of 116 patients, with grading implications. Cancer. 1999;85:2046-2056.
Perry A, Stafford SL, Scheithauer BW, et al. Meningioma grading: an
analysis of histologic parameters. Am J Surg Pathol. 1997;21:14551465.
Rouleau GA, Merel P, Lutchman M, et al. Alteration in a new gene
encoding a putative membrane-organizing protein causes neurofbromatosis type 2. Nature. 1993;363:515-521.
Trofatter JA, MacCollin MM, Rutter JL, et al. A novel moesin-, ezrin-,
radixin-like gene is a candidate for the neurofbromatosis 2 tumor suppressor. Cell. 1993;72:791-800.
Evans DG, Huson SM, Donnai D, et al. A genetic study of type 2 neurofbromatosis in the United Kingdom. I. Prevalence, mutation rate,
ftness, and confrmation of maternal transmission effect on severity.
J Med Genet. 1992;29:841-846.
Seizinger BR, de la Monte S, Atkins L, Gusella JF, Martuza RL. Molecular genetic approach to human meningioma: loss of genes on chromosome 22. Proc Natl Acad Sci U S A. 1987;84:5419-5423.
Dumanski JP, Carlbom E, Collins VP, et al. Deletion mapping of a locus on human chromosome 22 involved in the oncogenesis of meningioma. Proc Natl Acad Sci U S A. 1987;84:9275-9279.
Ruttledge MH, Xie YG, Han FY, et al. Deletions on chromosome 22 in
sporadic meningioma. Genes Chromosomes Cancer. 1994;10:122-130.
Dumanski JP, Rouleau GA, Nordenskjold M, et al. Molecular genetic
analysis of chromosome 22 in 81 cases of meningioma. Cancer Res.
1990;50:5863-5867.
Ruttledge MH, Sarrazin J, Rangaratnam S, et al. Evidence for the complete inactivation of the NF2 gene in the majority of sporadic meningiomas. Nat Genet. 1994;6:180-184.
Gutmann DH, Giordano MJ, Fishback AS, et al. Loss of merlin expression in sporadic meningiomas, ependymomas and schwannomas.
Neurology. 1997;49:267-270.
Curto M, McClatchey AI. Nf2/Merlin: a coordinator of receptor signaling and intercellular contact. Br J Cancer. 2008;98:256-262.
Wellenreuther R, Kraus JA, Lenartz D, et al. Analysis of the neurofbromatosis 2 gene reveals molecular variants of meningioma. Am J
Pathol. 1995;146:827-832.
Brastianos PK, Horowitz PM, Santagata S, et al. Genomic sequencing
of meningiomas identifes oncogenic SMO and AKT1 mutations. Nat
Genet. 2013;45:285-289.
Goutagny S, Yang HW, Zucman-Rossi J, et al. Genomic profling reveals alternative genetic pathways of meningioma malignant progression dependent on the underlying NF2 status. Clin Cancer Res. 2010;
16:4155-4164.
Hartmann C, Sieberns J, Gehlhaar C, et al. NF2 mutations in secretory
and other rare variants of meningiomas. Brain Pathol. 2006;16:15-19.
MENINGIOMA MANAGEMENT
32. Hansson CM, Buckley PG, Grigelioniene G, et al. Comprehensive genetic and epigenetic analysis of sporadic meningioma for macromutations on 22q and micro-mutations within the NF2 locus. BMC
Genomics. 2007;8:16.
33. Wada K, Maruno M, Suzuki T, et al. Chromosomal and genetic aberrations differ with meningioma subtype. Brain Tumor Pathol. 2004;21:
127-133.
34. Heinrich B, Hartmann C, Stemmer-Rachamimov AO, et al. Multiple
meningiomas: investigating the molecular basis of sporadic and familial forms. Int J Cancer. 2003;103:483-488.
35. Hsieh HY, Wu T, Wang CJ, et al. Neurological complications involving the central nervous system in neurofbromatosis type 1. Acta Neurol Taiwan. 2007;16:68-73.
36. Kalamarides M, Niwa-Kawakita M, Leblois H, et al. Nf2 gene inactivation in arachnoidal cells is rate-limiting for meningioma development
in the mouse. Genes Dev. 2002;16:1060-1065.
37. Kawashima M, Suzuki SO, Yamashima T, et al. Prostaglandin D synthase (beta-trace) in meningeal hemangiopericytoma. Mod Pathol.
2001;14:197-201.
38. Kalamarides M, Stemmer-Rachamimov AO, Niwa-Kawakita M, et al.
Identifcation of a progenitor cell of origin capable of generating diverse meningioma histological subtypes. Oncogene. 2011;30:23332344.
39. Clark VE, Erson-Omay EZ, Serin A, et al. Genomic analysis of nonNF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and
SMO. Science. 2013;339:1077-1080.
40. Sahm F, Bissel J, Koelsche C, et al. AKT1E17K mutations cluster with
meningothelial and transitional meningiomas and can be detected by
SFRP1 immunohistochemistry. Acta Neuropathol. 2013;126:757-762.
41. Carpten JD, Faber AL, Horn C, et al. A transforming mutation in the
pleckstrin homology domain of AKT1 in cancer. Nature. 2007;448:
439-444.
42. Bleeker FE, Felicioni L, Buttitta F, et al. AKT1(E17K) in human solid
tumours. Oncogene. 2008;27:5648-5650.
43. Reuss DE, Piro RM, Jones DT, et al. Secretory meningiomas are defned by combined KLF4 K409Q and TRAF7 mutations. Acta Neuropathol. 2013;125:351-358.
44. Rowland BD, Peeper DS. KLF4, p21 and context-dependent opposing
forces in cancer. Nat Rev Cancer. 2006;6:11-23.
45. Schmitz U, Mueller W, Weber M, et al. INI1 mutations in meningiomas at a potential hotspot in exon 9. Br J Cancer. 2001;84:199-201.
46. Rieske P, Zakrzewska M, Piaskowski S, et al. Molecular heterogeneity
of meningioma with INI1 mutation. Mol Pathol. 2003;56:299-301.
47. van den Munckhof P, Christiaans I, Kenter SB, et al. Germline
SMARCB1 mutation predisposes to multiple meningiomas and
schwannomas with preferential location of cranial meningiomas at the
falx cerebri. Neurogenetics. 2012;13:1-7.
48. Smith MJ, OSullivan J, Bhaskar SS, et al. Loss-of-function mutations
in SMARCE1 cause an inherited disorder of multiple spinal meningiomas. Nat Genet. 2013;45:295-298.
49. Gutmann C, Donahoe J, Perry A. Loss of DAL-1, a second protein 4.1
tumor suppressor, is an important early event in the pathogenesis of
meningioma. Hum Mol Genet. 2000;9:1495-1500.
50. Perry A, Cai DX, Scheithauer BW, et al. Merlin, DAL-1, and progesterone receptor expression in clinicopathologic subsets of meningioma: a correlative immunohistochemical study of 175 cases.
J Neuropathol Exp Neurol. 2000;59:872-879.
51. Nunes F, Shen Y, Niida Y, et al. Inactivation patterns of NF2 and DAL1/4.1B (EPB41L3) in sporadic meningioma. Cancer Genet Cytogenet.
2005;162:135-139.
52. Yi C, McCarty JH, Troutman SA, et al. Loss of the putative tumor sup-
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
e113
72. Surace EI, Lusis E, Haipek CA, et al. Functional signifcance of S6K
overexpression in meningioma progression. Ann Neurol. 2004;56:295298.
73. Pachow D, Andrae N, Kliese N, et al. mTORC1 inhibitors suppress
meningioma growth in mouse models. Clin Cancer Res. 2013;19:11801189.
74. Zhang X, Gejman R, Mahta A, et al. Maternally expressed gene 3, an
imprinted noncoding RNA gene, is associated with meningioma
pathogenesis and progression. Cancer Res. 2010;70:2350-2358.
75. Balik V, Srovnal J, Sulla I, et al. MEG3: a novel long noncoding potentially tumour-suppressing RNA in meningiomas. J Neurooncol. 2013;
112:1-8.
76. Lusis EA, Watson MA, Chicoine MR, et al. Integrative genomic analysis identifes NDRG2 as a candidate tumor suppressor gene frequently inactivated in clinically aggressive meningioma. Cancer Res.
2005;65:7121-7126.
77. Skiriute D, Tamasauskas S, Asmoniene V, et al. Tumor grade-related
NDRG2 gene expression in primary and recurrent intracranial meningiomas. J Neurooncol. 2011;102:89-94.
78. Yamaguchi S, Terasaka S, Kobayashi H, et al. Prognostic factors for
survival in patients with high-grade meningioma and recurrence-risk
stratifcation for application of radiotherapy. PLoS One. 2014;9:
e97108.
79. Ketter R, Henn W, Niedermayer I, et al. Predictive value of
progression-associated chromosomal aberrations for the prognosis of
meningiomas: a retrospective study of 198 cases. J Neurosurg. 2001;95:
601-607.
80. Maillo A, Orfao A, Sayagues JM, et al. New classifcation scheme for the
prognostic stratifcation of meningioma on the basis of chromosome
14 abnormalities, patient age, and tumor histopathology. J Clin Oncol.
2003;21:3285-3295.
81. Kim YJ, Ketter R, Henn W, et al. Histopathologic indicators of recurrence in meningiomas: correlation with clinical and genetic parameters. Virchows Arch. 2006;449:529-538.
82. Maillo A, Orfao A, Espinosa AB, et al. Early recurrences in histologically benign/grade I meningiomas are associated with large tumors
and coexistence of monosomy 14 and del(1p36) in the ancestral tumor
cell clone. Neuro Oncol. 2007;9:438-446.
, et al. Proposal for a new risk strat83. Domingues PH, Sousa P, Otero A
ifcation classifcation for meningioma based on patient age, WHO tumor grade, size, localization, and karyotype. Neuro Oncol. 2014;16:
735-747.
84. Weisman AS, Raguet SS, Kelly PA. Characterization of the epidermal
growth factor receptor in human meningioma. Cancer Res. 1987;47:
2172-2176.
85. Maxwell M, Galanopoulos T, Hedley-Whyte ET, et al. Human meningiomas co-express platelet-derived growth factor (PDGF) and PDGFreceptor genes and their protein products. Int J Cancer. 1990;46:16-21.
86. Baumgarten P, Brokinkel B, Zinke J, et al. Expression of vascular endothelial growth factor (VEGF) and its receptors VEGFR1 and
VEGFR2 in primary and recurrent WHO grade III meningiomas. Histol Histopathol. 2013;28:1157-1166.
87. Lichtor T, Kurpakus MA, Gurney ME. Expression of insulin-like
growth factors and their receptors in human meningiomas. J Neurooncol. 1993;17:183-190.
88. Johnson MD, Woodard A, Kim P, et al. Evidence for mitogenassociated protein kinase activation and transduction of mitogenic signals by platelet-derived growth factor in human meningioma cells.
J Neurosurg. 2001;94:293-300.
89. Mawrin C, Sasse T, Kirches E, et al. Different activation of mitogenactivated protein kinase and Akt signaling is associated with aggressive
e114
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
MENINGIOMA MANAGEMENT
109. Milosevic MF, Frost PJ, Laperriere NJ, et al. Radiotherapy for atypical
or malignant intracranial meningioma. Int J Radiat Oncol Biol Phys.
1996;34:817-822.
110. Miralbell R, Linggood RM, de la Monte S, Convery K, Munzenrider JE,
Mirimanoff RO. The role of radiotherapy in the treatment of subtotally
resected benign meningiomas. J Neurooncol. 1992;13:157-164.
111. Adeberg S, Hartmann C, Welzel T, et al. Long-term outcome after radiotherapy in patients with atypical and malignant meningiomas: clinical results in 85 patients treated in a single institution leading to
optimized guidelines for early radiation therapy. Int J Radiat Oncol
Biol Phys. 2012;83:859-864.
112. Aghi MK, Carter BS, Cosgrove GR, et al. Long-term recurrence rates of
atypical meningiomas after gross total resection with or without postoperative adjuvant radiation. Neurosurgery. 2009;64:56-60 (discussion, 60).
113. Stessin AM, Schwartz A, Judanin G, et al. Does adjuvant external-beam
radiotherapy improve outcomes for nonbenign meningiomas? A Surveillance, Epidemiology, and End Results (SEER)-based analysis.
J Neurosurg. 2012;117:669-675.
114. Pollock BE, Stafford SL, Link MJ, et al. Stereotactic radiosurgery of
World Health Organization grade II and III intracranial meningiomas:
treatment results on the basis of a 22-year experience. Cancer. 2012;
118:1048-1054.
115. Compter I, Zaugg K, Houben RM, et al. High symptom improvement
and local tumor control using stereotactic radiotherapy when given
early after diagnosis of meningioma: a multicentre study. Strahlenther
Onkol. 2012;188:887-893.
116. Combs SE, Adeberg S, Dittmar JO, et al. Skull base meningiomas: longterm results and patient self-reported outcome in 507 patients treated
with fractionated stereotactic radiotherapy (FSRT) or intensity modulated radiotherapy (IMRT). Radiother Oncol. 2013;106:186-191.
117. Duma CM, Lunsford LD, Kondziolka D, et al. Stereotactic radiosurgery of cavernous sinus meningiomas as an addition or alternative to
microsurgery. Neurosurgery. 1993;32:699-704 (discussion, 704-705).
118. Ganz JC, Schrottner O, Pendl G. Radiation-induced edema after
Gamma Knife treatment for meningiomas. Stereotact Funct Neurosurg. 1996;66 (suppl 1):129-133.
119. Kang CS, Zheng LG, Xu DS. Dose-volume effect in gamma knife radiosurgery of meningiomas. Stereotact Funct Neurosurg. 1999;73:7278.
120. Starke R, Kano H, Ding D, et al. Stereotactic radiosurgery of petroclival
meningiomas: a multicenter study. J Neurooncol. 2014;119:169-176.
121. Sheehan JP, Starke RM, Kano H, et al. Gamma Knife radiosurgery for
sellar and parasellar meningiomas: a multicenter study. J Neurosurg.
2014;120:1268-1277.
122. Solda` F, Wharram B, De Ieso PB, et al. Long-term effcacy of fractionated radiotherapy for benign meningiomas. Radiother Oncol. 2013;
109:330-334.
123. Engenhart-Cabillic R, Farhoud A, Sure U, et al. Clinicopathologic fea-
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
138.
e115
DEVELOPMENTAL THERAPEUTICS
AND TRANSLATIONAL RESEARCH
Antibody-Drug Conjugates:
New Horizons to Maximize
Efcacy and Minimize Toxicity
CHAIR
Beverly A. Teicher, PhD
National Cancer Institute at the National Institutes of Health
Bethesda, MD
SPEAKERS
Francisco J. Esteva, MD, PhD
NYU Langone Medical Center
New York, NY
Kathy Miller, MD
Indiana University Melvin and Bren Simon Cancer Center
Indianapolis, IN
to improvements in all aspects of antibody conjugate therapeutics and, hence, to renewed interest in ADC technology.4
Immunogenicity was overcome by replacing murine antibodies with humanized or fully human antibodies. Potency
was improved by using drugs that were 100- to 1,000-fold
more potent than previously used drugs. Selectivity was addressed by performing more careful target and antibody selection. As a result of such improvements, gemtuzumab
ozogamicin (Mylotarg; Pfzer, New York, NY) was granted
accelerated U.S. Food and Drug Administration (FDA) approval for the treatment of acute myelogenous leukemia in
2000, becoming the frst commercially available ADC. However, gemtuzumab ozogamicin was withdrawn from the market in 2010 because, in postmarketing follow-up clinical
trials, it failed to meet the prospective effcacy targets. Two
ADCs, trastuzumab emtansine (T-DM1, Kadcyla; Genentech/Roche, South San Francisco, CA) and brentuximab vedotin (SGN-35; Adcetris, Seattle Genetics, Seattle, WA;
Millennium/Takeda, Boston, MA), reached FDA approval in
2014 and 2011, respectively, for treatment of metastatic
breast cancer and refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, respectively. More
than 40 ADCs are in clinical trials (Table 1).
From the Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; National Cancer
Institute at the National Institutes of Health, Bethesda, MD.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Beverly A. Teicher, PhD, Molecular Pharmacology Branch, National Cancer Institute, 9609 Medical Center Dr., Room 4-W602, MSC 9735, Bethesda, MD 20892;
email: beverly.teicher@nih.gov.
2015 by American Society of Clinical Oncology.
e117
Target
Company
Gemtuzumab ozogamicin,
Mylotarg
CD33
Pzer
HER2
Roche-Genentech
CD30
Seattle GeneticsTakeda
Inotuzumab ozogamicin,
CMC-544
CD22
Pzer
CDX-011, Glembatumumab
vedotin
GPNMB
Celldex Therapeutics
SAR3419, huB4-DM4
CD19
Sano
Lorvotuzumab mertansine,
IMGN901
CD56 (NCAM)
ImmunoGen
Seattle Genetics
PSMA ADC
PSMA
Progenics
CD22
Roche
CD79b
Roche
RG7450
STEAP1
Roche
AGS-5ME
AGS-5 (SLC44A4)
Astellas
AGS-22M6E
Nectin-4
Astellas
SAR566658, huDS6-DM4
CA6 (Muc1)
Sano
DRUGS
The drugs most widely conjugated to form ADCs target tubulin or DNA and are uniformly highly potent cytotoxic
agents with 50% inhibitory concentration (IC50) values in the
picomolar range in cell culture.
Though ADCs are among the most tumor-selective anticancer therapeutics developed to date, only a small fraction of the
drug reaches the intracellular target. The maytansinoids and dolastatin analogs target tubulin, and both suppress microtubule
dynamics.10 The duocarmycins and calicheamicins target the
minor groove of DNA. The amatoxin analogs inhibit RNA polymerase II and III, and SN-38 targets toposiosmerase I, which
results in DNA double-strand breaks.11 These molecules have in
Milatuzumab-DOX
CD74
Immunomedics
BAY 94-9343
Mesothelin
Bayer Pharma
IMGN529
CD37
ImmunoGen
IMGN853
FOLR1
ImmunoGen
Labetuzumab-SN-38; IMMU-130
CEACAM5
Immunomedics
MLN0264
Guanylyl cyclase
Millennium-Takeda
IMMU-132
Trop-2
Immunomedics
AMG-595
EGFR vIII
Amgen
AMG-172
CD70
Amgen
AGS-15E
SLITRK6
Astellas
AGS-16C3F
ENPP3
Astellas
RG-7458
MUC16
Roche
GSK2857916
BCMA
GSK
IMMU-132
Trop-2
Immunomedics
HuMax-TF
Tissue factor
Genmab
IMGN-242
CanAg
ImmunoGen
IMGN-289
EGFR
ImmunoGen
IMGN-388
Alpha v-integrin
ImmunGen
IMGN-633
CD33
ImmunoGen/Sano
MEDI-547
EphA2
MedImmune
MLN-0264
GCC
Takeda
MLN-2704
PSMA
Takeda
PF-06263507
5T4
Pzer
SAR-566658
huDS6 (Mucin 1)
Sano
SC16LD6.5
SC-16
Stem CentRx
SGN-19A
CD19
Seattle Genetics
SGN-CD33A
CD33
Seattle Genetics
SGN-LIV1A
LIV1 (ZIP6)
Seattle Genetics
KEY POINTS
Most antibody-drug conjugate (ADC) targets are cell
surface proteins that are much more abundant on tumor
cells than on normal cells/tissues.
ADCs selectively deliver targeted chemotherapy and could
be important components of combination treatment
regimens.
ADCs are being targeted to solid tumors and to
hematologic malignancies.
The three components of ADCs, antibody, linker, and drug,
must be stable in circulation for days or weeks.
T-DM1 and brentuximab vedotin are the rst two ADCs to
gain regulatory approval for HER2-positive metastatic
breast cancer and Hodgkin lymphoma, respectively. Patient
selection and understanding about the toxicity proles of
these agents are critical for integration of ADCs into
inpatient care.
e118
The drug is linked through the epsilon amino groups of lysine, through the intrastrand sulfhydryl linkages, and through genetically engineered unnatural amino acids to provide specic binding
sites and, thus, a single chemical species.
LINKERS
Linkers are short spacers that covalently couple the drug to
the antibody protein and must be stable in circulation (Fig.
1). Inside the cell, most linkers are labile; however, some are
stable, requiring degradation of the antibody and linker to
release the cytotoxic agent.23,24 Many linkers react with lysine
side chains throughout the antibody or with the sulfhydryls
in the hinge regions of the antibody. Linkers in clinical use
include acid-labile hydrazone linkers that are degraded under the low pH conditions found in lysosomes. Disulfdebased linkers are selectively cleaved in the cytosol in the
reductive intracellular milieu. Noncleavable thioether linkers
release the drug after degradation of the antibody in the lysosome, and peptide linkers, such as citrulline-valine, are degraded by lysosomal proteases in cells. Linkers using L- and
D-alanine and beta-glucuronide linkers are being explored.
Linkers with polyethylene glycol spacers have been developed to increase the solubility of the conjugate.25,26
Linkers can influence the circulating half-life and safety of
conjugates by minimizing the release of the drug molecule in
circulation and optimizing the delivery of the conjugate to
the target tissue. Often, during drug development, investigators will test several linkers in safety and effcacy assays to
select the best candidate conjugate.
ADCs
Drug-loading stoichiometry and molecular homogeneity are
important determinants of the safety and effcacy of antibody
conjugates (Fig. 1). The goal is to develop ADCs that are sinasco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e119
gle chemical species or nearly single chemical species. Underconjugated antibody decreases ADC potency, and highlyconjugated antibody markedly decreases circulating half-life
and impairs binding to the target protein, thus decreasing
ADC potency and effcacy.27 For most ADCs, linkage of three
to four drug molecules per antibody molecule is optimal to
maintain the circulating half-life to near that of the naked
antibody, preserving antibody binding to the target protein,
and delivering a lethal number of drug molecules to the target
cell. Several site-specifc conjugation approaches are being
explored to achieve ADCs that are single chemical species.
Antibodies with site-specifc incorporation of non-native
amino acid linker sites can be effciently produced.28
T-DM1 binds HER2; the complex is internalized and degraded in lysosomes, releasing DM1. T-DM1 retains the mechanisms of action of trastuzumab, including antibody-dependent cellular
cytotoxicity and HER pathway signaling disruption.
e120
regimens32 and as frst-line therapy for HER2 MBC.33-35 Lapatinib is approved in combination with capecitabine for patients
whose tumors have progressed on trastuzumab-based therapy.36 A combination of lapatinib and trastuzumab has been
shown to improve overall survival rates in patients with HER2
MBC who have experienced progression after multiple regimens.37 For details regarding the management of HER2
MBC, please refer to the American Society of Clinical Oncology
(ASCO) clinical practice guideline.38 On the basis of the results
of the EMILIA randomized trial described below,39 the FDAapproved T-DM1 (Kadcyla, Genentech, South San Francisco)
in February 2013 for the treatment of patients with HER2overexpressing MBC who have received prior treatment with
trastuzumab and a taxane.
1,000 patients with HER2 MBC who had not received any
chemotherapy in the metastatic setting. In this study, patients were randomly assigned to receive a taxane/trastuzumab, T-DM1, or T-DM1 plus pertuzumab (Perjeta;
Genentech/Roche, South San Francisco, CA). However, this
trial did not include a comparator arm with taxane, trastuzumab, and pertuzumab, which is the standard frst-line
therapy for HER2 MBC.33 Though detailed data have not
yet been shared, the sponsor recently announced that the
MARIANNE trial did not reach its primary endpoint.41
On the basis of the encouraging results reported in patients
with metastatic disease, there is great interest in testing the
effcacy of T-DM1 for early-stage breast cancer. An ongoing,
single-arm, phase II trial (NCT01196052) is evaluating the
effcacy of T-DM1 in the adjuvant or neoadjuvant setting.
After completion of an anthracycline-based adjuvant/neoadjuvant chemotherapy regimen (doxorubicin/cyclophosphamide [AC] or 5-fluorouracil/epirubicin/cyclophosphamide
[FEC]), 153 patients will be treated with T-DM1 instead of
the conventional taxane/trastuzumab combination for 17 cycles. In the ATEMPT trial (NCT01853748), 500 patients with
stage I breast cancer will be randomly assigned to T-DM1
versus paclitaxel plus trastuzumab. In the KAITLIN trial
(NCT01966471), 2,500 patients will be randomly assigned after adjuvant AC/FEC to either a taxane, trastuzumab plus
pertuzumab, or T-DM1 plus pertuzumab. A randomized,
phase III trial (KATHERINE; NCT01772472) will evaluate
the effcacy of T-DM1 in patients who have residual disease
after neoadjuvant, trastuzumab-containing regimens. In this
study, patients are randomly assigned to continuation of
trastuzumab (standard treatment) or to T-DM1. This study
has a planned enrollment of more than 1,400 patients. The
KRISTINE trial will examine the combination of docetaxel,
carboplatin, trastuzumab, and pertuzumab (one of the FDAapproved neoadjuvant pertuzumab-containing regimens)
versus T-DM1 plus pertuzumab. All of these trials will provide key data to integrate T-DM1 in the treatment of HER2
early-stage breast cancer.
e121
Management
IRRs
Thrombocytopenia
Hemorrhage
Hepatotoxicity
Left Ventricular
Dysfunction
Pneumonitis
Neurotoxicity
tiation of T-DM1 and before each T-DM1 dose. Dose modifcations should be instituted as appropriate.
T-DM1 can cause serious hepatotoxicity, including liver failure and death. Serum transaminases and bilirubin must be
monitored before initiation of T-DM1 treatment and before
each T-DM1 dose. If serum transaminases or total bilirubin are
increased, the dose of T-DM1 should be reduced or discontinued.
T-DM1 administration may lead to reductions in left ventricular ejection fraction (LVEF). All patients should undergo evaluation of LVEF before and during treatment with
T-DM1. If a patient develops a clinically meaningful decrease
in left ventricular function, the treatment should be held.
objective response rates and progression-free survival in patients with advanced disease.54,55 The ADAPT HER2/
HR trial compared T-DM1 monotherapy to T-DM1 plus
endocrine therapy (premenopausal patients: tamoxifen;
postmenopausal patients: aromatase inhibitor or trastuzumab plus endocrine therapy as neoadjuvant therapy).
The treatment with T-DM1 plus endocrine therapy resulted in a greater median fractional decrease in proliferation (Ki67) after 3 weeks of therapy (40% in the T-DM1/
endocrine therapy arm vs. 14% and 25% in the T-DM1
monotherapy and trastuzumab/endocrine therapy arms,
respectively).56
T-DM1 is an ideal candidate to combine with agents that
have been diffcult to combine with chemotherapy because of
overlapping toxicities. Ongoing trials combine T-DM1 with
a variety of downstream signaling inhibitors and other mo-
Employment: None. Leadership Position: Francisco J. Esteva, Viatar CTC Solutions, Inc. Stock or Other Ownership Interests: None. Honoraria: None.
Consulting or Advisory Role: Francisco J. Esteva, Genentech/Roche, GSK, Novartis. Kathy Miller, Clovis Oncology, Imclone, Nektar. Speakers Bureau: None.
Research Funding: Kathy Miller, AVEO (Inst), BiPar Sciences (Inst), Eli Lilly (Inst), EntreMed (Inst), Genentech (Inst), Geron (Inst), ImClone Systems (Inst),
Macrogenics (Inst), Medivation (Inst), Medivation (Inst), Merrimack (Inst), Novartis (Inst), Pzer (Inst), Seattle Genetics (Inst), Taiho Pharmaceutical (Inst).
Patents, Royalties, or Other Intellectual Property: Francisco J. Esteva, Myriad Genetics (royalties). Expert Testimony: None. Travel, Accommodations,
Expenses: Francisco J. Esteva, Novartis. Other Relationships: None.
References
1. Sliwkowski MX, Mellman I. Antibody therapeutics in cancer. Science.
2013;341:1192-1198.
2. Sievers EL, Senter PD. Antibody-drug conjugates in cancer therapy.
Annu Rev Med. 2013;64:15-29.
3. Teicher BA, Chari RV. Antibody conjugate therapeutics: challenges and
potential. Clin Cancer Res. 2011;17:6389-6397.
4. Chari RV. Targeted delivery of chemotherapeutics: tumor-activated
prodrug therapy. Adv Drug Deliv Rev. 1998;31:89-104.
5. Teicher BA. Antibody-drug conjugate targets. Curr Cancer Drug Targets. 2009;9:982-1004.
6. Chari RV. Targeted cancer therapy: conferring specifcity to cytotoxic
drugs. Acc Chem Res. 2008;41:98-107.
7. Schrama D, Reisfeld RA, Becker JC. Antibody targeted drugs as cancer
therapeutics. Nat Rev Drug Discov. 2006;5:147-159.
8. Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy.
Cancer J. 2008;14:154-169.
9. Beck A, Haeuw JF, Wurch T, et al. The next generation of antibody-drug
conjugates comes of age. Discov Med. 2010;10:329-339.
10. Lopus M, Oroudjev E, Wilson L, et al. Maytansine and cellular metabolites of antibody-maytansinoid conjugates strongly suppress microtubule dynamics by binding to microtubules. Mol Cancer Ther. 2010;9:
2689-2699.
11. Anderl J, Faulstich H, Hechler T, et al. Antibody-drug conjugate payloads. In Laurent Ducry (ed). Antibody-Drug Conjugates, Methods in
Molecular Biology. New York, NY: Springer, 2013;51-70.
e123
e124
2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol.
2009;27:5529-5537.
56. Gluz O, Nitz U, Sherko K, et al. Distinct early proliferation response to
neoadjuvant anti-HER2 antibody drug conjugate /- endocrine therapy in early breast cancer in the WSG ADAPT HER2/HR trial. Presented at: San Antonio Breast Cancer Symposium; December 9-13,
2014; San Antonio, TX. Abstract P4-15-01.
e125
DEVELOPMENTAL THERAPEUTICS
AND TRANSLATIONAL RESEARCH
SPEAKERS
Stuart M. Lichtman, MD
Memorial Sloan Kettering Cancer Center
New York, NY
Carlos H. Barrios, MD
Latin American Cooperative Oncology Group
Porto Alegre, Brazil
The goals set forth by Drs. Yancik and Kennedy are yet to
be fully achieved; however, many strides have been made toward that end. There has been increased recognition of the
importance of the relationship between aging and cancer, as
well as an increase in evidence-based research to guide the
care of older adults with cancer. In addition, this research is
being performed by a growing number of investigators at institutions across the nation, as well as internationally. The
International Society of Geriatric Oncology, founded in the
year 2000, fosters the mission of developing health professionals in the feld of geriatric oncology to optimize treatment of older adults with cancer, through education, clinical
practice, and research. The Societys publication, the Journal
of Geriatric Oncology, is the frst journal devoted solely to the
feld. The Cancer in the Elderly Committee of the Cancer and
Leukemia Group B (now the Alliance for Clinical Trials in
Oncology) has supported furthering research in geriatric oncology through clinical trials and secondary data analyses.
The Cancer and Aging Research Group has developed an instrument to predict chemotherapy toxicity, initiated and
supported trials to validate this methodology in different
clinical settings, and, most importantly, mentored junior investigators in geriatric oncology. The Gynecologic Oncology Group Elderly Taskforce is supporting the frst
prospective trial in older women with ovarian cancer and
planning further studies in other diseases and modalities.
The American Society of Clinical Oncology has also fostered a number of initiatives in geriatric oncology. These
e127
STUART M. LICHTMAN
include a Geriatric Oncology Issue Exploration Team, educational materials including ASCO University, sessions
at the Annual Meeting including a Geriatric Oncology
track, the BJ Kennedy Award for Excellence in Geriatric
Oncology, and a Geriatric Oncology component of the
Cancer Education Committee.
Older patients have long been under-represented in clinical trials.3,4 There are many reasons for this, including fear
of toxicity, restrictive trial eligibility, and ageism, which
includes physician barriers.5-8 When older patients do participate, they are usually a disproportionately small representation of the patients and their data are under-reported.9 The
Institute of Medicine has issued a report describing the crisis
in cancer care for an aging population.10
ELIGIBILITY ISSUES
Restrictive eligibility issues are an important reason why
older patients are not accrued to clinical trials. Standard performance status measurements such as Karnofsky Performance Status or Eastern Cooperative Oncology Group
(ECOG) are inadequate to defne function in older patients.18
Populations need to be defned more specifcally to encompass the broad range of older patients (i.e., frail, vulnerable,
or well). This can best be determined by some form of geriatric assessment, which could help in defning the patient
population, aid in stratifcation, and improve analysis of the
results.19,20 The typical end-organ requirements for eligibility
need to be made more flexible. For example, renal function
requirements can be relaxed when the drug being studied
KEY POINTS
Aging of the general population will result in a large
increase in the number of older patients with cancer.
Older patients with cancer are under-represented in clinical
trials.
There are a number of barriers that prevent older patients
from participating in clinical trials.
Current clinical trial design is inadequate to appropriately
assess the value of newer therapies.
Components of clinical trials such as eligibility, endpoints,
survivorship, and dose-limiting toxicity need to be
re-evaluated.
e128
5,17
e129
STUART M. LICHTMAN
SURVIVORSHIP
Although not usually part of standard clinical trial design, the
issues of survivorship in older survivors of cancer need to be
explored.35-37 As a result of increased utilization of screening
and earlier detection of common cancers (i.e., breast, colorectal, and prostate), coupled with incremental improvements in cancer treatment and supportive care, the number
of cancer survivors in the United States has increased from
approximately 3 million in 1970 to almost 14 million in 2014.
Patients age 70 and older account for 46% of all survivors.38
Survivorship has become a separate, but related, discipline of
oncology that requires both expertise and the infrastructure
to provide optimal care for cancer survivors. Cancer survivors have unique problems. Pre-existing comorbid issues are
often compounded by the residual toxicity of cancer treatment and the possibility of late adverse effects. There are also
emotional issues regarding survivorship. The Institute of
Medicine has issued recommendations regarding cancer survivorship programs and a number of centers of excellence
have been developed to evaluate different survivorship clinical models. These are focusing on many different areas, including behavioral interventions, nutritional interventions,
cancer screening, studies of morbidity, physical activity, sexual function, and fatigue.39-41
DOSE-LIMITING TOXICITY
Schedule changes may alter the toxicity profle of chemotherapy in an older population. For example, weekly paclitaxel
versus paclitaxel and bolus 5-fluorouracil every 3 weeks versus infusional 5-fluorouracil may show differences in toxic-
PHASE I STUDIES
Only a limited number of phase I trials have involved older
patients, despite the fact that the heterogeneity of this population limits the applicability of results from phase I studies
performed in ft, younger patients.42 Traditionally, during
the phase I investigation, acute toxicities are identifed and
the potential duration and reversibility of the toxicities are
defned. Selecting appropriate patients to accurately evaluate
toxicity in a phase I clinical investigation is extremely important. Typically, patients included in phase I trials have a good
performance status and normal organ function. As a result,
entry criteria often exclude older patients from dose-fnding
trials. However, studies in the older person could be defned
differently from what has been done historically. For example, after a phase I dose is determined, older patients with
varying degrees of functional impairment or comorbidities
can be treated to determine whether the dose is appropriate.
ASCO has published a position paper on the importance of
phase I studies with suggestions to enhance accrual. They
mention the critical role that Medicare has in supporting
these trials and by inference, increasing the participation of
older patients. Although the position paper specifcally cites
issues regarding pediatric patients, there is no specifcity with
respect to older people.43
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Stuart M.
Lichtman, Bayer, Icore Health Care. Speakers Bureau: Stuart M. Lichtman, Plexus Communications. Research Funding: None. Patents, Royalties, or
Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: Stuart M. Lichtman, Bayer. Other Relationships: None.
References
1. Carbone PP, Yancik R (ed). Perspectives on prevention and treatment of
cancer in the elderly. New York, NY: Raven Press; 1983.
2. Kennedy BJ. Aging and cancer. J Clin Oncol. 1988;6:1903-1911.
e130
3. Hutchins LF, Unger JM, Crowley JJ, et al. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med.
1999;341:2061-2067.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
e131
lobalization can be defned as the integration of economies, industries, markets, cultures, and policy-making
processes around the world.1 Even though the concept is not
new, the current wave of globalization has been heavily
driven and influenced by fantastic and unprecedented advances in the information technology that will likely have a
long lasting effect in the process. Even though globalization is
frequently approached with a focus in economy, the concept
has been increasingly broadened to include a diverse range of
areas such as culture, media and technology, socioculture,
and the political arena, among others. Proponents of globalization argue that the ultimate result of this international
interaction should be economic development and improvement of the standards of living.
Until not so long ago, drug development and cancer clinical research were conducted almost exclusively in wealthy
developed regions of the world. However, over the last 2 or 3
decades, clinical trials have been progressively incorporated
in a challenging globalization process. As such, the conduct
of trials in a global scale represents a major aspect to be taken
into account when analyzing the future development of the
area. The globalization of clinical trials, as well as multinational and multi-institutional research collaboration, represents a scenario that requires permanent and concentrated
From the Latin American Cooperative Oncology Group, PUCRS School of Medicine, Porto Alegre, Brazil.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Carlos H. Barrios, MD, Department of Medicine, PUCRS School of Medicine, Padre Chagas 66, 203, Porto Alegre RS, 90 570 080, Brazil; email: chbe@via-rs.net.
2015 by American Society of Clinical Oncology.
e132
KEY POINTS
The nature of clinical research has changed substantially
over the last 2 decades, evolving from being centered
almost exclusively in developed countries to involve less
developed regions of the world.
Although early phase trials remain largely concentrated in
the United States and Western Europe, conrmatory phase
III studies have become increasingly global, sometimes with
the largest proportion of patients being recruited in
developing countries.
Although the process of globalization should be considered
largely unavoidable, we need to recognize both the
advantages and the challenges associated with
multiregional clinical trials.
Both logistical and ethical implications of globalization of
clinical research are important aspects to this discussion.
In low- and middle-income countries, less people are dying
from avoidable infectious diseases, and chronic
noncommunicable illnesses are playing an increasing role in
the mortality patterns justifying the inclusion of developing
countries in global cancer studies.
Although most of the discussion around globalization has been
focused in pharmaceutical industrysponsored research,
efforts to integrate academic research at a global level are
vital if we are going to succeed in advancing the science of
medicine and improve health for all.
decades.2 A 66% increase in the number of annually registered trials was identifed comparing 2005 (introduction of
International Committee of Medical Journal Editors registration requirements) and 2012. From 2005 through 2012,
approximately 67% of the registered clinical trials were conducted in North America or Western Europe. The United
States was the country with the single largest activity, conducting approximately 30% of the studies. However, the
number of registered clinical trials has increased in all geographic regions during this time period, with the average annual growth greatest in the Asian (30%) and Latin American/
Caribbean (12%) regions. During the same period, the
average yearly increase was only 2% in North America.2
These data indicate a large and unrealized potential for
growth; the average clinical trial density (number of trials/
population) of low-income countries averaged one clinical
trial for every 3 million people, whereas Denmark demonstrated the highest density, with 107 trials for per 1 million
individuals.2
Over the last decade, the number of U.S. Food and Drug
Administration (FDA)regulated clinical investigators has
declined by 5.5% every year, whereas the percentage of investigators based outside the United States has grown yearly by
an overall percentage of 15%. The annual growth has been
29% in Asia, 13% in Latin America, and 16% in Central and
Eastern Europe.3 A recent estimate indicates that one-third
of all phase III trials sponsored by the 20 largest pharmaceutical companies are being conducted solely outside the
United States.4 Early trials seem to be conducted more frequently in North America (62%), whereas confrmatory trials
are more frequent in Eastern Europe, Latin America, and
Asia.5 Data from ClinicalTrials.gov shows that over 70% of
the registered cancer phase I trials are conducted in the
United States, whereas less than 1% are conducted in Latin
America. In larger registered phase III studies, 40% are conducted in the United States, 43% in Western Europe, and 17%
in Latin America.6
Although pharmaceutical companies are sponsoring most
of these multinational trials, we also have examples of increasing international cooperation in the academic research
arena. The European Organization for Research and Treatment of Cancer (EORTC) has fostered clinical trials that
bring together investigators and research groups from many
different countries. The NCI and its cooperative groups have
established guidelines for international collaboration.7 The
Breast International Group (BIG) has conducted large pivotal practice-changing studies that involved global participation and has recently launched an initiative addressing
clinical research in Latin America organizing a retreat with
the Latin American Cooperative Oncology Group (LACOG)
and other research groups in the region (Argentine Group
for Clinical Research in Oncology [GAICO], Uruguayan Oncology Cooperative Group [GOCUR], Peruvian Oncology
Clinical Studies Group [GECOPERU], Brazilian Group of
Breast Cancer Studies [GBECAM], Chilean Cooperative
Group for Oncologic Research [GOCCHI]). The discussion
identifed major areas with need for improvement and genasco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e133
erated a number of projects that will facilitate global integration and development of local expertise.8 Although these are
initiatives signaling a positive direction, they still fall short of
what is really needed and a wider and more consistent international integration of academic research remains a challenge that should be addressed with much more emphasis in
the future.
e134
Solution
Regulatory Standards
Harmonize regulatory standards, processes, and procedures for the pharmaceutical industry (e.g., ICH, ICH Global
Cooperation Group Members)
Share science-based goals and standards for product safety, quality, and efcacy
Use nite resources strategically and more efciently, sharing knowledge and information, leveraging inspection
resources (share inspection data, plan joint inspections, provide parallel advice to sponsors, organize regular
discussions that increase communication)
Actively engage global partners to harness scientic development, resources, and brainpower to support
science-based regulatory decision making and pursue the best possible public health solutions
Use innovative strategies and tools to identify sites for clinical inspection (e.g., GCP risk-based site selection
tool for clinical inspection)
Incorporate prevention strategies to avoid critical errors, and monitor for those errors
Decentralize laboratories developing regional expertise that will have signicant carry-over benets once the
trial is completed
In the planning stages of the protocol, consider potential regional variations in standards of care and the
impact they may have in trial results
Abbreviations: ICH, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; GCP, good clinical practices.
e135
extremely successful in making possible the conduct of clinical research in different countries and health care scenarios.
Although local regulatory standards may still vary, most respect the basic principles of GCP for clinical trials.
As quality is a fundamental principle in the conduct of clinical research, we need to address monitoring, auditing, and
inspections as a basic element in the process of globalization.
The mandatory requirement for GCP inspections in different
parts of the world is costly, logistically challenging, and results in the need for qualifed human resources. Barriers in
communication (languages, dialects, and translation requirements), different qualifcation, interaction with national regulatory authorities, and confdentiality agreement
issues are all very important considerations that can be diffcult to address. As results are usually used to fle for registration of new drugs, foreign data should be in accordance with
FDA regulations.15 Greater cooperation between national
regulatory bodies and all involved in clinical research, including patient representatives, ethics committee, sponsors,
and investigators needs to be stimulated to guarantee transparency in the whole process.
One other important aspect of globalization is the fact that
the inclusion of geographically distinct populations with different lifestyles, ethnicities, and genetic profles can influence
the safety and effcacy of drugs. Global trials need to consider
this genetic diversity, both when designing the study and at
the time of interpreting or reporting the results. Safety concerns need to be taken into consideration, as several studies
have shown that Asians metabolize drugs differently from
other patients. As an example, for 31.2% of the new drugs
approved in Japan between 2003 and 2005, the recommended standard doses were different from those in the
Western population. In part as a result of this diversity, some
countries like China and Japan require phase I trials to be
performed in national subjects for all new drugs not already
registered in another country.16 As a consequence, early
phase trials (usually performed in developed regions) are relatively more frequent there than in other countries. Another
telling example comes from a study looking at the genetic
makeup of the very heterogeneous Brazilian population, which
demonstrated that well beyond self-characterization as white,
brown or black, a large proportion of the population has substantial degrees of genetically defned African, Amerindian,
and European ancestry with obviously important pharmacogenetic implications.17 In our opinion, the explanation for
this complex issue should widely link not only the genetic
make-up of a population, but also take into account cultural
and social differences in diet, way of life, education, physical
activity, nutritional status, and religion, as they all could be
contributing factors. Global studies should consider these
important aspects that, in parallel, may represent a great opportunity to advance the investigation in this area.
Finally, a few words about the methodology and statistics
of multiregional clinical studies. Global studies can answer
global scientifc questions and address global objectives, but
at the same time they allow us to analyze regional aspects that
could be extremely important. The ability of a study to reach
e136
CONCLUSION
Globalization of clinical research is vital to speed up availability of life-saving medicines throughout the world. Challenges
of conducting multiregional clinical trials can be successfully
addressed through strategic and tactical planning as part of a
global drug development program. Implementations of International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human
Use guidelines, particularly GCPs, do help standardize procedures and are instrumental to conduct trials at a global
level.
Although some global initiatives have addressed biomedical education and suggested strategies to strengthen health
care systems, we still need much more emphasis in the discussion of improving clinical research capacity with a worldwide perspective. Clinical trials are needed in low-income
and middle-income countries to answer questions on prevalent conditions. At the same time, they improve local clinical
research training and infrastructure, as well as facilitate early
access to technology. The positive and lasting effects of global
trials in less developed regions are certainly unquestionable
but unfortunately yet to be realized. As more trials are conducted in resource-limited settings, good clinical practices
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e137
and ethical assurances must be secured. Human participation in clinical research is essential to advance medicine and
public health, and expanding clinical trials mandates constant oversight to ensure research quality and protection of
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Carlos H. Barrios, GSK, Novartis, Pzer,
Roche/Genentech, Sano. Consulting or Advisory Role: Carlos H. Barrios, Astellas Pharma, Boehringer Ingelheim, gsk, Novartis, Roche/Genentech.
Speakers Bureau: None. Research Funding: Carlos H. Barrios, Novartis, Pzer. Patents, Royalties, or Other Intellectual Property: None. Expert
Testimony: None. Travel, Accommodations, Expenses: Carlos H. Barrios, GlaxoSmithKline, GlaxoSmithKline, Novartis, Roche/Genentech, Sano. Other
Relationships: None.
References
1. FinancialTimes.Defnitionofglobalization.http://lexicon.ft.com/Term?
termglobalisation. Accessed January 28, 2015.
2. Drain PK, Robine M, Holmes KK, et al. Trail watch: global migration of
clinical trials. Nat Rev Drug Discov. 2014;13:166-167.
3. Getz AK. Global clinical trials activity in the details. 2007. http://
www.appliedclinicaltrialsonline.com/node/230040?relcanonical. Accessed January 28, 2015.
4. Glickman SW, McHutchison JG, Peterson ED, et al. Ethical and scientifc implications of the globalization of clinical research. N Engl J Med.
2009;360:816-823.
5. Thiers FA, Sinskey AJ, Ernst R. Trends in the globalization of clinical
trials. Nature Reviews Drug Discovery. 2008;7:13-14.
6. ClinicalTrials.gov. https://clinicaltrials.gov/. Accessed February 2, 2015.
7. Schilsky RL. Personalizing cancer care: American Society of Clinical
Oncology presidential address 2009. J Clin Oncol. 2009;27:3725-3730.
8. Breast International Group. Cancer clinical research in Latin America
must be considered as a priority. http://www.bigagainstbreastcancer.
org/news/cancer-clinical-research-latin-america-must-be-consideredpriority. Accessed February 2, 2015.
9. Manne S, Kashy D, Albrecht T, et al. Attitudinal barriers to participation
in oncology clinical trials: factor analysis and correlates of barriers. Eur
J Cancer Care (Engl). 2015;24:28-38. Epub 2014 Jan 28.
10. Sharrocks K, Spicer J, Camidge DR, et al. The impact of socioeconomic
status on access to cancer clinical trials. Br J Cancer. 2014;111:16841687.
11. Bansal N. The opportunities and challenges in conducting clinical trials
globally. Clin Res Regul Aff. 2012;29:9-14.
12. Rowland C. Clinical trials seen shifting overseas. Int J Health Serv. 2004;
34:555-556.
13. Smith WT. FDA requires foreign clinical studies be in accordance with
good clinical practices to better protect human subjects. ABA Health
eSource. 2008;5:1-3.
14. Kaitin KI. The Landscape for pharmaceutical innovation: drivers of
cost- effective clinical research. Pharm Outsourcing. 2010;2010:
3605.
15. Investigational New Drug Application, 21 USCFR. Food and Drugs,
Chapter I. Food and Drug Administration, Department of Health and
Human Services, part 312. Washington, DC: US Code of Federal Regulations; 2006.
e138
16. Bjornsson TD, Wagner JA, Donahue SR, et al. A review and assessment
of potential sources of ethnic differences in drug responsiveness. J Clin
Pharmacol. 2003;43:943-967.
17. Suarez-Kurtz G. Pharmacogenetics in the Brazilian population. Front
Pharmacol. 2010;1:118. eCollection 2010.
18. Martnez-Mesa J, Gonzalez-Chica DA, Bastos JL, et al. Sample size: how
many participants do I need in my research? An Bras Dermatol. 2014;
89:609-615.
19. Saad ED, Katz A, Buyse M. Overall survival and post-progression survival in advanced breast cancer: a review of recent randomized clinical
trials. J Clin Oncol. 2010;28:1958-1962.
20. Santosa A, Wall S, Fottrell E, et al. The development and experience of
epidemiological transition theory over four decades: a systematic review. Glob Health Action. 2014;7:23574. eCollection 2014.
21. Nappo SA, Iafrate GB, Sanchez ZM. Motives for participating in a clinical research trial: a pilot study in Brazil. BMC Public Health. 2013;13:19.
22. European Federation of Pharmaceutical Industries and Associations.
The Pharmaceutical Industry in Figures. Key Data 2014. Published
2014. http://www.efpia.eu/uploads/Figures_2014_Final.pdf. Accessed
February 12, 2015.
23. Experts in Chronic Myeloid Leukemia. The price of drugs for chronic
myeloid leukemia (CML) is a reflection of the unsustainable prices of
cancer drugs: from the perspective of a large group of CML experts.
Blood. 2013;121:4439-4442. Epub 2013 April.
24. Kahneman D. Thinking Fast and Slow. New York: Farrar, Straus and
Giroux; 2011.
25. Pentz RD, White M, Harvey RD, et al. Therapeutic misconception, misestimation, and optimism in participants enrolled in phase 1 trials.
Cancer. 2012;118:4571-4578.
26. Weinfurt KP, Seils DM, Lin L, et al. Research participants high expectations of beneft in early-phase oncology trials: are we asking the right
question? J Clin Oncol. 2012;30:4396-4400.
27. Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant
chemotherapy for human epidermal growth factor receptor 2-positive
breast cancer: planned joint analysis of overall survival from NSABP
B-31 and NCCTG N9831. J Clin Oncol. 2014;32:3744-3752.
28. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med.
2005;353:1673-1684.
the CLEOPATRA study of frst-line (1L) pertuzumab (Ptz), trastuzumab (T), and docetaxel (D) in patients (pts) with HER2-positive metastatic breast cancer (MBC). Paper presented at: European Society for
Medical Oncology 2014 Congress; November 2014; Madrid, Spain.
32. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy
in advanced ALK-positive lung cancer. N Engl J Med. 2013;368:23852394.
e139
DEVELOPMENTAL THERAPEUTICS
AND TRANSLATIONAL RESEARCH
SPEAKERS
Richard Simon, DSc
National Institutes of Health
Bethesda, MD
Suzanne E. Dahlberg, PhD
Dana-Farber Cancer Institute
Boston, MA
and adaptive enrichment strategies represent a class of novel designs for testing targeted therapeutics in oncology.3 This review
will aim to address the following, using examples of ongoing or
completed trials to present the concepts: (1) when it is appropriate to use enrichment or targeted trial design strategies, (2) use
of umbrella trials in improving clinical trial effciency to assess
the effect of different drugs on different mutations (molecular
subtypes) within a single tumor type, and (3) the role of basket
trials in screening agents effciently to identify the exceptional
responders, such as the effect of a single drug across multiple
tumor types and/or histologic subtypes harboring the same mutation (molecular profle).
These design strategies challenge the historic paradigm of
drug development. New statistical approaches, extensive multidisciplinary collaboration, and state of the art data capture technologies are needed to implement these strategies in practice.
Logistical challenges to implementation arising from centralized assay testing, requirement of multiple specimens, multidisciplinary collaboration, and infrastructure requirements will
also be discussed using illustrative examples where appropriate.
From the Mayo Clinic, Rochester, MN; Dana-Farber Cancer Institute, Boston, MA; National Institutes of Health, Rockville, MD.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Sumithra J. Mandrekar, PhD, Department of Health Sciences Research, Mayo Clinic, 200 First St. SW, Rochester, MN 55905; email: mandrekar.sumithra@mayo.edu.
2015 by American Society of Clinical Oncology.
e141
KEY POINTS
Oncology is increasingly understood at the molecular level;
therapeutic research has largely shifted from a focus of
cytotoxic agents to newer targeted drugs that inhibit
specic cancer cell growth and survival mechanisms.
Novel clinical trial design strategies that challenge the
historic paradigm of drug development are needed to
accelerate the drug development process so that the right
therapies can be delivered to the right patients.
Patient selection and enrichment approaches are becoming
increasingly relevant; however, sufcient biologic rationale,
understanding of the mechanism of action of the drug,
assay characteristics, and validated cut points are needed
to support the enrichment strategy.
Umbrella trials incorporate a central infrastructure for
screening and identication of patients with a focus on a
single tumor type or histology; multiple subtrials that test
targeted therapeutics within molecularly dened subsets
are embedded within the umbrella framework.
Basket trial designs offer the possibility to include multiple
molecularly dened subpopulations, across histologic
subtypes or tumor types, in one cohesive design to
evaluate the targeted therapy in question.
e142
between the test drug and best supportive care. See Fig. 1 for a
schematic of the enrichment trial design strategy.
Patients who are not marker-positive are not eligible for
the study. Consequently, the design is best suited to settings
where there is a strong biologic rationale or phase II data indicating that marker-negative patients are unlikely to beneft
from the test drug. This was the case for the pivotal trials of
vemurafenib for melanoma, in which the companion diagnostic was a sequencing test for a point mutation in the kinase domain of the BRAF gene.4 It was also the case for
crizotinib, in which the companion diagnostic was an assay
for a translocation that activates the ALK gene.5 One of the
frst uses of the enrichment design in oncology was for the
pivotal trial of trastuzumab in women with metastatic breast
cancer.6 The companion diagnostic in that case was overexpression of the HER2 protein or amplifcation of the HER2
gene. In these cases, there was a close linkage between the
target of the test drug and the diagnostic test measuring a
genomic alteration known to constitutively activate an oncogene target of the test drug. Kinase inhibitors generally have
multiple targets; therefore, such drugs may be active for some
patients who are test-negative. The proportion of patients
who are test-negative who beneft from such a drug and the
degree of beneft are generally much less than the treatment
effect of the drug for test-positive patients. Hence, use of the
enrichment design is appropriate. Test-negative patients can
later be the focus of a separate clinical trial of the same drug
after the drug is demonstrated to beneft those for whom it is
designed to beneft. The test-negative patients can be spared
the toxicity of a drug from whom few are expected to beneft.
One of the main benefts of the enrichment design is effciency; that is, reduced sample size requirements.7 The sample
size of a clinical trial can generally be expressed in terms of the
signifcance level, the statistical power, and the treatment effect
to be detected with that power. For example, in comparing two
treatments with regard to survival, the number of endpoint
events, D, that must be observed can be written as:
D4
k k 2
logHR2
e143
multi-stage13,14 (MAMS) design for predefned molecular cohorts. Similar to Lung MAP, for patients whose biomarker
panel results are unclassifable or for those whose molecular
cohort is temporarily not open for recruitment, and for
any patients unable or unwilling to travel, a concurrent
nonbiomarker-driven trial comparing capecitabine against
no treatment is available. Four prespecifed interim analyses
are planned for each trial: stage I (assess safety), stage II (assess lack of beneft), stage III (assess effcacy for PFS), and
stage IV (assess effcacy for OS). Stages I and II mirror a conventional phase II trial design, and stages III and IV are similar to a phase III trial design paradigm.
only by the presence of a single molecular aberration; however the term basket trial has also been used to describe studies in which patients are assigned to cohorts by their cancer
type. Whether cohort eligibility criteria are histology- or
mutation-specifc, these trials are generally conducted within
the context of a single protocol. Figure 3 provides a generic
representation of a basket trial design schema. There is perceived effciency in running multiple cohorts in this way,
since conducting a stand-alone study within each cohort separately would be exponentially more resource-intensive.
However, basket trials are not without their limitations. Paramount to their conduct is a strong scientifc rationale for the
molecular marker-drug pairing, as well as reliable assay development for the marker of interest. Genomic variants have unknown or differential variability across tumor types,19 and there
is often uncertainty about whether a particular mutation in a
tumor of a particular histologic type should be considered actionable for treatment with a given drug. Resolving these uncertainties, however, is the reason for doing the study. These trials
often study cancers so rare that it may be impossible to study
them in a randomized setting, and usually require coordination
and participation from multiple institutions to meet accrual objectives.20 They can depend heavily on tumor availability for genetic screening, which can be diffcult to obtain or to ethically
justify in certain types of cancer. This design also depends on the
availability of a suffcient number of drugs targeting diverse deregulated pathways.
Basket trials are discovery trials and there has been uncertainty about how to design such trials statistically. Consequently, in some basket trials, justifcation of sample sizes has
been absent despite increased interest in effcacy endpoints,
such as response, and the amendment process is frequently
used to expand cohorts to sample sizes that would otherwise
be suffcient for the proper conduct of a randomized phase II
or III study.21,22 The practice of not justifying sample size is
particularly worrisome since it counters the intent of minimizing the number of patients exposed to toxic or ineffective
drugs, and in light of this, investigators should consider early
stopping rules and provide clearly defned criteria for study
completion.21 Additional steps should also be taken to ac-
e145
CONCLUSION
The fundamental assumption of precision medicine is that
using the genetic makeup of the tumor and the genotype of
the patient will enable targeted therapeutics to improve clinical outcomes.3 Although there have been notable successes
with this approach, the methods for matching drugs to tumors is still rudimentary and numerous challenges remain to
be addressed adequately. These include an understanding of
the interaction of signaling pathways, the clonal evolution
and heterogeneity of tumors, ability to obtain tumor biopsies
(often multiple and over time), technical limitations with assays, centralized molecular testing, adequate resources and
infrastructure for a quick turnaround of biomarker results to
make these designs feasible, and effective multidisciplinary
collaborations. Nevertheless, genomic technology has already become a part of routine clinical practice. Enrichment,
umbrella, and basket trial designs are gaining popularity as
they present novel strategies to accelerate the drug development process so that the right therapies can be delivered to
the right patients quickly.
References
1. Mandrekar SJ, Sargent DJ. Drug designs fulflling the requirements of clinical
trials aiming at personalizing medicine. Chin Clin Oncol. 2014;3:14.
2. Hammond ME, Taube SE. Issues and barriers to development of clinically useful tumor markers: a development pathway proposal. Semin
Oncol. 2002;29:213-221.
3. Andre F, Mardis E, Salm M, et al. Prioritizing targets for precision cancer medicine. Ann Oncol. 2014;25:2295-2303.
4. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med.
2011;364:2507-2516.
e146
5. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368:2385-2394.
6. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med.
2005;353:1673-1684.
7. Simon R, Maitournam A. Evaluating the effciency of targeted designs
for randomized clinical trials. Clin Cancer Res. 2004;10:6759-6763.
8. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and
beneft from cetuximab in advanced colorectal cancer. N Engl J Med.
2008;359:1757-1765.
9. Hong F, Simon R. Run-in phase III design with post-treatment predictive biomarkers. J Natl Cancer Inst. 2013;105:1628-1633.
10. Simon N, Simon R. Adaptive enrichment designs for clinical trials.
Biostatistics. 2013;14:613-625. Epub 2013 Mar 21.
11. Fizazi K, Pagliaro L, Laplanch A, et al. Personalised chemotherapy based
on tumour marker decline in poor prognosis germ-cell tumours
(GETUG 13): a phase 3, multicentre, randomised trial. Lancet Oncol.
2014;15:1442-1450. Epub 2014 Nov 13.
12. Kaplan R, Maughan T, Crook A, et al. Evaluating many treatments and
biomarkers in oncology: a new design. J Clin Oncol. 2013;31:4562-4568.
13. Royston P, Parmar MK, Qian W. Novel designs for multi-arm clinical
trials with survival outcomes with an application in ovarian cancer. Stat
Med. 2003;22:2239-2256.
14. Parmar MK, Barthel FM, Sydes M, et al. Speeding up the evaluation of
new agents in cancer. J Natl Cancer Inst. 2008;100:1204-1214.
15. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specifc inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia
chromosome. N Engl J Med. 2001;344:1038-1042.
16. Druker BJ, Talpaz M, Resta DJ, et al. Effcacy and safety of a specifc
17.
18.
19.
20.
21.
22.
23.
e147
DEVELOPMENTAL THERAPEUTICS
AND TRANSLATIONAL RESEARCH
SPEAKERS
Christine M. Lovly, MD, PhD
Vanderbilt University School of Medicine
Nashville, TN
Josep Tabernero, MD, PhD
Vall dHebron University Hospital
Barcelona, Spain
From the Sage Bionetworks, Fred Hutchinson Cancer Research Center, Seattle, WA; Medical Oncology Department, Vall dHebron University Hospital and Institute of Oncology, Universitat
Auto`noma de Barcelona, Barcelona, Spain; Department of Medical Oncology, Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, LHospitalet
de Llobregat, Barcelona, Spain.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Josep Tabernero, MD, PhD, Medical Oncology Department, Vall dHebron University Hospital, Vall dHebron Institute of Oncology, P. Vall dHebron 119-129, 08035 Barcelona,
Spain; email: jtabernero@vhio.net.
2015 by American Society of Clinical Oncology.
e149
KEY POINTS
EGFR is a validated target for cancer therapeutics, with
cetuximab and panitumumab leading to signicant overall
survival benets when added to rst-line chemotherapy in
patients with genomically selected (all RAS wild type)
metastatic colorectal cancer.
Multiple genetic alterations driving resistance to antiEGFR
monoclonal antibodies have been described, with signicant
overlap in primary and secondary resistance mechanisms,
supporting clonal selection as a major determinant of the
nal outcome.
Resistance to anti-EGFR therapy in colorectal cancer is
also related to nongenetic mechanisms, such as
compensatory activation of parallel receptor tyrosine
kinases and overexpression of ligands involved in paracrine
signaling networks in the tumor microenvironment.
Increased knowledge of anti-EGFR resistance mechanisms
has guided the development of effective therapies, with
promising second-generation antibodies and combinations
with pan-ERBB, the MET signaling pathway, or MEK
inhibitors.
The immune system has a crucial role in modulating
response to monoclonal antibody therapy in cancer, with
novel agents inducing potent cytotoxicity and combinations
with immune checkpoint inhibitors worth exploring in the
anti-EGFR resistance setting.
e150
(A) Genomic alterations linked to primary (de novo) resistance. Separated from the chart
are quadruple-negative tumors, which have higher chances of response. (B) Secondary
(acquired) resistance mechanisms, suggesting clonal selection as the major determinant of
the nal outcome.
Abbreviations: EGFR, epidermal growth factor receptor; CRC, colorectal cancer; ampl,
amplied; mut, mutated; wt, wild type.
e151
TABLE 1. Resistance Mechanisms to Anti-EGFR Therapies and Drug Development Strategies in Advanced CRC
Setting
Mechanism of Resistance
First-Line Anti-EGFR
Therapy
Nongenetic
Strategy
Example
Trial
KRAS/NRAS/BRAF/PIK3CA wt
Panitumumab FOLFIRI
Immune evasion
Cetuximab pembrolizumab
Cetuximab complement
receptor 3 modulator
Anti-EGFR/HER3 mAbs
Cetuximab afatinib
Panitumumab everolimus
irinotecan
Cetuximab neratinib
ERBB2 amplication
Trastuzumab pertuzumab
or lapatinib
MET amplication
RAS mutations
Not available
PI3K-mTOR
Progressing in Third-Line Setting Nongenetic
After Response to Anti-EGFR
KRAS/NRAS/BRAF wt
Therapy in First-Line Setting
Acquired Resistance to
Anti-EGFR Therapy
Nongenetic
KRAS/NRAS/BRAF/PIK3CA wt
Sustained EGFR addiction
Genetic
Not available
Abbreviations: EGFR, epidermal growth factor receptor; CRC, colorectal cancer; wt, wild type; mAb, monoclonal antibody; FOLFIRI, uorouracil, leucovorin, and irinotecan; TKIs, tyrosine kinase
inhibitors; PI3K, phosphoinositide kinase-3; mTOR, mammalian target of rapamycin.
activity. Recently, with the hypotheses that the effect of pharmacologic treatment represents a selective pressure and that
(preexisting) sensitive subclones may emerge after treatment
breaks, the idea of re-exposure to anti-EGFR therapies has
been revisited. As shown in Table 1, clinical trials are prospectively evaluating rechallenge with anti-EGFR mAbs in
the third-line setting after a response to targeted therapies in
the frst-line setting. To increase the chances of treatment
beneft, only patients with KRAS/NRAS/BRAF wild-type disease are being enrolled.
Second-generation anti-EGFR mAbs engineered to induce
enhanced antibody dependent cell-mediated cytotoxicity
(ADCC) or increased receptor internalization/downregulation also have been tested in the context of acquired resistance to cetuximab or panitumumab.48,52-54 Imgatuzumab
(GA201) is a dual-acting mAb glycoengineered for enhanced
ADCC in addition to EGFR signaling inhibition, which has
demonstrated superior preclinical in vivo effcacy to cetuximab in both KRAS wild-type and KRAS mutant xenograft
models.52 Although promising clinical effcacy was seen in a
phase I trial of patients with mCRC,52 a recently presented,
randomized, phase II study comparing imgatuzumab with
cetuximab in KRAS exon 2 wild-type or with irinotecanbased chemotherapy alone in patients with KRAS exon 2 mutant disease has not shown any improvement in survival
outcomes.53 Another example is Sym004, a combination of
two chimeric mAbs targeting nonoverlapping epitopes of the
EGFR extracellular domain III designed to induce a much
higher degree of receptor degradation. Encouraging results
have been observed in the expansion of the phase I trial, with
one-third of patients with anti-EGFRrefractory mCRC experiencing signifcant tumor shrinkage and prolonged disease stabilization.54 This suggests that the dependency on
EGFR ligands remains an oncogenic driver in this setting.
Sym004 is under clinical evaluation in a randomized, proofof-concept, phase II study in patients with RAS wild-type
mCRC that is refractory to anti-EGFR mAbs.
Because acquired anti-EGFR resistance may result from
compensatory signaling through ERBB receptors, cetuximab
was investigated in combination with pertuzumab (an HER2
heterodimerization inhibitor) in patients with cetuximabresistant KRAS wild-type mCRC (irrespective of ERBB2
amplifcation). In a phase I trial, this regimen was not tolerated because of overlapping toxicities, but partial responses and disease stabilization were reported in some
patients.55 The results of clinical trials evaluating alternative combinations in genomically selected populations are
highly anticipated.
When a genetic mechanism for secondary resistance is
identifed, promising strategies under investigation include
the combination of anti-EGFR mAbs with MEK inhibitors
(when RAS mutant clones emerge) or with HER2- or METtargeted therapy (in the context of acquired receptor amplifcation). In principle, a parallel RTK pathway may be
activated by compensatory ligand overexpression (nongenetic mechanisms), and the effcacy of these combinations
may not be restricted to tumors with gene amplifcations. Patients who have tumors that show the EGFR S492R mutation
at relapse could be offered panitumumab-based therapy (in
the setting of resistance to cetuximab), because panitumumab binds to a distinct epitope of the molecule. Indeed,
investigators published a case report of a 5-month clinically
benefcial response.46 The novel anti-EGFR mAb Sym004 is
active in preclinical models of acquired EGFR extracellular
domain mutations.44
(PETACC-8), a subgroup analysis showed that chemotherapy plus cetuximab was only advantageous for high-risk patients who had pT4pN2, which suggests that they resembled
patients who have advanced disease.56 Investigators also have
raised the possibility of a negative interaction between the
antibody and oxaliplatin. There is limited clinical evidence
from a subgroup analysis (study N0147) suggesting that irinotecan could have been a better choice for combination
with cetuximab.58 Another interesting explanation comes
from preclinical experiments that show reduced cellular dependence on EGFR signaling when a tumor cell has transitioned to a mesenchymal phenotype, which is known to
support invasion and metastatic seeding of carcinomas.59 In
line with this hypothesis is the fnding that early-stage CRC
tumors with intrinsic mesenchymal signatures have reduced
benefts from treatment with anti-EGFR mAbs given at the
time of relapse.60,61 In preclinical models, mesenchymal CRC
cell lines were particularly sensitive to MET inhibitors.60
CONCLUSION
The elucidation of de novo and acquired resistance mechanisms arising in the setting of targetable tumor dependencies
is guiding the development of rational therapeutic strategies.
It is likely that a combination of targeted therapies will be
necessary to effectively prevent and/or treat drug-resistant
cancers. Colorectal tumors that initially respond to and then
relapse after anti-EGFR targeted therapy eventually become
highly molecularly heterogeneous. The signifcant overlap of
genetic events associated with primary and secondary resistance supports clonal selection linked to tumor heterogeneity
as a major determinant of treatment outcome. It also indicates that the same therapies used for acquired resistance
that is, salvage regimens could be potentially useful in upfront therapy. The ultimate goals are to increase the
magnitude and/or duration of clinical response and to delay
the emergence of resistance when such combinations are administered as initial therapy. As recently highlighted by Misale et al,2 the plethora of alterations that emerge at relapse
biochemically converge to activate the EGFR/RAS/MAPK
pathway (i.e., convergent evolution), which may facilitate
drug development strategies in this setting.
Knowledge of the specifc genetic mechanisms of drug resistance and the compensatory parallel signaling activation
that occurs during anti-EGFR exposure have been fundamental for the study of alternative kinase inhibitors. Examples include combinations of pan-ERBB, MET, or MEK
inhibitors with anti-EGFR mAbs, both in frst-line and refractory settings, with promising results in early clinical trials. An alternative approach is to develop second-generation
inhibitors of the oncoprotein. For a subset of mCRC tumors,
this strategy also has been proven effcacious clinically, but
the mechanisms underlying the sensitivity, such as sustained
EGFR addiction as a result of ligand overexpression or increased ADCC at the tumor site, are still unknown.
Furthermore, because targeted gene analysis does not always explain the mechanism by which CRC becomes resisasco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e153
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Josep
Tabernero, Amgen, Celgene, Chugai Pharma, ImClone Systems, Lilly, Merck KGaA, Millennium Takeda, Novartis, Roche/Genentech, Sano, Symphogen, Taiho
Pharmaceutical. Ramon Salazar, Merck Serono, Amgen. Speakers Bureau: Ramon Salazar, Amgen, Roche, Novartis. Research Funding: Ramon Salazar,
Roche. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: Ramon Salazar, Merck,
Roche, Amgen, Novartis. Other Relationships: None.
References
1. Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CACancer J Clin. 2014;64:104-117.
2. Misale S, Di Nicolantonio F, Sartore-Bianchi A, et al. Resistance to antiEGFR therapy in colorectal cancer: from heterogeneity to convergent
evolution. Cancer Discov. 2014;4:1269-1280.
3. Saltz LB, Meropol NJ, Loehrer PJ Sr, et al. Phase II trial of cetuximab in
patients with refractory colorectal cancer that expresses the epidermal
growth factor receptor. J Clin Oncol. 2004;22:1201-1208.
4. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of
panitumumab plus best supportive care compared with best supportive
care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25:1658-1664.
5. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for
panitumumab effcacy in patients with metastatic colorectal cancer.
J Clin Oncol. 2008;26:1626-1634.
6. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and
beneft from cetuximab in advanced colorectal cancer. N Engl J Med.
2008;359:1757-1765.
7. Price TJ, Peeters M, Kim TW, et al. Panitumumab versus cetuximab in
patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, openlabel, non-inferiority phase 3 study. Lancet Oncol. 2014;15:569-579.
8. Bokemeyer C, Van Cutsem E, Rougier P, et al. Addition of cetuximab to
chemotherapy as frst-line treatment for KRAS wild-type metastatic
colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012;48:1466-1475.
9. Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy
as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;
360:1408-1417.
10. Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of
panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin
(FOLFOX4) versus FOLFOX4 alone as frst-line treatment in patients
with previously untreated metastatic colorectal cancer: the PRIME
study. J Clin Oncol. 2010;28:4697-4705.
e154
11. Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of
panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI)
compared with FOLFIRI alone as second-line treatment in patients with
metastatic colorectal cancer. J Clin Oncol. 2010;28:4706-4713.
12. De Roock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF,
NRAS, and PIK3CA mutations on the effcacy of cetuximab plus
chemotherapy in chemotherapy-refractory metastatic colorectal
cancer: a retrospective consortium analysis. Lancet Oncol. 2010;11:
753-762.
13. Loupakis F, Ruzzo A, Cremolini C, et al. KRAS codon 61, 146 and BRAF
mutations predict resistance to cetuximab plus irinotecan in KRAS
codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer.
2009;101:715-721.
14. Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369:
1023-1034.
15. Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as frst-line treatment for
patients with metastatic colorectal cancer (FIRE-3): a randomised,
open-label, phase 3 trial. Lancet Oncol. 2014;15:1065-1075.
16. Schwartzberg LS, Rivera F, Karthaus M, et al. PEAK: a randomized,
multicenter phase II study of panitumumab plus modifed fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus
mFOLFOX6 in patients with previously untreated, unresectable, wildtype KRAS exon 2 metastatic colorectal cancer. J Clin Oncol. 2014;32:
2240-2247.
17. Seymour MT, Brown SR, Middleton G, et al. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type,
fluorouracil-resistant advanced colorectal cancer (PICCOLO): a
prospectively stratifed randomised trial. Lancet Oncol. 2013;14:749759.
18. Bendell JC, Atreya CE, Andre T, et al. Effcacy and tolerability in an
open-label phase I/II study of MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36. Weickhardt AJ, Price TJ, Chong G, et al. Dual targeting of the epidermal
growth factor receptor using the combination of cetuximab and erlotinib: preclinical evaluation and results of the phase II DUX study in
chemotherapy-refractory, advanced colorectal cancer. J Clin Oncol.
2012;30:1505-1512.
37. Van Cutsem E, Eng C, Nowara E, et al. Randomized phase Ib/II trial of
rilotumumab or ganitumab with panitumumab versus panitumumab
alone in patients with wild-type KRAS metastatic colorectal cancer. Clin
Cancer Res. 2014;20:4240-4250.
38. Tamayo ME, Cornelio GH, Bautista JB, et al. Safety and effcacy of Imprime PGG plus cetuximab with irinotecan and without irinotecan in
patients with advanced colorectal cancer (CRC): a phase 1b/2 study with
KRAS subpopulation analysis. Ann Oncol. 2010;21 (suppl 6; abstr
PD0009).
39. Perez EA, Thompson EA, Ballman KV, et al. Genomic analysis reveals
that immune function genes are strongly linked to clinical outcome in
the North Central Cancer Treatment Group N9831 adjuvant trastuzumab trial. J Clin Oncol. Epub 2015 Jan 20.
40. Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS mutations and
acquired resistance to anti-EGFR therapy in colorectal cancer. Nature.
2012;486:532-536.
41. Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor
DNA in early- and late-stage human malignancies. Sci Transl Med.
2014;6:224ra24.
42. Arena S, Bellosillo B, Siravegna G, et al. Emergence of multiple EGFR
extracellular mutations during cetuximab treatment in colorectal cancer. Clin Cancer Res. Epub 2015 Jan 27.
43. Diaz LA Jr., Williams RT, Wu J, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012;486:537-540.
44. Montagut C, Bellosillo B, Gonzalez I, et al. Evolution of heterogeneous
mechanisms of acquired resistance to cetuximab-based therapy in colorectal cancer. J Clin Oncol. 2014;32:5s (suppl; abstr 3526).
45. Troiani T, Martinelli E, Napolitano S, et al. Increased TGF-alpha as a
mechanism of acquired resistance to the anti-EGFR inhibitor cetuximab through EGFR-MET interaction and activation of MET signaling
in colon cancer cells. Clin Cancer Res. 2013;19:6751-6765.
46. Montagut C, Dalmases A, Bellosillo B, et al. Identifcation of a mutation
in the extracellular domain of the epidermal growth factor receptor conferring cetuximab resistance in colorectal cancer. Nat Med. 2012;18:
221-223.
47. Price TJ, Newhall J, Peeters M, et al. Prevalence and outcomes of patients (pts) with EGFR S492R ectodomain mutations in ASPECCT: Panitumumab (pmab) vs. cetuximab (cmab) in pts with chemorefractory
wild-type KRAS exon 2 metastatic colorectal cancer (mCRC). J Clin Oncol. 2015;33 (suppl 3; abstr 740).
48. Iida M, Brand TM, Starr MM, et al. Sym004, a novel EGFR antibody
mixture, can overcome acquired resistance to cetuximab. Neoplasia.
2013;15:1196-1206.
49. Hobor S, Van Emburgh BO, Crowley E, et al. TGF alpha and amphiregulin paracrine network promotes resistance to EGFR blockade in
colorectal cancer cells. Clin Cancer Res. 2014;20:6429-6438.
50. Wadlow RC, Hezel AF, Abrams TA, et al. Panitumumab in patients with
KRAS wild-type colorectal cancer after progression on cetuximab. Oncologist. 2012;17:14.
51. Saif MW, Kaley K, Chu E, et al. Safety and effcacy of panitumumab
therapy after progression with cetuximab: experience at two institutions. Clin Colorectal Cancer. 2010;9:315-318.
52. Paz-Ares LG, Gomez-Roca C, Delord JP, et al. Phase I pharmacokinetic
and pharmacodynamic dose-escalation study of RG7160 (GA201), the
frst glycoengineered monoclonal antibody against the epidermal growth
e155
53.
54.
55.
56.
e156
factor receptor, in patients with advanced solid tumors. J Clin Oncol. 2011;
29:3783-3790.
Bridgewater JA, Cervantes A, Markman B, et al. GAIN-(C): Effcacy and
safety analysis of imgatuzumab (GA201), a novel dual-acting monoclonal antibody (mAb) designed to enhance antibody-dependent cellular
cytotoxicity (ADCC), in combination with FOLFIRI compared to cetuximab plus FOLFIRI in second-line KRAS exon 2 wild type (e2WT) or
with FOLFIRI alone in mutated (e2MT) metastatic colorectal cancer
(mCRC). J Clin Oncol. 2015;33 (suppl; abstr 669).
Dienstmann R, Tabernero J, Van Cutsem E, et al. Proof-of-concept study of
Sym004, an anti-EGFR monoclonal antibody (mAb) mixture, in patients
(pts) with anti-EGFR mab-refractory KRAS wild-type (wt) metastatic colorectal cancer (mCRC). J Clin Oncol. 2013;31 (suppl; abstr 3551).
Rubinson DA, Hochster HS, Ryan DP, et al. Multi-drug inhibition of the
HER pathway in metastatic colorectal cancer: results of a phase I study
of pertuzumab plus cetuximab in cetuximab-refractory patients. Invest
New Drugs. 2014;32:113-122.
Taieb J, Tabernero J, Mini E, et al. Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon
57.
58.
59.
60.
61.
ER2 is a member of a membrane tyrosine kinase receptor family (HER1 4). Although HER2 does not have
any known ligands, there are more than 10 different ligands
that activate other family receptors (Fig. 1).1-7 On binding,
ligands induce receptor homo- and heterodimerization activating a phosphorylation-signaling cascade. HER2 in cancer
cells can be activated by either heterodimerization with other
ligand-bound HER family members or, when overexpressed,
by homodimerization.8 The resulting downstream signaling
regulates transcription of genes responsible for cell proliferation, survival, angiogenesis, invasion, and metastasis.1-4,6,9,10
HER2 is amplifed or overexpressed in 20% to 25% of breast
cancers and results in aggressive behavior with rapid growth
and frequent metastasis. Therefore, targeting HER2 represents an attractive treatment option, and that approach has
been successful in the clinic.
The frst targeted therapy against HER2 was the humanized monoclonal antibody trastuzumab. The mechanism of
action of trastuzumab is not completely understood but it interacts with the extracellular domain of HER2 to inhibit its
function. Trastuzumab has been suggested to inhibit signaling from HER2 homodimers better than heterodimers with
HER1 (epidermal growth factor receptor [EGFR]) or
HER3.11-13 The resulting downregulation of the PI3K/AKT
pathway signaling leads to induction of apoptosis in human
tumors.6,9,14 Trastuzumab has also been shown to work in
part by inducing antibody-dependent cellular cytotoxicity.
Although trastuzumab combined with chemotherapy reduces the risk for recurrence of HER2-positive tumors, many
patients have tumors that exhibit de novo or acquired
resistance.15-18
Many mechanisms for resistance to anti-HER2 therapy
with trastuzumab have been suggested.18,19 Those broadly
fall under three major categories. The frst category is redundancy within the HER receptor layer: the ability of the pathway to continue to signal despite being partially inhibited
because of redundant ligands and receptors that enable alternative dimerization patterns. The second category is reactivation: the ability to reactivate pathway signaling at or
downstream of the receptor layer such as with activating
HER or downstream mutations, or loss of downstream pathway negative-regulating mechanisms. The third category is
escape: the use of other pathways, which may pre-exist or be
acquired at the time of resistance, but are not usually driving
the cancer cell when HER2 is uninhibited. For purposes of
this review, we will give an example from each of those resistance categories, focusing on mechanisms of resistance that
have been best explored preclinically and in clinical trials: incomplete receptor family inhibition as an example of redundancy, deregulation of the PI3K pathway as an example of
reactivation, and the role of the estrogen receptor (ER) in resistance as an example of escape. Additional roles for multiple other pathways and mechanisms involved in intrinsic and
acquired resistance to HER-targeted therapy, including various receptor and cellular tyrosine kinases (e.g., MET,
IGFR-1, c-SRC, and EphA2),19-23 mucins,24 regulators of cell
cycle and apoptosis19,25-27 and various elements of the tumor
microenvironment and the host immune system,28-31 have
been recently thoroughly reviewed,18 and are beyond the focus of the current paper.
From the Lester and Sue Smith Breast Center and Dan L. Duncan Cancer Center at Baylor College of Medicine, Houston, TX.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Mothaffar Rimawi, MD, Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza BCM600, Houston, TX 77030; email: rimawi@bcm.edu.
2015 by American Society of Clinical Oncology.
e157
HER2 is a member of the HER network consisting of three additional transmembrane receptor tyrosine kinases, HER1 (epidermal growth factor receptor [EGFR]), HER3, and HER4 plus more than
10 ligands. HER2 is the only receptor member for which a specic ligand has not been identied; whereas, HER3 lacks intrinsic kinase activity. On ligand binding, HER receptors form
homodimers or heterodimers that, after transphosphorylation of their kinase domains, trigger downstream signaling cascades via key intermediates such as the phosphatidylinositol-3 kinase
(PI3K)/AKT and the RAS/mitogen-activated protein kinase (MAPK) pathways. Activation of these downstream signaling intermediates promotes the expression of genes involved in tumor cell
proliferation, survival, angiogenesis, invasion, and metastasis. HER2 is the preferred heterodimerization partner for other HER proteins and HER2/HER3 is considered the most oncogenic
heterodimer. When HER2 is gene-amplied and/or overexpressed (20% of breast cancers), it can also be activated by homodimerization.
all HER family dimer pairs and, thus, do not fully inhibit
downstream signaling. Several preclinical studies have explored regimens that more completely block HER2 as the
major driver pathway and increase effcacy of anti-HER2
therapy by using combinations of targeted agents.
In addition to trastuzumab, several other drugs are available
to inhibit the HER receptor layer more completely. Table 1 lists
these inhibitors, with a focus on key agents that are already in
clinical use or that have been rigorously investigated alone or in
combination in preclinical and clinical studies of HER2-positive
breast cancer. Pertuzumab binds to the heterodimerization domain of HER2 and blocks its interaction with HER1 and
HER3.32 Lapatinib, afatinib, and neratinib are dual kinase inhibitors (HER1, HER2).33 T-DM1 (ado-trastuzumab emtansine) is
an antibody-drug conjugate.34 Geftinib and erlotinib are potent
kinase inhibitors of HER1.35
In animal models, various doublet and triplet combinations for HER2-positive tumor xenografts were studied. One
e158
KEY POINTS
Successful targeting of HER2 has improved outcomes in
HER2-positive breast cancer, but treatment resistance
remains a problem.
Treatment resistance can be caused by pathway
redundancy, pathway reactivation, or escape pathways.
Use of combination anti-HER2 treatments for potent
inhibition of the HER family signaling is biologically sound
and offers great clinical promise.
Estrogen receptor (ER) is a potential resistance pathway to
anti-HER2 treatments. Concomitant inhibition of ER with
potent HER2 inhibition is being investigated in clinical
trials.
PI3K pathway activation is also a potential mechanism of
resistance and represents another attractive therapeutic
target to overcome or prevent anti-HER2 treatment
resistance.
TABLE 1. Key Monoclonal Antibodies and Small Molecules Targeting HER Family Receptors
Drug
Category
Mechanism
Phase of Development
Pertuzumab
Monoclonal antibody
Clinically available
T-DM1
Antibodydrug conjugate
Clinically available
MM-121
Monoclonal antibody
HER3-targeted antibody
II
MM-111
Monoclonal antibody
Afatinib
Small molecule
Neratinib
Small molecule
III
Getinib
Small molecule
Development stopped
Erlotinib
Small molecule
Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; EGFR, epidermal growth factor receptor; T-DM1, trastuzumab-derivative of maytansine.
mors, endocrine therapy was also required for optimal antitumor effects.36,37 Moreover, these studies showed that even
lower drug doses and intermittent therapy with this lapatinib/trastuzumab regimen was effective in eradicating most
tumors.37
These and other studies provided a strong biologic rationale for clinical trials that combined two anti-HER2 agents
(dual inhibition). These trials showed increased effcacy
when combined with chemotherapy in the metastatic setting,39,40 and improved outcomes for patients. This approach
was also extensively studied in the neoadjuvant and adjuvant
setting, with some trials still ongoing.
TABLE 2. Randomized Neoadjuvant Trials Testing Dual HER2-Targeted Therapy in Combination with
Chemotherapy42-47
Study
Phase
Patient Population
No. of
Patients
NeoALTTO
III
455
Regimen
Chemotherapy
Anti-HER2 Therapy
Duration
(Weeks)
Paclitaxel
Trastuzumab
18
pCR (%)
29.5
Lapatinib
24.7
Trastuzumab lapatinib
NSABP B-41
III
Operable BC
519
AC 3 paclitaxel
Trastuzumab
51.3
28
53.5
Lapatinib
52.5
Trastuzumab lapatinib
CALGB 40,601
TRYPHAENA
CHER-LOB
NeoSphere
III
II
II
II
305
225
121
417
Paclitaxel
Trastuzumab
46
Lapatinib
Trastuzumab lapatinib
56
Trastuzumab pertuzumab
FEC 3 docetaxel
62.0
16
18
61.6
Trastuzumab pertuzumab
57.3
Carboplatin docetaxel
Trastuzumab pertuzumab
66.2
Paclitaxel 3 FEC
Trastuzumab
Docetaxel
26
25.0
Lapatinib
26.3
Trastuzumab lapatinib
46.7
Trastuzumab
12
29.0
Pertuzumab
24.0
Trastuzumab pertuzumab
45.8
Abbreviations: BC, breast cancer; AC, doxorubicin and cyclophosphamide; CALGB, Cancer and Leukemia Group B; CHER-LOB, Chemotherapy Herceptin and Lapatinib in Operable Breast Cancer; FEC,
5-uorouracil, epirubicin, and cyclophosphamide; NeoALTTO, Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization; NeoSphere, Neoadjuvant Study of Pertuzumab and Herceptin in
Early Regimen Evaluation; NSABP, National Surgical Adjuvant Breast and Bowel Project; pCR, pathologic complete response; Pts, Patients.
*Excluding inammatory breast cancer.
**Including inammatory and locally advanced (no prior chemotherapy).
e159
TABLE 3. Completed and Ongoing Neoadjuvant Trials Testing Dual HER2-Targeted Therapy without
Chemotherapy43,49,66
Regimen
Study
Phase
No. of
Patients
NeoSphere
II
107
TBCRC 006
II
64
Trastuzumab lapatinib
TBCRC 023
II
33
12%
28%
Not available
Hormonal Therapy
HER2-Targeted Therapy
pCR
None
Trastuzumab pertuzumab
17%
27%
61
PAMELA
II
150
Abbreviations: ER, estrogen receptor; NeoSphere, Neoadjuvant Study of Pertuzumab and Herceptin in Early Regimen Evaluation; TBCRC, Translational Breast Cancer Research Consortium; pCR,
pathologic complete response; Pts, patients.
*In combination with ovarian suppression in premenopausal women.
**Letrozole or tamoxifen according to patients menopausal status.
Paclitaxel will be added to dual HER2 blockade if tumor progression is observed by ultrasound at week 6.
The percentage of patients who obtained a pathologic complete response (pCR) are
reported for each treatment arm (L, lapatinib; P, pertuzumab; T, trastuzumab). Orange bars
represent patients harboring phosphatidylinositol-3 kinase (PIK3CA) mutations; blue bars
represent patients with PIK3CA wild type (WT).
superiority compared with trastuzumab plus a taxane. Results are expected to be presented at the 2015 ASCO Annual
Meeting. Close examination of these results is important but,
so far, it appears that T-DM1 will remain as a therapeutic
option for HER2-positive metastatic breast cancer that is resistant to frst-line chemotherapy plus trastuzumab and pertuzumab. Further investigation into the mechanism of action
of T-DM1 and how best to combine it with other agents is
warranted.
TABLE 4. Impact of Hormone Receptor Status on Pathological Complete Response Rate in Neoadjuvant Studies
with HER2-Targeted Therapies42,43,45,49,67
Regimen
Study
No. of
Patients
Concurrent Therapy
Anti-HER2 Therapy
Overall pCR
Rate (%)
HR
HR
NeoALTTO
455
Paclitaxel
Trastuzumab
29.5
22.7
37.5
Lapatinib
24.7
16.1
33.7
Trastuzumab lapatinib
51.3
41.6
61.3
Trastuzumab
30.3
25.8
38.7
28.3
GEPARQUINTO
620
EC 3 docetaxel
NeoSphere
417
Docetaxel
TRYPHAENA
TBCRC 006
225
64
Lapatinib
22.7
16.2
Trastuzumab
29.0
20
36.8
Pertuzumab
24
17.4
30
63.2
Trastuzumab pertuzumab
45.8
26
None
Trastuzumab pertuzumab
16.8
5.9
29.1
FEC 3 docetaxel
Trastuzumab pertuzumab
61.6
49
65
Trastuzumab pertuzumab
57.3
46
79
Carboplatin docetaxel
Trastuzumab pertuzumab
66.2
50
84
Trastuzumab lapatinib
27
21
36
Abbreviations: ER, estrogen receptor; HR, hormone receptor; NeoALTTO, Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization; EC, epirubicin/cyclophosphamide; NeoSphere,
Neoadjuvant Study of Pertuzumab and Herceptin in Early Regimen Evaluation; pCR, pathological complete response; TBCRC, Translational Breast Cancer Research Consortium; FEC; 5FU/epirubicin/
cyclophosphamide; Pts, patients.
*In combination with ovarian suppression in premenopausal patients.
e161
tentially be related to different PTEN assays and cutoff values.59 Low levels of PTEN, but not necessarily complete loss,
can activate the PI3K pathway and reduce treatment effcacy.58 Preclinical studies suggest that the addition of PI3K/
mTOR/AKT inhibitors to anti-HER2 treatment can
overcome resistance in tumors with PIK3CA mutations,53,54
a strategy currently being investigated in the clinic.
ESTROGEN RECEPTOR
About half of HER2-positive breast cancer tumors also express ER. The ER and the HER pathways, via a complex bidirectional cross talk, positively and negatively regulate each
other,18,60 so that one pathway can become the escape route
to therapy targeted against the other pathway. Indeed, multiple preclinical studies using various HER2-positive breast
cancer models have demonstrated the role of ER and its signaling in evading HER2 inhibition and promoting resistance.
In ER-positive/HER2-positive breast cancer cells, it has been
shown that pre-existing or restored ER levels and/or activity
can mediate de novo or acquired resistance to potent antiHER2 therapy.27,61 In these resistant cells with sustained
HER2 inhibition, ER and its downstream antiapoptotic protein Bcl2 provide key alternative survival stimuli, which in
turn sensitize the cells to anti-ER therapies.61 A study using
specimens from a neoadjuvant trial with lapatinib62 demonstrated a parallel increase in ER and Bcl2 levels after
lapatinib treatment.26 Finally, several studies using ER-
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: None.
Speakers Bureau: None. Research Funding: Mothaffar F. Rimawi, GlaxoSmithKline (Inst). Rachel Schiff, AstraZeneca. Patents, Royalties, or Other
Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Maurer CA, Friess H, Kretschmann B, et al. Increased expression of
erbB3 in colorectal cancer is associated with concomitant increase in the
level of erbB2. Hum Pathol. 1998;29:771-777.
2. Alimandi M, Romano A, Curia MC, et al. Cooperative signaling of
ErbB3 and ErbB2 in neoplastic transformation and human mammary
carcinomas. Oncogene. 1995;10:1813-1821.
3. Wallasch C, Weiss FU, Niederfellner G, et al. Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with
HER3. Embo J. 1995;14:4267-4275.
4. Agus DB, Akita RW, Fox WD, et al. Targeting ligand-activated ErbB2
signaling inhibits breast and prostate tumor growth. Cancer Cell. 2002;
2:127-137.
5. Tzahar E, Yarden Y. The ErbB-2/HER2 oncogenic receptor of adenocarcinomas: from orphanhood to multiple stromal ligands. Biochim
Biophys Acta. 1998;1377:M25-M37.
e162
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32. Franklin MC, Carey KD, Vajdos FF, et al. Insights into ErbB signaling
from the structure of the ErbB2-pertuzumab complex. Cancer Cell.
2004;5:317-328.
33. Xia W, Mullin RJ, Keith BR, et al. Anti-tumor activity of GW572016: a
dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2
and downstream Erk1/2 and AKT pathways. Oncogene. 2002;21:62556263.
34. Junttila TT, Li G, Parsons K, et al. Trastuzumab-DM1 (T-DM1) retains
all the mechanisms of action of trastuzumab and effciently inhibits
growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat.
2011;128:347-356.
35. Brand TM, Iida M, Li C, et al. The nuclear epidermal growth factor receptor signaling network and its role in cancer. Discovery Medicine.
2011;12:419-432.
36. Arpino G, Gutierrez C, Weiss H, et al. Treatment of human epidermal
growth factor receptor 2-overexpressing breast cancer xenografts with
multiagent HER-targeted therapy. J Natl Cancer Inst. 2007;99:694-705.
37. Rimawi MF, Wiechmann LS, Wang YC, et al. Reduced dose and intermittent treatment with lapatinib and trastuzumab for potent blockade
of the HER pathway in HER2/neu-overexpressing breast tumor xenografts. Clin Cancer Res. 2011;17:1351-1361.
38. Scaltriti M, Verma C, Guzman M, et al. Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity. Oncogene. 2009;28:
803-814.
39. Swain SM, Kim SB, Cortes J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA
study): overall survival results from a randomised, double-blind,
placebo-controlled, phase 3 study. Lancet Oncol. 2013;14:461-471.
40. Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival beneft
with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: fnal results from the EGF104900 study. J Clin Oncol. 2012;30:25852592.
41. Wang YC, Morrison G, Gillihan R, et al. Different mechanisms for resistance to trastuzumab versus lapatinib in HER2-positive breast
cancers-role of estrogen receptor and HER2 reactivation. Breast Cancer
Res. 2011;13:R121.
42. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for
HER2-positive early breast cancer (NeoALTTO): a randomised, openlabel, multicentre, phase 3 trial. Lancet. 2012;379:633-640.
43. Gianni L, Pienkowski T, Im YH, et al. Effcacy and safety of neoadjuvant
pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:
25-32.
44. Robidoux A, Tang G, Rastogi P, et al. Evaluation of lapatinib as a component of neoadjuvant therapy for HER2 operable breast cancer:
NSABP protocol B-41. J Clin Oncol. 2012;30:18s (suppl; abstr LBA506).
45. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in
combination with standard neoadjuvant anthracycline-containing and
anthracycline-free chemotherapy regimens in patients with HER2positive early breast cancer: a randomized phase II cardiac safety study
(TRYPHAENA). Ann Oncol. 2013;24:2278-2284.
46. Guarneri V, Frassoldati A, Piacentini F, et al. Preoperative chemotherapy plus lapatinib or trastuzumab or both in HER2-positive operable
breast cancer (CHERLOB Trial). Clin Breast Cancer. 2008;8:192-194.
47. Carey LA, Barry DA, Ollila D, et al. Clinical and translational results of
CALGB 40601: A neoadjuvant phase III trial of weekly paclitaxel and
trastuzumab with or without lapatinib for HER2-positive breast cancer.
J Clin Oncol. 2013;31:15s (suppl; abstr 500).
48. Piccart-Gebhart MJ, Holmes AP, Baselga J, et al. First results from the
e163
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab
alone (T), their sequence (T3 L), or their combination (TL) in the
adjuvant treatment of HER2-positive early breast cancer (EBC). J Clin
Oncol. 2014;32:18s (suppl; abstr LBA4).
Rimawi MF, Mayer IA, Forero A, et al. Multicenter phase II study of
neoadjuvant lapatinib and trastuzumab with hormonal therapy and
without chemotherapy in patients with human epidermal growth factor
receptor 2-overexpressing breast cancer: TBCRC 006. J Clin Oncol.
2013;31:1726-1731.
Krop IE, Kim SB, Gonzalez-Martn A, et al. Trastuzumab emtansine
versus treatment of physicians choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3
trial. Lancet Oncol. 2014;15:689-699.
Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2positive advanced breast cancer. N Engl J Med. 2012;367:1783-1791.
Berns K, Horlings HM, Hennessy BT, et al. A functional genetic approach identifes the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12:395-402.
Miller TW, Rexer BN, Garrett JT, et al. Mutations in the phosphatidylinositol 3-kinase pathway: Role in tumor progression and therapeutic
implications in breast cancer. Breast Cancer Res. 2011;13:224.
Brady SW, Zhang J, Seok D, et al. Enhanced PI3K p110 signaling confers acquired lapatinib resistance that can be effectively reversed by a
p110-selective PI3K inhibitor. Mol Cancer Ther. 2014;13:60-70.
Xia W, Husain I, Liu L, et al. Lapatinib antitumor activity is not dependent upon phosphatase and tensin homologue deleted on chromosome
10 in ErbB2-overexpressing breast cancers. Cancer Res. 2007;67:11701175.
Loibl S, von Minckwitz G, Schneeweiss A, et al. PIK3CA mutations are
associated with lower rates of pathologic complete response to antihuman epidermal growth factor receptor 2 (HER2) therapy in primary
HER2-overexpressing breast cancer. J Clin Oncol. 2014:32:3212-3220.
Majewski IJ, Nuciforo P, Mittempergher L, et al. PIK3CA mutations are
associated with decreased beneft to neoadjuvant human epidermal
growth factor receptor 2-targeted therapies in breast cancer. J Clin Oncol. Epub 2015 Jan 5.
Contreras A, Herrera S, Wang T, et al. PIK3CA mutations and/or low
PTEN predict resistance to combined anti-HER2 therapy with lapatinib
and trastuzumab and without chemotherapy in TBCRC006, a neoadju-
e164
59.
60.
61.
62.
63.
64.
65.
66.
67.
herapeutic targeting of oncogenes has emerged as a preeminent treatment paradigm for patients with non
small cell lung cancer (NSCLC). Beginning in 2004 with the
initial identifcation of epidermal growth factor receptor
(EGFR) mutations in a subset of lung adenocarcinomas,1-3
molecular profling of lung cancer, particularly lung adenocarcinoma, has evolved into a complex spectrum of clinically
relevant and therapeutically actionable genomic alterations.
These alterations occur at varying frequencies and, at present, have varying levels of clinical evidence to support the use
of targeted inhibitors in each setting. To date, the most welldescribed molecular cohorts of NSCLC are those defned by
the presence of EGFR mutations and ALK rearrangements.
Treatment for patients with EGFR-mutant and ALKrearranged NSCLC with specifc tyrosine kinase inhibitors
(TKIs) that target the EGFR and ALK tyrosine kinases, respectively, has led to remarkable clinical responses, including
often-dramatic tumor shrinkage and increased progressionfree survival (PFS) compared with standard cytotoxic
chemotherapy.4-10
Unfortunately, despite the exciting results, virtually every patient who receives TKI therapy and has an antitumor response
will eventually experience disease progression. This tumor relapse while the patient is still receiving drug therapy is called acquired resistance and typically occurs within 1 to 2 years after
the initiation of the TKI.4-8,11,12 The development of drug resistance remains a major limitation to the successful treatment for
patients with advanced NSCLC. Therefore, numerous preclinical and clinical studies have been directed at identifying and understanding on a mechanistic level the tumor-specifc factors
that lead to acquired resistance in NSCLC. Given the complexity
of the topic, we will specifcally focus in this review on EGFRmutant and ALK-rearranged NSCLC as paradigms for the use of
targeted therapies and the battle to overcome acquired TKI resistance in this disease.
EGFR-MUTANT NSCLC
EGFR is the gene that encodes for the EGFR tyrosine kinase.
EGFR propagates growth and survival signals through several
downstream pathways within the cell, including the RAS-RAFMEK-ERK (mitogen-activated protein [MAP] kinase) and the
phosphoinositide 3-kinase (PI3K)AKTmammalian target of
rapamycin (mTOR) pathways. In NSCLC, EGFR mutations are
typically detected in exons 18 to 21, which encode part of the
EGFR tyrosine kinase domain. Approximately 90% of these mutations are small in-frame deletions in exon 19 or point mutations in exon 21 (L858R).13 These mutations activate EGFR
kinase activity and are typically detected in lung adenocarcinomas with a frequency of approximately 10% of patients with
NSCLC in the United States and of approximately 35% in
Asia.1-3
EGFR mutations confer sensitivity to and are strong predictors of effcacy for the EGFR TKIs. Several classes of EGFR
From the Division of Hematology-Oncology, Vanderbilt University School of Medicine, Nashville, TN.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Christine M. Lovly, MD, PhD, Division of Hematology-Oncology, Vanderbilt University School of Medicine, 2220 Pierce Ave. South, 777 Preston Research Building, Nashville,
TN 37232; email: christine.lovly@vanderbilt.edu.
2015 by American Society of Clinical Oncology.
e165
CHRISTINE M. LOVLY
KEY POINTS
The identication of clinically relevant molecular cohorts of
patients with nonsmall cell lung cancer (NSCLC), dened
by the presence of actionable genomic alterations, has
revolutionized the care of patients with this disease.
Treatment for patients whose lung tumors harbor specic
oncogenic mutations often results in dramatic response to
targeted therapies, such as tyrosine kinase inhibitors
(TKIs). This is best exemplied by EGFR-mutant and ALKrearranged NSCLCs treated with EGFR TKIs and ALK TKIs,
respectively.
Resistance to TKI therapy appears to be an inevitable
consequence of this treatment approach. Resistance can be
either primary (de novo) or acquired. Specically, acquired
resistance is dened by tumor growth after initial tumor
regression while the patient is still receiving the TKI
therapy.
Mechanisms of acquired resistance include drug target
gene modication (amplication, second-site mutations),
activation of bypass tracks, which serve as compensatory
signaling loops, and/or histologic transformation.
Rebiopsy at the time of acquired resistance is essential for
understanding the specic mechanism(s) of resistance at
play in the tumor and for directing the patient to the most
appropriate line of therapy. Several strategies to overcome
acquired resistance, including novel, more potent inhibitors
and rational combinations of targeted inhibitors, have
already proven successful in clinical trials.
e166
FIGURE 1. Mechanisms of Acquired Resistance to First- and Second-Generation EGFR TKIs in EGFR-Mutant NSCLC
EGFR target modicaon
Bypass Signaling
AXL
FGFR
IGF-1R
MET
3rd generaon
(mutant specic)
EGFR inhibitors
HER3
* T790M
HER2
EGFR
Cetuximab in
combinaon
with afanib
Downstream signaling
RAS
PI3K
MEK
inhibitors
RAF
AKT
PI3K
inhibitors
Small Cell
Transformaon
MEK
mTOR
ERK
Cisplan/
Etoposide
Resistance can be mediated by EGFR target modications, most commonly the EGFR T790M second-site mutation, through bypass signaling pathways that circumvent the inhibited driver
oncogene (EGFR) and through histologic transformation (in this case, change in histology from NSCLC to SCLC). Potential strategies to overcome resistance are noted in the white boxes.
Abbreviations: EGFR, epidermal growth factor receptor; TKIs, tyrosine kinase inhibitors; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer.
e167
CHRISTINE M. LOVLY
EGFR TKIs appear to be the most effective therapeutic strategy tested to date to overcome T790M-mediated acquired resistance to erlotinib, geftinib, and afatinib. In fact, both
AZD9291 and rociletinib received FDA breakthrough status
in 2014.
Despite the excitement surrounding the shown effcacy of
mutant-specifc EGFR TKIs in T790M-positive tumors,
there still remains a large cohort (40% to 50%) of patients
with T790M-negative tumors who have developed acquired
resistance to erlotinib, geftinib, or afatinib. One potential
strategy that has been postulated for this cohort includes a
combination of the EGFR monoclonal antibody cetuximab
with afatinib in patients with acquired resistance. This combination, which dually targets EGFR, has been studied preclinically36 and in phase I clinical trials.37 Among the 126
patients treated with this combination, the objective RR was
29% and was comparable in patients with T790M-positive
and T790M-negative tumors (32% vs. 25%; p 0.341). The
median PFS was 4.7 months. Adverse events included expected toxicities of EGFR inhibitors, such as rash, diarrhea,
and fatigue. Therapy-related grades 3 and 4 adverse events
occurred in 44% and 2% of patients, respectively. Studies of
afatinib and cetuximab in the frst-line setting and at the time
of acquired resistance are being planned.
ALK-REARRANGED NSCLC
ALK is the gene that encodes for the anaplastic lymphoma
kinase (ALK). ALK is a receptor tyrosine kinase that is normally expressed in the developing nervous system48; however, genomic alterations in ALKincluding ALK
amplifcation, activating point mutations in the ALK kinase
domain, and ALK chromosomal rearrangementsare found
in a wide variety of malignancies.49 In NSCLC, ALK is activated through chromosomal rearrangements, most commonly EML4-ALK, which is a fusion between the
echinoderm microtubule-associated protein-like 4 gene
EML4 and ALK, both on chromosome 2. Analogous to
EGFR, ALK fusion proteins signal downstream through the
MAP kinase and the PI3K-AKT-mTOR pathways. ALK rearrangements are typically detected in lung adenocarcinoma
and occur at a frequency of approximately 3% to 7%.11,50
Several large clinical trials have shown now that patients
who have advanced NSCLC and harbor ALK rearrangements
derive clinical benefts from treatment with ALK TKI therapy. Crizotinib is the frst-in-class ALK TKI to be tested in
this patient population. Of note, in addition to ALK, crizotinib also targets MET and ROS1. In the phase I, frst-in-man
study (PROFILE 1005) of crizotinib in patients who have advanced NSCLC and harbor an ALK rearrangement, the objective RR was 60.8% (87/143 patients), and the median PFS
was 9.7 months.11,12 On the basis of the high RRs documented in this study, crizotinib was granted FDA approval in
2011 for the treatment of advanced, ALK-rearranged
NSCLC. Crizotinib also has been studied in randomized,
phase III trials. In PROFILE 1007, crizotinib was compared
with single-agent chemotherapy (pemetrexed or docetaxel)
in patients with ALK-rearranged NSCLC who had experienced disease progression after frst-line platinum-based
chemotherapy. Crizotinib therapy resulted in higher RRs
(65% with crizotinib vs. 20% with chemotherapy) and a signifcantly longer PFS (7.7 months with crizotinib vs. 3.0
months with chemotherapy).9 There was no difference in
overall survival between the groups (20.3 months with crizotinib vs. 22.8 months with chemotherapy), likely because of
signifcant crossover of patients from the chemotherapy arm
at the time of disease progression. In the PROFILE 1014
study, crizotinib was evaluated in the frst-line setting versus
chemotherapy (cisplatin or carboplatin plus pemetrexed) in
Kinase
Domain
EML4
ALK
Kinase
Domain
EML4
ALK
Kinase
Domain
EML4
ALK
Kinase
Domain
EML4
ALK
Kinase
Domain
EML4
ALK
c-KIT
ALK
Bypass Signaling
IGF-1R
EML4
Mutaon in the
ALK kinase domain
EGFR
Amplicaon of
the ALK fusion
EGFR
inhibitors
IGF-1R
inhibitors
KIT
inhibitors
Kinase
Domain
1151Tins
L1152R
C1156Y
I1171T
F1174L/C
L1196M
G1202R
G1269A
Second generaon
ALK inhibitors
KRASmut
SRC
MEKmut
MEK
inhibitors
Src
inhibitors
Resistance can be mediated by ALK target modications, including ALK amplication and ALK kinase domain mutations, and through bypass signaling pathways that circumvent the inhibited
driver oncogene (the ALK fusion). Potential strategies to overcome resistance are noted in the white boxes.
Abbreviation: NSCLC, non-small cell lung cancer.
e169
CHRISTINE M. LOVLY
(NCT01625234); preliminary results indicate that 59% of patients (10/17 patients) achieved a partial response, including
patients who had received prior crizotinib.64 Adverse events
were mild and included rash, nausea, vomiting, fatigue, and
edema. AP26113, which targets ALK and has activity against
the EGFR T790M mutation in vitro, has been tested in a
phase I/II study (NCT01449461). The objective RR was 72%
and the median PFS was 56 weeks in the 72 patients who had
ALK-positive NSCLC at the time of data cutoff.65 In the 65
patients who had received prior crizotinib, the RR was 69%,
and the median PFS was 47.3 weeks. CNS responses were
documented. Finally, PF-06463922 is a derivative of crizotinib designed to be a more potent ALK/ROS1 inhibitor. This
agent also was optimized to overcome some of the pharmacokinetic limitations of crizotinib.66 A phase I/II trial is ongoing (NCT01970865).
CONCLUSIONS
The identifcation and prospective targeting of oncogenic
driver mutations have revolutionized the care of patients
who have NSCLC. However, therapeutic resistance remains a
signifcant barrier to the successful management of this disease. Using the two most well-established molecular cohorts
of NSCLC, those defned by EGFR mutations and ALK rearrangements, we have reviewed the molecular mechanisms of
acquired resistance and the strategies to overcome resistance.
The development of more potent and more selective secondand third-generation oncogenic kinase inhibitors appears to
be the strategy with the most momentum and the most documented clinical success to date in both of these cohorts of
patients with lung cancer.
However, there are several challenges to address and opportunities to explore moving forward, including:
How do we effectively address the heterogeneity of resistance mechanisms between different individuals
and even in one individual patient? Will multiple biopsies at different sites of disease be necessary, or fea-
ACKNOWLEDGEMENT
Christine M. Lovly was supported by National Institutes of
Health Awards R01CA121210 and P01CA129243, a Damon
Runyon Clinical Investigator Award, and a LUNGevity
CAreer Development Award.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Christine M. Lovly, Harrison and Star. Consulting
or Advisory Role: Christine M. Lovly, Novartis, Pzer. Speakers Bureau: Christine M. Lovly, Abbot Molecular, Qiagen. Research Funding: Christine M. Lovly,
Astra Zeneca, Novartis. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: None.
Other Relationships: None.
References
1. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are
common in lung cancers from never smokers and are associated with
sensitivity of tumors to geftinib and erlotinib. Proc Natl Acad Sci U S A.
2004;101:13306-13311.
2. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell
lung cancer to geftinib. N Engl J Med. 2004;350:2129-2139.
3. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to geftinib therapy. Science. 2004;304:
1497-1500.
4. Mok TS, Wu YL, Thongprasert S, et al. Geftinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947957.
5. Maemondo M, Inoue A, Kobayashi K, et al. Geftinib or chemotherapy
for non-small cell lung cancer with mutated EGFR. N Engl J Med. 2010;
362:2380-2388.
6. Mitsudomi T, Morita S, Yatabe Y, et al. Geftinib versus cisplatin plus
docetaxel in patients with non-small-cell lung cancer harbouring
mutations of the epidermal growth factor receptor (WJTOG3405):
an open label, randomised phase 3 trial. Lancet Oncol. 2010;11:121128.
7. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as frst-line treatment for European patients with advanced
8.
9.
10.
11.
12.
13.
14.
EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13:
239-246.
Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or
cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327-3334.
Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy
in advanced ALK-positive lung cancer. N Engl J Med. 2013;368:23852394.
Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371:
2167-2177.
Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase
inhibition in non-small cell lung cancer. N Engl J Med. 2010;363:16931703.
Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in
patients with ALK-positive non-small cell lung cancer: updated results
from a phase 1 study. Lancet Oncol. 2012;13:1011-1019.
Ladanyi M, Pao W. Lung adenocarcinoma: guiding EGFR-targeted
therapy and beyond. Mod Pathol. 2008;21(suppl 2):S16-S22.
Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and fnal
overall survival results from a phase III, randomized, open-label, frstline study of geftinib versus carboplatin/paclitaxel in clinically selected
e171
CHRISTINE M. LOVLY
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
e172
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49. Roskoski R Jr. Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and pharmacological inhibition. Pharmacol Res. 2013;
68:68-94.
50. Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene
and effcacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res.
2008;14:4275-4283.
51. Katayama R, Khan TM, Benes C, et al. Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the
fusion oncogene EML4-ALK. Proc Natl Acad Sci U S A. 2011;108:75357540.
52. Choi YL, Soda M, Yamashita Y, et al. EML4-ALK mutations in lung
cancer that confer resistance to ALK inhibitors. N Engl J Med. 2010;363:
1734-1739.
53. Sasaki T, Koivunen J, Ogino A, et al. A novel ALK secondary mutation
and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer
Res. 2011;71:6051-6060.
54. Sasaki T, Okuda K, Zheng W, et al. The neuroblastoma-associated
F1174L ALK mutation causes resistance to an ALK kinase inhibitor in
ALK-translocated cancers. Cancer Res. 2010;70:10038-10043.
55. Tanizaki J, Okamoto I, Okabe T, et al. Activation of HER family signaling as a mechanism of acquired resistance to ALK inhibitors in EML4ALK-positive non-small cell lung cancer. Clin Cancer Res. 2012;18:
6219-6226.
56. Lovly CM, McDonald NT, Chen H, et al. Rationale for co-targeting
IGF-1R and ALK in ALK fusion-positive lung cancer. Nat Med. 2014;
20:1027-1034.
57. Crystal AS, Shaw AT, Sequist LV, et al. Patient-derived models of acquired resistance can identify effective drug combinations for cancer.
Science. 2014;346:1480-1486.
58. Friboulet L, Li N, Katayama R, et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov. 2014;4:662-673.
59. Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged nonsmall cell lung cancer. N Engl J Med. 2014;370:1189-1197.
60. Sakamoto H, Tsukaguchi T, Hiroshima S, et al. CH5424802, a selective
61.
62.
63.
64.
65.
66.
67.
68.
ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell. 2011;19:679-690.
Seto T, Kiura K, Nishio M, et al. CH5424802 (RO5424802) for patients with
ALK-rearranged advanced non-small cell lung cancer (AF-001JP study): a
single-arm, open-label, phase 1-2 study. Lancet Oncol. 2013;14:590-598.
Gadgeel SM, Gandhi L, Riely GJ, et al. Safety and activity of alectinib
against systemic disease and brain metastases in patients with crizotinibresistant ALK-rearranged non-small cell lung cancer (AF-002JG): results
from the dose-fnding portion of a phase 1/2 study. Lancet Oncol. 2014;15:
1119-1128.
Lovly CM, Heuckmann JM, de Stanchina E, et al. Insights into ALKdriven cancers revealed through development of novel ALK tyrosine kinase inhibitors. Cancer Res. 2011;71:4920-4931.
Horn LIJ, Blumenshcein G, Wakelee H, et al. A phase I trial of X-396, a
novel ALK inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2014;32:5s (suppl; abstr 8030).
Gettinger S, Bazhenova L, Salgia R, et al. ALK inhibitor AP26113 in patients with advanced malignancies, including ALK non-small cell
lung cancer (NSCLC): updated effcacy and safety data. Presented at:
39th Annual Congress of the European Society for Medical Oncology;
October 2014; Madrid, Spain.
Johnson TW, Richardson PF, Bailey S, et al. Discovery of (10R)-7amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,
4-(m etheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical
brain exposure and broad-spectrum potency against ALK-resistant mutations. J Med Chem. 2014;57:4720-4744.
Sang J, Acquaviva J, Friedland JC, et al. Targeted inhibition of the molecular chaperone Hsp90 overcomes ALK inhibitor resistance in nonsmall cell lung cancer. Cancer Discov. 2013;3:430-443.
Sequist LV, Gettinger S, Senzer NN, et al. Activity of IPI-504, a novel
heat-shock protein 90 inhibitor, in patients with molecularly defned
non-small cell lung cancer. J Clin Oncol. 2010;28:4953-4960.
e173
DEVELOPMENTAL THERAPEUTICS
AND TRANSLATIONAL RESEARCH
SPEAKERS
Michael F. Berger, PhD
Memorial Sloan Kettering Cancer Center
New York, NY
Martine Piccart-Gebhart, MD, PhD
Jules Bordet Institute
Brussels, Belgium
enomic sequencing technologies have enabled identifcation of actionable targets (e.g., BRAF in melanoma,
EGFR in lung cancer) thus facilitating treatment selection beyond what is offered by conventional histopathologic methods (Fig. 1). Although NGS has helped identify genomic
alterations and uncover novel targets for therapies, there are
several barriers for translating this into clinical practice, such
as informed consent, choosing a scalable cost-effective testing strategy, turnaround time, and clinical interpretation of
results. Several pilot studies have addressed some of these
hurdles and demonstrated the feasibility of offering genomic
testing for patients with advanced cancer within a clinically
relevant time frame and interpreting the results to facilitate
new treatment options for patients.1-6 Today, cancer genomic
testing has become more widely available in academic cancer
centers and commercial testing labs.
Although whole-genome, whole-exome, and wholetranscriptome sequencing offer an unbiased approach and
opportunities for discovery, their immediate effect on clinical decision making is limited, as only a fraction of cancer
genes are well characterized in terms of biology and therapeutic relevance. Further, these unbiased sequencing approaches remain expensive and time consuming and are
burdensome for computational analysis. All of these limitations make these approaches less amenable to meet standards
required for clinical testing, such as Clinical Laboratory Im-
From the Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH; Memorial Sloan Kettering Cancer Center, New York, NY; Department of
Pharmacology, The Ohio State University, Columbus, OH.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Sameek Roychowdhury, MD, PhD, The Ohio State University, 460 West 12th Ave., Room 508, Columbus, OH 43210; email: sameek.roychowdhury@osumc.edu.
2015 by American Society of Clinical Oncology.
e175
Cancer genomic sequencing assays can aid clinical decision making with potential
implications for diagnosis, prognosis, and treatment. Several assays are available to aid in
identifying tissue-of-origin in cancer of unknown primary, which may lead to identication
of potential favorable subsets and their appropriate treatment options. For patients with
metastatic or refractory cancer, multiple testing strategies are available to identify
genomic alterations that may provide molecular eligibility for novel targeted therapies in
clinical trials.
KEY POINTS
Targeted gene capture panels are more commonly
employed in clinical practice because of reduced costs and
faster turnaround time.
In addition to gene expression and fusions, RNA sequencing
also facilitates the proling of noncoding RNAs.
Germ-line DNA testing can help distinguish somatic
mutations from inherited variants but has logistic
challenges.
Tumor heterogeneity, discerning drivers from passenger
mutations, and acquired resistance are potential challenges
with developing genomics-driven targeted therapies.
Genomic tumor sequencing can explain how some patients
develop exceptional response to therapies and help further
development of a therapy.
e176
fndings, and disclosure.12 This requires substantial resources and time and limits the broader use of germ-line tissue in oncology practices. Consequently, most commercial
vendors offer tumor only testing.
IMPLEMENTATION OF A CLINICAL
SEQUENCING WORKFLOW
Challenges and Considerations
When developing clinical sequencing workflows, academic
and commercial laboratories must confront many challenges. In contrast to the research setting, where large, highpurity, fresh-frozen tumors can be prioritized for analysis,
clinical laboratories must be equipped to analyze specimens
of all sizes and qualities. These may include small biopsies,
fne-needle aspirates, or FFPE samples that are heterogeneous or admixed with normal tissue. Sequencing protocols
must be optimized for low-quality specimens and low-input
quantities and still deliver deep coverage sequence data for
the reliable detection of mutations with low allele frequency.
Further, laboratories must be able to deliver results with a
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e177
rapid turnaround time at a reasonable cost. The use of germline DNA from blood or healthy tissue as a normal control
has major benefts for the analysis and interpretation of somatic mutations, but it creates logistic challenges involving
tracking and transporting separate samples from the same
patient. As multiple tumor samples from a given patient may
occasionally be sequenced to monitor tumor progression and
acquired resistance to therapy, flexible workflows are necessary to accommodate longitudinal analysis. Though the
nature of these issues may vary for different laboratories
depending on their throughput and sequencing platforms,
they represent technical challenges common to all clinical
laboratories.
Bioinformatics and analysis requirements collectively represent another important challenge in establishing a clinical
sequencing workflow. The bioinformatics algorithms and
software required to call different classes of genomic alterations (sequence mutations, insertions, deletions, copy number gains and losses, and structural rearrangements) are
constantly evolving, and there remains no consensus on the
best approach or standardized pipeline. Laboratories performing NGS have the choice of utilizing third-party software for data analysis, which can be costly and limits
flexibility, or developing custom pipelines in-house, which
requires considerable time and expertise to build and maintain. Either way, a signifcant informatics infrastructure is
needed to manage, store, and archive the data generated by
the sequencing instruments and the results produced by
bioinformatics pipelines. Access to high-performance computing resources for processing and analyzing sequence data
is required. Laboratory information management systems
and associated databases are typically also needed to track
samples, experiments, and results. For hospitals and clinical
laboratories that have not traditionally employed many
computational biologists and software engineers, the recruitment and training of bioinformatics staff is challenging yet
essential.
Regulatory requirements, including the up-front analytic
and clinical validation of assays, must also be met in any clinical sequencing workflow. Clinical laboratories producing results that are returned to patients and used in treatment
decisions are subject to legal obligations designed to ensure
that tests are reproducible and adhere to high standards of
sensitivity and specifcity. Such labs, whether commercial or
academic, must be compliant with the CLIA, under the oversight of the Centers for Medicare & Medicaid Services. Accordingly, extensive documentation and technical validation
of diagnostic assays are a requirement for patient testing and
subsequent billing to insurance companies and Medicare.
The model that some institutions have adopted wherein
large-scale sequencing is performed in research labs, followed by confrmation in CLIA-compliant labs, is unsustainable over the long-term if the costs of NGS cannot be
recovered through reimbursement.
To achieve maximum clinical beneft from a diagnostic
sequencing assay, results must be reported to clinicians in
a clear and easily digestible way, yet with all supporting ine178
formation necessary to interpret the signifcance of the collection of genomic alterations that were detected.28 The
interpretation of results is frequently dependent on tumor
type and other clinical factors and must be considered in that
context. Also, although the goal is to identify actionable
driver mutations, clinical sequencing assays typically turn up
far more passenger mutations with unclear biologic and clinical signifcance. This is especially true in tumors with a high
background mutation rate because of environmental exposures or abnormalities in DNA mismatch repair. It can be
very diffcult for a clinician to distinguish between key driver
alterations that should affect treatment and passenger mutations with no apparent signifcance. Many academic cancer
centers have created genomic or molecular tumor boards
to collectively discuss and interpret challenging cases and
recommend a course of action that the treating physician can
take.4,29 As this process does not easily scale to accommodate
the large number of tumors being sequenced today, groups
have attempted to curate and codify biologic and clinical information about mutations into databases that can be queried or utilized to annotate molecular diagnostic reports.9,30
These knowledge bases must be granular enough to account for the fact that different sequence variants in the same
gene may have opposite effects, and the same variant in different tumor types may have different clinical consequences.
They should also enable the enumeration of clinical trials that
might be benefcial to the patient, given their molecular profle. Nevertheless, no knowledge base is comprehensive or
will ever include information on all possible alterations that a
sequencing assay may reveal. Further, the co-occurrence of
multiple driver mutations may have implications that cannot
be inferred from the functions or clinical consequences of
each individual mutation alone.
With the exception of targeted panels focused on mutational hotspots, germ-line DNA is typically used as a normal
control to distinguish somatic mutations from inherited
variants. In the absence of germ-line DNA, variants identifed from tumor sequencing must be fltered according to databases of common single nucleotide polymorphisms. This
can lead to false-positive mutation calls at sites of rare inherited single nucleotide polymorphisms, including cancer susceptibility alleles. The inclusion of germ-line DNA enables
somatic mutations to be unambiguously called; yet it also enables the detection of pathogenic variants in the genes that
are sequenced. This has considerable ethical and logistic
implications. Incidental fndings may emerge as a result of
tumor sequencing that relate to a patients inherited susceptibility to cancer or other diseases, with unanticipated yet signifcant consequences for family members who share these
variants.31,32 At present, tests specifcally designed to search
for inherited genetic variants typically require that patients
sign informed consent and are properly educated of the benefts and risks of the test by a genetic counselor. For laboratories setting up large-volume tumor sequencing initiatives,
individual pretest genetic counseling of all patients may be
untenable. Computational subtraction of germ-line variants
during mutation calling may circumvent the requirement for
Name
No. of Genes
Results
Time
Foundation Medicine
Foundation One
12-14 days
MI Prole
46
Hotspot mutations
14 days
ParadigmDx
PCDx
114
4-5 days
ARUP Labs
48
Hotspot mutations
14 days
PathGroup
SmartGenomics
35
Hotspot mutations
7-10 days
38
Hotspot mutations
10-14 days
Life Technologies
25
SNVs, fusions
7 days
Abbreviations: SNV, single nucleotide variation or point mutation; CNV, copy number variation; NGS, next-generation sequencing.
pretest counseling, but it also has the consequence that inherited variants with potential clinical signifcance are willfully
disregarded.33 Regardless of the circumstances, when an inherited predisposition to cancer (or another disease) is discovered, care must be taken to ensure the privacy and
autonomy of patients and their families and to help manage
the emotional and psychologic consequence of such a
diagnosis.
As discussed above, the sustainability of clinical NGS
initiatives depends on reimbursement from insurance companies and Medicare. However, at present, molecular diagnostic testing is only reimbursed in a small number of tumor
types where there are approved drugs whose administration
depends on a positive or negative test result and where there
are clear clinical guidelines mandating the use of molecular
testing. Examples include lung adenocarcinoma, colorectal
cancer, and melanoma. In other tumor types where comparable guidelines do not exist, more data are needed to determine the clinical utility of NGS-based molecular profling. As
a result, large academic cancer centers are investing considerable philanthropic and other institutional funds into clinical sequencing of nonbillable tumor types. Demonstrating
the clinical utility of tumor sequencing across additional cancer types is essential to ensure greater reimbursement and
promote broader access to testing outside of the largest centers. A related issue emerges when actionable mutations are
detected in unexpected tumor types, and insurance companies are not always willing to reimburse the cost of the drug
for an off-label indication. The emergence of molecularly
guided clinical trials encompassing multiple tumor types, or
basket clinical trials, may help some patients in this situation.
e179
CONCLUSION
Although the application of clinical tumor sequencing has
enabled identifcation of actionable genomic alterations that
could provide molecular eligibility to matching targeted
therapies, clinical application and interpretation does have
some challenges. Intratumor heterogeneity, discerning drivers from passenger mutations, lack of sustained response,
and acquired resistance to targeted therapies are some of the
issues that limit the potential of genomics-driven targeted
therapies. Further, responses to targeting tend to vary across
tumors and within a tumor depending on the treatment context. Biopsies at multiple time points, rational combination
therapies, and basket trial designs can help address some of
these issues. As oncology is migrating to a more molecularly
matched therapy paradigm, a strong collaboration between
basic scientists, molecular pathologists, bioinformaticians,
and oncologists is paramount in an effort to identify novel
cancer therapies that lead to improvement in patient
survival.
ACKNOWLEDGMENT
Thanks to Cassie Hershberger for administrative support.
Thanks to ASCO for organizing this education session.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: Sameek Roychowdhury, Johnson and Johnson (I). Honoraria: None.
Consulting or Advisory Role: Michael F. Berger, Cancer Genetics, Inc. Speakers Bureau: None. Research Funding: Sameek Roychowdhury, Ariad
Pharmaceuticals, Novartis. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses:
None. Other Relationships: None.
References
1. Weiss GJ, Liang WS, Izatt T, et al. Paired tumor and normal whole genome sequencing of metastatic olfactory neuroblastoma. PLoS One.
2012;7:e37029.
2. NCT01670877. Neratinib in Metastatic HER2 Non-amplifed But HER2
Mutant Breast Cancer. https://clinicaltrials.gov/ct2/show/NCT01670877.
Accessed February 8, 2015.
3. Welch JS, Westervelt P, Ding L, et al. Use of whole-genome sequencing
to diagnose a cryptic fusion oncogene. JAMA. 2011;305:1577-1584.
4. Roychowdhury S, Iyer MK, Robinson DR, et al. Personalized oncology
through integrative high-throughput sequencing: a pilot study. Sci
Transl Med. 2011;3:111ra121.
5. Link DC, Schuettpelz LG, Shen D, et al. Identifcation of a novel TP53
cancer susceptibility mutation through whole-genome sequencing of a
patient with therapy-related AML. JAMA. 2011;305:1568-1576.
6. Jones SJ, Laskin J, Li YY, et al. Evolution of an adenocarcinoma in response to selection by targeted kinase inhibitors. Genome Biol. 2010;11:
R82.
7. Frampton GM, Fichtenholtz A, Otto GA, et al. Development and validation of a clinical cancer genomic profling test based on massively
parallel DNA sequencing. Nat Biotechnol. 2013;31:1023-1031.
8. Xuan J, Yu Y, Qing T, et al. Next-generation sequencing in the clinic:
promises and challenges. Cancer Lett. 2013;340:284-295.
9. Van Allen EM, Wagle N, Stojanov P, et al. Whole-exome sequencing
and clinical interpretation of formalin-fxed, paraffn-embedded tumor
samples to guide precision cancer medicine. Nat Med. 2014;20:682-688.
10. Shyr D, Liu Q. Next generation sequencing in cancer research and clinical application. Biol Proced Online. 2013;15:4.
11. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and
branched evolution revealed by multiregion sequencing. N Engl J Med.
2012;366:883-892.
12. Everett JN, Gustafson SL, Raymond VM. Traditional roles in a nontraditional setting: genetic counseling in precision oncology. J Genet
Couns. 2014;23:655-660.
13. Cottrell CE, Al-Kateb H, Bredemeyer AJ, et al. Validation of a nextgeneration sequencing assay for clinical molecular oncology. J Mol Diagn. 2014;16:89-105.
14. Pritchard CC, Salipante SJ, Koehler K, et al. Validation and implementation of targeted capture and sequencing for the detection of actionable
mutation, copy number variation, and gene rearrangement in clinical
cancer specimens. J Mol Diagn. 2014;16:56-67.
15. Wagle N, Berger MF, Davis MJ, et al. High-throughput detection of ac-
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
tionable genomic alterations in clinical tumor samples by targeted, massively parallel sequencing. Cancer Discov. 2012;2:82-93.
Won HH, Scott SN, Brannon AR, et al. Detecting somatic genetic alterations in tumor specimens by exon capture and massively parallel sequencing. J Vis Exp. 2013;e50710.
Lipson D, Capelletti M, Yelensky R, et al. Identifcation of new ALK and
RET gene fusions from colorectal and lung cancer biopsies. Nat Med.
2012;18:382-384.
Takeuchi K, Soda M, Togashi Y, et al. RET. ROS1 and ALK fusions in
lung cancer. Nat Med. 2012;18:378-381.
Roberts KG, Li Y, Payne-Turner D, et al. Targetable kinase-activating
lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014;371:
1005-1015.
Zheng Z, Liebers M, Zhelyazkova B, et al. Anchored multiplex PCR for
targeted next-generation sequencing. Nat Med. 2014;20:1479-1484.
Qadir MA, Zhan SH, Kwok B, et al. ChildSeq-RNA: a next-generation
sequencing-based diagnostic assay to identify known fusion transcripts
in childhood sarcomas. J Mol Diagn. 2014;16:361-370.
Iyer MK, Niknafs YS, Malik R, et al. The landscape of long noncoding
RNAs in the human transcriptome. Nat Genet. Epub 2015 Jan 19.
Quinodoz S, Guttman M. Long noncoding RNAs: An emerging link
between gene regulation and nuclear organization. Trends Cell Biol.
2014;24:651-663.
Garzon R, Marcucci G, Croce CM. Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug Discov. 2010;9:775-789.
Rosenfeld N, Aharonov R, Meiri E, et al. MicroRNAs accurately identify
cancer tissue origin. Nat Biotechnol. 2008;26:462-469.
Pentheroudakis G, Pavlidis N, Fountzilas G, et al. Novel microRNAbased assay demonstrates 92% agreement with diagnosis based on clinicopathologic and management data in a cohort of patients with
carcinoma of unknown primary. Mol Cancer. 2013;12:57.
Sozzi G, Boeri M, Rossi M, et al. Clinical utility of a plasma-based
miRNA signature classifer within computed tomography lung cancer
screening: a correlative MILD trial study. J Clin Oncol. 2014;32:768-773.
Van Allen EM, Wagle N, Levy MA. Clinical analysis and interpretation
of cancer genome data. J Clin Oncol. 2013;31:1825-1833.
Tran B, Brown AM, Bedard PL, et al. Feasibility of real time next generation sequencing of cancer genes linked to drug response: results from
a clinical trial. Int J Cancer. 2013;132:1547-1555.
Levy MA, Lovly CM, Pao W. Translating genomic information into clinical
medicine: lung cancer as a paradigm. Genome Res. 2012;22:2101-2108.
e181
31. Green RC, Berg JS, Grody WW, et al. ACMG recommendations for reporting of incidental fndings in clinical exome and genome sequencing.
Genet Med. 2013;15:565-574.
32. Catenacci DV, Amico AL, Nielsen SM, et al. Tumor genome analysis
includes germline genome: are we ready for surprises? Int J Cancer.
2015;136:1559-1567.
33. Bombard Y, Robson M, Offt K. Revealing the incidentalome when targeting the tumor genome. JAMA. 2013;310:795-796.
34. Iyer G, Hanrahan AJ, Milowsky MI, et al. Genome sequencing identifes
a basis for everolimus sensitivity. Science. 2012;338:221.
35. Wagle N, Grabiner BC, Van Allen EM, et al. Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of
everolimus and pazopanib. Cancer Discov. 2014;4:546-553.
36. Bose R, Kavuri SM, Searleman AC, et al. Activating HER2 mutations in HER2
gene amplifcation negative breast cancer. Cancer Discov. 2013;3:224-237.
37. Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged nonsmall-cell lung cancer. N Engl J Med. 2014;370:1189-1197.
38. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693-1703.
39. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy
e182
40.
41.
42.
43.
44.
45.
46.
From the Breast International Group, Brussels, Belgium; Institut Jules Bordet, Brussels, Belgium.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Martine Piccart-Gebhart, MD, PhD, Institut Jules Bordet, Blvd de Waterloo, 121, 1000 Brussels, Belgium; email: martine.piccart@bordet.be.
2015 by American Society of Clinical Oncology.
e183
TABLE 1. Molecular Aberrations Dening Administration of Approved Targeted Agents in Different Solid Tumor
Diagnoses
Cancer Type
Molecular Target
Aberration
Method of Assessment
Breast Cancer
ER
Overexpression
IHC
Tamoxifen
AIs
Fulvestrant
PgR
Overexpression
IHC
Tamoxifen
AIs
Fulvestrant
HER2
IHC
Trastuzumab
FISH
Lapatinib
Pertuzumab
T-DM1
Colorectal Cancer
KRAS*
Mutation
DNA
Cetuximab
Panitumumab
Gastric Cancer
HER2
IHC
Trastuzumab
FISH
GIST
KIT
Mutation
IHC
Imatinib
Melanoma
BRAF
Mutation
DNA
Vemurafenib
Dabrafenib
EGFR
Mutation
DNA
Getinib
Erlotinib
ALK
Rearrangement
FISH
Crizotinib
RET
Rearrangement
FISH
Vandetanib
ROS
Rearrangement
FISH
Crizotinib
Abbreviations: AI, aromatase inhibitor; ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; ER, estrogen receptor; FISH, fluorescent in situ hybridization; GIST,
gastrointestinal stromal tumor; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; PgR, progesterone receptor; T-DM1, trastuzumab DM1.
*KRAS mutations predict lack of benet derived from EGFR-blocking agents.
the tumor microenvironment. An expanding arsenal of targeted agents is currently under clinical development, aiming
to block specifc molecular aberrations9 ; however, the extended tumor heterogeneity seen poses impediments to their
success.10 The increasing number of targeted agents warranting clinical assessment, coupled with the increasing molecu-
KEY POINTS
The success stories of trastuzumab and endocrine
treatment for patients with HER2-positive and hormone
receptor-positive breast cancer exemplify the potential of
personalized cancer medicine.
High-throughput molecular proling techniques reveal the
extensive molecular diversity of breast cancer, leading to
an increased molecular fragmentation.
There is an increasing number of targeted agents that
need to be assessed in the setting of breast cancer.
Clinical assessment of targeted agents within small
molecularly dened breast cancer segments poses
challenges to the design and conduct of clinical trials.
New, innovative study designs are being introduced to
overcome these challenges.
e184
Advantages
Disadvantages
Whole-Genome Sequencing
Targeted Sequencing
Lower costs
Whole-Exome Sequencing
Easier
Lower
Easier
Ready
Higher costs
Longer turnaround time
Laborious bioinformatics work
High storage capacity needed
Challenging clinical interpretation/reporting
Low reproducibility of FFPE tumor material analysis
data interpretation
data storage capacity needed
clinical interpretation/reporting
to be used for FFPE
sequenced being that of a cytogenetically normal acute myeloid leukemia.29 Subsequently, several studies have employed this approach in the setting of breast cancer.22,30,31
However, the implementation of WGS in clinical practice has
been questioned, since the use of archived formalin-fxed
paraffn-embedded tumor material is problematic. Additionally, high computational power and delicate bioinformatic
tools are needed for data interpretation, posing further challenges in the clinical implementation of WGS.32 (2) Targeted
sequencing, referring to either whole-exome sequencing, or
targeted-gene sequencing, is conducted using panels of selected cancer-related genes. Such approaches have certain
advantages (Table 2), such as shorter turn-around times,
lower costs, and less laborious data interpretation; presently,
they are available in several Clinical Laboratory Improvement Amendments (CLIA) certifed laboratories; however,
there is a compromise in the ability to detect translocations
and other structural rearrangements.33
e185
TABLE 3. Challenges Encountered in Current Clinical Trials Assessing Targeted Anticancer Agents and Proposed
Mechanisms to Circumvent Them
Phenomenon
Consequence
Potential Solution
Innovative study designs such as master protocols to reduce
screening failures
Statistical tools to reduce sample sizes needed (e.g., relaxing
type I error)
Revisiting regulatory pathways for approval
Risk-sharing strategies
Greater pharmaceutical industry participation
Functional validation
Well-characterized xenograft tumor models
Intratumor heterogeneity Need to assess multiple molecular aberrations from one tumor sample Multiplexed molecular proling to reduce tissue requirements
Liquid biopsies/plasma-based molecular proling
Increased costs for molecular proling
Clonal evolution
Risk-sharing strategies
Greater pharmaceutical industry participation
outcome. An already completed initiative from this category is the SAFIR01 program that recruited 423 patients
with metastatic breast cancer.38 Patients were subjected to biopsy of metastatic site, with the tissue analyzed by comparative genomic hybridization as well as Sanger sequencing of
the PIK3CA and AKT1 genes. This study, with a primary endpoint of the proportion of patients that could be entered into
trials of targeted agents, demonstrated that personalization
of treatment for patients with this disease is feasible in clinical
practice. A subsequent effort, SAFIR02, is currently recruiting patients with HER2-negative metastatic breast cancer
who have received no more than one line of chemotherapy.
Metastatic tissue from these patients will be analyzed by
NGS; after six to eight cycles of cytotoxic chemotherapy, patients with no progression of their disease will be randomly
assigned to receive the standard of care or targeted therapy
according to a list of 51 molecular alterations.
This study design can be exemplifed by the AURORA (Aiming to Understand the Molecular Aberrations in Metastatic
Breast Cancer) program initiated by the Breast International
Group.36 This represents a collaborative effort of European
hospitals to conduct large-scale molecular profling of patients with metastatic breast cancer who are prospectively
followed (Fig. 1). This molecular profling, of one metastatic
lesion and of the primary tumor, can support the conduct of
genotype-driven nested or downstream clinical trials,37
offering a dual beneft: (1) facilitate the molecular preselection of patients eligible to be enrolled in genotype-driven
clinical trials and (2) identify potential predictive biomarkers, through the coupling of the molecular and clinical outcome data captured for the patients enrolled in such a
program. An important additional beneft that can be expected through this approach is the fact that clinicians become familiarized to the reporting of genomic data.
Furthermore, such programs can improve our knowledge
of prognosis for molecularly defned subsets of cancer,
through the prospective follow-up of patients for clinical
Phase
(No. of Patients)
Genotype Targeted
Agent
Molecular Target
Design
Primary
Endpoint
NCT01277757
II (40)
MK2206
AKT
Single-arm, monotherapy
ORR
NCT01219699
I (200)
PIK3CA mutations
BYL719
Alpha-isoform PI3K
MTD
NCT01589861
I/II (106)
BKM120
MTD, ORR
NCT01670877
II (29)
ERBB2 mutation
Neratinib
EGFR/HER2/HER4
Single-arm, monotherapy
CBR
Abbreviations: CBR, clinical benet rate; EGFR, epidermal growth factor receptor; MTD, maximum tolerated dose; ORR, objective response rate; PI3K, phosphatidylinositol-4,5-bisphosphate
3-kinase; PTEN, phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase.
e186
Improved
understanding
Can driver
mutaons be
captured by
plasma tumour
DNA?
Relave importance
of driver
mutaons in the
trunk or in the
branches
Which clones are
going to play a
major role
in the lethal
evoluon
of the disease?
of the disease
Up-scaling of
the number of MBC
paents candidate
for clinical trials
with new targeted
therapies
NIF Trust
choosing targeted therapeutics based on the molecular profling as compared with conventional treatment. This design
does not assess individual targeted agents and should be
therefore perceived as proof of concept. Tsimberidou et al
reported promising results from a nonrandomized, phase I
clinical trials program, according to which tumor tissue from
patients with several advanced solid tumors diagnoses (1,144
tumors) were analyzed by molecular profling: disease in patients having one molecular aberration who were treated
based on the genotype of their disease (175 patients) demonstrated an increased overall response rate (27% vs. 5%; p
0.0001), longer time-to-treatment failure (5.2 months vs. 2.2
months; p 0.0001), and longer overall survival (13.4 vs. 9.0
months; p 0.017) compared with patients who received
conventional treatment (116 patients).35 Currently, there is an
ongoing randomized, proof-of-concept, phase II trial comparing targeted therapy based on tumor tissue molecular profling
compared with conventional treatment for patients with several
advanced cancer types called SHIVA (NCT01771458).39 This
study incorporated a feasibility part, which demonstrated the
feasibility and safety of incorporating biopsy of metastatic disease for the frst 100 patients who enrolled.40
Master-Protocol Trials
This study design can assess different targeted agents in parallel within independent cohorts of patients defned by specifc molecular aberrations that could predict sensitivity to
the investigational agent under assessment. This approach
e187
Basket Trials
N-of-1 Trials
This is a study design that has been more frequently employed in felds of clinical research other than oncology, such
as trials conducted for patients with musculoskeletal or pulmonary conditions.49,50 The defning characteristic is the recruitment of patients exposed to different experimental
agents or placebo in different sequencing, with washout periods in between.51 This type of design practically renders
each involved patient to serve as his or her own comparator,
through the comparison of the effcacy seen for the different
experimental agents that the patient receives. In oncology, a
modifed N-of-1 study design has been performed, which assessed the antitumor activity of different anticancer compounds matched to the genotype of the patients.52 This trial
recruited 86 patients with different types of advanced tumor
who had been heavily pretreated, that had molecular profling. Sixty-six of these patients were treated according to these
results. Concerning the effcacy, 18 patients had a PFS ratio of
1.3 or higher (95% CI, 17% to 38%; one-sided, one-sample
p 0.007). The study met its primary endpoint, which was
the comparison of PFS obtained by the targeted treatment
with the PFS achieved by the previous systemic treatment
within each individual patient. This is an approach that could
be of help for molecular aberrations of really low prevalence,
where randomized studies are extremely challenging.
Adaptive Trials
Adaptive trials represent another transformative study design, recently exemplifed by the BATTLE (BiomarkerIntegrated Approaches of Targeted Therapy for Lung Cancer
Elimination)-1 and -2 clinical trials, focusing on patients
with metastatic NSCLC,44 or the I-SPY (The Investigation of
Serial Studies to Predict Your Therapeutic Response with
Imaging and Biomarker Analysis) 1 and 2 trials conducted in
the neoadjuvant setting of breast cancer.45-47 These are dynamically evolving trials, with the particular aspect of during
the initial phase of the adaptive study patients are recruited in
the different arms at an equal ratio; however, as more patients
are enrolled and effcacy data are being generated and pooled
from the different treatment arms, the adaptive phase follows. During this second, adaptive phase, randomization ratios can be changed and treatment arms can be dropped
e188
Window-of-Opportunity Trials
Window-of-opportunity trials incorporate a design assessing
the administration of an investigational agent over a short
period of time, most often in the presurgical setting allowing
serial tumor biopsies, though such studies can be conducted
in the metastatic setting as well.53,54 These trials do not have
an effcacy endpoint, since it is the in vivo biologic effects of
an experimental agent and not the antitumor activity with
offcially predefned measures of outcome that they aim to
assess. An ongoing study utilizing this innovative design is
the D-beyond trial, a preoperative window study evaluating
denosumab, a RANK ligand inhibitor, and its biologic effects
for premenopausal women with early breast cancer.55 Patients entering this trial receive preoperatively two doses
of 120 mg of denosumab subcutaneously 1 week apart that
will be followed by surgery. Ten to 21 days after the frst
administration, surgical excision of the primary tumor
will take place; the primary objective is the antiproliferative effect exerted by denosumab, as indicated by Ki67
immunohistochemistry-based assessment. Another example
of a window-of-opportunity trial that will soon be initiated is
the RHEA (Biomarker Research Study for PF-03084014 in
CONCLUSION
To the present day, great progress has been made in the molecular profling of breast cancer, with an expanding array of
molecular aberrations being identifed. The subsequent development of experimental targeted agents promises to
improve cancer treatment for patients bearing specifc molecular aberrations. A major challenge is the assessment of
the functional signifcance of such aberrations and the veri-
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Martine
J. Piccart-Gebhart, Amgen, Astellas, AstraZeneca, Bayer, Eli Lilly, Invivis, MSD, Novartis, Pzer, Roche-Genentech, sano Aventis, Symphogen, Synthon,
Verastem. Speakers Bureau: None. Research Funding: Martine J. Piccart-Gebhart, Amgen (Inst), Astellas (Inst), AstraZeneca (Inst), Bayer (Inst), Eli Lilly
(Inst), Invivis (Inst), MSD (Inst), Novartis (Inst), Pzer (Inst), Roche-Genentech (Inst), Sano Aventis (Inst), Symphogen (Inst), Synthon (Inst), Verastem (Inst).
Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships:
None.
References
1. National Cancer Institute. NCI Dictionary of Cancer Terms. Personalized Medicine. http://www.cancer.gov/dictionary?cdrid561717. Accessed January 29, 2015.
2. Zardavas D, Pugliano L, Piccart M. Personalized therapy for breast cancer: a dream or a reality? Future Oncol. 2013;9:1105-1119.
3. Ward HW. Anti-oestrogen therapy for breast cancer: a trial of tamoxifen at two dose levels. Br Med J. 1973;1:13-14.
4. Lerner HJ, Band PR, Israel L, et al. Phase II study of tamoxifen: report of
74 patients with stage IV breast cancer. Cancer Treat Rep. 1976;60:14311435.
5. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a
monoclonal antibody against HER2 for metastatic breast cancer that
overexpresses HER2. N Engl J Med. 2001;344:783-792.
6. Zardavas D, Ades F, de Azambuja E. Clinical practice-changing trials:
the HERA study paradigm. Expert Rev Anticancer Ther. 2013;13:12491256.
7. Zardavas D, Cameron D, Krop I, et al. Beyond trastuzumab and lapatinib: new options for HER2-positive breast cancer. Am Soc Clin Oncol
Educ Book. 2013.
8. Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and fnal
overall survival results from a phase III, randomized, open-label, frstline study of geftinib versus carboplatin/paclitaxel in clinically selected
patients with advanced non-small-cell lung cancer in Asia (IPASS).
J Clin Oncol. 2011;29:2866-2874.
e189
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
e190
DEVELOPMENTAL THERAPEUTICS
AND TRANSLATIONAL RESEARCH
SPEAKERS
F. Stephen Hodi, MD
Dana-Farber Cancer Institute
Boston, MA
Michael A. Postow, MD
Memorial Sloan Kettering Cancer Center
New York, NY
MICHAEL A. POSTOW
From the Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medical College, New York, NY.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Michael A. Postow, MD, Melanoma and Immunotherapeutics Oncology Service, Memorial Sloan Kettering Cancer Center, 300 East 66th St., New York, NY 10065; email:
postowm@mskcc.org.
2015 by American Society of Clinical Oncology.
76
Reprinted with permission. 2012 American Society of Clinical Oncology. All rights
reserved. Weber J, et al: J Clin Oncol 30(21), 2012:2691-2697.
KEY POINTS
Immune checkpoint-blocking antibodies can cause immunemediated adverse events involving the skin, liver,
gastrointestinal, endocrine, neurologic, and other organ
systems.
If appropriate immunosuppressive treatment is used,
patients generally completely recover from immunemediated adverse events.
The use of immunosuppressive treatment to treat an
immune-mediated adverse event does not impair the
efcacy of immune-checkpoint blockade.
There does not appear to be a strong correlation between
the occurrence of an immune-mediated adverse event and
long-term outcomes to immune checkpoint-blocking
antibody therapy.
Patients who stop immunotherapy because of side effects
can still have excellent long-term outcomes.
DIARRHEA/COLITIS
Diarrhea is common in patients undergoing treatment with
checkpoint-blocking antibodies. However, there is a much
higher incidence of diarrhea in patients receiving CTLA-4
blocking antibodies compared to those targeting PD-1/PDL1. When considering the occurrence of this irAE, distinguishing diarrhea (increase in frequency of stool) from colitis
(abdominal pain, radiographic or endoscopic fndings of colonic inflammation) is important. For patients with melanoma undergoing CTLA-4 blockade with ipilimumab,
approximately 30% had diarrhea of any grade and less than
10% had severe (grade 3/4) diarrhea.1 Rates of grade 3/4 colitis have been found to affect only approximately 5% of
treated patients.1,14 Patients should be informed that diarrhea/colitis does not typically begin with initiation of checkpoint blockade; instead, it usually begins approximately 6
weeks into treatment (Fig. 1).15
Diarrhea/colitis with CTLA-4 blockade is more common
than with PD-1/PD-L1 blockade. The rate of grade 3/4 diarrhea in patients treated with PD-1/PD-L1 agents is very low
(1% to 2%).8,13,16 Although the precise safety profle is still
under evaluation, patients who had signifcant diarrhea/colitis during CTLA-4 blockade have been treated with PD-1
therapy without diarrhea/colitis recurrence.17 Nonetheless,
ongoing trials and clinical experience are necessary to more
fully understand the safety of PD-1/PD-L1 blockade in this
setting.
When a patient presents with mild diarrhea, clinicians
should consider other etiologies that may be responsible,
such as Clostridium diffcile infection or other bacterial/viral
pathogens. Patients should be counseled on the importance
of maintaining oral hydration. Some clinicians fnd that
the American Dietary Associations colitis diet and antimotility agents (oral diphenoxylate HCl and atropine
sulfate 4 times a day) can be helpful. If symptoms persist
for more than 3 days, or increase, and/or no infectious
causes are readily identifed, the use of oral or intravenous
corticosteroids are required.
In severe cases or situations in which symptoms do not improve with oral corticosteroids, hospitalization for intravenous corticosteroids, hydration, and electrolyte management
is required. A colonoscopy is not necessarily indicated unless
the diagnosis is unclear. If intravenous corticosteroids (up to
2 mg/kg methylprednisolone twice a day) do not lead to
symptom resolution, infliximab (Remicade; Janssen Biotech,
Horsham, PA) at a dose of 5 mg/kg, once every 2 weeks can be
helpful.18-20 The use of infliximab in this setting is based on its
use in patients with inflammatory bowel diseases.21 In very
rare cases, colitis can result in bowel perforation that can potentially require colostomy.
Unfortunately, there are no proven treatments to prevent
the occurrence of diarrhea. In one study, prophylactic use of
the matrix-release corticosteroid budesonide was not found
to be helpful.22 Nevertheless, some clinicians fnd budesonide to be helpful in early treatment for mild noninfectious
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
77
MICHAEL A. POSTOW
HEPATOTOXICITY
Hepatitis, as determined by elevations in aspartate aminotransferase (AST), aminotransferase (ALT) and less commonly, total bilirubin, occasionally is seen in patients treated
with checkpoint blockade. Although most episodes present
only as asymptomatic laboratory abnormalities, some patients have an associated fever. Rates of AST and ALT elevations with CTLA-4 blockade vary among clinical trials, but
they typically have been reported in less than 10% of patients.14,23,24 In large trials of PD-1 blocking antibodies, the
rates of hepatitis were similarly low (below 5%) and grade 3/4
toxicity was even rarer.3,13,16
Among patients who develop hepatitis, the most common
onset is 8 to 12 weeks after initiation of treatment, although
early or delayed events also may be seen (Fig. 1).10 Radiographic fndings are not typical. In severe cases, however,
fndings on CT scans may include mild hepatomegaly, periportal edema, or periportal lymphadenopathy.25 Liver biopsies have described pathologic changes that include severe
panlobular hepatitis with prominent perivenular infltrate
with endothelialitis or a primary biliary pattern with mild
portal mononuclear infltrate around bile ductules.25,26
Hepatic function (transaminases and bilirubin) should be
monitored before each dose of ipilimumab. If AST and ALT
increase, viral and other drug-induced causes of hepatitis
should be excluded. As with treating other irAEs, if no other
cause is obvious, prompt treatment with corticosteroids is
necessary. In rare cases, elevations in AST and ALT are
steroid-refractory and 500 mg every 12 hours of mycophenolate mofetil (CellCept; Genentech, South San Francisco, CA)
may be helpful. The use of antithymocyte globulin therapy
also was described in a case report.27 Unlike for patients with
diarrhea/colitis, infliximab should not be given to patients
with hepatitis because infliximab carries a risk of hepatotoxicity. Hepatitis may persist for quite some time and require
prolonged or repeated corticosteroid tapers (minimum of 3
weeks suggested) and/or additional immunosuppression.
ENDOCRINOPATHY
Immune-related adverse events that affect the pituitary, adrenal, and thyroid glands often present with nonspecifc
symptoms such as nausea, headache, and fatigue. The incidence of endocrinopathy has been diffcult to precisely determine because of the variable methods of assessment,
diagnosis, and monitoring in each clinical trial. Nonetheless,
hypophysitis (pituitary inflammation) and hypothyroidism
are the most common endocrinopathies and are typically believed to occur in up to 10% of patients treated with CTLA-4
blockade.28,29
When hypophysitis is suspected, all or some of the hormones released by the pituitary may be reduced (adrenocor78
Eye
Inflammation of components of the eye has been described
with CTLA-4 blockade. These include episcleritis, conjunctivitis, and uveitis. Typically, the incidence is believed to be
less than1%, and symptoms can include photophobia, pain,
dryness of the eyes, and blurry vision.39 Consultation with an
ophthalmologist is recommended, and treatment with topical intraocular corticosteroids such as 1% prednisolone acetate suspension may be helpful. Oral corticosteroids can be
used for more severe (grade 3/4 or refractory) cases. The incidence of ophthalmologic toxicity in patients treated with
PD-1/PD-L1 blockade is less-well described, but it is likely an
infrequent side effect.
Kidney
Several case reports have described patients treated with ipilimumab who have developed renal insuffciency believed to
be related to treatment. Histopathologic analyses of kidney
biopsies have described several different pathologic processes, including acute granulomatous interstitial nephritis40
and lupus membranous nephropathy.41 Treatment with oral
or intravenous corticosteroids in these cases has been associated with improvement in renal function.42,43 Renal insuffciency with PD-1 agents and the combination of CTLA-4 and
PD-1 blockade similarly has been reported in several patients
with anecdotal fndings of interstitial nephritis and response
to corticosteroids.16,44
Pancreas
The routine monitoring of amylase and lipase values in otherwise asymptomatic patients treated with checkpoint blockade is not recommended. Similarly, corticosteroids are not
indicated in patients with asymptomatic elevations in amylase/lipase without other symptoms of pancreatitis. Nevertheless, when pancreatitis is suspected clinically, amylase and
lipase should be checked since immune-related pancreatitis
has been reported in patients treated with CTLA-4 and PD-1
blockade.38,45 The high rate of asymptomatic elevations in
Neurologic Syndromes
Neurologic syndromes have been associated with checkpoint
blockade with ipilimumab. These include posterior reversible encephalopathy syndrome,47 aseptic meningitis,48 enteric neuropathy,49 and transverse myelitis.50 Cases of
Guillain-Barre syndrome are particularly notable51 because
one case resulted in a treatment-related death in a postsurgical adjuvant study of ipilimumab.52 As with other irAEs,
corticosteroids can be helpful. In consultation with a neurologist, plasmapheresis and intravenous immunoglobulin may
be considered.
Hematologic Syndromes
Red cell aplasia,53 neutropenia,54 and acquired hemophilia
A55 also have been described in patients treated with ipilimumab, as has thrombocytopenia.56 Similar to many of the
irAEs described above, the standard approach remains initial
immunosuppression with corticosteroids. A bone marrow
biopsy may be necessary in some cases, particularly when the
diagnosis remains unclear.
79
MICHAEL A. POSTOW
OPPORTUNISTIC INFECTIONS IN
IMMUNOSUPPRESSED PATIENTS
Since prolonged immune suppression is occasionally used to
treat irAEs, patients can be at risk for unusual or opportunistic infections. Though anecdotal cases of these infections,
such as Aspergillus pneumonia, have been reported,75 the
true incidence of these opportunistic infections remains unknown. Pneumocystis jiroveci prophylaxis with cotrimoxazole, atovaquone, or pentamidine should be considered in
patients treated with 20 mg of prednisone equivalent daily for
at least 4 weeks, based on the National Comprehensive Cancer Network guidelines for the Prevention and Treatment of
Cancer-Related Infections (Category 2B recommendation).
The role of prophylactic antiviral or antifungal therapy in this
setting is unclear.
CONCLUSION
Immunologic-checkpoint inhibition targeting CTLA-4 and
PD-1/PD-L1 has dramatically improved the care of patients
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Michael
A. Postow, Bioconnections LLC, FirstWord, Millennium Takeda. Speakers Bureau: None. Research Funding: Michael A. Postow, Bristol-Myers Squibb (Inst).
Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: Michael A. Postow, BristolMyers Squibb. Other Relationships: None.
References
1. Hodi FS, ODay SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:
711-723.
2. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine
for previously untreated metastatic melanoma. N Engl J Med. 2011;364:
2517-2526.
3. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated
melanoma without BRAF mutation. N Engl J Med. 2015;372:320-330.
Epub 2014 Nov 16.
4. Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-deathreceptor-1 treatment with pembrolizumab in ipilimumab-refractory
advanced melanoma: a randomised dose-comparison cohort of a phase
1 trial. Lancet. 2014.
5. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune
correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:
2443-2454.
6. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkins lymphoma. N Engl J Med.
2015;372:311-319. Epub 2014 Dec 6.
7. Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol.
Epub 2014 Dec 1.
8. Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response
to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature.
2014;515:563-567.
9. Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment
leads to clinical activity in metastatic bladder cancer. Nature. 2014;515:
558-562.
10. Weber JS, Kahler KC, Hauschild A. Management of immune-related
adverse events and kinetics of response with ipilimumab. J Clin Oncol.
2012;30:2691-2697.
11. Lacouture ME, Wolchok JD, Yosipovitch G, et al. Ipilimumab in patients with cancer and the management of dermatologic adverse events.
J Am Acad Dermatol. 2014;71:161-169.
12. Pintova S, Sidhu H, Friedlander PA, et al. Sweets syndrome in a patient
with metastatic melanoma after ipilimumab therapy. Melanoma Res.
2013;23:498-501.
13. Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving
nivolumab. J Clin Oncol. 2014;32:1020-1030. Epub 2014 Mar 3.
14. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in
patients with pretreated advanced melanoma: a randomised, doubleblind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11:
155-164. Epub 2009 Dec 8.
15. Weber JS, Dummer R, de Pril V, et al. Investigators MDX. Patterns of onset
and resolution of immune-related adverse events of special interest with
ipilimumab: detailed safety analysis from a phase 3 trial in patients with
advanced melanoma. Cancer. 2013;119:1675-1682. Epub 2013 Feb 7.
16. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with
lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369:134144. Epub 2013 Jun 2.
17. Weber JS, Kudchadkar RR, Yu B, et al. Safety, effcacy, and biomarkers
of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013;31:4311-4318.
18. Page`s C, Gornet JM, Monsel G, et al. Ipilimumab-induced acute severe
colitis treated by infliximab. Melanoma Res. 2013;23:227-230.
19. Minor DR, Chin K, Kashani-Sabet M. Infliximab in the treatment of
anti-CTLA4 antibody (ipilimumab) induced immune-related colitis.
Cancer Biother Radiopharm. 2009;24:321-325.
20. Merrill SP, Reynolds P, Kalra A, et al. Early administration of infliximab
for severe ipilimumab-related diarrhea in a critically ill patient. Ann
Pharmacother. 2014;48:806-810.
21. Stidham RW, Lee TC, Higgins PD, et al. Systematic review with network
meta-analysis: the effcacy of anti-TNF agents for the treatment of
Crohns disease. Aliment Pharmacol Ther. 2014;39:1349-1362.
22. Weber J, Thompson JA, Hamid O, et al. A randomized, double-blind,
placebo-controlled, phase II study comparing the tolerability and effcacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin
Cancer Res. 2009;15:5591-5598.
23. Ribas A, Kefford R, Marshall MA, et al. Phase III randomized clinical
trial comparing tremelimumab with standard-of-care chemotherapy in
patients with advanced melanoma. J Clin Oncol. 2013;31:616-622.
24. Bernardo SG, Moskalenko M, Pan M, et al. Elevated rates of transami-
81
MICHAEL A. POSTOW
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
82
44. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab
in advanced melanoma. N Engl J Med. 2013;369:122-133.
45. Di Giacomo AM, Danielli R, Guidoboni M, et al. Therapeutic effcacy of
ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with
metastatic melanoma unresponsive to prior systemic treatments: clinical and immunological evidence from three patient cases. Cancer Immunol Immunother. 2009;58:1297-1306.
46. Banks PA, Bollen TL, Dervenis C, et al. Acute Pancreatitis Classifcation
Working Group. Classifcation of acute pancreatitis-2012: revision of
the Atlanta classifcation and defnitions by international consensus.
Gut. 2013;62:102-111. Epub 2012 Oct 25.
47. Maur M, Tomasello C, Frassoldati A, et al. Posterior reversible encephalopathy syndrome during ipilimumab therapy for malignant melanoma. J Clin Oncol. 2012;30:e76-e78. Epub 2011 Dec 27.
48. Bot I, Blank CU, Boogerd W, et al. Neurological immune-related adverse events of ipilimumab. Pract Neurol. 2013;13:278-280. Epub 2013
Mar 13.
49. Bhatia S, Huber BR, Upton MP, et al. Inflammatory enteric neuropathy
with severe constipation after ipilimumab treatment for melanoma: a
case report. J Immunother. 2009;32:203-205.
50. Liao B, Shroff S, Kamiya-Matsuoka C, et al. Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma.
Neuro Oncol. 2014;16:589-593. Epub 2014 Jan 30.
51. Wilgenhof S, Neyns B. Anti-CTLA-4 antibody-induced Guillain-Barre
syndrome in a melanoma patient. Ann Oncol. 2011;22:991-993. Epub
2011 Feb 28.
52. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Ipilimumab vs. placebo after complete resection of stage III melanoma: initial effcacy and
safety results from the EORTC 18071 phase III trial. J Clin Oncol. 2014;
32:5s (suppl; abstr LBA9008).
53. Gordon IO, Wade T, Chin K, et al. Immune-mediated red cell aplasia
after anti-CTLA-4 immunotherapy for metastatic melanoma. Cancer
Immunol Immunother. 2009;58:1351-1353.
54. Akhtari M, Waller EK, Jaye DL, et al. Neutropenia in a patient treated
with ipilimumab (anti-CTLA-4 antibody). J Immunother. 2009;32:322324.
55. Delyon J, Mateus C, Lambert T. Hemophilia A induced by ipilimumab.
N Engl J Med. 2011;365:1747-1748.
56. Kopecky J, Trojanova P, Kubecek O, et al. Treatment possibilities of
ipilimumab-induced thrombocytopenia-case study and literature review. Jpn J Clin Oncol. Epub 2015 Jan 12.
57. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med.
2011;364:2507-2516.
58. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated
metastatic melanoma: a multicentre, open-label, phase 3 randomised
controlled trial. Lancet. 2012;380:358-365.
59. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK
inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107114.
60. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in
melanoma with combined dabrafenib and trametinib. N Engl J Med.
2015;372:30-39.
61. Larkin J, Ascierto PA, Dreno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371:18671876.
62. Johnson DB, Flaherty KT, Weber JS, et al. Combined BRAF (dabrafenib) and MEK inhibition (trametinib) in patients with BRAFV600mutant melanoma experiencing progression with single-agent BRAF
inhibitor. J Clin Oncol. 2014;32:3697-3704.
63. Callahan MK, Masters G, Pratilas CA, et al. Paradoxical activation of T
64.
65.
66.
67.
68.
69.
70.
71.
72.
73. Hodi FS, Lee S, McDermott DF, et al. Ipilimumab plus sargramostim vs.
ipilimumab alone for treatment of metastatic melanoma: a randomized
clinical trial. JAMA. 2014;312:1744-1753.
74. Goldstein JI, Kominsky DJ, Jacobson N, et al. Defective leukocyte GMCSF receptor (CD116) expression and function in inflammatory bowel
disease. Gastroenterology. 2011;141:208-216.
75. Kyi C, Hellmann MD, Wolchok JD, et al. Opportunistic infections in
patients treated with immunotherapy for cancer. J Immunother Cancer.
2014;2:19.
76. Attia P, Phan GQ, Maker AV, et al. Autoimmunity correlates with
tumor regression in patients with metastatic melanoma treated with
anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol. 2005;23:60436053.
77. Downey SG, Klapper JA, Smith FO, et al. Prognostic factors related to
clinical response in patients with metastatic melanoma treated by CTLassociated antigen-4 blockade. Clin Cancer Res. 2007;13:6681-6688.
Epub 2007 Nov 2.
78. Wang HB, Shi FD, Li H, et al. Anti-CTLA-4 antibody treatment triggers
determinant spreading and enhances murine myasthenia gravis. J Immunol. 2001;166:6430-6436.
79. Luhder F, Hoglund P, Allison JP, et al. Cytotoxic T lymphocyteassociated antigen 4 (CTLA-4) regulates the unfolding of autoimmune
diabetes. J Exp Med. 1998;187:427-432.
80. Kyi C, Carvajal RD, Wolchok JD, et al. Ipilimumab in patients with
melanoma and autoimmune disease. J Immunother Cancer. 2014;
2:35.
81. Pedersen M, Andersen R, Nrgaard P, et al. Successful treatment with
ipilimumab and interleukin-2 in two patients with metastatic melanoma and systemic autoimmune disease. Cancer Immunol Immunother. 2014;63:1341-1346.
82. Gettings EJ, Hackett CT, Scott TF. Severe relapse in a multiple sclerosis
patient associated with ipilimumab treatment of melanoma. Mult Scler.
Epub 2014 Sep 25.
83
SPEAKERS
Zhen Zhang, MD, PhD
Fudan University, Shanghai Cancer Center
Shanghai, China
Deborah Schrag, MD, MPH
Dana-Farber Cancer Institute
Boston, MA
From the Memorial Sloan Kettering Cancer Center, New York, NY; Shanghai Cancer Center, Fudan University, Shanghai, China; Dana-Farber Cancer Institute, Boston, MA.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Martin R. Weiser, MD, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: weiser1@mskcc.org.
2015 by American Society of Clinical Oncology.
e192
KEY POINTS
Combined modality therapyincluding chemotherapy,
radiation, and surgeryis the standard for locally advanced
rectal cancer.
Pelvic radiation reduces local recurrence but does not
reduce distant relapse or improve overall survival.
A noteworthy portion of patients are unable to complete
the prescribed treatment for rectal cancer.
Total neoadjuvant therapy attempts to deliver all therapy
prior to surgery.
PROSPECT is an international randomized trial attempting
to individualize rectal cancer treatment.
e193
The fnal analysis of the Intergroup 0114 trial reported similar fndings24; however, these are based on limited data and
the conclusions are diffcult to substantiate because all patients received radiation therapy. A second pooled analysis
attempted to dissect the effect of treatment on outcome.25
Data from fve phase III North American rectal cancer trials
conducted over a 13-year period (NSABP R01, NSABP R02,
NCCTG 794751, NCCTG 864751, and U.S. GI Intergroup
0114) were aggregated, and the subsequent analysis of 3,791
patients compared outcomes according to TN stage and
various treatment regimens: surgery alone (179 patients),
surgery and radiation (281 patients), surgery and chemoradiotherapy (2,799 patients), or surgery and chemotherapy
(532 patients). In the setting of intermediate-risk tumors
(T1/2N1 and T3N0), no additional beneft in disease-free
survival or overall survival was observed when adding radiation to chemotherapy after surgery. These analyses demonstrate heterogeneity in the risk of local recurrence, and
provide a rationale for individualizing treatment.
A small pilot trial explored the use of initial therapy with
FOLFOX-based chemotherapy, without planned radiation
therapy, for locally advanced rectal cancer. The study cohort
included 30% stage II and 70% stage III mid- to low rectal
cancers. Of the 30 patients receiving chemotherapy alone, all
had complete R0 resection and eight (27%) achieved a pathologic complete response with no viable tumor detected in the
resection specimen.26 All three patients who suffered recurrence
had pulmonary metastasis, but no locally recurrent disease was
observed. Nevertheless, delivery of preoperative chemotherapy
without the routine use of radiation remains an experimental
approach. It is currently being evaluated in the National Cancer
Institute Cooperative Group PROSPECT trial, and at the present time should not be routinely used outside of a clinical trial.
PROSPECT (Fig. 1) is a large-scale, multi-institutional
phase II/III randomized prospective trial comparing neoadjuvant FOLFOX with selective use of chemoradiation
(NCCTG-N1048, NCT01515787). The study randomly and
This ongoing phase II/III trial investigates whether standard combined modality treatment (CMT: 5-FU or capecitabine-based chemoradiation) can be replaced with selective use of neoadjuvant
FOLFOX.
e194
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Deborah
Schrag, New Century Health, The Ohio State University. Speakers Bureau: None. Research Funding: Zhen Zhang, Varian Medical Systems. Patents,
Royalties, or Other Intellectual Property: Zhen Zhang, PBG passive breath control device. Expert Testimony: None. Travel, Accommodations,
Expenses: None. Other Relationships: Deborah Schrag, Journal of the American Medical Association.
References
1. NIH consensus conference. Adjuvant therapy for patients with colon
and rectal cancer. JAMA. 1990;264:1444-1450.
2. Prolongation of the disease-free interval in surgically treated rectal carcinoma. Gastrointestinal Tumor Study Group. N Engl J Med. 1985;312:
1465-1472.
3. Fisher B, Wolmark N, Rockette H, et al. Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. J Natl Cancer Inst. 1988;80:21-29.
4. Tepper JE, OConnell MJ, Petroni GR, et al. Adjuvant postoperative
fluorouracil-modulated chemotherapy combined with pelvic radiation
therapy for rectal cancer: initial results of intergroup 0114. J Clin Oncol.
1997;15:2030-2039.
5. Krook JE, OConnell MJ, Wieand HS, et al. A prospective, randomized
evaluation of intensive-course 5-fluorouracil plus doxorubicin as surgical adjuvant chemotherapy for resected gastric cancer. Cancer. 1991;67:
2454-2458.
6. Wolmark N, Rockette H, Fisher B, et al. The beneft of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary
colon cancer: results from National Surgical Adjuvant Breast and Bowel
Project protocol C-03. J Clin Oncol. 1993;11:1879-1887.
7. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351:
1731-1740.
8. Bokey EL, Ojerskog B, Chapuis PH, et al. Local recurrence after curative
excision of the rectum for cancer without adjuvant therapy: role of total
anatomical dissection. Br J Surg. 1999;86:1164-1170.
9. Heald RJ, Moran BJ, Ryall RD, et al. Rectal cancer: the Basingstoke experience of total mesorectal excision, 1978-1997. Arch Surg. 1998;133:
894-899.
10. Merchant NB, Guillem JG, Paty PB, et al. T3N0 rectal cancer: results
following sharp mesorectal excision and no adjuvant therapy. J Gastrointest Surg. 1999;3:642-647.
11. Nagtegaal ID, van de Velde CJ, van der Worp E, et al. Macroscopic
evaluation of rectal cancer resection specimen: clinical signifcance
of the pathologist in quality control. J Clin Oncol. 2002;20:17291734.
12. Peeters KC, Marijnen CA, Nagtegaal ID, et al. The TME trial after a
median follow-up of 6 years: increased local control but no survival beneft in irradiated patients with resectable rectal carcinoma. Ann Surg.
2007;246:693-701.
13. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer.
N Engl J Med. 2001;345:638-646.
14. Roh MS, Yothers GA, OConnell MJ, et al. The impact of capecitabine
and oxaliplatin in the preoperative multimodality treatment in patients
with carcinoma of the rectum: NSABP R-04. J Clin Oncol. 2011;29
(suppl; abstr 3503).
15. Aschele C Pinto C, Cordio S, et al. Preoperative fluorouracil (FU)-based
chemoradiation with and without weekly oxaliplatin in locally advanced
rectal cancer: pathologic response analysis of the Studio Terapia Adiuvante Retto (STAR)-01 randomized phase III trial. J Clin Oncol. 2009;
27:18s (suppl; abstr CRA4008).
e195
e196
22.
23.
24.
25.
26.
combined with continuous 5-FU infusion for locally advanced gastrointestinal malignancies. Eur J Surg Oncol. 2004;30:650-657.
Temple LK, Wong WD, Minsky B. The impact of radiation on functional outcomes in patients with rectal cancer and sphincter preservation. Semin Radiat Oncol. 2003;13:469-477.
Gunderson LL, Sargent DJ, Tepper JE, et al. Impact of T and N substage
on survival and disease relapse in adjuvant rectal cancer: a pooled analysis. Int J Radiat Oncol Biol Phys. 2002;54:386-396.
Tepper JE, OConnell M, Niedzwiecki D, et al. Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control-fnal report of intergroup 0114. J Clin Oncol. 2002;20:1744-1750.
Gunderson LL, Sargent DJ, Tepper JE, et al. Impact of T and N stage and
treatment on survival and relapse in adjuvant rectal cancer: a pooled
analysis. J Clin Oncol. 2004;22:1785-1796.
Schrag D, Weiser MR, Goodman KA, et al. Neoadjuvant chemotherapy
without routine use of radiation therapy for patients with locally advanced rectal cancer: a pilot trial. J Clin Oncol. 2014;32:513-518.
SPEAKERS
Marwan Fakih, MD
City of Hope Comprehensive Cancer Center
Duarte, CA
Cornelis J.A. Punt, MD, PhD
University of Amsterdam
Amsterdam, Netherlands
e197
MARWAN FAKIH
KEY POINTS
There is no role for biologic therapy in the adjuvant
treatment of colorectal cancer.
In the setting of resectable metastatic disease to the liver,
there is no evidence to suggest a benet from adding either
antiangiogenic or anti-epidermal growth factor receptor
(EGFR) therapy. The addition of anti-EGFR therapy to
chemotherapy in the neoadjuvant treatment of KRAS-wild type
(WT) resectable liver metastases has been associated with a
detrimental effect on disease-free survival.
In patients with unresectable but potentially resectable
disease, consideration for neoadjuvant FOLFOXIRI/bevacizumab
(good performance status) or combination chemotherapy plus
anti-EGFR agents (RAS-WT) should be made to increase the
chances of curative-intent surgery.
In RAS-mutant type or BRAF-MT metastatic colorectal cancer
(mCRC), the continuum of angiogenesis targeting during the
rst two lines of treatment is recommended.
Bevacizumab or anti-EGFR therapy in the rst-line therapy
of RAS-WT and BRAF-WT mCRC is acceptable with no clear
evidence of superiority of one approach compared with
another.
e198
e199
MARWAN FAKIH
PFS/OS
Study Design
Treatment Arm
FOLFOXIRI/BV
Ye et al24 2013
FOLFOX
FOLFOX/Cmab
Abbreviations: RR, response rate; PFS, median progression-free survival; OS, median overall survival; HR, hazard ratio; BV, bevacizumab; Cmab, cetuximab; WT, wild type.
studies have consistently confrmed an advantage to the addition of bevacizumab to several fluoropyrimidine-based
backbones, albeit with a PFS primary endpoint.35-37 The advantage of the incorporation of bevacizumab in frst-line
treatment of mCRC has been particularly notable in the setting of fluoropyrimidine monotherapy.37 The addition of bevacizumab to FOLFOX or XELOX has resulted in a clinically
modest improvement in PFS and insignifcant improvement
in OS.35 Given the favorable toxicity profle of bevacizumab
and its reproducible positive effect on PFS, it is recommended that this agent is considered in the frst-line treatment of patients with RAS-MT or BRAF-MT cancer (and as
an option for RAS-WT as discussed below). Since anti-EGFR
therapy is not an option in this setting, this is considered the
only viable option for targeted therapy in this population.
The reader is directed to our recent review on targeted therapy for further details on this topic.
There is no convincing evidence that patients with
BRAF-MT mCRC derive a clinically signifcant beneft from
anti-EGFR therapy.35,38 Signifcant progress is being made
through the concurrent targeting of EGFR and BRAF (with
or without MEK) in this population.39,40 However, such strategies are still considered investigational. Therefore, consideration of front-line addition of bevacizumab should be
made in this subgroup of patients. However, the outlook of
these patients continues to be dismal. Recent subgroup analysis from the TRIBE clinical trial has suggested a beneft from
FOLFOXIRI/bevacizumab in comparison with FOLFIRI in
patients with BRAF-MT disease.1 Given the aggressive biology of BRAF-MT cancers, consideration for up-front
FOLFOXIRI/bevacizumab should be considered in the
younger ft individuals.
FOLFOX control arm (Table 2). However, in clinical practice, most patients who proceed to second-line treatment
have had prior bevacizumab exposure. Three randomized
phase III clinical trials have now reported on angiogenesis
targeting post-bevacizumab progression.41-43 The results of
these studies are summarized in Table 2. Both the ML18147
and RAISE clinical trials mandated prior progression on a
bevacizumab-based therapy and resulted in signifcant improvements in PFS and OS in favor of bevacizumab and ramucirumab.44 The VELOUR clinical trial included both
patients with bevacizumab-naive and bevacizumab pretreated disease and resulted in signifcant improvement in
PFS and OS in the overall population. None of the three trials
showed an improvement in response rate in the patients who
were bevacizumab-pretreated. The three agents investigated
are different biologically with bevacizumab being directed
toward VEGF-A, aflibercept toward VEGF-A, VEGF-B and
PlGF, and ramucirumab toward VEGFR-2. Although no
head-to-head comparison among these agents have been
performed to date, bevacizumab has been associated with the
most favorable safety profle, whereas, concerns have been
raised regarding the increased toxicity of aflibercept when
combined with chemotherapy.43 All three antiangiogenic
agents are considered acceptable options for second-line
treatment, with a preference toward bevacizumab given its
more established safety profle. Although bevacizumab can
be considered across different backbones in the second-line
treatment, aflibercept and ramucirumab should only be considered with FOLFIRI. No clinical or biologic biomarkers
have been identifed to direct treatment toward any of these
three biologicals in the setting of second-line FOLFIRI.
Control Arm
Experimental
Arm
Efcacy Objectives
Giantonio et al41
ECOG 3200
study
FOLFOX4
FOLFOX4/BV
Primary: OS
Secondary: PFS, RR
Bennouna et al44
ML18147 Study
Chemotherapy
Chemotherapy/BV
Primary: OS
Secondary: PFS, RR
FOLFIRI
FOLFIRI/
ziv-aibercept
Primary: OS
Secondary: PFS, RR
Tabernero et al42
RAISE Study
FOLFIRI
FOLFIRI/RAM
Primary: OS
Secondary: PFS, RR
Abbreviations: OS, overall survival; RR, response rate; PFS, progression-free survival; HR, hazard ratio; BV, bevacizumab; RAM, ramucirumab.
e201
MARWAN FAKIH
Control Arm
Experimental
Arm(s)
Efcacy
Objectives
Tveit et al48
NORDIC VII
Study
FLOX/Cmab (Arm B)
Primary:
KRAS-WT population: PFS: 7.9
PFS
(Arm B) vs. 8.6 months
Secondary:
(Arm A) (HR 1.06, p 0.66)
RR, OS
FOLFOX4/Pmab
Primary:
KRAS exon 2 WT: PFS: 9.6
KRAS exon 2 WT: OS: 23.8
PFS
(FOLFOX4/Pmab) vs.
(FOLFOX4/Pmab) vs.
Secondary:
8 months (FOLFOX4) (HR 0.8,
19.4 months (FOLFOX4)
RR, OS
p 0.02)
(HR 0.83, p 0.03)
RAS-WT: PFS: 10.8 (FOLFOX4/
RAS-WT: OS: 25.8
Pmab) vs. 9.2 months
(FOLFOX4/Pmab) vs.
(FOLFOX4) (HR 0.72,
20.2 months (FOLFOX4)
p 0.004)
(HR 0.77, p 0.009)
Van Cutsem
et al46,47
CRYSTAL
Study
FOLFIRI/cetuximab
Abbreviations: mCRC, metastatic colorectal cancer; OS, overall survival; Cmab, cetuximab; Pmab, panitumumab; RR, response rate; PFS, progression-free survival; HR, hazard ratio; EGFR,
epidermal growth factor receptor; OR, odds ratio; WT, wild type.
TABLE 4. Anti-EGFR Versus Bevacizumab Plus Chemotherapy Studies in the First-Line Treatment of Metastatic
Colorectal Cancer
Control
Arm
Experimental
Arm(s)
Efcacy
Objectives
Randomized phase II
clinical trial in
KRAS-WT (exon 2)
285 patients
FOLFOX/BV
FOLFOX/Pmab
Primary:
PFS
Secondary:
OS, RR
KRAS-WT
PFS: 10.9 (Pmab) vs.
10.1 months (BV)
(HR 0.87, p
0.353)
KRAS-WT
RR: 57.8% (Pmab) vs.
53.5% (BV)
OS: 34.2 (Pmab) vs. 24.3
months (BV) (HR
0.62, p 0.009)
FOLFIRI/BV
FOLFIRI/Cmab
Primary:
RR
Author/Study
Study Design
Schwartzberg et al31
PEAK Study
Heinemann et al49
Stintzing et al50
FIRE-3 Study
Secondary:
PFS, OS
RAS-WT
PFS: 13 m (Pmab) vs.
9.5 months (BV)
(HR 0.65, p
0.029)
(OR 2, p 0.003)
Venook et al2
Lenz et al27
CALGB 80405
(FOLFOX or (FOLFOX or
FOLFRI)/BV FOLFIRI)/
Cmab
Primary:
OS
Secondary:
PFS
RAS-WT
RR: 63.6% (Pmab) vs.
60.5% (BV)
OS: 41.3 (Pmab) vs. 28.9
months (BV) (HR
0.63, p 0.058)
Abbreviations: EGFR, epidermal growth factor receptor; Pmab, panitumumab; Cmab, cetuximab; BV, bevacizumab; PFS, progression-free survival; OS, overall survival; RR, response rate; HR, hazard
ratio; OR, odds ratio; WT, wild type.
evaluated cetuximab and panitumumab in the setting of singleagent irinotecan.38,51 The EPIC trial did not select patients
based on RAS status but reported improvements in response rate and PFS.51 The PICCOLO study excluded patients with KRAS codon 12, 13, and 61 mutations and
showed an improvement in response rate and PFS, but no
beneft in OS.38 The 20050181 study randomized patients
to FOLFIRI plus panitumumab compared with FOLFIRI
in patients with KRAS (exon-2) WT disease.52 A signifcant improvement in response rate and PFS was noted on
the panitumumab arm. A recent update on this study
showed further accentuation of beneft in favor of panitumumab in the RAS-WT population (Table 5).53
It is unclear at this time what the best strategy is for a biologic
therapy in the second-line setting of RAS-WT tumors after progression on frst-line bevacizumab-based combinations. The
TABLE 5. EGFR Targeting in the Second-Line Treatment in KRAS-WT Metastatic Colorectal Cancer
Peeters et al52
20050181 Study
Study Design
Control Arm
Experimental
Arm(s)
Efcacy
Objectives
Primary Efcacy
Endpoint
Second-line randomized
phase III clinical
trial
KRAS exon 2 WT: 597
patients
FOLFIRI
FOLFIRI Pmab
Primary:
PFS: 5.9 m (FOLFIRI
PFS
Pmab) versus
Secondary:
3.9 m (FOLFIRI)
OS
(HR 0.73,
p 0.004)
Abbreviations: EGFR, epidermal growth factor receptor; OS, overall survival; RR, response rate; PFS, progression-free survival; HR, hazard ratio; OR, odds ratio; WT, wild type.
e203
MARWAN FAKIH
Control
Arm
Experimental
Arm(s)
Efcacy Objectives
Karapetis et al
NCI-CO17 Study
BSC
Cmab
Primary: OS
Secondary: PFS, RR
Price et al55
ASPECCT Study
Cmab
Pmab
Primary: OS
Secondary: PFS, RR
Abbreviations: mCRC, metastatic colorectal cancer; OS, overall survival; RR, response rate; PFS, progression-free survival; HR, hazard ratio; EGFR, epidermal growth factor receptor; Cmab,
cetuximab; Pmab, panitumumab; OR, odds ratio; BSC, best supportive care; WT, wild type.
anti-EGFR therapy. It is possible that prolonged breaks after anti-EGFR progression allow for tumor reconstitution
with anti-EGFR sensitive clones resulting in further beneft
from anti-EGFR rechallenge. A small phase II clinical trial
supports this concept; however, more studies are needed to
confrm these fndings and to identify the patients who would
best beneft from this strategy.57
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Marwan Fakih, Amgen, Genentech, Sano, Sirtex
Medical. Consulting or Advisory Role: Marwan Fakih, Amgen, Sano, Sirtex Medical, Taiho Pharmaceutical. Speakers Bureau: Marwan Fakih, Amgen, Bayer,
Genentech, Sano, Sirtex Medical. Research Funding: Marwan Fakih, Amgen (Inst), Novartis (Inst). Patents, Royalties, or Other Intellectual Property:
None. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Loupakis F, Cremolini C, Masi G, et al. Initial therapy with FOLFOXIRI
and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014;
371:1609-1618.
2. Venook A, Niedzwiecki D, Lenz H-J, et al. CALGB/SWOG 80405: phase
III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/
leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET)
for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). J Clin Oncol. 2014;32:5s
(suppl; abst LBA4).
3. Allegra CJ, Yothers G, OConnell MJ, et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP
protocol C-08. J Clin Oncol. 2011;29:11-16.
4. Allegra CJ, Yothers G, OConnell MJ, et al. Bevacizumab in stage
II-III colon cancer: 5-year update of the National Surgical Adjuvant
Breast and Bowel Project C-08 trial. J Clin Oncol. 2013;31:
359-364.
5. Pogue-Geile K, Yothers G, Taniyama Y, et al. Defective mismatch repair
and beneft from bevacizumab for colon cancer: fndings from NSABP
C-08. J Natl Cancer Inst. 2013;105:989-992.
6. de Gramont A, Van Cutsem E, Schmoll HJ, et al. Bevacizumab plus
oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer
e204
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
tastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008;371:1007-1016.
Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a
randomised, controlled, phase 3 trial. Lancet Oncol. 2013;14:1208-1215.
Nasti G, Piccirillo MC, Izzo F, et al. Neoadjuvant FOLFIRIbevacizumab
in patients with resectable liver metastases from colorectal cancer: a
phase 2 trial. Br J Cancer. 2013;108:1566-1570.
Gruenberger B, Tamandl D, Schueller J, et al. Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer. J Clin Oncol. 2008;26:18301835.
Gruenberger T, Bridgewater J, Chau I, et al. Bevacizumab plus
mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver
metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial. Ann Oncol. Epub 2014 Dec 23.
Ribero D, Wang H, Donadon M, et al. Bevacizumab improves pathologic response and protects against hepatic injury in patients treated
with oxaliplatin-based chemotherapy for colorectal liver metastases.
Cancer. 2007;110:2761-2767.
Gruenberger T, Arnold D, Rubbia-Brandt L. Pathologic response to
bevacizumab-containing chemotherapy in patients with colorectal liver
metastases and its correlation with survival. Surg Oncol. 2012;21:309315.
Klinger M, Eipeldauer S, Hacker S, et al. Bevacizumab protects against
sinusoidal obstruction syndrome and does not increase response rate in
neoadjuvant XELOX/FOLFOX therapy of colorectal cancer liver metastases. Eur J Surg Oncol. 2009;35:515-520.
Turan N, Benekli M, Koca D, et al. Adjuvant systemic chemotherapy
with or without bevacizumab in patients with resected liver metastases
from colorectal cancer. Oncology. 2013;84:14-21.
Primrose J, Falk S, Finch-Jones M, et al. Systemic chemotherapy with or
without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial. Lancet Oncol. 2014;15:
601-611.
Nordlinger B, Poston GJ, Goldberg RM. Should the Results of the New
EPOC Trial Change Practice in the Management of Patients With Resectable Metastatic Colorectal Cancer Confned to the Liver? J Clin Oncol. 2015;33:241-243.
Adam R, Avisar E, Ariche A, et al. Five-year survival following hepatic
resection after neoadjuvant therapy for nonresectable colorectal. Ann
Surg Oncol. 2001;8:347-353.
Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict
long-term survival. Ann Surg. 2004;240:644-657; discussion 657-658.
Ye LC, Liu TS, Ren L, et al. Randomized controlled trial of cetuximab
plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013;31:1931-1938.
Garuf C, Torsello A, Tumolo S, et al. Cetuximab plus chronomodulated
irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant
chemotherapy in colorectal liver metastases: POCHER trial. Br J Cancer.
2010;103:1542-1547.
Folprecht G, Gruenberger T, Bechstein WO, et al. Tumour response and
secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2
trial. Lancet Oncol. 2010;11:38-47.
Venook A, Niedzwiecki D, Lenz H, et al. CALGB/SWOG 80405: analysis of patients undergoing surgery as part of treatment strategy. Ann
Oncol. 2014;25:1-41 LBA10.
Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treat-
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
e205
MARWAN FAKIH
43.
44.
45.
46.
47.
48.
49.
e206
50.
51.
52.
53.
54.
55.
56.
57.
CHEMOTHERAPY
Effective cytotoxic drugs in mCRC include the fluoropyrimidines, irinotecan, and oxaliplatin. These drugs are the backbone of systemic treatment of mCRC. There is no outright
preference for either oxaliplatin or irinotecan in frst-line
combination schedules.2 Retrospective studies have shown
that the exposure to these three cytotoxics during the course
of disease appears more important than their up-front combined use.3-5 This has been confrmed by the results of subsequent prospective studies, of which the results showed no
beneft for up-front combination treatment over sequential
treatment starting with fluoropyrimidine monotherapy.6,7
The choice between combination or sequential therapy may
depend on several factors, such as tumor-related symptoms,
potential resectability of metastases, and performance sta-
From the Department of Medical Oncology, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands; Department of Medical Oncology, University Medical Centre Utrecht,
Utrecht, Netherlands.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Cornelis J.A. Punt, MD, PhD, Department of Medical Oncology, Room F4-224, Academic Medical Center, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam,
Netherlands; email: c.punt@amc.uva.nl.
2015 by American Society of Clinical Oncology.
85
KEY POINTS
Maintenance treatment with capecitabine plus bevacizumab
is effective.
Current data do not support the use of bevacizumab
monotherapy.
The optimal treatment duration of anti-EGFR therapy is unknown.
For chemotherapy, current data do not allow a rm
conclusion on the safety of a full treatment break.
Oxaliplatin can be safely discontinued and re-introduced at
progression of disease.
86
stable disease or better after eight cycles of irinotecan in second line were randomly assigned to continuation or discontinuation of irinotecan until disease progression.13 Only 17%
of the patients who received second-line irinotecan were eligible for randomization, leaving 55 evaluable patients. There
was no difference in median progression-free survival or
overall survival between the two treatment arms. Furthermore, QoL was comparable in both arms. Although these results suggest that irinotecan can be safely discontinued after
eight cycles, this study was underpowered. In the GISCAD
study,14 a total of 337 patients were randomly selected to receive
intermittent treatment with FOLFIRI given in a 2-months-on
2-months-off schedule or continuous treatment with FOLFIRI
both until disease progression. The intermittent schedule was
not inferior to continuous treatment for the primary endpoint
of overall survival nor for progression-free survival or response
rate. Furthermore, toxicity profles were comparable, which is
not surprising, as the toxicities of irinotecan are usually not cumulative. QoL was not evaluated in this study. The authors concluded that the intermittent use of FOLFIRI does not decrease
its effcacy compared to its continued use.
These data show that QoL has been investigated in only a few
studies that address the beneft of intermittent compared with
continuous treatment. Although palliative chemotherapy by
defnition should primarily strive for the relief or the delay of
symptoms, it has been shown that patients main incentive to
accept palliative chemotherapy in advanced CRC trials is prolongation of life rather than improvement of QoL.15,16 With the
observed small or absent differences between the treatment
strategies in the aforementioned trials, data on QoL would
therefore be helpful to discuss these strategies with patients.
TARGETED THERAPY
Targeted drugs with effcacy in mCRC include bevacizumaban antibody against vascular endothelial growth
factor A (VEGF)and cetuximab and panitumumabantibodies against the EGFR.17 More recently, aflibercepta
recombinant fusion protein that blocks the activity of VEGF
and placental growth factor18and regorafeniba multikinase inhibitor that blocks the activity of several protein kinases involved in tumor angiogenesis, oncogenesis, and the
tumor microenvironment have shown effcacy in patients
with mCRC.19 Bevacizumab and aflibercept are used in combination with chemotherapy, and the anti-EGFR antibodies
may also be used as monotherapy. The currently available
data support use of regorafenib only as monotherapy. Bevacizumab has shown survival benefts with fluoropyrimidinecontaining chemotherapy and is currently considered as a
standard frst-line treatment option for patients with mCRC.20-24
In second line, bevacizumab also improved progression-free
survival and overall survival in combination with FOLFOX
chemotherapy.25 This latter study showed no beneft for bevacizumab monotherapy. The beneft of the anti-EGFR antibodies panitumumab and cetuximab is restricted to patients
with a RAS wild-type tumor.26 These antibodies have shown
survival benefts with chemotherapy in frst line27-29 and
second line,30 as well as monotherapy in late line.31,32 Bevacizumab should not be combined with an anti-EGFR antibody.33,34 In patients with RAS wild-type tumors, there
appears no outright beneft for either bevacizumab or antiEGFR antibody treatment in combination with frst-line chemotherapy, although some studies show a yet unexplained
survival beneft for starting with anti-EGFR treatment.35-37
Aflibercept has shown effcacy in combination with FOLFIRI
for patients with mCRC previously treated with an oxaliplatincontaining regimen, with or without bevacizumab.18 For patients with mCRC whose disease progressed on these standard
therapies, regorafenib increased overall survival compared with
best supportive care.19
87
AIO 207
Patients
556
476
Design
Two-arm
superiority
Three-arm
noninferiority
Primary Endpoint
PFS2
TFS
4.5 mo
6 mo
Yes
No
47%-60%
21%-45%
CONCLUSION
For the palliative treatment of patients with mCRC with chemotherapy alone, current data do not allow a frm conclusion on
the safety of a full treatment break. The beneft of a drug holiday
with a possible detrimental effect on outcome must be weighed
against the toxicity and possibly decreased QoL that is associated with continuous treatment. In case of the use of combination chemotherapy with oxaliplatin, the chemotherapy may be
reduced to fluoropyrimidine monotherapy during the maintenance phase, with reintroduction of oxaliplatin on progression.
As to the use of targeted therapy, current data do not support the
use of maintenance treatment with bevacizumab monotherapy.
No data are available on the optimal duration of anti-EGFR antibody treatment. Data from the CAIRO3 and AIO 207 study
support the use of maintenance treatment with chemotherapy
and bevacizumab. Therefore, with bevacizumab being part of
standard frst-line treatment schedules, current data support the
use of maintenance treatment with bevacizumab in combination with chemotherapy. Further studies should provide data on
specifc subgroups in which maintenance treatment is most
effective.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Cornelis
J.A. Punt, Roche, Merck-Serono, Bayer, Amgen. Miriam Koopman, Amgen, Merck Serono, Bayer, Roche/Genetech, Lilly. Speakers Bureau: None. Research
Funding: Miriam Koopman, Merck Serono, Bayer, Roche, Sano. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None.
Travel, Accommodations, Expenses: Miriam Koopman, Bayer, Amgen, Roche. Other Relationships: None.
88
References
1. Simkens LH, Koopman M, Punt CJ. Optimal duration of systemic treatment in metastatic colorectal cancer. Curr Opin Oncol. 2014;26:448-453.
2. Punt CJ. Irinotecan or oxaliplatin for frst-line treatment of advanced
colorectal cancer? Ann Oncol. 2005;16:845-846.
3. Grothey A, Sargent D, Goldberg RM, et al. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracilleucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin
Oncol. 2004;22:1209-1214.
4. Grothey A, Sargent D. Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and
oxaliplatin regardless of whether doublet or single-agent therapy is used
frst line. J Clin Oncol. 2005;23:9441-9442.
5. Koopman M, Punt CJ. Chemotherapy, which drugs and when. Eur J
Cancer. 2009;45 Suppl 1:50-56.
6. Koopman M, Antonini NF, Douma J, et al. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled
trial. Lancet. 2007;370:135-142.
7. Seymour MT, Maughan TS, Ledermann JA, et al. Different strategies of
sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet. 2007;370:143-152.
8. Koopman M, Seymour MT, Punt CJ. The CAIRO and FOCUS studies:
which lesson is to be learned? Oncologist. 2009;14:192-193.
9. Maughan TS, James RD, Kerr DJ, et al. Comparison of intermittent and
continuous palliative chemotherapy for advanced colorectal cancer: a
multicentre randomised trial. Lancet. 2003;361:457-464.
10. Tournigand C, Cervantes A, Figer A, et al. OPTIMOX1: a randomized
study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go
fashion in advanced colorectal cancer-a GERCOR study. J Clin Oncol.
2006;24:394-400.
11. Chibaudel B, Maindrault-Goebel F, Lledo G, et al. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer?
The GERCOR OPTIMOX2 Study. J Clin Oncol. 2009;27:5727-5733.
12. Adams RA, Meade AM, Seymour MT, et al. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for
frst-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol. 2011;12:642-653.
13. Lal R, Dickson J, Cunningham D, et al. A randomized trial comparing
defned-duration with continuous irinotecan until disease progression
in fluoropyrimidine and thymidylate synthase inhibitor-resistant advanced colorectal cancer. J Clin Oncol. 2004;22:3023-3031.
14. Labianca R, Sobrero A, Isa L, et al. Intermittent versus continuous chemotherapy in advanced colorectal cancer: a randomised GISCAD trial.
Ann Oncol. 2011;22:1236-1242.
15. de Kort SJ, Willemse PH, Habraken JM, et al. Quality of life versus prolongation of life in patients treated with chemotherapy in advanced
colorectal cancer: a review of randomized controlled clinical trials. Eur J
Cancer. 2006;42:835-845.
16. Koedoot CG, de Haan RJ, Stiggelbout AM, et al. Palliative chemotherapy or best supportive care? A prospective study explaining patients
treatment preference and choice. Br J Cancer. 2003;89:2219-2226.
17. Cunningham D, Atkin W, Lenz HJ, et al. Colorectal cancer. Lancet.
2010;375:1030-1047.
18. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to
fluorouracil, leucovorin, and irinotecan improves survival in a phase III
randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30:
3499-3506.
89
90
44.
45.
46.
47.
48.
49.
50.
bevacizumab followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy in patients with metastatic colorectal cancer: the phase III MACRO TTD study. Oncologist. 2012;17:15-25.
Strickler JH, Hurwitz HI. Maintenance therapy for frst-line metastatic
colorectal cancer: activity and sustainability. Oncologist. 2012;17:9-10.
Koeberle D, Betticher DC, von Moos R, et al. Bevacizumab continuation
versus no continuation after frst-line chemotherapy plus bevacizumab
in patients with metastatic colorectal cancer: a randomized phase III
non-inferiority trial (SAKK 41/06). Ann Oncol. Epub 2015 Jan 20.
Simkens LH, Van Tinteren H, May A, et al. Maintenance treatment with
capecitabine and bevacizumab in metastatic colorectal cancer, the phase
3 CAIRO3 study of the Dutch Colorectal Cancer Group (DCCG).
Lancet. In press.
Arnold D, Graeven U, Lerchenmuller C, et al. Maintenance strategy
with fluoropyrimidines (FP) plus bevacizumab (Bev), Bev alone, or no
treatment, following a standard combination of FP, oxaliplatin (Ox),
and Bev as frst-line treatment for patients with metastastic colorectal
cancer (mCRC): a phase III non-inferiority trial (AIO KRK 0207). J Clin
Oncol. 2014;32:5s (suppl; abstr 3503).
Tveit KM, Guren T, Glimelius B, et al. Phase III trial of cetuximab with
continuous or intermittent fluorouracil, leucovorin, and oxaliplatin
(Nordic FLOX) versus FLOX alone in frst-line treatment of metastatic
colorectal cancer: the NORDIC-VII study. J Clin Oncol. 2012;30:17551762.
Tournigand C, Chibaudel B, Samson B, et al. Maintenance therapy with
bevacizumab with or without erlotinib in metastatic colorectal cancer
according to KRAS: results of the GERCOR DREAM phase III trial.
J Clin Oncol. 2013;31 (suppl; abstr 3515).
Johnsson A, Hagman H, Frodin JE, et al. A randomized phase III trial
on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial. Ann Oncol. 2013;24:
2335-2341.
SPEAKERS
Andrea Cercek, MD
Memorial Sloan Kettering Cancer Center
New York, NY
James C. Cusack Jr, MD
Massachusetts General Hospital
Boston, MA
In response to these challenges, investigators have attempted to treat patients with isolated peritoneal carcinomatosis using cytoreductive surgery (CRS) and hyperthermic
intraperitoneal chemotherapy (HIPEC). Earlier studies estimated that peritoneal carcinomatosis occurs as the sole site of
disease in as many as 25% of patients, but a recent study evaluating the subset of patients with peritoneal carcinomatosis
in the North Central Cancer Treatment Group studies 9741
and 9841 demonstrated that 17% of patients (364 of 2,101)
enrolled in these two studies had peritoneal carcinomatosis
as a component of multisite disease, and only 2.1% of patients
(44 of 2,101) had peritoneal carcinomatosis as the sole site of
disease.3 Although the topic of CRS and HIPEC is often debated, the applicability to the management of metastatic colon cancer is uncommon.
From the Memorial Sloan Kettering Cancer Center, New York, NY; Massachusetts General Hospital, Boston, MA.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Andrea Cercek, MD, Memorial Sloan Kettering Cancer Center, 505 E. 79th St., New York, NY 10075; email: cerceka@mskcc.org.
2015 by American Society of Clinical Oncology.
e208
KEY POINTS
Isolated peritoneal carcinomatosis related to colorectal
cancer occurs infrequently and is associated with a poor
prognosis.
Therapeutic cytoreduction may be achieved using systemic
chemotherapy and/or cytoredcutive surgery (CRS) and
intraperitoneal heated chemotherapy (HIPEC).
Optimal management of peritoneal carcinomatosis is
determined by a multidisciplinary care team (medical
oncologist and surgeon).
Stringent selection criteria for patients undergoing CRS/
HIPEC may reduce associated morbidity and mortality.
The timing of CRS/HIPEC should be coordinated by the
multidisciplinary care team.
e209
e210
are required to improve operative and oncologic outcomes, respectively.21 These data exemplify the importance of developing well-organized, multidisciplinary
teams that consists of surgeons, perfusionists, anesthesiologists, intensivists, nutritionists, oncologists, and nurse
specialists to work together in lowering the associated
morbidity and mortality of CRS/HIPEC procedures.
Stringent patient selection is also critical to optimizing operative and oncologic outcomes of patients undergoing CRS/
HIPEC. Patients older than 70 and those with signifcant
comorbidities have higher rates of perioperative morbidity
and mortality after CRS/HIPEC.22 To avoid treatmentrelated morbidity and mortality associated with CRS/
HIPEC, high-risk patients may be offered alternative
treatments such as systemic therapy alone or CRS alone, particularly in the absence of prospective data that demonstrates
the superiority of CRS/HIPEC. The timing of surgery also affects patient outcomes. To coordinate the timing of CRS/
HIPEC, patients with metastatic disease confned to the
peritoneal cavity should be seen by both the experienced CRS/
HIPEC surgeon and the medical oncologist at the time of
diagnosis of carcinomatosis or isolated peritoneal disease recurrence. Considerations that influence the timing of CRS/
HIPEC include response to systemic chemotherapy,
availability of chemotherapy options, and the emergence of
treatment-related toxicities. Treatment with effective systemic chemotherapy prior to CRS/HIPEC provides the advantage of reducing the bulk of disease identifed at surgery,
and, thereby, potentially lowering the initial PCI at the time
of CRS/HIPEC.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: David P. Ryan, UpToDate. Consulting or
Advisory Role: David P. Ryan, Medimmune. Speakers Bureau: None. Research Funding: James C. Cusack, Karyopharm Therapeutics. Patents, Royalties,
or Other Intellectual Property: David P. Ryan, McGraw Hill chapter royalties. Expert Testimony: None. Travel, Accommodations, Expenses: David P.
Ryan, Merck Serono, Threshold Pharmaceuticals. Other Relationships: None.
References
1. Dy GK, Hobday TJ, Nelson G, et al. Long-term survivors of metastatic
colorectal cancer treated with systemic chemotherapy alone: a North
Central Cancer Treatment Group review of 3811 patients, N0144. Clin
Colorectal Cancer. 2009;8:88-93.
2. Benson AB 3rd, Venook AP, Bekaii-Saab T, et al. Colon cancer, version
3.2014. J Natl Compr Canc Netw. 2014;12:1028-1059.
3. Franko J, Shi Q, Goldman CD, et al. Treatment of colorectal peritoneal
carcinomatosis with systemic chemotherapy: a pooled analysis of north
central cancer treatment group phase III trials N9741 and N9841. J Clin
Oncol. 2012;30:263-267.
4. Brooks GA, Abrams TA, Meyerhardt JA, et al. Identifcation of potentially avoidable hospitalizations in patients with GI cancer. J Clin Oncol.
2014;32:496-503.
5. Laval G, Marcelin-Benazech B, Guirimand F, et al. Recommendations
for bowel obstruction with peritoneal carcinomatosis. J Pain Symptom
Manage. 2014;48:75-91.
6. Sugarbaker PH. Peritonectomy procedures. Ann Surg. 1995;221:29-42.
7. Sugarbaker PH, Welch LS, Mohamed F, et al. A review of peritoneal
mesothelioma at the Washington Cancer Institute. Surg Oncol Clin N
Am. 2003;12:605-621, xi.
8. Culliford AT 4th, Brooks AD, Sharma S, et al. Surgical debulking and
intraperitoneal chemotherapy for established peritoneal metastases
from colon and appendix cancer. Ann Surg Oncol. 2001;8:787-795.
9. Sugarbaker PH, Landy D, Pascal R. Intraperitoneal chemotherapy for peritoneal carcinomatosis from colonic or appendiceal cystadenocarcinoma:
rationale and results of treatment. Prog Clin Biol Res. 1990;354B:141-170.
10. Cavaliere R, Ciocatto EC, Giovanella BC, et al. Selective heat sensitivity of
cancer cells. Biochemical and clinical studies. Cancer. 1967;20:1351-1381.
11. Overgaard J. Effect of hyperthermia on malignant cells in vivo. A review
and a hypothesis. Cancer. 1977;39:2637-2646.
12. Gonzalez-Moreno S, Gonzalez-Bayon LA, Ortega-Perez G. Hyperthermic intraperitoneal chemotherapy: rationale and technique. World J
Gastrointest Oncol. 2010;2:68-75.
13. Klaver YL, Hendriks T, Lomme RM, et al. Hyperthermia and intraperitoneal chemotherapy for the treatment of peritoneal carcinomatosis: an
experimental study. Ann Surg. 2011;254:125-130.
14. Verwaal VJ, van Ruth S, de Bree E, et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with
peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003;21:
3737-3743.
15. Verwaal VJ, Bruin S, Boot H, et al. 8-year follow-up of randomized trial:
cytoreduction and hyperthermic intraperitoneal chemotherapy versus
systemic chemotherapy in patients with peritoneal carcinomatosis of
colorectal cancer. Ann Surg Oncol. 2008;15:2426-2432.
16. Elias D, Delperro JR, Sideris L, et al. Treatment of peritoneal carcinomatosis from colorectal cancer: impact of complete cytoreductive surgery and diffculties in conducting randomized trials. Ann Surg Oncol.
2004;11:518-521.
17. Elias D, Gilly F, Boutitie F, et al. Peritoneal colorectal carcinomatosis
treated with surgery and perioperative intraperitoneal chemotherapy:
retrospective analysis of 523 patients from a multicentric French study.
J Clin Oncol. 2010;28:63-68.
18. Yan TD, Black D, Savady R, et al. Systematic review on the effcacy of
cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal carcinoma.
J Clin Oncol. 2006;24:4011-4019.
19. Chua TC, Esquivel J, Pelz JO, et al. Summary of current therapeutic options for peritoneal metastases from colorectal cancer. J Surg Oncol.
2013;107:566-573.
20. Kusamura S, Baratti D, Deraco M. Multidimensional analysis of the
learning curve for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal surface malignancies. Ann Surg. 2012;
255:348-356.
21. Polanco PM, Ding Y, Knox JM, et al. Institutional learning curve of cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion
for peritoneal malignancies. Ann Surg Oncol. Epub 2014 Nov 7.
22. Votanopoulos KI, Newman NA, Russell G, et al. Outcomes of Cytoreductive Surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients older than 70 years; survival beneft at
considerable morbidity and mortality. Ann Surg Oncol. 2013;20:34973503.
e211
SPEAKERS
Riccardo Lencioni, MD, PhD
Pisa University Hospital and School of Medicine
Pisa, Italy
John Renz, MD, PhD
The University of Chicago
Chicago, IL
Jorge Marrero, MD
The University of Texas Southwestern Medical Center
Dallas, TX
epatocellular carcinoma is a leading cause of cancerrelated death, with a rising global incidence.1 The vast
majority of HCC cases occur in the setting of liver cirrhosis,
usually because of chronic HCV or HBV, alcohol consumption, nonalcoholic fatty liver disease, among others. Because
the majority of patients with HCC have cirrhosis, it is important to understand it and its complications, while we focus on
the recent advancements in prevention of cirrhosis-causing
etiologies, specifcally HCV. This manuscript also addresses
the recent developments in the curative and palliative whole
treatment armamentarium for HCC from surgery and transplant through local therapies, up to systemic treatment including targeted and immunotherapies.
monary hypertension. Cirrhosis can be compensated or decompensated, with a 2-year survival of 90% compared with
54%, respectively.2 HCC is the other important complication
of cirrhosis and occurs at an annual incidence rate of 2% to
3%.3 The presence of cirrhosis and its complications will affect the prognosis and management of patients with HCC.
Multidisciplinary management including hepatology is critical in the care for patients with advanced HCC.
The Child-Turcotte classifcation system was developed in
1964 to risk-stratify patients undergoing shunt surgery for
portal decompression at the University of Michigan. In 1972,
Pugh modifed the Child-Turcotte system, and it became
known as the Child-Turcotte-Pugh score, also known for
short as the Child-Pugh score. The Child-Pugh score is composed of levels of albumin, prothrombin time, and total bilirubin and also with the presence or absence of clinical hepatic
encephalopathy and ascites. Based on these variables, points
are assigned and patients are classifed as A, B, or C. Although
empirically derived, the Child-Pugh has been shown to accurately predict outcomes in patients with cirrhosis and portal
hypertension, and it continues to be used today. Because it is
simple and does not require complicated calculation, this
tool is widely used by clinicians to assess the risk of mortality
in patients with cirrhosis. Another important system to as-
From the Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medical College, New York, NY; The University of Texas Southwestern, Dallas, TX; The University of Chicago,
Chicago, IL; and Pisa University Hospital and School of Medicine, Pisa, Italy.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center, 300 East 66th St., New York, NY: 10065; email: abou-alg@mskcc.org.
2015 by American Society of Clinical Oncology.
e213
ABOU-ALFA ET AL
CURATIVE THERAPIES
Curative therapies for the treatment of HCC are evolving.
Improvements in surgical techniques and risk stratifcation
for orthotopic liver transplantation (OLT) have expanded access and improved the outlook for patients suffering from
HCC.
Liver Transplantation
KEY POINTS
Hepatocellular carcinoma (HCC) continues to have a rising
global incidence.
A 12-week course of treatement with NS5A inhibitors
ledipasvir and sofosbuvir has shown a sustained virologic
response up to 96% for patients with hepatitis C viral
infection genotype 1.
The Metro Ticket algorithm asserts that the further one
deviates from the Milan criteria with respect to tumor
burden in applying liver transplant, the higher the price
one pays with long-term disease recurrence.
Despite the theoretical potential synergies between
locoregional and systemic therapies with antiangiogenic
properties such as sorafenib all clinical trials completed so
far have failed to provide evidence of a clinical benet in
that setting.
Sorafenib remains the sole standard of care for advanced
HCC with an improvement in survival to 10.7 months
compared to 7.9 months for placebo (0.69; 95% CI, 0.55
to 0.87).
e214
When considering OLT for HCC, transplantation is not restricted to patients within Milan criteria. Indeed, there are no
limits to the tumor burden that can be addressed by OLT.
The only requirements are identifcation of a recipient, availability of a donor allograft, and a stable mechanism to pay for
services and post-OLT immunosuppressive medications.
Two groups widely recognized as performing well after OLT
who do not meet Milan criteria are patients without cirrhosis
with a larger tumor burden and patients who are subsequently downstaged to within Milan criteria by locoregional
therapy.14 Few long-term data exist on the outcomes of
down-staging; however, at the present time, down-staging
HCC to within Milan criteria is recognized within the transplant community as an indication to resume automatic prioritization toward OLT.
Other institutions, including the University of Chicago,
have specifc programs to address OLT for patients with cirrhosis with disease burden exceeding the Milan criteria.
These programs typically employ aggressive locoregional
therapy to obtain local control, with a period of watchful
waiting to exclude extra-hepatic disease. Locoregional therapy typically includes transarterial chemoembolization
(TACE) or yttrium-90 (Y90) microsphere embolization in
conjunction with percutaneous or laparoscopic radio frequency ablation (RFA). Patients who tolerate therapy and
demonstrate no evidence disease progression qualify for
OLT utilizing extended-criteria donor allografts. Multiple
centers have reported excellent long-term survival based on
the Metro Ticket algorithm for management of HCC.15
The Metro Ticket algorithm, initially proposed by Mazzaferro, simply asserts that the further one deviates from the
Milan criteria with respect to tumor burden in applying OLT
for HCC, the higher the price one pays with long-term disease recurrence.16 Several groups have proposed alternative
classifcation strategies for HCC. The most notable is the
University of California San Francisco criteria that represents a modest expansion of the Milan criteria but lacks longterm follow-up data.17
Additional information outside the total number of lesions
and their maximal diameter that are valuable in assessing the
applicability of OLT to HCC include alpha-fetoprotein, tumor differentiation, and evidence of vascular invasion.
Alpha-fetoprotein levels in excess of 1,000 ng/mL at presentation are a poor prognostic indicator for maturation to OLT
and should trigger triage to a high-risk protocol.18 Although
not formally a component of an OLT evaluation for HCC,
histology consistent with poorly differentiated HCC is also a
negative prognostic indicator for maturation to OLT. Our
practice does not mandate histology during the evaluation
process but to routinely obtain histology at the time of RFA
therapy if indicated. Similarly, the observance of vascular invasion, either macroscopically as venous thrombosis/invasion or microscopically on histology, should direct the
patient to a high-risk protocol.18,19
The UCSF group reported a large series of long-term outcomes among patients who underwent downstaging for potential liver transplantation compared with patients within
Surgical Resection
Surgical resection remains the standard of care for the
treatment of HCC. Traditionally, surgical resectability has
been a function of disease burden as well as estimation of
functional hepatic reserve as determined by the ChildPugh score. New surgical techniques combined with improved understanding of disease progression in patients
with cirrhosis are now challenging this traditional rationale. The surgical technique of associating liver partition
with portal vein ligation for staged hepatectomy as advocated by Schadde and others offers the potential to expand
surgical resection to a larger tumor burden within the
liver.22 Their data demonstrate that this technique may allow a larger amount of multifocal disease within the liver
to be surgically approached and may enhance regeneration. Promising early data suggest effcacy among patients
with cirrhosis who are not candidates for OLT. The current donor shortage and the psychosocial/medical/insurance restrictions placed upon candidacy for liver
transplantation precludes this from ever displacing surgical resection as the standard of care.
Salvage Transplantation
Improved understanding of the limitations of salvage transplantation has signifcantly advanced triage of patients between surgical resection and OLT. Salvage transplantation is
the practice of OLT following curative surgical resection.
Early data supporting the practice of salvage transplantation
re-enforced the traditional mantra of exhausting all surgical
options before progressing to OLT. However, recent data examining the role of salvage transplantation stratifed by indication for cirrhosis is challenging conventional wisdom.
When the indication for cirrhosis has been removed from
the patients physiology, as in abstinence from alcohol or
eradication of a viral hepatitis, the benefts of salvage transplantation are preserved. However, attempting salvage transplantation in the setting of patients who have ongoing liver
injury, as in hemachromatosis, primary biliary cirrhosis, or
an untreated viral hepatitis, has very low effcacy. Therefore,
a thorough understanding of the patients underlying liver
disease and recognition of continuing liver injury are essential to appropriate selection of therapy. Patients without conasco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e215
ABOU-ALFA ET AL
Ablation
Ablation techniques have evolved considerably over the past
20 years and are increasingly used to defnitively treat small
HCC tumors. Several methods for focal tumor destruction
have been developed and clinically tested. Although RFA has
been the most popular technique to date, several alternate
technologiesincluding thermal and nonthermal methods have recently been adopted, as they seem to overcome
some of the specifc limitations of RFA.24
Several studies have reported long-term outcomes of RFA
in patients with small, unresectable tumors and Child-Pugh
class A liver disease, and they demonstrate 5-year survival
rates as high as 50% to 70%.25 The question remains whether
RFA can compete with surgical resection as a frst-line treatment for HCC. Randomized clinical trials of RFA and surgery reported to date have failed to provide an unequivocal
answer to this question.
Recurrence after surgery or ablation remains a serious concern. A randomized phase III study comparing adjuvant
sorafenib to placebo after curative resection or ablation
showed no difference in recurrence-free survival (33.4 for
sorafenib versus 33.8 months for placebo, hazard ratio [HR]
0.940; 95% CI, 0.780 to 1.134; p 0.26).26
Although 18F-FDG PET-CT is not part of current routine
diagnostic work-up for patients with HCC, studies have suggested that uptake of 18F-FDG is associated with poor tumor
differentiation and may be a predictor of recurrence and
worse outcomes following surgical or locoregional treatment.27,28 These results will need to be validated in larger prospective cohorts.
Conventional TACE regimens are based on the administration of an anticancer-in-oil emulsion followed by embolic
agents. The key component of this procedure is lipiodol,
which is used both as a vehicle to carry and localize the chemotherapeutic agent inside the tumor and as an embolic
agent for tiny tumor vessels. Randomized, controlled trials
and meta-analyses have shown that TACE improves survival
with respect to best supportive care, extending the median
survival from 16 to 19 20 months.
However, such trials were performed more than a decade
ago. Distinct technical advances in the performance of TACE
and improved patient selection and management have taken
place since the completion of these studies.31 In a randomized phase II study comparing TACE using LC Bead loaded
with 150 mg of doxorubicin to bland transarterial embolization (TAE) with Bead Block microspheres, there was no difference in median progression-free survival (6.2 vs. 2.8
months; p 0.11) or overall survival (19.6 versus 20.8
months; p 0.40) for Bead Block and LC Bead, respectively.32 Given a comparable safety profle, and similar outcomes, the advancement in technology and super selectivity
in arterial blockade place the role of added doxorubicin into
question.
An unsettled issue in the management of patients treated
with embolization is the assessment of tumor response and
the criteria for treatment discontinuation. Several recent investigations conducted in the United States, Europe, and
Asia have shown that the assessment of tumor response by
modifed Response Evaluation Criteria in Solid Tumors predicts overall survival in patients with HCC treated with
TACE.33 It has been suggested that TACE should be discontinued in patients in whom an objective response in the
treated tumor has not been achieved after two treatment
cycles.34
Radioembolization
Radioembolization is a form of intra-arterial radiation therapy that was developed to capitalize on the arterial perfusion
of HCC, with the aim of delivering radiation tumoricidal
doses to liver tumors.35 Radioembolization with Y90 is challenging the current paradigm of HCC treatment. Multiple
centers around the world have provided compelling data that
suggest a clinical role in patients with portal vein thrombosis
as well as in downstaging to transplantation or conversion of
patients with surgically inoperable disease (because of small
liver remnant) to potential cure with resection. This approach, however, still lacks randomized, controlled study
data.
proach failed to provide a clinically meaningful improvement in time-to-progression (TTP) compared with drugeluting bead TACE alone in the randomized phase II SPACE
study.37 Median TTP was 169 days in the sorafenib group and
166 days in the placebo group, (HR 0.797; 95% CI, 0.588 to
1.080; p 0.072). The phase III trial that compared the effcacy and safety of brivanib with placebo as adjuvant therapy
to TACE in patients with unresectable HCC has similarly disappointing results: the median overall survival was 26.4 compared with 26.1 month, respectively (HR 0.90; 95% CI, 0.66 to
1.23; log-rank p 0.5280).38
The combination of locoregional and systemic therapy has
so far been investigated mostly in patients with limited tumor
burden, for whom antiangiogenic treatment was administered on top of the standard locoregional approach. Another
developing idea views systemic and interventional therapies
as complimentary modalities, which allows patients with
advanced-stage disease to be candidates for locoregional
treatments.39
SYSTEMIC THERAPY
The advent of sorafenib as a standard of care with an improvement in survival to 10.7 months compared to 7.9
months for placebo (0.69; 95% CI, 0.55 to 0.87; p 0.001)40
was a major breakthrough in the treatment of advanced
HCC, after decades of disappointing attempts to identify a
standard of care therapeutic agent.41 The past 8 years, however, have been disappointing with mounting negative data
from multiple clinical trials. Few studies with promising early
robust results may turn the tide around.
First-Line Therapy
A phase II study compared doxorubicin plus sorafenib to
doxorubicin plus placebo in 96 patients with advanced HCC
and Child-Pugh A.42 The primary endpoint, median TTP,
was 9 months for the doxorubicin and sorafenib arm compared with 5 months for the doxorubicin and placebo arm.
An exploratory comparison of overall survival between the
two arms showed a signifcant difference of 13.7 months in
favor of doxorubicin and sorafenib compared with 6.5
months for doxorubicin and placebo (p 0.0049, HR 0.45).
A potential synergistic effect between doxorubicin and
sorafenib that is based on the dissolve of an inhibitory dimer
of ASk-1 and Raf, plus other putative mechanisms, may explain the improved outcome.43 A large randomized phase III
trial comparing the combination of sorafenib and doxorubicin with sorafenib alone in the frst-line setting44 and a phase
II study of this regimen in the second-line setting after
sorafenib failure45 are currently underway.
Second-Line Therapy
Several studies evaluating novel therapeutics in the secondline setting have been met with disappointment. These include brivanib46 and otherwise known active therapies such
as everolimus47 and ramucirumab.48 The perception of low-
hanging fruit when comparing to a placebo in the secondline setting is a reminder of the continued advancement in
the total care of patients with HCC who generally are living
longer than previously perceived.
The biosynthesis of the nonessential amino acid arginine occurs as part of the urea cycle and is dependent on
the enzymes argininosuccinate synthetase and argininosuccinate lyase. Messenger RNA encoding argininosuccinate synthetase is not present in subsets of HCCs;
therefore, arginine must be extracted from the circulation. Pegylated arginine deiminase (ADI-PEG 20) is an
arginine-degrading enzyme isolated from Mycoplasma
that is formulated with polyethylene glycol (molecular
weight 20 kd). Based on encouraging phase II data,49 ADIPEG20 is currently being evaluated in a phase III trial in
comparison to placebo with patients with advanced HCC
in the second-line setting.50
Overexpression of c-MET and its ligand HGF occur in up
to 80% of human HCC tumors.51 Tivantinib, a selective MET
receptor tyrosine kinase inhibitor, was evaluated at two doses
in a randomized, placebo-controlled phase II trial for patients with advanced HCC in the second-line setting. It was
found that patients with high MET-expressing tumors, tivantinib therapy resulted in a median overall survival of 7.2
months compared with 3.8 months for placebo (HR 0.38;
95% CI, 0.18 to 0.81). Considering that high tumoral MET
expression was associated with an improved overall survival
when compared with low tumoral MET expression (3.8
months versus 9 months, HR 2.94; 95% CI, 1.16 to 7.43), a
randomized phase III study of patients with advanced HCC
and high MET-expressing tumors only in the second-line
setting followed and is currently underway.52 Cabozantinib,
an inhibitor of MET and vascular endothelial growth factor
receptor 2, has also shown promising effcacy data in a cohort
of 41 patients with advanced HCC.53 Median progressionfree survival for the cohort was estimated at 4.2 months. A
phase III study cabozantinib is underway.54 Because tivantinib and cabozantinib are both multitargeted tyrosine kinases, their antitumor activity is not solely dependent on
MET pathway inhibition, and selection for MET overexpressing tumors, such as for tivantinib, may not be warranted
when using such class of drug.
Immunotherapy
Immune escapes have been identifed to carry a poor
outcome with a high likelihood of metastatic spread.55
Tremelimumab, a monoclonal antibody to cytotoxic
T-lymphocyte antigen-4, has demonstrated antitumor activity in patients with heavy pretreated unresectable and
metastatic hepatitis Crelated HCC.56 Partial response
rate was 17.6% and TTP was 6.48 months (95% CI, 3.95 to
9.14). Similarly data have suggested that program death
receptor-1 and program death receptor-1 ligand (PDL-1)
can suppress HCC,57 and several studies are investigating
these agents in HCC as monotherapy.58,59 Preliminary
data from a multiarm expansion study of MEDI4736, an
anti-PDL-1 antibody in patients with advanced solid tuasco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e217
ABOU-ALFA ET AL
CUSTOMIZED THERAPY
Recent work by many groups has attempted to recognize
the key drivers and potential targets for advanced
HCC.61,62 No clear patterns have evolved so far, short of
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Ghassan
K. Abou-Alfa, Aduro Biotech (I), Astellas Pharma, AstraZeneca (I), Celgene, Celsion, Cipla, Exelixis, IntegraGen, Jennerex, Lilly/ImClone, MedImmune, Novartis,
Pharmacyclics (I), Sano (I), Silenseed (I), Vicus Therapeutics. Jorge A. Marrero, Bayer/Onyx, Onyx. Speakers Bureau: None. Research Funding: Ghassan
K. Abou-Alfa, Abbott Laboratories (Inst), Amgen (Inst), Bayer (Inst), Exelixis (Inst), Genentech (Inst), Lilly/ImClone (Inst), Novartis (Inst), Polaris (Inst), Roche
(Inst), Vicus Therapeutics (Inst). Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations,
Expenses: Ghassan K. Abou-Alfa, Polaris. Other Relationships: None.
References
1. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;
379:1245-1255.
2. Singal AG, Conjeevaram HS, Volk ML, et al. Effectiveness of hepatocellular carcinoma surveillance in patients with cirrhosis. Cancer Epidemiol Biomarkers Prev. 2012;21:793-799.
3. DAmico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic
indicators of survival in cirrhosis: a systematic review of 118 studies.
J Hepatol. 2006;44:217-231.
4. Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology. 2003;124:
91-96.
5. Huitzil Melendez FD, Capanu M, OReilly EM, et al. Advanced hepatocellular carcinoma: which staging systems best predict prognosis? J Clin
Oncol. 2010;28:2889-2895.
6. Gao M, Nettles RE, Belema M, et al. Chemical genetics strategy identifes
an HCV NS5A inhibitor with a potent clinical effect. Nature. 2010;465:
96-100.
7. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370:18891898.
8. Bourliere M, Sulkowski MS, Omata M, et al. An integrated safety and
effcacy analysis of 500 patients with compensated cirrhosis treated
with ledipasvir/sofosbuvir with or without ribavirin. 65th Annual Meeting of the American Association for the Study of Liver Diseases. November 7-11, 2014. Boston, Massachusetts. Abstract 82.
9. Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014;370:
1594-1603.
10. Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med. 2014;
370:1973-1982.
e218
11. Kulik L, Chokechanachaisakul A. Evaluation and management of hepatocellular carcinoma. Clin Liver Dis. 2015;19:23-43.
12. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the
treatment of small hepatocellular carcinomas in patients with cirrhosis.
N Engl J Med. 1996;334:693-699.
13. Pomfret E, Washburn K, Wald C, et al. Report of a national conference
on liver allocation in patients with hepatocellular carcinoma. Liver
Transpl. 2010;16:262-278.
14. Yao F, Kerlan R, Hirose R, et al. Excellent outcome following downstaging of hepatocellular carcinoma prior to liver transplantation: an
intent-to-treat analysis. Hepatology. 2008;48:819-827.
15. Clavien P, Lesurtel M, Bossuyt P, et al. Recommendations for liver
transplantation for hepatocellular carcinoma: an international consensus report. Lancet Oncol. 2012;13:11-22.
16. Prasad K, Young R, Burra P, et al. Summary of candidate selection and
expanded criteria for liver transplantation for hepatocellular carcinoma:
a review and consensus statement. Liver Transpl. 2011;Suppl 2:S81-S89.
17. Yao F, Ferrell L, Bass N, et al. Liver transplantation for hepatocellular
carcinoma: expansion of the tumor size limits does not adversely impact
survival. Hepatology. 2001;33:1394-1403.
18. Kashkoush S, El Moghazy W, Kawahara T, et al. Three-dimensional tumor volume and serum alpha-fetoprotein are predictors of hepatocellular carcinoma recurrence after liver transplantation: refned selection
criteria. Clin Transplant. 2014;28:728-736.
19. Yao FY, Mehta N, Flemming J, et al. Downstaging of hepatocellular cancer before liver transplant: long-term outcome compared to tumors
within Milan criteria. Hepatology. Epub 2015 Feb 18.
20. Yao FY. Liver transplantation for hepatocellular carcinoma: beyond the
Milan criteria. Am J Transplant. 2008;8:1982-1989.
21. Takada Y, Tohyama T, Watanbe J. Biological markers of hepatocellular
carcinoma for use as selection criteria for liver transplantation. J Hepatobiliary Pancreat Sci. 2014;19:195-205.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
lar carcinoma: does it exist and has it been reached? Lancet Oncol. 2013;
14:e283-e288.
Abou-Alfa GK, Johnson P, Knox JK, et al. Randomized, double-blind
study of doxorubicin plus sorafenib and doxorubicin plus placebo in
patients with advanced hepatocellular carcinoma. JAMA. 2010;304:
2154-2160.
Alavi AS, Acevedo L, Min W, et al. Chemoresistance of endothelial cells
induced by basic fbroblast growth factor depends on Raf-1-mediated
inhibition of the proapoptotic kinase, ASK1. Cancer Res. 2007;67:27662772.
NCT01015833. Sorafenib Tosylate With or Without Doxorubicin Hydrochloride in Treating Patients With Locally Advanced or Metastatic
Liver Cancer. https://clinicaltrials.gov/ct2/show/NCT01015833. Accessed February 26, 2015.
NCT01840592. Sorafenib Plus Doxorubicin in Patients With Advanced
Hepatocellular Carcinoma With Disease Progression on Sorafenib.
https://clinicaltrials.gov/ct2/show/NCT01840592. Accessed February
26, 2015.
Llovet JM, Decaens T, Raoul J-L, et al. Brivanib versus placebo in patients with advanced hepatocellular carcinoma who failed or were intolerant to sorafenib: Results from the phase 3 BRISK-PS study. J Clin
Oncol. 2013;31:3509-3516.
Zhu AZ, Kudo M, Assenat E, et al. Effect of everolimus on survival in
advanced hepatocellular carcinoma after failure of sorafenib: the
EVOLVE-1 randomized clinical trial. JAMA. 2014;312:57-67.
Zhu AX, Ryoo B, Yen CJ, et al. Ramucirumab (RAM) as second-line
treatment in patients (pts) with advanced hepatocellular carcinoma
(HCC) following frst-line therapy with sorafenib. Ann Onc. 2014;2:
1-41.
Glazer ES, Piccirillo M, Albino V, et al. Phase II study of pegylated arginine deiminase for nonresectable and metastatic hepatocellular carcinoma. J Clin Oncol. 2010;28:2220-2226.
NCT01287585. Ph 3 ADI-PEG 20 Versus Placebo in Subjects With Advanced Hepatocellular Carcinoma Who Have Failed Prior Systemic
Therapy. https://clinicaltrials.gov/ct2/show/NCT01287585. Accessed
February 26, 2015.
Santoro A, Rimassa L, Borbath I, et al. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebocontrolled phase 2 study. Lancet Oncol. 2013;14:55-63.
NCT01755767. Study of Tivantinib in Subjects With Inoperable Hepatocellular Carcinoma Who Have Been Treated With One Prior Therapy
(METIV-HCC). https://clinicaltrials.gov/ct2/show/NCT01755767. Accessed February 26, 2015.
Verslype C, Cohn AL, Kelley RK, et al. Activity of cabozantinib (XL184)
in hepatocellular carcinoma: results from a phase II randomized discontinuation trial (RDT). J Clin Oncol. 2012;30 (suppl; abstr 4007).
NCT01908426. Study of Cabozantinib (XL184) vs Placebo in Subjects
With Hepatocellular Carcinoma Who Have Received Prior Sorafenib
(CELESTIAL). https://clinicaltrials.gov/ct2/show/NCT01908426. Accessed February 26, 2015.
Pardee AD, Butterfeld LH. Immunotherapy of hepatocellular carcinoma: unique challenges and clinical opportunities. Oncoimmunology.
2012;1:48-55.
Sangro B, Gomez-Martin C, de la Mata M, et al. A clinical trial of
CTLA-4 blockade with tremelimumab in patients with hepatocellular
carcinoma and chronic hepatitis C. J Hepatol. 2013;59:81-88.
Kuang DM, Zhao Q, Peng C, et al. Activated monocytes in peritumoral
stroma of hepatocellular carcinoma foster immune privilege and disease
progression through PD-L1. J Exp Med. 2009;206:1327-1337.
NCT01658878. Study to Evaluate the Effectiveness, Safety and Tolerability of Nivolumab in Subjects With Advanced Liver Cancer Anti-PD-1
e219
ABOU-ALFA ET AL
e220
61. Abou-Alfa GK, Miura JT, Gamblin TC, et al. Comprehensive multiplatform biomarker analysis of 313 hepatocellular carcinoma to
identify potential therapeutic options. J Clin Oncol. 2015;33 (suppl 3;
abstr 283).
62. Quetglas IM, Moeini A, Pinyol R, et al. Molecular profling of liver tumors: classifcation and clinical translation for decision making. Semin
Liver Dis. 2014;34:363-375.
SPEAKERS
Andrew H. Ko, MD
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, CA
Neal J. Meropol, MD
University Hospitals Seidman Cancer Center, Case Western Reserve University
Cleveland, OH
AHN ET AL
onventional cytotoxic chemotherapy remains the standard of care for pancreatic cancer. Table 1 highlights
major fndings from key clinical trials in advanced pancreatic
cancer. Before recent advances, the last signifcant therapy
approved for pancreatic cancer was erlotinib in 2007, based
on a phase III randomized control trial showing that this
agent when added to gemcitabine improved survival.3 However, because the degree of survival improvement was of
questionable clinical signifcance and at the expense of signifcant toxicities (62% grade 3 to 4 adverse events), the combination has never found signifcant traction in the treatment
of pancreatic cancer. During the past several years, two chemotherapy regimens, FOLFIRINOX and gemcitabine/nabpaclitaxel, have emerged as new standards of care for the
frst-line treatment of metastatic pancreatic cancer, both
based on randomized phase III trials that show more clinically meaningful benefts when compared with gemcitabine.
Despite these recent advances, the median survival for patients with metastatic disease remains less than a year, highlighting a desperate need to continue the developmental
therapeutic path in pancreatic cancer.
From the The Ohio State University Wexner Medical Center, Columbus, OH; UCSF Helen Diller Comprehensive Cancer Center, San Francisco, CA; University Hospitals Seidman Cancer Center, Case
Comprehensive Cancer Center, Case Western University, Cleveland, OH.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Tanios S. Bekaii-Saab, MD, The Ohio State University Wexner Medical Center, A454 Starling Loving Hall, 320 W. 10th Ave., Columbus, OH 43215; email:
tanios.saab@osumc.edu.
2015 by American Society of Clinical Oncology.
e222
Sample
Size
Survival,
Median (Months)
Hazard Ratio
126
Not reported
Gemcitabine/erlotinib
vs. gemcitabine
569
342
Gemcitabine/nab-paclitaxel
vs. gemcitabine
5-FU/leucovorin MM-398
vs. 5-FU
Toxicities (Grade 3 to 4)
Author
5.4
Neutropenia 25.9%
0.82
8.6
Moore et al 20073
0.57
31.6
Conroy et al 201145
861
0.72
23
417
0.57
16
KEY POINTS
Pancreatic cancer remains a devastating disease with an
increasing prevalence and the highest mortality rate of any
malignancy.
Cytotoxic chemotherapy remains the primary treatment for
advanced pancreatic cancer, with several new combination
regimens emerging as rst-line standards.
New agents targeting the tumor microenvironment and
cancer-signaling pathways are being investigated in
pancreatic cancer.
Although pancreatic cancer has been mostly considered an
immunosuppressive malignancy, developments have
renewed interest in immunotherapy as a treatment option
in this disease.
Attention to the value of new therapeutics is critical to
prioritizing efforts and selecting treatment for individual
patients.
ment strategy. Synthetic lethality occurs when a combination of mutations in two or more genes leads to cell death,
whereas, a single mutation does not and by itself remains
viable. Tumors harboring defective DNA repair mechanisms render them vulnerable to synthetic-lethality approaches, leading to the use of targeted agents that
induced the death of tumor cells while sparing normal
cells. Mutations in genes, including tumor suppressor
genes (BRCA 1/2, ATM), may confer an increased sensitivity to DNA-damaging cytotoxic chemotherapy including platinum analogs and PARP inhibitors because of the
associated defective homologous recombination and an
inability to mount effcient DNA repair.18,19 In specifc
subgroups of patients, including those of Ashkenazi
Jewish descent and individuals with a family history of
pancreatic cancer, the prevalence of germ-line mutations
of BRCA1 and BRCA2 has been reported in as many as
19%.20,21 For patients with germ-line BRCA1/BRCA2 mutations, a phase III randomized, double-blind study, the
POLO trial, is investigating the use of the PARP inhibitor
olaparib in patients with metastatic pancreatic cancer
whose disease has not progressed on frst-line platinumbased chemotherapy (ClinicalTrials.gov NCT02184195).
IMMUNOTHERAPEUTIC APPROACHES IN
PANCREAS CANCER
Targeting PD-1/PD-L1
Except for melanoma, renal cell carcinoma, and prostate
cancer, immunotherapy for solid tumors remains experimental. Tumors resist an immune response by inducing
tolerance in tumor-specifc T cells and by expressing ligands that bind to inhibitory receptors, or immune checkpoints on T cells, which dampen their immune response
against tumors. Immunotherapeutic approaches, notably
agents targeting negative regulatory molecules on activated T cells, such as cytotoxic T lymphocyte antigen-4
(CTLA-4), programmed death-1 (PD-1), and its binding
ligand, programmed death ligand 1 (PD-L1), are showing
promise in a number of malignancies. Antagonism of
these immune checkpoints can augment the nascent antitumor response from the immune system.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e223
AHN ET AL
Pancreatic cancer has been mostly considered an immunosuppressive malignancy, with pancreatic cancer cells producing cytokines (transforming growth factor-beta) and
surface molecules that mediate immunosuppression
(FAsL, PDL-1). Moreover, it has been mostly considered a
nonimmunogenic malignancy, since tumor-infltrating
effector T lymphocytes do not represent a histopathologic
hallmark for this disease. Therapeutic approaches focusing on overcoming T-cell immunologic checkpoints with
anti-CTLA-4 and anti-PD1 monoclonal antibodies alone
have failed to demonstrate any meaningful activity in pancreatic cancer to date.22,23 However, studies investigating
the combination of checkpoint inhibitors with immune
resensitizing agents are currently in development in this
disease, as described below.
VACCINE THERAPIES
With molecular identifcation of human tumor antigens,
antitumor vaccine therapies specifcally sensitize immune
cells against tumor antigens. Several types of vaccinations
are under investigation against pancreatic cancer, including whole-cell, peptide, DNA, and vaccines with microorganisms.
GVAX
GVAX is an irradiated whole-cell modifed vaccine composed of two irradiated pancreatic cancer cell lines (PANC
6.03 and PANC 10.05) engineered to express granulocytemacrophage colony-stimulating factor (GM-CSF), a
growth factor that plays a key role in stimulating the immune system response by inducing dendritic cell differentiation. Administration of GVAX in addition to standard
5-FU-based chemoradiation as part of adjuvant therapy
after pancreatic cancer resection demonstrated promising
results in a single-institution phase II trial.24 Moreover,
several studies investigating the immunologic effects of
GVAX have demonstrated its ability to create an inflammatory reaction causing an upregulation of PD-L1, suggesting the potential utility of combining this vaccine with
immune checkpoint inhibitors.25,26
CRS-207
An alternative immune-based strategy undergoing clinical investigation in pancreatic cancer is CRS-207, a
live-attenuated Listeria monocytogenes (LM) vaccine
(CRS-207, Aduro Biosciences, Berkeley, CA) genetically
modifed to express mesothelin, which is often overexpressed in pancreatic cancer. A recent randomized phase
II trial in patients with chemotherapy-refractory metastatic pancreatic cancer suggested a signifcant improvement in overall survival when sequential treatment with
GVAX/CRS-207 was administered, as compared with
GVAX alone (median OS, 6.1 vs. 3.9 months; hazard ratio
e224
[HR] 0.59, p 0.02).27 These fndings have led to an ongoing phase IIB randomized control trial comparing CRS207 alone to CRS-207 in combination with GVAX or to
chemotherapy in previously treated metastatic pancreatic
cancer (ClinicalTrials.gov NCT02004262). Another phase
II study is investigating the use of GVAX in combination
with CRS-207 with or without nivolumab, an anti-PD-1
monoclonal antibody, in previously treated metastatic
pancreatic cancer (ClinicalTrials.gov NCT02243371).
ALGENPANTUCEL-L
Algenpantucel-L (NewLink Genetics Corporation, Ames,
Iowa) is a whole-cell vaccine made of two human pancreatic
cancer cell lines (HAPa-1 and HAPa-2) that are genetically
modifed to express alpha1,3-galactosyl epitopes (alphaGAL),
a carbohydrate present in the cells of most mammals except
humans, which have developed pre-existing immunity. On
injection, algenpantucel-L induces an immune response that
parallels the hyperacute rejection that can occur postorgan
transplant. An open-label phase II trial of this vaccine in
combination with adjuvant chemotherapy and chemoradiation in resected pancreatic cancer demonstrated promising
1-year disease-free survival and OS rates (62% and 86%,
respectively).28 On this basis, a large phase III trial was
recently completed in the United States, evaluating standard adjuvant chemotherapy or chemoradiation with or
without algenpantucel-L in resected pancreatic cancer
(ClinicalTrials.gov NCT01072981).
ONCOLYTIC VIROTHERAPY
Because of their tumor selectivity and ability to cause cancer
cell lysis, oncolytic viruses continue to represent an area of
considerable interest in cancer treatment. These viruses selectively target tumor cells through engineered mutations
that prevent the binding and replication of the virus in normal, healthy cells and attack specifc tumor epitopes that lead
to cancer cell death.
Reovirus is a family of naturally occurring, ubiquitous nonenveloped human virus whose replication is dependent on cellular
activity of RAS; specifcally, it is cytopathic in transformed
cells possessing an activated RAS signaling pathway.29-32
Given the prevalence of KRAS mutations in pancreatic cancer, reovirus has represented a promising and attractive candidate as an oncolytic virus in this disease. Bekaii-Saab et al
reported the results of a phase II randomized trial in which 73
patients with metastatic pancreatic adenocarcinoma were
randomly assigned to receive carboplatin/paclitaxel alone or
in combination with Reolysin.33 Although this agent was well
tolerated overall, it failed to show an improvement in outcomes, including in those patients with KRAS mutations. Investigation into other oncolytic viruses (adenovirus,
parvovirus, pox virus, measles virus) continues in patients
with pancreatic cancer.
Regimen
Gemcitabine
Gemcitabine/
nab-paclitaxel
FOLFIRINOX
Gemcitabine/
erlotinib
Monthly
Costs
of Drugs
Total
Monthly
Cost
Monthly Cost
of Administration
Monthly Cost
of Toxicities**
$188
$143
$1,0322
$1,363
$9,008
$522
$2,692
$12,221
$763
$531
$5,940
$7,234
$6,831
$143
$1,0322
$8,007
*All costs were calculated in U.S. dollars ($). The unit price of each drug was determined
from the 2013 average sales price from the Centers for Medicare & Medicaid Services. Fees
for administration and toxicities were calculated according to the 2013 physician fee
schedule.49
**The cost of growth factor is included.
The cost of growth factor is based on data extrapolated from the gemcitabine arm in the
MPACT trial.46
e225
AHN ET AL
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Tanios S.
Bekaii-Saab, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Genentech/Roche, Lilly, NCCN, Regeneron. Andrew H. Ko, Celgene, Incyte Corporation,
Oncogenex, Threshold Pharmaceuticals. Neal J. Meropol, BioMotiv. Daniel Ahn, Celltrion (I). Speakers Bureau: None. Research Funding: Tanios S.
Bekaii-Saab, NCCN, NCI, Oncolytics Biotech. Andrew H. Ko, Aduro Biosciences (Inst), Celgene (Inst), ImClone Systems (Inst), Innity (Inst), PharmaEngine (Inst),
PRISM BioLab (Inst), Seattle Genetics (Inst). Patents, Royalties, or Other Intellectual Property: Neal J. Meropol, US Patent (20020031515): Methods of
therapy for cancers characterized by over expression of the HER2 receptor protein. Expert Testimony: None. Travel, Accommodations, Expenses: None.
Other Relationships: Tanios S. Bekaii-Saab, Exelixis DSMB, Polaris DSMB.
References
1. Weir HK, Thun MJ, Hankey BF, et al. Annual report to the nation on the
status of cancer, 1975-2000, featuring the uses of surveillance data for
cancer prevention and control. J Natl Cancer Inst. 2003;95:1276-1299.
2. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin.
2014;64:9-29.
3. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical
Trials Group. J Clin Oncol. 2007;25:1960-1966.
4. Chu GC, Kimmelman AC, Hezel AF, et al. Stromal biology of pancreatic
cancer. J Cell Biochem. 2007;101:887-907.
5. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation.
Cell. 2011;144:646-674.
6. Hwang RF, Moore T, Arumugam T, et al. Cancer-associated stromal
fbroblasts promote pancreatic tumor progression. Cancer Res. 2008;68:
918-926.
7. Vonlaufen A, Phillips PA, Xu Z, et al. Pancreatic stellate cells and
pancreatic cancer cells: an unholy alliance. Cancer Res. 2008;68:
7707-7710.
8. Ikenaga N, Ohuchida K, Mizumoto K, et al. CD10 pancreatic stellate
cells enhance the progression of pancreatic cancer. Gastroenterology.
2010;139:1041-1051, 1051.e1-8.
9. Lunardi S, Muschel RJ, Brunner TB. The stromal compartments in pancreatic cancer: are there any therapeutic targets? Cancer Lett. 2014;343:
147-155.
10. Von Hoff DD, Ramanathan RK, Borad MJ, et al. Gemcitabine plus nabpaclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011;29:4548-4554.
11. Infnity Pharmaceuticals. Infnity reports update from phase 2 study of
saridegib plus gemcitabine in patients with metastatic pancreatic
cancer. http://phx.corporate-ir.net/phoenix.zhtml?c121941&pirolnewsArticle&ID1653550. Accessed January 10, 2015.
12. Provenzano PP, Cuevas C, Chang AE, et al. Enzymatic targeting of the
stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21:418-429.
13. Hingorani SR, Harris WP, Beck JT, et al. Final results of a phase Ib study
of gemcitabine plus PEGPH20 in patients with stage IV previously untreated pancreatic cancer. J Clin Oncol. 2015;33:3s (suppl; abstr 359).
14. Morris JP 4th, Wang SC, Hebrok M. KRAS, Hedgehog, Wnt and the
twisted developmental biology of pancreatic ductal adenocarcinoma.
Nat Rev Cancer. 2010;10:683-695.
15. Kanda M, Matthaei H, Wu J, et al. Presence of somatic mutations in
most early-stage pancreatic intraepithelial neoplasia. Gastroenterology.
2012;142:730-733.e9.
e226
16. Hruban RH, Goggins M, Parsons J, et al. Progression model for pancreatic cancer. Clin Cancer Res. 2000;6:2969-2972.
17. Ko AH, Tempero MA, Bekaii-Saab TB, et al. Dual MEK/EGFR inhibition for advanced, chemotherapy-refractory pancreatic cancer: A multicenter phase II trial of selumetinib (AZD6244; ARRY-142886) plus
erlotinib. J Clin Oncol. 2013;31 (suppl; abstr 4014).
18. Lee JM, Ledermann JA, Kohn EC. PARP Inhibitors for BRCA1/2 mutationassociated and BRCA-like malignancies. Ann Oncol. 2014;25:32-40.
19. Yap TA, Sandhu SK, Carden CP, et al. Poly(ADP-ribose) polymerase
(PARP) inhibitors: exploiting a synthetic lethal strategy in the clinic. CA
Cancer J Clin. 2011;61:31-49.
20. Stadler ZK, Salo-Mullen E, Patil SM, et al. Prevalence of BRCA1 and
BRCA2 mutations in Ashkenazi Jewish families with breast and pancreatic cancer. Cancer. 2012;118:493-499.
21. Murphy KM, Brune KA, Griffn C, et al. Evaluation of candidate genes
MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer:
deleterious BRCA2 mutations in 17%. Cancer Res. 2002;62:3789-3793.
22. Royal RE, Levy C, Turner K, et al. Phase 2 trial of single agent ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic
adenocarcinoma. J Immunother. 2010;33:828-833.
23. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune
correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:
2443-2454.
24. Lutz E, Yeo CJ, Lillemoe KD, et al. A lethally irradiated allogeneic
granulocyte-macrophage colony stimulating factor-secreting tumor
vaccine for pancreatic adenocarcinoma. A Phase II trial of safety, effcacy, and immune activation. Ann Surg. 2011;253:328-335.
25. Lutz ER, Wu AA, Bigelow E, et al. Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol Res. 2014;2:616-631.
26. Soares KC, Rucki AA, Wu AA, et al. PD-1/PD-L1 blockade together
with vaccine therapy facilitates effector T-cell infltration into pancreatic tumors. J Immunother. 2015;38:1-11.
27. Le DT, Wang-Gillam A, Picozzi V, et al. Safety and survival with GVAX
pancreas prime and listeria monocytogenes-expressing mesothelin
(CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol.
Epub 2015 Jan 12.
28. Hardacre JM, Mulcahy M, Small W, et al. Addition of algenpantucel-L immunotherapy to standard adjuvant therapy for pancreatic cancer: a phase 2
study. J Gastrointest Surg. 2013;17:94-100; discussion p. 100-101.
29. Bodkin DK, Nibert ML, Fields BN. Proteolytic digestion of reovirus in
the intestinal lumens of neonatal mice. J Virol. 1989;63:4676-4681.
30. Rosen L, Evans HE, Spickard A. Reovirus infections in human volunteers. Am J Hyg. 1963;77:29-37.
31. Battcock SM, Collier TW, Zu D, et al. Negative regulation of the alpha
interferon-induced antiviral response by the Ras/Raf/MEK pathway.
J Virol. 2006;80:4422-4430.
32. Strong JE, Coffey MC, Tang D, et al. The molecular basis of viral oncolysis: usurpation of the Ras signaling pathway by reovirus. EMBO J.
1998;17:3351-3362.
33. Bekaii-Saab T, Noonan AM, Lesinksi G, et al. A multi-institutional randomized phase 2 trial of the oncolytic virus reolysin in the frst line treatment metastatic adenocarcinoma of the pancreas. Ann Oncol. 2014;25:
1-41 doi: 10.1093/annonc/mdu438.19.
34. Lesina M, Kurkowski MU, Ludes K, et al. Stat3/Socs3 activation by IL-6
transsignaling promotes progression of pancreatic intraepithelial neoplasia
and development of pancreatic cancer. Cancer Cell. 2011;19:456-469.
35. Fearon KC, Barber MD, Falconer JS, et al. Pancreatic cancer as a model:
inflammatory mediators, acute-phase response, and cancer cachexia.
World J Surg. 1999;23:584-588.
36. Hurwitz H, Uppal N, Wagner SA, et al. A randomized double-blind
phase 2 study of ruxolitinib (RUX) or placebo (PBO) with capecitabine
(CAPE) as second-line therapy in patients (pts) with metastatic pancreatic cancer (mPC). J Clin Oncol. 2014;32:5s (suppl; abstr 4000).
37. Maus MV, Haas AR, Beatty GL, et al. T cells expressing chimeric antigen
receptors can cause anaphylaxis in humans. Cancer Immunol Res. 2013;
1:26-31.
38. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for
sustained remissions in leukemia. N Engl J Med. 2014;371:1507-1517.
39. Meropol NJ, Schulman KA. Cost of cancer care: issues and implications.
J Clin Oncol. 2007;25:180-186.
40. Meropol NJ, Schrag D, Smith TJ, et al. American Society of Clinical Oncology guidance statement: the cost of cancer care. J Clin Oncol. 2009;
27:3868-3874.
41. Attard CL, Brown S, Alloul K, et al. Cost-effectiveness of folfrinox for frst-line
treatment of metastatic pancreatic cancer. Curr Oncol. 2014;21:e41-e51.
42. Hollman S, Alloul K, Attard C, et al. PD-0018. An indirect treatment
comparison and cost-effectiveness analysis comparing FOLFIRINOX
with nab-paclitaxel plus gemcitabine for frst-line treatment for patients
with metastatic pancreatic cancer. Ann Oncol. 2014;25:ii11-ii12.
43. Ellis LM, Bernstein DS, Voest EE, et al. American Society of Clinical
Oncology perspective: raising the bar for clinical trials by defning clinically meaningful outcomes. J Clin Oncol. 2014;32:1277-1280.
44. Burris HA 3rd, Moore MJ, Andersen J, et al. Improvements in survival
and clinical beneft with gemcitabine as frst-line therapy for patients
with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;
15:2403-2413.
45. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine
for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817-1825.
46. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic
cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:
1691-1703.
47. Von Hoff D, Li CP, Wang-Gilliam A, et al. NAPOLI-1: randomized
phase 3 study of MM-398, with or without 5-fluorouracil and leucovorin, versus 5-fluorouracil and leucovorin, in metastatic pancreatic
cancer progressed on or following gemcitabine-based therapy. Ann Oncol. 2014;25:ii105-ii106.
48. Goldstein DA, Krishna K, Flowers C, et al. Cost description of chemotherapy regimens for the treatment of metastatic pancreas cancer
(mPC). J Clin Oncol. 2015;33:3s (suppl; abstr 368).
49. Goldstein DA, Chen Q, Ayer T, et al. First- and second-line bevacizumab in addition to chemotherapy for metastatic colorectal cancer: a
United States-based cost-effectiveness analysis. J Clin Oncol. Epub 2015
Feb 17.
e227
Nutritional Support in
Gastrointestinal Malignancies
CHAIR
Vincent J. Picozzi, MD
Virginia Mason Medical Center
Seattle, WA
SPEAKERS
Maria Q.B. Petzel, RD, CSO
The University of Texas MD Anderson Cancer Center
Houston, TX
Egidio Del Fabbro, MD
Virginia Commonwealth University
Richmond, VA
Current and Future Care of Patients with the Cancer AnorexiaCachexia Syndrome
Egidio Del Fabbro, MD
OVERVIEW
Many important advances have occurred in the eld of cancer cachexia over the past decade, including progress in understanding the
mechanisms of the cancer anorexia-cachexia syndrome (CACS) and the development of promising pharmacologic and supportive care
interventions. However, no approved agents for cancer cachexia currently exist, emphasizing the unmet need for an effective
pharmacologic therapy. This article reviews the key elements of CACS assessment in daily practice, the contribution of nutritional
impact symptoms (NIS), the evidence for current pharmacologic options, and promising anticachexia agents in perclinical and clinical
trials. It also proposes a model for multimodality therapy and highlights issues pertinent to CACS in patients with pancreatic, gastric,
and esophageal cancer.
even at lower doses.6 Outpatients with esophageal or pancreatic cancer have the highest nutritional risk scores, and more
than 80% experience anorexia and weight loss even when
they have a performance status (PS) of 1.7
ASSESSMENT OF PATIENTS
A consensus defnition of cancer cachexia is important for
clinical trial design and for identifying patients with the syndrome in clinical practice. Ideally, patients who are at risk
should be identifed early to provide the greatest opportunity
for effective intervention. A delay could result in uncontrolled symptoms, poorer quality of life, and more rapid entry into the refractory stage of cachexia. A recent study of
body composition imaging by CT of 368 patients shows 5%
or less of patients gained muscle within 90 days of death, suggesting the anabolic opportunity for intervention probably
exists early in the disease trajectory.8
Denition
Cancer cachexia is defned as a multifactorial syndrome characterized by ongoing loss of skeletal muscle mass (with or
without loss of fat) leading to progressive functional impairment, which cannot be fully reversed by conventional nutritional support.9 Based on the current defnition, detection of
cancer cachexia centers on involuntary weight loss of more
than 5% over 6 months (or 2% when evidence of sarcopenia is
present).9,10 Recently, attempts have been made to incorporate anorexia severity, PS, and markers of inflammation, such
as C-reactive protein, into staging criteria for the identifca-
From the Palliative Care Program, Virginia Commonwealth University, Richmond, VA.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Egidio del Fabbro, MD, Virginia Commonwealth University, 1101 E. Marshall St., Richmond, VA 23298; email: edelfabbro@vcu.edu.
2015 by American Society of Clinical Oncology.
e229
tion of precachexia, cachexia, and refractory cachexia. A simple, objective, systemic inflammationbased approach using
C-reactive protein and albumin has prognostic value independent of tumor stage, PS, and treatment in a variety of advanced tumors, but it has yet to be incorporated into the
screening or staging of cancer cachexia.11,12 More research is
required to identify simple patient-reported outcomes or
biomarkers that could help classify patients into early and
late stages of cachexia.
Assessment Tools
A brief standardized assessment that includes NIS such as
nausea, depression, and severe pain should be performed on
all oncology patients who are at risk for CACS (Fig. 1). Unfortunately, the American Society of Clinical Oncologys
Quality Oncology Practice Initiative does not currently include any specifc questions about appetite,13 and without
systematic inquiry, symptoms such as anorexia may not be
identifed by oncologists, since patients volunteer few symptoms relative to their total symptom experience.14
The 10-item Edmonton Symptom Assessment Scale
(ESAS) has shown a high prevalence of multiple symptoms in
ambulatory patients with cancer, similar to the symptom
burden reported in palliative care populations.15 The ESAS
assesses symptom severity, including appetite, but does not
include other CACS-relevant symptoms such as constipation, early satiety, or dysgeusia. A more comprehensive evaluation requires an additional assessment measure such as the
Patient-Generated Subjective Global Assessment (PG-SGA):
an American Dietetic Society endorsed questionnaire that
identifes additional reversible factors contributing to poor
oral intake. A recently validated brief version, the a-PG-SGA,
can be completed in less than 5 minutes and provides additional diagnostic and prognostic value for patients with cancer.16 Using these simple tools for symptom and nutritional
assessment, along with a history of 5% or more weight loss
during the past 6 months would identify many patients with
CACS.
KEY POINTS
The cancer anorexia-cachexia syndrome (CACS) is common
in patients with upper gastrointestinal cancers and is
associated with decreased survival and poor tolerance to
chemotherapy.
No approved drugs currently exist for CACS, suggesting an
unmet need.
Preliminary studies using multimodality therapy with
pharmacologic and nonpharmacologic interventions have
demonstrated improved clinical outcomes.
A brief standardized assessment to identify CACS and the
symptoms contributing to decreased caloric intake is
necessary.
Recent phase II trials have shown improved clinical
outcomes for a number of single agents.
e230
CURRENT MANAGEMENT
The clinical assessment and management should focus on
nutrition (quantity and composition), symptoms contributing to poor oral intake, weight and body composition, and
identifcation of any reversible metabolic abnormalities
(Figs. 2 and 3).
Symptom Management
NIS such as nausea, depression, severe pain, dysgeusia, gastroparesis, and constipation can contribute to decreased caloric intake and weight loss in patients with CACS (Fig. 3). In
addition, comorbid metabolic abnormalities such as hypogo-
nadism, thyroid dysfunction, and vitamin B12 and D defciencies may contribute to fatigue, muscle weakness, and
poor appetite. Other causes of weight loss that have a predominant starvation component such as gastrointestinal
obstruction should be identifed, especially if they are reversible and respond to endoscopic or surgical treatment
e231
PHARMACOLOGIC INTERVENTIONS
Current Agents
Progestational agents. Systematic reviews indicate that
megestrol acetate (MA) plays a role in CACS by increasing
e232
appetite and body weight compared to placebo.39-41 However, these improved outcomes found in a minority of patients should be weighed against potentially serious side
effects and a failure to show better quality of life compared to
other interventions.42 In addition, the weight gain MAinduced weight gain may be predominantly fat or fluid,
rather than muscle.43
An updated Cochrane review in 201342 evaluated 35 trials
(23 with cancer), including 928 patients with gastrointestinal
or pancreatic cancer. Approximately one in four patients taking MA for cachexia (e.g., to treat cancer or AIDS) had an
increase in appetite, while one in 12 experienced weight increase. Safety was evaluated in 3,180 patients. Dyspnea,
edema, impotence, and thromboembolic phenomena were
more common in patients taking MA, and deaths were increased, especially with higher doses. Since the median treatment duration was 8 weeks and follow-up length was short,
the authors suggest adverse events may become even more
relevant with prolonged use. Although some earlier studies
showed improvement in fatigue as a secondary endpoint,44,45
there are concerns prolonged suppression of gonadal and adrenal function by MA could exacerbate symptoms such as
fatigue and poor libido.46 Symptomatic adrenal suppression
may be particularly problematic in pediatric patients with
cancer, and stress-dose hydrocortisone is suggested for patients with acute illness or undergoing surgery.47
Because of the increased risk for mortality and thromboembolism, patients should be informed of the potentially serious side effects. MA should be reserved for patients placing
a high priority on improved appetite, since MA may have an
antianabolic effect by decreasing muscle size.48 Given that increased mortality is associated with higher doses of MA, it
may be prudent to start at lower doses and monitor response.
The optimal dose for weight gain is more than 400 mg/day,
although improvements in appetite have been reported at
160 mg/day4.
Corticosteroids. Although small randomized trials have
shown corticosteroids improve symptoms of anorexia and
fatigue,49,50 only recently have two randomized, placebocontrolled trials confrmed their effcacy. In patients with
advanced cancer (predominantly head and neck or gastrointestinal tumors), 4 mg dexamethasone twice daily for 14 days
signifcantly improved fatigue (p 0.008) and anorexia
(p 0.013) compared to placebo, with similar adverse
events.51 Notably, the physical domain of health-related,
rather than the psychologic, quality of life improved. A prior
positive trial in advanced gastrointestinal cancers had speculated the benefts of corticosteroids were largely caused by
mood elevation.17 A second recent study compared 7 days of
16 mg methylprednisolone twice daily to placebo and similarly showed improvements in fatigue and anorexia but no
difference in the primary outcome of pain intensity.52
Despite improvement in appetite and fatigue in the short
term, no studies have demonstrated any beneft on LBM, and
prolonged use can cause proximal myopathy.53 Although
dexamethasone is considered preferable over other corticosteroids because of its lower mineralocorticoid effect,
common toxicities include candidiasis, edema, cushingoid
changes, depression, and anxiety.54 Based on recent placebocontrolled clinical trials and the rapid onset of effect, dexamethasone seems most appropriate for short-term use in
patients near the end of life.
Cannabinoids. Cannabinoids such as dronabinol and
nabilone are approved for chemotherapy-related nausea in
patients not responding to conventional antiemetics.55
Dronabinol is also approved for treatment of anorexia in patients with AIDS,56 but unfortunately, the evidence for any
beneft in cancer cachexia is very limited. A multicenter
randomized trial of 289 patients with advanced cancer compared the effects of cannabis extract delta-9-tetrahydrocannabinol (2.5 mg twice daily) and placebo on appetite and
quality of life.57 Consistent with other symptom intervention
studies, there was a signifcant placebo effect and improved
appetite in all three groups but no differences between the
groups (p 0.15). A lack of intrapatient dose escalation may
be considered a limitation; however, the dose was based an
earlier phase II study showing a higher risk of adverse psychotropic effects and dropouts in patients taking higher
doses of dronabinol (5 vs. 2.5 mg).58
A multicenter randomized controlled trial (RCT) of 469
patients compared MA and dronabinol combination therapy
to either agent alone for appetite stimulation in patients with
lung or gastrointestinal cancer.59 MA was superior to dronabinol alone, and combination therapy did not provide any
additional beneft. Despite the consistently negative results in
large trials, a recent single RCT showed that dronabinol improved taste and protein consumption in patients with cancer who had dysgeusia.60
Fish oil or eicosapentanoic acid. Despite eicosapentanoic
acid (EPA) showing initial benefts for CACS and fatigue in
patients with pancreatic cancer,61 three systematic reviews
found insuffcient evidence for EPA in the management of
cancer cachexia.62-64 Although no serious adverse effects
were reported, abdominal discomfort, belching, nausea, and
diarrhea often affected quality of life. More recently, there is
renewed interest in fsh oil after two small RCTs showed improved weight and muscle mass in patients with nonsmall
cell lung cancer (NSCLC) at initiation of frst-line chemotherapy.65,66
Thalidomide. A recent Cochrane review of thalidomide in
cancer cachexia found insuffcient evidence for clinical practice.67 Unfortunately, the review follows a study in patients
with esophageal cancer showing no beneft and poor tolerability to thalidomide,68 despite earlier trials in pancreatic69
and esophageal cancer70 that found improvements in LBM
and minimal side effects after 4 weeks of 200 mg/day. More
recently a phase II trial found improved appetite and minimal side effects with doses of 50 and 100 mg.71 More trials are
probably warranted; however, other studies of thalidomide
have experienced diffculty in patient accrual.72
New Agents
Despite a number of promising interventions on the horizon,
enobosarm and anamorelin are the only agents completing
phase III RCTs.
Androgens. Hypogonadism is common in male patients with
cancer and is associated with increased symptom burden including fatigue, anorexia, and diminished libido.41-45 Although testosterone replacement has improved muscle mass
and strength in HIV-positive men,46 it has not been studied
in large, RCTs for patients with cancer. A preliminary,
double-blind, placebo-controlled trial of testosterone replacement in men with advanced cancer who had hypogonadism showed signifcant improvement in fatigue after 10
weeks (p 0.003) but no effect on appetite or weight.47
Selective androgen receptor modulators theoretically produce greater anabolic effects with fewer side effects such as
prostatic hypertrophy. A phase II RCT of enobosarm for patients with advanced cancer who had cachexia found increased LBM and physical function compared to baseline
with minimal side effects.73 Preliminary results from a phase
III placebo-controlled trial showed an increase in LBM (p
0.036) in patients with NSCLC on enobosarm treated with
platinum plus taxane.74 Physical function as assessed by stairclimb power was not signifcantly better in patients receiving
enobosarm. Final results are awaited.
Ghrelin and ghrelin mimetics. Ghrelin, an orexigenic hormone, enhances appetite and food intake in humans. A phase
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e233
geting the myostatin pathway reversed muscle wasting, increased grip strength, stimulated appetite, and prolonged
survival, independently of tumor progression.78,79
Few recent clinical trials have targeted proinflammatory
cytokines, except for a phase I trial of a mAB against interleukin alfa-1 that showed a median weight gain of 1 kg from
baseline and no dose-limiting toxicities.80
Multimodal therapy for the cancer anorexia-cachexia syndrome. Even though new single agents show potential for
improving outcomes, a more effective approach might be
simultaneous, multifaceted therapy targeting the different
mechanisms contributing to CACS (Fig. 4).81 Several studies have used a combination of pharmacologic agents for
CACS.
A progestin in combination with an EPA, L-carnitine, and
thalidomide signifcantly increased appetite, LBM (p
0.007), and spontaneous physical activity, although there was
no placebo arm.82 Beta blockers83 and insulin84 have also
been used as multimodality therapy in combination with
nonsteroidal anti-inflammatories (NSAIDs), showing bene-
e234
fts in reducing elevated resting energy expenditure and attenuation of weight loss and also improvements in survival
(p 0.03). Although NSAIDs have been combined with
other agents and have demonstrated improvement in some
clinical outcomes, a systematic review concluded that the risk
of side effects and insuffcient evidence suggest NSAIDs
should be restricted to clinical trials.85
CONCLUSION
Because the causes of muscle wasting and poor caloric intake
in patients with CACS are multifactorial, a comprehensive
multidimensional approach using pharmacologic and non-
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Egidio Del
Fabbro, Helsinn Therapeutics. Speakers Bureau: None. Research Funding: Egidio Del Fabbro, Helsinn Therapeutics, Novartis. Patents, Royalties, or
Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Bachmann J, Heiligensetzer M, Krakowski-Roosen H, et al. Cachexia
worsens prognosis inpatients with resectable pancreatic cancer. J Gastrointest Surg. 2008;12:1193-1201.
2. Hauser CA, Stockler MR, Tattersall MH. Prognostic factors in patients
with recently diagnosed incurable cancer: a systematic review. Support
Care Cancer. 2006;14:999-1011.
3. Quinten C, Coens C, Mauer M, et al. Baseline quality of life as a prognostic indicator of survival: a meta-analysis of individual patient data
from EORTC clinical trials. Lancet Oncol. 2009;10:865-871.
4. Dewys WD, Begg C, Lavin PT, et al. Prognostic effect of weight loss prior
to chemotherapy in cancer patients. Am J Med. 1980;69:491-497.
5. Jatoi A. Weight loss in patients with advanced cancer: effects, causes, and potential management. Curr Opin Support Palliat Care. 2008;2:45-48.
6. Andreyev HJ, Norman AR, Oates J, et al. Why do patients with weight
loss have a worse outcome when undergoing chemotherapy for gastrointestinal malignancies? Eur J Cancer. 1998;34:503-509.
7. Bozzetti F, Mariani L, Lo Vullo S, et al. The nutritional risk in oncology:
a study of 1,453 cancer outpatients. Support Care Cancer. 2012;20:19191928.
8. Prado CM, Sawyer MB, Ghosh S, et al. Central tenet of cancer cachexia
therapy: do patients with advanced cancer have exploitable anabolic potential? Am J Clin Nutr. 2013;98:1012-1019.
9. Fearon K, Strasser F, Anker SD, et al. Defnition and classifcation of cancer
cachexia: an international consensus. Lancet Oncol. 2011;12:489-495.
10. Vigano A, Del Fabbro E, Bruera E, et al. The cachexia clinic: from staging to managing nutritional and functional problems in advanced cancer patients. Crit Rev Oncog. 2012;17:293-303.
11. Douglas E, McMillan DC. Towards a simple objective framework for the
investigation and treatment of cancer cachexia: the Glasgow Prognostic
Score. Cancer Treat Rev. 2014;40:685-691.
12. McMillan DC. An inflammation-based prognostic score and its role in
13.
14.
15.
16.
17.
18.
19.
20.
21.
e235
e236
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61. Fearon KC, Von Meyenfeldt MF, Moses AG, et al. Effect of a protein and
energy dense N-3 fatty acid enriched oral supplement on loss of weight
and lean tissue in cancer cachexia: a randomised double blind trial. Gut.
2003;52:1479-1486.
62. Dewey A, Baughan C, Dean T, et al. Eicosapentaenoic acid (EPA, an
omega-3 fatty acid from fsh oils) for the treatment of cancer cachexia.
Cochrane Database Syst Rev. 2007;1:CD004597.
63. Ries A, Trottenberg P, Elsner F, et al. A systematic review on the role of
fsh oil for the treatment of cachexia in advanced cancer: an EPCRC
cachexia guidelines project. Palliat Med. 2012;26:294-304.
64. Mazzotta P, Jeney CM. Anorexia-cachexia syndrome: a systematic review of the role of dietary polyunsaturated fatty acids in the management of symptoms, survival, and quality of life. J Pain Symptom Manage.
2009;37:1069-1077.
65. Murphy RA, Mourtzakis M, Chu QS, et al. Nutritional intervention with
fsh oil provides a beneft over standard of care for weight and skeletal
muscle mass in patients with nonsmall cell lung cancer receiving chemotherapy. Cancer. 2011;117:1775-1782.
66. van der Meij BS, Langius JA, Spreeuwenberg MD, et al. Oral nutritional
supplements containing n-3 polyunsaturated fatty acids affect quality of
life and functional status in lung cancer patients during multimodality
treatment: an RCT. Eur J Clin Nutr. 2012;66:399-404.
67. Reid J, Mills M, Cantwell M, et al. Thalidomide for managing cancer
cachexia. Cochrane Database Syst Rev. 2012;4:CD008664.
68. Wilkes EA, Selby AL, Cole AT, et al. Poor tolerability of thalidomide in
end-stage oesophageal cancer. Eur J Cancer Care. 2011;20:593-600.
69. Gordon JN, Trebble TM, Ellis RD, et al. Thalidomide in the treatment of
cancer cachexia: a randomized placebo controlled trial. Gut. 2005;54:
540-545.
70. Khan Z H, Simpson EJ, Cole AT, et al. Oesophageal cancer and cachexia:
the effect of short-term treatment with thalidomide on weight loss and
lean body mass. Aliment Pharmacol Ther. 2003;17,677-682.
71. Davis M, Lasheen W, Walsh D, et al. A phase II dose titration study of
thalidomide for cancer-associated anorexia. J Pain Symptom Manage.
2012;43:78-86.
72. Yennurajalingam S, Willey JS, Palmer JL, et al. The role of thalidomide
and placebo for the treatment of cancer-related anorexia-cachexia
symptoms: results of a double-blind placebo-controlled randomized
study. J Palliat Med. 2012;15:1059-1064.
73. Dobs AS, Boccia RV, Croot CC, et al. Effects of enobosarm on muscle
wasting and physical function in patients with cancer: a double-blind,
randomised controlled phase 2 trial. Lancet Oncol. 2013;14:335-345.
74. Crawford J, Dalton JT, Hancock ML, et al. Enobosarm, a selective androgen receptor modulator (SARM), increases lean body mass (LBM) in
advanced non-small cell lung cancer patients in two pivotal, international Phase 3 trials. Presented at the MASCC/ISOO International Symposium on Supportive Care in Cancer. Miami, FL. June 26-28, 2014.
Abstract MASCC-0546.
75. Inui A. Ghrelin: an orexigenic and somatotrophic signal from the stomach. Nat Rev Neurosci. 2001;2:551-560.
76. Garcia JM, Friend J, Allen S. Therapeutic potential of anamorelin, a
novel, oral ghrelin mimetic, in patients with cancer-related cachexia: a
multicenter, randomized, double-blind, crossover, pilot study. Support
Care Cancer. 2013;21:129-137.
77. Temel J, Currow D, Fearon K, et al. Anamorelin for the treatment of
cancer anorexia-cachexia in NSCLC: results from the phase 3 studies
ROMANA 1 and 2. Ann Oncol. 2014;25:1-41.
78. Smith RC, Lin BK. Myostatin inhibitors as therapies for muscle wasting
associated with cancer and other disorders. Curr Opin Support Palliat
Care. 2013;7:352-360.
79. Zhou X, Wang JL, Lu J, et al. Reversal of cancer cachexia and muscle
wasting by ActRIIB antagonism leads to prolonged survival. Cell. 2010;
142:531-543.
80. Hong DS, Hui D, Bruera E, et al. An open-label, phase 1 dose-escalation
and expansion study. Lancet Oncol. 2014;15:656-666.
81. Del Fabbro E. More is better: a multimodality approach to cancer cachexia. Oncologist. 2010;15:119-121.
82. Mantovani G, Maccio` A, Madeddu C, et al. Randomized phase III clinical trial of fve different arms of treatment in 332 patients with cancer
cachexia. Oncologist. 2010;15:200-211.
83. Hyltander A, Daneryd P, Sandstrom R, et al. Potential therapeutic targets for cardiac cachexia. Int J Biochem Cell Biol. 2013;45:2322-2332.
84. Lundholm K, Korner U, Gunnebo L, et al. Insulin treatment in cancer
cachexia: effects on survival, metabolism, and physical functioning. Clin
Cancer Res. 2007;13:2699-2706.
85. Solheim TS, Fearon KC, Blum D, et al. Non-steroidal anti-inflammatory
treatment in cancer cachexia: a systematic literature review. Acta Oncol.
2013;52:6-17.
e237
SPEAKERS
David S. Klimstra, MD
Memorial Sloan Kettering Cancer Center
New York, NY
Rogerio Lilenbaum, MD
Yale Cancer Center
New Haven, CT
Himisha Beltran, MD
Weill Cornell Medical College
New York, NY
KLIMSTRA ET AL
euroendocrine neoplasms are a diverse group of neoplasms. Although these share certain pathologic features regardless of where they arise, they have largely been
studied and classifed in an organ-specifc manner (which has
led to a variety of different terminological variations) and
their grading and staging remain site specifc. Nonetheless,
conceptual commonalities cross organ boundaries. This review will introduce some of the common features of neuroendocrine neoplasms and will also explore the differences
in pathology, classifcation, biology, and clinical management between tumors of different anatomic sites, specifcally
the lungs, pancreas, and prostate.
From the Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medical College, New York, NY; Yale Cancer Center, New Haven, CT; UCSF Helen Diller Family Comprehensive Cancer
Center, San Francisco, CA.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Emily Bergsland, MD, UCSF Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero St., Room A727, San Francisco, CA 94143; email: emily.bergsland@ucsf.edu.
2015 by American Society of Clinical Oncology.
92
In addition to WD-NETs, which closely resemble nonneoplastic neuroendocrine cells, there also exist poorly differentiated neuroendocrine neoplasms, which are high grade
carcinomas that exhibit neuroendocrine differentiation.
These neoplasms also have characteristic histologic features
(some of which are shared with WD-NETs) and they typically express the same general neuroendocrine markers described above, albeit less intensely and in fewer of the tumor
cells. PD-NECs are usually classifed as a small cell carcinoma
or large cell neuroendocrine carcinoma (LCNEC), variants
which are distinguished based on the cell size and specifc
nuclear morphology.4 The histologic features of small cell
carcinoma are suffciently distinctive and can often be diagnosed without the need to demonstrate neuroendocrine differentiation by immunohistochemistry, whereas LCNEC must
demonstrate immunexpression in at least one neuroendocrine marker to distinguish them from poorly differentiated
carcinomas of an exocrine type (e.g., poorly differentiated
adenocarcinoma or large cell undifferentiated carcinoma).
PD-NECs are primarily distinguished from WD-NETs by
having a substantially higher proliferative rate, although
there are many other differences.
Despite sharing neuroendocrine differentiation and certain histologic features associated with the neuroendocrine
phenotype, accumulating evidence demonstrates that, in
most organs, WD-NETs and PD-NECs are actually two very
different families of neoplasms.4 They are etiologically different in some organs, and only the WD-NETs typically arise in
patients with neuroendocrine neoplasia syndromes, such as
MEN1 or von Hippel Lindau syndrome. The WD-NETs are
variably aggressive, but most are relatively indolent with a
KEY POINTS
Neuroendocrine neoplasms are a diverse in terms of sites
of origin, functional status, and degrees of aggressiveness.
Despite sharing neuroendocrine differentiation and histologic
evidence of the neuroendocrine phenotype, accumulating
evidence suggests that in most organs, well-differentiated
neuroendocrine tumors (WD-NETs)s (grade 1 and grade 2) and
poorly differentiated neuroendocrine carcinomas PD-NECs
(grade 3) are two very different families of neoplasms.
WD-NETs arise in the lungs and throughout the
gastrointestinal tract and pancreas; WD-NETs of the
prostate gland are uncommon.
Surgical resection is the mainstay of therapy for WD-NETs;
treatment of unresectable disease depends on the site of origin.
PD-NECs of all sites often demonstrate P53 mutations and
loss of Rb, exhibit an aggressive clinical course, and are
treated with platinum-based chemotherapy.
PD-NECs of the prostate should be suspected in patients
who develop rapid progression in the setting of a
disproportionately low prostate specic antigen; TMPRSS2ERG gene rearrangement (present in 50% of patients)
distinguishes PD-NECs of the prostate from small cell
carcinomas of other primary sites.
93
KLIMSTRA ET AL
Grade
Lung
Pancreas
Well differentiated
Low grade
Carcinoid tumor
Combined
High grade
Prostate
An important subset of neuroendocrine neoplasms exhibits inappropriate secretion of one or more bioactive hormones, causing distinctive paraneoplastic syndromes, such
as carcinoid syndrome, Cushing syndrome, and ZollingerEllison syndrome. The clinical picture of patients with these
functional neuroendocrine tumors can be dominated by the
paraneoplastic symptoms, which creates challenges in management unique to each tumor. Also, certain functional tumor types have a characteristic prognosis, such as the low
rate of malignant behavior in pancreatic insulinomas. Although it is important to recognize functional tumors, the
defnition of these entities requires the presence of the corresponding clinical syndrome. Therefore, detection of specifc
hormones by immunohistochemistry is rarely useful in the
pathologic characterization of neuroendocrine tumors.1
Denition
94
Morphology
Mitoses
Necrosis
Immunohistochemistry
2 per 10 HPF
Absent
10 per HPF
10 per HPF
Abbreviations: IASLC, International Association for the Study of Lung Cancer; WHO, World Health Organization; HPF, high power microscopic elds.
95
KLIMSTRA ET AL
the master repressor of neuronal differentiation, RE1silencing transcription factor (REST),51 increased expression
of cell cycle programs (e.g., AURKA, AURKB, PLK1),47,50,52
and overexpression of the chromatin modifer DEK53 and the
polycomb complex gene, EZH2.47,54 The role of these molecular alterations as diagnostic or predictive biomarkers remains to be determined.
These highly aggressive carcinomas can occur in pure form
oras in the lung, GI tract, and pancreasthey can be combined with elements of conventional adenocarcinoma.
Mixed tumors are often heterogeneous with both AR positive
and AR negative cells coexisting. Further demonstrating the
relationship of these PD-NECs with conventional prostatic
adenocarcinoma, some cases retain focal PSA immunoexpression. The prostate cancer-specifc TMPRSS2-ERG gene
rearrangement is detectable by fluorescence in situ hybridization (FISH) in approximately 50% of PD-NECs of the
prostate (similar to the frequency in prostate adenocarcinomas) and distinguishes PD-NECs of the prostate from small
cell carcinomas in other primary sites.47,55
The majority of PanNETs (40% to 91%) are welldifferentiated and nonfunctional, thus they are not associated with a clinical syndrome from hormone excess.
Historically diagnosed at a late stage, advances in diagnostic
imaging techniques (including endoscopic ultrasound) have
facilitated detection of incidentally discovered small nonfunctional tumors, which now comprise up to 40% of newly
diagnosed tumors.61-63 Interestingly, asymptomatic secretion of peptides can be documented in 60% to 100% of
nonfunctional tumors (e.g., chromogranin, pancreatic polypeptide, and others).64 In contrast, a minority of patients
(22% in a recent series) presents with a clinical syndrome
stemming from hormone excess.65 Insulin-producing tumors are the most common (90% of which exhibit benign
behavior), followed by gastrinomas, glucagonomas, and
other rarer syndromes.64
The initial work-up of a patient suspected to have a PanNET typically involves cross-sectional imaging with multiphasic CT or MRI to assess the primary tumor site and extent
of disease. Endoscopic ultrasound, radiolabeled somatostatin receptor scintigraphy, and biochemical evaluations are
recommended as clinically indicated.64-66 Serum chromogranin A levels are elevated in 60% or more patients with a
PanNET.67
Although indolent, PanNETs have malignant potential, as
manifested by local invasion, lymph node involvement, and
distant metastases. Most studies suggest that the risk of malignant behavior correlates with tumor size, as at least 50% of
PanNETs recur or metastasize.68 The presence of lymph
node metastases also portends a worse prognosis in resected
PanNETs (5-year survival is 49.4%).69 Survival also depends
on age, histologic grade, and functional status.57 In contrast
to other PanNETs, nearly all insulinomas are cured by complete resection.64
The etiology of PanNETs is largely unknown. Most tumors
appear to be sporadic, but a small proportion of tumors arise
in the setting of an inherited cancer syndrome (most commonly MEN1).64 The potential for an accompanying inherited syndrome should always be considered, particularly if
the patient has a compelling personal or family history, multifocal disease, a gastrinoma, or an insulinoma.64
Treatment
In addition to controlling tumor growth, it is critical to recognize the need for medical management of the hormoneexcessive state in PanNETs. Somatostatin analogs (SSTa) are
often employed for symptom control, but medications to
control gastric acid hypersecretion and hypoglycemia are essential for patients with gastrinomas and insulinomas, respectively.64,66 Of note, SSTa should generally be avoided in
patients with insulinomas whose tumors test negative by somatostatin receptor scintigraphy.66
Patients with localized PanNETs are typically treated with
surgical resection with regional lymph node dissection as
there are no data to support neoadjuvant or adjuvant therapy. The optimal surgical technique depends on the location
of the tumor. For some patients, enucleation may suffce
97
KLIMSTRA ET AL
Treatment
Carcinoid. The treatment of carcinoid tumors consists of surgical resection (including a nodal dissection) because of the
98
Treatment
Few patients with pure NEPC present with localized disease,
and therefore there are limited data on treatment of patients
with organ-confned disease. These patients are very likely to
have occult metastatic disease not detected on a bone or CT
scan, but PET scans may be useful in confrming localized
disease.103 For localized PD-NEC, a multimodality approach
similar to SCLC should be considered, which consists of chemotherapy with concurrent or consolidative radiotherapy.
Very limited data are available regarding the use of surgery in
this clinical setting.
Chemotherapy is commonly used as front-line therapy for
metastatic PD-NEC that either presents as de novo or occurs
after therapy.95,100 Since PD-NEC can show mixed or hybrid
features (as described above with both PD-NEC and prostate
adenocarcinoma components), androgen deprivation therapy is also often given either frst or in combination with chemotherapy, depending on the clinical context. Platinum-
Special Considerations
Primary diagnostic challenge. Not all patients with aggressive
androgen independentCRPC demonstrate clear evidence of
PD-NEC morphology on a metastatic biopsy.
Clinically aggressive tumors in the setting of a low PSA and
poor clinical response to AR therapies (suggestive of AR
independence) do not always demonstrate morphologic features of PD-NEC. This may be a result of disease heterogeneity and/or overlapping molecular features. Therefore, tumor
morphology does not always predict clinical behavior. Chemotherapy including platinum is often considered, based on
studies in anaplastic prostate cancer. The role of alternative
AR therapies in this setting is not known.
Secondary diagnostic challenge. PD-NEC is not always androgen independent. At times, morphologic features or immunohistochemical profles of metastatic tumors suggest
PD-NEC, but AR expression and/or signaling are active.106
These tumors are often either mixed or show hybrid features
with both AR and neuroendocrine markers present. Clinically, these are less aggressive than most cases of PD-NEC,
and patients are sometimes recommended for hormonal
therapies. Future molecular markers to distinguish ARdriven CRPC from AR-independent disease will aid in patient selection for therapy.
CONCLUSION
Neuroendocrine neoplasms are a diverse group of neoplasms
distinguished by site of origin, functional status, and degree
of aggressiveness. Although a variety of pathologic features
are shared, NETs have largely been classifed in an organspecifc manner and their grading and staging remain sitespecifc. Nonetheless, several themes cross organ boundaries.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
99
KLIMSTRA ET AL
WD-NETs (grade 1 and 2) are relatively indolent (with a natural history that can evolve over many years or decades),
closely resemble non-neoplastic neuroendocrine cells, and
demonstrate production of neurosecretory proteins, such as
chromogranin A and synaptophysin. Only WD-NETs arise
in patients with inherited neuroendocrine neoplasia syndromes (e.g., MEN1). Surgery is the mainstay of therapy for
WD-NETs, which are relatively unresponsive to chemotherapy (although several cytostatic agents have proven activity).
In contrast, PD-NECs (grade 3) are uniformly highly aggressive, demonstrate a high proliferative rate, and are classifed
as small cell carcinoma or LCNEC. PD-NECs typically harbor molecular alterations distinctive from WD-NETs (leading to loss of Rb and P53 function), and some alterations are
site-specifc (e.g., TMPRSS2-ERG gene rearrangement in
NEPC). PD-NECs exhibit marked but transient sensitivity to
platinum-based chemotherapy and are usually metastatic at
diagnosis. Although validated biomarkers of response are
not yet available, advances in the understanding of the molecular basis of NETs may lead to new diagnostic and therapeutic strategies, and holds the promise of an individualized
therapy.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Emily
Bergsland, Celgene, Genentech/Roche, Lexicon, Inc., Novartis. David Klimstra, Ipsen, Wren Laboratories. Rogerio Lilenbaum, Boehringer Ingelheim, Genentech/Roche. Speakers Bureau: None. Research Funding: Emily Bergsland, Genentech/Roche (Inst), Lexicon (Inst), Novartis (Inst), Sano (Inst). Patents,
Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: Emily Bergsland, Lexicon. Rogerio
Lilenbaum, Roche. Other Relationships: None.
References
Klimstra DS, Modlin IR, Adsay NV, et al. Pathology reporting of neuroendocrine tumors: application of the Delphic consensus process to
the development of a minimum pathology data set. Am J Surg Pathol.
2010;34:300-313.
2. Klimstra DS, Modlin IR, Coppola D, et al. The pathologic classifcation
of neuroendocrine tumors: a review of nomenclature, grading, and
staging systems. Pancreas. 2010;39:707-712.
3. Yang Z, Tang LH, Klimstra DS. Gastroenteropancreatic neuroendocrine neoplasms: historical context and current issues. Semin Diagn
Pathol. 2013;30:186-196.
4. Sorbye H, Strosberg J, Baudin E, et al. Gastroenteropancreatic highgrade neuroendocrine carcinoma. Cancer. 2014;120:2814-2823.
5. Strosberg J, Nasir A, Coppola D, et al. Correlation between grade and
prognosis in metastatic gastroenteropancreatic neuroendocrine tumors. Hum Pathol. 2009;40:1262-1268.
6. Sorbye H, Welin S, Langer SW, et al. Predictive and prognostic factors
for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC
study. Ann Oncol. 2013;24:152-160.
7. Kunz PL, Reidy-Lagunes D, Anthony LB, et al. Consensus guidelines
for the management and treatment of neuroendocrine tumors.
Pancreas. 2013;42:557-577.
8. Basturk O, Tang L, Hruban RH, et al. Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44
cases. Am J Surg Pathol. 2014;38:437-447.
9. Panzuto F, Boninsegna L, Fazio N, et al. Metastatic and locally advanced pancreatic endocrine carcinomas: analysis of factors associated
with disease progression. J Clin Oncol. 2011;29:2372-2377.
10. Rindi G, Kloppel G, Alhman H, et al. TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2006;449:395-401.
11. Rindi G, Kloppel G, Couvelard A, et al. TNM staging of midgut and
1.
100
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
assessment of Ki67 labeling index in well-differentiated neuroendocrine tumors metastatic to the liver: implications for prognostic stratifcation. Am J Surg Pathol. 2011;35:853-860.
Khan MS, Luong TV, Watkins J, et al. A comparison of Ki-67 and mitotic count as prognostic markers for metastatic pancreatic and midgut
neuroendocrine neoplasms. Br J Cancer. 2013;108:1838-1845.
McCall CM, Shi C, Cornish TC, et al. Grading of well-differentiated
pancreatic neuroendocrine tumors is improved by the inclusion of
both Ki67 proliferative index and mitotic rate. Am J Surg Pathol. 2013;
37:1671-1677.
Singh S, Hallet J, Rowsell C, et al. Variability of Ki67 labeling index in
multiple neuroendocrine tumors specimens over the course of the disease. Eur J Surg Oncol. 2014;40:1517-1522.
Klimstra DS. Pathology reporting of neuroendocrine tumors: essential
elements for accurate diagnosis, classifcation, and staging. Semin Oncol. 2013;40:23-36.
Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX. MEN1, and mTOR pathway
genes are frequently altered in pancreatic neuroendocrine tumors.
Science. 2011;331:1199-1203.
Yachida S, Vakiani E, White CM, et al. Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and
distinct from well-differentiated pancreatic neuroendocrine tumors.
Am J Surg Pathol. 2012;36:173-184.
Kulke MH, Hornick JL, Frauenhoffer C, et al. O6-methylguanine DNA
methyltransferase defciency and response to temozolomide-based
therapy in patients with neuroendocrine tumors. Clin Cancer Res.
2009;15:338-345.
Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic
neuroendocrine tumors. N Engl J Med. 2011;364:514-523.
Han X, Ji Y, Zhao J, et al. Expression of PTEN and mTOR in pancreatic
neuroendocrine tumors. Tumour Biol. 2013;34:2871-2879.
Travis WD, Linnoila RI, Tsokos MG, et al. Neuroendocrine tumors of
the lung with proposed criteria for large-cell neuroendocrine carcinoma. an ultrastructural, immunohistochemical, and flow cytometric
study of 35 cases. Am J Surg Pathol. 1991;15:529-553.
Travis WD, Rush W, Flieder DB, et al. Survival analysis of 200 pulmonary neuroendocrine tumors with clarifcation of criteria for atypical
carcinoid and its separation from typical carcinoid. Am J Surg Pathol.
1998;22:934-944.
Skov BG, Krasnik M, Lantuejoul S, et al. Reclassifcation of neuroendocrine tumors improves the separation of carcinoids and the prediction of survival. J Thorac Oncol. 2008;3:1410-1415.
Rindi G, Klersy C, Inzani F, et al. Grading the neuroendocrine tumors
of the lung: an evidence-based proposal. Endocr Relat Cancer. 2013;21:
1-16.
Travis WD. Pathology and diagnosis of neuroendocrine tumors: lung
neuroendocrine. Thorac Surg Clin. 2014;24:257-266.
Oba H, Nishida K, Takeuchi S, et al. Diffuse idiopathic pulmonary
neuroendocrine cell hyperplasia with a central and peripheral carcinoid and multiple tumorlets: a case report emphasizing the role of neuropeptide hormones and human gonadotropin-alpha. Endocr Pathol.
2013;24:220-228.
Yokota J, Akiyama T, Fung YK, et al. Altered expression of the retinoblastoma (RB) gene in small-cell carcinoma of the lung. Oncogene.
1988;3:471-475.
Rusch VW, Klimstra DS, Venkatraman ES. Molecular markers help
characterize neuroendocrine lung tumors. Ann Thorac Surg. 1996;62:
798-809.
Fernandez-Cuesta L, Peifer M, Lu X, et al. Frequent mutations in
chromatin-remodelling genes in pulmonary carcinoids. Nat Commun.
2014;5:3518.
Epstein JI, Amin MB, Beltran H, et al. Proposed morphologic classif-
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
101
KLIMSTRA ET AL
63. Ito T, Sasano H, Tanaka M, et al. Epidemiological study of gastroenteropancreatic neuroendocrine tumors in Japan. J Gastroenterol. 2010;
45;234-243.
64. Ito T, Igarashi H, Jensen RT. Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances. Best Pract Res
Clin Gastroenterol. 2012;26:737-753.
65. Choti MA, Bobiak S, Strosberg JR, et al. Prevalence of functional tumors in neuroendocrine carcinoma: an analysis from the NCCN NET
database. J Clin Oncol. 2012;30 (suppl; abstr 4126).
66. Kulke MH, Shah MH, Benson AB 3rd, et al. Neuroendocrine tumors,
version 1.2015. J Natl Compr Canc Netw. 2015;13:78-108.
67. Campana D, Nori F, Piscitelli L, et al. Chromogranin A: is it a useful
marker of neuroendocrine tumors? J Clin Oncol. 2007;25:1967-1973.
68. Fendrich V, Waldmann J, Bartsch DK, et al. Surgical management of
pancreatic endocrine tumors. Nat Rev Clin Oncol. 2009;6:419-428.
69. Bettini R, Boninsegna L, Mantovani W, et al. Prognostic factors at diagnosis and value of WHO classifcation in a mono-institutional series
of 180 non-functioning pancreatic endocrine tumours. Ann Oncol.
2008;19:903-908.
70. Furukori M, Imai K, Karasaki H, et al. Clinicopathological features of
small nonfunctioning pancreatic neuroendocrine tumors. World J
Gastroenterol. 2014;20:17949-17954.
71. Strosberg JR, Cheema A, Kvols LK. Stage I nonfunctioning neuroendocrine tumors of the pancreas: surgery or surveillance? J Clin Oncol.
2011;29 (suppl; abstr 349).
72. Mayo SC, de Jong MC, Pulitano C, et al. Surgical management of hepatic neuroendocrine tumor metastasis: results from an international
multi-institutional analysis. Ann Surg Oncol. 2010;17:3129-3136.
73. Saxena A, Chua TC, Perera M, et al. Surgical resection of hepatic metastases from neuroendocrine neoplasms: a systemic review. Surg Oncol. 2012;21:e131-e141.
74. Capurso G, Archibugi L, Delle Fave G. Molecular pathogenesis and
targeted therapy of sporadic pancreatic neuroendocrine tumors.
J Hepatobiliary Pancreat Sci. Epub 2015 Jan 25.
75. Rinke A, Muller HH, Schade-Brittinger C, et al. Placebo-controlled,
double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic
neuroendocrine midgut tumors: a report from the PROMID Study
Group. J Clin Oncol. 2009;27:4656-4663.
wikla JB, et al. Lanreotide in metastatic entero76. Caplin ME, Pavel M, C
pancreatic neuroendocrine tumors. N Engl J Med. 2014;371:224-233.
77. Kwekkeboom DJ, de Herder WW, Kam BL, et al. Treatment with the
radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate:
toxicity, effcacy, and survival. J Clin Oncol. 2008;26:2124-2130.
78. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:
501-513.
79. Hobday TJ, Qin R, Reidy-Lagunes D, et al. Multicenter phase II trial of
temsirolimus and bevacizumab in pancreatic neuroendocrine tumors.
J Clin Oncol. Epub 2014 Dec 8.
80. Moertel CG, Lefkopoulo M, Lipsitz S, et al. Streptozocin-doxorubicin,
streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992;326:519-523.
81. Cheng PN, Saltz LB. Failure to confrm major objective antitumor activity for streptozocin and doxorubicin in the treatment of patients
with advanced islet cell carcinoma. Cancer. 1999;86:944-948.
82. Kouvaraki MA, Ajani JA, Hoff P, et al. Fluorouracil, doxorubicin, and
streptozocin in the treatment of patients with locally advanced and
metastatic pancreatic endocrine carcinomas. J Clin Oncol. 2004;22:
4762-4771.
102
83. Strosberg JR, Fine RL, Choi J, et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011;117:268-275.
84. Ducreux M, Dahah L, Smith D, et al. Bevacizumab combined with
5-FU/streptozocin in patients with progressive metastatic welldifferentiated pancreatic neuroendocrine tumors (BETTER trial)-A
phase II non-randomised trial. Eur J Cancer. 2014;50:3098-3106.
85. Kennedy A, Bester L, Salem R, et al. Role of hepatic intra-arterial therapies in metastatic neuroendocrine tumours (NET): guidelines from
the NET-Liver-Metastases Consensus Conference. HPB (Oxford).
2015;17:29-37.
86. Devcic Z, Rosenberg J, Braat AJ, et al. The effcacy of hepatic 90Y resin
radioembolization for metastatic neuroendocrine tumors: a metaanalysis. J Nucl Med. 2014;55:1404-1410.
87. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of
small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin
Oncol. 2006;24:4539-4544.
88. Glisson BS, Moran CA. Large-cell neuroendocrine carcinoma: controversies in diagnosis and treatment. J Natl Compr Canc Netw. 2011;9:
1122-1129.
89. Divisi D, Crisci R. Carcinoid tumors of the lung and multimodal therapy. Thorac Cardiovasc Surg. 2005;53:168-172.
90. National Comprehensive Cancer Network. Small cell lung cancer guidelines.
version 1.2015. http://www.nccn.org/professionals/physician_gls/pdf/sclc.
pdf.
91. Phan AT, Oberg K, Choi J, et al. NANETS consensus guidelines for the
diagnosis and management of neuroendocrine tumors: welldifferentiated neuroendocrine tumors of the thorax. Pancreas. 2010;
39:784-798.
92. Janne P, Freidlin B, Saxman S, et al. Twenty-fve years of clinical research for patients with limited-stage small cell lung carcinoma in
North America. Cancer. 2002;95:1528-1538.
93. Slotman BJ, van Tinteren H, Pragg JO, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised
controlled trial. Lancet. 2015;385:36-42.
94. Varlotto JM, Medford-Davis LN, Recht A, et al. Should large cell neuroendocrine lung carcinoma be classifed and treated as a small cell
lung cancer of with other large cell carcinomas? J Thorac Oncol. 2011;
6:1050-1058.
95. Aggarwal R, Zhang T, Small EJ, et al. Neuroendocrine prostate cancer:
subtypes, biology, and clinical outcomes. J Natl Compr Canc Netw.
2014;12:719-726.
96. Aparicio A, Tzelepi V. Neuroendocrine (small-cell) carcinomas: why
they teach us essential lessons about prostate cancer. Oncology (Williston Park). 2014;28:831-838.
97. Beltran H, Tomlins S, Aparicio A, et al. Aggressive variants of castrationresistant prostate cancer. Clin Cancer Res. 2014;20:2846-2850.
98. Small EJ, Youngren J, Alumkal J, et al. Neuroendocrine prostate cancer
(NEPC) in patients (pts) with metastatic castration resistant prostate
cancer (mCRPC) resistant to abiraterone and enzalutamide: preliminary results from the SU2C/PCF/AACR west coast prostate cancer
dream team. Ann Oncol. 2014;25 (suppl; 4 abstr 760PD).
99. Wang HT, Yao YH, Li BG, et al. Neuroendocrine Prostate Cancer
(NEPC) progressing from conventional prostatic adenocarcinoma:
Factors associated with time to development of NEPC and survival
from NEPC diagnosis-a systematic review and pooled analysis. J Clin
Oncol. 2014;32:3383-3390.
100. Beltran H, Tagawa ST, Park K, et al. Challenges in recognizing
treatment-related neuroendocrine prostate cancer. J Clin Oncol. 2012;
30:e386-e389.
with doxorubicin, etoposide, and cisplatin in patients with fully characterized small-cell carcinoma of the prostate. J Clin Oncol. 2002;20:
3072-3080.
105. Aparicio AM, Harzstark AL, Corn PG, et al. Platinum-based chemotherapy for variant castrate-resistant prostate cancer. Clin Cancer Res.
2013;19:3621-3630.
106. Azad AA, Jones EC, Chi KN. Metastatic large-cell neuroendocrine
prostate carcinoma: successful treatment with androgen deprivation
therapy. Clin Genitourin Cancer. 2014;12:e151-e153.
103
GENITOURINARY CANCER
SPEAKERS
Martin Voss, MD
Memorial Sloan Kettering Cancer Center, Weill Cornell
Medical College
New York, NY
Axel Bex, MD, PhD
Netherlands Cancer Institute
Amsterdam, Netherlands
effcacy of the earlier generation of agents, and sunitinib remains a standard of care for the frst-line treatment of advanced disease in 2015. Furthermore, all of the approved
targeted agents, with the exception of the antiVEGF
monoclonal antibody bevacizumab, are either mTOR inhibitors or multitargeted kinase inhibitors. Moreover, the
multitargeted kinase inhibitors all inhibit at least one
isoform of the VEGF receptor in addition to, sometimes,
dozens of other targets. Notably, there is currently no
strong evidence that any of the other targets inhibited by
these agents is of therapeutic relevance in clear cell renal
carcinoma.
From the Netherlands Cancer Institute, Amsterdam, Netherlands; The Royal Marsden NHS Foundation Trust, London, United Kingdom; Memorial Sloan Kettering Cancer Center, New York, NY; Weill
Cornell Medical College, New York, NY.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Axel Bex, MD, PhD, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands; email: a.bex@nki.nl.
2015 by American Society of Clinical Oncology.
e239
progression-free survival (PFS) for patients treated with apitolisib.1 The results of further trials, such as those investigating the dual TORC inhibitor AZD2014 in comparison with
everolimus, are awaited with interest.
Preclinical data have suggested that a number of targets
may be relevant for resistance, both intrinsic and acquired, to
anti-VEGF therapy in advanced kidney cancer. In this context, the phase III GOLD trial investigated the VEGF receptor
(VEGFR) and FGFR inhibitor dovitinib compared with
sorafenib in patients who had experienced failure of both
VEGF- and mTOR-targeted therapy (i.e., in the third-line
setting).2 This trial showed activity for dovitinib, but the activity was not superior to that of sorafenib; as such, the trial
was negative for its primary endpoint of PFS. A null hypothesis in interpreting the effcacy data from this trial is that
the activity of dovitinib was a sole consequence of activity
against the VEGF pathway and that the activity against
FGFR was not relevant to effcacy, but this contention remains unproven.
A further target of recent interest in RCC is the tyrosine
kinase c-MET. Analogous to the GOLD trial, the phase III
METEOR trial is investigating the VEGFR and c-MET inhibitor cabozantinib in patients who have experienced failure of
prior anti-VEGF therapy. However, even if cabozantinib has
superior effcacy to everolimus in this setting, c-MET is not
necessarily validated as a bona fde target in clear cell kidney
cancer, given that cabozantinib also targets VEGF. It is noteworthy in this regard that two recent trials have shown superior effcacy for anti-VEGF therapy compared with mTORtargeted therapy. Specifcally, a phase III trial of sorafenib
versus temsirolimus in patients in whom frst-line therapy
with sunitinib had failed3 reported similar PFS in both arms,
but overall survival (OS) was superior in the sorafenib arm.
The reason for this is unclear. Furthermore, a randomized,
KEY POINTS
Since the advent of molecularly targeted therapy for the
treatment of advanced renal cell carcinoma (RCC), further
improvement in outcomes with subsequent approval of
additional agents has been modest, at best.
Two key strategies of developing novel agents have been
(1) broader targeting of the phosphoinositide
3-kinase/mammalian target of rapamycin signaling pathway
and (2) combined inhibition of other targets with vascular
endothelial growth factordirected therapies.
Targeted immunotherapy with checkpoint inhibitors is
rapidly emerging as a new class of agents in this disease.
Ongoing studies test its utility alone and in combinations
with approved agents.
A growing body of data supports the use of
metastasectomy to improve outcome in patients with
metastatic RCC.
Clinical and radiographic parameters could help optimize
the selection of patients with metastatic disease for
surgical intervention and should be validated prospectively.
e240
e241
nivolumab and standard-dose sunitinib, for instance, demonstrated encouraging antitumor activity, with an ORR of
52% across 33 patients, but grade 3 to 4 treatment-related
adverse events were recorded in greater than 70% of patients.21 Such fndings make this combination hardly appear
suitable for further development on a larger scale. With the
suggestion of synergism, however, and in consideration of
the notion that immunotherapy may extend the duration of
disease control, the feld should not prematurely abandon
combinations of TKI and checkpoint inhibition. For further
development, however, we may need to explore alternate
treatment schedules, such as lower dosing levels, sequenced
introduction of agents, or alternating dosing schedules.
Safety data from other TKI/PD-1 combination trials is
awaited, including the two combination trials pairing the
PD-1 directed monoclonal antibody pembrolizumab plus
pazopanib (NCT02014636) or axitinib (NCT02133742).
Similar to prior experiences combining VEGF-targeted
therapy with other agents, bevacizumab seems to pair with
checkpoint inhibition without notable increases in toxicity.
Data from a phase I study combining bevacizumab and the
monoclonal PD-L1 directed antibody MPDL3280 suggested a favorable safety profle, with less than 5% grade 3 to
4 adverse events and four of 10 patients achieving a partial
response; nine of 10 patients remained on study at the time of
the report.22 This result prompted a large, randomized, phase
II study (NCT01984242) that is presently enrolling untreated
patients with 1:1:1 random assignment among standarddose sunitinib, MPDL3280 monotherapy, and the combination of MPDL3280 plus bevacizumab. Thus, its favorable
tolerance when used as a partner with other agents may
bring attention to bevacizumab, an agent previously approved in the frst-line setting but currently underutilized
in that setting.
Vaccine Studies
A number of vaccination strategies, including autologous,
multipeptide, and antigen-directed vaccines, are being tested
in metastatic RCC.23 Although it is unlikely that these could
replace the current standard of targeted therapy in treatmentnaive patients, immunomodulatory effects argue in favor of
pairing vaccines with approved targeted therapies. In the
phase III ADAPT trial (NCT1582672) patients undergoing
cytoreductive nephrectomy were randomly assigned to standard targeted therapy plus autologous vaccination with AGS003 or to standard therapy alone. This trial is based on
encouraging data from a previous open-label, phase II study
of sunitinib plus AGS-003 that reported a median PFS of 11.2
months and a median OS of 30.2 months.23 Another phase III
study (NCT01265901) is comparing standard sunitinib to
vaccination with sunitinib plus IMA901, a multipeptide vaccine of nine tumor-associated peptides administered after a
single dose of cyclophosphamide. Both studies have OS as a
primary endpoint, because successful vaccination should
have a longer-lasting immunomodulatory anticancer effect.
The substantial efforts to bring checkpoint inhibitors into
routine practice now raise questions for the further develop-
e243
ysis identifed in a lung-specifc prognostic score developed from 200 patients with pulmonary metastases.53
Three risk groups were discriminated with median OS
times of 90, 31, and 14 months for low-, intermediate-, and
high-risk groups, respectively. This score is not yet externally validated.
Resection of bone metastasis is mainly performed for palliation but may result in 5-year survival rates of 75%, particularly in metachronous and appendicular solitary bone
lesions.54 For symptomatic bone metastases, surgery is superior to radiotherapy. A randomized, prospective trial in patients with bone metastasis from various malignancies,
which included a minority of RCC, revealed that direct decompressive surgery plus postoperative radiotherapy was superior to treatment with radiotherapy alone for patients with
spinal cord compression caused by metastatic cancer.55
The best approach for asymptomatic solitary bone lesions
is unclear. If surgery is chosen, wide excision with fxation
or reconstruction is preferable. For brain metastases, SRS
has largely replaced surgery as local treatment. However,
surgery may be preferable in lesions greater than 2 to 3 cm,
with rapid onset of symptoms, and in lesions with a midline shift. Selection factors in patients for local therapy of
brain metastases regardless of the primary tumor site include performance status, extracranial tumor load, and
the course of disease, as summarized in the Radiation
Therapy Oncology Group (RTOG) recursive partition
analysis (RPA).56 SRS yields a median OS of 24 months in
patients with RTOG-RPA prognostic class I. Whole-brain
radiotherapy is only adequate for patients who have a poor
performance status.57-59
For most other metastatic sites, detailed selection criteria
are not available, and indication for resection should follow
the factors associated with a favorable outcome (Sidebar).
Hepatic metastasis is associated with poor prognosis. Nevertheless, after complete resection for solitary lesions, 5-year
survival rates of 62% have been reported.60 Liver metastasectomy may cause signifcant morbidity and mortality, and it is
unclear if surgery is superior to ablative percutaneous techniques. Synchronous solitary adrenal metastases are usually
resected at the time of nephrectomy.61 Management of isolated metachronous ipsi- and contralateral adrenal lesions is
often reported in series of local recurrences. Survival of up to
70 months has been reported after metastasectomy after a
long disease-free interval.62 Though not regarded as a distant
metastatic site in the tumor-node-metastasis staging system
classifcation, lymph node metastases are frequent and associated with a poor outcome, similar to systemic disease.63,64
Synchronous regional lymph node metastases often are resected at nephrectomy. Isolated lymph node metastasis without further systemic disease is rare,65,66 but resection may be
curative. Resection of metachronous isolated lymphonodular metastases often is reported in series on local recurrences.67 Complete metastasectomy of solitary lesions in the
pancreas, thyroid, and other less frequently involved sites results in 5-year survival rates comparable to those observed
after pulmonary metastasectomy.68 Remarkably, repeat complete metastasectomy and complete resection of multiple
metastatic sites are associated with long-term survival and a
50% decrease in the risk of death.36 Multiple case reports and
series on the integration of targeted therapy with surgery report neoadjuvant targeted therapy to downsize lesions or
select candidates for complete resection.69 However, the approach is experimental and not supported by prospective
studies. Ultimately, to derive a higher quality of evidence regarding metastasectomy and other local treatment options in
RCC, larger and prospective, randomized studies need to be
performed.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Martin Voss, Novartis. Consulting or Advisory
Role: Axel Bex, Novartis (Inst), Pzer (Inst). Martin Voss, Bayer, Novartis. Speakers Bureau: Axel Bex, Pzer. Research Funding: Axel Bex, Pzer (Inst).
James Larkin, Novartis (Inst), Pzer (Inst). Martin Voss, BMS, Pzer. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None.
Travel, Accommodations, Expenses: Martin Voss, Novartis. Other Relationships: None.
References
1. Powles TO, Oudard S, Escudier B, et al. A randomized phase II study of
GDC-0980 versus everolimus in metastatic renal cell carcinoma
(mRCC) patients (pts) after VEGF-targeted therapy (VEGF-TT). J Clin
Oncol. 2014;32:5 (suppl; abstr 4525).
2. Motzer RJ, Porta C, Vogelzang NJ, et al. Dovitinib versus sorafenib for
third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15:
286-296.
3. Hutson TE, Escudier B, Esteban E, et al. Randomized phase III trial of
temsirolimus versus sorafenib as second-line therapy after sunitinib in
patients with metastatic renal cell carcinoma. J Clin Oncol. 2014;32:760767.
4. Motzer RJ, Barrios CH, Kim TM, et al. Phase II randomized trial comparing sequential frst-line everolimus and second-line sunitinib versus
frst-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014;32:2765-2772.
5. Feldman DR, Baum MS, Ginsberg MS, et al. Phase I trial of bevacizumab
plus escalated doses of sunitinib in patients with metastatic renal cell
carcinoma. J Clin Oncol. 2009;27:1432-1439.
6. Molina AM, Feldman DR, Voss MH, et al. Phase 1 trial of everolimus
plus sunitinib in patients with metastatic renal cell carcinoma. Cancer.
2012;118:1868-1876.
7. Negrier S, Gravis G, Perol D, et al. Temsirolimus and bevacizumab, or
sunitinib, or interferon alfa and bevacizumab for patients with advanced
renal cell carcinoma (TORAVA): a randomised phase 2 trial. Lancet Oncol. 2011;12:673-680.
8. Patel PH, Senico PL, Curiel RE, et al. Phase I study combining treatment
with temsirolimus and sunitinib malate in patients with advanced renal
cell carcinoma. Clin Genitourin Cancer. 2009;7:24-27.
9. Atkins MB VM, Plimack ER, Rini BI, et al. A two-part phase 2 randomized study of dalantercept and axitinib versus placebo plus axitinib in
advanced renal cell carcinoma: results from the part 1 dose escalation
cohorts. J Clin Oncol. 2014;32:4566.
10. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and
branched evolution revealed by multiregion sequencing. N Engl J Med.
2012;366:883-892.
11. Gerlinger M, Horswell S, Larkin J, et al. Genomic architecture and evo-
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
lution of clear cell renal cell carcinomas defned by multiregion sequencing. Nat Genet. 2014;46:225-233.
McDermott DF, Atkins MB. Immune therapy for kidney cancer: A second dawn? Semin Oncol. 2013;40:492-498.
Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol.
Epub 2014 Dec 1.
Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378:1931-1939.
Motzer RJ, Escudier B, Oudard S, et al. Effcacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebocontrolled phase III trial. Lancet. 2008;372:449-456.
Cho DS, Sosman JA, Sznol M. Clinical activity, safety, and biomarkers of
MPDL3280A, an engineered PD-L1 antibody in patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2013;31 (suppl; abstr
4505).
Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:21892199.
Hammers HJ PE, Infante JR. Phase I study of nivolumab in combination
with ipilimumab in metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2014;32:4504.
Vanneman M, Dranoff G. Combining immunotherapy and targeted
therapies in cancer treatment. Nat Rev Cancer. 2012;12:237-251.
Rini BI, Stein M, Shannon P, et al. Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma.
Cancer. 2011;117:758-767.
Amin APE, Infante JR, Ernstoff MS, et al. Nivolumab (anti-PD-1; BMS936558, ONO-4538) in combination with sunitinib or pazopanib in patients (pts) with metastatic renal cell carcinoma (mRCC). J Clin Oncol.
2014;32:5 (suppl; abstr 5010).
Lieu C. Safety and effcacy of MPDL3280A (anti-PDL1) in combination
with bevacizumab (bev) and/or chemotherapy (chemo) in patients (pts)
with locally advanced or metastatic solid tumors. Paper presented at:
ESMO 2014 Congress; September 2014; Madrid, Spain.
e245
23. Pal SK, Hu A, Figlin RA. A new age for vaccine therapy in renal cell
carcinoma. Cancer J. 2013;19:365-370.
24. Ferlay J, Autier P, Boniol M, et al. Estimates of the cancer incidence and
mortality in Europe in 2006. Ann Oncol. 2007;18:581-592.
25. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin.
2014;64:9-29.
26. Bianchi M, Sun M, Jeldres C, et al. Distribution of metastatic sites in
renal cell carcinoma: a population-based analysis. Ann Oncol. 2012;23:
973-980.
27. Escudier B, Goupil MG, Massard C, et al. Sequential therapy in renal cell
carcinoma. Cancer. 2009;115:2321-2326.
28. De Meerleer G, Khoo V, Escudier B, et al. Radiotherapy for renal-cell
carcinoma. Lancet Oncol. 2014;15:e170-e177.
29. Dutcher JP, Mourad WF, Ennis RD. Integrating innovative therapeutic
strategies into the management of renal cell carcinoma. Oncology (Williston Park). 2012;26:526-530, 532, 534.
30. Alt AL, Boorjian SA, Lohse CM, et al. Survival after complete surgical
resection of multiple metastases from renal cell carcinoma. Cancer.
2011;117:2873-2882.
31. Eggener SE, Yossepowitch O, Pettus JA, et al. Renal cell carcinoma recurrence after nephrectomy for localized disease: predicting survival
from time of recurrence. J Clin Oncol. 2006;24:3101-3106.
32. Oddsson SJ, Hardarson S, Petursdottir V, et al. Synchronous pulmonary
metastases from renal cell carcinoma: a whole nation study on prevalence and potential resectability. Scand J Surg. 2012;101:160-165.
33. Lokich J. Spontaneous regression of metastatic renal cancer. Case report
and literature review. Am J Clin Oncol. 1997;20:416-418.
34. Vogelzang NJ, Priest ER, Borden L. Spontaneous regression of histologically proved pulmonary metastases from renal cell carcinoma: a case
with 5-year followup. J Urol. 1992;148:1247-1248.
35. Dabestani S, Marconi L, Hofmann F, et al. Local treatments for metastases of renal-cell carcinoma: a systematic review. Lancet Oncol. 2014;
15:e549-e561.
36. Kavolius JP, Mastorakos DP, Pavlovich C, et al. Resection of metastatic
renal cell carcinoma. J Clin Oncol. 1998;16:2261-2266.
37. Kierney PC, van Heerden JA, Segura JW, et al. Surgeons role in the
management of solitary renal cell carcinoma metastases occurring subsequent to initial curative nephrectomy: an institutional review. Ann
Surg Oncol. 1994;1:345-352.
38. Tosco L, Van Poppel H, Frea B, et al. Survival and impact of clinical
prognostic factors in surgically treated metastatic renal cell carcinoma.
Eur Urol. 2013;63:646-652.
39. Leibovich BC, Cheville JC, Lohse CM, et al. A scoring algorithm to predict survival for patients with metastatic clear cell renal cell carcinoma:
a stratifcation tool for prospective clinical trials. J Urol. 2005;174:17591763.
40. Russo P, Synder M, Vickers A, et al. Cytoreductive nephrectomy and
nephrectomy/complete metastasectomy for metastatic renal cancer.
ScientifcWorldJournal. 2007;7:768-778.
41. Han KR, Pantuck AJ, Bui MH, et al. Number of metastatic sites rather
than location dictates overall survival of patients with node-negative
metastatic renal cell carcinoma. Urology. 2003;61:314-319.
42. Antonelli A, Zani D, Cozzoli A, et al. Surgical treatment of metastases
from renal cell carcinoma. Arch Ital Urol Androl. 2005;77:125-128.
43. Naito S, Yamamoto N, Takayama T, et al. Prognosis of Japanese metastatic renal cell carcinoma patients in the cytokine era: a cooperative
group report of 1463 patients. Eur Urol. 2010;57:317-325.
44. Motzer RJ, Mazumdar M, Bacik J, et al. Survival and prognostic strati-
e246
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
fcation of 670 patients with advanced renal cell carcinoma. J Clin Oncol.
1999;17:2530-2540.
Eggener SE, Yossepowitch O, Kundu S, et al. Risk score and metastasectomy independently impact prognosis of patients with recurrent renal
cell carcinoma. J Urol. 2008;180:873-878.
Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large,
multicenter study. J Clin Oncol. 2009;27:5794-5799.
Patil S, Figlin RA, Hutson TE, et al. Prognostic factors for progressionfree and overall survival with sunitinib targeted therapy and with cytokine as frst-line therapy in patients with metastatic renal cell carcinoma.
Ann Oncol. 2011;22:295-300.
Saitoh H, Nakayama M, Nakamura K, et al. Distant metastasis of renal
adenocarcinoma in nephrectomized cases. J Urol. 1982;127:1092-1095.
Assouad J, Petkova B, Berna P, et al. Renal cell carcinoma lung metastases surgery: pathologic fndings and prognostic factors. Ann Thorac
Surg. 2007;84:1114-1120.
Pfannschmidt J, Hoffmann H, Muley T, et al. Prognostic factors for survival after pulmonary resection of metastatic renal cell carcinoma. Ann
Thorac Surg. 2002;74:1653-1657.
Piltz S, Meimarakis G, Wichmann MW, et al. Long-term results after
pulmonary resection of renal cell carcinoma metastases. Ann Thorac
Surg. 2002;73:1082-1087.
Winter H, Meimarakis G, Angele MK, et al. Tumor infltrated hilar and
mediastinal lymph nodes are an independent prognostic factor for decreased survival after pulmonary metastasectomy in patients with renal
cell carcinoma. J Urol. 2010;184:1888-1894.
Meimarakis G, Angele M, Staehler M, et al. Evaluation of a new prognostic score (Munich score) to predict long-term survival after resection
of pulmonary renal cell carcinoma metastases. Am J Surg. 2011;202:158167.
Althausen P, Althausen A, Jennings LC, et al. Prognostic factors and
surgical treatment of osseous metastases secondary to renal cell carcinoma. Cancer. 1997;80:1103-1109.
Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive surgical
resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet. 2005;366:643-648.
Gaspar LE, Scott C, Murray K, et al. Validation of the RTOG recursive
partitioning analysis (RPA) classifcation for brain metastases. Int J Radiat Oncol Biol Phys. 2000;47:1001-1006.
Muacevic A, Kreth FW, Horstmann GA, et al. Surgery and radiotherapy
compared with gamma knife radiosurgery in the treatment of solitary
cerebral metastases of small diameter. J Neurosurg. 1999;91:35-43.
Muacevic A, Kreth FW, Mack A, et al. Stereotactic radiosurgery without
radiation therapy providing high local tumor control of multiple brain
metastases from renal cell carcinoma. Minim Invasive Neurosurg. 2004;
47:203-208.
Shuch B, La Rochelle JC, Klatte T, et al. Brain metastasis from renal cell
carcinoma: presentation, recurrence, and survival. Cancer. 2008;113:
1641-1648.
Staehler MD, Kruse J, Haseke N, et al. Liver resection for metastatic
disease prolongs survival in renal cell carcinoma: 12-year results from a
retrospective comparative analysis. World J Urol. 2010;28:543-547.
Siemer S, Lehmann J, Kamradt J, et al. Adrenal metastases in 1635 patients with renal cell carcinoma: outcome and indication for adrenalectomy. J Urol. 2004;171:2155-2159.
Itano NB, Blute ML, Spotts B, et al. Outcome of isolated renal cell carcinoma fossa recurrence after nephrectomy. J Urol. 2000;164:322-325.
63. Pantuck AJ, Zisman A, Dorey F, et al. Renal cell carcinoma with retroperitoneal lymph nodes. Impact on survival and benefts of immunotherapy. Cancer. 2003;97:2995-3002.
64. Pantuck AJ, Zisman A, Dorey F, et al. Renal cell carcinoma with retroperitoneal lymph nodes: role of lymph node dissection. J Urol. 2003;169:
2076-2083.
65. Freedland SJ, Dekernion JB. Role of lymphadenectomy for patients undergoing radical nephrectomy for renal cell carcinoma. Rev Urol. 2003;
5:191-195.
66. Phillips CK, Taneja SS. The role of lymphadenectomy in the surgical
e247
GENITOURINARY CANCER
SPEAKERS
Alan Horwich, MBBS, MRCP, FRCR, PhD
The Institute of Cancer Research, Royal Marsden Hospital
Sutton, United Kingdom
Lawrence H. Einhorn, MD
Indiana University
Indianapolis, IN
SURVEILLANCE
This management policy involves regular monitoring of
patients postorchiectomy to detect any development of clinically overt metastases at a stage in which the disease would
still be highly curable. Initially, there was anxiety about allowing subclinical disease to progress, and consequently, surveillance was rather intensive. There are few prospective
studies, but a Medical Research Council trial that randomly
assigned 414 patients who were undergoing surveillance for
stage I nonseminomas to receive fve scans at months 3, 6, 9,
12, and 24, or two scans at months 3 and 12 reported similar
outcomes.2 The Royal Marsden schedule for the surveillance
of patients with nonseminoma involves monthly tumor
markers and chest radiographs for the frst year, chest radiographs every 3 months for the second year, and chest radiographs every 4 months in the third year, as well as CT scans of
the abdomen at 3, 12, and 24 months. However, a number of
guidelines recommend fewer assessments without clear
detriment. Similarly, there are few prospective seminoma
studies; an ongoing U.K. trial is comparing CT scan schedules and MRI versus CT imaging. The Royal Marsden schedule has clinic assessments every 3 months in the frst and
From the Department of Clinical Oncology, Institute of Cancer Research and Royal Marsden Hospital, London, United Kingdom.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Alan Horwich, MBBS, MRCP, FRCR, PhD, Department of Clinical Oncology, Royal Marsden NHS Trust, Downs Rd., Sutton, Surrey, SM2 5PT, United Kingdom; email:
alan.horwich@icr.ac.uk.
2015 by American Society of Clinical Oncology.
e249
ALAN HORWICH
KEY POINTS
Men with stage I testicular germ cell cancer have an
excellent prognosis with reported cure rates of 99%,
regardless of the management option chosen
postorchiectomy.
In unselected patients with nonseminoma, there is a
relapse risk of 25% to 30% during surveillance, and the
most widely recognized risk factor is lymphovascular
invasion.
In unselected patients with seminoma, there is a relapse
risk of 15% to 20% during surveillance, and the most
widely recognized risk factors are tumor diameter and rete
testis invasion.
Radiotherapy has the relative disadvantage that it is
carcinogenic.
The primary management options following orchiectomy are
surveillance or adjuvant chemotherapy, and patient
preferences should be respected. Risk-adapted selection
for adjuvant chemotherapy markedly reduces the risk of
recurrence during the remainder of the time spent in
surveillance.
e250
ADJUVANT CHEMOTHERAPY
The rationale for considering adjuvant chemotherapy following orchiectomy is based on the avoidance of the risk of
toxicities that may occur during a full treatment of relapsed
disease, as well as the disappointment and natural anxiety experienced when relapse occurs. For nonseminoma, initial
studies suggested a beneft of two cycles of BEP9; however,
more recently there have been persuasive reports suggesting
a beneft with a single cycle. A German Testicular Group trial
randomly assigned patients to undergo RPLND and one cycle of BEP.10 Of 191 patients treated with BEP, the relapse risk
was only 0.5%. Similarly, a community protocol by the
SWENOTECA group that included 517 patients who received one cycle of adjuvant BEP reported relapse rates of
1.6% for patients with LVI-negative and 3.2% for patients
with LVI-positive tumors.7 An ongoing U.K. prospective
trial (The 111 Trial) that will evaluate the outcomes of one
cycle of BEP completed recruitment of 246 high risk patients in July 2014 and results are expected to be reported
soon.
In patients with seminoma, the decision to offer adjuvant
chemotherapy has been based on a low toxicity approach using single agent carboplatin. A large, prospective, randomized, controlled trial compared traditional adjuvant RT to
one cycle of carboplatin at a dose intended to achieve an area
under the curve (AUC) of 7 mg mins/mL.11 Of 573 men
randomly assigned to receive carboplatin, the relapse rate
was 4%, which was similar to RT. This result for carboplatin
was similar to the SWENOTECA community study conducted in 188 patients with seminoma, in whom the relapse
rate was 4% after a median follow-up of 3.4 years.12 In the
Spanish Testicular Germ Cell Group trials, the relapse rate
after two cycles of carboplatin was 3.2%.8
Group multicenter trial discussed previously had 15 recurrences in 191 patients who were randomly assigned to undergo RPLND (92% of patients achieved 2 years of relapsefree survival), of which seven patients had disease
involvement in the retroperitoneal nodes.10 Single, specialized center experience suggests that careful staging and selection for adjuvant chemotherapy can increase the proportion
of patients with stage II found to have low volume node disease and achieve a very low recurrence.13
RADIOTHERAPY
This has been a standard adjuvant approach in patients with
stage I seminoma, traditionally to a feld including both paraaortic and ipsilateral pelvic lymph nodes. Many series reported recurrence risk of less than 5%. More recently,
prospective, randomized trials have shown that reducing the
feld to just the para-aortic region14 and reducing the dose to
only 20 Gy15 did not reduce effcacy. The disadvantage of RT
is that it is carcinogenic. For example, a multicenter U.K. and
Norwegian study of 2,692 patients with stage I seminoma
demonstrated a cancer Standardized Incidence Ratio of 1.53
when second testicular cancers were excluded,16 with increased risk mainly affecting cancers of abdominal organs.
This risk has led to the option of adjuvant RT for patients
DISCUSSION
In most oncology centers, the primary management options
in 2015 for patients who have undergone an orchiectomy for
stage I testicular cancer are surveillance or adjuvant chemotherapy. There are advocates in favor of surveillance for almost all patients with stage I testicular cancer on the grounds
that it is safe in terms of ultimate cure rate and that it confnes
the potential toxicities of treatment to the minority of patients whose disease has already formed subclinical metastases.20 The arguments for adjuvant chemotherapy suggest that
the limited total drug doses in one treatment cycle are safer for
patients than the drug doses in a full treatment for metastatic
relapse. In addition, adjuvant chemotherapy has a particular indication in patients with high risk features, in patients who are
unlikely to adhere to surveillance, and in patients with comorbidities that might compromise a full course of treatment for
metastases. This leads to a so-called risk-adapted strategy, with
surveillance for patients at low risk and adjuvant chemotherapy
for patients at a high risk of developing metastasis, as promoted
particularly in the Spanish Germ Cell Cancer Group trials.21
There is a strong argument to involve the individual patient in
the discussion of both approaches.22
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Alan Horwich, Astellas Pharma. Consulting or
Advisory Role: None. Speakers Bureau: None. Research Funding: None. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony:
None. Travel, Accommodations, Expenses: Alan Horwich, Astellas Pharma. Other Relationships: None.
References
1. Powles TB, Bhardwa J, Shamash J, et al. The changing presentation of
germ cell tumours of the testis between 1983 and 2002. BJU Int. 2005;
95:1197-1200.
2. Rustin GJ, Mead GM, Stenning SP, et al. Randomized trial of two or fve
computed tomography scans in the surveillance of patients with stage I
nonseminomatous germ cell tumors of the testis: Medical Research
Council Trial TE08, ISRCTN56475197-the National Cancer Research
Institute Testis Cancer Clinical Studies Group. J Clin Oncol. 2007;25:
1310-1315.
3. van As NJ, Gilbert DC, Money-Kyrle J, et al. Evidence-based pragmatic
guidelines for the follow-up of testicular cancer: optimising the detection of relapse. Br J Cancer. 2008;98:1894-1902.
4. Groll RJ, Warde P, Jewett MA. A comprehensive systematic review of
testicular germ cell tumor surveillance. Crit Rev Oncol Hematol. 2007;
64:182-197.
5. Kollmannsberger C, Tandstad T, Bedard PL, et al. Patterns of relapse in
patients with clinical stage I testicular cancer managed with active surveillance. J Clin Oncol. 2015;33:51-57.
e251
ALAN HORWICH
11.
12.
13.
14.
15.
e252
16. Horwich A, Fossa SD, Huddart R, et al. Second cancer risk and mortality
in men treated with radiotherapy for stage I seminoma. Br J Cancer.
2014;110:256-263.
17. Cohn-Cedermark G, Stahl O, Tandstad T; SWENOTECA. Surveillance vs. adjuvant therapy of clinical stage I testicular tumors - a
review and the SWENOTECA experience. Andrology. Epub 2014
Oct 1.
18. Kohut RM Jr., Minnillo BJ, Kypriotakis G, et al. Changes in adjuvant
therapy utilization in stage I seminoma: are they enough to prevent
overtreatment? Urology. 2014;84:1319-1324.
19. Cafferty FH, Gabe R, Huddart RA, et al. UK management practices in
stage I seminoma and the Medical Research Council Trial of Imaging
and Schedule in Seminoma Testis managed with surveillance. Clin
Oncol (R Coll Radiol). 2012;24:25-29. Epub 2011 Sep 28.
20. Nichols CR, Roth B, Albers P, et al. Active surveillance is the preferred approach to clinical stage I testicular cancer. J Clin Oncol. 2013;31:3490-3493.
21. Aparicio J, Maroto P, del Muro XG, et al. Risk-adapted treatment in
clinical stage I testicular seminoma: the third Spanish Germ Cell Cancer
Group study. J Clin Oncol. 2011;29:4677-4681.
22. Oldenburg J, Aparicio J, Beyer J, et al. Personalizing, not patronizing:
the case for patient autonomy by unbiased presentation of management
options in stage I testicular cancer. Ann Oncol. Epub 2014 Nov 6.
MANAGEMENT OF SURVIVORS
An individual is considered a cancer survivor from the time
of diagnosis to the balance of his or her life (Offce of Cancer
Survivorship) and survivorship deals with the full spectrum of survivorship issues related to living with, through,
and beyond the cancer diagnosis (National Coalition of
Cancer Survivors).5,6 Hence, men with GCT should be followed long after being rendered free of disease. Indeed, the
oncologist may be the only physician that these young patients have. Although persistent peripheral neuropathy, ototoxicity, and hypogonadism are observed, cardiovascular
disease and second malignant neoplasms are the most important late effects since they can be life threatening.
Cardiovascular Disease
Both acute and late toxicities exist for men with GCTs. Venous and arterial vascular events may occur during cisplatinbased chemotherapy (and rarely carboplatin), including
myocardial infarction, stroke, peripheral arterial thrombosis,
and pulmonary emboli.7,8,9 Delayed vascular toxicity presenting as Raynauds phenomenon occurs in 6% to 7% of patients receiving bleomycin as part of chemotherapy for
GCT.10,11,12 Cardiac and rare cerebrovascular morbidity and
mortality may occur 10 to 20 years (or more) after the completion of chemotherapy.13,14,15 Although the mechanism is
not understood, insulin resistance, increased abdominal visceral fat, and hyperlipidemia may appear shortly after che-
From the Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: George J. Bosl, MD, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: boslg@mskcc.org.
2015 by American Society of Clinical Oncology.
e253
GEORGE J. BOSL
KEY POINTS
Late effects of cisplatin-based chemotherapy for GCT are
known and should be discussed with all patients who
require it.
In good-risk disease, new guidelines list four cycles of
etoposide/cisplatin and three cycles of
bleomycin/etoposide/cisplatin as options for clinical stage
IIA and IIB seminoma.
Treatment outcome in patients with intermediate-, poorrisk, and relapsed disease may improve because of recent
and ongoing trials.
Most data indicate that few GCTs display driver mutations
and a better knowledge of tumor biology is needed to
identify potential therapeutic targets.
Progress will require a national and international trial
effort including participation by community oncologists to
accrue adequate patients and tumor sample for studies.
e254
Salvage Therapy
Patients who have relapsed after complete remission or responded but failed to achieve a complete remission (incomplete response) have potentially curable disease.35-38 Some
groups favor standard-dose therapy for relapse after a complete response and high-dose therapy restricted to incomplete responders, whereas others favor the administration of
high-dose chemotherapy to all patients.36,37 Disagreement
exists as to the proper management of patients with mediastinal and nontesticular NSGCT (e.g., ovarian, pineal).36,37
Other investigators question the beneft of high-dose therapy.38 A randomized trial in Europe and the United States
stratifed for prognostic subgroups will test the hypothesis
that high-dose chemotherapy is better than standard-dose
chemotherapy as initial salvage treatment for patients with
relapsed or progressive GCT.39,40
e255
GEORGE J. BOSL
TABLE 1. Late Effects Spectrum of Germ Cell Tumors and Hodgkins Lymphoma to Include in Your Treatment
Discussion28,62,63
Disease
Modality
Event
15 Years (Approximate)
25 Years (Approximate)
Hodgkins Lymphoma
Not stated
CVD
3%
8%
SMN
5%
15%
GCT
RPLND
CVD SMN
2%
8%
RT
CVD SMN
4% to 5%
13%
Chemotherapy
CVD SMN
4% to 5%
13%
RT chemotherapy
CVD SMN
12%
32%
Abbreviations: CVD, cardiovascular disease; GCT, germ cell tumor; RT, radiation therapy; RPLND, retroperitoneal lymph node dissection; SMN, second malignant neoplasm.
Summary
Knowledge about GCTs continues to expand. Postchemotherapy vascular disease, metabolic syndrome, second malignant neoplasms, and hypogonadism occur with a latency
resembling that seen in patients treated for Hodgkin lymphoma
(Table 1).62,63 Acute leukemia has been reported with the use of
etoposide 500 mg/m2 to 1,000 mg/m2 (one to two cycles) and
even a single dose of cisplatin has a measurable effect on renal
function.24,64 Although chemotherapy will cure most metastatic
disease, its use should be carefully considered in adjuvant settings and patients should be informed not only of the near term
effects of chemotherapy (experienced during or shortly after its
administration), but also its delayed and late effects that require
lifelong surveillance for late outcomes, including late relapse.65
Clinical trials designed to improve treatment outcome in patients with intermediate-risk, poor-risk, and relapsed GCTs are
feasible, but require collaboration for adequate accrual. Finally,
GCT is a disease of PGCs, and differentiation is clinically evident
in vivo and probably related to chemotherapy resistance. This
biology has much relevance, some of which is already in clinical
use. More study is needed.
References
1. Hanna N, Einhorn LH. Testicular cancer: a reflection on 50 years of
discovery. J Clin Oncol. 2014;32:3085-3092.
2. Kondagunta GV, Motzer RJ. Adjuvant chemotherapy for stage II nonseminomatous germ cell tumors. Urol Clin North Am. 2007;34:179-185;
abstract ix.
3. Cancer Treatment & Survivorship. Facts & Figures. 2014-2015. http://
www.cancer.org/acs/groups/content/@research/documents/
document/acspc-042801.pdf. Accessed January 21, 2015.
4. Stat bite: average years of life lost from cancer. J Natl Cancer Inst. 2001;
93:341.
e256
9. OReilly A, MacEneaney P, Mayer N, et al. Testicular cancer and platinum: a double-edged sword. J Clin Oncol. 2014;32:e46-e48.
10. Vogelzang NJ, Bosl GJ, Johnson K, et al. Raynauds phenomenon: a
common toxicity after combination chemotherapy for testicular cancer.
Ann Intern Med. 1981;95:288-292.
11. Williams SD, Birch R, Einhorn LH, et al. Treatment of disseminated
germ-cell tumors with cisplatin, bleomycin, and either vinblastine or
etoposide. N Engl J Med. 1987;316:1435-1440.
12. de Wit R, Stoter G, Kaye SB, et al. Importance of bleomycin in combination chemotherapy for good-prognosis testicular nonseminoma: a
randomized study of the European Organization for Research and
Treatment of Cancer Genitourinary Tract Cancer Cooperative Group.
J Clin Oncol. 1997;15:1837-1843.
13. Meinardi MT, Gietema JA, van der Graaf WT, et al. Cardiovascular
morbidity in long-term survivors of metastatic testicular cancer. J Clin
Oncol. 2000;18:1725-1732.
14. Haugnes HS, Bosl GJ, Boer H, et al. Long-term and late effects of germ
cell testicular cancer treatment and implications for follow-up. J Clin
Oncol. 2012;30:3752-3763.
15. Chaudhary UB, Haldas JR. Long-term complications of chemotherapy
for germ cell tumours. Drugs. 2003;63:1565-1577.
16. Sagstuen H, Aass N, Foss SD, et al. Blood pressure and body mass index
in long-term survivors of testicular cancer. J Clin Oncol. 2005;23:49804990.
17. Willemse PP, van der Meer RW, Burggraaf J, et al. Abdominal visceral
and subcutaneous fat increase, insulin resistance and hyperlipidemia in
testicular cancer patients treated with cisplatin-based chemotherapy.
Acta Oncol. 2014;53:351-360.
18. Haugnes HS, Aass N, Foss SD, et al. Components of the metabolic syndrome in long-term survivors of testicular cancer. Ann Oncol. 2007;18:
241-248.
19. Feldman DR, Bosl GJ, Sheinfeld J, et al. Medical treatment of advanced
testicular cancer. JAMA. 2008;299:672-684.
20. Travis LB, Foss SD, Schonfeld SJ, et al. Second cancers among 40,576
testicular cancer patients: focus on long-term survivors. J Natl Cancer
Inst. 2005;97:1354-1365.
21. Fung C, Fossa SD, Milano MT, et al. Solid tumors after chemotherapy or
surgery for testicular nonseminoma: a population-based study. J Clin
Oncol. 2013;31:3807-3814.
22. Hauptmann M, Fossa SD, Stovall M, et al. Increased stomach cancer
risk following radiotherapy for testicular cancer. Br J Cancer. 2015;
112:44-51.
23. Henderson TO, Oeffnger KC, Whitton J, et al. Secondary gastrointestinal malignancies in childhood cancer survivors: a cohort study. Ann
Intern Med. 2012;156:757-766, W-260.
24. Schneider DT, Hilgenfeld E, Schwabe D, et al. Acute myelogenous leukemia after treatment for malignant germ cell tumors in children. J Clin
Oncol. 1999;17:3226-3233.
25. Raghavan D, Zalcberg JR, Grygiel JJ, et al. Multiple atypical nevi: a cutaneous marker of germ cell tumors. J Clin Oncol. 1994;12:2284-2287.
26. Garcia-del-Muro X, Maroto P, Guma` J, et al. Chemotherapy as an alternative to radiotherapy in the treatment of stage IIA and IIB testicular
seminoma: a Spanish Germ Cell Cancer Group Study. J Clin Oncol.
2008;26:5416-5421.
27. Giannis M, Aristotelis B, Vassiliki K, et al. Cisplatin-based chemotherapy for advanced seminoma: report of 52 cases treated in two institutions. J Cancer Res Clin Oncol. 2009;135:1495-1500.
28. van den Belt-Dusebout AW, de Wit R, Gietema JA, et al. Treatmentspecifc risks of second malignancies and cardiovascular disease in
5-year survivors of testicular cancer. J Clin Oncol. 2007;25:4370-4380.
29. National Comprehensive Cancer Network Guidelines Version 1.2015.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
e257
GEORGE J. BOSL
46.
47.
48.
49.
50.
51.
52.
53.
54.
e258
55. Feldman DR, Iyer G, Van Alstine L, et al. Presence of somatic mutations
within PIK3CA, AKT, RAS, and FGFR3 but not BRAF in cisplatinresistant germ cell tumors. Clin Cancer Res. 2014;20:3712-3720.
56. Rao PH, Houldsworth J, Palanisamy N, et al. Chromosomal amplifcation is associated with cisplatin resistance of human male germ cell tumors. Cancer Res. 1998;58:4260-4263.
57. Houldsworth J, Xiao H, Murty VV, et al. Human male germ cell tumor
resistance to cisplatin is linked to TP53 gene mutation. Oncogene. 1998;
16:2345-2349.
58. Einhorn LH, Brames MJ, Heinrich MC, et al. Phase II study of imatinib
mesylate in chemotherapy refractory germ cell tumors expressing KIT.
Am J Clin Oncol. 2006;29:12-13.
59. Albany C, Feldman D, Garbo L, et al. Antitumor activity of brentuximab
vedotin in CD30 positive refractory germ cell tumors. J Clin Oncol.
2013;31:6s (suppl; abstr 327).
60. Feldman DR, Turkula S, Ginsberg MS, et al. Phase II trial of sunitinib in
patients with relapsed or refractory germ cell tumors. Invest New Drugs.
2010;28:523-528.
61. Feldman DR, Einhorn LH, Quinn DI, et al. A phase II multicenter evaluation of ARQ 197 monotherapy in patients with relapsed or refractory
germ cell tumors (GCTs). J Clin Oncol. 2011;29:15s (suppl; abstr 4638).
62. Aleman BM, van den Belt-Dusebout AW, Klokman WJ, et al. Longterm cause-specifc mortality of patients treated for Hodgkins disease.
J Clin Oncol. 2003;21:3431-3439.
63. Aleman BM, van den Belt-Dusebout AW, De Bruin ML, et al. Late cardiotoxicity after treatment for Hodgkin lymphoma. Blood. 2007;109:
1878-1886.
64. Schilsky RL. Renal and metabolic toxicities of cancer chemotherapy. Semin Oncol. 1982;9:75-83.
65. Bajorin DF. The graying of testis cancer patients: what have we learned?
J Clin Oncol. 2007;25:4341-4343.
SALVAGE CHEMOTHERAPY
e259
LAWRENCE H. EINHORN
investigators compared standard-dose with high-dose chemotherapy as initial salvage chemotherapy in 1,594 patients. Seven
hundred and seventy-three patients received a standard dose
and 821 received high-dose chemotherapy with 2-year
progression-free survival being 27.8% versus 49.6% and 5-year
survival being 40.8% versus 53.2%.11 High-dose chemotherapy
is the preferred option for patients with platinum refractory disease or for patients with disease progressing after standard-dose
salvage chemotherapy. However, there are no prospective randomized studies proving superiority of high-dose chemotherapy. An argument can also be made that there are no phase III
trials proving the merit of standard-dose cisplatin plus ifosfamide combination chemotherapy. A randomized trial comparing TIP versus TI-CE is on the drawing board for initial
salvage chemotherapy. If this trial can be completed, it would
answer the question comparing these two regimens.
Testis cancer is clearly a remarkably chemosensitive and
chemocurative tumor. However, it is also the most curable
cancer with surgery alone as initial therapy for node-positive
disease. Salvage surgery is the preferred option for initial salvage therapy if progression is anatomically confned and surgically resectable.12
KEY POINTS
Optimal strategy for management of relapse after initial
cisplatin combination chemotherapy can be complicated.
Occasionally localized relapsed disease can be cured with
salvage surgery rather than salvage chemotherapy.
Standard-dose cisplatin-combination salvage chemotherapy
incorporates active drugs not previously utilized.
Paclitaxel plus ifosfamide plus cisplatin or vinblastine plus
ifosfamide plus cisplatin are examples of standard-dose
salvage chemotherapy.
High-dose chemotherapy with carboplatin plus etoposide
with peripheral blood stem cell transplant has a high cure
rate with acceptable toxicity.
SPECIAL CONSIDERATIONS
A rising tumor marker (e.g., serum hCG or AFP) usually implies progressive cancer. However, marijuana, recent mononucleosis, or cross-reactivity with luteinizing hormone can
cause double-digit hCG elevation. Benign liver disease can
cause high AFP levels. A rising LDH should never be an indication for salvage chemotherapy. Also, a rising hCG or
AFP in the absence of radiographic progression might indicate a sanctuary site relapse in the brain or a second primary
in the contralateral testis. Patients with persistent elevated tumor markers after initial chemotherapy should not be considered for salvage chemotherapy unless there is a clear
increase in hCG or AFP. This is especially true for patients
with advanced disease presenting with serum hCG higher
than 50,000 mIU/mL. Such patients will have a rapid descent
in hCG after the frst two courses and then have a plateau in
further decline. It might take several months postchemotherapy to normalize an hCG in this patient population.18
Radiographic progression with normal markers might indicate a
growing teratoma rather than progressive germ cell cancer.
Late relapse ( 2 years postchemotherapy) occurs in 2% to
3% of patients. Disease in these patients is rarely curable with
any form of salvage chemotherapy in the absence of surgery.
Resection, if feasible, is the preferred option.19
Progressive primary mediastinal nonseminomatous germ
cell tumors are particularly diffcult to cure with salvage therapy.20 Standard-dose salvage therapy will virtually always fail
to produce a durable remission. Options are high-dose chemotherapy or surgical resection of a localized relapse.8,21
CONCLUSION
Patients with relapsing disease after being managed with cisplatin combination chemotherapy are still curable, but it is
very complicated. It is recommended that such patients be
seen, or at least consulted, at tertiary centers with surgical and
medical oncology expertise in germ cell tumors.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: Lawrence H. Einhorn, Amgen, Biogenidec. Honoraria: None.
Consulting or Advisory Role: None. Speakers Bureau: Lawrence H. Einhorn, Celgene, ZIOPHARM Oncology. Research Funding: None. Patents, Royalties,
or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
e260
SALVAGE CHEMOTHERAPY
References
1. Einhorn LH, Donohue J. Cis-diamminedichloroplatinum, vinblastine,
and bleomycin combination chemotherapy in disseminated testicular
cancer. Ann Intern Med. 1977;87:293-298.
2. Williams SD, Einhorn LH, Greco FA, et al. VP-16-213 salvage therapy
for refractory germinal neoplasms. Cancer. 1980;46:2154-2158.
3. Loehrer PJ Sr, Lauer R, Roth BJ, et al. Salvage therapy in recurrent germ
cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide.
Ann Intern Med. 1988;109:540-546.
4. Loehrer PJ Sr, Gonin R, Nichols CR, et al. Vinblastine plus ifosfamide
plus cisplatin as initial salvage therapy in recurrent germ cell tumor.
J Clin Oncol. 1998;16:2500-2504.
5. Kondagunta GV, Bacik J, Donadio A, et al. Combination of paclitaxel,
ifosfamide, and cisplatin is an effective second-line therapy for patients
with relapsed testicular germ cell tumors. J Clin Oncol. 2005;23:65496555.
6. Nichols CR, Tricot G, Williams SD, et al. Dose-intensive chemotherapy
in refractory germ cell cancer-a phase I/II trial of high-dose carboplatin
and etoposide with autologous bone marrow transplantation. J Clin Oncol. 1989;7:932-939.
7. Einhorn LH, Williams SD, Chamness A, et al. High-dose chemotherapy
and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med.
2007;357:340-348.
8. Feldman DR, Sheinfeld J, Bajorin DF, et al. TI-CE high-dose chemotherapy for patients with previously treated germ cell tumors: results
and prognostic factor analysis. J Clin Oncol. 2010;28:1706-1713.
9. Lorch A, Kleinhans A, Kramar A, et al. Sequential versus single highdose chemotherapy in patients with relapsed or refractory germ cell tumors: long-term results of a prospective randomized trial. J Clin Oncol.
2012;30:800-805.
10. International Prognostic Factors Study Group, Lorch A, Beyer J, et al.
Prognostic factors in patients with metastatic germ cell tumors who fail
cisplatin-based frst-line chemotherapy. J Clin Oncol. 2010;28:49064911.
11. Lorch A, Bascoul-Mollevi C, Kramar A, et al. Conventional-dose versus
high-dose chemotherapy as frst salvage treatment in male patients with
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
metastatic germ cell tumors: evidence from a large international database. J Clin Oncol. 2011;29:2178-2184.
Murphy BR, Breeden ES, Donohue JP, et al. Surgical salvage of
chemorefractory germ cell tumors. J Clin Oncol. 1993;11:324-329.
Einhorn LH, Brames MJ, Juliar B, et al. Phase II study of paclitaxel plus
gemcitabine salvage chemotherapy for germ cell tumors after progression following high-dose chemotherapy with tandem transplant. J Clin
Oncol. 2007;25:513-516.
Kollmannsberger C, Beyer J, Liersch R, et al. Combination chemotherapy with gemcitabine plus oxaliplatin in patients with intensively pretreated or refractory germ cell cancer: a study of the German Testicular
Cancer Study Group. J Clin Oncol. 2014;22:108-114.
Bokemeyer C, Oechsle K, Honecker F, et al. Combination chemotherapy with gemcitabine, oxaliplatin, and paclitaxel in patients with
cisplatin-refractory or multiply relapsed germ cell tumors: a study of the
Germ Testicular Cancer Study Group. Ann Oncol. 2008;19:448-453.
Feldman DR, Patil S, Trinos MJ, et al. Progression-free and overall survival in patients with relapsed/refractory germ cell tumors treated with
single-agent chemotherapy: endpoints for clinical trial design. Cancer.
2012;118:981-986.
Miller J, Einhorn LH. Phase II study of daily oral etoposide in refractory
germ cell tumors. Semin Oncol. 1990;17:36-39.
Zon RT, Nichols C, Einhorn LH. Management strategies and outcomes
in germ cell patients with very high human chorionic gonadotropin levels. J Clin Oncol. 1998;16:1294-1297.
Baniel J, Foster RS, Gonin R, et al. Late relapse of testicular cancer. J Clin
Oncol. 1995;13:1170-1176.
Hartmann JT, Einhorn L, Nichols CR, et al. Second-line chemotherapy
in patients with relapsed extragonadal nonseminomatous germ cell tumors: results of an international multicenter analysis. J Clin Oncol. 2001;
19:1641-1648.
Radaideh SM, Cook VC, Kesler KA, et al. Outcome following resection
for patients with primary mediastinal nonseminomatous germ-cell tumors and rising markers post- chemotherapy. Ann Oncol. 2010;21:804807.
e261
GENITOURINARY CANCER
Debate on Chemotherapy
and Radium 223 for the Optimal
Treatment of Advanced Prostate
Cancer
CHAIR
Tanya Barauskas Dorff, MD
USC Norris Comprehensive Cancer Center
Los Angeles, CA
SPEAKERS
Howard I. Scher, MD
Memorial Sloan Kettering Cancer Center
New York, NY
Maha Hussain, MD, FACP, FASCO
University of Michigan Comprehensive Cancer Center
Ann Arbor, MI
This began with the key discoveries indicating that emergence of resistance to ADT is in part an adaptive process via
AR-dependent and AR-independent mechanisms.2-4
Microtubule targeting chemotherapy, docetaxel and cabazitaxel, have demonstrated activity in advanced prostate cancer, supporting the concept that castration-resistant cells are
inhibited by chemotherapy.5-7 The effect of targeting the AR
signaling in patients with advanced prostate cancer is now
well established with the survival benefts demonstrated by
abiraterone and enzalutamide in men with castration resistance disease irrespective of prior chemotherapy.8-11 Drugs
targeting other pathways such as sipuleucel-T (dendritic cellbased vaccine) and radium-223 (alpha-emitter and calcium
mimetic) have also shown improved survival benefts in patients with mCRPC.12-13 Despite the recent success of novel
therapies, the overall effects on survival are still modest. Furthermore, the quality/quantity of responses observed in patients being treated with AR-signaling agents decrease in the
context of prior treatment with another AR-signaling agent
in mCRPC.14
Although docetaxel was the frst agent approved for
mCRPC, the rapid proliferation of newer non chemotherapeutics particularly oral AR targeted therapy has shifted the
dynamics to delay chemotherapy. Population based studies
have shown that only about a third of patients with mCRPC
From the Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Maha Hussain, MD, FACP, FASCO, University of Michigan Comprehensive Cancer Center, 7314 Cancer Center, 1500 East Medical Center Dr., Ann Arbor, MI 48109; email:
mahahuss@umich.edu.
2015 by American Society of Clinical Oncology.
e263
are receiving docetaxel.15 Although speculative, one explanation may be the poor performance status of patients in the
context of disease progression after receiving several lines of
therapy. Anecdotal experience and recent report by Azad et
al14 on a retrospective study investigating the effcacy of enzalutamide following abiraterone in docetaxel-nave and
docetaxel-exposed patients indicated that the antitumor activity of enzalutamide following abiraterone is limited. The
median duration of enzalutamide treatment was 4.1 months.
Importantly, the effcacy of enzalutamide was comparable in
docetaxel-nave and docetaxel-exposed patients in terms of
PSA response rates (26% vs 22%; p 0.8), median time to
radiologic/clinical progression (6.6 vs. 4.6 months; p 0.6),
and median OS (8.6 vs. 10.6 months; p 0.2). These fndings
are important given the increasing evidence suggesting benefts with earlier use of docetaxel in advanced prostate cancer.
KEY POINTS
The established therapeutic limitation of ADT coupled with
the biologic heterogeneity of prostate cancer with the
presence of androgen-sensitive and androgen-insensitive
clones provide the rationale for a preemptive multitargeted
strategy with the addition of chemotherapy to ADT.
Before docetaxel, trials investigating the addition of
different chemotherapy regimens to ADT in mHSPC did not
show signicant benets.
The proven efcacy of docetaxel in the castration-resistant
setting provided rationale to investigate this drug earlier in
the course of the disease.
Results of E3805 (CHAARTED trial), a phase III clinical trial
conducted in patients with mHSPC comparing ADT alone to
ADT plus docetaxel chemotherapy, demonstrated a
signicant 13.6-month improvement in median overall
survival for the chemo-hormonal approach. Importantly, in
patients with high-volume disease, there is a 17-month
survival improvement for ADT plus docetaxel. In patients
with low-volume disease, longer follow-up is needed to
assess effect.
Six cycles of docetaxel in addition to ADT is an appropriate
therapeutic approach for men with newly diagnosed mHSPC
initiating ADT, particularly those with high volume disease,
and who are otherwise medically candidates for docetaxel
therapy.
Emerging data suggest that sequential use of current AR
targeted agents in metastatic castration resistant prostate
cancer (mCRPC) is not associated with optimal efcacy.
The latter coupled with disease related impact on
performance status and medical condition provides the
rational for integrating docetaxel chemotherapy earlier in
the treatment course of patients with mCRPC.
e264
searchers over several decades. Molecular adaptation of cancer cells to an androgen-deprived environment, including
AR-driven pathways, activation of survival pathways bypassing AR, and clonal selection of androgen-insensitive clones,
appear to be some of the major mechanisms of resistance.
Molecular adaptation involves the activation of the AR
through different mechanisms including AR-gene amplifcation, AR-overexpression or mutation, extragonadal production of androgens, ligand-independent activation by growth
factors, or alteration in survival pathways bypassing AR.2-4 In
clonal selection, androgen ablation creates a host environment in which the androgen-insensitive tumor cells have a
selective growth advantage over the androgen-dependent
cells. The continuous proliferative growth of these androgenindependent tumor cells leads to the relapse phenomenon.16
Isaacs and Coffey conducted the initial studies to show
that progression from an androgen-sensitive to androgeninsensitive state is dependent on the initial heterogeneity of
the tumor with preexisting clones of both androgendependent and androgen-independent cells.16 Following castration, adult male rats bearing the androgen-sensitive
Dunning R-3327-H tumor showed an initial response with
decreased growth rate. However, after 60 days, androgen ablation causes selection and growth advantage of androgenindependent cells. In this model, the continuous exponential
growth of the androgen-insensitive tumor cells eventually
kills the host animals.16
The heterogeneity with regard to androgen sensitivity and
the selection of resistant cells supports the need for a multitargeted treatment approach early in the course of the disease
to maximize the antitumor effect and prevent development
of resistance. The use of early chemotherapy may address the
phenotypically heterogeneous subpopulation of tumor cells
and eliminate androgen-independent clones, allowing for a
potentially improved therapeutic effect.
Traditionally, chemotherapy including docetaxel is offered
to patients with mCRPC, often when symptomatic and with
large disease burden. In fact, several of the recently designed
trials had delay time to chemotherapy as a metric for clinical success. However, delaying chemotherapy to this point
may very well limit the effcacy of chemotherapy possibly because of a larger proportion of resistant cells, including chemotherapy-resistant cells within the bigger population of
castration-resistant cells. The early use of cytotoxic chemotherapy may improve outcomes by attacking clones resistant to
ADT before they expand or acquire more resistance or simply
killing more cancer cells when they are more vulnerable.
Preclinical data by Tang et al17 evaluated different sequences of docetaxel and androgen ablation in severe combined immunodefcient mice inoculated with the LNCaP
prostate cell line. Tumor volume was at least 50% smaller in
all docetaxel groups compared with castration alone. The
smallest tumors at week 4 and the greatest growth delay were
found in mice treated with docetaxel for 2 weeks, followed by
castration. Apoptosis assays also indicated a greater degree of
apoptosis in the docetaxel followed by castration group. As in
other studies, the bax-to-bcl-2 ratio decreased following cas-
TABLE 1. Early Clinical Trials of Androgen Deprivation Therapy with or without Chemotherapy in Hormone-Naive
Metastatic Prostate Cancer
First Author and
Accrual
No. of Patients
Treatment Arms
Median OS (Months)
Murphy24, 19761980
246
A: DES/orch
Not reported
23 mo in all arms
15 mo in all arms
33 mo in all arms
B: DES CTX
C: CTX estramustine
Murphy25, 19801983
319
A: DES/orch
B: CTX 5FU DES
C: Estramustine
Osborne26, 19821986
Pummer27, 19881991
Janknegt28, 19891990
Boel29, 19881991
De Reijke30, 19901995
Kuriyama , 19901992
31
Noguchi , 19951998
32
Millikan33, 19962003
143
145
419
148
189
136
51
286
A: DES/orch
A: 15
A: 25.6
B: 18
B: 22.0
(p 0.8)
(p 0.55)
A: Flut/orch
A: 12
A: 18
B: Flut/orch epirubicin
B: 22
B: 30
(p 0.02)
(p 0.12)
A: Orchiectomy
A: 17
A: 24
B: Orch estramustine
B: 24
B: 27
(p 0.3)
(NS)
A: Orchiectomy
A: 29
A: 31
B: Orch mitomycin C
B: 26
B: 31
(p 0.64)
(NS)
A: Orchiectomy
A: 12
A: 26
B: Orch mitomycin C
B: 12
B: 22
(p 0.67)
(p 0.04)
A: DES or orchiectomy
A: 30
A: 67
B: 72
B: 96
(p .06)
(p 0.13)
A: LHRH FLT
A: 14.6
A: 30
B: LHRH estramustine
B: 25.4
B: 30
(p 0.03)
(NS)
A: LHRH or orch
A: 24
A: 64
B: 35
B: 72
(p 0.39)
(p 0.41)
Abbreviations: orch, bilateral orchiectomy; DES, diethylstilbestrol; dox, doxorubicin; NS, not signicant; LHRH, super agonist of luteinizing hormone-releasing hormone; CTX, cyclophosphamide; FU,
uorouracil; UFT, uracil plus tegafur (an oral uoropyrimidine); FLT, utamide; ketoc, ketoconazole; vinb, vinblastine.
Adapted from Millikan et al.33
e265
TABLE 2. Randomized Clinical Trials of ADT with or without Docetaxel in Hormone-Naive Metastatic Prostate
Cancer
Trial, Accrual Period
No. of
Patients
Median Follow-up
(Months)
GETUG-AFU 15 , 20042008
385
82.9
36
790
29
Treatment Arms
Median OS (Months)
A: ADT
A: 12.9
A: 46.5
B: 22.9
B: 60.9
A: ADT
A: 19.8
A: 44
B: 32.7
B: 57.6
Abbreviations: PFS, progression-free survival; OS, overall survival; ADT, androgen-deprivation therapy; HR, hazard ratio.
e267
CONCLUSION
The heterogeneity of prostate cancer and the diverse
mechanisms of resistance support a multitargeted approach to maximize the antitumor impact. The totality of
the current data would favor not delaying the use of docetaxel chemotherapy; pending the fnal peer-review publication of the CHAARTED trial, results strongly suggest that
survival benefts of docetaxel are signifcantly higher when
given in combination with ADT early in the course of mHSPC and that the combination has a more profound return
on investment as compared with sequential therapy. The unprecedented survival benefts of this chemo-hormonal approach
appear to be related to the better antitumor effect as reflected
by higher rates of undetectable PSA levels and longer median
time to castration resistance and clinical progression. Overall, patients tolerated therapy very well. Therefore, patients
with newly diagnosed mHSPC who are deemed chemotherapy eligible, especially those with high-volume disease,
should be counseled regarding this data and offered combination therapy.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Maha
Hussain, J&J, Synthon Biopharmaceuticals. Speakers Bureau: None. Research Funding: Maha Hussain, Astellas Pharma (Inst), Bayer (Inst), Genentech
(Inst), Medivation (Inst), Millennium (Inst), Pzer (Inst). Patents, Royalties, or Other Intellectual Property: Maha Hussain, Method of Treating Cancer,
Serial No. 61/481/671. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Tangen CM, Hussain MH, Higano CS, et al. Improved overall survival
trends of men with newly diagnosed M1 prostate cancer: a SWOG phase
III trial experience (S8494, S8894 and S9346). J Urol. 2012;188:11641169.
2. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10:33-39.
3. Waltering KK, Helenius MA, Sahu B, et al. Increased expression of androgen receptor sensitizes prostate cancer cells to low levels of androgens. Cancer Res. 2009;69:8141-8149.
4. Steinkamp MP, OMahony OA, Brogley M, et al. Treatment-dependent
androgen receptor mutations in prostate cancer exploit multiple mechanisms to evade therapy. Cancer Res. 2009;69:4434-4442.
5. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or
mitoxantrone plus prednisone for advanced prostate cancer. N Engl
J Med. 2004;351:1502-1512.
6. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513-1520.
7. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel
e268
8.
9.
10.
11.
12.
13.
14. Azad AA, Eigl BJ, Murray RN, et al. Effcacy of enzalutamide following
abiraterone acetate in chemotherapy-naive metastatic castrationresistant prostate cancer patients. European Urology. 2015;67:23-29.
15. Zielinski RR, Tyldesley S, Chi KN. Population-based impact on overall
survival (OS) after the introduction of docetaxel as standard therapy for
metastatic castration resistant prostate cancer (CRPC). J Clin Oncol.
2013;31(suppl 6; abstr 77).
16. Isaacs JT, Coffey DS. Adaptation versus selection as the mechanism responsible for the relapse of prostatic cancer to androgen ablation therapy as studied in the Dunning R-3327-H adenocarcinoma. Cancer Res.
1981;41:5070-5075.
17. Tang Y, Khan MA, Goloubeva O, et al. Docetaxel followed by castration
improves outcomes in LNCaP prostate cancer-bearing severe combined
immunodefcient mice. Clin Cancer Res. 2006;12:169-174.
18. Grasso CS, Wu YM, Robinson DR, et al. The mutational landscape of
lethal castration-resistant prostate cancer. Nature. 2012;487:239-243.
19. Friedlander TW, Roy R, Tomlins SA, et al. Common structural and epigenetic changes in the genome of castration-resistant prostate cancer.
Cancer Res. 2012;72:616-625.
20. Taylor BS, Schultz N, Hieronymus H, et al. Integrative genomic profling of human prostate cancer. Cancer Cell. 2010;18:11-22.
21. Rubin MA, Maher CA, Chinnaiyan AM. Common gene rearrangements in prostate cancer. J Clin Oncol. 2011;29:3659-3668.
22. Sarker D, Reid AH, Yap AH, et al. Targeting the PI3K/AKT pathway for
the treatment of prostate cancer. Clin Cancer Res. 2009;15:4799-4805.
23. Clarke JM, Armstrong AJ. Novel therapies for the treatment of advanced prostate cancer. Curr Treat Options Oncol. 2013;14:109-126.
24. Murphy GP, Beckley S, Brady MF. Treatment of newly diagnosed metastatic prostate cancer patients with chemotherapy agents in combination
with hormones versus hormones alone. Cancer. 1983;51:1264-1272.
25. Murphy GP, Huben RP, Priore R. Results of another trial of chemotherapy with and without hormones in patients with newly diagnosed metastatic prostate cancer. Urology. 1986;28:36-40.
26. Osborne CK, Blumestein B, Crawford ED, et al. Combined versus sequential chemo-endocrine therapy in advanced prostate cancer: fnal
results of a randomized Southwest Oncology Group study. J Clin Oncol.
1990;8:1675-1682.
27. Pummer K, Lehner M, Stettner H, et al. Randomized comparison of
total androgen blockade alone versus combined with weekly epirubicin
in advanced prostate cancer. Eur Urol. 1997;32(Suppl 3):81-85.
28. Janknegt RA, Bloon TA, van de Beek C, et al. Combined hormono/chemotherapy as primary treatment for metastatic prostate cancer: A randomized, multicenter study of orchiectomy alone versus orchiectomy
plus estramustine phosphate. The Dutch Estracyt Study Group. Urology.
1997;49:411-420.
29. Boel K, Van Poppel H, Goethuys H, et al. Mitomycin C for metastatic
prostate cancer: fnal analysis of a randomized trial. Anticancer Res.
1999;19(3B):2157-2161.
30. de Reijke TM, Keuppens FI, Whelan P, et al. Orchiectomy and orchiectomy plus mitomycin C for metastatic prostate cancer in patients with
poor prognosis: The fnal results of a European organization for research in cancer therapy genitourinary group trial. J Urol. 1999;162:
1658-1664.
31. Kuriyama M, Takanhashi Y, Sahashi M, et al. Prospective and randomized comparison of combined androgen blockade versus combination
with oral UFT as an initial treatment for prostate cancer. Jpn J Clin Oncol. 2001;31:18-24.
32. Noguchi M, Noda Shinshi, Yoshida M, et al. Chemohormonal therapy
as primary treatment for metastatic prostate cancer: A randomized
study of estramustine phosphate plus luteinizing hormone- releasing
hormone agonist versus flutamide plus luteinizing hormone-releasing
hormone agonist. Int J Urol. 2004;11:103-109.
33. Millikan RE, Wen S, Pagliaro LC, et al. Phase III trial of androgen ablation with or without three cycles of systemic chemotherapy for advanced prostate cancer. J Clin Oncol. 2008;26:5936-5942.
34. Haldar S, Basu A, Croce CM. Bcl2 is the guardian of microtubule integrity. Cancer Res. 1997;57:229-233.
35. Thadani-Mulero M, Portella L, Sun S, et al. Androgen receptor splice
variants determine taxane sensitivity in prostate cancer. Cancer Res.
2014;74:2270-2282.
36. Gravis G, Boher JM, Joly F, et al. Androgen deprivation therapy (ADT)
plus docetaxel (D) versus ADT alone for hormone-nave metastatic
prostate cancer (PCa): long-term analysis of the GETUG-AFU 15 phase
III trial. J Clin Oncol. 2015;33:(suppl 7; abstr 140).
37. Sweeney C, Chen Y, Carducci MA, et al. Impact of overall survival
(OS) with chemohormonal therapy versus hormonal therapy for
hormone-sensitive newly metastatic prostate cancer (mPrCa): An
ECOG-led phase III randomized trial. J Clin Oncol. 2014;32;3s
(suppl; abstr LBA2).
e269
adium 223 is a calcium-mimetic alpha-emitting radiopharmaceutical that was approved by the U.S. Food
and Drug Administration for the management of mCRPC
in 2013. Unlike previous radiopharmaceuticals, such as
samarium-153-lexidronam and strontium chloride Sr 89 that
provide pain palliation without having a known effect on survival,1,2 radium 223 has been found to prolong survival in patients with mCRPC.3 The approved dosing of radium 223 is 50
kBq/kg given intravenously over 1 minute every 28 days for 6
doses. Questions remain as to its optimal application, particularly in terms of patient selection and sequencing of this therapy
relative to other approved life-extending therapies for mCRPC.
There are a paucity of real-world data, and key limitations for
the use of radiopharmaceuticals include special licensing requirements to administer therapy and lack of comparative data.
Ongoing studies aim to address questions of sequence and combination, but we will discuss patient selection and timing for radium 223 therapy in the context of the limited available data.
WHICH PATIENTS?
The ALSYMPCA trial randomly assigned 928 men with pain of
any intensity related to bone metastases from mCRPC and
whose disease had either progressed on docetaxel or who were
not docetaxel candidates, to receive 50 kBq/kg of radium 223
intravenously over 1 minute each month for 6 doses or placebo
IV each month for 6 doses in conjunction with standard care
(Table 1).3 Men with known visceral metastases were excluded,
but malignant lymphadenopathy smaller than 3 cm in short axis
diameter was allowed. Adequate hematologic function is required. Before the frst administration of radium 223, the abso-
From the Genitourinary Cancers Program, USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Tanya Dorff, MD, Genitourinary Cancers Program, USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, 1441 Eastlake
Ave. #3440, Los Angeles, CA 90033; email: dorff@usc.edu.
2015 by American Society of Clinical Oncology.
e270
Eligible Patients
Optimal Patients
All grades
120 (35%)
67 (27%)
Grade 3
42 (12%)
24 (10%)
Grade 4
8 (2%)
3 (1%)
Grade 5
No visceral metastases
Prior docetaxel (or ineligible/
declined docetaxel)
Prior Docetaxel
(347 Patients)
No Prior Docetaxel
(253 Patients)
Anemia
Neutropenia
KEY POINTS
Radium 223 delays time to symptomatic skeletal-related
events and prolongs overall survival for men with mCRPC
and more than two bone metastases with pain attributed
to bone metastases.
Greater benet may occur in subgroups of men with more
than six bone metastases and elevated serum alkaline
phosphatase over 220 U/L.
There is a modestly higher rate of hematologic toxicity in men
receiving radium 223 after previous docetaxel therapy, but no
data exist regarding the effect of radium 223 on bone marrow
reserve for subsequent chemotherapy.
Follow-up data are limited regarding the possibility of long-term
myelosuppression and secondary myelodysplasia or leukemia.
Prostate-specic antigen changes should not be used to
determine response to treatment or duration of treatment.
All grades
24 (7%)
6 (2%)
Grade 3
8 (2%)
1 ( 1%)
Grade 4
3 (1%)
1 ( 1%)
Grade 5
All grades
53 (15%)
16 (6%)
Grade 3
15 (4%)
5 (2%)
Grade 4
16 (5%)
2 (1%)
Grade 5
1 ( 1%)
Thrombocytopenia
e271
223 may confer fewer benefts when administered frst, before docetaxel as well as against the theoretical concern for
compromised marrow reserve affecting future docetaxel
therapy. Data are still awaited to answer these questions with
greater certainty. However, given the relatively mild myelosuppression and previous experience with samarium in combination with docetaxel, combination therapy is undergoing
study (NCT01106352). In the phase I experience of radium
223 and docetaxel, substantial hematologic toxicity limited
administration of full doses and thus further combination
studies will utilize a reduced dose of docetaxel 60 mg/m2.6
Another signifcant concern when the potential for earlier
administration is considered is the risk of secondary myelodysplasia. Very limited long-term data are currently available. The long-term report presented at 2014 American
Society of Clinical Oncology Genitourinary Cancers Symposium consisted of median follow-up of 10.4 months.7 At that
time point, no myelodysplastic syndrome or acute myeloid
leukemia had been reported, and secondary solid tumors
were similar in the radium 223 and placebo arms. However,
longer follow-up will be critical to address this concern.
Much less is known about the timing and interaction between radium 223 and the newer antiandrogen agents (abiraterone or enzalutamide). Both agents have demonstrated
noteworthy clinical activity defned by increases in overall
survival in patient subsets defned by the presence of cancerrelated bone pain. Further, both agents have shown important benefts in quality-of-life measures including palliation
in bone pain or delay to skeletal-related events in certain patient subpopulations.8,9 ALSYMPCA allowed standard care,
including ketoconazole and older androgen receptor antagonists, but this cannot be extrapolated to assume that newer
agents such as abiraterone and enzalutamide can be safely
combined with radium 223. No data exist to suggest that
combination use is superior to single sequential therapy. The
open-access protocol did allow abiraterone, and the safety
and effcacy of these combinations will be formally evaluated
in an ongoing clinical trial (NCT02034552).
DURATION
Just as questions emerge as to the optimal timing for initiation of radium 223 dichloride, many questions also arise as to
when it should be discontinued. The approved treatment
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Tanya Dorff, Astellas Pharma, Bayer, Dendreon,
Medivation, Pzer, Sano. Consulting or Advisory Role: Tanya Dorff, Dendreon. Speakers Bureau: Tanya Dorff, Bayer, Medivation, Pzer. Research
Funding: Tanya Dorff, Bristol-Myers Squibb. Mitchell Gross, Novartis, Janssen Biotech. Patents, Royalties, or Other Intellectual Property: None. Expert
Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
e272
References
1. Sartor O, Reid RH, Hoskin PJ, et al. Samarium-153-Lexidronam complex for treatment of painful bone metastases in hormone-refractory
prostate cancer. Urology. 2004;63:940-945.
2. Lewington VJ, McEwanAJ, Ackery DM, et al. A prospective, randomised double-blind crossover study to examine the effcacy of
strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone. Eur J Cancer. 1991;27:954-958.
3. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and
survival in metastatic prostate cancer. N Engl J Med. 2013;369:213223.
4. Hoskin P, Sartor O, OSullivan JM, et al. Effcacy and safety of radium
223 in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecifed subgroup analysis from the randomised, double-blind, phase 3
ALSYMPCA trial. Lancet Oncol. 2014;15:1397-1406.
5. Sartor O, Coleman R, Nilsson S, et al. Effect of radium 223 on symptomatic skeletal events in patients with castration-resistant prostate cancer
and bone metastases: results from a phase 3, double-blind, randomised
trial. Lancet Oncol. 2014;15:738-746.
6. Morris MJ, Hammers HJ, Sweeney CJ, et al. Safety of radium 223 (Ra223) with docetaxel (D) in patients with bone metastases from
castration-resistant prostate cancer (CRPC): A phase I Prostate Cancer
7.
8.
9.
10.
11.
e273
GENITOURINARY CANCER
SPEAKERS
Piyush K. Agarwal, MD
National Cancer Institute at the National Institutes of Health
Bethesda, MD
David F. McDermott, MD
Beth Israel Deaconess Medical Center
Boston, MA
From the Genitourinary Oncology Service, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center, New York, NY.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Susan F. Slovin, MD, PhD, Genitourinary Oncology Service, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center, New York, NY,
10065; email: slovins@mskcc.org.
2015 by American Society of Clinical Oncology.
e275
SUSAN F. SLOVIN
KEY POINTS
Sipuleucel-T remains a standard for patients with
asymptomatic or minimally symptomatic castrationresistant prostate cancer.
The checkpoint inhibitor ipilimumab has shown activity in
phase I, II, and III trials in patients with prostate cancer
with durable responses; however, the phase III trial did not
show a survival benet.
A subset analysis of patients with castration-resistant
prostate cancer who had visceral metastases did not show
a survival benet with ipilimumab and radiation, suggesting
that there may be some advantage to patients without
visceral metastases.
Future work with combination approaches with
immunotherapy, including chimeric antigen receptordirected T lymphocytes, represents novel approaches.
Establishment of appropriate immunologic biomarkers that
are associated with disease response/outcome is needed.
e276
e277
SUSAN F. SLOVIN
ipilimumab.17-19 Preliminary clinical trials suggest that administering a therapeutic vaccine followed by ipilimumab
enhances immune responses and tumor reduction in prostate and ovarian cancers as well as melanoma.20-23 In a noncomparative phase I trial (30 patients) of ipilimumab plus the
PSA-TRICOM24 vaccine in prostate cancer, OS was 31.8
months compared with an expected survival of 18.5 months
based on baseline factors (Halabi nomogrampredicted survival [HPS]25).
Fong et al26 used microarrays spotted with more than 8,000
human proteins to assess the diversity of antibody responses
modulated by treatment with CTLA-4 blockade and GMCSF. Patients with advanced prostate cancer who had clinical
responses developed robust antibody responses to a higher
number of antigens than nonresponders. The antibody responses appeared to target antigens on which preexisting antibodies were likely to be present in patients who responded
compared with nonresponders. Although the majority of antibody responses were patient-specifc, there appeared to be a
commonality of immune responses to shared antigens within
the responder population. They identifed one shared antigen, PAK6, which is also expressed in prostate cancer and to
which CD4 T cell responses were induced.
DNA VACCINES
For the frst time in CRPC, a phase III clinical trial of a viralbased vaccine, rilimogene galvacirepvec/rilimogene glafolivec (PROSTVAC).32-34 Many viral-based cancer vaccines
are produced via the insertion of a plasmid encoding tumor
proteins (i.e., PSA, prostate-specifc membrane antigen
[PSMA]) into a viral vector, often a poxvirus (e.g., vaccinia,
fowlpox).35-37 After administration, host epithelial cells are
infected and can, on lysis, continue to release a variety of encoded antigens that are taken up and processed by APCs for
presentation to the T cell. This is accompanied by activation
of CD4 and CD8 T cells. Alternatively, as in PROSTVAC,
not only are plasmids used that encode tumor associated antigens (i.e., PSA) but there is inclusion of costimulatory molecules. In the case of PROSTVAC, three T-cell costimulatory
molecules, that is, B7.1, intercellular adhesion molecule-1
(ICAM) and leukocyte function-associated antigen-3
(LFA-3) are included. As in all vaccine strategies, there are
limitations especially when preclinical studies showed
marked tumor regressions but the responses in man are disappointing. One shortcoming of the viral-based vaccine
preparation lies in that the antibody response to vector antigens may be more exaggerated compared with the response
to the plasmid encoded tumor antigens. This can induce neutralization of the vaccine with recurrent administrations.38
PROSTVAC circumvents this by using an immunologic
prime boost that by sequencing two different viruses, a vaccinia virus prime followed by a fowlpox virus boost, results in
potent immune responses. Although there has been an effect on cancer cellular proliferation, the cancer cell rate of
growth was also affected.39 The authors suggest that this
may provide an alternative explanation to why vaccines
that yield an improved OS are not accompanied by a delayed time to progression.
A recent paper by Madan et al40 showed that ipilimumab
could be safely combined with the PSA-targeted vaccine
PSA-Tricom without signifcantly exacerbating the agents
immune-related adverse event profle. Those patients who
were chemotherapy-naive experienced a PSA decrease from
baseline levels. In support of this approach, another phase I
study also confrmed that ipilimumab could safely be combined with GVAX prostate.41 Preclinical models continue
to be performed to assess the translatability of these combinatorial approaches. A combination of GVAX and antiCTLA-4 in an autochthonous prostate cancer model
expressing hyaluronic acid in a prostate-restricted manner
reported on the importance of timing and dosage in this kind
of regimen, which may have importance in future trials with
ipilimumab combinations.42 GVAX plus anti-CTLA-4 combination therapy reduced peripheral tolerance and promoted
Concerns
BUILDING ON IMMUNOTHERAPYROLE OF
BIOLOGICS AND/OR CYTOTOXIC AGENTS
There have been numerous reports touting the role of chemotherapy given before an immunotherapeutic agent particularly as it pertains to reducing the Treg cell population and
making the immune milieu more sensitive to immune modulation. There are three basic unknowns with respect to
chemotherapy administered with an immunotherapy: identifying the optimum chemotherapy, the maximum tolerated
dose, and in which sequence the agents be given (Table 1).
Chemotherapeutics of interest, with an ongoing body of preclinical and early human data, notably include taxanes, anthracyclines, and cyclophosphamide, which seem to offer
some positive immune modulation that might enhance the
response to a therapeutic vaccine. Chemotherapy could be
administered at standard or maximum-tolerated doses if the
purpose is to kill the most malignant cells, or trigger lymphopenia and reset immune homeostasis. As discussed,
lower-than-therapeutic doses may be favored, as those may
selectively alter cell populations and inhibit angiogenesis.43
Higher doses set the tumor back further, allowing greater immune activity and more antigenicity because of tumor debulking and cell death.44 Lower doses and/or abbreviated
courses would be less toxic overall, and also less immunosuppressive. They would also allow frequent, even daily, dosing
(metronomic administration) for a steady effect over time.
Induction of tumor resistance to chemotherapy, including
multidrug resistance, is a possibility when giving suboptimal
drug doses.45-47 The vaccine, possibly enhanced by the chemotherapy, might provide a barrier against tumor escape.
Metronomic taxanes and other agents have supplemental antiangiogenic effects as well.45,48
Sequencing of chemotherapy, like dosing, depends on the
agents mechanism of action. Initiation of chemotherapy before vaccination would be an option if the goal was to reset
the immune system by reducing the level of suppressive cells.
e279
SUSAN F. SLOVIN
Malignancy
Receptor Type
CD19, 20
B-cell malignancies
scFv-CD3zeta
PSMA
Tumor neovasculature
scFv-CD3zeta
PSCA
Pan-carcinoma
Under study
ERBB2
scFv-CD28-CD3zeta
GD2
Neuroblastoma
scFv-CD3zeta, scFv-CD28
MDM2
Pan-carcinomas
CEA
Colorectal cancer
scFv-CD28-CD3zeta
VEGF-R2
Tumor neovasculature
scFv-CD3zeta
KDR
Tumor neovasculature
scFv-Fc xi Rl gamma
EGP2
Colorectal cancer
chain (Table 2, Figs. 2 and 3). Our group has shown that the
zeta chainbased CARs could induce strong activation capable of sustaining T-cell proliferation and permitting secondary antigenic restimulation in vitro provided that antigen was
presented in the context of CD28-mediated costimulation.54,58,59 In an effort to determine if T cellsparticularly
human T cellsexpanded in this manner could mediate tumor eradication in vivo and if further in vivo costimulation
would be needed to sustain their function, three tumors
models using severe combined immunodefciency-beige/
beige mice were developed that showed that PSMA-targeted
T cells could effectively eliminate prostate cancer. T cells were
transduced with Pz1, a CAR-targeting human PSMA.60,61 The
Pz1 receptor encompasses the zeta chain of the CD3 complex
as its activation domain and specifcally redirects in vitro cytolysis again PSMA-positive tumor cells lines. The tumor
models included orthotopic, subcutaneous, and pulmonary
e280
Many chimeric antigen receptors (CARs) interact with antigen through ScFvsthe antigen binding regions of immunoglobin that consist of rearranged Heavy (VH) and light VL chains linked by a
short peptide linker. The CD8/zeta fusion receptor engages HLA class I molecules. Other CARS specically bind trinitrophenol (TNP), carcinoembryonic antigen (CEA), CD 19, GD2 ganglioside, and
prostate specic membrane antigen (PSMA). They incorporate various portions of the B-cell antigen receptor (light green), T-cell receptor-CD3 complex (ivory), CD8alpha (brown), FcRgamma
(blue ITAM domains), and CD28 (yellow) cytoplasmic activation domains (blue ovals). The P28 zeta receptor, which recognizes PSMA, includes signaling domains from both CD28 and CD3 zeta.
Reproduced with permission of publisher.54
time to progression (as defned by Prostate Cancer Clinical Trials Working Group 2 criteria [NCT01867333]). The results of
the phase III multinational randomized trial of PROSTVAC in
patients with asymptomatic of minimally symptomatic CRPC
are eagerly awaited. This 800-patient trial has reached its target
accrual and is comparing the OS and proportion of patients who
remain event-free (radiological or pain progression, initiation of
chemotherapy, or death) at 6 months.
CONCLUSION
The mix and match approachthat is, combining immunologic agents with different mechanisms of action or even
within the same class66supports the rationale for continuing research in immunotherapy for prostate cancer. While
understanding mechanistically how antitumor effects may
occur,67 it is important to keep in mind that the manner in
which a therapy induces an antitumor response may be unclear, and as such should not deter investigators from using
the drug.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Susan F.
Slovin, Eisai. Speakers Bureau: None. Research Funding: None. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None.
Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Groopman J. The Transformation. Is it possible to control cancer without killing it? The New Yorker. 2014;Sept 15:14.
2. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for
castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.
3. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalut-
e281
SUSAN F. SLOVIN
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
e282
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53. Arlen PM, Gulley JL, Parker C, et al. A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgenindependent prostate cancer. Clin Cancer Res. 2006;12:1260-1269.
54. Sadelain M, Rivie`re I, Brentjens R. Targeting tumours with genetically
enhanced T lymphocytes. Nature Rev. 2003;3:35-45.
55. Rivie`re I, Gallardo HF, Hagani AB, et al. Retroviral-mediated gene
transfer in primary murine and human T-lymphocytes. Mol Biotechnol.
2000;15:133-142.
56. Shibagaki N, Ki H, Yamashita H, et al. Overexpression of CD82 on human T cells enhances LFA-1/ICAM-1-mediated cell-cell adhesion:
functional association between CD82 and LFA-1 in T cell activation.
Immunol. 1999;29:4081-4091.
57. Jensen M, Tan G, Forman S, et al. CD20 is a molecular target for scFvFc:
zeta receptor redirected T cells: implications for cellular immunotherapy of CD20 malignancy. Bio Blood Marrow Transplant. 1998;
4:75-83.
58. Maher J, Brentjens R, Gunset G, et al. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta/CD28 receptor. Nat Biotechnol. 2002;20:70-75.
59. Wang X, Olszewska M, Capacio V, et al. Quantitative analysis of clinically
relevant mutations occurring in lymphoid cells harboring gammaretrovirus-encoded hsvtk suicide genes. Gene Ther. 2008;15:454-1459.
60. Gade TP, Hassen W, Santos E, et al. Targeted elimination of prostate
cancer by genetically directed human T lymphocytes. Cancer Res. 2005;
65:9080-9088.
61. Koehne G, Doubrovin M, Doubrovina E, et al. Serial in vivo imaging of
the targeted migration of human HSV-TK-transduced antigen-specifc
lymphocytes. Nat Biotechnol. 2003;21:405-413.
62. Junghans RP. Phase IB trial redesign to test role of IL2 with anti-psma
designer T cells to yield responses in advanced prostate cancer. J Clin
Oncol. 2012;30:5s (suppl; abstr 70).
63. Slovin SF, Wang X, Hullings M, et al. Chimeric antigen receptor
(CAR) modifed T cells targeting prostate-specifc membrane antigen
(PSMA) in patients (pts) with castrate metastatic prostate cancer
(CMPC). J Clin Oncol. 2013;31:6s (suppl; abstr 72).
64. Jensen SM, Maston LD, Gough MJ, et al. Signaling through OX40 enhances anti-tumor immunity. Semin Oncol. 2010;37:524-532.
65. Kovacsovics-Bankowski M, Chisholm L, Vercellini J, et al. Phase I/II
clinical trial of anti-OX40, radiation and cyclophosphamide in patients
with prostate cancer: immunological analysis. J Immunother Cancer.
2013;1:p255.
66. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab
in advanced melanoma. N Engl J Med. 2013;369:122-133.
67. Vanderlugt CL, Miller SD. Epitope spreading in immune-mediated diseases:
implications for immunotherapy. Nat Rev Immunol. 2002;2:85-95.
e283
n 2013, cancer immunotherapy was declared the breakthrough of the year by Science magazine.1 Since then, there
has been a frenetic dash toward the development and implementation of immune-based therapies in all cancers, including urothelial cancer. However, immunotherapy has a long
and successful history in the treatment of bladder cancer,
with BCG intravesical immunotherapy as the leading therapy
for nonmuscle-invasive bladder cancer (NMIBC). We will
review the current and future immunotherapy treatment options for patients with urothelial cancer.
BCG
BCG is a live attenuated strain of Mycobacterium bovis developed initially in 1921 as a vaccine for tuberculosis. In 1976,
Morales et al2 reported the frst successful use of intravesical
BCG therapy in the treatment of recurrent superfcial bladder
cancer. It has been demonstrated to reduce recurrence rates and
progression to muscle-invasive disease in patients with carcinoma in situ (CIS) and with superfcial bladder tumors.3-5 BCG
has gone on to become the standard of care in the treatment of
high-grade NMIBC after transurethral resection.
Although BCG has been a mainstay treatment of NMIBC
for more than 3 decades, the exact mechanism by which BCG
achieves its therapeutic effect remains an area of investigation. Zbar and Rapp6 in 1974 discovered several conditions
required to obtain an antitumor effect with BCG, including
the ability to develop an immune response, a suffcient number of live BCG, close contact between BCG and cancer cells,
and a low tumor burden.
As early as 1959, it was recognized that the antitumor effect
of BCG was mediated through the activation of an immune
response and induction of the inflammatory response.7 Additional studies have confrmed that an intact immune system, particularly the cellular system, is required for
achievement of a therapeutic response. Abundant evidence
indicates that intravesical BCG results in an extensive influx
of inflammatory cells and cytokine production, which results
in an immune response against tumor cells.
The immune response is preceded by the attachment of
BCG to urothelial cells. The normal urothelium is lined with
glycosaminoglycans (GAGs), which have been suggested as a
primary defense mechanism against noxious elements in
urine.8 The antibacterial properties of GAGs are secondary to
its hydrophilic, highly negative charge, imposing a barrier
between the urothelium and urine. After instillation into the
bladder, BCG adheres to urothelial cells via fbronectin, a glycoprotein that is part of the extracellular matrix. BCG attaches to fbronectin through its fbronectin attachment
protein. The importance of this interaction has been demonstrated in a mouse model, in which blocking fbronectin
attachment reduced the delayed-type hypersensitivity response and antitumor activity.9 Internalization of BCG by
urothelial, tumor, and inflammatory cells triggers an inflammatory cascade of cytokine release and immune cell recruitment. This results in an influx of granulocytes, macrophages,
natural killer cells, dendritic cells, and lymphocytes. Many
studies have examined the cytokines present in the urine of
patients treated with BCG and found elevated amounts of interleukin (IL)-1, IL-2, IL-6, IL-8, tumor necrosis factor
(TNF)alpha, interferon (IFN)-gamma, and granulocytemacrophage colony-stimulating factor (GM-CSF).10,11 In addition, an anti-BCGspecifc immune response via antigen
From the Urologic Oncology Branch, National Cancer Institute at the National Institutes of Health, Bethesda, MD.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Piyush K. Agarwal, MD, Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, 10 Center Dr., Room 2-5952, MSC 1210, Bethesda, MD 20892;
email: piyush.agarwal@nih.gov.
2015 by American Society of Clinical Oncology.
e284
RECOMBINANT BCG
Recombinant BCG (rBCG) options have been engineered to
address the stated limitations of BCG. rBCG consists either of
Th1 cytokine-secreting rBCG strains or of non-live rBCG
strains that contain BCG subcomponents (see Table 1).
KEY POINTS
Bacillus Calmette-Guerin (BCG) represents one of the most
successful applications of immunotherapy and currently is
the most effective treatment for high-grade nonmuscleinvasive bladder cancer.
Recombinant BCG may enhance the cytotoxic T-cell
response required for BCG-mediated antitumor effects
while reducing local side effects.
Checkpoint blockade inhibitors are a novel class of
immunotherapeutics agents that target and interfere with
immune stop signals.
Vaccines present the opportunity for long-term success and
are the ultimate goal.
Adoptive T-cell immunotherapy can induce rapid immunity
but carries the risk of off-target toxicities.
Target(s)
rBCG
Th1, cytokine secreting
Monoclonal Antibodies
Checkpoint blockade inhibitors
CTLA-4, PD-L1
-HCG
Vaccine
AdHER2 dendritic cell vaccine
HER2/neu
CTAs
NY-ESO-1, recMAGE-A3
PANVAC
MUC-1, CEA
CART
TAA
Abbreviations: rBCG, recombinant bacillus Camille-Guerin; Th1, T helper cell 1; IL, interleukin;
CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PD-L1, programmed death ligand 1;
HCG, human chorionic gonadotropin; CTA, cancer testis antigen; TIL, tumor-inltrating
lymphocyte; CART, chimeric antigen receptor T cell; TAA, tumor-associated antigen.
e285
MONOCLONAL ANTIBODIES
Most excitement in immunotherapy is focused on monoclonal antibodies directed against tumor-associated antigens
(e.g., beta-HCG, cytotoxic T-lymphocyteassociated antigen
4 [CTLA-4], programmed death ligand 1 [PD-L1]). BetaHCG is expressed in 35% to 75% of bladder cancers, and expression correlates with a worse prognosis.38 CDX-1307 is an
interesting monoclonal antibody that functions like a vaccine
in the body. It consists of the beta-HCG subunit genetically
fused to the human monoclonal antibody B11 that is specifc
for the mannose receptor on antigen-presenting cells
(APCs). On administration, CDX-1307 is internalized by
APCs and, in processing, presents beta-HCG as an antigen to
CD4 and CD8 T cells.39 Thus, it has been proposed as a
therapy in beta-HCG expressing bladder cancers.
Checkpoint blockade inhibitors are extremely popular
now, because they target inhibitors of the immune response.
T cells engage APCs via their T-cell receptor as the primary
signal; however, a secondary costimulatory signal is provided
by CD28 (on the T cell) and B7 (on the APC). To prevent
excessive T-cell proliferation, an inhibitory signal, CTLA-4,
e286
The median time to frst response was 42 days, and the median overall survival times were 4.2 months for the strong
IHC expression group and 2.7 months for the weak IHC expression group. Importantly, the main toxicity of the therapy
was fatigue, and grade 3 adverse events only occurred in 4%
of patients (no grade 4 or 5 toxicity noted). On the basis of the
encouraging results of this trial, the U.S. Food and Drug Administration (FDA) granted MPDL3280A a breakthrough
designation in June 2014.
VACCINES
HER2 status has prognostic and therapeutic value in breast
cancer. Recently reported results from The Cancer Genome
Atlas48 found that HER2 alterations were almost as frequent
in urothelial carcinoma compared to the TCGA breast cancer
study. A meta-analysis of nine retrospective studies (2,242
patients) indicated that HER2 expression signifcantly correlated with poorer disease-specifc survival (hazard ratio [HR]
2; 95% CI, 1.22 to 3.29; p 0.006) and disease-free survival
(HR 1.68; 95% CI, 1.33 to 2.14; p 0.0001) of patients with
bladder cancer.49 DN24 02 is an investigational active cellular immunotherapy targeted at the HER2 receptor. It consists
of autologous PBMCs, including APCs, which are activated
ex vivo with a recombinant fusion protein. A randomized
phase II study comparing adjuvant DN24 02 to the standard
of care in patients with high-risk urothelial cell carcinoma
met accrual and results are pending at this time. Colleagues at
the National Institutes of Health Clinical Center are investigating the use of another HER2/neu vaccine in a phase I trial
(NCT01730118). This trial investigates a novel therapeutic
autologous AdHER2 dendritic cell vaccine in patients with
HER2-expressing metastatic solid tumors as well as in patients with adjuvant bladder cancer who have HER2-positive
tumors. In preclinical animal models, the vaccine was documented to eradicate large established tumors through the induction of polyclonal, anti-HER2 antibodies.
M phase phosphoprotein 1 and disheveled, EGL-10, and
pleckstrin (DEP) domain have roles in the growth of bladder
cancer cells. In addition, human leukocyte antigen (HLA)A24 restricted peptide epitopes corresponding to parts of
these two proteins have been identifed that can induce
peptide-specifc cytotoxic T cells. Of the six patients with
metastatic bladder cancer enrolled in a phase I trial, four developed vaccine-specifc cytotoxic T cells.50
Cancer testis antigens (CTAs) are a group of tumorassociated antigens with restricted expression in normal tissues but with expression in a variety of tumors. Sharma et al51
examined the expression patterns of nine CTA by IHC and
reverse transcriptase (RT) polymerase chain reaction (PCR)
in a panel of 95 high-grade bladder tumors. They found that
at least one CTA was expressed in 77% of the tumors and that
61% of the tumors expressed more than one. A recombinant
NY-ESO-1 protein vaccine coadministered with GM-CSF
and BCG as immunologic adjuvant was tested in six patients
with organ-confned disease.52 NY-ESO-1specifc antibody responses were induced in fve patients, CD8 T-cell responses oc-
curred in one patient, and CD4 T-cell responses were seen in all
six patients. A phase II trial (NCT01435356) evaluating the effcacy of the recMAGE-A3 vaccine after cystectomy is currently
recruiting; a phase I trial (NCT01498172) evaluating MAGE-A3
plus BCG has just completed, and results are pending.
PANVAC is a poxviral cancer vaccine that has demonstrated therapeutic effcacy against a variety of carcinomas.
PANVAC consists of a primary vaccination with a
replication-competent recombinant vaccinia vector followed
by multiple boosts with a replication-incompetent recombinant fowlpox vector. These vectors contain transgenes for
both human T-cell costimulatory molecules and tumorassociated antigens against Mucin-1 (MUC-1)53,54 and carcinoembryonic antigen (CEA).55 MUC-1 and CEA are
expressed in approximately 93% and 76% of high-grade bladder tumors, respectively. A phase II study (NCT02015104)
assessing PANVAC in combination with intravesical BCG in
patients who have experience treatment failure with prior
BCG therapy is recruiting patients at the NCI and the Rutgers
Cancer Institute of New Jersey.
e287
frequency in some tumors. For example, NY-ESO-1 is expressed in 80% of patients with synovial cell carcinoma patients. In a trial of patients who had metastatic synovial cell
carcinoma, four of six patients achieved objective clinical
responses after treatment with a TCR directed against NYESO-1.59 This technology still requires the presence of the
target antigen on the tumors and is restricted to patients
who have certain HLA alleles. Also, if the tumor responds
by MHC downregulation, then this therapy may be limited. However, this therapy seems attractive to apply toward urothelial tumors, given their high expression of
CTAs.
A novel form of adoptive immunotherapy has evolved that
can avoid the MHC restriction and the immune escape phenomenon that may be seen with genetically engineered
TCRs. Chimeric antigen receptor T-cell therapy entails
isolation of a patients peripheral T cells and subsequent
transduction by a chimeric receptor that consists of a
single-chain variable region of an antibody domain (scFv)
that is specifc for a desired tumor-associated antigen
(TAA) with a CD3/T cell. Because the antibody portion of
the chimeric receptor is binding to the TAA, the binding is
non-MHC restricted. The T-cell portion engages the native T-cell receptormediated activation on binding.
Therefore, this approach combines the cytotoxicity of a
CONCLUSION
Immunotherapy has become a popular approach to target tumors in the last decade. Urothelial cancer is a malignancy
that has a long history of successful treatment with BCG. Despite this success, the high recurrence and progression rates
of localized disease along with the dismal prognosis of metastatic disease warrant improvement in the current treatment.
Recombinant BCG strategies are promising for BCGrefractory disease or for patients who cannot tolerate further
BCG. Monoclonal antibodies, and specifcally checkpoint
blockade inhibitors, have been especially exciting and are the
newest therapies for metastatic urothelial cancer. These therapies likely will be applied to localized, BCG-refractory disease also. Vaccines that target TAAs, such as HER2, CTA,
and MUC-1/CEA are promising, given the high expression
in urothelial cancer and the tolerability of these treatments.
Finally, adoptive T-cell therapy is very promising; although
this area of immunotherapy has not been explored fully in
urothelial cancer, the high rate of mutations in urothelial
cancer and the prevalence of urothelial-specifc TAAs make
this a promising area of future research.
References
1. Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science. 2013;342:1432-1433.
2. Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus CalmetteGuerin in the treatment of superfcial bladder tumors. J Urol. 1976;116:
180-183.
3. Herr HW, Laudone VP, Badalament RA, et al. Bacillus Calmette-Guerin
therapy alters the progression of superfcial bladder cancer. J Clin Oncol.
1988;6:1450-1455.
4. Pawinski A, Sylvester R, Kurth KH, et al. A combined analysis of European Organization for Research and Treatment of Cancer and Medical
Research Council randomized clinical trials for the prophylactic treatment
of stage TaT1 bladder cancer. European Organization for Research and
Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and
the Medical Research Council Working Party on Superfcial Bladder Cancer. J Urol. 1996;156:1934-1940; discussion, 1940-1941.
5. Sylvester RJ, van der Meijden AP, Witjes JA, et al. Bacillus Calmette-Guerin
versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: a meta-analysis of the published results of randomized clinical trials. J Urol. 2005;174:86-91; discussion, 91-92.
6. Zbar B, Rapp HJ. Immunotherapy of guinea pig cancer with BCG. Cancer. 1974;34 (4 suppl):1532-1540.
7. Old LJ, Clarke DA, Benacerraf B. Effect of Bacillus Calmette-Guerin infection on transplanted tumours in the mouse. Nature. 1959;184:291292.
e288
15. Brausi M, Oddens J, Sylvester R, et al. Side effects of bacillus CalmetteGuerin (BCG) in the treatment of intermediate- and high-risk Ta, T1
papillary carcinoma of the bladder: results of the EORTC genitourinary
cancers group randomised phase 3 study comparing one-third dose
with full dose and 1 year with 3 years of maintenance BCG. Eur Urol.
2014;65:69-76.
16. Wang Y, Yang M, Yu Q, et al. Recombinant bacillus Calmette-Guerin in
urothelial bladder cancer immunotherapy: current strategies. Expert
Rev Anticancer Ther. 2015;15:85-93.
17. Henney CS, Kuribayashi K, Kern DE, et al. Interleukin-2 augments natural killer cell activity. Nature. 1981;291:335-338.
18. Ratliff TL, Haaff EO, Catalona WJ. Interleukin-2 production during intravesical bacille Calmette-Guerin therapy for bladder cancer. Clin Immunol Immunopathol. 1986;40:375-379.
19. Slobbe L, Lockhart E, ODonnell MA, et al. An in vivo comparison of
bacillus Calmette-Guerin (BCG) and cytokine-secreting BCG vaccines.
Immunology. 1999;96:517-523.
20. Murray PJ, Aldovini A, Young RA. Manipulation and potentiation of
antimycobacterial immunity using recombinant bacille CalmetteGuerin strains that secrete cytokines. Proc Natl Acad Sci U S A. 1996;93:
934-939.
21. ODonnell MA, Luo Y, Hunter SE, et al. Interleukin-12 immunotherapy
of murine transitional cell carcinoma of the bladder: dose dependent
tumor eradication and generation of protective immunity. J Urol. 2004;
171:1330-1335.
22. Zaharoff DA, Hoffman BS, Hooper HB, et al. Intravesical immunotherapy of superfcial bladder cancer with chitosan/interleukin-12. Cancer
Res. 2009;69:6192-6199.
23. Riemensberger J, Bohle A, Brandau S. IFN-gamma and IL-12 but not
IL-10 are required for local tumour surveillance in a syngeneic model of
orthotopic bladder cancer. Clin Exp Immunol. 2002;127:20-26.
24. Weiss GR, ODonnell MA, Loughlin K, et al. Phase 1 study of the intravesical administration of recombinant human interleukin-12 in patients
with recurrent superfcial transitional cell carcinoma of the bladder.
J Immunother. 2003;26:343-348.
25. Luo Y, Chen X, ODonnell MA. Role of Th1 and Th2 cytokines in BCGinduced IFN-gamma production: cytokine promotion and simulation
of BCG effect. Cytokine. 2003;21:17-26.
26. Luo Y, Yamada H, Chen X, et al. Recombinant Mycobacterium bovis
bacillus Calmette-Guerin (BCG) expressing mouse IL-18 augments Th1
immunity and macrophage cytotoxicity. Clin Exp Immunol. 2004;137:
24-34.
27. Papageorgiou A, Dinney CP, McConkey DJ. Interferon-alpha induces
TRAIL expression and cell death via an IRF-1-dependent mechanism in
human bladder cancer cells. Cancer Biol Ther. 2007;6:872-879.
28. Slaton JW, Perrotte P, Inoue K, et al. Interferon-alpha-mediated downregulation of angiogenesis-related genes and therapy of bladder cancer
are dependent on optimization of biological dose and schedule. Clin
Cancer Res. 1999;5:2726-2734.
29. Joudi FN, Smith BJ, ODonnell MA. Final results from a national multicenter phase II trial of combination bacillus Calmette-Guerin plus interferon alpha-2B for reducing recurrence of superfcial bladder cancer.
Urol Oncol. 2006;24:344-348.
30. Luo Y, Chen X, Han R, et al. Recombinant bacille Calmette-Guerin
(BCG) expressing human interferon-alpha 2B demonstrates enhanced
immunogenicity. Clin Exp Immunol. 2001;123:264-270.
31. Liu W, ODonnell MA, Chen X, et al. Recombinant bacillus CalmetteGuerin (BCG) expressing interferon-alpha 2B enhances human mononuclear cell cytotoxicity against bladder cancer cell lines in vitro. Cancer
Immunol Immunother. 2009;58:1647-1655.
32. Hawkyard SJ, Jackson AM, James K, et al. The inhibitory effects of in-
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
e289
e290
lizing gene-modifed T cells: from the bench to the clinic. Mol Immunol.
Epub 13 Jan 2015.
57. Sherif A, Hasan MN, Marits P, et al. Feasibility of T-cell-based adoptive
immunotherapy in the frst 12 patients with advanced urothelial urinary
bladder cancer: preliminary data on a new immunologic treatment
based on the sentinel node concept. Eur Urol. 2010;58:105-111.
58. Tran E, Turcotte S, Gros A, et al. Cancer immunotherapy based on
mutation-specifc CD4 T cells in a patient with epithelial cancer.
Science. 2014;344:641-645.
59. Robbins PF, Morgan RA, Feldman SA, et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol.
2011;29:917-924.
fcking to tumors, such as tumor vaccination); and an inflamed phenotype in which tumors have rich chemokine
levels and variable T-cell infltration, but also contain increased levels of immunosuppressive Tregs and immune
checkpoint modulators (and therefore might beneft from
therapies designed to inhibit Tregs or immune checkpoint
molecules).26
Although there is evidence that immunotherapy can be an
effective therapeutic modality for mRCC, further efforts are
needed to take full advantage of this approach for both tumors that display the inflamed phenotype and tumors that
have the noninflamed phenotype. Novel immunotherapy
strategies, including immune checkpoint inhibitors, suppressors of Tregs, T-cell agonists, and tumor vaccines, and
combinations of these various modalities with FDAapproved therapies, have produced interesting preliminary
data in ongoing clinical trials.
From the Beth Israel Deaconess Medical Center, Boston, MA; Dana-Farber/Harvard Cancer Center, Harvard Medical School, Boston, MA.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: David F. McDermott, MD, Department of Hematology/Oncology, Beth Israel Deaconess Medical Center, 375 Longwood Ave., MASCO 412, Boston, MA 02215;
email: dmcdermo@bidmc.harvard.edu.
2015 by American Society of Clinical Oncology.
e291
may lead to improved antitumor effects compared to inhibition of either pathway alone.46-52 Preliminary results of phase
I clinical trials of these combinations have demonstrated encouraging response rates (e.g., 43 to 48% with nivolumab/
ipilimumab and 52% with nivolumab/sunitinib) at the
expense of markedly increased rates of toxicity.53-54 Several
other phase I trials of different combinations are currently
under investigation (Table 1).55-64 Randomized phase III
studies will be necessary to better defne the optimal combination of these agents and their proper sequence in relation
to standard approaches.65
T-Cell Agonists
Therapies that increase T-cell activity, including IL-2, CD137
agonist antibodies, and interleukin-21 (IL-21), may improve
the effectiveness of immune checkpoint inhibitors.66 CD137
(also known as 4 1BB), which serves as a costimulatory molecule for T cells and leads to increased cytokine production, effector cytolytic activity, and T-cell survival, has been
demonstrated to eradicate mRCC in murine models.67-73 A
phase IB clinical trial of a CD137 agonist monoclonal antibody (PF-05082566) in combination with antiPD-1
therapy in humans with advanced solid malignancies is
currently ongoing.74
The cytokine IL-21 is produced by activated CD4 T
helper cells and has been demonstrated to increase the density of CD8 T cells in murine models of both melanoma and
mRCC and lead to antitumor responses against these malignancies when administered to mice.75-76 A phase I clinical
trial of intravenous recombinant IL-21 in metastatic RCC
demonstrated partial responses in 4 of 19 patients, with a tolerable toxicity profle.77 Although a subsequent phase I trial
of recombinant IL-21 in combination with sunitinib demonstrated dose-limiting hematologic toxicities,78 a phase I/II
trial of IL-21 and sorafenib revealed an acceptable toxicity
profle with a response rate of 21%.79 A trial of IL-21 and
PD-1 blockade might therefore be a rational combination to
test in mRCC.
Elimination of Tregs
KEY POINTS
Immune checkpoint blockade has the potential to usher in
a new era of immunotherapy for metastatic renal cell
carcinoma (mRCC).
In spite of the activity of immune checkpoint blockade,
only a subset of patients derive substantial and persistent
clinical benet after the cessation of therapy.
Combinations of immune checkpoint inhibitors and U.S.
Food and Drug Administrationapproved agents may provide
higher clinical activity at the expense of increased toxicity.
Novel immunotherapies worthy of study include tumor
vaccines, T-cell agonists, and regulatory T-cell inhibitors.
More accurate predictive biomarker models are necessary
to ensure that immunotherapy is applied to patients who
are most likely to benet.
e292
TABLE 1. Ongoing Trials of Combinations of PD-1/PD-L1 Inhibition and Angiogenesis or Other Immune Checkpoint
Inhibitors in mRCC
Estimated Enrollment
ClinicalTrials.gov
Identier
PD-1/PD-L1 Inhibitor
Phase
Nivolumab
BMS-986016 (anti-LAG-3)
168
NCT01968109
Pembrolizumab
228
NCT02014636
Pembrolizumab
60
NCT02133742
Pembrolizumab
Ipilimumab (anti-CTLA4)
I/II
343*
NCT02089685
MEDI4736
Tremelimumab (anti-CTLA4)
102**
NCT01975831
MEDI4736
MEDI0680 (anti-PD-L1)
150**
NCT02118337
MPDL3280A
II
300
NCT01984242
Nivolumab
Ipilimumab (anti-CTLA4)
III
1,070
NCT02231749
Abbreviations: PD-1, programmed death; PD-L1, programmed death ligand-1; mRCC, metastatic renal cell carcinoma; CTLA4, cytotoxic T lymphocyte associated protein-4.
*This study will enroll patients with both mRCC and metastatic melanoma.
**This study will enroll patients with various advanced solid malignancies (not solely mRCC).
e293
CONCLUSION
Novel immunotherapies have produced encouraging initial
results in the treatment of metastatic RCC; however, these
agents are unlikely to be effective as monotherapy in the majority of patients. At present, intensive clinical study is focused on devising combinations of therapies and developing
more accurate predictive biomarker models in an effort to
improve clinical outcomes.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: David F.
McDermott, BMS, Genentech/Roche, Merck, Pzer. Speakers Bureau: None. Research Funding: David F. McDermott, Prometheus. Patents, Royalties, or
Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
Fairlamb DJ. Spontaneous regression of metastases of renal cancer: a
report of two cases including the frst recorded regression following
irradiation of a dominant metastasis and review of the world literature.
Cancer. 1981;47:2102-2106.
2. Vogelzang NJ, Priest ER, Borden L. Spontaneous regression of histologically proved pulmonary metastases from renal cell carcinoma: a
case with 5-year followup. J Urol. 1992;148:1247-1248.
3. Minasian LM, Motzer RJ, Gluck L, et al. Interferon alfa-2a in advanced
renal cell carcinoma: treatment results and survival in 159 patients
with long-term follow-up. J Clin Oncol. 1993;11:1368-1375.
4. Medical Research Council Renal Cancer Collaborators. Interferonalpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet. 1999;353:14-17.
5. Fisher RI, Coltman CA Jr, Doroshow JH, et al. Metastatic renal cancer
treated with interleukin-2 and lymphocyte-activated killer cells. A
phase II clinical trial. Ann Intern Med. 1988;108:518-523.
6. Fyfe G, Fisher RI, Rosenberg SA, et al. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995;13:688-696.
7. Negrier S, Escudier B, Lasset C, et al. Recombinant human
interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais dImmunotherapie.
N Engl J Med. 1998;338:1272-1278.
8. Yang JC, Sherry RM, Steinberg SM, et al. Randomized study of highdose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003;21:3127-3132.
9. McDermott DF, Regan MM, Clark JI, et al. Randomized phase III trial
of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol.
2005;23:133-141.
10. Gnarra JR, Tory K, Weng Y, et al. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet. 1994;7:85-90.
1.
e294
11. Gallou C, Joly D, Mejean A, et al. Mutations of the VHL gene in sporadic renal cell carcinoma: defnition of a risk factor for VHL patients
to develop an RCC. Hum Mut. 1999;13:464-475.
12. Herman JG, Latif F, Weng Y, et al. Silencing of the VHL tumorsuppressor gene by DNA methylation in renal carcinoma. Proc Natl
Acad Sci U S A. 1994;91:9700-9704.
13. Abraham RT, Gibbons JJ. The mammalian target of rapamycin signaling pathway: twists and turns in the road to cancer therapy. Clin Cancer Res. 2007;13:3109-3114.
14. Sabatini DM. mTOR and cancer: insights into a complex relationship.
Nat Rev Cancer. 2006;6:729-734.
15. Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003;349:427-434.
16. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon
alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115124.
17. Escudier B, Elsen T, Stadler WM, et al. Sorafenib in advanced clear-cell
renal-cell carcinoma. N Engl J Med. 2007;356:125-134.
18. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370:2103-2111.
19. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa,
or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:
2271-2281.
20. Motzer RJ, Escudier B, Oudard S, et al. Effcacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebocontrolled phase III trial. Lancet. 2008;372:449-456.
21. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of
axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a
randomised phase 3 trial. Lancet. 2011;378:1931-1939.
22. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in
metastatic renal-cell carcinoma. N Engl J Med. 2013;369:722-731.
23. National Cancer Institute. SEER stat fact sheets: kidney and renal pelvis cancer. 2014. http://seer.cancer.gov/statfacts/html/kidrp.html. Accessed March 13, 2015.
24. Topalian SL, Weiner GJ, Pardoll DM. Cancer immunotherapy comes
of age. J Clin Oncol. 2011;29:4828-4836.
25. Disis ML. Immune regulation of cancer. J Clin Oncol. 2010;28:45314538.
26. Gajewski TF, Fuertes M, Spaapen R, et al. Molecular profling to identify relevant immune resistance mechanisms in the tumor microenvironment. Curr Opin Immunol. 2011;23:286-292.
27. Thompson RH, Kuntz SM, Leibovich BC, et al. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with longterm follow-up. Cancer Res. 2006;66:3381-3385.
28. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1 (PDL1) pathway to activate anti-tumor immunity. Curr Opin Immunol.
2012;24:207-212.
29. Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4
blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S
A. 2003;100:8372-8377.
30. Hodi FS, ODay SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;
363:711-723.
31. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine
for previously untreated metastatic melanoma. N Engl J Med. 2011;
364:2517-2526.
32. Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance
and immunity. Annu Rev Immunol. 2008;26:677-704.
33. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol. 2002;2:116-126.
34. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for
PD-1 and inhibits T cell activation. Nat Immunol. 2001;2:261-268.
35. Tseng SY, Otsuji M, Gorski K, et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med. 2001;
193:839-846.
36. Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439:
682-687.
37. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion.
Nat Med. 2002;8:793-800.
38. Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumor cells
in the escape from host immune system and tumor immunotherapy by
PD-L1 blockade. Proc Natl Acad Sci U S A. 2002;99:12293-12297.
39. Strome SE, Dong H, Tamura H, et al. B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res.
2003;63:6501-6505.
40. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent
anti-programmed death-1 (MDX-1106) in refractory solid tumors:
safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28:3167-3175.
41. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune
correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:
2443-2454.
42. Motzer RJ, Rini BI, McDermott DJ, et al. Nivolumab for metastatic
renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol. Epub 2014 Dec 1.
43. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of antiPD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;
366:2455-2465.
44. Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients.
Nature. 2014;515:563-567.
45. Tykodi SS. PD-1 as an emerging therapeutic target in renal cell carcinoma: current evidence. Onco Targets Ther. 2014;7:1349-1359.
46. Fife BT, Pauken KE, Eagar TN, et al. Interactions between PD-1 and
PD-L1 promote tolerance by blocking the TCR-induced stop signal.
Nat Immunol. 2009;10:1185-1192.
47. Selby MJ, Engelhardt JJ, Quigley M, et al. Anti-CTLA-4 antibodies of
IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol Res. 2013;1:32-42.
48. Peggs KS, Quezada SA, Chambers CA, et al. Blockade of CTLA-4 on
both effector and regulatory T cell compartments contributes to the
antitumor activity of anti-CTLA-4 antibodies. J Exp Med. 2009;206:
1717-1725.
49. Manning EA, Ullman JG, Leatherman JM, et al. A vascular endothelial
growth factor receptor-2 inhibitor enhances antitumor immunity
through an immune-based mechanism. Clin Cancer Res. 2007;13:
3951-3959.
50. Shrimali RK, Yu Z, Theoret MR, et al. Antiangiogenic agents can increase lymphocyte infltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res. 2010;70:61716180.
51. Kusmartsev S, Eruslanov E, Kubler H, et al. Oxidative stress regulates
expression of VEGFR1 in myeloid cells: link to tumor-induced immune suppression in renal cell carcinoma. J Immunol. 2008;181:346353.
52. Roland CL, Lynn KD, Toombs JE, et al. Cytokine levels correlate with
immune cell infltration after anti-VEGF therapy in preclinical mouse
models of breast cancer. PLoS One. 2009;4:e7669.
53. Hammers HJ, Plimack ER, Infante JR, et al. Phase I study of nivolumab
in combination with ipilimumab in metastatic renal cell carcinoma
(mRCC). Ann Oncol. 2014;25 (suppl 4):iv361-iv362.
54. Amin A, Plimack ER, Infante JR, et al. Nivolumab (anti-PD-1; BMS936558, ONO-4538) in combination with sunitinib or pazopanib in
patients (pts) with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2014;32 (suppl; abstr 5010).
55. NCT01472081. Nivolumab (BMS-936558; MDX-1106) in combination with sunitinib, pazopanib, or ipilimumab in subjects with metastatic renal cell carcinoma (RCC) (CheckMate 016). https://
www.clinicaltrials.gov/ct2/show/NCT01472081. Accessed January 28,
2015.
56. Lieu C, Bendell J, Powderly JD, et al. Safety and combination of
MPDL3280A (anti-PDL1) in combination with bevacizumab (bev)
and/or chemotherapy (chemo) in patients (pts) with locally advanced
or metastatic solid tumors. Ann Oncol. 2014;25 (suppl 4):iv361.
57. NCT01984242. A Phase 2 study of MPDL3280A (an engineered antipdl1 antibody) as monotherapy or in combination with avastin
(bevacizumab) compared to sunitinib in patients with untreated advanced renal cell carcinoma. https://www.clinicaltrials.gov/ct2/show/
NCT01984242. Accessed January 28, 2015.
58. NCT02089685. Safety and tolerability of pembrolizumab (MK-3475)
pegylated interferon alfa-2b and pembrolizumab ipilimumab in
participants with advanced melanoma or renal cell carcinoma
(MK-3475-029/KEYNOTE-29). https://www.clinicaltrials.gov/ct2/
show/NCT02089685. Accessed January 28, 2015.
59. NCT01633970. A phase 1b study of MPDL3280A (an engineered antipdl1 antibody) in combination with avastin (bevacizumab) and/or
with chemotherapy in patients with locally advanced or metastatic
solid tumors. https://www.clinicaltrials.gov/ct2/show/NCT01633970.
Accessed February 19, 2015.
60. NCT01968109. Safety study of anti-LAG-3 with and without anti-
e295
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
e296
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
sorafenib for metastatic renal cell carcinoma: a phase 1/2 study. J Immunother Cancer. 2014;2:2.
Gershon RK, Kondo K. Cell interactions in the induction of tolerance:
the role of thymic lymphocytes. Immunology. 1970;18:723-737.
Janeway CA, Sharrow SO, Simpson E. T cell populations with different
functions. Nature. 1975;253-254.
Yagi H, Nomura T, Nakamura K, et al. Crucial role of FOXP3 in the
development and function of human CD25CD4 regulatory T cells.
Int Immunol. 2005;16:1643-1656.
Iellem A, Mariani M, Lang R, et al. Unique chemotactic response profle and specifc expression of chemokine receptors CCR4 and CCD8
by CD4()CD25() regulatory T cells. J Exp Med. 2001;194:847-853.
Yoshie O, Fujisawa R, Nakayama T, et al. Frequent expression of
CCD4 in adult T-cell leukemia and human T-cell leukemia virus type
1-transformed T cells. Blood. 2002;99:1505-1511.
Ishida T, Ueda R. CCR4 as a novel molecular target for immunotherapy of cancer. Cancer Sci. 2006;97:1139-1146.
Sugiyama D, Nishikawa H, Maeda Y, et al. Anti-CCR4 mAb selectively
depletes effector-type FoxP3CD4 regulatory T cells, evoking antitumor immune responses in humans. Proc Natl Acad Sci U S A. 2013;
110:17945-17950.
Cozar JM, Canton J, Tallada M, et al. Analysis of NK cells and chemokine receptors in tumor infltrating CD4 T lymphocytes in human renal carcinomas. Cancer Immunol Immunother. 2005;54:858-866.
Dannull J, Su Z, Rizzieri D, et al. Enhancement of vaccine-mediated
antitumor activity in cancer patients after depletion of regulatory T
cells. J Clin Invest. 2005;115:3623-3633.
Rech AJ, Vonderheide RH. Clinical use of anti-CD25 antibody daclizumab to enhance immune responses to tumor antigen vaccination by
targeting T regulatory cells. Ann N Y Acad Sci. 2009;1174:99-106.
Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy
for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.
Aubert S, Fauquette V, Hemon B, et al. MUC1, a new hypoxia inducible factor target gene, is an actor in clear renal cell carcinoma tumor
progression. Cancer Res. 2009;69:5707-5715.
Griffths RW, Gilham DE, Dangoor A, et al. Expression of the 5T4 oncofoetal antigen in renal cell carcinoma: a potential target for T-cellbased immunotherapy. Br J Cancer. 2005;93:670-677.
Rochlitz C, Figlin R, Squiban P, et al. Phase I immunotherapy with a
modifed vaccinia virus (MVA) expressing human MUC1 as antigenspecifc immunotherapy in patients with MUC1-positive advanced
cancer. J Gene Med. 2003;5:690-699.
Oudard S, Rixe O, Beuselinck B, et al. A phase II study of the cancer
vaccine TG4010 alone and in combination with cytokines in patients
with metastatic renal clear-cell carcinoma: clinical and immunological
fndings. Cancer Immunol Immunother. 2011;60:261-271.
Amato RJ, Hawkins RE, Kaufman HL, et al. Vaccination of metastatic renal cancer patients with MVA-5T4: a randomized, double-blind, placebocontrolled phase III study. Clin Cancer Res. 2010;16:5539-5547.
Motzer RJ, Mazmudar M, Bacik J, et al. Survival and prognostic stratifcation of 670 patients with advanced renal cell carcinoma. J Clin Oncol. 1999;17:2530-2540.
Pal SK, Hu A, Figlin RA. A new age for vaccine therapy in renal cell
carcinoma. Cancer J. 2013;19:365-370.
Walter S, Weinschenk T, Stenzl A, et al. Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide
associates with longer patient survival. Nat Med. 2012;18:1254-1261.
NCT01265901. IMA901 in patients receiving sunitinib for advanced/
metastatic renal cell carcinoma. https://clinicaltrials.gov/ct2/show/
NCT01265901. Accessed February 6, 2015.
Figlin RA, Nicolette CA, Amin A, et al. Monitoring T-cell responses in a
phase II study of AGS-003, an autologous dendritic cell-based therapy in
101.
102.
103.
104.
105.
106.
107. McDermott DF, Sznol M, Sosman JA, et al. Immune correlates and
long-term follow-up of a Phase Ia study of MDPL3280A, an engineered PD-L1 antibody, in patients with metastatic renal cell carcinoma (mRCC). Ann Oncol. 2014;25 (suppl 4):iv280-iv304.
108. Choueiri TK, Fishman MN, Escudier BJ, et al. Immunomodulatory
activity of nivolumab in previously treated and untreated metastatic
renal cell carcinoma (mRCC): Biomarker-based results from a randomized trial. J Clin Oncol. 2014;32 (suppl; abstr 5012).
109. Callea M, Genega EM, Gupta M, et al. PD-L1 expression in primary
clear cell renal cell carcinomas (ccRCCs) and their metastases. J Clin
Oncol. 2014;32 (suppl; abstr 467).
110. Rozali EN, Hato SV, Robinson BW, et al. Programmed death ligand 2
in cancer-induced immune suppression. Clin Dev Immunol. Epub
2012 Apr 29.
111. Parsa AT, Waldron JS, Panner A, et al. Loss of tumor suppressor PTEN
function increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2007;13:84-88.
112. Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large,
multicenter study. J Clin Oncol. 2009;27:5794-5799.
e297
GENITOURINARY CANCER
SPEAKERS
Dan Theodorescu, MD, PhD
University of Colorado Cancer Center
Denver, CO
Andrea B. Apolo, MD
National Cancer Institute at the National Institutes of Health
Bethesda, MD
ancer is a genetic disease.1 A cancer cell inherits or acquires mutations that enable it to grow effciently, replicate indefnitely, support angiogenesis, avoid apoptosis,
and in some cases, metastasize.2 Molecular profles obtained
by host and tumor DNA sequencing, single nucleotide polymorphism, RNA, and protein microarrays, and methylation
screens are helping to pinpoint which mutations drive the cancerous phenotype and which are merely passengers on the malignant journey. Notwithstanding the role of individual genes,
aggregate molecular profles provide patient- and tumorspecifc information that details the biologic complexity of a
particular cancer and can be exploited for its clinical implications, therapeutic insights, and diagnostic beneft.
UC are among the highest for all cancers.4 The major problem associated with NMIBC is that after initial TURBT, 50%
to 70% of patients develop multiple recurrences; 10% to 20%
of these will progress to MIBC.5 This risk of recurrence and
progression calls for life-long surveillance. The current standard procedure is to perform cystoscopy and evaluate urine
cytology every 3 to 4 months in the frst 2 years, twice per year
in years 3 to 4, and yearly thereafter.5
The burden of this follow-up on the patient, as well as the direct and indirect costs for the patient and society in terms of lost
wages, have led to extensive efforts to develop noninvasive urine
biomarkers for UC. However, to date, none have demonstrated
suffcient specifcity and sensitivity to monitor the general population or replace cystoscopy and cytology in monitoring for recurrence.6 Urine cytology is particularly insensitive for
detecting low-grade tumors. However, advances in genomics
have clearly demonstrated that DNA alterations offer great
promise for detecting primary or secondary bladder cancer.
NMIBC and MIBC are genetically different.7-10 NMIBC is
characterized by a high frequency of mutations in the FGFR3
oncogene, leading to constitutive activation of the RAS/
MAPK pathway. In MIBC, mutations in the TP53 gene prevail. In general, mutations in FGFR3 and TP53 are mutually
exclusive, suggesting that NMIBC and MIBC develop along
different oncogenetic pathways. However, these mutations
often occur simultaneously in stage pT1 tumors that invade
the connective tissue layer underlying the urothelium. Re-
From the Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute at the National Institutes of Health, Bethesda, MD; US Oncology Research, Houston, TX and
Comprehensive Cancer Centers of Nevada, Las Vegas, NV; University of Colorado Cancer Center, Denver, CO.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Andrea B. Apolo, MD, Bladder Cancer Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute at the National Institutes of Health,
10 Center Dr. 12N226, MSC 1906, Bethesda, MD 20892; email: andrea.apolo@nih.gov.
2015 by American Society of Clinical Oncology.
105
FGFR3
FGFR3 mutations occur in around 50% of both lower and
upper urinary tract tumors, clustering in three distinct hotspots in exons 7, 10, and 15.12 The most common mutations
in exon 7 and 10 favor ligand-independent dimerization,
transactivation, and signaling.13-17 Mutations in exon 15 are
rare and induce a conformational change in the kinase domain, resulting in ligand-independent receptor activation
and signaling, as well as FGFR3 cellular localization, with aberrant endoplasmic reticulum signaling.18 FGFR3 mutations
are thought to occur early during urothelial transformation,
as they are reported in over 80% of preneoplastic lesions,13,14
pointing to an overall benign effect of FGFR3 mutation in
the bladder.17,19 FGFR3-mutant tumors are more chromosomally stable than their wild-type counterparts. A mutually
exclusive relationship between FGFR3 mutation and overrepresentation of 8q was observed in NMIBC.20 A recent
study found that around 80% of NMIBC and 54% of MIBC
have dysregulated FGFR3 with discordant mutation and protein expression patterns, suggesting a key role for FGFR3 in
both NMIBC and MIBC, either through mutation, overex-
KEY POINTS
Detection of mutations in genes such as RAS, FGFR3,
PIK3CA, and TP53, and methylation pathways in urine
sediment are promising noninvasive strategies for diagnosis
of bladder cancer.
The EORTC randomized phase III trial did not show a
substantial improvement in overall survival with adjuvant
cisplatin-based chemotherapy. Although the trial was
limited in power, there was a 22% decrease in the risk of
death (p 0.13 trend) and a 55% decrease in the risk of
recurrence.
Cisplatin-based neoadjuvant chemotherapy remains the
standard of care in muscle-invasive bladder cancer.
Immune checkpoint inhibitors have shown efcacy in
pretreated patients with metastatic bladder cancer,
offering new hope for potential therapeutic strategies in
this disease.
Multiple clinical trials are ongoing and in development in all
stages of urothelial carcinoma, testing checkpoint inhibitors
alone or in combination with other active agents that
enhance the immune system.
106
pression, or both.21 These discrepancies may reflect differential downstream signaling of wild-type and mutant receptors
or the different molecular pathways instigating the development of these tumors. The mechanisms driving FGFR3 overexpression in UC are largely unknown, although a recent
study demonstrated the regulation of FGFR3 expression in
urothelial cells by two microRNAs (miR-99a/100) that are
often downregulated in UC, particularly in low-grade and
low-stage tumors.22
FGFR3 mutations were among the frst to be used as urine
biomarkers of recurrent disease, especially low-grade disease,
which is challenging to detect by urine cytology. van Rhijn et al23
reported that combined microsatellite and FGFR3 mutation
analysis could detect UC in voided urine. FGFR3 mutations
were found in 44% of urothelial tumors (59 tumors), but were
absent in 15 G3 tumors. The sensitivity of microsatellites to detect cancer in voided urine was lower for tumors harboring
FGFR3 mutations (15 out of 21 tumors; 71%) than for FGFR3
wild-type UC (29 out of 32 tumors; 91%). By including the
FGFR3 mutation, the sensitivity of molecular cytology increased
from 71% to 89% and was superior to the sensitivity of morphologic cytology (25%) for every clinical subdivision. These fndings highlighted the potential of molecular biology as an adjunct
to cystoscopy and cytology in informing follow-up care.
HRAS
The HRAS gene, which codes for p21 Ras (or Ras), a small GTPase, was the frst identifed human oncogene. It was found in
the T24/EJ urothelial cell line.24-26 In the normal urothelium,
normal Ras protein diminishes with differentiation, with highest expression in the basal (progenitor) cells.27 The role of Ras in
UC is supported by its ability to transform Simian vacuolating
virus 40 (SV40)-immortalized human urothelial cells into invasive transitional-cell carcinomas.28,29 In addition, in elegant
transgenic studies, Ras overexpression has been shown to lead to
NMIBC.30 Ras interacts with Raf, a serine/threonine kinase,
which is activated in tumor cells containing enhanced growth
signaling pathways in both NMIBC, MIBC, and metastatic disease with subsequent activation of MAPK.31,32
P53
The p53 tumor suppressor encoded by the TP53 gene located
on chromosome 17p13.133 inhibits phase-specifc cell cycle
progression (G1-S) through transcriptional activation of
p21WAF1/CIP1.34 Most UCs exhibit loss of a single 17p allele.
Additional mutations in the remaining allele can inactivate
TP53, leading to increased nuclear accumulation of the mutant protein, which has a longer half-life than its wild-type
counterpart.35 TP53 deletion was correlated with grade and
stage of UC.36-41 Invasive carcinoma can also progress from
recurrent papillary carcinoma by acquiring additional alterations in TP53, RB1, PTEN, EGFRs, CCND1, MDM2, or
E2F.42 In addition, oncogenic HRas has been shown to promote the malignant potency of UC cells that have acquired
107
TABLE 1. Summary of Phase III Perioperative Cisplatin-Based Chemotherapy Clinic Trials in Patients with
Muscle-Invasive Bladder Cancer
Paz-Ares
Sternberg
Grossman
MRC/EORTC
Chemotherapy
Stadler (p53)
Cognetti
Adjuvant PGC 4
Adjuvant ddMVAC/
GC/MVAC 4
Neoadjuvant
MVAC
Neoadjuvant CMV
Patients
T1 and T2 negative
LN
T3 to T4, N0 to N2
T3 to T4 and/or
pT N1 to N3
T2 to T4aN0
T2 to T4aN0
Design
error
Power
Endpoint
Hazard Ratio
Planned Sample Size
5%
5%
5%
5%
5%
5%
90%
80%
80%
80%
80%
90%
Recurrence
OS
OS
OS
OS
0.5 to 0.3 at 3
years (20%)
50% to 60% at
2 years (10%)
50% to 65% at
2 years (15%)
35% to 42% at
5 years (7%)
0.52
0.75
0.77
OS
0.826
190
610
340
660 (originally
1,344)
298
915
192
142
284
307
976
11
Results
Patients randomized
Years to Accrue
5-Year Recurrence
(Observation vs
Chemotherapy)
TTR, 0.20; p 0.62; DFS, 42.3% vs. 37.2%; 3 years 44% vs. 73%; PFS, 31.8% vs. 47.6%;
HR, 0.78
p 0.70; HR, 1.08;
p 0.0001; HR,
p 0.0001;
all, 40%
0.36; all, 54%
HR, 0.54
Median Follow-up
35 months
7 years
8.7 years
8 years
5.4 years
30 months
Abbreviations: CMV, cisplatin/methotrexate/vinblastine; dd, dose-dense; DFS, disease-free survival; EORTC, European Organisation for Research and Treatment of Cancer; GC, gemcitabine/cisplatin;
HR, hazard ratio; MVAC, methotrexate/vinblastine/doxorubicin/cisplatin; OS, overall survival; PFS, progression-free survival; PGC, paclitaxel/gemcitabine/cisplatin; TTR, time to progression.
was limited in power to show a signifcant improvement in overall survival with adjuvant chemotherapy, it is possible that some
subgroups of patients might beneft from adjuvant chemotherapy. Cisplatin-based neoadjuvant chemotherapy remains the
standard of care in MIBC. Table 1 summarizes neoadjuvant and
adjuvant clinic trials in MIBC.
ACKNOWLEDGMENT
The authors thank Bonnie L. Casey for editorial assistance in
the preparation of this manuscript.
Employment: Nicholas J. Vogelzang, US Oncology. Leadership Position: None. Stock or Other Ownership Interests: Dan Theodorescu, Aurora Oncology,
Keygenomics, Myriad. Nicholas J. Vogelzang, Caris Life Sciences. Honoraria: Nicholas J. Vogelzang, Abbvie, Bavarian Nordic, DAVAOncology, Endocyte,
Mannkind, UpToDate. Consulting or Advisory Role: Nicholas J. Vogelzang, Amgen, AVEO, BIND Biosciences, Janssen Biotech, Inc. Speakers Bureau:
Nicholas J. Vogelzang, Bayer, Caris MPI, Dendreon, GlaxoSmithKline, Medivation, Millennium Takeda, Sano. Research Funding: Nicholas J. Vogelzang,
Endocyte (Inst), Exelixis (Inst), GlaxoSmithKline (Inst), PAREXEL International (Inst), Progenics (Inst), US Oncology (Inst), Viamet Pharmaceuticals (Inst).
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
109
Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: Nicholas J. Vogelzang,
Bayer/Onyx, Celgene, Dendreon, Exelixis, Genentech/Roche, Novartis, Pzer, US Oncology. Other Relationships: None.
References
1. Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature.
2009;458:719-724.
2. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:
57-70.
3. Grossman HB, Messing E, Soloway M, et al. Detection of bladder
cancer using a point-of-care proteomic assay. JAMA. 2005;293:810816.
4. Botteman MF, Pashos CL, Redaelli A, et al. The health economics of
bladder cancer: a comprehensive review of the published literature.
Pharmacoeconomics. 2003;21:1315-1330.
5. Theodorescu D, Wittke S, Ross MM, et al. Discovery and validation of
new protein biomarkers for urothelial cancer: a prospective analysis.
Lancet Oncol. 2006;7:230-240.
6. van Rhijn BW, van der Poel HG, van der Kwast TH. Urine markers for
bladder cancer surveillance: a systematic review. Eur Urol. 2005;47:736748.
7. Ehdaie B, Theodorescu D. Molecular markers in transitional cell carcinoma of the bladder: new insights into mechanisms and prognosis. Indian J Urol. 2008;24:61-67.
8. Theodorescu D. Molecular pathogenesis of urothelial bladder cancer.
Histol Histopathol. 2003;18:259-274.
9. Gui Y, Guo G, Huang Y, et al. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat Genet.
2011;43:875-878.
10. Guo G, Sun X, Chen C, et al. Whole-genome and whole-exome sequencing of bladder cancer identifes frequent alterations in genes involved in
sister chromatid cohesion and segregation. Nat Genet. 2013;45:14591463.
11. Korkolopoulou P, Levidou G, Trigka EA, et al. A comprehensive immunohistochemical and molecular approach to the PI3K/AKT/mTOR
(phosphoinositide 3-kinase/v-akt murine thymoma viral oncogene/
mammalian target of rapamycin) pathway in bladder urothelial carcinoma. BJU Int. 2012;110:E1237-E1248.
12. di Martino E, Tomlinson DC, Knowles MA. A decade of FGF receptor
research in bladder cancer: past, present, and future challenges. Adv
Urol. 2012;2012;429213.
13. Bernard-Pierrot I, Brams A, Dunois-Larde C, et al. Oncogenic properties of the mutated forms of fbroblast growth factor receptor 3b.
Carcinogenesis. 2006;27:740-747.
14. Chaffer CL, Dopheide B, Savagner P, et al. Aberrant fbroblast growth
factor receptor signaling in bladder and other cancers. Differentiation.
2007;75:831-842.
15. Hart KC, Robertson SC, Kanemitsu MY, et al. Transformation and Stat
activation by derivatives of FGFR1, FGFR3, and FGFR4. Oncogene.
2000;19:3309-3320.
16. Knowles MA. Role of FGFR3 in urothelial cell carcinoma: biomarker
and potential therapeutic target. World J Urol. 2007;25:581-593.
17. van Rhijn BW, Montironi R, Zwarthoff EC, et al. Frequent FGFR3 mutations in urothelial papilloma. J Pathol. 2002;198:245-251.
18. Lievens PM, Roncador A, Liboi E. K644E/M FGFR3 mutants activate
Erk1/2 from the endoplasmic reticulum through FRS2 alpha and PLC
gamma-independent pathways. J Mol Biol. 2006;357:783-792.
19. van Rhijn BW, van der Kwast TH, Vis AN, et al. FGFR3 and P53 characterize alternative genetic pathways in the pathogenesis of urothelial
cell carcinoma. Cancer Res. 2004;64:1911-1914.
20. Hurst CD, Platt FM, Taylor CF, et al. Novel tumor subgroups of urothe-
110
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
111
77.
78.
79.
80.
81.
82.
83.
112
84. Inman BA, Sebo TJ, Frigola X, et al. PD-L1 (B7-H1) expression by urothelial
carcinoma of the bladder and BCG-induced granulomata: associations
with localized stage progression. Cancer. 2007;109:1499-1505.
85. Wang Y, Zhuang Q, Zhou S, et al. Costimulatory molecule B7-H1 on the
immune escape of bladder cancer and its clinical signifcance. J Huazhong Univ Sci Technolog Med Sci. 2009;29:77-79.
86. Xylinas E, Robinson BD, Kluth LA, et al. Association of T-cell coregulatory protein expression with clinical outcomes following radical
cystectomy for urothelial carcinoma of the bladder. Eur J Surg Oncol.
2014;40:121-127.
87. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune
correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:
2443-2454.
88. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of antiPD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;
366:2455-2465.
89. Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment
leads to clinical activity in metastatic bladder cancer. Nature. 2014;515:
558-562.
90. Plimack ER, Gupta S, Bellmunt J, et al. A phase 1b study of pembrolizumab (Pembro; MK-3475) in patients (Pts) with advanced urothelial
tract cancer. Ann Oncol. 2014;25:1-41 (suppl; abstr LBA23).
GYNECOLOGIC CANCER
SPEAKERS
Linda R. Mileshkin, MD
Peter MacCallum Cancer Centre
Melbourne, Australia
Lari B. Wenzel, PhD
University of California, Irvine
Irvine, CA
ervical cancer remains one of the leading causes of cancerrelated morbidity and mortality worldwide and is the
fourth leading cause of cancer death in women.1 Human papillomavirus (HPV), particularly types 16 and 18, is associated with
subsequent development of cervical cancer, with an increased
risk also seen among smokers.2 The incidence and mortality
rates of cervical cancer are substantially higher in resource-poor
regions of the world; the age standardized incidence of cervical
cancer being 1.6 times higher in less developed countries. These
regional discrepancies are attributable to reductions made in the
incidence of cervical cancer in resource-rich countries with the
introduction of widely accessed screening programs.3 This decline is expected to continue as a result of the implementation
and increased availability of vaccination against HPV.4 These
gains,however,remainchallengingtoreplicateinresource-poorregions, which lack the infrastructure and funding to implement
screeningandvaccinationprograms,andwhereaccesstotreatment
remains an important problem. Within the United States, over
12,000 women will be diagnosed with cervical cancer in 2015 with
approximately 4,000 women expected to die from their disease.
Cervical cancer is disproportionately more common in women of
African American or Hispanic ethnicity and in patients with limited access to health care.3 Despite the advances in cervical cancer
prevention and diagnosis, the outcome for patients diagnosed with
later-stage and recurrent disease remains poor.
From the Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre/Deptartment of Medicine, University of Toronto, Ontario, Canada; Department of Medicine and Public
Health, University of California, Irvine, Irvine, CA; Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, Australia.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Helen Mackay, MD, Princess Margaret Hospital, 610 University Ave., Toronto, ON M5G 2M9, Canada; email: helen.mackay@uhn.on.ca.
2015 by American Society of Clinical Oncology.
e299
Inltrative corpus invasive cervix cancer has higher local failure rates, increased frequency
of nodal metastases at presentation, and poor survival compared with exophytic tumor of
similar volume.
KEY POINTS
Cervical cancer remains one of the leading causes of
cancer-related morbidity and mortality in women
worldwide.
A number of ongoing clinical trials are examining the role
of adjuvant chemotherapy in addition to the standard-ofcare treatment, low-dose chemotherapy (cisplatin)
concurrent with pelvic radiotherapy for locally advanced
cervical cancer.
Women undergoing treatment for locally advanced cervical
cancer experience signicant psychosocial distress.
Multidisciplinary supportive care may reduce the magnitude
of long-term sequelae and improve quality of life.
Outcome for women diagnosed with metastatic or recurrent
cervical cancer remains poor; there are a number of
potential therapeutic targets actively under investigation.
The rst biologic agent, in combination with chemotherapy,
to show a survival benet was bevacizumab.
International collaboration and engagement of medically
underserved communities are essential to making progress
in the treatment of cervical cancer.
e300
The left ultrasound image shows the tandem position and superimposed isodoses in the
treatment position. The ultrasound images correlates very well with the corresponding MRI
image.
cess in head and neck cancers, the combination of the epidermal growth factor receptor (EGFR) inhibitor cetuximab,
cisplatin, and radiotherapy proved toxic in patients with cervical cancer.26 RTOG 0417 investigated 10 mg/kg of intravenous bevacizumab every 2 weeks (for three doses only) in
combination with chemoradiation in 47 patients.27 Results
were promising and the toxicity profle was acceptable with
no perforations or fstulas observed; further investigation is
warranted.28
Multidisciplinary care is essential during chemoradiation
for cervical cancer. In addition to monitoring side effects
such as diarrhea and nausea, given the nature of the disease
and the patient demographic, fnancial and psychosocial
concerns are common. Early involvement of social work and
psychology may assist women to cope with these issues.
Younger women may require referral to discuss options for
fertility preservation and hormone-replacement therapy.
Smoking cessation is highly encouraged as ongoing smoking
during chemoradiation may reduce the effectiveness of treatment, as well as increase the risk for the development of a
second malignancy.29 Treatment of anemia may also be required and it is generally recommended that the hemoglobin
is maintained at 10 g/dL or higher during treatment.30 Erythropoietin during chemoradiation, however, is not recommended because of an increased risk of thromboembolic
events.31
Adjuvant Chemotherapy
Although chemoradiation is effective treatment for the primary disease, relapsed disease most commonly develops as
distant metastatic disease.32 It is therefore reasonable to predict that the addition of further cycles of adjuvant chemotherapy following completion of chemoradiation may
decrease the development of distant metastases and thus improve survival. GOG109 was a U.S. study that randomly assigned patients who had been initially treated with radical
hysterectomy and pelvic lymphadenectomy, and subsequently found to have positive pelvic nodes and/or positive
margins and/or microscopic parametrial involvement, to receive adjuvant radiation alone or adjuvant chemoradiation.
The chemotherapy consisted of four cycles of cisplatin and
5-FU, given as two cycles concurrent with radiation and two
e301
problems, including mood disorders, could target the patients who have the greatest need for more immediate care
and attention, as well as future cancer control studies. Therefore, further study of supportive care interventions to improve distress and decrease gynecologic problems in this
vulnerable population appear warranted, particularly for
women whose cancer treatment extends beyond surgery.
A recent supportive care study examined the effect of a psychosocial telephone counseling (PTC) intervention on QOL
domains and associations with biomarkers. In this randomized clinical trial, after adjusting for age and baseline scores,
participants receiving PTC had signifcantly improved depression and improved gynecologic and cancer-specifc concerns at 4 months compared with usual care participants (all
p 0.05); signifcant differences in gynecologic and cancerspecifc concerns (p 0.05) were sustained at 9 months. Participants with decreasing interleukins-4, -5, -10, and -13 had
substantially greater improvement in QOL than patients
with increasing cytokine levels. This trial confrms that PTC
benefts mood, QOL regarding cancer-specifc and gynecologic concerns, for a multiethnic underserved cancer
survivor population. The improvement in patient-reported
outcomes with decreases in T-helper type 2, and counterregulatory cytokines support a potential bio-behavioral pathway relevant to cancer survivorship.74 Providing supportive
care during treatment, and evaluating the effects of supportive care, may reduce the prevalence and magnitude of longterm sequelae of cervical cancer, which will in turn improve
QOL and quality of care.
Targeting Angiogenesis
Persistent HPV infection leads to neovascularization and tumor growth promotion, with many studies having demon-
Abbreviations: TSP-1, thrombospondin-1; VEGF, vascular endothelial growth factor; HIF1, hypoxia inducible factor 1.
e303
TABLE 1. Agents Currently under Investigation for the Treatment of Recurrent, Persistent, and Metastatic
Cervical Cancer
Target
Phase of Study
Agent(s)
CTLA
II
Ipilumimab
NCT01693783
PD-1
II
Nivolomab
NCT02257528
TiLs
NCT01585428
HPV16 only
T cells
NCT02280811
RAS/ERK/PI3K/AKT/MTOR
II
NCT01958112
PI3K
II
BKM120
NCT01613677
RTK/Angiogenesis
II
Pazopanib/topotecan
NCT02348398
RTK/Angiogenesis
II
NCT02009579
II
NCT01693783
Therapeutic vaccine
I-II
NCT02164461
HPV 16 only
NCT02128126
II
Albumin-bound paclitaxel/nedaplatin
NCT01667211
II
Eribulin mesylate
NCT0167818
II
Selinexor
NCT02025985
Immunotherapy
TiLs
T-cell immunotherapy
Pathway-Targeted Therapy
HPV-Related Therapy
I-II
Cytotoxic Agents
Other
Chromosome Region 1 Maintenance Protein
hibitor temsirolimus for the treatment of women with metastatic or recurrent cervical cancer demonstrated limited
activity.109 However, further investigation of newer agents
(such as PI3K inhibitors) alone or in combination are warranted, potentially in patient populations enriched for
PIK3CA mutations. Other potential therapeutic directions
include exploring MAPK1 inhibition or ERBB2 inhibition
in patients with activating mutations and mitogenactivated protein kinase/extracellular signal-regulated kinase (MEK) inhibitors in patients with KRAS mutations
(extrapolating from the experience in low-grade serous
ovarian cancer).
Immunotherapy
There is a strong rationale for investigating immunotherapy
in cervical cancer given the host/HPV-induced immune
evasion, which leads to persistent infection and carcinogenesis. Regulatory T cells are known to modulate the
maintenance of an immunologically tolerant environment to
HPV-associated preinvasive and malignant lesions.110,111
Furthermore, the presence of tumor-infltrating lymphocytes (TiLs) in tumor specimens has been associated with
improved outcomes.112,113 Currently, investigation of immunomodulating agents and strategies which either enhance the
innate immune response to cervical cancer or repress
immune-protective pathways are a very active area of cervical
cancer research (Table 1). Upregulation of cytotoxic T
lymphocyte-associated molecule-4 (CTLA-4) receptor on T
lymphocytes is a negative regulator of T-cell activation. Ipilimumab is a fully human immunoglobulin (IgG1 kappa) that
blocks CTLA-4. CTLA-4 blockade results in the expansion of
activated T-cell clones directed at tumor epitopes, theoretically increasing immunovigilance and eradication of tumor
cells.114-116 Ipilimumab has demonstrated substantial clinical
activity in patients with metastatic melanoma and is currently being investigated in two clinical trials enrolling
women with advanced cervical cancer with results expected
soon. (GOG 9929/NCT01711515; NCT01693783). A second
attractive immunomodulatory strategy under investigation
utilizes antibodies directed against another coinhibitory
pathway on activated T-cells, the inhibitory receptor programmed cell death 1 (PD-1) and its ligand PD-L1. It remains
to be seen if this approach will yield results in cervical cancer.117 The use of bacterial vectors directed against E7 has
been shown to induce tumor regression in preclinical models, and a phase II trial conducted in India with a liveattenuated Listeria monocytogenes vaccine suggests that this
approach may be successful with further studies ongoing
(GOG 265/NCT01266460).118 Finally, patients with cervical
cancer are being included in adoptive immunotherapy programs exploring the potential of TiLs harvested from patient
tumor samples and then reinfused after immunodepletion
(NCT01266460).
e305
FINAL REMARKS
Much progress is still needed in the treatment of cervical cancer. It is important that we remember that the majority of
women affected globally by cervical cancer are unlikely to be
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: None.
Speakers Bureau: None. Research Funding: None. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel,
Accommodations, Expenses: Helen Mackay, AstraZeneca. Other Relationships: None.
References
Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer
J Clin. 2011;61:69-90.
2. Australian Institute of Health and Welfare, Australasian Association
of Cancer Registries 2010. Cancer in Australia: an overview 2010. Canberra, Australia: Australian Institute of Health and Welfare; 2010. http://
www.aihw.gov.au/WorkArea/DownloadAsset.aspx?id6442472684.
Published 2010. Accessed February 26, 2015.
3. World Cancer Research Fund International. Cervical cancer statistics.
www.wcrf.org/int/cancer-facts-fgures/data-specifc-cancers/cervicalcancer-statistics. Accessed February 26, 2015.
4. Choi YH, Jit M, Gay N, et al. Transmission dynamic modelling of the
impact of human papillomavirus vaccination in the United Kingdom.
Vaccine. 2010;28:4091-4102.
5. Greer BE, Koh WJ, Abu-Rustum NR, et al. Cervical cancer. J Natl
Compr Canc Netw. 2010;8:1388-1416.
6. Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration. Reducing uncertainties about the effects of chemoradiotherapy
for cervical cancer: a systematic review and meta-analysis of individual
patient data from 18 randomized trials. J Clin Oncol. 2008;26:58025812.
7. Eifel PJ, Burke TW, Delclos L, et al. Early stage I adenocarcinoma of the
uterine cervix: treatment results in patients with tumors less than or
equal to 4 cm in diameter. Gynecol Oncol. 1991;41:199-205.
8. Gien LT, Covens A. Lymph node assessment in cervical cancer: prognostic and therapeutic implications. J Surg Oncol. 2009;99:242-247.
9. Grigsby PW. The prognostic value of PET and PET/CT in cervical cancer. Cancer Imaging. 2008;8:146-155.
10. Trimble EL. Cervical cancer state-of-the-clinical-science meeting on
pretreatment evaluation and prognostic factors, September 27-28,
2007: proceedings and recommendations. Gynecol Oncol. 2009;114:
145-150.
11. Goudy G, Stoeckle E, Thomas L, et al. [Prognostic impact of tumour
1.
e306
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
corpus uteri invasion in cervical cancer patients treated by radiotherapy. Int J Gynecol Cancer. 2006;16:623-630.
Narayan K, McKenzie AF, Hicks RJ, et al. Relation between FIGO
stage, primary tumor volume, and presence of lymph node metastases
in cervical cancer patients referred for radiotherapy. Int J Gynecol Cancer. 2003;13:657-663.
Schwarz JK, Grigsby PW, Dehdashti F, et al. The role of 18F-FDG PET
in assessing therapy response in cancer of the cervix and ovaries. J Nucl
Med. 2009;50 Supl 1:64S-73S.
Tod M, Meredith W. A dosage system for use in the treatment of cancer of the uterine cervix. Br J Radiol. 1938;11:809-824.
Narayan K, van Dyk S, Bernshaw D, et al. Ultrasound guided conformal brachytherapy of cervix cancer: survival, patterns of failure, and
late complications. J Gynecol Oncol. 2014;25:206-213.
Moore KN, Sill MW, Miller DS, et al. A phase I trial of tailored radiation therapy with concomitant cetuximab and cisplatin in the treatment of patients with cervical cancer: a gynecologic oncology group
study. Gynecol Oncol. 2012;127:456-461.
Schefter TE, Winter K, Kwon JS, et al. A phase II study of bevacizumab
in combination with defnitive radiotherapy and cisplatin chemotherapy in untreated patients with locally advanced cervical carcinoma:
preliminary results of RTOG 0417. Int J Radiat Oncol Biol Phys. 2012;
83:1179-1184.
Schefter T, Winter K, Kwon JS, et al. RTOG 0417: effcacy of bevacizumab in combination with defnitive radiation therapy and cisplatin
chemotherapy in untreated patients with locally advanced cervical carcinoma. Int J Radiat Oncol Biol Phys. 2014;88:101-105.
Mileshkin L, Paramanathan A, Kondalsamy-Chennakesavan S, et al.
Smokers with cervix cancer have more uterine corpus invasive disease
and an increased risk of recurrence after treatment with chemoradiation. Int J Gynecol Cancer. 2014;24:1286-1291.
Bishop AJ, Allen PK, Klopp AH, et al. Relationship between low hemoglobin levels and outcomes after treatment with radiation or
chemoradiation in patients with cervical cancer: has the impact of anemia been Ooerstated? Int J Radiat Oncol Biol Phys. 2014;pii:S03603016.
Thomas G, Ali S, Hoebers FJ, et al. Phase III trail to evaluate the effcacy
of maintaining hemoglobin levels above 12.0 g/dL with erythropoietin
vs above 10.0 g/dL without erythropoietin in anemic patients receiving
concurrent radiation and cisplatin for cervical cancer. Gynecol Oncol.
2008;108:317-325.
Friedlander M, Grogan M, U.S. Preventative Services Task Force.
Guidelines for the treatment of recurrent and metastatic cervical cancer. Oncologist. 2002;7:342-347.
Peters WA 3rd, Liu PY, Barrett RJ 2nd, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk earlystage cancer of the cervix. J Clin Oncol 2000;18:1606-1613.
Kantardzic N, Beslija S, Begic D. [Comparative parameters of myelotoxicity in patients treated with simultaneous chemotherapy and radiotherapy or only radiotherapy]. Med Arh. 2004;58:19-22.
Duenas-Gonzalez A, Zarba JJ, Patel F, et al. Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and
radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix. J Clin Oncol. 2011;29:1678-1685.
Thomas G. Are we making progress in curing advanced cervical cancer? J Clin Oncol. 2011;29:1654-1656.
Ryu SY, Lee WM, Kim K, et al. Randomized clinical trial of weekly vs.
triweekly cisplatin-based chemotherapy concurrent with radiotherapy
in the treatment of locally advanced cervical cancer. Int J Radiat Oncol
Biol Phys. 2011;81:e577-e581.
e307
59. Frumovitz M, Sun CC, Schover LR, et al. Quality of life and sexual
functioning in cervical cancer survivors. J Clin Oncol. 2005;23:74287436.
60. Mantegna G, Petrillo M, Fuoco G, et al. Long-term prospective longitudinal evaluation of emotional distress and quality of life in cervical
cancer patients who remained disease-free 2-years from diagnosis.
BMC Cancer. 2013;13:127.
61. Bradley S, Rose S, Lutgendorf S, et al. Quality of life and mental health
in cervical and endometrial cancer survivors. Gynecol Oncol. 2006;100:
479-486.
62. Herzog TJ, Wright JD. The impact of cervical cancer on quality of
lifethe components and means for management. Gynecol Oncol.
2007;107:572-577.
63. Ashing-Giwa KT, Lim JW, Gonzalez P. Exploring the relationship between physical well-being and healthy lifestyle changes among
European- and Latina-American breast and cervical cancer survivors.
Psychooncology. 2010;19:1161-1170.
64. Nelson EL, Wenzel LB, Osann K, et al. Stress, immunity, and cervical
cancer: biobehavioral outcomes of a randomized clinical trail. Clin
Cancer Res. 2008;14:2111-2118.
65. Antoni MH. Psychosocial intervention effects on adaptation, disease
course and biobehavioral processes in cancer. Brain Behav Immun.
2013;30:S88-S98 (suppl).
66. Powell ND, Tarr AJ, Sheridan JF. Psychosocial stress and inflammation in cancer. Brain Behav Immun. 2013;30:S41-S47 (suppl).
67. Chida Y, Hamer M, Wardle J, et al. Do stress-related psychosocial factors contribute to cancer incidence and survival? Nat Clin Pract Oncol.
2008;5:466-475.
68. Chase DM, Huang HQ, Wenzel L, et al. Quality of life and survival in
advanced cervical cancer: a Gynecologic Oncology Group study. Gynecol Oncol. 2012;125:315-319.
69. Cella DF, Tulsky DS, Gray G, et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure.
J Clin Oncol. 1993;11:570-579.
70. Tewari KS, Sill MW, Long HJ 3rd, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014;370:734743.
71. Wenzel L, Osann K, Hsieh S, et al. Quality of life outcomes of a randomized counseling trial for cervical cancer survivors. Qual Life Res.
2012;21:15 (suppl; abstr 108.3).
72. Wenzel L. Late effects and quality of life following aggressive management. Paper presented at: 1st American Brachytherapy Society GYN
School; July 2014; Chicago, IL.
73. Osann K, Hsieh S, Nelson EL, et al. Factors associated with poor quality
of life among cervical cancer survivors: implications for clinical care
and clinical trials. Gynecol Oncol. 2014;135:266-272.
74. Wenzel L, Osann K, Hsieh S, et al. Psychosocial telephone counseling
for survivors of cervical cancer: results of a randomized biobehavioral
trial. J Clin Oncol. Epub 2015 Feb 23.
75. Waggoner SE. Cervical cancer. Lancet. 2003;361:2217-2225.
76. Monk BJ, Sill MW, McMeekin DS, et al. Phase III trial of four cisplatincontaining doublet combinations in stage IVB, recurrent, or persistent
cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2009;27:4649-4655.
77. Moore DH, Tian C, Monk BJ, et al. Prognostic factors for response to
cisplatin-based chemotherapy in advanced cervical carcinoma: a Gynecologic Oncology Group Study. Gynecol Oncol. 2010;116:44-49.
78. Rose PG, Blessing JA, Gershenson DM, et al. Paclitaxel and cisplatin as
frst-line therapy in recurrent or advanced squamous cell carcinoma of
the cervix: a gynecologic oncology group study. J Clin Oncol. 1999;17:
2676-2680.
79. Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358:2039-2049.
e308
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
can and cisplatin for the treatment of advanced cervical cancer: a phase
II GINECO trial. Gynecol Oncol. 2009;113:16-20.
Schilder RJ, Sill MW, Lee YC, et al. A phase II trial of erlotinib in recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group Study. Int J Gynecol Cancer. 2009;19:929-933.
Goncalves A, Fabbro M, Lhomme C, et al. A phase II trial to evaluate
geftinib as second- or third-line treatment in patients with recurring
locoregionally advanced or metastatic cervical cancer. Gynecol Oncol.
2008;108:42-46.
Bosch FX, Lorincz A, Munoz N, et al. The causal relation between human papillomavirus and cervical cancer. J Clin Pathol. 2002;55:244265.
Janku F, Lee JJ, Tsimberidou AM, et al. PIK3CA mutations frequently
coexist with RAS and BRAF mutations in patients with advanced cancers. PLoS One. 2011;6:e22769.
Bertelsen BI, Steine SJ, Sandvei R, et al. Molecular analysis of the PI3KAKT pathway in uterine cervical neoplasia: Frequent PIK3CA amplifcation and AKT phosphorylation. Int J Cancer. 2006;118:1877-1883.
McIntyre JB, Wu JS, Craighead PS, et al. PIK3CA mutational status
and overall survival in patients with cervical cancer treated with radical
chemoradiotherapy. Gynecol Oncol. 2013;128:409-414.
Ojesina AI, Lichtenstein L, Freeman SS, et al. Landscape of genomic
alterations in cervical carcinomas. Nature. 2014;506:371-375.
Galic V, Herzog TJ, Lewin SN, et al. Prognostic signifcance of adenocarcinoma histology in women with cervical cancer. Gynecol Oncol.
2012;125:287-291.
Wright AA, Howitt BE, Myers AP, et al. Oncogenic mutations in cervical cancer: genomic differences between adenocarcinomas and squamous cell carcinomas of the cervix. Cancer. 2013;119:3776-3783.
Tinker AV, Ellard S, Welch S, et al. Phase II study of temsirolimus
(CCI-779) in women with recurrent, unresectable, locally advanced or
metastatic carcinoma of the cervix. A trial of the NCIC Clinical Trials
Group (NCIC CTG IND 199). Gynecol Oncol. 2013;130:269-274.
Sasagawa T, Takagi H, Makinoda S. Immune responses against human
papillomavirus (HPV) infection and evasion of host defense in cervical
cancer. J Infect Chemother. 2012;18:807-815.
Patel S, Chiplunkar S. Host immune responses to cervical cancer. Curr
Opin Obstet Gynecol. 2009;21:54-59.
Piersma SJ, Jordanova ES, van Poelgeest MI, et al. High number of
intraepithelial CD8 tumor-infltrating lymphocytes is associated
with the absence of lymph node metastases in patients with large earlystage cervical cancer. Cancer Res. 2007;67:354-361.
Shah W, Yan X, Jing L, et al. A reversed CD4/CD8 ratio of tumorinfltrating lymphocytes and a high percentage of CD4()FOXP3()
regulatory T cells are signifcantly associated with clinical outcome
in squamous cell carcinoma of the cervix. Cell Mol Immunol. 2011;
8:59-66.
Tuve S, Chen BM, Liu Y, et al. Combination of tumor site-located
CTL-associated antigen-4 blockade and systemic regulatory T-cell depletion induces tumor-destructive immune responses. Cancer Res.
2007;67:5929-5939.
Calabro` L, Danielli R, Sigalotti L, et al. Clinical studies with antiCTLA-4 antibodies in non-melanoma indications. Semin Oncol. 37:
460-467.
Hodi FS, ODay SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;
363:711-723.
117. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune
correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:
2443-2454.
118. Basu P, Petit RG. ADXS11-001 immunotherapy targeting HPV-E7:
preliminary survival data from a phase II study in Indian women with
recurrent/refractory cervical cancer. J Clin Oncol. 2012;30 (suppl; abstr
5106).
119. Pulido HA, Fakruddin MJ, Chatterjee A, et al. Identifcation of a 6-cM
minimal deletion at 11q23.1-23.2 and exclusion of PPP2R1B gene as a
deletion target in cervical cancer. Cancer Res. 2000;60:6677-6682.
120. Narayan G, Arias-Pulido H, Nandula SV, et al. Promoter hypermethylation of FANCF: disruption of Fanconi Anemia-BRCA pathway in
cervical cancer. Cancer Res. 2004;64:2994-2997.
121. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;
361:123-134.
122. Kuo ML, Kinsella TJ. Expression of ribonucleotide reductase after ionizing radiation in human cervical carcinoma cells. Cancer Res.1998;58:
2245-2252.
123. Kunos CA, Radivoyevitch T, Kresak A, et al. Elevated ribonucleotide reductase levels associate with suppressed radiochemotherapy response in
human cervical cancers. Int J Gynecol Cancer. 2012;22:1463-1469.
124. Brana I, Mackay HJ. WEE1 inhibition as an anticancer strategy: frst
advances. Drugs Fut. 2014;39:207.
125. Dizon DS, Mackay HJ, Thomas GM, et al. State of the science in cervical cancer: where we are today and where we need to go. Cancer.
2014;120:2282-2288.
126. Ford JG, Howerton MW, Lai GY, et al. Barriers to recruiting underrepresented populations to cancer clinical trials: a systematic review.
Cancer. 2008;112:228-242.
127. Lara PN Jr, Paterniti DA, Chiechi C, et al. Evaluation of factors affecting awareness of and willingness to participate in cancer clinical trials.
J Clin Oncol. 2005;23:9282-9289.
128. Murthy VH, Krumholz HM, Gross CP. Participation in cancer clinical
trials: race-, sex-, and age-based disparities. JAMA. 2004;291:27202726.
129. Comis RL, Miller JD, Aldige CR, et al. Public attitudes toward participation in cancer clinical trials. J Clin Oncol. 2003;21:830-835.
130. Roberson NL. Clinical trial participation. Viewpoints from racial/ethnic groups. Cancer. 1994;74(9 Suppl):2687-2691.
131. Lara PN Jr, Higdon R, Lim N, et al. Prospective evaluation of cancer
clinical trial accrual patterns: identifying potential barriers to enrollment. J Clin Oncol. 2001;19:1728-1733.
132. Braunstein JB, Sherber NS, Schulman SP, Ding EL, Powe NR. Race,
medical researcher distrust, perceived harm, and willingness to participate in cardiovascular prevention trials. Medicine. 2008;87:1-9.
133. Giarelli E, Bruner DW, Nguyen E, et al. Research participation
among Asian American women at risk for cervical cancer: exploratory pilot of barriers and enhancers. J Immigr Minor Health. 2011;
13:1055-1068.
134. Corbie-Smith G, Thomas SB, Williams MV, et al. Attitudes and beliefs
of African Americans toward participation in medical research. J Gen
Intern Med. 1999;14:537-546.
135. Guadagnolo BA, Petereit DG, Helbig P, et al. Involving American Indians and medically underserved rural populations in cancer clinical
trials. Clin Trials. 2009;6:610-617.
e309
GYNECOLOGIC CANCER
SPEAKERS
Kathleen N. Moore, MD
University of Oklahoma
Oklahoma City, OK
William P. Tew, MD
Memorial Sloan Kettering Cancer Center
New York, NY
lose to half (45%) of women diagnosed with ovarian cancer will be older than age 64, and 25% will be older than
age 74 (20.7%, age 65 to 74; 16.6%, age 75 to 84; and 8.1%,
older than age 84).1 The mean age at diagnosis of ovarian
cancer is 63 years.1,2 In addition, the percentage of older
women with ovarian cancer is expected to increase in the
coming decades as our population ages and life expectancy
improves.3,4 Unfortunately, as the age of the patients increases, cancer outcomes steadily worsen. One report
showed age-standardized relative survival rates at 1 year of
57% for women age 65 to 69, 43% to 45% for those age 70 to
79, and 25% to 33% for those age 80 to 99.5 There have been
various theories put forward to account for the decreased
survival in older women, including the following: (1) more
aggressive tumor biology, including higher grade and more
advanced stage, (2) inherent resistance to chemotherapy, (3)
individual patient factors, such as multiple concurrent medical problems, functional decline, and malnutrition leading
to greater anticipated treatment toxicity, and (4) physician
and health care biases toward older adults that lead to inadequate surgery, and suboptimal chemotherapy.6
To improve the outcomes of older women with ovarian
cancer, we need to develop better decision aids to discriminate those patients who will and will not tolerate standard
cytoreductive surgery (CRS) and chemotherapy. Our trials
cannot continue to focus exclusively on younger, ft women
and the healthiest subsection of older women. In the South-
From the University of Virginia, Charlottesville, VA; Memorial Sloan Kettering Cancer Center, New York NY; University of Oklahoma, Oklahoma City, OK.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Linda R. Duska, MD, University of Virginia, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, PO Box 800712, Charlottesville, VA 22908;
email: lduska@virginia.edu.
2015 by American Society of Clinical Oncology.
e311
KEY POINTS
Almost half of women with ovarian cancer are older than
age 64 years, and 25% are older than 74 years.
Older patients may benet from a less aggressive surgical
approach and, in appropriate cases, may be candidates for
neoadjuvant chemotherapy.
Validated modalities exist for assessing an older womans
ability to tolerate surgery and chemotherapy, and these
tools should be utilized when caring for this population in
making treatment decisions.
e312
FIGURE 1. Risks of Cytoreductive Surgery in Advanced Ovarian Cancer Increase with Age
e313
e315
than 50% of all patients were able to complete four or more cycles of the intraperitoneal regimen because of toxicity.
How does an oncologist apply these results to their older
population? First, the major limitation to the study was that
patients received intraperitoneal cisplatin. By age 70, renal
function may have declined by as much as 40%, and this reduction in glomerular fltration rate may lead to enhanced
toxicity of drugs, particularly those with signifcant renal excretion, such as cisplatin. On GOG 172, patients were re-
e317
mal CA125 was associated with assistance with IADL, low PS,
chemotherapy toxicity, and dose reductions.68
The French GINECO group has developed a GVS from a
series of up-front trials in older women with ovarian cancer.
The GVS includes the high-risk variables of low albumin (less
than 35 g/L), low ADL score (less than 6), low IADL score
(less than 25), lymphopenia (less than 1G/L), and a high hospital
anxiety and depression (HADS) score (greater than 14).44
Women with a high GVS score (3 or greater) had a worse overall
survival (11.5 vs. 21.7 months; HR, 2.94; p 0.001), experienced
a lower rate of chemotherapy completion (65% vs. 82%; OR
0.41; p 0.04), had higher incidences of severe adverse events
(53% vs. 29%; OR 2.8; p 0.009), and more unplanned hospitalizations (53% vs. 30%; OR 2.6, p 0.02). The use of the
GVS appears helpful in selecting those at greatest risk; validation
studies with larger cohorts are underway.
CONCLUSION
As designated treatment trials for the older and
performance-challenged woman with ovarian cancer increase, our understanding of and ability to discern best practices for treatment planning increase. In addition, the
ongoing planned trials evaluating pretreatment assessment
for older patients will provide objective, feasible, clinical
tools for applying our treatment-based knowledge. These important works will hopefully eliminate much of the gestalt
decision making in this potentially vulnerable population
and improve outcomes for all.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Kathleen
N. Moore, Advaxis, AstraZeneca, Genentech/Roche, Immunogen. Speakers Bureau: Kathleen N. Moore, Genentech/Roche. Research Funding: Linda R.
Duska, BMS (Inst), GSK (Inst), Millenium (Inst). Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: Kathleen N. Moore, Astra Zeneca. Other Relationships: None.
References
1. Surveillance, Epidemiology, and End Results (SEER) Program. SEER
Stat Fact Sheets: Ovary Cancer. http://seer.cancer.gov/statfacts/html/
ovary.html. Accessed January 2, 2015.
2. Oberaigner W, Minicozzi P, Bielska-Lasota M, et al. Survival for ovarian
cancer in Europe: the across-country variation did not shrink in the past
decade. Acta Oncologica. 2012;51:441-453.
3. Edwards BK, Howe HL, Ries LA, et al. Annual report to the nation on
the status of cancer, 1973-1999, featuring implications of age and aging
on U.S. cancer burden. Cancer. 2002;94:2766-2792.
4. Yancik R, Ries LA. Cancer in older persons: an international issue in an
aging world. Semin Oncol. 2004;31:128-136.
5. Vercelli M, Capocaccia R, Quaglia A, et al. Relative survival in elderly
European cancer patients: evidence for health care inequalities. The
6.
7.
8.
9.
e319
10. Griffths CT. Surgical resection of tumor bulk in the primary treatment
of ovarian carcinoma. Natl Cancer Inst Monogr. 1975;42:101-104.
11. Bristow RE, Tomacruz RS, Armstrong DK, et al. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the
platinum era: a meta-analysis. J Clin Oncol. 2002;20:1248-1259.
12. Landrum LM, Java J, Mathews CA, et al. Prognostic factors for stage III
epithelial ovarian cancer treated with intraperitoneal chemotherapy: a
Gynecologic Oncology Group study. Gynecol Oncol. 2013;130:12-18.
13. Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and
paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group
study. J Clin Oncol. 2003;21:3194-3200.
14. Bookman MA, Brady MF, McGuire WP, et al. Evaluation of new
platinum-based treatment regimens in advanced-stage ovarian cancer:
a phase III trial of the Gynecologic Cancer Intergroup. J Clin Oncol.
2009;27:1419-1425.
15. Hou JY, Kelly MG, Yu H, et al. Neoadjuvant chemotherapy lessens surgical morbidity in advanced ovarian cancer and leads to improved survival in stage IV disease. Gynecol Oncol. 2007;105:211-217.
16. Aletti GD, Eisenhauer EL, Santillan A, et al. Identifcation of patient
groups at highest risk from traditional approach to ovarian cancer treatment. Gynecol Oncol. 2011;120:23-28.
17. Hightower RD, Nguyen HN, Averette HE, et al. National survey of ovarian carcinoma. IV: patterns of care and related survival for older patients. Cancer. 1994;73:377-383.
18. Ries LA. Ovarian cancer. Survival and treatment differences by age.
Cancer. 1993;71(2 suppl):524-529.
19. Markman M, Lewis JL Jr, Saigo P, et al. Epithelial ovarian cancer in the
elderly. The Memorial Sloan-Kettering Cancer Center experience. Cancer. 1993;71(2 suppl):634-637.
20. Bruchim I, Altaras M, Fishman A. Age contrasts in clinical characteristics and pattern of care in patients with epithelial ovarian cancer. Gynecol Oncol. 2002;86:274-278.
21. Fairfeld KM, Lucas FL, Earle CC, et al. Regional variation in cancerdirected surgery and mortality among women with epithelial ovarian
cancer in the Medicare population. Cancer. 2010;116:4840-4848.
22. Carney ME, Lancaster JM, Ford C, et al. A population-based study of
patterns of care for ovarian cancer: who is seen by a gynecologic oncologist and who is not? Gynecol Oncol. 2002;84:36-42.
23. Sharma S, Driscoll D, Odunsi K, et al. Safety and effcacy of cytoreductive surgery for epithelial ovarian cancer in elderly and high-risk surgical patients. Am J Obstet Gynecol. 2005;193:2077-2082.
24. Wright JD, Herzog TJ, Powell MA. Morbidity of cytoreductive surgery
in the elderly. Am J Obstet Gynecol. 2004;190:1398-1400.
25. McLean KA, Shah CA, Thompson SA, et al. Ovarian cancer in the elderly: outcomes with neoadjuvant chemotherapy or primary cytoreduction. Gynecol Oncol. 2010;118:43-46.
26. Moore KN, Reid MS, Fong DN, et al. Ovarian cancer in the octogenarian: does the paradigm of aggressive cytoreductive surgery and chemotherapy still apply? Gynecol Oncol. 2008;110:133-139.
27. Alphs HH, Zahurak ML, Bristow RE, et al. Predictors of surgical outcome and survival among elderly women diagnosed with ovarian and
primary peritoneal cancer. Gynecol Oncol. 2006;103:1048-1053.
28. Thrall MM, Goff BA, Symons RG, et al. Thirty-day mortality after primary cytoreductive surgery for advanced ovarian cancer in the elderly.
Obstet Gynecol. 2011;118:537-547.
29. Wright JD, Lewin SN, Deutsch I, et al. Defning the limits of radical
cytoreductive surgery for ovarian cancer. Gynecol Oncol. 2011;123:467473.
30. Wright JD, Herzog TJ, Neugut AI, et al. Effect of radical cytoreductive
surgery on omission and delay of chemotherapy for advanced-stage
ovarian cancer. Obstet Gynecol. 2012;120:871-881.
e320
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
e321
GYNECOLOGIC CANCER
SPEAKERS
Judy Ellen Garber, MD, MPH
Dana-Farber Cancer Institute
Boston, MA
Stanley B. Kaye, MD, FRCP, FRSE
The Royal Marsden NHS Foundation Trust
London, United Kingdom
he BRCA1/2 tumor suppressor genes are critical for the maintenance of cellular genomic stability through the error-free repair of DNA double-strand breaks (DSBs) via the high-fdelity
homologous-recombination repair (HR) pathway.1,2 Loss of
BRCA1/2 function may occur because of somatic mutations or epigenetic silencing, which results in a dependency on alternative
error-prone (low-fdelity) DNA repair pathways and potential
genomic instability.2 The absence of BRCA1/2 function is associated with a cumulative lifetime risk for developing epithelial
ovarian cancer (EOC) of 40% to 50% in patients who are
BRCA1-mutation carriers and 20% to 25% in patients who are
BRCA2-mutationcarriers.3 Germ-linemutationsinBRCA1/2have
been observed in 14% of patients with nonmucinous EOC, including 17% of patients with high-grade serous histology, with 44% of
thesepatientshavingnoreportedfamilyhistoryofbreastorovarian
cancer,whereassomaticmutationsinBRCA1/2havebeenfoundin
6% of patients with high-grade serous EOCs.4,5
(PR) and complete response (CR) rates to platinumcontaining regimens and longer treatment-free intervals, has
been observed in retrospective studies of patients who are
BRCA1/2-mutant carriers with ovarian cancer compared
with patients who are non-BMOC.5-10 This BRCAness
phenotype, with superior outcomes following platinumbased therapy in patients with BMOC, has been attributed to
HR defciency in the absence of BRCA1/2 function. This results in an impaired ability of BRCA-defcient tumor cells to
repair platinum-induced DSBs, which confers increased sensitivity to chemotherapy.8,9,11 Similarly, inhibition of
poly(ADP-ribose) polymerase (PARP) enzymes (which repair single-stranded DNA breaks mainly through the baseexcision repair pathway) in HR-defcient cells by PARP
inhibitors (PARPi) results in DSBs that are subjected to lowfdelity repair by nonhomologous end joining.2,12 The absence of high-fdelity DNA-repair mechanisms following
PARPi treatment in HR-defcient cells leads to synthetic lethality through an accumulation of DNA damage that results
in mitotic catastrophe and cell death.13 PARP inhibitors are
active agents in patients with BMOC, but they also may be
effective in a subset of sporadic ovarian cancers.14 Mutations
From the National University Cancer Institute, Singapore; National University Hospital, Singapore; The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Stanley B. Kaye, MD, FRCP, FRSE, The Royal Marsden NHS Foundation Trust, London, United Kingdom; email: stan.kaye@rmh.nhs.uk.
2015 by American Society of Clinical Oncology.
114
KEY POINTS
Improved prognosis and response to platinum-based
chemotherapy are hallmarks of BRCA1/2-mutated ovarian
cancer (BMOC).
Increased platinum sensitivity is attributed to underlying
homologous-recombination repair deciency in BMOC,
leading to impaired ability to repair platinum-induced
double-strand breaks, thereby conferring increased
sensitivity to chemotherapy.
Chemotherapeutic strategies for patients with BMOC should
focus on platinum-based chemotherapy at rst-line and
recurrent-disease settings, and include measures to
increase the platinum-free interval in patients with early
platinum-resistant relapse (i.e., progression-free survival
of 6 months from last platinum-based chemotherapy) by
using nonplatinum cytotoxic agents, with the aim of
reintroducing platinum at a later date.
In recurrent disease, patients with BMOC appear to have
increased sensitivity to pegylated liposomal doxorubicin
and other DNA-damaging agents, including trabectedin and
mitomycin C, also may have a therapeutic role.
With recent approval for the use of the poly(ADP-ribose)
polymerase (PARP) inhibitor (PARPi) olaparib in BMOC in
Europe and the United States, further work to dene the
optimal choice, timing, and sequence of chemotherapy and/
or PARPi therapy will be crucial to improve outcomes for
patients with BMOC.
115
Platinum-Based Chemotherapy
First Line
87%a BRCA1 (83 patients)
References
Vencken et al9
Vencken et al9
Tan et al8
Alsop et al5
Tan et al8
Tan et al8
Leunen et al20
Paclitaxel Monotherapy
Tan et al21
Adams et al22
Kaye et al23
Trabectedin
Lorusso et al24
Topotecan
0% (0/9 patients)
e
Hyman et al25
Mitomycin C
Moiseyenko et al26
Melphalan
CR in 1 patient
Osher et al27
Abbreviations: ORR, overall response rate; BMOC, BRCA1- and BRCA2-mutated ovarian cancer.
a
World Health Organization criteria were used to evaluate response to chemotherapy.
b
Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
c
Response dened as a 50% decrease in CA-125, maintained for 28 days.
d
RECIST PR/CR and Gynecologic Cancer Intergroup (GCIG) CA-125 criteria.
e
RECIST PR/CR or more than 50% reduction in CA-125.
improved drug delivery properties that could potentially enhance its antitumor effect).31,32 Furthermore, a recent study
demonstrated that although the cytotoxic response to PLD
was similar in BRCA1-defcient and wild-type cells in vitro,
BRCA1 inactivation resulted in higher expression of Fas and
MHC-I both before and after PLD exposure.33 Additionally,
PLD prolonged the survival of BRCA1-defcient tumorbearing mice and increased intratumoral T-cell recruitment.
Subsequent depletion of CD4 T cells combined with PLD
treatment also substantially prolonged overall survival in
BRCA1-defcient tumor-bearing mice.33 Therefore, the increased effcacy of PLD also may be related to the amplifcation of its immunomodulatory effects in BMOC tumors,
which may, in turn, enhance host antitumor responses.
Trabectedin, a minor groove DNA-binding agent derived
from the marine organism Ecteinascidia turbinate, is approved in some countries for treating relapsed ovarian cancer
in combination with PLD. Preclinical data suggest enhanced
activity in HRD cells. Furthermore, at the 2014 American Society of Clinical Oncology Annual Meeting, Lorusso et al reported data on 88 patients with EOC with documented
BRCA1/2 mutation or BRCAness phenotype (defned as at
least two previous responses to platinum) treated with singleagent trabectedin. An overall response rate of 41% was noted,
with a median PFS of 18 weeks and a median OS not
reached.24 However, the signifcance of this is uncertain because the patient group was described as moderately or
highly platinum-sensitive, and in previous phase II studies of
single-agent trabectedin in unselected patients, the response
117
119
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Stanley B. Kaye, AstraZeneca. David Tan, Roche.
Consulting or Advisory Role: None. Speakers Bureau: David Tan, Roche. Research Funding: David Tan, Karyopharm Therapeutics. Patents, Royalties,
or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: David Tan, Novartis, Roche, Bayer. Other
Relationships: None.
References
1. Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose
polymerase inhibitors for the treatment of cancers defcient in DNA
double-strand break repair. J Clin Oncol. 2008;26:3785-3790. Epub 2008
Jun 30.
2. Lee JM, Ledermann JA, Kohn EC. PARP Inhibitors for BRCA1/2
mutation-associated and BRCA-like malignancies. Ann Oncol. 2014;25:
32-40. Epub 2013 Nov 12.
3. Jazaeri AA. Molecular profles of hereditary epithelial ovarian cancers
and their implications for the biology of this disease. Mol Oncol. 2009;
3:151-156. Epub 2009 Feb 7.
4. Cancer Genome Atlas Research Network. Integrated genomic analyses
of ovarian carcinoma. Nature. 2011;474:609-615.
5. Alsop K, Fereday S, Meldrum C, et al. BRCA mutation frequency and
patterns of treatment response in BRCA mutation-positive women with
ovarian cancer: a report from the Australian Ovarian Cancer Study
Group. J Clin Oncol. 2012;30:2654-2663. Epub 2012 Jun 18.
6. Bolton KL, Chenevix-Trench G, Goh C, et al. Association between
BRCA1 and BRCA2 mutations and survival in women with invasive
epithelial ovarian cancer. JAMA. 2012;307:382-390.
7. Pal T, Permuth-Wey J, Kapoor R, et al. Improved survival in BRCA2
carriers with ovarian cancer. Fam Cancer. 2007;6:113-119.
8. Tan DS, Rothermundt C, Thomas K, et al. BRCAness syndrome in
ovarian cancer: a case-control study describing the clinical features
and outcome of patients with epithelial ovarian cancer associated
with BRCA1 and BRCA2 mutations. J Clin Oncol. 2008;26:55305536.
9. Vencken PM, Kriege M, Hoogwerf D, et al. Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after
frst-line chemotherapy compared with sporadic ovarian cancer patients. Ann Oncol. 2011;22:1346-1352.
10. Sun C, Li N, Ding D, et al. The role of BRCA status on the prognosis of
patients with epithelial ovarian cancer: a systematic review of the literature with a meta-analysis. PLoS One. 2014;9:e95285.
11. Pennington KP, Walsh T, Harrell MI, et al. Germline and somatic mutations in homologous recombination genes predict platinum response
and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin
Cancer Res. 2014;20:764-775.
12. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in
BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917-921.
13. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;
361:123-134.
14. Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with
recurrent high-grade serous or poorly differentiated ovarian carcinoma
or triple-negative breast cancer: a phase 2, multicentre, open-label, nonrandomised study. Lancet Oncol. 2011;12:852-861.
120
15. Edwards SL, Brough R, Lord CJ, et al. Resistance to therapy caused by
intragenic deletion in BRCA2. Nature. 2008;451:1111-1115.
16. Sakai W, Swisher EM, Karlan BY, et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature. 2008;
451:1116-1120.
17. Norquist B, Wurz KA, Pennil CC, et al. Secondary somatic mutations
restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. J Clin Oncol. 2011;29:3008-3015.
18. Fojo T, Bates S. Mechanisms of resistance to PARP inhibitors-three and
counting. Cancer Discov. 2013;3:20-23.
19. Drost R, Bouwman P, Rottenberg S, et al. BRCA1 RING function is essential for tumor suppression but dispensable for therapy resistance.
Cancer Cell. 2011;20:797-809.
20. Leunen K, Cadron I, Van Gorp T, et al. Does paclitaxel-carboplatin chemotherapy in a dose-dense regimen enhance survival of BRCA-related
ovarian cancer patients? Int J Gynecol Cancer. 2009;19:1501-1504.
21. Tan DS, Yap TA, Hutka M, et al. Implications of BRCA1 and BRCA2
mutations for the effcacy of paclitaxel monotherapy in advanced ovarian cancer. Eur J Cancer. 2013;49:1246-1253.
22. Adams SF, Marsh EB, Elmasri W, et al. A high response rate to liposomal
doxorubicin is seen among women with BRCA mutations treated for recurrent epithelial ovarian cancer. Gynecol Oncol. 2011;123:486-491.
23. Kaye SB, Lubinski J, Matulonis U, et al. Phase II, open-label, randomized, multicenter study comparing the effcacy and safety of olaparib, a
poly(ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent
ovarian cancer. J Clin Oncol. 2012;30:372-379.
24. Lorusso D, Ferrandina G, Pignata S, et al. Phase II prospective study on
trabectedin (T) in BRCA-mutated and BRCAness phenotype advanced
ovarian cancer (AOC) patients (pts): the MITO 15 trial. J Clin Oncol.
2014;32:5s (suppl; abstr 5530).
25. Hyman DM, Zhou Q, Arnold AG, et al. Topotecan in patients with
BRCA-associated and sporadic platinum-resistant ovarian, fallopian
tube, and primary peritoneal cancers. Gynecol Oncol. 2011;123:196-199.
26. Moiseyenko VM, Chubenko VA, Moiseyenko FV, et al. Evidence for
clinical effcacy of mitomycin C in heavily pretreated ovarian cancer
patients carrying germ-line BRCA1 mutation. Med Oncol. 2014;31:199.
27. Osher DJ, Kushner YB, Arseneau J, et al. Melphalan as a treatment for
BRCA-related ovarian carcinoma: can you teach an old drug new tricks?
J Clin Pathol. 2011;64:924-926.
28. Safra T, Borgato L, Nicoletto MO, et al. BRCA mutation status and determinant of outcome in women with recurrent epithelial ovarian cancer treated with pegylated liposomal doxorubicin. Mol Cancer Ther.
2011;10:2000-2007.
29. Tewey KM, Rowe TC, Yang L, et al. Adriamycin-induced DNA damage
mediated by mammalian DNA topoisomerase II. Science. 1984;226:466468.
30. Safra T, Rogowski O, Muggia FM. The effect of germ-line BRCA mutations on response to chemotherapy and outcome of recurrent ovarian
cancer. Int J Gynecol Cancer. 2014;24:488-495.
31. Rose PG. Pegylated liposomal doxorubicin: optimizing the dosing
schedule in ovarian cancer. Oncologist. 2005;10:205-214.
32. Thorn CF, Oshiro C, Marsh S, et al. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics. 2011;21:440446.
33. Mantia-Smaldone G, Ronner L, Blair A, et al. The immunomodulatory
effects of pegylated liposomal doxorubicin are amplifed in BRCA1defcient ovarian tumors and can be exploited to improve treatment response in a mouse model. Gynecol Oncol. 2014;133:584-590.
34. del Campo JM, Sessa C, Krasner CN, et al. Trabectedin as single agent in
relapsed advanced ovarian cancer: results from a retrospective pooled
analysis of three phase II trials. Med Oncol. 2013;30:435.
35. Krasner CN, McMeekin DS, Chan S, et al. A Phase II study of trabectedin single agent in patients with recurrent ovarian cancer previously
treated with platinum-based regimens. Br J Cancer. 2007;97:1618-1624.
36. Monk BJ, Ghatag P, Parekh T, et al. Effect of BRCA1 and XPG mutations
on treatment response to trabectedin and pegylated liposomal doxorubicin in subjects with advanced ovarian cancer: exploratory analysis of
phase III OVA-301 study. Paper presented at: 45th Annual Meeting of
Society of Gynecologic Oncology; March 2014; Tampa, FL.
37. Yun J, Zhong Q, Kwak JY, et al. Hypersensitivity of BRCA1-defcient
MEF to the DNA interstrand crosslinking agent mitomycin C is associated with defect in homologous recombination repair and aberrant
S-phase arrest. Oncogene. 2005;24:4009-4016.
38. Evers B, Schut E, van der Burg E, et al. A high-throughput pharmaceutical screen identifes compounds with specifc toxicity against BRCA2defcient tumors. Clin Cancer Res. 2010;16:99-108.
39. McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and
cisplatin compared with paclitaxel and cisplatin in patients with stage III
and stage IV ovarian cancer. N Engl J Med. 1996;334:1-6.
40. Baird RD, Tan DS, Kaye SB. Weekly paclitaxel in the treatment of recurrent ovarian cancer. Nat Rev Clin Oncol. 2010;7:575-582.
41. Tagliaferri P, Ventura M, Baudi F, et al. BRCA1/2 genetic backgroundbased therapeutic tailoring of human ovarian cancer: hope or reality?
J Ovarian Res. 2009;2:14.
42. Quinn JE, James CR, Stewart GE, et al. BRCA1 mRNA expression levels
predict for overall survival in ovarian cancer after chemotherapy. Clin
Cancer Res. 2007;13:7413-7420.
43. Quinn JE, Carser JE, James CR, et al. BRCA1 and implications for response to chemotherapy in ovarian cancer. Gynecol Oncol. 2009;113:
134-142.
44. Tassone P, Tagliaferri P, Perricelli A, et al. BRCA1 expression modulates
chemosensitivity of BRCA1-defective HCC1937 human breast cancer
cells. Br J Cancer. 2003;88:1285-1291.
45. Chabalier C, Lamare C, Racca C, et al. BRCA1 downregulation leads to
premature inactivation of spindle checkpoint and confers paclitaxel resistance. Cell Cycle. 2006;5:1001-1007.
46. Zhou C, Smith JL, Liu J. Role of BRCA1 in cellular resistance to paclitaxel and ionizing radiation in an ovarian cancer cell line carrying a defective BRCA1. Oncogene. 2003;22:2396-2404.
47. Sylvain V, Lafarge S, Bignon YJ. Dominant-negative activity of a BRCA1
truncation mutant: effects on proliferation, tumorigenicity in vivo, and
chemosensitivity in a mouse ovarian cancer cell line. Int J Oncol. 2002;
20:845-853.
121
SPEAKERS
Amanda Psyrri, MD, PhD
Attikon Hospital University of Athens
Athens, Greece
Tanguy Y. Seiwert, MD
The University of Chicago
Chicago, IL
From the Second Department of Internal Medicine, Attikon Hospital University of Athens, Athens, Greece; Department of Radiation Oncology, Lausanne University Medical Center, Lausanne,
Switzerland.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Amanda Psyrri, MD, PhD, Attikon Hospital, Rimini 1, Athens, Greece 12461; email: dpsyrri@med.uoa.gr.
2015 by American Society of Clinical Oncology.
e323
KEY POINTS
In vivo preclinical data suggest that HPV vaccination could
act as an immune-stimulating agent resulting in
improvement of response rates of HPV-positive
oropharyngeal cancers to anti-PD-1 checkpoint inhibitor.
A better-designed staging system of HPV-positive
carcinoma that also encompasses prognostic factors such
as age and tobacco use could alter treatment of these
patients.
A reduction in the overall treatment time of postoperative
radiotherapy in patients with head and neck squamous cell
carcinoma (HNSCC) with adverse factors for locoregional
failure does not improve outcomes in terms of locoregional
control, progression-free survival, and overall survival.
LUX-Head and Neck 1 clinical trials comparing the efcacy
of afatinib as monotherapy compared to single-agent
methotrexate as second-line treatment in HNSCC met its
primary endpoint showing an increase in progression-free
survival of 0.9 months with afatinib compared to
methotrexate, but in practical terms this modest effect is
of unknown clinical importance.
An individual patient data network meta-analysis of the
treatment of nonmetastatic nasopharyngeal carcinoma
suggests that incorporating induction chemotherapy or
adjuvant chemotherapy to chemoradiotherapy may further
improve the outcome in terms of tumor control probability
and survival over chemoradiotherapy alone.
e324
e325
patient test results; identifcation of targetable molecular aberration; and the availability of a targeted drug known to inhibit the function of the molecular alteration.39 Highthroughput sequencing technology provides the means to
conduct a comprehensive analysis of all somatic alterations
in the cancer genomes. However, interpretation of the large
amount of genomic data that emerge from these genomescale investigations for the development of new therapeutic
strategies requires the effcient validation of genomic data
and the characterization of mutations. It is important to determine whether the identifed mutations are responsible for
disease pathogenesis (driver mutations) or have been generated as the consequence of genomic instability but without
obvious advantage to the cancerous cells (benign mutations).
To address the challenge of fragmentation of cancer research
in Europe that generates diffculties in translating preclinical
discoveries into benefts that improve patients lives, the Eurocan Plus project aims for the establishment of a European
platform for translational cancer research by linking comprehensive cancer centers and basic/preclinical research centers.39 The Eurocan Platform project was approved by the
European Commission in 2010 and aims to develop a consortium for translational cancer research by linking 23 cancer
research centers and fve European cancer organizations.
One of the most important aims is to promote personalized
cancer medicine that is based on the better understanding of
the biology of the tumor and normal tissues so that personalized treatment can be applied at an early stage of the disease. Furthermore, prevention strategies should be
established in cancer biology to identify and target high-risk
individuals.
NASOPHARYNGEAL CANCER
What Is the Best Treatment in Nasopharyngeal
Carcinoma? An Individual Patient Data Network
Meta-Analysis
With the improvement in local control accomplished by more
precise imaging and RT, the predominant pattern of failure for
nasopharyngeal carcinoma (NPC) is distant metastases. Concurrent cisplatin and RT with or without adjuvant PF (cisplatin/
CONCLUSION
HNSCC comprises a heterogeneous disease in terms of epidemiology, etiologic factors, and clinical and biologic behavior.
HPV status is the most important biomarker in this disease. Research efforts concentrate on identifcation of prognostic and
predictive biomarkers for the personalization of treatment, deintensifcation of treatment to reduce late toxicity in goodprognosis HPV subsets, and the discovery of new treatments
in poor-prognosis HPV HNSCC. Immunotherapy, such as
checkpoint inhibitors, is being explored as treatment strategy in
HNSCC in different settings. In Europe and the United States,
research funding for new treatments in HNSCC is rather limited, and progress against this disease has been diffcult. Intergroup efforts may allow the execution of large, randomized trials
that will improve the outcome of this devastating disease.
References
1. Pfster DG, Spencer S, Brizel DM, et al. Head and neck cancers, version
2.2014. Clinical practice guidelines in oncology. J Natl Compr Canc
Netw. 2014;12:1454-1487.
2. Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck
cancers. J Natl Cancer Inst. 2000;92:709-720.
e327
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
e328
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
SPEAKERS
Matthew G. Fury, MD
Memorial Sloan Kettering Cancer Center
New York, NY
J. Silvio Gutkind, PhD
National Institute of Dental and Craniofacial Research at the National Institutes of Health
Bethesda, MD
ead and neck squamous cell carcinoma is a heterogeneous disease originating from the mucosal epithelia in
the head and neck region, most commonly the oral cavity,
oropharynx, hypopharynx, and larynx. The risk factors are
tobacco use, alcohol consumption, and HPV infection, particularly in the oropharynx.1,2 The HPV-positive HNSCC is
now established as a separate entity with distinct clinical
characteristics, including younger age of onset, better performance status, less smoking history, and its association with
high-risk sexual behaviors compared to the HPV-negative
HNSCC.3,4 In addition, the HPV-positive HNSCC has a
distinct molecular profle compared to the HPV-negative
HNSCC, including lack of TP53 and CDKN2A mutations;
however, mutations or copy number variations of genes
within the PI3K pathway are frequent in both HPV-positive
and HPV-negative HNSCC as it is the most frequently
altered oncogenic pathway with a gain-of-function in
HNSCC.5 This article reviews the basic biology and clinical
data from trials involving the PI3K pathway inhibitors in patients with HNSCC.
From the Department of Clinical Oncology, Instituto do Cancer do Estado de Sao Paulo, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil; Department of Oncology and
Department of Head and Neck Surgery-Otolaryngology, The Johns Hopkins Medical Institutions, Baltimore, MD.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Christine H. Chung, MD, Department of Oncology and Department of Head and Neck Surgery-Otolaryngology, Johns Hopkins University School of Medicine, Sidney Kimmel
Comprehensive Cancer Center, 1550 Orleans St. CRB-2 Room 546, Baltimore, MD 21287-0014; email: cchung11@jhmi.edu.
2015 by American Society of Clinical Oncology.
123
RTK
P
P
PIP3
P
P
SGK
p85
PTEN
Class I
Pi3K
RAS
PIP2
P
mTOR
RICTOR
GL
PKA
PDK1
AKT
PKC
RAF
TSC1/2
PRAS40
IRS1
P70S6K
MEK
mTOR
ERK
RPS6
RAPTOR
GL
EIF4B
Forkhead
GSK3
Cyclin D1
BAD
4EBP
FAS
L
EEF2K
n of
protein synthesis
and cell growth
BCL2
Glucose metabolism
Survival
Class I PI3Ks are heterodimeric kinases consisting of a p110 catalytic subunit (class 1A-p110-alpha, p110-beta, and p110-delta, and class 1B-p110-gamma proteins) and a p85 regulatory subunit. PI3Ks
are activated by receptor tyrosine kinases and GPCRs. PI3Ks phosphorylate PIP2 to PIP3, which functions as a second messenger. PIP3 acts by recruiting downstream protein kinases, such as
PDK1 and AKT, to the cell membrane that results in their activation. Subsequently, further downstream signaling network is activated and inuence important cellular functions, such as cell
proliferation, cell cycle, metabolism, and cell survival.
Abbreviations: 4EBP1, 4E binding protein 1; BCL-2, B-cell lymphoma 2; EEF2K, eukaryotic elongation factor-2 kinase; EIF4B, eukaryotic translation initiation factor 4B; ERK, extracellular signalregulated kinase; FASL, Fas ligand; GPCR, G-protein coupled receptor; IRS1, insulin receptor substrate 1; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; PIP2,
phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate; PTEN, phosphatase and tensin homolog; RICTOR, rapamycin-insensitive companion of mTOR; RPS6, ribosomal
protein S6; SGK3, serine/threonine-protein kinase 3; TSC, tuberous sclerosis protein.
KEY POINTS
Deregulations within the phosphatidylinositol 3-kinase
(PI3K) pathway are frequent in both HPV-positive and HPVnegative HNSCC.
PIK3CA is the most commonly mutated oncogene in HNSCC.
There are numerous clinical trials involving PI3K and
mammalian target of rapamycin (mTOR) inhibitors, but
clinical benets of these agents in unselected patients with
HNSCC are unclear.
Predictive biomarkers of PI3K and mTOR inhibitor response
are still under development.
Further studies are required to develop the PI3K pathway
targeted agents with favorable toxicity proles.
124
tor (EGFR) and PI3K signaling are required for the viral entry into the cells that may be pertinent in this HNSCC
subtype.21,22 Pretreatment of patients with keratinocytes or
cervical cancer cells in vitro with an EGFR inhibitor (geftinib) and two different PI3K inhibitors (PI-103 and wortmannin) is suffcient to inhibit HPV-16 endocytosis and
capable of preventing viral entry. In addition, PI3K/mTOR
activation and suppression of autophagy in the early stages of
patients with HPV16 infection are crucial for viral entry and
infection.22 Following HPV infection, the PI3K pathway appears to play an important role in established HPV-positive
HNSCC as well. Gene-expression profle analysis of HNSCC
has determined that HPV-positive HNSCC upregulates
genes within the 3q26 29 chromosomal region, which is the
locus containing PIK3CA. Further analyses by RT-PCR and
reverse phase protein arrays confrm that PIK3CA is upregulated in patients with HPV-positive HNSCC compared to
HPV-negative HNSCC.20,23
survival (211 days in the PX-866 and cetuximab arm vs. 256 days
in the cetuximab alone arm).
In addition, although there was no clear beneft of adding
PX-866 in these previously heavily treated patients with
HNSCC, the toxicities were more pronounced in the combination arm compared to the cetuximab alone arm. These toxicities included worse nausea (53% vs. 23%), vomiting (45%
vs. 15%), fatigue (43% vs. 23%), diarrhea (40% vs. 21%), rash
(45% vs. 31%), hypokalemia (25% vs. 10%), and dysphagia
(18% vs. 3%). The clinical development of NVP-BEZ235 has
been halted because of intolerable toxicities. For the further
development, additional studies with appropriate patient selection with the activation of PI3K pathway and improved
toxicity profles are required.
Furthermore, numerous mTOR inhibitors also are being
evaluated in patients with HNSCC. These mTOR inhibitors
include everolimus and temsirolimus through phase II studies in neoadjuvant (or induction) chemotherapy and recurrent and/or metastatic settings. Rapamycin analogs, such as
temsirolimus and everolimus, specifcally inhibit mTORC1
and already are approved by the U.S. Food and Drug Administration in renal cell carcinoma, subependymal giant cell
astrocytoma, pancreatic neuroendocrine tumors, and hormone receptorpositive, HER2-negative breast cancer in
combination with exemestane in the United States.26-30 In a
phase II trial, a combination of temsirolimus and low-dose
weekly carboplatin and paclitaxel was well tolerated in patients with recurrent and/or metastatic HNSCC.31 When 30
patients were treated with the combination regimen, the
overall radiological response rate was 43% with one complete
response and 12 partial responses; median overall survival
was 12.9 months. Overall, this regimen was well tolerated. The
most common (greater than three) adverse events were neutropenia, dysphagia, and anemia. However, other combination trials evaluating temsirolimus and erlotinib in a similar recurrent
and/or metastatic population of patients with HNSCC revealed
intolerable toxicities such as fatigue, diarrhea, and infection,
which resulted in early closure of the study.32
There are additional drugs that target other proteins within
the PI3K pathway beyond PI3Ks and mTORs. Novel Akt inhibitors, such as MK2206, AZD5363, and GSK690693, are in
development through phase I and II clinical trials.33 Although it
is not a direct inhibitor of mTOR, metformin, which is commonly used in type II diabetes, also is being investigated as an
anticancer agent in patients with HNSCC.34 Metformin indirectly inhibits mTORC1 by increasing intracellular adenosine
monophosphate (AMP) levels mediated by AMP-activated
protein kinase (AMPK) dependent and independent mechanisms, and may play a role in management of HNSCC.35,36
125
Table 1. Active Clinical Trials Evaluating PI3K/AKT/mTOR Targeted Agents in Patients with Locally Advanced,
Recurrent, and/or Metastatic HNSCC*
Targeted Agent
Additional Therapy
Inclusion Criteria
Phase
PI3K Inhibitor
PX-866
Docetaxel
I/II
NCT01204099
PX-866
Cetuximab
I/II
NCT01252628
BYL-719
II
NCT02145312
BYL-719
Cetuximab
I/II
NCT01602315
Paclitaxel
NCT02051751
NCT01527877
BYL-719
Buparlisib
II
Buparlisib
Cetuximab
I/II
NCT01816984
Buparlisib
Paclitaxel
II
NCT01852292
Buparlisib
IMRT, cisplatin
Ib
NCT02113878
NCT01343498
PI3K/mTOR Inhibitor
NVP-BEZ235
NVP-BEZ235
NVP-BKM120
Paclitaxel
NCT01285466
NVP-BEZ235
MEK-162
NCT01337765
NVP-BEZ235
Everolimus
I/II
NCT01508104
Everolimus
II
NCT01111058
Everolimus
II
NCT01051791
Everolimus
Cetuximab
Carboplatin
I/II
NCT01283334
Everolimus
Erlotinib
II
NCT00942734
Everolimus
Vatalinib
NCT00655655
Everolimus
IMRT, cisplatin
NCT00858663
Everolimus
Docetaxel, cisplatin
NCT00935961
Everolimus
Carboplatin, paclitaxel
I/II
NCT01333085
Everolimus
Cetuximab
Cisplatin, paclitaxel
II
NCT01133678
Temsirolimus
II
NCT01172769
Temsirolimus
Carboplatin, paclitaxel
I/II
NCT01016769
Temsirolimus
Cetuximab
II
NCT01256385
Temsirolimus
Cetuximab
Cisplatin
I/II
NCT01015664
Temsirolimus
Erlotinib
II
NCT01009203
Sirolimus
I/II
NCT01195922
Sirolimus
Grapefruit juice
NCT00375245
Ridaforolimus
Cetuximab
NCT01212627
Metformin
Paclitaxel
II
NCT01333852
mTOR Inhibitor
Abbreviations: HNSCC, head and neck squamous cell carcinoma; IMRT, intensity modulated radiation therapy; NSCLC, non-small cell lung cancer; CRC, colorectal cancer; BRC, breast cancer.
*All trial data are available at www.clinicaltrials.gov.
response. PIK3CA mutations were detected in 17% of patients, but no response was seen in these eight patients with
the PIK3CA mutation-harboring tumors.
In addition, the PI3K pathway activation through compensatory receptor tyrosine kinase activation, such as MET and
HER3, has been proposed as one of the resistance mechanisms of EGFR inhibitors in preclinical studies, suggesting
PI3K/mTOR inhibitors may be developed in patients who
are EGFR inhibitorresistant in addition to patients with the
PIK3CA mutations.38,39 In a recent preclinical study, the
combined activity of cetuximab and mTOR inhibitors in patients with HNSCC was evaluated. Cetuximab-sensitive
CONCLUSION
Advancements in genomic and proteomic technology are
providing a glimpse of the complexity of cancer biology and
generating rich hypotheses for potential therapeutic targets.
In addition, respective companion diagnostic biomarkers are
being developed for clinical application. Currently, a large
body of preclinical data indicate the PI3K pathway is important and a promising therapeutic target in patients with
HNSCC. However, they have not always translated to clinically meaningful effcacy in clinical studies. Additional studies to determine an appropriate method of patient selection
with the activation of PI3K pathway and to develop targeted
agents with favorable toxicity profles are required. Existing
data on PIK3CA mutations as a predictive biomarker to
PI3K/mTOR inhibitor response or the EGFR inhibitor resistance are not yet fully developed. Potential differences in the
gene/protein function based on the location and amino acid
changes resulting from the PIK3CA mutations in appropriate
genetic context of other coexisting pathologic signaling network, must be delineated further before proceeding with a
broader clinical application.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Christine
H. Chung, Novartis. Gilberto Castro, Teva, Boehringer Ingelheim, Eurofarma, Pzer, Bayer. Speakers Bureau: Gilberto Castro, Speakers Bureau (Lilly,
AstraZeneca, Bayer, Novartis, Roche, Eurofarma, Merck Serono). Research Funding: Christine H. Chung, Boehringer Ingelheim, Immunogen. Patents,
Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: Christine H. Chung, Merck. Gilberto
Castro, Merck Sharp & Dohme, Lilly, Novartis, Pzer, Roche, AstraZeneca, Boehringer Ingelheim, Eurofarma, Bayer. Other Relationships: None.
References
1. Maier H, Dietz A, Gewelke U, et al. Tobacco and alcohol and the risk of
head and neck cancer. Clin Investig. 1992;70:320-327.
2. DSouza G, Kreimer AR, Viscidi R, et al. Case-control study of human
papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356:
1944-1956.
3. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival
of patients with oropharyngeal cancer. N Engl J Med. 2010;363:24-35.
4. Gillison ML, DSouza G, Westra W, et al. Distinct risk factor profles for
human papillomavirus type 16-positive and human papillomavirus type
16-negative head and neck cancers. J Natl Cancer Inst. 2008;100:407420.
5. Cancer Genome Atlas Network. Comprehensive genomic characteriza-
6.
7.
8.
9.
127
10. Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5trisphosphate. J Biol Chem. 1998;273:13375-13378.
11. Agrawal N, Frederick MJ, Pickering CR, et al. Exome sequencing of
head and neck squamous cell carcinoma reveals inactivating mutations
in NOTCH1. Science. 2011;333:1154-1157.
12. Stransky N, Egloff AM, Tward AD, et al. The mutational landscape of
head and neck squamous cell carcinoma. Science. 2011;333:1157-1160.
13. Seiwert TY, Zuo Z, Keck MK, et al. Integrative and comparative
genomic analysis of HPV-positive and HPV-negative head and neck
squamous cell carcinomas. Clin Cancer Res. 2015;21:632-641.
14. Chung CH, Guthrie VB, Masica DL, et al. Genetic alterations in head
and neck squamous cell carcinoma determined by cancer gene-targeted
sequencing. Ann Oncol. Epub 2015 Feb 23.
15. Shao X, Tandon R, Samara G, et al. Mutational analysis of the PTEN
gene in head and neck squamous cell carcinoma. Int J Cancer. 1998;77:
684-688.
16. Pedrero JM, Carracedo DG, Pinto CM, et al. Frequent genetic and biochemical alterations of the PI 3-K/AKT/PTEN pathway in head and
neck squamous cell carcinoma. Int J Cancer. 2005;114:242-248.
17. Lui VW, Hedberg ML, Li H, et al. Frequent mutation of the PI3K pathway in head and neck cancer defnes predictive biomarkers. Cancer Discov. 2013;3:761-769.
18. Suda T, Hama T, Kondo S, et al. Copy number amplifcation of the PIK3CA
gene is associated with poor prognosis in non-lymph node metastatic head
and neck squamous cell carcinoma. BMC Cancer. 2012;12:416.
19. Iglesias-Bartolome R, Martin D, Gutkind JS. Exploiting the head and
neck cancer oncogenome: widespread PI3K-mTOR pathway alterations
and novel molecular targets. Cancer Discov. 2013;3:722-725.
20. Sewell A, Brown B, Biktasova A, et al. Reverse-phase protein array profling of oropharyngeal cancer and signifcance of PIK3CA mutations in
HPV-associated head and neck cancer. Clin Cancer Res. 2014;20:23002311.
21. Schelhaas M, Shah B, Holzer M, et al. Entry of human papillomavirus
type 16 by actin-dependent, clathrin- and lipid raft-independent endocytosis. PLoS Pathog. 2012;8:e1002657.
22. Surviladze Z, Sterk RT, DeHaro SA, et al. Cellular entry of human papillomavirus type 16 involves activation of the phosphatidylinositol 3-kinase/Akt/mTOR pathway and inhibition of autophagy. J Virol. 2013;87:
2508-2517.
23. Slebos RJ, Yi Y, Ely K, et al. Gene expression differences associated with
human papillomavirus status in head and neck squamous cell carcinoma. Clin Cancer Res. 2006;12:701-709.
24. Maira SM, Stauffer F, Brueggen J, et al. Identifcation and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol
3-kinase/mammalian target of rapamycin inhibitor with potent in vivo
antitumor activity. Mol Cancer Ther. 2008;7:1851-1863.
128
25. Jimeno A, Shirai K, Choi M, et al. A randomized, phase II trial of cetuximab with or without PX-866, an irreversible oral phosphatidylinositol
3-kinase inhibitor, in patients with relapsed or metastatic head and neck
squamous cell cancer. Ann Oncol. 2014:26:556-561.
26. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa,
or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:
2271-2281.
27. Motzer RJ, Escudier B, Oudard S, et al. Phase 3 trial of everolimus for
metastatic renal cell carcinoma: fnal results and analysis of prognostic
factors. Cancer. 2010;116:4256-4265.
28. Franz DN, Belousova E, Sparagana S, et al. Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex:
2-year open-label extension of the randomised EXIST-1 study. Lancet
Oncol. 2014;15:1513-1520.
29. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514-523.
30. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal
hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;
366:520-529.
31. Fury MG, Xiao H, Baxi SS, et al. A phase II trial of temsirolimus plus
low-dose weekly carboplatin and paclitaxel for recurrent/metastatic
HNSCC. J Clin Oncol. 2014;32:5s (suppl; abstr 6019).
32. Bauman JE, Arias-Pulido H, Lee S-J, et al. A phase II study of temsirolimus and erlotinib in patients with recurrent and/or metastatic,
platinum-refractory head and neck squamous cell carcinoma. Oral Oncol. 2013;49:461-467.
33. Altomare DA, Zhang L, Deng J, et al. GSK690693 delays tumor onset
and progression in genetically defned mouse models expressing activated Akt. Clin Cancer Res. 2010;16:486-496.
34. Amornphimoltham P, Leelahavanichkul K, Molinolo A, et al. Inhibition
of mammalian target of rapamycin by rapamycin causes the regression
of carcinogen-induced skin tumor lesions. Clin Cancer Res. 2008;14:
8094-8101.
35. Gwinn DM, Shackelford DB, Egan DF, et al. AMPK phosphorylation of
raptor mediates a metabolic checkpoint. Mol Cell. 2008;30:214-226.
36. Nathan CO, Amirghahari N, Rong X, et al. Mammalian target of rapamycin inhibitors as possible adjuvant therapy for microscopic residual
disease in head and neck squamous cell cancer. Cancer Res. 2007;67:
2160-2168.
37. Kang H, Kiess A, Chung CH. Emerging biomarkers in head and neck
cancer in the era of genomics. Nat Rev Clin Oncol. 2015;12:11-26.
38. Hatakeyama H, Cheng H, Wirth P, et al. Regulation of heparin-binding
EGF-like growth factor by miR-212 and acquired cetuximab-resistance
in head and neck squamous cell carcinoma. PLoS One. 2010;5:e12702.
39. Wang Z, Martin D, Molinolo AA, et al. mTOR co-targeting in cetuximab resistance in head and neck cancers harboring PIK3CA and RAS
mutations. J Natl Cancer Inst. Epub 2014 Aug 5.
Introduction to Methods in
Comparative Effectiveness
Research
CHAIR
Sharon H. Giordano, MD, MPH
The University of Texas MD Anderson Cancer Center
Houston, TX
SPEAKERS
Caprice Christian Greenberg, MD, MPH
University of Wisconsin School of Medicine and Public Health
Madison, WI
Natasha K. Stout, MS, PhD
Harvard Medical School and Harvard Pilgrim Health Care Institute
Boston, MA
SHARON H. GIORDANO
From the Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Sharon H. Giordano, MD, MPH, Department of Health Services Research, The University of Texas MD Anderson Cancer Center, 1400 Pressler, Unit 1444, Houston, TX 77030;
email: sgiordan@mdanderson.org.
2015 by American Society of Clinical Oncology.
e330
KEY POINTS
Observational studies are particularly useful when
randomized studies are not feasible or have not included
the population or outcome of interest.
Selection biases are the primary threat to validity of
observational studies.
Multivariable regression models, propensity score analyses,
and instrumental variable analyses can be used to help
address selection biases and confounding.
ANALYTIC TECHNIQUES
Several approaches can be taken to address bias in observational studies. Most studies will use multivariable regression
analyses to adjust for confounders and to address issues related to nonrandom treatment assignment. This method can
provide statistical adjustment for all measured variables but
cannot adjust for unmeasured confounders. Propensity score
analysis is another approach to improve the balance of unasco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e331
SHARON H. GIORDANO
Type of Data
Population
SEER
Cancer registry
1973-2013
100% Medicare
Through 2012
SEER-Medicare
Registry-linked claims
1973-2011
SEER-MHOS
Registry-linked to survey
1998-2011
Age 65
SEER-NLMS
Registry-linked to survey
1979-2011
All ages
HCCI
2009-2013
Marketscan
2003-2013
NCDB
Clinical database
Since 1985
Abbreviations: SEER, Surveillance, Epidemiology, and End Results; MHOS, Medicare Health Outcomes Survey; NLMS, National Longitudinal Mortality Study; HCCI, Health Care Cost Institute; NCDB,
National Cancer Database; CoC, Commission on Cancer.
e332
Medicare
Medicare is the primary health insurer for 97% of the U.S.
population age 65 and older. The Medicare Claims Data System collects information on all services provided to Medicare
benefciaries under its hospital (Part A), supplemental (Part
B), and prescription drug (Part D) insurance plans. Part A
covers inpatient hospitalizations and care in skilled nursing
homes, whereas Part B covers physician services; hospital
outpatient services; durable medical equipment; home health
services; and other outpatient medical services, such as diagnostic x-rays and laboratory tests. Part D data includes information on prescription drug use and has been available since
2006. The unlinked Medicare data are comprised of enrollment fles and health care claims. These data do not have information on the dates of diagnosis, stage, histology, or
recurrence, and this lack of registry data has limited the use of
the unlinked Medicare fles for cancer research. For several
cancer types, such as breast cancer, validated algorithms have
been developed to identify incident cases.13 The strength of
these data is in studies of patterns of care, geographic variation, and costs of therapy. To obtain the data set with identifers, an application should be submitted to the Research
Data Assistance Center (ResDAC). The cost is dependent on
the specifc data request.
supplement data from the SEER registry and provide information on diagnostic testing and additional treatment information, such as chemotherapy use and patterns of
surveillance. In addition, the data can be linked to the Area
Resource File and the American Medical Associations Physician Masterfle, which can provide additional information
about health resources and physician characteristics, respectively. These data do have some substantial limitations. First
and foremost, these data are administrative data generated
for billing, so they lack the detail of clinical data. The claims
are only complete for those patients in the fee-for-service
plans (rather than in the HMO plans) and do not capture
services provided by the U.S. Department of Veterans Affairs. Finally, as with the SEER data, cancer recurrences are
not captured. To obtain these data, an application must be
submitted to the NCI for review. Cost estimates can be found
on the SEER-Medicare website.15 All publications resulting
from these data must be reviewed before publication to ensure that patient confdentiality is protected.
e333
SHARON H. GIORDANO
CONCLUSION
In summary, observational data can be a powerful resource
for comparative effectiveness studies in cancer research. Observational studies are particularly useful to fll in gaps in data
from randomized studies or when randomized studies cannot be conducted. Researchers must be cognizant of the risk
of selection biases and confounding in observational research and must design studies carefully to minimize the risk
of bias. The Agency for Healthcare Research and Qualitys
Effective Health Care Program has provided a checklist for
considerations in study design when observational comparative effectiveness studies are proposed.4 Given careful and
thoughtful study design, observational studies can provide
important and clinically relevant comparative effectiveness
information in real-world populations. Finally, with the increasing use of electronic medical records and the ability to
access large national data sets, this area of research is likely to
continue to grow in scope and impact.
References
1. Patient-Centered Outcomes Research Institute. www.pcori.org-aboutus. Accessed February 9, 2015.
2. Sox HC, Greenfeld S. Comparative effectiveness research: a report from
the Institute of Medicine. Ann Intern Med. 2009;151:203-205.
3. Hutchins LF, Unger JM, Crowley JJ, et al. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med.
1999;341:2061-2067.
4. Agency for Health Care Research and Quality. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. AHRQ Publication no.
e334
8.
9.
10.
11.
12.
13. Nattinger AB, Laud PW, Bajorunaite R, et al. An algorithm for the use of
Medicare claims data to identify women with incident breast cancer.
Health Serv Res. 2004;39:1733-1750.
14. Warren JL, Klabunde CN, Schrag D, et al. Overview of the SEERMedicare data: content, research applications, and generalizability to
the United States elderly population. Med Care. 2002;40(8 suppl):IV3-18.
15. National Cancer Institute. SEER-Medicare Linked Database. http://
appliedresearch.cancer.gov/seermedicare. Accessed February 9, 2015.
16. Ambs A, Warren JL, Bellizzi KM, et al. Overview of the SEER-Medicare
Health Outcomes Survey linked dataset. Health Care Financ Rev. 2008;
29:5-21.
17. American College of Surgeons. National Cancer Data Base. www.
facs.org/qualityprograms/cancer/ncdb. Accessed February 9, 2015.
e335
SPEAKERS
Richard B. Gaynor, MD
Eli Lilly and Company
Indianapolis, IN
Reshma Jagsi, MD, DPhil
University of Michigan
Ann Arbor, MI
Mark J. Ratain, MD
The University of Chicago
Chicago, IL
MOY ET AL
From the Massachusetts General Hospital Cancer Center, Boston, MA; University of Michigan, Ann Arbor, MI; Eli Lilly and Company, Indianapolis, IN; The University of Chicago, Chicago, IL.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Beverly Moy, MD, MPH, Center for Breast Cancer, Massachusetts General Hospital, 55 Fruit St., Yawkey 9A, Boston, MA 02114; email: bmoy@mgh.harvard.edu.
2015 by American Society of Clinical Oncology.
130
tion and academic advancement may lead to unethical behavior. The presence of fnancial interests might influence
decision making and research conduct. These relationships
have the potential to compromise research integrity, create
scientifc bias for researchers, and lead to public and patient
mistrust. Proft motives by the manufacturer, shared with the
clinical researcher through FCOI, could potentially lead to
poor or inaccurate science and ultimately harm the public
interest.10
To date, management of FCOI has been based on rules or
policies mandating disclosure of industry relationships.
These policies aim to increase transparency to engender public trust for the medical research community, and by acknowledging the presence of these relationships, they ideally
lead to an open dialogue between the public and oncologists.
As policies call for wider disclosure of potential FCOI, and at
times prohibition of specifc fnancial relationships, there is
both a need and an opportunity to better understand the
prevalence of investigator and research relationships with industry and the effect of these relationships on research and
dissemination of results.6,7 However, despite the widespread
implementation of conflicts of interest policies in academic
centers, federal agencies, and professional medical societies,
little is known about how FCOI influences research conduct,
outcomes, and dissemination.11-13
These conflict of interest policies also do not address nonfnancial conflicts of interest that address professional or
ideologic issues, such as academic advancement, promotion,
and publication. The desire for academic advancement could
lead academic cancer researchers to seek out relationships
with industry that has proprietary technology in an effort to
participate in more important and influential research. These
nonfnancial conflicts have not been as well studied. Greater
examination of the benefts and risks of these relationships
should be paid.
Currently, most FCOI policies rely on disclosure alone to
address conflicts of interest. In part because of the diffculty
of relying on disclosure alone to address the problematic con-
KEY POINTS
Financial relationships between industry and oncology
physicians are common.
Conict of interest policies historically have relied on
disclosure to maintain transparency, but little is known
about the effect and inuence of these relationships on
research conduct, outcomes, and dissemination.
The goal of the Sunshine Act is to enhance transparency
about these relationships, but its implementation has
raised multiple concerns.
Direct-to-consumer advertising has a substantial effect on
medical practice and inuences drug utilization.
Partnerships between pharmaceutical companies and
oncology researchers are essential for the development of
new treatments and innovations.
SUNSHINE ACT
The direct goal of the Sunshine Act is to enhance transparency about relationships between health care providers and
purveyors of health care products and services. When the
original bill was frst introduced in 2007 (S.2029), one of the
cosponsors, Senator Claire McCaskill, stated, I believe that
by bringing light to these relationships, this legislation will go
far in reducing big drug companies influence on the business
of medicine. Another cosponsor, Senator Charles Schumer,
stated, This bill will shine a much needed ray of sunlight on
a situation that contributes to the exorbitant cost of health
care. Patients have the right to know if drug and device
makers are attempting to influence physician prescribing
decisions with gifts, consultations, and travel. Thus, the
Sunshine Act requires companies to submit information regarding their fnancial relationships with providers to the
U.S. Department of Health and Human Services (HHS) and for
such information to be publicly available. This led to the creation of a database, Open Payments, so that patients can theoretically identify providers whose professional judgment may be
clouded by personal fnancial interests, enabling informed patients to question their physicians prescribing decisions. Furthermore, particularly concerned patients could simply choose
physicians who had no fnancial relationships, based on a search
of the Open Payments database.
It is too soon to assess whether or not patients are utilizing
the Open Payments database in the manner Congress inasco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
131
MOY ET AL
DIRECT-TO-CONSUMER ADVERTISING
Since 1962, the FDA has had regulatory authority over prescription drug advertising.25 Although professionals have
historically been the primary target of advertisements, DTC
advertising began as early as the 1980s, primarily in print
form. DTC advertising expanded dramatically after 1997,
when the FDA issued draft guidance on broadcast advertisements26 that was later fnalized in 1999.27 Industry spent approximately $150 million on DTC advertising in 1993, which
rose to $1.1 billion by 1997, reached $3.2 billion by 2003,
peaked at $4.9 billion in 2007 (also the peak of overall promotional spending for pharmaceutical products), and was
$3.9 billion in 2011.28,29
DTC advertising has substantial influence on medical practice and affects drug utilization.30-34 A public survey revealed
that 30% of respondents had initiated conversations with
their physicians about a medicine they saw advertised, and, of
these, 44% reported actually receiving a prescription for the
drug as the outcome of the conversation.35 Many DTC advertisements target patients with cancer,36 and a survey found
that 86.2% of oncology patients reported awareness of such
ads.37 In another survey, 94% of oncology nurse practitioners
reported having received medication requests prompted by
DTC ads, and 40% indicated that they received one to fve
such requests per week.38 DTC advertising relevant to oncology extends well beyond the marketing of prescription drugs,
to include advertising for genetic testing and medical imaging other industries with which physicians often have
ties.39-41
133
MOY ET AL
by the physician or institution for their own work. In addition, the Open Payments regulations require reporting of
indirect payments, such that physicians who may not have
a direct relationship with any particular pharmaceutical
company are still being reported as having received something of value. These complexities, combined with the lack of
context, can paint a false picture for the layperson.
CONCLUSION
Effect on Clinical Oncology Practice
As our understanding of oncology deepens to reveal that
what was once believed to be a single disease (or a collection
of diseases differentiated on where a tumor primarily presents) is, in fact, more than 200 disparate diseases whose nature depends more on an individual patients specifc
molecular constitution than where the primary tumor frst
presented in that patient clinically, we will need to design and
implement smaller, smarter, more nimble clinical trials to
develop the suite of tailored medicines (and combinations
thereof) that have the greatest potential to treat an individual
patients unique disease. This democratization of clinical trial
design is likely to require an even greater absolute number of
Relationships are considered self-held and compensated unless otherwise noted. Relationships marked L indicate leadership positions. Relationships marked I are those held by an immediate
family member; those marked B are held by the author and an immediate family member. Institutional relationships are marked Inst. Relationships marked U are uncompensated.
Employment: Richard B. Gaynor, Eli Lilly and Company. Reshma Jagsi, University of Michigan. Leadership Position: Richard B. Gaynor, Eli Lilly and Company.
Stock or Other Ownership Interests: Richard B. Gaynor, Eli Lilly and Company. Mark J. Ratain, AspenBio Pharma, Biscayne Pharmaceuticals. Honoraria:
Reshma Jagsi, International Journal of Radiation Oncology Biology Physics. Consulting or Advisory Role: Reshma Jagsi, Eviti. Beverly Moy, MOTUS (I),
Olympus (I). Mark J. Ratain, AbbVie, Agios Pharmaceuticals, Biscayne Pharmaceuticals, Cantex Pharmaceuticals, Cerulean Pharma, Cyclacel, Daiichi Sankyo,
EMD Serono, Genentech/Roche, Kinex, Onconova Therapeutics, Sano, Shionogi, XSpray. Speakers Bureau: None. Research Funding: Reshma Jagsi, AbbVie
(Inst). Mark J. Ratain, Bristol-Myers Squibb (Inst), Dicerna (Inst), OncoTherapy Science (Inst), PharmaMar (Inst). Patents, Royalties, or Other Intellectual
Property: Mark J. Ratain, pending patent related to a genomic prescribing system, pending patent related to a genomic prescribing system (Inst), royalties
related to UGT1A1 genotyping for irinotecan, royalties related to UGT1A1 genotyping for irinotecan (Inst). Expert Testimony: Mark J. Ratain, Apotex,
Fresenius Kabi, Mylan, Teva. Travel, Accommodations, Expenses: Richard B. Gaynor, Eli Lilly and Company. Other Relationships: None.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
135
MOY ET AL
References
1. Bekelman JE, Li Y, Gross CP. Scope and impact of fnancial conflicts of
interest in biomedical research: a systematic review. JAMA. 2003;289:
454-465.
2. Hampson LA, Joffe S, Fowler R, et al. Frequency, type, and monetary
value of fnancial conflicts of interest in cancer clinical research. J Clin
Oncol. 2007;25:3609-3614.
3. Peppercorn J, Blood E, Winer E, et al. Association between pharmaceutical involvement and outcomes in breast cancer clinical trials. Cancer.
2007;109:1239-1246.
4. Riechelmann RP, Wang L, OCarroll A, et al. Disclosure of conflicts of
interest by authors of clinical trials and editorials in oncology. J Clin
Oncol. 2007;25:4642-4647.
5. Moy B, Bradbury AR, Helft PR, et al. Correlation between fnancial relationships with commercial interests and research prominence at an
oncology meeting. J Clin Oncol. 2013;31:2678-2684.
6. Campbell EG, Moy B, Feibelmann S, et al. Institutional academic industry relationship: results of interviews with university leaders. Account
Res. 2004;11:103-118.
7. Campbell EG, Weissman JS, Ehringhaus S, et al. Institutional academic
industry relationships. JAMA. 2007;298:1779-1786.
8. Lo B. Serving two masters-conflicts of interest in academic medicine.
N Engl J Med. 362:669-671.
9. Cho MK, Shohara R, Schissel A, et al. Policies on faculty conflicts of
interest at US universities. JAMA. 2000;284:2203-2208.
10. Moy B. Medical integrity up in smoke? Conflicts of interest and the lung
cancer screening controversy. Oncologist. 2008;13:474-476.
11. Boyd EA, Cho MK, Bero LA. Financial conflict-of-interest policies in
clinical research: Issues for clinical investigators. Acad Med. 2003;78:
769-774.
12. Lipton S, Boyd EA, Bero LA. Conflicts of interest in academic research:
policies, processes, and attitudes. Account Res. 2004;11:83-102.
13. Lexchin J, Sekeres M, Gold J, et al. National evaluation of policies on
individual fnancial conflicts of interest in Canadian academic health
science centers. J Gen Intern Med. 2008;23:1896-1903.
14. Brennan TA, Rothman DJ, Blank L, et al. Health industry practices that
create conflicts of interest: a policy proposal for academic medical centers. JAMA. 2006;295:429-433.
15. Centers for Medicare & Medicaid Services. Natures of Payment.
www.cms.gov/OpenPayments/About/Natures-of-Payment.html. Accessed February 14, 2015.
16. Ratain MJ. Forecasting unanticipated consequences of The Sunshine
Act: mostly cloudy. J Clin Oncol. 2014;32:2293-2295.
17. International Society for Medical Publication Professionals. ISMPP
Sunshine Act Information Update. http://www.ismpp.org/assets/docs/
Inititives/Sunshine_Act/sunshine%20act%20interpretation%20update_
february%202014_fnal.pdf. Accessed January 8, 2015.
18. Gray SW, Hlubocky FJ, Ratain MJ, et al. Attitudes toward research participation and investigator conflicts of interest among advanced cancer
patients participating in early phase clinical trials. J Clin Oncol. 2007;25:
3488-3494.
19. Korownyk C, Kolber MR, McCormack J, et al. Televised medical talk
shows-what they recommend and the evidence to support their recommendations: a prospective observational study. BMJ. 2014;g7346.
20. Biegler P, Vargas P. Ban the sunset? Nonpropositional content and regulation of pharmaceutical advertising. Am J Bioeth. 2013;13:3-13.
21. Citizen.org. Title XX. http://www.citizen.org/Page.aspx?pid3246.
Accessed February 25, 2015.
22. Every-Palmer S, Duggal R, Menkes DB. Direct-to-consumer advertising
136
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42. World Health Organization. Ethical Criteria for Medicinal Drug Promotion.1988.http://apps.who.int/iris/bitstream/10665/38125/1/924154239X_
eng.pdf?ua1. Accessed February 14, 2015.
43. Calfee JE. The role of marketing in pharmaceutical research and development. Pharmacoeconomics. 2002;3:77-85.
44. Holmer AF. Direct-to-consumer advertising-strengthening our health
care system. N Engl J Med. 2002;346:526-528.
45. Kelly P. DTC advertisings benefts far outweigh its imperfections.
Health Aff (Millwood). 2004;W4-246-248.
46. Angell M. The Truth About Drug Companies: How They Deceive Us and
What to Do About It. New York: Random House, 2004.
47. Kravitz R. MSJAMA: direct to consumer advertising of prescription
drugs: implications for the physician-patient relationship. JAMA. 2000;
284:2244.
48. Wolfe SM. Direct-to-consumer advertising education or emotion
promotion? N Engl J Med. 2002;346:524-526.
49. Weissman JS, Blumenthal D, Silk AJ, et al. Physicians report on patient
encounters involving direct-to-consumer advertising. Health Aff (Millwood). 2004:W4-219-233.
50. Weissman JS, Blumenthal D, Silk AJ, et al. Consumers reports on the
health effects of direct-to-consumer drug advertising. Health Aff (Millwood). 2003;W3-82-95.
51. Rosenthal MB, Berndt ER, Donohue JM, et al. Promotion of prescription drugs to consumers. N Engl J Med. 2002;346:498-505.
52. Abel GA, Chen K, Taback N, et al. Impact of oncology-related directto-consumer advertising: Association with appropriate and inappropriate prescriptions. Cancer. 2013;119:1065-1072.
53. Drazen JM. The consumer and the learned intermediary in health care.
N Engl J Med. 2002;346:523-524.
54. Jagsi R. Conflicts of interest and the physician-patient relationship in
the era of direct-to-patient advertising. J Clin Oncol. 2007;25:902-905.
55. Avorn J. Powerful Medicines: The Benefts, Costs, and Risks of Prescription Drugs. New York: Alfred A. Knopf, 2004.
56. Kassirer JP. On the Take: How Medicines Complicity with Big Business Can Endanger Your Health. Oxford: Oxford University Press,
2005.
57. Dana J, Loewenstein G. A social science perspective on gifts to physicians from industry. JAMA. 2003;290:252-255.
58. Wazana A. Physicians and the pharmaceutical industry: is a gift ever just
a gift? JAMA. 2000;283:373-380.
59. Ben-Shahar O, Schneider CE. The failure of mandated disclosure. Law
&EconomicsWorkingPapers.2010;Paper9.http://repository.law.umich.
edu/law_econ_current/art9.
60. Hall MA, Kidd KE, Dugan E. Disclosure of physician incentives: do
practices satisfy purposes? Health Aff (Millwood). 2000;19:156-164.
61. Miller TE, Horowitz CR. Disclosing doctors incentives: will consumers understand and value the information? Health Aff (Millwood). 2000;19:149-155.
62. Miller TE, Sage WM. Disclosing physician fnancial incentives. JAMA.
1999;281:1424-1430.
63. Pharmaceutical Research and Manufacturers of America. 2013 Profle:
Biopharmaceutical Research Industry. July 2013. http://www.phrma.
org/sites/default/fles/pdf/PhRMA%20Profle%202013.pdf. Accessed
on January 21, 2015.
137
SPEAKERS
Craig Earle, MD, MSc
Institute for Clinical Evaluative Sciences
Toronto, ON, Canada
Lawrence N. Shulman, MD
Dana-Farber Cancer Institute
Boston, MA
uality of any medical care is important, but it is particularly important in cancer care. Quality can be viewed
through different lenses, including safety of practice, adherence to treatment guidelines (process measures), and outcomes that include overall survival, cancer-related survival,
and quality of life. It is important to consider each of these
quality metrics.
SAFETY
In the 1990s, there was a great deal of focus on patient safety.
An Institute of Medicine report, To Err is Human: Building
a Safer Health System, published in 1999, examined medical
safety and vulnerabilities that can lead to patient harm.1 A
critical component of this process was the acknowledgment
that humans, in this case even medical personnel with appropriate training such as physicians, nurses, and other key
health care personnel, can make errors that could lead to patient harm or death.
Cancer care is complex and multidisciplinary. A patient
with locally advanced rectal cancer may receive concurrent
chemotherapy and radiation that might be followed by a surgical resection, the safety of which can be influenced by the
toxicity from preoperative therapy. A medical oncologist
would prescribe the chemotherapy, including agents, dosing
(e.g., based on body-surface area calculations relying on accurate measurements of height and weight), and schedules; a
pharmacist would prepare the therapies; and an oncology
nurse would administer the drugs. At the same time, a radiation oncologisttogether with physicists, dosimetrists, and
otherswould plan the radiation ports and daily and total
e337
LAWRENCE N. SHULMAN
PROCESS QUALITY
Much of current cancer care quality measurement is focused
on process measures. Based on a high level of evidence from
randomized clinical trials, a patient with stage III colon cancer should receive adjuvant chemotherapy. Most quality
programs, however, only determine if the patient received
chemotherapy. They do not assess whether the patient received the right chemotherapy, whether it was given in appropriate doses and schedule, and they do not assess patient
toxicity, quality of life, or survival. There is an implication
that if the patient received chemotherapy in this circumstance, appropriate therapy was given, and, by inference, outcomes would be ideal. These are big assumptions.
Additionally, much of what oncology providers deal with on
a day-to-day basis involves decisions where no high-level ev-
KEY POINTS
Cancer care providers have an obligation to measure the
quality of their treatment to be certain they understand its
current state and can design interventions to continually
improve performance and patient outcomes.
Cancer care quality encompasses the safety of care
delivered, process measures assessing whether appropriate
treatments were administered, and outcome measures that
include survival and quality of life.
Cancer care is complex, provided by medical, radiation, and
surgical oncologists, and oncology nurses, with key support
from pathologists and radiologists, and spans in-patient and
out-patient venues, which makes quality assessment and
improvement challenging.
The Commission on Cancers Quality program using the
National Cancer Data Base and the American Society of
Clinical Oncologys Quality Oncology Practice Initiative are
examples of broad-based national quality programs.
The use of health information technology will play a key
role in future measurement of cancer care quality.
e338
idence exists, which narrows the number of important clinical decisions that can be assessed for quality.
Process measures are used for many reasons. They can be
defned, measured, and assessed on recently treated patients.
There is an assumption that receiving the right therapy will
result in optimal ultimate outcomes. This assumption, however, can be variably defned. Did the patient with stage III
colon cancer receive chemotherapy? Do we know what chemotherapy he or she received? Do we know if dosing and
schedule was appropriate? Do we know if toxicities were
managed appropriately? Care processes can be evaluated on a
small random sample of patients or on all patients meeting
defned criteria. ASCOs QOPI assesses a random subset of
patients with a particular diagnosis and stage for appropriate
therapy. For example, patients who have stage III colon cancer should receive adjuvant chemotherapy.3 The Commission on Cancer (CoC) uses the National Cancer Data Base
(NCDB), which will be described in more detail later in this article, to assess all patients treated at a CoC-accredited hospital
for this same metric.5 Process measures are most useful for a
practice or hospital when data from other practices and hospitals are available to compare performance. This is true for both
the QOPI program and the CoC quality program. In neither
case, though, are the specifc chemotherapeutic agents assessed,
nor are the appropriateness of dosing and schedule.
Process measures can assess the current state of practice for
a particular physician group or hospital. They also can be
used as a quality improvement tool if performance is suboptimal. The QOPI program examined chemotherapy given
during the last 2 weeks of life as a quality metric for end-oflife care. A group in Michigan realized that its rates of utilization of chemotherapy during the last 2 weeks of life were
much higher than other QOPI programs. The group then designed interventions to influence practice and their performance quickly improved substantially.6
Some process measures derived from very high-level evidence represent relatively low bars to which excel. Both
QOPI and CoC examine hormone therapy rates for women
with certain stage, hormone receptorpositive breast cancer.
Most programs rate very high on this metric. As such, most
programs have little room for improvement and the measure
does not represent a good approach to comparing performance across programs.
OUTCOMES MEASURES
Patient outcomes, such as overall survival, which takes into
account survival from the cancer as well as potential complications of therapy, might be the ultimate quality metric. Survival as a quality metric, however, presents many challenges.
Survival depends not only on the stage of disease, but also
on a number of related and unrelated factors. Gender and age
have profound effects on survival, and these data are always
available in databases for stratifcation. Socioeconomic status,
ethnicity, performance status at presentation, comorbidities,
and distance from the patients home to his or her treating center all affect survival rates, but not all of these factors may be
e339
LAWRENCE N. SHULMAN
1,500 hospitals in the United States are accredited. Accredited hospitals transfer their registry data into a de-identifed
database, the NCDB, which is cosupported by CoC and the
American Cancer Society. Accredited hospitals can enter a
portal to view their performance against many quality measures and compare them with other CoC-accredited hospitals.
In addition, an annual report is produced for each accredited
hospitalThe Cancer Quality Improvement Program (CQIP).
The CQIP contains the hospitals performance for 12 quality
measures (in the 2014 report), 30- and 90-day postoperative
mortality for six complex cancer surgeries (thoracotomy,
esophagectomy, cystectomy, gastrectomy, rectal cancer resection, and pancreatectomy), and survival data for several more
common cancers.
A major advantage of the NCDB quality program is that
manual chart abstraction is not necessary. Quality data are
derived electronically from the database for all patients who
have cancer with a particular diagnosis and stage. It should be
noted, however, that the NCDB is registry-derived data and
registry data are manually entered by registrars. An individual hospitals data can be compared against all other CoCaccredited hospitals, or just hospitals in their region, or
hospitals of similar type (e.g., community vs. academic cancer center). Disadvantages include registry data that are often
1 to 2 years old before completely entered into the database.
Furthermore, not all desired data are housed in the NCDB.
Programs such as the CoCs Rapid Quality Reporting System
are driving more timely entry of registry data to affect quality
of ongoing care.13 Specifcally, there is little granular data on
specifc systemic therapies administered and disease-free
survival and cancer-related mortality data often are not there.
Measures must be designed around what data are available in
the NCDB.
FUTURE DIRECTIONS
THE COMMISSION ON CANCER QUALITY PROGRAM
The CoC is an arm of the American College of Surgeons that
accredits hospital cancer programs.13 Currently, more than
e340
References
1. Institute of Medicine. To err is human: building a safer health system.
http://iom.edu/reports/1999/to-Err-is-human-building-a-safer-healthsystem.aspx. Accessed January 1, 2015.
2. Neuss MN, Polovich M, McNiff K, et al. 2013 updated American Society
of Clinical Oncology/Oncology Nursing Society chemotherapy administration safety standards including standards for the safe administration and management of oral chemotherapy. J Oncol Pract.
2013;9:5s-13s.
3. Blayney DW, McNiff K, Eisenberg PD, et al. Development and future of
the American Society of Clinical Oncologys Quality Oncology Practice
Initiative. J Clin Oncol. 2014;32:3907-3913. Epub 2014 Sep 15.
4. Meisenberg BR, Wright RR, Brady-Copertino CJ. Reduction in chemotherapy order errors with computerized physician order entry. J Oncol
Pract. 2013;10:e5-9. Epub 2013 Sep 3.
5. Commission on Cancer, National Cancer Data Base. https://www.facs.
org/quality%20programs/cancer/ncdb. Accessed January 1, 2015.
6. Blayney DW, Severson J, Martin CJ, et al. Michigan oncology practices
showed varying adherence rates to practice guidelines, but quality interventions improved care. Health Aff (Millwood). 2012;31:718-728.
e341
LEUKEMIA, MYELODYSPLASIA,
AND TRANSPLANTATION
SPEAKERS
David I. Marks, MB, BS, PhD, FRACP, FRCPath
University Hospitals Bristol NHS Foundation Trust
Bristol, United Kingdom
Adele K. Fielding, MB, MS, PhD, FRCP, FRCPath
UCL Cancer Institute
London, United Kingdom
his article will focus on patients with ALL older than age
50 who are known to have a poor outcome in terms of
complete remission (CR) rates and long-term survival (Tables 1
and 2, Fig. 1).1 However, different investigators have used various age limits in defning older patients with ALL. Outcome
worsens markedly when patients are older than age 40 and is
considerably worse in patients older than age 60. Furthermore,
Surveillance, Epidemiology, and End Results (SEER) Program
data from the United States show that, unlike every other age
group, there has been no signifcant improvement in outcomes
during the last 25 years. In 1984, 8.4 ( 3.4%) of patients older
than 60 survived compared with 12.7 ( 2.9%) from 2000 to
2004, a nonsignifcant increase of 4.3%.2
In adults, the median age at diagnosis is older than age 60,
making effective therapy of the older patient an important
area of unmet need.3-6 The age-specifc annual incidence in
individuals older than age 60 is 0.9 to 1.6 per 100,000 compared with 0.4 to 0.6 per 100,000 in the 25-year to 50-year age
group. The number of cases of ALL occurring in older patients will increase as the general population ages.
THERAPEUTIC DIFFERENCES
Available agents for remission induction therapy include steroids, vincristine, doxorubicin, and various formulations of
asparaginase. Choosing the right agents for each patient
should take into account reduced renal function, a tendency
to more mucositis, and a higher probability of confusion with
steroids, infection, and metabolic derangement. Steroids are
also more likely to result in symptomatic myopathy and, undoubtedly, contribute to infection. Drug interactions are also
more likely in this age group. Concomitant medications
From the University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: David I. Marks, MB, BS, PhD, FRACP, FRCPath, Adult BMT Unit, University Hospitals Bristol NHS Foundation Trust, Bristol BS2 8ED, United Kingdom;
email: david.marks@UHBristol.nhs.uk.
2015 by American Society of Clinical Oncology.
e343
DAVID I. MARKS
Complete Remission
Rate (%)
Median Survival
(Months)
Kantarjian 1994
65
11
Bassan 1996
59
Delannaoy 1997
85
14
Delannaoy 2002
58
Ofdiani 2003
73
Not stated
KEY POINTS
Older patients with ALL require an individualized
assessment of comorbidities and therapy adapted to their
performance status, disease response, and personal
treatment goals. Newer targeted therapies are likely to
play a larger role.
Optimal postremission therapies in older patients are
unknown as are their effects on quality of life and in
maintaining complete remission (CR). Reduced intensity
conditioning (RIC) allografting in t patients who have
responded well to therapy and have high-quality donors
deserves further exploration.
Arguably, older patients with Philadelphia-positive (Ph-pos)
ALL have better outcomes than older patients with Phnegative disease. This patient group can reliably achieve
CR with vincristine, steroids, and a tyrosine kinase inhibitor
(TKI) with minimal toxicity. Medium-term survival can be
achieved in many older patients with gentle maintenance
therapy and a TKI. Using a different agent at relapse may
prolong survival.
Internationally, ALL investigators need to target this
neglected group of patients by opening clinical trials that
ask questions aimed at improving survival and the quality
of that survival. Physicians who manage these patients are
urged to enter patients into these clinical trials so that we
can learn which therapy can be tolerated and is most
efcacious. These basic studies would provide the
background data that will enable study of newer targeted
therapies that have less marrow and extramedullary
toxicity.
e344
posomal daunorubicin deserves further testing and liposomal vincristine may result in less autonomic neuropathy.
HOVON
The fairly small-scale data by the HOVON group highlights
the uncertainties of how to manage this disease.9 In 24 patients age 61 to 70 (who were undoubtedly highly selected),
79% achieved CR, and overall survival at 3 years was a remarkable 50%. However, the price for these results was 21%
induction mortality. Patients and physicians might accept
this NRM as it was accompanied by a realistic chance of
medium-term survival. Three of the 24 patients underwent
an allogeneic transplant.
TABLE 2. Outcome Data Concerning Older Patients with Acute Lymphoblastic Leukemia
Group/Study
Age
No. of
Patients
CR Rate (%)
OS (at 3 to 8 Yrs)
Author
UK NCRI
55-64
100
70
19% at 8 yrs
Sive 2012
CALGB
60
129
57
12% at 3 yrs
Larson 2005
MD Anderson
60
44
79
17% at 5 yrs
Kantarjian 2000
SWOG 8419
50-84
85
41
Not reported
Petersdorf 2001
GIMEMA 0208
50-60
121
68
15% at 8 yrs
Annino 2002
PETHEMA ALL96
56-67
33
58
39% at 5 yrs
Sancho 2007
SWOG 9400
50-65
43
63
23% at 5 yrs
Pullarkat 2008
EWALL
56-73
40
85
Not reported
Gokbuget 2008
SIVE ET AL
The United Kingdom Medical Research Council (MRC)/
Eastern Cooperative Oncology Group (ECOG) collaborative
group reported outcomes of therapy in 100 patients older
than age 55 out of a total of 1,914 recruited to United Kingdom ALL XII/ECOG2993 (median age 56, range 55 to 65).10
Patients were treated with the full protocol as detailed in
Goldstone et al,7 with no planned dose reductions. Com-
ALL 60
e345
DAVID I. MARKS
FIGURE 2. Survival of Patients by Age at Entry to Study Showing (A) Overall Survival and (B) Event-Free
Survival in All Patients and (C) Overall Survival in Just Those Who Received Chemotherapy
e346
FIGURE 3. Treatment Schema for United Kingdom ALL 60 Trial Showing Four Treatment Arms and One
Registration Arm
Informed Consent and Registraon
Di
c
bone
marrow*
Treatment Choice*
PH +ve
PH -ve
PHILADELPHIA POSITIVE
PHILADELPHIA NEGATIVE
(INTENSIVE)
PHILADELPHIA NEGATIVE
(INTENSIVE +)
REGISTRATION
ONLY
PHILADELPHIA NEGATIVE
(NON-INTENSIVE)
Phase 1
Bone marrow
for MRD*
se 2
Bone marrow
for MRD*
Bone marrow
for MRD*
Consolid
Bone marrow
for MRD*
on 2
* Sample
sent to
central lab
Maintenance (2 years)
Four treatment arms ranging from very low to high intensity are available to patients enrolled in the study (United
Kingdom CRN ID 12988; Fig. 3). The primary endpoints of
the study are CR rate after two cycles, event-free survival at 1
year, and treatment-related mortality. Further aims include
assessing quality of life (QOL), inpatient stays, and the prognostic value of MRD at three time points. We will further
assess tolerability of treatment by assessing certain adverse
events.
The trial is accruing slowly, but to date we have preliminary
data about 39 patients from 21 centers. The median age of
patients is 67 and seven patients are Ph-pos. Twenty one have
been assigned to the intensive or very intensive arms. Only 18
patients are currently evaluable for response after phase II.
There has been no NRM, and 13 have achieved CR. Two patients have died of ALL. These data will be updated just before the 2015 ASCO Annual Meeting. HOVON and New
Zealand are planning to join the study.
During the next 3 years, we will collect data about postremission therapy and its effect on QOL and need for hospitalization. Having analyzed these data, in the next study we will
add in some novel agents aiming to improve effcacy without
worsening toxicity.
Data
collecon
only
n of mai
e347
DAVID I. MARKS
PH-POS ALL
Ph-pos ALL will be only discussed briefly as it will be dealt
with in detail in a subsequent manuscript. One-quarter of all
adults are Ph-pos, and the incidence is approximately 50% in
patients older than age 50. Until the results of recent studies
in older patients became available, most patients with Ph-pos
ALL were managed with intensive chemotherapy and a tyrosine kinase inhibitor. Imatinib has improved the CR rate in
a number of trials to greater than 90% and makes more pae348
HEPATOTOXICITY
Some patients older than age 50 will be treated with asparaginase; this is the major cause of induction-associated liver
dysfunction. There is an association between inductionassociated liver dysfunction and anthracycline use and possibly with imatinib. Patients are generally given asparaginase
in the third week from the start of chemotherapy. Liver function tests should be carefully monitored, and asparaginase
should not be given to patients with signifcantly abnormal
liver function tests. Hepatotoxic drugs such as cotrimoxazole, omeprazole, and many antifungals should be stopped.
RENAL DYSFUNCTION
Many older patients have abnormal baseline renal function.
Careful attention should be paid to hydration and the avoidance of nephrotoxic drugs unless there is no alternative. Allowing patients to become fluid overloaded can necessitate
the later use of furosemide, which depletes intravascular fluid
with downstream effects on the kidneys.
91
60
Median age
49
Sibling donor
36 (60%)
ECOG PS 1-2
24 (40%)
WBC 30 10e9/L
12 (20%)
High-risk cytogenetics
27/51*
29%
Chronic GVHD
14 (23%)
16/41**
Relapse
4 (2 survive)
Transplant-related mortality
Total deaths
FUTURE DEVELOPMENTS
The newer agents, blinatumomab and inotuzumab,14,16 have
not been tested specifcally in this age group, but there will be
some data from the ongoing phase III studies (Inovate and
Tower). Both drugs have been tested mainly in the relapsed/
refractory setting, but blinatumomab is very impressive at
converting persistent MRD positivity (after 3 months of chemotherapy) to negativity (78% of 116 patients in the phase II
study).22,23 As most older patients have dose reductions that
may result in higher incidences of persistent MRD positivity,
it is attractive to add in a 28-day course of blinatumomab to
deepen remission states before further consolidative or
maintenance chemotherapy. However, frst we need data
comparing this agent with conventional chemotherapy and
to know if older patients tolerate the cytokine release syndrome and neurotoxicity. Similarly, the effcacy and safety of
inotuzumab will need to be compared with conventional salvage therapy before we can assess the place of this drug in
older patients.
In the United Kingdom, we are working to establish a backbone of chemotherapy that older patients can tolerate, with
reasonable CR rates and 1-year survival. We then plan to add
in novel agents to improve those outcomes without increasing toxicity and NRM. The collection of diagnostic specimens in these patients and correlation with clinical data may
improve our understanding of the biologic differences that
exist in older patients with ALL.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e349
DAVID I. MARKS
CONCLUSION
Effective management of older patients with ALL is a major
unmet need. The different biology of the disease and the patient is recognized, and we now need the systematic trials that
have improved the outcome of ALL in children and adults to
be applied to the older age group. Many ft patients between
age 50 and 65 will be able to tolerate conventional aggressive
chemotherapy with reasonable outcomes and acceptable
NRM. However, older and less-ft patients require lessaggressive chemotherapy, and strategies are needed to improve CR rates in this group. It is essential that we better
understand the comorbidities that affect tolerance to chemotherapy so that we can rationally adjust therapy and not rely
on end-of-the-bed impressions. Trials such as the United
Kingdom ALL 60 study that assess comorbidities and include objective and subjective QOL endpoints will hopefully
advance the feld. Leukemia physicians are urged to enter
older patients into trials in order that we may improve the
outcome of this diffcult clinical management problem.
ACKNOWLEDGEMENT
David I. Marks would like to thank Adele Fielding for helpful
discussions and kindly permitting access to unpublished
work. Jenny Bird reviewed the manuscript, making helpful
suggestions.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: David I.
Marks, Amgen. Speakers Bureau: None. Research Funding: None. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None.
Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Rowe JM, Buck G, Burnett AK, et al. Induction therapy for adults with
acute lymphoblastic leukemia: results of more than 1500 patients from
the international ALL trial: MRC UKALL XII/ECOG 2993. Blood. 2005;
106:3760-3767.
2. Pulte D, Gondos A, Brenner H. Improvement in survival in younger
patients with acute lymphoblastic leukemia from the 1980s to the early
21st century. Blood. 2009;113:1408-1411.
3. Larson RA. Acute lymphoblastic leukemia: older patients and newer
drugs. Hematology Am Soc Hematol Educ Program. 2005;131136.
4. Marks DI. Treating the older adult with acute lymphoblastic leukemia. Hematology 2010 30th edition. American Society of Hematology
Education Program Book. 2010;13-20.
5. Gokbuget N. How I treat older patients with ALL. Blood. 2013;122:13661375.
6. Goldstone AH, Richards SM, Lazarus HM, et al. In adults with
standard-risk acute lymphoblastic leukemia, the greatest beneft is
achieved from a matched sibling allogeneic transplantation in frst complete remission, and an autologous transplantation is less effective than
conventional consolidation/maintenance chemotherapy in all patients:
fnal results of the International ALL Trial (MRC UKALL XII/ECOG
E2993). Blood. 2008;111:1827-1833.
7. Moorman AV, Harrison CJ, Buck GA, et al. Karyotype is an independent prognostic factor in acute lymphoblastic leukemia (ALL): analysis
of cytogenetic data from patients treated on the Medical Research
Council (MRC) UKALLXII/Eastern Cooperative Oncology Group
(ECOG) 2993 trial. Blood. 2007;109:3189-3197.
e350
8. Moorman AV, Chilton L, Wilkinson J, et al. A population-based cytogenetic study of adults with acute lymphoblastic leukemia. Blood. 2010;
115:206-214.
9. Daenen S, van der Holt B, Dekker AW, et al. Intensive chemotherapy to
improve outcome in patients with acute lymphoblastic leukemia over
the age of 40: a phase II study for effcacy and feasibility by HOVON.
Leukemia. 2012;26:1726-1729.
10. Sive JI, Buck G, Fielding A, et al. Outcomes in older adults with acute
lymphoblastic leukaemia (ALL): results from the international MRC
UKALL XII/ECOG2993 trial. Br J Haematol. 2012;157:463-471.
11. Klepin HD, Geiger AM, Tooze JA, et al. Geriatric assessment predicts
survival for older adults receiving induction chemotherapy for acute
myelogenous leukemia. Blood. 2013;121:4287-4294.
12. Larson RA, Dodge RK, Linker CA, et al. A randomized controlled trial
of flgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111.
Blood. 1998;92:1556-1564.
13. Thomas DA, OBrien S, Kantarjian HM. Monoclonal antibody therapy
with rituximab for acute lymphoblastic leukemia. Hematol Oncol Clin
North Am. 2009;23:949-971, v.
14. Topp MS, Kufer P, Gokbuget N, et al. Targeted therapy with the T-cellengaging antibody blinatumomab of chemotherapy-refractory minimal
residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin
Oncol. 2011;29:2493-2498.
15. Gokbuget N, Basara N, Baurmann H, et al. High single-drug activity of
nelarabine in relapsed T-lymphoblastic leukemia/lymphoma offers cu-
16.
17.
18.
19.
20.
21.
22.
23.
24.
e351
ADELE K. FIELDING
cute lymphoblastic leukemia (ALL) in which the Philadelphia (Ph) chromosome t(9;22) is detected (i.e., Ph
ALL) is a genetically, biologically, and clinically distinct
subtype of B-precursor ALL, and it comprises approximately
20% of the total ALL incidence. The incidence of Ph ALL
increases with age, from less than 5% in younger children to
20% to 25% in older adults,1,2 although population-based
studies indicate that the incidence does not continue to increase beyond the fourth decade.3 Standard ALL chemotherapy treatment alone results in a complete remission (CR) rate
of at least 10% lower than in Ph-negative ALL,4,5 with a median survival of around 8 months.2 However, in recent years,
the addition of TKIs to remission induction treatment
combined with earlier and more frequent allogeneic donor
identifcation, facilitating allogeneic hematopoietic stem cell
transplantation (alloHSCT) has made a considerable
change to the outcome. However, the relatively rapid expansion of the range of realistic therapeutic possibilities in an
uncommon disease has generated some genuine therapeutic
dilemmas in an arena where testing all of the possibilities in
well-designed trials has not yet occurred. Furthermore, there
is international variability and even local variability in the
availability of some of the therapeutic options and of what
may be considered standard-of-care choices in some geographic locations is not relevant to others. In this summary, I
will focus on key decision points in the treatment of Ph
ALL, posing the relevant therapeutic questions and evaluat-
ing evidence that supports common approaches. I will highlight areas in which there is no clear best practice, providing
my personal opinion only when no prevailing consensus
exists.
e352
KEY POINTS
The outcome of treatment of Philadelphia chromosome
positive (Ph) acute lymphoblastic leukemia (ALL) has
changed considerably for the better over the last 10 years,
with up to 60% 5-year overall survival rates with tyrosine
kinase inhibitor (TKI) induction followed by allogeneic
hematopoietic stem cell transplantation (alloHSCT).
Complete remission can now be achieved with minimal
toxicity TKIs with little or no chemotherapy, but the longterm outcome of chemotherapy-free induction regimens is
not known.
The optimal TKI for induction of remission is not known.
BCR-ABL1 transcript monitoring demonstrates that complete
molecular remission can be achieved in some patients.
Whether this may indicate that future treatment
intensication with alloHSCT can be omitted or reserved
for disease progression is a totally open question.
Presently, alloHSCT retains an important role in the
management of Ph ALL; nonmyeloablative conditioning
regimens are now widely used, but results of prospective
evaluations of this strategy are still unknown.
e353
ADELE K. FIELDING
confounded by the heterogeneous therapy given subsequently. An ongoing trial, GIMEMA LAL 1509, used a
similar chemotherapy-free induction with dasatinib and
corticosteroid induction treatment, but added chemotherapy
and/or alloHSCT for patients who did not reach a sustained
complete molecular response (CMR; i.e., no detectable BCRABL1 transcripts). This approach has been reported so far
only in abstract form,24 but the results are very interesting.
The CR rate was 97%, with no induction-related deaths,
which included CMR in 18%. Interestingly, BCR-ABL1 p210
(45% of cases in the report) had a worse prognosis, with lower
initial susceptibility to TKIs and a 58% incidence of relapse.
The report provocatively suggests that the subset of patients
who had deep molecular remissions may be spared further
intensive treatment. The long-term follow-up of this study
will be of major importance to the feld. A recently completed, but also not yet published, study (GRAAPH-2005)
from the French Group for Research on Adult Acute Lymphocytic Leukemia Study (GRAALL) also highlights the
value of a lower intensity of chemotherapy during induction.
Chalandon et al25 randomly assigned 265 previously untreated patients with Ph ALL to receive induction with
imatinib/hyperCVAD or imatinib with dexamethasone/
vincristine (DIV). Very high CR rates were noted in both
arms (DIV, 98%; hyperCVAD, 91%); the lower CR rate in the
hyperCVAD arm was a result of higher induction mortality.26 DIV induction was noninferior to hyperCVAD, with no
difference in 3-year EFS (46% vs. 38%; p 0.25) and OS (53%
vs. 49%; p 0.61).
Although the long-term outlook of treating patients without chemotherapy is unknown, this is a reasonable treatment
approach in older patients and should be considered. A detailed discussion of the treatment of older people with ALL in
general is given in the chapter by Dr. David Marks.
alloHSCT, which would be a major advance, must be considered. Evidence in support of this has so far been gathered in
patients in whom alloHSCT has not been possible; these patients are never a comparable group to those in whom alloHSCT could be and was performed. Nonrecipients are typically
older, have more comorbidities, and are more likely to have experienced relapse by the median time to alloHSCT.5,13
Studies in which alloHSCT was not the primary focus may
nonetheless contribute to our understanding of its role. As
always, though, the circumstances under which patients did
not receive alloHSCT must be taken into account. One of the
frst studies to suggest omission of alloHSCT as a realistic
possibility in the TKI era was a Childrens Oncology Group
study in which patients up to age 21 were treated with imatinib added to chemotherapy.32 Postremission treatment
with sibling alloHSCT was included in the protocol, but the
trial did not allow for matched unrelated donor (MUD) alloHSCT on the basis of a previous, international study in
children33 that showed a 43% treatment-related mortality
(TRM) for MUD alloHSCT. Hence, this study left a small cohort of children who received an imatinib/chemotherapy
combination without alloHSCT. There was relatively high
rate of off-protocol MUD alloHSCT that confounded data
interpretation. However, at 3 years, the outcomes for those
treated with imatinib/chemotherapy (25 patients) compared
favorably with those treated with alloHSCT (21 patients); the
3-year DFS without alloHSCT was 85%. Although the study
was neither designed nor powered to answer the question of
whether imatinib/chemotherapy could replace sibling alloHSCT for children with Ph, the data introduced the
hypothesis that children with Ph ALL can be treated successfully without alloHSCT. In combination with emerging
data of improved overall outcomes for adults with Ph ALL,
this study has reasonably sparked consideration of the omission of alloHSCT from treatment. A multivariate analysis of
patients treated at the MDACC with hyperCVAD and TKI
regimens,34 which excluded those who had received alloHSCT, revealed that achievement of major molecular response (MMR), namely a BCR-BCR-ABL ratio of 0.1, was
associated with better survival outcomes. However, the selection of the MMR as a cutoff remains somewhat arbitrary, although it is explained in the paper, and the numbers of
patients on whom this analysis is based are limited. The authors reasonably take the data to support the role of minimal
residual disease (MRD) monitoring but wisely do not suggest
that these data currently support the omission of alloHSCT.
In my opinion, the most robust evidence to date on the
present need to continue considering alloHSCT as a core
therapy comes from trials groups that have reported on the
outcome of patients who received chemotherapy and a TKI
alone and have been able to compare that group with those
who received alloHSCT. Among the few published studies to
report on the outcome of a substantial group of patients of
transplantable age who did not undergo transplantation was
the ALL202 trial from the Japanese Adult Leukemia Study
Group,11 in which the combination of imatinib and chemotherapy was evaluated in 80 adult patients, 31 of whom did
not undergo alloHSCT. When compared with historic controls in whom there were no event-free survivors at 24
months, the 2-year estimated EFS was signifcantly better for
those patients receiving imatinib as part of their therapy. In
the largest such study internationally, the Ph arm of the
U.K. ALL12/E2993 trial examined the outcome of treatment
in 266 patients enrolled on the preimatinib era and was compared with the outcome in 175 patients receiving the same
chemotherapy treatment and alloHSCT approach but with
the addition of imatinib.13 There was a large and statistically
signifcant outcome beneft with imatinib cohort; at 4 years,
the OS of all patients in the imatinib cohort was 38%, versus
22% in the preimatinib cohort. However, the rate of alloHSCT was 46% in the imatinib cohort and was 31% in the
preimatinib cohort.13 This raises the question of what proportion of the beneft accrued was a direct result of imatinib
alone, rather than the contribution made by imatinib to a signifcantly better initial therapeutic response facilitating more
frequent alloHSCT. A Cox multivariate analysis, which took
alloHSCT into account, showed only a modest additional
beneft with the addition of imatinib (hazard ratio for EFS,
0.64; 95% CI, 0.44 to 0.93; p 0.02). Importantly, there was
signifcant beneft for OS and RFS. The investigating team, of
whom I was a member, concluded that the addition of imatinib to standard therapy considerably improved the CR rate
and long-term OS for adults with ALL. However, our data
showed that a proportion of the OS beneft derived from imatinib facilitation of alloHSCT. Studies in which the long-term
outcome of patients who have been selected by good risk criteria to postpone alloHSCT will eventually inform a more
strategic deployment of alloHSCT in this disease. Additionally, non-alloHSCT immunotherapies, such as the bispecifc
antibody against CD19 and CD3, blinatumomab,35 and chimeric antigen receptor T cells (discussed in the companion
article by Sadelain et al), may fnd a role in postremission
therapy of high-risk ALL as a potential alternative to alloHSCT.
e355
ADELE K. FIELDING
PH-LIKE ALL
In the so-called Ph-like ALL, t(9;22) is absent, but the leukemia is characterized by a range of genomic alterations that
activate a limited number of signaling pathways similar to
those activated in Ph ALL,56 some of which may be amenable to inhibition with approved TKIs. The precise defnition
of these targetable, kinase-activating lesions in clinical practice using standard techniques is not yet clear, but suggested
algorithms have emerged that provide practical advice on
when and how to consider this subtype of ALL.57 TKIs have
yet to be formally evaluated, except in case reports.58 Nonetheless, there will be patients in whom physicians wish to
consider a TKI as an option, and requests for insurers or
health systems to reimburse these agents will have to be taken
into account soon.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Adele K.
Fielding, Amgen. Speakers Bureau: None. Research Funding: Adele K. Fielding, Sigma Tau. Patents, Royalties, or Other Intellectual Property: None.
Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Moorman AV, Harrison CJ, Buck GA, et al. Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia
(ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood. 2007;109:3189-3197.
2. Secker-Walker LM, Craig JM, Hawkins JM, et al. Philadelphia positive
acute lymphoblastic leukemia in adults: age distribution, BCR breakpoint and prognostic signifcance. Leukemia. 1991;5:196-199.
3. Moorman AV, Chilton L, Wilkinson J, et al. A population-based cytogenetic study of adults with acute lymphoblastic leukemia. Blood. 2010;
115:206-214.
4. Dombret H, Gabert J, Boiron JM, et al. Outcome of treatment in adults
with Philadelphia chromosome-positive acute lymphoblastic leukemia:
results of the prospective multicenter LALA-94 trial. Blood. 2002;100:
2357-2366.
5. Fielding A, Rowe JM, Richards SM, et al. Prospective outcome data on
267 unselected adult patients with Philadelphia chromosome-positive
acute lymphoblastic leukemia confrms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the
international ALL trial MRC UKALLXII/ECOG2993. Blood. 2009;113:
4489-4496.
6. Muller MC, Saglio G, Lin F, et al. An international study to standardize
7.
8.
9.
10.
11.
e357
ADELE K. FIELDING
e358
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
e359
SADELAIN ET AL
himeric antigen receptors (CARs) are recombinant receptors for antigens, which in a single molecule, redirect
the specifcity and function of T lymphocytes. A general
premise for their use in cancer immunotherapy is to rapidly
generate tumor-targeted T cells, bypassing the barriers to and
incremental kinetics of active immunization.1 Second generation CARs not only redirect cytotoxicity, but also reprogram
T cell function and longevity, thus conferring supraphysiological properties on T cells, which then become living
drugs that exert both immediate and sustained therapeutic
effects.2
T cells normally recognize their target antigen through the
T cell receptor (TCR), which binds to human leukocyte antigen (HLA)-peptide complexes displayed on the surface of
target cells. The TCR does not itself signal, but it does determine, based on its affnity for the HLA-peptide complex, the
strength of the activation signals the T cell generates on contacting the tumor. The strength of these signals is further
modifed by costimulatory receptors, which may be either activating (such as CD28 and 4 1BB) or inhibitory (such as
CTLA-4 and PD-1).3 The ligands for these receptors are not
ubiquitously expressed, and therefore place costimulation
under the control of the target cell engaged by the T cell.
Thus, professional antigen presenting cells, such as B cells
and dendritic cells, may express powerful ligands for CD28
and 4 1BB, but tumors typically do not, as is the case for
ALL. The concept underlying second generation CARs is to
provide costimulatory support to T cells irrespective of the
presence of a ligand on tumor cells (Fig. 1). In this context, T
cells that engage the tumor through the CAR are given a costimulatory signal within the tumor microenvironment it-
From the Center for Cell Engineering and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Michel Sadelain, MD, PhD, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: m-sadelain@ski.mskcc.org.
2015 by American Society of Clinical Oncology.
e360
Number/Age of Subjects
Complete
Remission Rate
5 (adults)
100%
2 (children)
100%
16 adults
88%
21 (children)
67%
90%
33 adults
91%
the B cell lineage. Thus, a successful therapy would be expected to induce a B cell aplasia, which was indeed observed
in murine models7,8 and later in patients treated with CD19
CAR therapy. Furthermore, we thought that the role of CD19
in B cell development may extend to a role in tumor survival,
which would ensure that CD19 is expressed on most malignant cells and uncommonly lost.6,9 We provided the frst
proof of principle that CAR-modifed human peripheral
blood T cells targeted to CD19 could eradicate a broad range
of B cell malignancies, including ALL, using immunodefcient mice bearing medullary and systemic disease. In these
mice, a single intravenous infusion of CD19 CARtargeted T
cells could eradicate a tumor and induce long-term remissions.10 Successful B cell tumor eradication was eventually
obtained with a range of different CD19 CARs,11-15 paving
the way for several ongoing clinical trials.
KEY POINTS
CAR therapy is an emerging immunotherapy based on
engineering of T cells.
Second generation CARs, which provide costimulatory
support to engineered T cells, have transformed the
prospects of adoptive cell therapy.
CD19 CARs have induced dramatic complete responses in
patients with relapsed, chemorefractory ALL.
The two toxicities of CD19 CAR therapy are B cell aplasia
(destruction of normal cells that express CD19) and sCRS
(which occurs in some patients following in vivo activation
of the infused CAR T cells).
It is reasonable to anticipate that CD19 CAR T cells will
become part of the armamentarium for B-cell ALL and
other B cell malignancies.
e361
SADELAIN ET AL
PERSPECTIVE
The past 2 decades have seen the creation of a new toolbox of
recombinant receptors for cancer immunotherapy. Second
generation CARs have transformed the adoptive T-cell
therapy feld. CD19 has become the poster child for CAR
therapies. The most remarkable results have been reported
to date in ALL, in both adults and children. Remarkably,
the CR rate remains high irrespective of patients age or
prior treatments. sCRS may occur in patients with high
tumor burden, but means to control it are available.
CD19-negative relapse may occur (possibly more commonly in children), for which CD22 CAR therapy may
provide an effective recourse.26 CD19 CARs, which received breakthrough designation by the U.S. Food and
Drug Administration at CHOP and at MSKCC in 2014,
will soon become part of the armamentarium for B cellALL and other B cell malignancies.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: Renier Brentjens, Juno Therapeutics. Michel Sadelain, Juno
Therapeutics. Isabelle Riviere, Juno Therapeutics. Honoraria: None. Consulting or Advisory Role: Renier Brentjens, Juno Therapeutics. Jae Park, Amgen,
Juno Therapeutics. Michel Sadelain, Juno Therapeutics. Isabelle Riviere, Juno Therapeutics. Speakers Bureau: None. Research Funding: Renier Brentjens,
Juno Therapeutics. Jae Park, Juno Therapeutics, Genentech/Roche. Isabelle Riviere, Juno Therapeutics (Inst). Patents, Royalties, or Other Intellectual
Property: Renier Brentjens, Scientic Cofounder of Juno Therapeutics. Michel Sadelain, Scientic Co-Founder of Juno Therapeutics. Isabelle Riviere, royalty
sharing agreement. Expert Testimony: None. Travel, Accommodations, Expenses: Isabelle Riviere, Juno Therapeutics. Other Relationships: None.
References
1. Sadelain M, Rivie`re I, Brentjens R. Targeting tumours with genetically enhanced T lymphocytes. Nat Rev Cancer. 2003;3:35-45.
2. Sadelain M, Brentjens R, Rivie`re I. The promise and potential pitfalls
of chimeric antigen receptors. Curr Opin Immunol. 2009;21:215223.
e362
16. Hollyman D, Stefanski J, Przybylowski M, et al. Manufacturing validation of biologically functional T cells targeted to CD19 antigen for
autologous adoptive cell therapy. J Immunother. 2009;32:169-180.
17. Brentjens RJ, Davila ML, Rivie`re I, et al. CD19-targeted T cells rapidly
induce molecular remissions in adults with chemotherapy-refractory
acute lymphoblastic leukemia. Sci Transl Med. 2013;5:177ra138.
18. Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptormodifed T cells for acute lymphoid leukemia. N Engl J Med. 2013;
368:1509-1518.
19. Davila ML, Rivie`re I, Wang X, et al. Effcacy and toxicity management of
19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci
Transl Med. 2014;6:224ra225.
20. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing
CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in
children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;
385:517-528.
21. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for
sustained remissions in leukemia. N Engl J Med. 2014;371:1507-1517.
22. Davila ML, Brentjens R, Wang X, et al. How do CARs work?: early insights from recent clinical studies targeting CD19. Oncoimmunology.
2012;1:1577-1583.
23. Maude SL, Barrett D, Teachey DT, et al. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 2014;
20:119-122.
24. Fedorov VD, Sadelain M, Kloss CC. Novel approaches to enhance the
specifcity and safety of engineered T cells. Cancer J. 2014;20:160-165.
25. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;
124:188-195.
26. Haso W, Lee DW, Shah NN, et al. Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood.
2013;121:1165-1174.
e363
LEUKEMIA, MYELODYSPLASIA,
AND TRANSPLANTATION
Management of Hematologic
Malignancies in Older Adults
CHAIR
H. Joachim Deeg, MD
Fred Hutchinson Cancer Research Center, University
of Washington
Seattle, WA
SPEAKERS
Maxwell M. Krem, MD, PhD
University of Louisville Brown Cancer Center
Louisville, KY
Paul A. Hamlin, MD
Memorial Sloan Kettering Cancer Center
New York, NY
formance status, a higher comorbidity score, and more advanced disease at treatment initiation,13 highlighting the
need for agents that have effcacy and tolerability in older patients. Furthermore, age-related host factors reduce treatment tolerability and increase the risk of grade 3 to 5
toxicities,14 making adverse effects key considerations.
Both the classes and numbers of targeted therapies have
rapidly proliferated, resulting in an evolving and more complex treatment landscape. Available classes that have
spawned second-generation agents include monoclonal antibodies, cell-signaling pathway inhibitors, immunomodulators, and proteasome inhibitors. Several new classes of agents
are in clinical trials and show promise (Table 2). We will discuss these classes of agents, their proposed mechanisms of
action, and the clinical data regarding their effcacy and tolerability in older patients. Our emphasis will be on those that
are currently marketed, have been studied in older populations, and have later-phase clinical data.
ANTI-CD20 ANTIBODIES
CD20 is a glycosylated phosphoprotein antigen found on the
surface of B lymphocytes at most stages of B-cell development, starting at the pro-B-cell phase but ending before differentiation into plasma cells. Its function is believed to be
optimization of antibody responses, but it has no known natural ligand.15,16 Monoclonal antibodies directed against
CD20 neutralize both benign and malignant B cells; antiCD20 antibody cytotoxicity mechanisms include antibodydependent cell-mediated cytotoxicity (ADCC), complement-
From the University of Louisville Brown Cancer Center, Louisville, KY; Fred Hutchinson Cancer Research Center, Seattle, WA.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Maxwell M. Krem, MD, PhD, University of Louisville Brown Cancer Center, 529 South Jackson St., Louisville, KY 40202; email: mkrem@uw.edu.
2015 by American Society of Clinical Oncology.
e365
Reference(s)
CLL/SLL
72
12
LPL
60-64
10, 11
MZL
72
12
FL
65
12
Abbreviations: iNHL, indolent B-cell malignancies; CLL, chronic lymphocytic leukemia; SLL,
small lymphocytic lymphoma; LPL, lymphoplasmacytic lymphoma; MZL, marginal-zone
lymphoma; FL, follicular lymphoma.
KEY POINTS
Older patients are more prone to comorbidities, reduced
performance status, and grade 3 or higher toxicities,
making safety and tolerability key considerations in the
choice of treatment for indolent B-cell malignancies.
New anti-CD20 monoclonal antibodies, administered in
combination with chlorambucil, have demonstrated efcacy
in patients with chronic lymphocytic leukemia who are
older or have comorbidities.
The phosphatidyl-3-kinase inhibitor idelalisib and the
Brutons tyrosine kinase inhibitor ibrutinib have
demonstrated good efcacy and tolerability in patients
with chronic lymphocytic leukemia, including patients with
high-risk cytogenetics.
mTOR inhibitors, immunomodulatory drugs, and proteasome
inhibitors have efcacy across several indolent B-cell
malignancy histologies but have not resulted in high
tolerability in all patient subtypes.
Immunotherapies such as programmed cell death 1
blockade show promise of efcacy with excellent
tolerability.
e366
TABLE 2. Selected Molecular Pathways and Marketed Novel iNHL Therapies That Target Them
Pathway
Molecular
Target
Agent
Dosing
Disease(s)
FDA Indication(s)
Phase(s) of
Clinical
Trial Data
CD20
CD20
Ofatumumab
CLL, FL
II, III
Obinutuzumab
CLL
CLL (rst-line)
III
iNHL or FL (relapsed); FL
(rst-line consolidation)
II, III
PI3K
Idelalisib
150 mg PO BID
CLL, FL,
LPL, MZL
CLL/SLL, FL (relapsed)
II, III
mTOR complex 1
Everolimus
10 mg PO QD
CLL, MZL,
WM
II
Temsirolimus
25 mg IV every week
CLL, FL,
WM
II
Ibrutinib
420 mg PO QD
CLL/SLL
560 mg PO QD
FL
PI3K/Akt/mTOR
BTK
420 mg PO QD
WM
Immunomodulation Cereblon
Lenalidomide
FL, MZL,
SLL, WM
Proteasome
Bortezomib
I, II, III
Carlzomib
CLL/SLL, FL,
WM
I, II
Vorinostat
FL, MZL
I, II
75 mg/m2 SC on days
1-7 every 3 to 8
weeks
CLL
MDS
II
Decitabine
CLL
MDS
Nivolumab
3 mg/kg IV day 1 of
14-day cycles
FL
melanoma
I, II
Epigenetics
20S subunit
chymotryptic
site
Histone deacetylase
DNA
5-azacitidine
methyltransferase
Immunotherapy
PD-1
II
Abbreviations: IV, intravenous; CLL, chronic lymphocytic leukemia; FL, follicular lymphoma; PO, by mouth; SC, subcutaneous; Bq, becquerels; QD, once daily; BID, twice daily; MZL, marginal-zone
lymphoma; LPL, lymphoplasmacytic lymphoma; WM, Waldenstrm macroglobulinemia; SLL, small lymphocytic lymphoma; MCL, mantle cell lymphoma; MDS, myelodysplastic syndrome.
arm were older than age 75. Of those patients, 45% experienced serious adverse events, and 5% of patients experienced
adverse events that led to death; similar rates were seen in the
comparator arms.27 It is interesting to note that the CLL11
and COMPLEMENT-1 trials used different chlorambucil
regimens. A 65-kg person with body-surface area 1.8 m2
would have received a substantially higher dose of chlorambucil per cycle (126 vs. 65 mg) if enrolled in the
COMPLEMENT-1 trial, possibly accounting for the lower
response rate and PFS observed for the chlorambucil arm of
the CLL11 trial.
A cost-effectiveness study of obinutuzumab versus rituximab in combination with chlorambucil found that obinutuzumab increased QALYs by 0.56 compared with rituximab,
with an 89% probability that obinutuzumab was cost-
e367
TABLE 3. Selected Randomized Controlled Trial Data for Chemoimmunotherapy in Untreated CLL with Novel
Anti-CD20 Monoclonal Antibodies
ORR
(%)
PFS
(Months)
Grade 3
or Higher
Toxicity (%)
Infusion Reaction
(Grade 3 or
Higher, %)
Infection
(Grade 3 or
Higher, %)
Death
(%)
2
Study, Reference
Regimen
Median Age
(Years)
COMPLEMENT-1,
Hillmen et al 201325
69
82
22.4
50
10
15
Chlorambucil
70
69
13.1
43
n/a
14
CLL11, Goede
et al 201427
74
77
26.7
73
21
11
73
66
16.3
56
13
Chlorambucil
72
31
11.1
50
n/a
14
Regimen
Disease
Subtype(s)
Median
Age
(Years)
Overall
Response
Rate (%)
Progression-Free
Survival (Months)
Treatment-Related
Deaths (%)
Toxic
Discontinuation (%)
Reference
Everolimus
MZL
71
25
14
42
40
Everolimus
WM
63
50
21
67
10
41
Everolimus
CLL
74
18
5.1
68 hematologic, 41 nonhematologic
14
43
Temsirolimus
FL
59
54
12.7
18
42
CLL, WM
57
11
4.6
Abbreviations: MZL, marginal-zone lymphoma; WM, Waldenstrm macroglobulinemia; CLL, chronic lymphocytic leukemia; FL, follicular lymphoma.
quirements for serial CT scanning to assess response.47 The effcacy of ibrutinib (versus placebo) is also being studied in
combination with bendamustine and rituximab in refractory
and relapsed CLL; the phase III HELIOS trial is currently
ongoing.48
Ibrutinib has also shown effcacy in relapsed or refractory
WM. In a phase II study of 63 patients of median age 63 who
had received a median of two prior therapies, ibrutinib induced PRs in 57% of patients and minor responses in 24% of
patients. Treatment was discontinued by 6% of patients.
Common grade 2 or higher toxicities included thrombocytopenia (14%) and neutropenia (19%).49 On January 29, 2015,
the FDA approved ibrutinib for treatment of WM. In FL, a
phase II study of ibrutinib in 38 evaluable patients of median
age 64, demonstrated a more modest 30% ORR in the ibrutinib arm, but 65% of patients had tumor size reduction. Grade
3 to 4 events occurred in 30% of patients, and 5% of patients
discontinued treatment because of adverse events. There was
one death due to gastric hemorrhage.50
Ibrutinib has developed a track record as an effcacious and
well-tolerated agent in CLL, especially in older patients. The
potential for bleeding in patients treated with ibrutinib and
the exclusion of patients on warfarin from most clinical trials
suggest that ibrutinib should be avoided in anticoagulated
patients or those patients with a history of serious bleeding
(such as intracranial hemorrhage). Importantly, it also offers
effcacy for patients without regard to cytogenetic risk. Ibrutinib has shown effcacy in mantle cell and diffuse large cell
histologies as well. Later-generation BTK inhibitors are also
in development.51,52
IMMUNOMODULATORY AGENTS
The immunomodulatory drugs (IMiDs) are thalidomide
analogs that have the capacity to alter immune microenvironments, have antiangiogenic effects, promote T-cell costimulation, and activate NK cells.53 Lenalidomide has been
shown to stimulate T-cell and NK-cellmediated cytotoxicity in indolent lymphomas.54 Molecularly, IMiDs interfere
with the function of the ubiquitin ligase cereblon (CRBN),
which may be the key mediator for their microenvironmental
and immunomodulatory effects. CRBN has been shown to
interact with potassium and chloride channels, AMPasco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e369
PROTEASOME INHIBITORS
Proteasome inhibitors such as bortezomib and carflzomib
inhibit the chymotrypsin-like sites of the proteasomes
20S subunit. That inhibition disrupts protein homeostasis and
protein folding quality control, resulting in proteotoxic stress
and activation of the unfolded protein response, leading to cell
death; cancer cells experience higher toxicity as they are more
susceptible to proteotoxic stress.62 Bortezomib has been in use
for the treatment of multiple myeloma for more than a decade,
and its use in mantle cell NHL dates back several years, having
received approval for relapsed or refractory disease in 2006 and
approval for frst-line therapy in October 2014. Bortezomib is
still being studied for use in indolent lymphoma.
Three phase II studies have established effcacy of bortezomib in relapsed or refractory iNHL.63-65 Results varied,
with response rates ranging from 13% to 53%; the study with
the lowest ORR was notable for a 64% stable disease rate.64
None of the studies reported grade 3 neuropathy higher
than 10%. Notably, Di Bella et al enrolled a cohort of median age 70,64 with grade 3 or 4 adverse events including
thrombocytopenia (20%), fatigue (10%), neutropenia
(8.5%), neuropathy (6.8%), and diarrhea (6.8%).64 Thus,
bortezomib may be a reasonably well-tolerated option
with modest effcacy in an older population. de Vos et al compared biweekly (1.3 mg/m2 on days 1, 4, 8, and 11 of 21-day cycles) with weekly (1.6 mg/m2 on days 1, 8, 15, and 22 of 35-day
cycles) bortezomib in combination with rituximab and found
the weekly regimen to be better tolerated, with fewer grade 3 or
higher adverse events, including neuropathy (10% biweekly versus 5% weekly).65
These initial favorable results led to a randomized, phase
III trial of bortezomib plus rituximab versus rituximab
alone for patients with relapsed or refractory FL. In the
study, 1.6 mg/m2 of bortezomib was administered intravenously on days 1, 8, 15, and 22 of 35-day cycles. A total of
676 patients were enrolled with a median age of 57; 28% of
patients were older than age 65. The addition of bortezomib resulted in a modest increase of PFS from 11 to 13 months. Grade
3 or higher adverse events were higher in the combination arm,
46% compared with 21%. Grade 3 or higher infection (11% vs.
4%), neutropenia (11% vs. 4%), diarrhea (7% vs. 0%), and neuropathy (3% vs. 1%) favored rituximab alone. The combination
arm experienced 1% possible treatment-related deaths.66 Given
the higher toxicity of the combination regimen, the modest
2-month improvement in PFS was disappointing.
However, recent data in high-tumor burden iNHL suggest
that combination therapy with bortezomib and rituximab
may still be desirable. A front-line phase II trial with 42
patients of median age 61 with primarily FL received 1.6
mg/m2 of bortezomib intravenously on days 1, 8, 15, and
22 of 35-day cycles. The ORR was 70% with a CR rate of
TABLE 5. Early-Phase Data for Selected Miscellaneous Investigational (Nonmarketed) Agents for iNHL Under
Preliminary Testing
Agent
Molecular Target/Pathway
Disease(s)
Notable Outcomes
Reference(s)
ABT-199
BCL-2
FL, MZL
73% RR in FL
81
CAR T cells
CLL, FL
7780
HDAC
FL, CLL
71
Pidilizumab
PD-1
FL
82
Polatuzumab vedotin
FL
75
SAR3419
FL
74
SMIP: CD37
FL, SLL
83% ORR
76
Abbreviations: FL, follicular lymphoma; MZL, marginal-zone lymphoma; RR, response rate; CAR, chimeric antigen receptor; CLL, chronic lymphocytic leukemia; PR, partial response; HDAC, histone
deacetylase; ORR, overall response rate; ADC, antibody-drug conjugate; SD, stable disease; SMIP, monospecic protein therapeutic; SLL, small lymphocytic lymphoma.
ACKNOWLEDGMENT
This work was supported by research funding from NIH
P01CA044991, K24CA184039, and Fred Hutchinson Cancer
Research CenterUniversity of Washington Cancer Consortium Cancer Center Support Grant of the National Institutes
of Health (P30 CA015704); philanthropic gifts from Frank
and Betty Vandermeer.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: Maxwell M. Krem, BMS (I), Celgene (I). Honoraria: Ajay Gopal, Pzer,
Seattle Genetics, Janssen Oncology, Millennium Takeda, Gilead Sciences. Consulting or Advisory Role: Ajay Gopal, Pzer, Seattle Genetics, Janssen
Oncology, Millennium Takeda, Gilead Sciences. Speakers Bureau: Ajay Gopal, Seattle Genetics. Research Funding: Ajay Gopal, Merck, GSK, Bristol-Myers
Squibb, Gilead Sciences, Seattle Genetics, Teva, Piramal Life Science, Spectrum Pharmaceuticals, Pzer, Abraxis BioScience, Janssen Oncology, Millennium
Takeda. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other
Relationships: None.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e371
References
1. Coiffer B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab
compared with CHOP alone in elderly patients with diffuse large-B-cell
lymphoma. N Engl J Med. 2002;346:235-242.
2. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to
fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;
376:1164-1174.
3. Marcus R, Imrie K, Solal-Celigny P, et al. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in
patients with previously untreated advanced follicular lymphoma. J Clin
Oncol. 2008;26:4579-4586. Epub 2008 Jul 28.
4. Herold M, Haas A, Srock S, et al. Rituximab added to frst-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed
by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study. J Clin Oncol. 2007;25:1986-1992. Epub
2007 Apr 9.
5. Salles G, Mounier N, de Guibert S, et al. Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: results of the
GELA-GOELAMS FL2000 study. Blood. 2008;112:4824-4831.
6. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with
rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) signifcantly improves the outcome for patients with advanced-stage follicular lymphoma compared
with therapy with CHOP alone: results of a prospective randomized
study of the German Low-Grade Lymphoma Study Group. Blood. 2005;
106:3725-3732. Epub 2005 Aug 25.
7. Byrd JC, Jones JJ, Woyach JA, et al. Entering the era of targeted therapy
for chronic lymphocytic leukemia: impact on the practicing clinician.
J Clin Oncol. 2014;32:3039-3047.
8. Merli M, Ferrario A, Basilico C, et al. Novel agents in indolent lymphomas. Ther Adv Hematol. 2013;4:133-148.
9. Campo E, Swerdlow SH, Harris NL, et al. The 2008 WHO classifcation
of lymphoid neoplasms and beyond: evolving concepts and practical
applications. Blood. 2011;117:5019-5032.
10. Garca-Sanz R, Montoto S, Torrequebrada A, et al. Waldenstrom macroglobulinaemia: presenting features and outcome in a series with 217
cases. Br J Haematol. 2001;115:575-582.
11. Seng JE, Peterson BA. Indolent B-cell non-Hodgkins lymphomas. Oncology. 1997;11:1883-1894, 1987; discussion 1901-1902, 1.
12. Smith A, Howell D, Patmore R, et al. Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network. Br J Cancer. 2011;105:1684-1692.
13. Sharman JP, Mato A, Kay NE, et al. Demographics by age group (AG)
and line of therapy (LOT) in chronic lymphocytic leukemia (CLL) patients (Pts) treated in US practices from the Connect CLL registry. Paper
presented at: 56th Annual ASH Meeting and Exposition; December
2014; San Francisco, CA.
14. Wildes TM, Goede V, Hamlin P. Personalizing therapy for older adults
with lymphoid malignancies: options and obstacles. Am Soc Clin Oncol
Educ Book. 2014;e240-248.
15. Cragg MS, Walshe CA, Ivanov AO, et al. The biology of CD20 and its
potential as a target for mAb therapy. Curr Dir Autoimmun. 2005;8:140174.
16. Kuijpers TW, Bende RJ, Baars PA, et al. CD20 defciency in humans
results in impaired T cell-independent antibody responses. J Clin Invest.
2010;120:214-222.
17. Johnson P, Glennie M. The mechanisms of action of rituximab in the
elimination of tumor cells. Semin Oncol. 2003;30 (1 Suppl 2):3-8.
e372
18. Maloney DG. Concepts in radiotherapy and immunotherapy: antiCD20 mechanisms of action and targets. Semin Oncol. 2005;32:S19S26.
19. Desai AV, El-Bakkar H, Abdul-Hay M. Novel agents in the treatment of
chronic lymphocytic leukemia: a review about the future. Clin Lymphoma Myeloma Leuk. Epub 2014 Sep 30.
20. van Oers MH. CD20 antibodies: type II to tango? Blood. 2012;119:50615063.
21. Samaniego F, Berkova Z, Romaguera JE, et al. 90Y-ibritumomab
tiuxetan radiotherapy as frst-line therapy for early stage low-grade
B-cell lymphomas, including bulky disease. Br J Haematol. 2014;167:
207-213.
22. Ibatici A, Pica GM, Nati S, et al. Safety and effcacy of (90) yttriumibritumomab-tiuxetan for untreated follicular lymphoma patients. An
Italian cooperative study. Br J Haematol. 2014;164:710-716.
23. Morschhauser F, Radford J, Van Hoof A, et al. 90Yttrium-ibritumomab
tiuxetan consolidation of frst remission in advanced-stage follicular
non-Hodgkin lymphoma: updated results after a median follow-up of
7.3 years from the International, Randomized, Phase III First-Line Indolent trial. J Clin Oncol. 2013;31:1977-1983.
24. Wierda WG, Kipps TJ, Mayer J, et al. Ofatumumab as single-agent
CD20 immunotherapy in fludarabine-refractory chronic lymphocytic
leukemia. J Clin Oncol. 2010;28:1749-1755.
25. Hillmen P, Robak T, Janssens A, et al. Ofatumumab chlorambucil
versus chlorambucil alone in patients with untreated chronic lymphocytic leukemia (CLL): results of the phase III study Complement 1
(OMB110911). Paper presented at: 55th Annual ASH Meeting and Exposition; December 2013; New Orleans, LA.
26. Herring W, Pearson I, Purser M, et al. Cost-effectiveness of ofatumumab plus chlorambucil in frst line chronic lymphocytic leukemia in
Canada. Value Health. 2014;17:A633.
27. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in
patients with CLL and coexisting conditions. N Engl J Med. 2014;370:
1101-1110.
28. Veenstra DL, Reyes CM, Ramsey SD. Is obinutuzumab cost-effective in
the frst-line treatment of CLL? Paper presented at: 2014 ASCO Annual
Meeting; June 2014; Chicago, IL.
29. Gray N. NICE rejects funding for Roches leukemia drug. BioPharma
Dive, October 3, 2014. http://www.biopharmadive.com. Accessed December 15, 2014.
30. McKee S. NICE no for Roches Gazyvaro in CLL. PharmaTimes, October 3, 2014. http://www.pharmatimes.com. Accessed December 28,
2014.
31. Masangkay EG. NICE set to recommend Roches Gazyvaro for CLL.
Outsourced Pharma, December 9, 2014. http://www.outsourcedpharma.com. Accessed December 28, 2014.
32. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9:550-562.
33. Westin JR. Status of PI3K/Akt/mTOR pathway inhibitors in lymphoma.
Clin Lymph Myeloma Leuk. 2014;14:335-342. Epub 2014 Feb 7.
34. Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on
a theme. Oncogene. 2008;27:5497-5510.
35. Gopal AK, Kahl BS, de Vos S, et al. PI3K inhibition by idelalisib in
patients with relapsed indolent lymphoma. N Engl J Med. 2014;370:
1008-1018.
36. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in
relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370:9971007.
37. Flinn I, Oki Y, Patel M, et al. a Phase 1 evaluation of duvelisib (IPI-145),
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
a PI3K-, inhibitor, in patients with relapsed/refractory iNHL. Presented at: The 56th Annual Meeting of the American Society of Hematology; December 2014; San Francisco, California.
OBrien S, Patel M, Kahl BS, et al. Duvelisib (IPI-145), a PI3K-, inhibitor, is clinically active in patients with relapsed/refractory chronic
lymphocytic leukemia. Presented at: The 56th Annual Meeting of the
American Society of Hematology; December 2014; San Francisco,
California.
Hidalgo M, Rowinsky EK. The rapamycin-sensitive signal transduction
pathway as a target for cancer therapy. Oncogene. 2000;19:6680-6686.
Conconi A, Raderer M, Franceschetti S, et al. Clinical activity of everolimus in relapsed/refractory marginal zone B-cell lymphomas: results of a
phase II study of the International Extranodal Lymphoma Study Group.
Br J Haematol. 2014;166:69-76.
Ghobrial IM, Witzig TE, Gertz M, et al. Long-term results of the phase II
trial of the oral mTOR inhibitor everolimus (RAD001) in relapsed or
refractory Waldenstrom Macroglobulinemia. Am J Hematol. 2014;89:
237-242.
Smith SM, van Besien K, Karrison T, et al. Temsirolimus has activity in
non-mantle cell non-Hodgkins lymphoma subtypes: The University of
Chicago phase II consortium. J Clin Oncol. 2010;28:4740-4746.
Zent CS, LaPlant BR, Johnston PB, et al. The treatment of recurrent/
refractory chronic lymphocytic leukemia/small lymphocytic lymphoma
(CLL) with everolimus results in clinical responses and mobilization of
CLL cells into the circulation. Cancer. 2010;116:2201-2207.
Sharma A, Janocha AJ, Hill BT, et al. Targeting mTORC1-mediated
metabolic addiction overcomes fludarabine resistance in malignant B
cells. Mol Cancer Res. 2014;12:1205-1215.
Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in
relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32-42.
OBrien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for
elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet
Oncol. 2014;15:48-58.
Byrd JC, Brown JR, OBrien S, et al. Ibrutinib versus ofatumumab in
previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:
213-223.
Hallek M, Kay NE, Osterborg A, et al. The HELIOS trial protocol: a
Phase III study of ibrutinib in combination with bendamustine and
rituximab in relapsed/refractory chronic lymphocytic leukemia. Future
Oncol. 2015;11:51-59.
Treon SP, et al. A prospective multicenter study of the Brutons tyrosine
kinase inhibitor ibrutinib in patients with relapsed or refractory Waldenstroms macroglobulinemia. Paper presented at: 55th Annual ASH
Meeting and Exposition; December 2013; New Orleans, LA.
Bartlett NL, LaPlant BR, Qi J, et al. Ibrutinib monotherapy in relapsed/
refractory follicular lymphoma (FL): preliminary results of a Phase 2
Consortium (P2C) trial. Paper presented at: 56th Annual ASH Meeting
and Exposition; December 2014; San Francisco, CA.
Akinleye A, Chen Y, Mukhi N, et al. Ibrutinib and novel BTK inhibitors
in clinical development. J Hematol Oncol. 2013;6:59.
Akinleye A, Furqan M, Adekunle O. Ibrutinib and indolent B-cell lymphomas. Clin Lymphoma Myeloma Leuk. 2014;14:253-260.
Quach H, Ritchie D, Stewart AK, et al. Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma. Leukemia. 2010;24:
22-32.
Nowakowski GS, Ansell SM. Therapeutic targeting of microenvironment in follicular lymphoma. Hematology Am Soc Hematol Educ Program. 2014;2014;169-173.
Chang XB, Stewart AK. What is the functional role of the thalidomide
binding protein cereblon? Int J Biochem Mol Biol. 2011;2:287-294.
Zhu YX, Kortuem KM, Stewart AK. Molecular mechanism of action of
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma. Leuk Lymphoma. 2013;54:683-687.
Lu G, Middleton RE, Sun H, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science.
2014;343:305-309.
Witzig TE, Wiernik PH, Moore T, et al. Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent
non-Hodgkins Lymphoma. J Clin Oncol. 2009;27:5404-5409.
Fowler NH, Davis RE, Rawal S, et al. Safety and activity of lenalidomide
and rituximab in untreated indolent lymphoma: an open-label, phase 2
trial. Lancet Oncol. 2014;15:1311-1318.
Gertz MA. Waldenstrom macroglobulinemia: 2013 update on diagnosis, risk stratifcation, and management. Am J Hematol. 2013;88:703711.
Treon SP, Soumerai JD, Branagan AR, et al. Lenalidomide and rituximab in Waldenstroms macroglobulinemia. Clin Cancer Res. 2009;15:
355-360.
Deshaies RJ. Proteotoxic crisis, the ubiquitin-proteasome system, and
cancer therapy. BMC Biol. 2014;12:94.
OConnor OA, Wright J, Moskowitz C, et al. Phase II clinical experience
with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkins lymphoma and mantle cell lymphoma. J Clin Oncol.
2005;23:676-684.
Di Bella N, Taetle R, Kolibaba K, et al. Results of a phase 2 study of
bortezomib in patients with relapsed or refractory indolent lymphoma.
Blood. 2010;115:475-480.
de Vos S, Goy A, Dakhil SR, et al. Multicenter randomized phase II study
of weekly or twice-weekly bortezomib plus rituximab in patients with
relapsed or refractory follicular or marginal-zone B-cell lymphoma.
J Clin Oncol. 2009;27:5023-5030.
Coiffer B, Osmanov EA, Hong X, et al. Bortezomib plus rituximab
verus rituximab alone in patients with relapsed, rituximab-nave or
rituximab-sensitive, follicular lymphoma: a randomised phase 3 trial.
Lancet Oncol. 2011;12:773-784.
Evens AM, Smith MR, Lossos IS, et al. Frontline bortezomib and rituximab for the treatment of newly diagnosed high tumour burden indolent non-Hodgkin lymphoma: a multicentre phase II study. Br J
Haematol. 2014;166:514-520. Epub 2014 Apr 25.
Treon SP, Tripsas CK, Meid K, et al. Carflzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy-sparing approach for
treating Waldenstroms macroglobulinemia. Blood. 2014;124:503-510.
Alsina M, Trudel S, Furman RR, et al. A phase I single-agent study of
twice-weekly consecutive-day dosing of the proteasome inhibitor carflzomib in patients with relapsed or refractory multiple myeloma or lymphoma. Clin Cancer Res. 2012;18:4830-4840.
Oki Y, Buglio D, Fanale M, et al. Phase I study of panobinostat plus
everolimus in patients with relapsed or refractory lymphoma. Clin Cancer Res. 2013;19:6882-6890.
Kirschbaum M, Frankel P, Popplewell L, et al. Phase II study of vorinostat for treatment of relapsed or refractory indolent non-Hodgkins lymphoma and mantle cell lymphoma. J Clin Oncol. 2011;29:1198-1203.
Malik A, Shoukier M, Garcia-Manero G, et al. Azacitidine in
fludarabine-refractory chronic lymphocytic leukemia: a phase II study.
Clin Lymphoma Myeloma Leuk. 2013;13:292-295.
Blum KA, Liu Z, Lucas DM, et al. Phase I trial of low dose decitabine targeting
DNA hypermethylation in patients with chronic lymphocytic leukaemia and
non-Hodgkin lymphoma: dose-limiting myelosuppression without evidence
of DNA hypomethylation. Br J Haematol. 2010;150:189-195.
Coiffer B, Morschhauser F, Dupuis J, et al. Phase I study cohort evaluating an optimized administration schedule of SAR3419, an anti-CD19
DM4-loaded antibody drug conjugate (ADC), in patients (pts) with
CD19 positive relapsed/refractory b-cell non-Hodgkins lymphoma
e373
75.
76.
77.
78.
79.
e374
80.
81.
82.
83.
lthough high-dose chemotherapy may cure a small subset of patients with MDS, allogeneic HCT is currently
the only modality shown to be curative for 30% to 80% of
patients, depending on patient and disease characteristics,
the source of stem cells, and the transplant strategy applied.
The availability of human leukocyte antigen (HLA)-matched
unrelated donors, HLA-identical siblings, (HLA-nonidentical)
cord blood, and HLA-haploidentical relatives allows for the
identifcation of suitable stem cell donors for the vast majority of patients. However, despite considerable progress, problems remain in regards to the prevention of GVHD while
maintaining the desired graft-versus-leukemia (GVL) effectan essential factor in disease eradication and optimization of transplant conditioning regimens.
Older age has long been considered a contraindication for transplantation. Studies over the past decade have shown that more
than chronologic age, comorbid conditions that may be associated with advanced age (but could also be present in younger
patients) are the dominant factors that negatively affect transplant outcome. Those conditions have been cataloged in the
HCT-CI, and results clearly show inferior outcome with increasing HCT-CI scores, which include prior diagnosis of a solid
From the Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, WA.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: H. Joachim Deeg, MD, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. North, D1-100, Seattle, WA 98109; email: jdeeg@fredhutch.org.
2015 by American Society of Clinical Oncology.
e375
H. JOACHIM DEEG
DonorHost Immunity
Allogeneic HCT carries the risk of the adverse effects of the bidirectional reactivity of donor and host cells. Host-versus-donor
reactivity leading to rejection of the graft is an infrequent event.
Donor-versus-host reactivity leading to clinical manifestations,
however, occurs in about half of all patients.15,16 Although GVT
effects contribute to disease eradication, those effects are most
prominent in patients who also show clinical evidence of
GVHD. In fact, the most prominent GVL effects are observed in
patients who develop chronic GVHD, which occurs in 40% to
60% of patients transplanted with unmanipulated donor cells17;
the incidence tends to be lower in patients receiving T celldepleted grafts18 and, possibly, patients administered posttransplant cyclophosphamide,19 which appears to be capable of
inactivating host-reactive donor cells.
KEY POINTS
Hematopoietic cell transplantation provides curative
therapy for patients with myelodysplastic syndrome.
The clonal karyotype is the strongest predictor of posttransplant relapse.
The availability of human leukocyte antigen (HLA)-matched
related and unrelated donors, HLA-haploidentical relatives,
and umbilical cord blood helps identify donors for the vast
majority of patients.
Additional research is needed to prevent graft-versus-host
disease while maintaining the graft-versus-tumor effect.
As myelodysplastic syndrome is primarily a disease of
older age and quality of life is a top priority for most older
individuals, discussions regarding transplantation in older
patients must include not only the acute effects of
transplantation but also delayed effects.
e376
Blood Findings
Unicytopenia or bicytopenia*
5% blasts
Anemia
No blasts
RCMD
Cytopenia(s)
RAEB-1
5% blasts in marrow
No Auer rods
No Auer rods
1 109/L monocytes
Cytopenia(s)
5% blasts**
5%-9% blasts**
No Auer rods
No Auer rods
1 10 /L monocytes
9
RAEB-2
Cytopenia(s)
5%-19% blasts
10%-19% blasts
Auer rods
Auer rods
1 109/L monocytes
MDS-U
Cytopenias
1% blasts**
5% blasts
Anemia
5% blasts
Abbreviations: WHO, World Health Organization; RCUD, refractory cytopenia with unilineage dysplasia; RA, refractory anemia; RN, refractory neutropenia; RT, refractory thrombocytopenia; RARS,
refractory anemia with ring sideroblasts; RCMD, refractory cytopenia with multilineage dysplasia; RAEB, refractory anemia with excess blasts; MDS-U, Myelodysplastic syndrome-unclassied.
*Bicytopenia may occasionally be observed. Cases with pancytopenia should be classied as MDS-U.
**If the marrow myeloblasts percentage is 5% but there are 2% to 4% myeloblasts in the blood, the diagnostic classication is RAEB-1; cases of RCUD and RCMD with 1% myeloblasts in the
blood should be classied as MDS-U.
Cases with Auer rods and 5% myeloblasts in the blood and less than 10% in the marrow should be classied as RAEB-2. Although the nding of 5% to 19% blasts in the blood is, in itself,
diagnostic of RAEB-2, cases of RAEB-2 may have 5% blasts in the blood if they have Auer rods or 10% to 19% blasts in the marrow or both. Similarly, cases of RAEB-2 may have 10%
blasts in the marrow but may be diagnosed by the other two ndings, Auer rod, and/or 5% to 19% blasts in the blood.
Cytogenetics
Very Good
0.5
1
Good
Intermediate
Poor
Very Poor
2 5
510
10
Hemoglobin
10
Platelets
100
50 100
Neutrophils
0.8
0.8
8 10
1.5
50
e377
H. JOACHIM DEEG
OUTLOOK
Clearly, more effective strategies are needed for the prevention of GVHD and relapse. Various strategies of postHCT therapy, for example, with hypomethylating agents
or cellular therapy with natural killer cells or genetically
modifed T cells (directed, for example, at Wilms tumor 1),
are currently being explored in efforts to prevent relapse.39
The use of post-HCT administration of cyclophosphamide, in the hands of several investigators, has been effective in preventing GVHD after HLA-haploidentical
transplants and is also being tested in patients receiving
HLA-matched transplants where acute or chronic GVHD
(or both) occur about in half of all patients and, particularly with unrelated HCT, involvement of the intestinal
tract proves life threatening.23
The use of HCT in growing numbers of older patients with
MDS, even in their 70s, poses special challenges, particularly
with the intensity of conditioning. Currently those patients
are highly selected, and results cannot be extrapolated to that
age segment in general. Further, frst-line therapy with steroids, although effective in a portion of patients, is often
poorly tolerated in older individuals.40 Metabolic abnormalities, infections, and long-term effects on muscles and skeleton can severely affect quality of life. Thus, not only
comorbidities before HCT but also complications developing after HCT must be prioritized when discussing HCT with
older patients, for whom quality of life (rather than quantity
of life) is often a top priority.
Clearly, the rapidly expanding understanding of the effect
of various mutations in clonal cells will affect disease risk
classifcation and may also lead to novel antirelapse strategies
aimed at molecular targets.41,42
ACKNOWLEDGMENT
I thank Helen Crawford and Bonnie Larson for assistance
with manuscript development.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: H. Joachim Deeg, Medac. Consulting or Advisory
Role: None. Speakers Bureau: None. Research Funding: H. Joachim Deeg, Celgene (Inst). Patents, Royalties, or Other Intellectual Property: None.
Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World
Health Organization (WHO) classifcation of myeloid neoplasms
and acute leukemia: rationale and important changes. Blood. 2009;
114:937-951.
e378
2. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classifcation of the myelodysplastic syndromes. Br J Haematol. 1982;51:
189-199.
3. Scott BL, Storer BE, Greene JE, et al. Marrow fbrosis as a risk factor
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22. Scaradavou A, Brunstein CG, Eapen M, et al. Double unit grafts successfully extend the application of umbilical cord blood transplantation in
adults with acute leukemia. Blood. 2013;121:752-758.
23. Luznik L, ODonnell PV, Fuchs EJ. Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow
transplantation. Semin Oncol. 2012;39:683-693.
24. Cutler CS, Lee SJ, Greenberg P, et al. A decision analysis of allogeneic
bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood. 2004;104:579-585.
25. Koreth J, Pidala J, Perez WS, et al. A decision analysis of reducedintensity conditioning allogeneic hematopoietic stem cell transplantation for older patients with de-novo myelodysplastic syndrome (MDS):
early transplantation offers survival beneft in higher-risk MDS. Blood.
2011;118 (Abstr 115).
26. Kroger N. Allogeneic stem cell transplantation for elderly patients with
myelodysplastic syndrome (Review). Blood. 2012;119:5632-5639.
27. Deeg HJ, Scott BL, Fang M, et al. Five-group cytogenetic risk classifcation, monosomal karyotype, and outcome after hematopoietic cell
transplantation for MDS or acute leukemia evolving from MDS. Blood.
2012;120:1398-1408.
28. Deeg HJ, de Lima M. Hematopoietic stem cell transplantation for older
patients with myelodysplastic syndromes. J Nat Compr Canc Netw.
2013;11:1227-1233.
29. Della Porta MG, Alessandrino EP, Bacigalupo A, et al. Predictive factors for
the outcome of allogeneic transplantation in patients with MDS stratifed
according to the revised IPSS-R. Blood. 2014;123:2333-2342.
30. Prebet T, Gore SD, Esterni B, et al. Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol. 2011;29:
3322-3327.
31. Eissa H, Gooley TA, Sorror ML, et al. Allogeneic hematopoietic cell
transplantation for chronic myelomonocytic leukemia: relapse-free survival is determined by karyotype and comorbidities. Biol Blood Marrow
Transplant. 2011;17:908-915.
32. Sorror ML, Martin PJ, Storb R, et al. Pretransplant comorbidities predict
severity of acute graft-versus-host disease and subsequent mortality.
Blood. 2014;124:287-295.
33. Koreth J, Pidala J, Perez WS, et al. Role of reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation in older patients
with de novo myelodysplastic syndromes: an international collaborative
decision analysis. J Clin Oncol. 2013;31:2662-2670.
34. Greenberg P, Cox C, LeBeau MM, et al. International scoring system for
evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:
2079-2088.
35. Nemecek ER, Guthrie KA, Sorror ML, et al. Conditioning with treosulfan and fludarabine followed by allogeneic hematopoietic cell transplantation for high-risk hematologic malignancies. Biol Blood Marrow
Transplant. 2011;17:341-350.
36. Gyurkocza B, Gutman J, Nemecek ER, et al. Treosulfan, fludarabine, and
2-Gy total body irradiation followed by allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome and acute myeloid
leukemia. Biol Blood Marrow Transplant. 2014;20:549-555.
37. Bejar R, Stevenson KE, Caughey B, et al. Somatic mutations predict poor
outcome in patients with myelodysplastic syndrome after hematopoietic stem-cell transplantation. J Clin Oncol. 2014;32:2691-2698.
38. Malcovati L, Papaemmanuil E, Bowen DT, et al. Clinical signifcance of
SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/
myeloproliferative neoplasms. Blood. 2011;118:6239-6246.
39. de Lima M, Giralt S, Thall PF, et al. Maintenance therapy with lowdose azacitidine after allogeneic hematopoietic stem cell transplan-
e379
H. JOACHIM DEEG
e380
LEUKEMIA, MYELODYSPLASIA,
AND TRANSPLANTATION
Progress in Myeloproliferative
Neoplasms: Biology to Bedside
CHAIR
Alison R. Moliterno, MD
The Johns Hopkins Hospital
Baltimore, MD
SPEAKERS
Jean-Jacques Kiladjian, MD, PhD
Hopital Saint-Louis
Paris, France
Michael W. Deininger, MD, PhD
University of Utah Huntsman Cancer Institute
Salt Lake City, UT
From the Huntsman Cancer Institute, Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Michael W. Deininger, MD, PhD, Huntsman Cancer Institute, Room 4280, 2000 Circle of Hope, Salt Lake City, UT 84112-5550; email: michael.deininger@hci.utah.edu.
2015 by American Society of Clinical Oncology.
e381
MICHAEL W. DEININGER
Accelerated Phase
WHO Criteria
IBMTR
Hb 8 g/dL
CCA/Ph
CCA/Ph
Extramedullary disease
CCA/Ph
Blood or marrow blasts 10%
Blood or marrow blasts plus promyelocytes
20%
Blood basophils and eosinophils 20%
Blastic Phase
were used (in some cases with minor adaptations) in the major practice-defning prospective clinical trials and therefore
are recommended.4-6 In the future, molecular classifcations
may replace morphology and blood counts. An uncommon
clinical presentation is chloroma, which establishes a diagnosis of BP-CML, irrespective of marrow and blood. Biopsy is
required and a diagnosis of chloroma requires the presence of
blasts, whereas mature granulocytic infltrates in extramedullary sites other than the spleen or liver may be reactive to
inflammation or infection and should not be confused with
BP-CML.
Calculation
Risk Groups
Sokal
Low: 0.8
KEY POINTS
Chronic myeloid leukemia (CML) progresses in phases that
represent the most fundamental risk stratication.
Multiple different somatic mutations have been associated
with transformation from chronic to advanced CML.
Disease progression while receiving rst-line tyrosine
kinase inhibitor (TKI) therapy and accelerated or blastic
phase CML are associated with reduced overall survival.
BCR-ABL1 kinase domain mutations are the best
characterized mechanism of TKI resistance, but fail to
explain many cases of clinical resistance.
Selection of salvage therapy depends on prior TKI
exposure, comorbidities, and BCR-ABL1 mutation status.
Intermediate: 0.81.2
High: 1.2
Hasford
Intermediate: 7811,480
High: 1480
EUTOS
Spleen 4 basophils 7
Low risk: 87
High risk: 87
e382
Low: 780
Clinical TKI resistance is grouped into primary and acquired resistance. At a mechanistic level, resistance can be
classifed as BCR-ABL1dependent or BCR-ABL1independent. In BCR-ABL1dependent resistance, there is
reactivation of BCR-ABL1 kinase, which implies that responses may be recaptured if BCR-ABL1 inhibition is restored. In BCR-ABL1independent resistance, alternative
pathways substitute for BCR-ABL1 kinase activity.20
Mutation/Mutated Gene
% Prevalence
Double Ph
38%
Isochromosome 17q
30% (myeloid)
Trisomy 8
53% (lymphoid)
Trisomy 19
23% (myeloid)
p53
2030% (myeloid)
p16
50% (lymphoid)
NUP98-HOXA9
NR
AML1-EVI1
NR
GATA-2
18% (lymphoid)
RUNX1
38% (myeloid)
CDKN2A/B
50% (lymphoid)
IKZF1
55% (lymphoid)
ASXL1
20.5% (myeloid)
TET2
7.7% (myeloid)
WT1
15.4% (myeloid)
NRAS/KRAS
5.1/5.1% (myeloid)
e383
MICHAEL W. DEININGER
the ATP-binding loop, preventing the rearrangements required for optimal drug binding. Examples include
Q252H, Y253(H/F), and E255(K/V). Last, mutations in
the activation loop such as H396P stabilize an open conformation, to which imatinib cannot bind.23 Although
imatinib is vulnerable to a broad range of mutations, the
spectrum is much more limited for nilotinib and dasatinib, reflecting their greater potency and, in the case of
dasatinib, less stringent binding requirements.24 Clinical
resistance mutations are precisely predicted by in vitro assays, which enable the development of preemptive strategies to overcome this type of resistance.25-27 Mutation
testing is recommended upon disease progression and if
milestones are not met. Most laboratories use Sanger sequencing, which has a sensitivity of approximately 20%
mutant allele. This level of sensitivity seems to provide the
right balance between sensitivity and specifcity. More
sensitive assays such as next-generation sequencing are
under development and may replace Sanger sequencing in
the future. Biochemical and cell proliferation data have
been used to rank kinase domain mutations according to
the degree of TKI resistance they confer.28 Although these
data are based on in vitro studies, they tend to correlate
with clinical responses.29,30 However, correlations are not
FIGURE 1. Activity of Imatinib, Bosutinib, Dasatinib, Nilotinib, and Ponatinib against Mutated Forms of BCR-ABL1
Cell proliferation IC50 values of the indicated TKIs are shown against BCR-ABL1 single mutants. The color gradient demonstrates IC50 sensitivity for each TKI relative to its activity against cells
expressing native BCR-ABL1. Note that clinical activity is also dependent on additional factors, such as drug concentrations achieved in the plasma of patients.
Adapted with permission from Redaelli et al.64
e384
The European Leukemia Net and the National Comprehensive Cancer Network have defned therapeutic milestones for
patients receiving TKI therapy (Table 4).6,44 Although both
systems are generally aligned, the European Leukemia Net
uses the category of warning to denote a situation that does
not meet the criteria for failure, but gives rise to concern that
a poor outcome is possible. Failure to achieve therapeutic
milestones is consistent with primary resistance. Loss of response from a given level suggests acquired TKI resistance.
Both should trigger a thorough evaluation. TKI resistance is a
clinically important diagnosis that is associated with inferior
outcomes compared with those of the average CML population. The frst call of order is to assess medication adherence
through a thorough history. Drug level testing may be useful
in isolated cases, but is not widely available. Additionally, patients have been found to make up for skipped doses during
the last few days before the offce visit.45 Second, drug interactions must be considered, especially in patients on multiple
comedications, including over-the-counter remedies such as
St. Johns Wort, which can drastically lower imatinib plasma
concentrations.46 Predicting drug interactions in patients on
polypharmacotherapy is challenging, particularly in cases
with impaired renal or hepatic function and consultation of a
clinical pharmacologist is advisable. A frequent challenge is a
rise in the level of BCR-ABL1 mRNA as assessed by quantitative polymerase chain reaction. Interpretation of changes
in BCR-ABL1 mRNA must take into account the performance of the diagnostic laboratory. In most cases, only rises
greater than fve-fold or greater than 10-fold are clinically relevant, particularly in patients with a low level of residual disease.47 In the absence of other signs of relapse, repeating the
BCR-ABL1 quantitative polymerase chain reaction in 4 to 6
weeks is recommended, before additional diagnostic studies
are initiated. If nonadherence or drug interactions are unlikely, a complete resistance work-up is indicated that includes a physical exam, complete blood count, bone marrow
aspirate and biopsy, bone marrow metaphase karyotyping,
and BCR-ABL1 mutation analysis. TKI resistance defnes a
high-risk situation and should be approached as a diagnosis
with important clinical implications. Key pieces of information derived from this workup are disease phase, BCR-ABL1
mutation status, and karyotype, including CCA/Ph.
TABLE 4. Therapeutic Milestones: National Cancer Center Network versus European Leukemia Net
Month
Optimal
Warning
Failure
ELN
No CHR or Ph 95%
NCCN
NA
ELN
Ph 0% and/or BCR-ABL1 1%
NCCN
NA
12
ELN
BCR-ABL1 0.1%
BCR-ABL1 0.11%
Ph 0% BCR-ABL1 1%
NCCN
Ph 0%
NA
Ph 0%
Abbreviations: ELN, European Leukemia Net; Ph, Ph bone marrow metaphases; NCCN, National Cancer Center Network; NA, not applicable; CHR, complete hematologic remission.
e385
MICHAEL W. DEININGER
Progression to Accelerated-Phase/Blastic-Phase
Chronic Myeloid Leukemia
Patients who progress to AP/BP-CML are treated with the appropriate TKI, taking into account prior TKI exposure history
and BCR-ABL1 mutation status. Given the limited therapeutic
options, more TKI toxicity is acceptable. Decisions whether or
not to combine TKI salvage with chemotherapy must be individualized based on performance status and the availability of
allogeneic stem cell transplant as a potentially curative salvage
strategy.19 Given the absence of controlled studies in this fortunately rare patient population, the value of adding chemotherapy is not completely clear, particularly in patients with myeloid
transformation. All eligible patients should be offered an allogeneic stem cell transplant, and avoiding unnecessary toxicity in
potential transplant patients is an important consideration.
PERSPECTIVE
Despite the unparalleled success of TKI in CML, progression
during frst-line TKI therapy, and transformation to
accelerated- or blastic-phase continue to carry a poor prognosis. Although BCR-ABL1 mutations are a well-established
mechanism of TKI resistance, many cases of clinical resistance remained mechanistically unexplained and are thought
to be a result of activation of alternative signaling pathways. In
these patients, salvage therapies are currently nonspecifc. The
hope is that diverse upstream pathways may activate a limited
set of downstream effector molecules, thus providing an opportunity for rationally targeted therapies that are applicable to a
wider population of patients. Early identifcation of patients
with TKI failure or at risk of transformation is critical, so that
therapy can be adjusted in a timely fashion to maximize the
chances of successful salvage therapy. Despite the introduction
of new TKIs such as ponatinib, the prediction is that allogeneic
stem cell transplant will retain its position as the salvage therapy
of choice for patients who progress to AP/BC-CML.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Michael W. Deininger, ARIAD, BMS, Incyte,
Novartis, Pzer. Consulting or Advisory Role: Michael W. Deininger, ARIAD, BMS, Incyte, Novartis, Pzer. Speakers Bureau: None. Research Funding:
Michael W. Deininger, BMS (Inst), Celgene (Inst), Incyte (Inst), Novartis (Inst). Patents, Royalties, or Other Intellectual Property: None. Expert
Testimony: Michael W. Deininger, BMS. Travel, Accommodations, Expenses: Michael W. Deininger, ARIAD, BMS, Novartis, Pzer. Other Relationships:
None.
References
1. Tanaka K, Takechi M, Hong J, et al. 9;22 translocation and bcr rearrangements in chronic myelocytic leukemia patients among atomic
bomb survivors. J Radiat Res. 1989;30:352-358.
2. Schmidt M, Rinke J, Schafer V, et al. Molecular-defned clonal evolution
in patients with chronic myeloid leukemia independent of the BCRABL status. Leukemia. 2014;28:2292-2299.
3. Deininger MW, Goldman JM, Melo JV. The molecular biology of
chronic myeloid leukemia. Blood. 2000;96:3343-3356.
4. Kantarjian HM, Deisseroth A, Kurzrock R, et al. Chronic myelogenous
leukemia: a concise update. Blood. 1993;82:691-703.
5. Talpaz M, Silver RT, Druker BJ, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase
chronic myeloid leukemia: results of a phase 2 study. Blood. 2002;99:
1928-1937.
6. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet
recommendations for the management of chronic myeloid leukemia:
2013. Blood. 2013;122:872-884.
7. Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in
good-risk chronic granulocytic leukemia. Blood. 1984;63:789-799.
8. Hasford J, Pfrrmann M, Hehlmann R, et al. A new prognostic score for
survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic
Factors Project Group. J Natl Cancer Inst. 1998;90:850-858.
9. Hasford J, Baccarani M, Hoffmann V, et al. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood. 2011;
118:686-692.
10. Jabbour E, Cortes J, Nazha A, et al. EUTOS score is not predictive for
survival and outcome in patients with early chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors: a single institution experience. Blood. 2012;119:4524-4526.
11. McWeeney SK, Pemberton LC, Loriaux MM, et al. A gene expression
signature of CD34 cells to predict major cytogenetic response in
chronic-phase chronic myeloid leukemia patients treated with imatinib.
Blood. 2010;115:315-325.
12. Yong AS, Szydlo RM, Goldman JM, et al. Molecular profling of CD34
cells identifes low expression of CD7, along with high expression of
proteinase 3 or elastase, as predictors of longer survival in patients with
CML. Blood. 2006;107:205-212.
13. Radich JP, Dai H, Mao M, et al. Gene expression changes associated with
progression and response in chronic myeloid leukemia. Proc Natl Acad
Sci U S A. 2006;103:2794-2799.
14. Fabarius A, Leitner A, Hochhaus A, et al. Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood. 2011;
118:6760-6768.
e387
MICHAEL W. DEININGER
30. Hughes T, Saglio G, Branford S, et al. Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol. 2009;27:4204-4210.
31. Apperley JF. Part I: mechanisms of resistance to imatinib in chronic
myeloid leukaemia. Lancet Oncol. 2007;8:1018-1029.
32. OHare T, Eide CA, Deininger MW. Bcr-Abl kinase domain mutations,
drug resistance, and the road to a cure for chronic myeloid leukemia.
Blood. 2007;110:2242-2249.
33. OHare T, Zabriskie MS, Eiring AM, et al. Pushing the limits of targeted
therapy in chronic myeloid leukaemia. Nat Rev Cancer. 2012;12:513526.
34. Donato NJ, Wu JY, Stapley J, et al. BCR-ABL independence and LYN
kinase overexpression in chronic myelogenous leukemia cells selected
for resistance to STI571. Blood. 2003;101:690-698.
35. Warsch W, Kollmann K, Eckelhart E, et al. High STAT5 levels mediate
imatinib resistance and indicate disease progression in chronic myeloid
leukemia. Blood. 2011;117:3409-3420.
36. Burchert A, Wang Y, Cai D, et al. Compensatory PI3-kinase/Akt/mTor
activation regulates imatinib resistance development. Leukemia. 2005;
19:1774-1782.
37. Aceves-Luquero CI, Agarwal A, Callejas-Valera JL, et al. ERK2, but not
ERK1, mediates acquired and de novo resistance to imatinib mesylate:
implication for CML therapy. PLoS One. 2009;4:e6124.
38. Gioia R, Leroy C, Drullion C, et al. Quantitative phosphoproteomics
revealed interplay between Syk and Lyn in the resistance to nilotinib in
chronic myeloid leukemia cells. Blood. 2011;118:2211-2221.
39. Wang Y, Cai D, Brendel C, et al. Adaptive secretion of granulocytemacrophage colony-stimulating factor (GM-CSF) mediates imatinib
and nilotinib resistance in BCR/ABL progenitors via JAK-2/STAT-5
pathway activation. Blood. 2007;109:2147-2155.
40. Weisberg E, Wright RD, McMillin DW, et al. Stromal-mediated protection of tyrosine kinase inhibitor-treated BCR-ABL-expressing leukemia
cells. Mol Cancer Ther. 2008;7:1121-1129.
41. Eiring AM, Page BD, Kraft IL, et al. Combined STAT3 and BCR-ABL1
inhibition induces synthetic lethality in therapy-resistant chronic myeloid leukemia. Leukemia. Epub 2014 Aug 19.
42. Khorashad JS, Eiring AM, Mason CC, et al. shRNA library screening
identifes nucleocytoplasmic transport as a mediator of BCR-ABL1
kinase-independent resistance. Blood. Epub 2015 Jan 8.
43. Walker CJ, Oaks JJ, Santhanam R, et al. Preclinical and clinical effcacy
of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in
Ph leukemias. Blood. 2013;122:3034-3044.
44. OBrien S, Radich JP, Abboud CN, et al. Chronic myelogenous leukemia, version 1.2015. J Natl Compr Canc Netw. 2014;12:1590-1610.
45. Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical factor for
achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol. 2010;28:2381-2388.
46. Frye RF, Fitzgerald SM, Lagattuta TF, et al. Effect of St Johns wort on imatinib mesylate pharmacokinetics. Clin Pharmacol Ther. 2004;76:323-329.
47. Hughes T, Deininger M, Hochhaus A, et al. Monitoring CML patients
responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting
BCR-ABL transcripts and kinase domain mutations and for expressing
results. Blood. 2006;108:28-37.
48. Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic
e388
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
From the Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD; the Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Alison R. Moliterno, MD, Department of Medicine, The Johns Hopkins Hospital, 720 Rutland Ave., Ross Research Building Room 1025, Baltimore, MD 21205; email:
amoliter@jhmi.edu.
2015 by American Society of Clinical Oncology.
139
Combined Frequency
Polycythemia Vera
JAK2V617F, JAK2
exon 12
99%
Essential Thrombocythemia
Approximately 80%
Primary Myelobrosis
Approximately 80%
Chronic Myelogenous
Leukemia
BCR-ABL1
100%
Chronic Neutrophilic
Leukemia
CSFR3
Approximately 80%
Mastocytosis
KIT
Approximately 80%
KEY POINTS
Genetic discovery has transformed the diagnosis of the
chronic myeloproliferative neoplasms (MPNs).
Risk stratication in MPNs has been redened by genetic
discovery.
Global risk assessment for MPNs includes disease-specic
and patient-specic risk factors.
Genetic discovery has informed both thrombosis and
disease transformation risk stratication.
Inclusion of constitutional symptoms into prognostic
scoring systems signies the continued importance of
patient-reported outcomes in risk stratication.
140
ists in the natural history of JAK2-, CALR-, MPL-, and KITmutationpositive disease. For instance, JAK2V617F in
many individuals is latent and may be asymptomatic or aphenotypic for undisclosed periods, as evidenced by its detection
in large unselected population surveys.20 Moreover, cells that
have acquired JAK2V617F often acquire an additional copy
of JAK2V617F via mitotic recombination events, such that
JAK2V617F mutation dosage is a variable to be accounted for
both at diagnosis and during disease monitoring. In these
diseases, particularly in JAK2V617F-positive MPN, factors
such as age at diagnosis, sex, treatment exposure, host genetic
background, gene dosage, and other acquired genetic lesions,
to a large part, contribute to risk for disease acquisition,21,22
disease evolution or progression, and thrombosis.23,24 Thus,
risk stratifcation in MPNs must take into account disease
class, specifc genetic lesions, lesion burden, and host factors
and requires large observational prospective cohorts to establish risk. Estimating risk throughout decades of disease is
challenging and often confounded by the individual, and by
the lack of knowledge of somatic mutations and their roles. In
diseases where survival is measured in decades, risk assessment includes not only long-term risks of disease evolution
or transformation, but also ongoing symptom burden risk
assessment.
Comments
MPN class
PV MF ET
Validated in PV
JAK2V617F
ET to PV
Disease duration
JAK2V617F, JAK2V617F
allele %
ET to MF
PV to PPVMF
Disease duration
MPN to AML
Polycythemia Vera
Historically, risk stratifcation in PV incorporated age of the patient (older than 65) and prior thrombotic history.34 More recently, Tefferi et al reviewed outcomes among a large group of
patients (1,545 patients) with WHO-specifed PV.24 In this multivariate analysis, the authors found that leukocytosis, advanced
age, abnormal cytogenetics, and history of a venous thrombotic
event portend a more adverse outcome in terms of overall survival. This model system also further analyzed factors important
for predicting transformation to AML, and found that three out
of the four factors for survival were still signifcant for this outcome (all but venous thrombotic event; Tables 2 and 3).
About 20% of patients with PV may experience a thrombotic event during the course of their disease. Thrombotic
events occur on the arterial and venous circulation, microvascular, or thromboembolic, such as transient ischemic attacks, myocardial infarction, deep venous thrombosis, or
pulmonary embolism. Venous thrombosis in unusual circulations may occur in the patient with PV, particularly in the
portal and hepatic (splanchnic), splenic vein, and cerebral venous sinuses. An important element in risk stratifcation of
the patient with PV is a comprehensive assessment of a patients underlying risk factors for thromboembolism, including an understanding of the patients cardiovascular risk
factors, including smoking use and history.35 The importance of hematocrit control, in addition to controlling traditional cardiovascular risks, was established by the CYTO-PV
Collaborative Group, whereby an aggressively pursued
threshold of hematocrit 45 or greater resulted in a three- to
four-times risk reduction in terms of cardiovascular morbidity and mortality, as compared with the group with less strict
hematocrit regulation.36
Thrombotic risk in MPNs has also led to risk stratifcation
in patients with occurrence of idiopathic Budd-Chiari synasco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
141
Myelobrosis
It has long been noted that patients with MF experience
markedly different outcomes.48,49 To better understand and
quantitate this phenomenon, a methodical approach to analyzing risk factors associated with higher-risk disease has resulted in the birth of several clinically useful scoring systems
142
that incorporate clinical and laboratory fndings in the patient with MF. Cervantes et al examined 1,054 patients with
PMF.50 In this study, the multivariate analysis demonstrated
that fve risk factors were signifcantly associated with determination of prognostic score when assessed at time of MF
diagnosis: (1) age older than 65 years, (2) leukocytosis (WBC
greater than 25 K/uL), (3) circulating blasts of 1% or greater,
(4) presence of constitutional symptoms, and (5) anemia of
hemoglobin less than 10 g/dL. This divided the patients into
groups of low-risk, intermediate-1, intermediate-2, and
high-risk, with median overall survivals of 135 months, 95
months, 48 months, and 27 months, respectively. This represents the most widely used scoring system for patients with
MF, and, although cytogenetic abnormalities and JAK2V617
mutation were considered, notably, neither reached independent signifcance to warrant inclusion in the fnal scoring
system in this original International Prognostic Scoring System (IPSS) model. It is of particular importance that the presence of constitutional symptoms were included and indeed
validated in the IPSS model for MF, as this highlights an important part of risk stratifcation for patients with MPNs: the
burden of symptoms experienced in these diseases, even in
those patients with lower risk scores, affect not only the quality of life, but also has effects on overall survival outcomes.51
Several clinical instruments have been developed and validated specifcally in patients with MPN, including for patients with MF, to help quantitate and follow these symptom
profles over time.52,53 These and other widely available instruments will likely continue to be an important part of recording and understanding MPNs risks, comorbidities, and
symptoms over time, and be a vital method to reliably follow
changes/improvements with disease-modifying agents starting
to be used in the clinic.54
The IPSS scoring method of risk stratifcation for patients
with MF has had a direct effect on therapeutic investigation
and decision making as it helped to select an appropriate patient population for the largest randomized clinical trials
testing a novel therapy in patients with MF.55 On the basis of
the IPSS, those patients with intermediate-2 or high-risk MF
were included on the original phase III clinical trials testing
ruxolitinib, a JAK1/2 inhibitor, against either best available
therapy or placebo (COMFORT 1 and 2), thus, identifying
the highest-risk/poorest-prognosis patients that might beneft from therapy.1,6 These trials ultimately led to U.S. Food
and Drug Administration approval of ruxolitinib, the frst
and only therapy specifcally approved for patients with MF
on the basis of risk stratifcation, taking into account patient
symptom burden and constitutional symptoms into the approval process.56
Building on this clinical risk factor model, several other
scoring systems for MF have been developed with the aim of
providing prognostication for overall survival at any time
during disease course, not just at diagnosis, (Dynamic International Prognostic Scoring System [DIPSS])57 and further
refnement with additional risk factors added (DIPSS-plus),
including thrombocytopenia, transfusion dependency, and
cytogenetic abnormalities.58 The identifcation and success-
CONCLUSION
In the 10 years since the discovery of the JAK2V617 mutation
in MPNs, the feld has experienced an exponential increase in
terms of clinical and basic science research. With improved
methods of stratifying risk for patients at the clinical, biologic, cytogenetic, and, now, molecular level, we are entering
a new era of recognizing MPNs total burden of disease, and
we are beginning to consider assigning targeted treatments
based on these assessments. The personalization of MPN diagnosis, prognosis, and treatment will likely include the congruence of clinical factors, formal MPN symptom burden
assessment, and cytogenetic and molecular analyses.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Alison R. Moliterno, Incyte. Naveen Pemmaraju,
Incyte. Consulting or Advisory Role: Alison R. Moliterno, Incyte. Naveen Pemmaraju, Incyte. Speakers Bureau: None. Research Funding: Naveen
Pemmaraju, Novartis. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: None.
Other Relationships: None.
References
1. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofbrosis. N Engl J Med.
2012;366:787-798.
2. Harrison CN, Mesa RA, Kiladjian JJ, et al. Health-related quality of life
and symptoms in patients with myelofbrosis treated with ruxolitinib
versus best available therapy. Br J Haematol. 2013;162:229-239.
3. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus
standard therapy for the treatment of polycythemia vera. N Engl J Med.
2015;372:426-435.
4. Kiladjian JJ, Mesa RA, Hoffman R. The renaissance of interferon
therapy for the treatment of myeloid malignancies. Blood. 2011;117:
4706-4715.
5. Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a
induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112:3065-3072.
6. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled
trial of ruxolitinib for myelofbrosis. N Engl J Med. 2012;366:799-807.
143
144
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52. Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative neoplasm
(MPN) symptom assessment form total symptom score: prospective international assessment of an abbreviated symptom burden scoring system among patients with MPNs. J Clin Oncol. 2012;30:4098-4103.
53. Scherber R, Dueck AC, Johansson P, et al. The myeloproliferative neoplasm
symptom assessment form (MPN-SAF): international prospective validation
and reliability trial in 402 patients. Blood. 2011;118:401-408.
54. Newberry KJ, Naqvi K, Nguyen KT, et al. Comorbidities predict worse
prognosis in patients with primary myelofbrosis. Cancer. 2014;120:
2996-3002.
55. Cervantes F. How I treat myelofbrosis. Blood. 2014;124:2635-2642.
56. Basch E. Toward patient-centered drug development in oncology.
N Engl J Med. 2013;369:397-400.
57. Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in primary myelofbrosis: a study by
the IWG-MRT (International Working Group for Myeloprolifera-
58.
59.
60.
61.
62.
145
Current Therapies and Their Indications for the PhiladelphiaNegative Myeloproliferative Neoplasms
Jean-Jacques Kiladjian, MD, PhD
OVERVIEW
The groundbreaking discovery of the Janus-associated kinase 2 (JAK2) V617F mutation 10 years ago resulted in an unprecedented
intensive basic and clinical research in Philadelphia-negative myeloproliferative neoplasms (MPNs). During these years, many new
potential targets for therapy were identied that opened the era of targeted therapy for these diseases. However, only one new drug
(ruxolitinib) has been approved during the past 40 years, and, although promising new therapies are evaluated, the armamentarium
to treat MPN still relies on conventional drugs, like cytotoxic agents and anagrelide. The exact role of interferon (IFN) alfa still needs
to be claried in randomized studies, although it has been shown to be effective in MPNs for more than 25 years. The current
therapeutic strategy for MPNs is based on the risk of vascular complication, which is the main cause of mortality and mortality in the
medium term. However, the long-term outcome may be different, with an increasing risk of transformation to myelodysplastic syndrome
or acute leukemia during follow-up times. Medicines able to change this natural history have not been clearly identied yet, and
allogeneic stem cell transplantation currently remains the unique curative approach, which is only justied for patients with high-risk
myelobrosis or for patients with MPNs that have transformed to myelodysplasia or acute leukemia.
or decades, the armamentarium to treat Philadelphianegative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia
(ET), and primary myelofbrosis (PMF), was reduced to a
small handful of cytotoxic drugs like hydroxyurea (HU);
busulfan; and, in some countries, pipobroman.1 Since the
discovery of the JAK2 V617F mutation 10 years ago followed
by the discovery of many other genetic alterations,2 our
knowledge of the pathophysiology of these disorders has dramatically changed, with the identifcation of deregulated crucial signaling pathways like the JAK-STAT (signal transducer
and activator of transcription) pathway or mutations affecting the epigenome. With these major advances, MPNs have
entered into a new era of targeted therapy, inaugurated with
the approval of ruxolitinib, a JAK1/JAK2 inhibitor to treat
myelofbrosis (MF)3,4 and PV.5
With conventional therapies, the treatment of MPNs
mainly aims at reducing the risk of vascular events (including
thrombosis and hemorrhage), which are the main causes of
mortality and morbidity over short and medium time periods.6,7 However, the outcome of patients with these chronic
malignancies is different over the long-term evaluations (i.e.,
after 15 to 20 years of evolution), when transformation to myelodysplastic syndrome (MDS) or acute myeloid leukemia
(AML) becomes a major concern, as demonstrated by the longterm analyses of a randomized study in patients with PV after
more than 16 years of median follow-up time.8 The development of new therapies raises the hope of new objectives, including reduction of the long-term risk of transformation to MDS or
AML; achievement of molecular or histopathologic complete
remissions; and, possibly, cure. However, to date, only allogeneic hematopoietic stem-cell transplantation (ASCT) can cure
selected high-risk patients with MF.
e389
JEAN-JACQUES KILADJIAN
lar risk factors (e.g., smoking, hypertension, diabetes, dyslipidemia) should not be neglected and require a particularly
careful evaluation in patients with PV, because thrombosis is
often multifactorial and caused by an accumulation of adverse factors. A strict control of these standard risk factors,
therefore, is a major component of successful PV therapy.
Regardless of their risk category, treatment recommendations1 for all patients with PV include antiplatelet therapy
with low-dose aspirin (100 mg/day) and phlebotomy to
maintain a hematocrit less than 45%. Patients who are age 60
or older and/or who have a history of thrombosis are highrisk patients and should receive cytoreduction with HU or
recombinant IFN-alfa. HU is the preferred option for highrisk patients in many countries where the off-label use of
IFN-alfa is not possible (Table 1).
First-Line Therapy
KEY POINTS
Therapy for myeloproliferative neoplasms currently is
based on the risk for vascular complications (thrombosis
and hemorrhage) and requires a strict control of other
well-known cardiovascular risk factors (e.g., smoking,
hypertension, diabetes, dyslipidemia).
Phlebotomy to maintain the hematocrit less than 45% and
low-dose aspirin are the cornerstone of therapy for
polycythemia vera, although patients older than age 60 or
who have a history of thrombosis (i.e., high-risk patients)
should receive a cytoreductive agent.
First-line therapy for high-risk polycythemia vera includes
hydroxyurea or interferon alfa, whereas ruxolitinib has
been approved recently for patients whose disease is
resistant to or who are intolerant to hydroxyurea.
Patients with essential thrombocythemia may receive low-dose
aspirin plus hydroxyurea when they are at high risk.
Anagrelide often is preferred as second-line therapy, whereas
interferon alfa also may be useful in subgroups of patients.
Treatment of myelobrosis is often symptom driven, and
ruxolitinib currently is the treatment of choice in patients
with intermediate- or high-risk disease who have
symptomatic splenomegaly and disabling symptoms.
e390
Phlebotomy can be an emergency therapy at diagnosis, in patients who present with very high hematocrit and clinical
signs of hyperviscosity, as well as a long-term maintenance
therapy to control the hematocrit in low-risk patients.19 The
optimal target of hematocrit levels was a matter of debate, but
a recent multicenter, randomized clinical trial (Cyto-PV)
showed that a hematocrit maintained strictly at less than 45%
during follow-up periods was signifcantly associated with a
lower incidence of thrombosis (p 0.007).19 Low-dose aspirin is the second cornerstone of PV therapy, because it
has been shown in a large European, double-blind, placebocontrolled, randomized trial (the ECLAP study) to signifcantly
reduce a primary combined endpoint that included cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and
major venous thromboembolism.6
In addition to this strategy, a cytoreductive drug should be
prescribed in high-risk patients with PV (i.e., age older than
60 and/or with a history of a vascular event). The European
LeukemiaNet (ELN) recommendations for the management
of PV suggested that HU and IFN-alfa were the cytoreductive
treatments of choice as frst-line therapy for high-risk patients with PV.1 HU is a well-known drug with good effcacy
and tolerance in the majority of patients. This effcacy is often
PV
All Patients
ET
Low-Risk Patients
Aspirin
Aspirin
Phlebotomy
High-Risk Patients
First line
Second line
HU or IFN-alfa
HU
Switch IFN-alfa or HU
Anagrelide
Ruxolitinib
Other
Busulfan
IFN-alfa
Abbreviations: PV, polycythemia vera; ET, essential thrombocythemia; HU, hydroxyurea; IFN,
interferon.
Second-Line Therapy
The choice of second-line myelosuppressive drugs for PV
should be evaluated carefully, because some drugs administered
after HU may enhance the risk of AML.30 Therefore, one may
switch drugs between HU or IFN-alfa when used as frst line
(Table 1).
Very recently, the JAK1/JAK2 inhibitor ruxolitinib was
evaluated in patients with PV who were intolerant of or resistant to HU in a phase III, randomized trial versus the best
e391
JEAN-JACQUES KILADJIAN
TREATMENT OF MYELOFIBROSIS
Because there is no curative therapy other than ASCT for myelofbrosis, treatment basically is palliative and usually is
guided by the principal disease manifestation.
lenalidomide, combined for the induction treatment with prednisone, provide a 20% to 30% response.39,40 Of note, lenalidomide as a single agent is the treatment of choice for patients with
MF who have a 5q deletion.41 Corticosteroids alone sometimes
may be helpful and provide a modest beneft for patients resistant to the above-mentioned therapies, especially if a hemolytic
part can be demonstrated. Last, splenectomy can be useful in
patients who have transfusion-dependent anemia that is refractory to any therapy,42 but it needs careful evaluation because of
the risks of complication.
throughout therapy, but they are strictly drug and dose dependent; a reduction in the dose will rapidly result in a slight reincrease in spleen size, whereas discontinuation of the drug will
lead to a return of signs and symptoms to their baseline levels
within a week. Of note, sudden ruxolitinib withdrawal has been
reported to potentially induce severe complications, like shocklike syndrome, because of the re-emergence of the suppressed
inflammatory cytokines.46 Although such dramatic adverse
events have not been observed in the two COMFORT phase III
studies, abrupt interruption should be avoided, and withdrawal
of the drug should be tapered. Thrombocytopenia is a frequent
adverse event observed with ruxolitinib (contraindicated in patients who have platelet counts less than 50 109/L), and it requires dose adaptation but very rarely drug discontinuation.
New onset or worsening of anemia also can be anticipated
when ruxolitinib therapy starts, especially during the frst 3 to
6 months of therapy. This drug also is associated with an increased risk of infection, which requires patient counseling
and sometimes prophylactic measures (as reviewed by Heine
et al47).
A survival advantage for patients treated with ruxolitinib
was frst shown from an historic comparison with matched
MF populations.48,49 Extended follow-up evaluation of the
phase III studies indicated a survival advantage for patients
who received ruxolitinib.50 However, there is still little evidence of a disease-modifying effect, although case reports
suggest that reduction in JAK2 mutant allele burden and
bone marrow fbrosis can be achieved with the long-term use
of ruxolitinib in selected patients.51
Other JAK inhibitors currently are being evaluated in clinical studies, but several clinical development programs have
been terminated because of emergent toxicity, in particular
neurologic toxicity, with some of these drugs.52 Among JAK
inhibitors currently being tested in phase III studies, pacritinib may have the peculiarity of a lack of toxicity on the
megakaryocytic lineage that allows its use in patients with
thrombocytopenia.53 Momelotinib, despite its potent antiJAK2 activity, may have a positive impact on the anemia of
transfusion-dependent patients.54 However, these potentially useful properties for subgroups of patients with MF
who have these two unmet needs have to be confrmed in the
ongoing phase III studies.
secondary AML.57 The best candidates for ASCT are highrisk patients with MF (intermediate 2 and high-risk categories according to IPSS), the limit of age being discussed
according to conditioning intensity.1 The use of ruxolitinib
before transplantation with the objective of spleen size reduction in patients who have massive splenomegaly (to avoid
pretransplantation splenectomy) and to improve general
performance status is evaluated in prospective studies and
should, therefore, be considered presently as experimental.
In patients with massive splenomegaly, pre-transplant splenectomy should be discussed to improve engraftment and
transplant outcome.5557
e393
JEAN-JACQUES KILADJIAN
they have a poorer life expectancy and often-complex mutational profles. To validate such a personalized approach,
there is a need for prospective studies in cohorts of patients fully characterized for mutations that may change
the response to therapies. This characterization could be
available soon in a number of centers with the rapid development and wider availability of next-generation sequencing techniques.
In terms of new therapies, two classes of drugs currently are
being evaluated in early-phase studies and may play a role in
MPN management in the future. First, histone deacetylase inhibitors have shown some effcacy, like panobinostat in PMF61
or givinostat in PV.62 The most promising results with these
drugs may result from a combination with JAK inhibitors by
targeting parallel signaling pathways involved in disease development. A telomerase inhibitor, imetelstat, also has had effcacy
in ET and PMF and currently is being evaluated for effcacy and
safety.63
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Jean-Jacques Kiladjian, Novartis, Shire.
Consulting or Advisory Role: Jean-Jacques Kiladjian, Novartis, Shire, Incyte. Speakers Bureau: None. Research Funding: Jean-Jacques Kiladjian, AOP
Orphan (Inst), Novartis (Inst). Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses:
Jean-Jacques Kiladjian, Novartis, Incyte. Other Relationships: None.
References
1. Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol. 2011;29:761-770.
2. Vainchenker W, Delhommeau F, Constantinescu SN, et al. New mutations and pathogenesis of myeloproliferative neoplasms. Blood. 2011;
118:1723-1735.
3. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofbrosis. N Engl J Med.
2012;366:787-798.
4. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled
trial of ruxolitinib for myelofbrosis. N Engl J Med. 2012;366:799-807.
5. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus
standard therapy for the treatment of polycythemia vera. N Engl J Med.
2015;372:426-435.
6. Landolf R, Marchioli R, Kutti J, et al. Effcacy and safety of low-dose
aspirin in polycythemia vera. N Engl J Med. 2004;350:114-124.
7. Harrison CN. Management of essential thrombocythemia: implications
of the medical research council primary thrombocythemia 1 trial. Semin
Thromb Hemost. 2006;32:283-288.
8. Kiladjian JJ, Chevret S, Dosquet C, et al. Treatment of polycythemia vera
with hydroxyurea and pipobroman: fnal results of a randomized trial
initiated in 1980. J Clin Oncol. 2011;29:3907-3913.
9. Passamonti F, Thiele J, Girodon F, et al. A prognostic model to predict
survival in 867 WHO-defned essential thrombocythemia at diagnosis: a
study by the IWG-MRT. Blood. 2012;120:1197-1201.
e394
10. Tefferi A, Rumi E, Finazzi G, et al. Survival and prognosis among 1545
patients with contemporary polycythemia vera: an international study.
Leukemia. 2013;27:1874-1881.
11. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofbrosis based on a study of the International Working Group
for Myelofbrosis Research and Treatment. Blood. 2009;113:2895-2901.
12. Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic
model to predict survival in primary myelofbrosis: a study by the IWGMRT (International Working Group for Myeloproliferative Neoplasms
Research and Treatment). Blood. 2010;115:1703-1708.
13. Gangat N, Caramazza D, Vaidya R, et al. DIPSS plus: a refned dynamic
international prognostic scoring system for primary myelofbrosis that
incorporates prognostic information from karyotype platelet count, and
transfusion status. J Clin Oncol. 2011;29:392-397.
14. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of
calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369:
2379-2390.
15. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;
369:2391-2405.
16. Vannucchi AM, Lasho TL, Guglielmelli P, et al. Mutations and prognosis in primary myelofbrosis. Leukemia. 2013;27:1861-1869.
17. El Nemer W, De Grandis M, Brusson M. Abnormal adhesion of red
blood cells in polycythemia vera: a prothrombotic effect? Thromb Res.
2014;133 (Suppl 2):S107-S111.
39. Mesa RA, Steensma DP, Pardanani A, et al. A phase 2 trial of combination low-dose thalidomide and prednisone for the treatment of myelofbrosis with myeloid metaplasia. Blood. 2003;101:2534-2541.
40. Mesa RA, Yao X, Cripe LD, et al. Lenalidomide and prednisone for myelofbrosis: Eastern Cooperative Oncology Group (ECOG) phase 2 trial
E4903. Blood. 2010;116:4436-4438.
41. Tefferi A, Lasho TL, Mesa RA, et al. Lenalidomide therapy in
del(5)(q31)-associated myelofbrosis: cytogenetic and JAK2V617F molecular remissions. Leukemia. 2007;21:1827-1828.
42. Tefferi A, Mesa RA, Nagorney DM, et al. Splenectomy in myelofbrosis
with myeloid metaplasia: a single-institution experience with 223 patients. Blood. 2000;95:2226-2233.
43. Martinez-Trillos A, Gaya A, Maffoli M, et al. Effcacy and tolerability of
hydroxyurea in the treatment of the hyperproliferative manifestations of
myelofbrosis: results in 40 patients. Ann Hematol. 2010;89:1233-1237.
44. Bouabdallah R, Coso D, Gonzague-Casabianca L, et al. Safety and effcacy of splenic irradiation in the treatment of patients with idiopathic
myelofbrosis: a report on 15 patients. Leuk Res. 2000;24:491-495.
45. Steensma DP, Hook CC, Stafford SL, et al. Low-dose, single-fraction,
whole-lung radiotherapy for pulmonary hypertension associated with
myelofbrosis with myeloid metaplasia. Br J Haematol. 2002;118:813816.
46. Tefferi A, Pardanani A. Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofbrosis. Mayo Clinic Proc.
2011;86:1188-1191.
47. Heine A, Brossart P, Wolf D. Ruxolitinib is a potent immunosuppressive compound: is it time for anti-infective prophylaxis? Blood. 2013;
122:3843-3844.
48. Verstovsek S, Kantarjian HM, Estrov Z, et al. Long term outcomes of
107 patients with myelofbrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls. Blood. 2012;120:1202-1209.
49. Passamonti F, Maffoli M, Cervantes F, et al. Impact of ruxolitinib on the
natural history of primary myelofbrosis: a comparison of the DIPSS and
the COMFORT-2 cohorts. Blood. 2014;123:1833-1835.
50. Cervantes F, Vannucchi AM, Kiladjian JJ, et al. Three-year effcacy,
safety, and survival fndings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofbrosis. Blood.
2013;122:4047-4053.
51. Wilkins BS, Radia D, Woodley C, et al. Resolution of bone marrow fbrosis in a patient receiving JAK1/JAK2 inhibitor treatment with ruxolitinib. Haematologica. 2013;98:1872-1876.
52. Zhang Q, Zhang Y, Diamond S, et al. The Janus kinase 2 inhibitor
fedratinib inhibits thiamine uptake: a putative mechanism for the
onset of Wernickes encephalopathy. Drug Metab Dispos. 2014;42:
1656-1662.
53. Geyer HL, Mesa RA. Therapy for myeloproliferative neoplasms: when,
which agent, and how? Blood. 2014;124:3529-3537.
54. Abdelrahman RA, Begna KH, Al-Kali A, et al. Revised assessment of
response and long-term discontinuation rates among 111 patients with
myelofbrosis treated with momelotinib or ruxolitinib. Leukemia. 2015;
29:498-500.
55. Kroger N, Holler E, Kobbe G, et al. Allogeneic stem cell transplantation
after reduced-intensity conditioning in patients with myelofbrosis: a
prospective, multicenter study of the Chronic Leukemia Working Party
of the European Group for Blood and Marrow Transplantation. Blood.
2009;114:5264-5270.
56. Ballen KK, Shrestha S, Sobocinski KA, et al. Outcome of transplantation for myelofbrosis. Biol Blood Marrow Transplant. 2010;16:
358-367.
57. Lussana F, Rambaldi A, Finazzi MC, et al. Allogeneic hematopoietic
stem cell transplantation in patients with polycythemia vera or essential
e395
JEAN-JACQUES KILADJIAN
thrombocythemia transformed to myelofbrosis or acute myeloid leukemia: a report from the MPN Subcommittee of the Chronic Malignancies Working Party of the European Group for Blood and Marrow
Transplantation. Haematologica. 2014;99:916-921.
58. Harrison CN, Robinson SE. Myeloproliferative disorders in pregnancy.
Hematol Oncol Clin North Am. 2011;25:261-275, vii.
59. Campbell PJ, Scott LM, Buck G, et al. Defnition of subtypes of essential
thrombocythaemia and relation to polycythaemia vera based on JAK2
V617F mutation status: a prospective study. Lancet. 2005;366:1945-1953.
60. Kiladjian JJ, Masse A, Cassinat B, et al. Clonal analysis of erythroid progenitors suggests that pegylated interferon alpha-2a treatment targets
e396
LEUKEMIA, MYELODYSPLASIA,
AND TRANSPLANTATION
SPEAKERS
Francesco Onida, MD
University of Milan
Milan, Italy
Eric Padron, MD
Moftt Cancer Center
Tampa, FL
he myelodysplastic syndromes are a clinically and molecularly heterogeneous group of clonal stem cell disorders with management options ranging from observation
and growth-factor therapy to more intensive approaches,
such as hypomethylating agent (HMA) based therapies, intensive induction chemotherapy, and alloSCT.1 During the
last decade, rapid developments centered around highthroughput molecular technologies have resulted in remarkable advancement toward the understanding of MDS
pathogenesis.2-6 These technologies are anticipated to translate to innovative targeted agents that will radically affect the
natural history of this disease. Presently, however, alloSCT
remains the only curative treatment option in patients with
MDS.2,7-9 Even if substantially reduced during the last 20
years, mortality and morbidity risks associated with alloSCT
continue to represent a major limit to the feasibility of such a
therapeutic strategy in the large number of patients.8,10,11
Therefore, the accurate selection of patientstogether with
optimal timing of transplantationrepresent critical issues
for maximum improvement of the alloSCT risk-beneft ratio
in MDS.
As such, important advancements have been made toward
the dissection of MDS clinical heterogeneity that have incor-
PROGNOSTIC STRATIFICATION IN
MYELODYSPLASTIC SYNDROMES
MDS is a disease found in older adults, with a median age at
diagnosis of age 71. The estimated 3-year survival rate of patients with MDS is 45%,12 although there is substantial variability in outcomes even within the same French-AmericanBritish (FAB)13 classifcation system and the more recent
World Health Organization (WHO) morphologic subtypes.14 This heterogeneity in outcomes underscores the
need for accurate prognostication and has fuelled the evolution of various prognostic scoring models.
From the Section of Hematology/Oncology, and the Comprehensive Cancer Center, The University of Chicago, Chicago, IL; Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, University
of Milan, Milan, Italy; Moftt Cancer Center, Tampa, FL.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Olatoyosi Odenike, MD, Section of Hematology/Oncology and the Comprehensive Care Center, The University of Chicago, 5841 S. Maryland Ave., MC 2115, Chicago, IL 60637;
email: todenike@medicine.bsd.uchicago.edu.
2015 by American Society of Clinical Oncology.
e398
KEY POINTS
Myelodysplastic syndromes (MDS) and myelodysplastic/
myeloproliferative neoplasms are clinically and molecularly
heterogeneous.
The choice of optimal front-line therapy in MDS depends on
accurate risk stratication; the revised international
prognostic scoring system (IPSS), IPSS-R, is the most
contemporary system in use.
Comprehensive molecular proling has the potential to
improve prognostication, risk stratication, and diagnosis.
Allogeneic hematopoietic stem cell transplant is
increasingly being used in older adults with MDS, and it
should be considered early in patients with higher risk
disease.
The identication of biologically relevant pathways is
anticipated to ultimately lead to targeted therapeutic
agents.
e399
Frequency (%)
4%
Karyotypic Abnormalities
Median
Survival (y)
-Y, del(11q)
5.4
Good
72%
4.8
9.4
Intermediate
13%
2.7
2.5
Poor
4%
1.5
1.7
Very poor
7%
Complex ( 3 abnormalities)
0.7
0.7
Abbreviations: MDS, myelodysplastic syndromes; y, years; AML, acute myeloid leukemia; NR, not reported.
FRONT-LINE THERAPY IN
MYELODYSPLASTIC SYNDROMES
This chart illustrates the mutational complexity of MDS, with mutations organized into
functional pathways affecting RNA splicing (includes: SF3B1, SRSF2, ZRSR2, U2AF1/2); DNA
methylation (includes TET2, DNMT3A, IDH1/2); chromatin modication (includes ASXL1, EZH2);
transcription factor (includes RUNX1, TP53, BCOR, PHF6, NCOR, CEBA, GATA2);
receptors/kinases (JAK2, MPL, FLT3, GNAS, KIT); RAS pathway (KRAS, NRAS, CBL, NF1, PTPN11);
DNA repair (ATM, BRCC3, DLRE1C, FANCL); and cohesins (STAG2, CTCF, SMC1A, RAD21). In
approximately 10%, no mutation could be identied. Overlapping mutations (co-occurrence
of two or more mutations in patients with MDS) are not depicted on this chart, thus
percentages add up to more than 100%. Chart is created from data derived largely from
targeted deep sequencing of 104 genes in a cohort of 944 patients with MDS, published by
Haferlach et al.27
e400
such as erythropoietin (in patients with anemia), to immunosuppressive therapy (in patients with multiple cytopenias).
Therefore, elements that factor into risk stratifcation are of
critical therapeutic importance. Contemporary approaches
to risk refnement, including the use of more discriminant
prognostic models, such as the IPSS-R, are highly encouraged. Data are evolving to support the potential utility and
applicability of models that combine comprehensive targeted molecular profling with clinical models, such as the
IPSS-R, in making treatment decisions, and they deserve
prospective validation.
Immunosuppressive Therapy
Immunosuppressive therapy (IST) with antithymocyte globulin (ATG)-based therapies33 are reasonable to consider in
lower-risk patients with MDS who have multiple cytopenias,
who are younger ( age 55), and who are positive for the
HLA DR15 allele. These latter factors were positive predictors of response to IST.34 A hypocellular marrow, which suggests a disease more closely aligned with aplastic anemia, also
has been found in some studies to be predictive of response,
but it has not been confrmed in others.35,36 Since activated T
cells are the target of IST, a predictive model that consists of
a T-cell activating signature and duration of disease also has
been proposed.37
Lenalidomide
In patients with deletion 5q (del[5q]) and lower-risk disease
who require red cell transfusions, the use of lenalidomide is
associated with a transfusion independence rate in the 70%
range, with a median duration of response of 2.2 years.38 In
lower-risk patients with MDS without the del(5q), the response rate is in the 25% range and response duration is substantially shorter.39 High karyotypic complexity, lower
platelet count, and TP53 mutations tend to be associated with
lenalidomide resistance, even in the presence of del(5q).40 Lenalidomide currently is being investigated in combination
with erythropoietin in a phase III trial in lower-risk patients
with MDS. In this trial, it is hypothesized that the combination of lenalidomide and EPO will potentiate erythroid response in patients who have failed to respond to EPO or in
whom EPO is predicted to have a low probability of being
effective. The trial is based at least in part on promising results from an early phase trial that investigated the combination.41 Recently, a novel mechanism of action involving
lenalidomide-induced degradation via cereblon of casein
Hypomethylating Agents
The U.S. Food and Drug Administration (FDA) has approved hypomethylating agents (HMAs) 5-azacytidine
(azacitidine) and 5-aza-2deoxycitidine (decitabine) for
treatment of patients with MDS. These compounds become
incorporated into DNAalthough azacitidine also gets incorporated into RNAand form a covalent complex with
the DNA methyltransferase (DNMT) enzyme, which results
in trapping and degradation of the enzyme and progressive
loss of DNMT activity within the cells and subsequent DNA
hypomethylation. When administered at very high doses, the
cytotoxic effects of the agents predominate. However, lower
doses in the range used for treating patients with MDS are
postulated to allow the hypomethylating effect and, thus, epigenetic modulation to occur.43
Both agents have been investigated in randomized trials of
patients with MDS. They are associated with similar objective
response rates of complete response and partial response in
the 15% range, although an additional 15% to 30% of patients
will experience hematologic improvement, manifested primarily as an improvement in cytopenias and transfusion
requirements.44-46 Improvements in quality of life also have
been demonstrated.
In addition, azacitidine has been associated with an overall
survival advantage in patients with higher-risk MDS, when
compared to prespecifed conventional care regimens (including supportive care, low-dose cytarabine, and acute myeloid leukemia (AML) typeinduction therapy), with median
survival of 24.5 months in the azacitidine arm compared with
15 months in the control arm.44 A population-based study
also confrmed this 24-month survival beneft with azacitidine use outside of a clinical trial setting.47
Although the beneft associated with the use of HMAs in
patients with MDS is indisputable, many patients will not
beneft from them. Furthermore, for those who respond, the
response is not immediate. The median time to best response
is in the range of 3 to 4 months. Therefore, biomarkers that
predict response to therapy would be of substantial value.
Our increasing knowledge of the molecular genetic landscape of MDSincluding the fact that mutations affecting
enzymes that are involved in DNA methylation are involved
in MDS pathogenesis has spurred additional efforts in recent years to fnd predictive biomarkers to HMA therapy.
As such, TET2 mutations or DNMT3A mutations were associated with a modest increase in response rates to HMA
therapy in earlier reports with conventional Sanger sequencing.48,49 A more recent report used a more comprehensive
molecular profling approach. It evaluated 40 recurrently
mutated genes in 213 patients with MDS treated with HMAs
and confrmed clonal TET2 mutations as predictive of response (odds ratio, 1.99).50 In contrast, TP53 and PTPN11
mutations were associated with shorter overall survival after
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e401
Combination Therapies
There remains an urgent need for the development of new
drug therapies and combinations to treat patients with MDS.
An early focus was the combination of HMAs with histone
deacetylase inhibitors (HDACi).51-55 This was based on
the hypothesis that inhibiting two pathways of epigenetic
deregulation would be potentially synergistic, and abundant preclinical evidence of synergy. Early phase trials investigating the combination of azacitidine with the
HDACi entinostat or vorinostat,52,56 or the immunomodulatory agent lenalidomide,57 yielded promising results, which has led to randomized trials conducted in the
intergroup setting.
The results of randomized trials conducted in the U.S.
intergroup setting (E1905) comparing azacitidine versus azacitidine plus entinostat,58 and preliminary results of the recently
concluded three-arm randomized phase II North American intergroup trial (S1117) comparing single-agent azacitidine to
azacitidine plus vorinostat and azacitidine plus lenalidomide
combinations,59 respectively, however, have shown no signifcant advantage to the combination arms as to improvement in
response rates. Therefore, azacitidine remains the standard of
care. Survival endpoints, either progression-free or overall survival, may be more relevant primary endpoints of future large
randomized efforts that compare single-agent HMA therapy to
novel combinations and approaches.
Disease Characteristics
In general, MDS includes an extremely heterogeneous group
of myeloid malignancies with different natural courses and
life expectations. Therefore, a risk-based approach for individual decision making on treatment strategy is highly suggested, and it is mandatory when referring patients for
alloSCT.8,10,60 Together with the nosological classifcation
methods (such as the FAB and, more recently, the WHO classifcation schemes), prognostic scoring systems in MDS have
been considered the most appropriate tools for treatment
stratifcation. For almost 15 years, the IPSS15 has been universally recognized as the landmark reference method for
risk-stratifcation with patients classifed in high-risk categoe402
ries (including intermediate-2 and high-risk groups) as generally being considered for early alloSCT. However, a
different treatment plan usually is recommended for patients
in the lower IPSS risk categories (i.e., low and intermediate1). In a foremost decision-analysis study that included patients younger than age 60, delayed transplantation was
shown to associate with maximal life expectancy, with an
even more marked survival advantage for patients under age
40.61 In 2007, a time-dependent WHO classifcation-based
prognostic scoring (WPSS) incorporating transfusion dependence was proposed for untreated patients.16 Different
from IPSS, the WPSS identifes fve risk groups of patients
with different survival, and it allows for real-time assessment
of prognosis in MDS. Its relevance after alloSCT was validated in a subsequent study from the GITMO group that included 406 patients,62 in which a multivariate Cox survival
analysis also included age and sex of patient, time between
diagnosis and alloSCT, year of transplantation, disease stage
at transplantation, source of stem cells, type of donor, and
type of conditioning, WPSS showed a prognostic signifcance
on both overall survival and probability of relapse. The validity of WPSS in predicting outcomes after alloSCT in patients
with MDS recently was confrmed in a population of 60
Southeast Asian patients.63
Cytogenetics appears to be the most critical factor in determining survival in patients with MDS. However, the cytogenetic categories included in all of the proposed prognostic
scoring systems were derived from large series of patients
who were only treated with supportive care. Because alloSCT
represents a treatment strategy that is potentially capable of
eradicating the hematopoietic malignant cell clone, it could
be postulated that the prognostic signifcance of cytogenetics
would persist using this treatment approach. However, the
negative effect of poor-risk cytogenetics on the outcomes of
patients with MDS undergoing alloSCT has been confrmed.6469 For example, a recent retrospective analysis from the European Society for Blood and Marrow Transplantation
(EBMT) demonstrated that poor-risk cytogenetics, as defned by standard IPSS scores, were associated with a relatively poor survival after alloSCT from HLA-identical
siblings, except in patients with low marrow blast count (i.e.,
RA/RARS) who were transplanted up front.69
In 2012, the revised IPSS (IPSS-R) for MDS was generated
by analyzing 7,012 patients in a new international collaborative effort. Based on a new comprehensive cytogenetic
score,20 and considering severity of cytopenias by incorporating different cutoff points, the IPSS-R stratifes fve risk
groups with different clinical outcomes.19
The ability of the new cytogenetic risk classifcation to predict post-transplant outcome was promptly confrmed in a
series of 1,007 patients who underwent alloSCT at the Fred
Hutchinson Cancer Research Center in Seattle. A substantially higher rate of relapse and mortality rate was found in
patients with very poor cytogenetics compared to patients
with good-risk cytogenetics.70
An additional disease characteristic recently has been
shown to negatively affect the prognosis of patients with
MDS. Not included in any of the previously described scoring systems is the presence of a monosomal karyotype (MK)
(i.e., the presence of two or more distinct autosomal monosomies or a single monosomy associated with a structural
abnormality).71-74 However, an association of MK with lower
survival, higher relapse incidence, and overall mortality after
alloSCT even among patients with a complex karyotype
has been reported consistently.70,75-77
The effect of the IPSS-R on alloSCT outcomes recently was
demonstrated in an analysis from the Italian GITMO cooperative group that included 374 patients with primary MDS.
Both IPSS-R and monosomal karyotypes were independently
associated to a lower overall survival and a higher relapse
probability by multivariate analysis.78 In this study, a predictive model of post-transplant outcome in patients with MDS
(Transplantation Risk Index) was originated based on the age
of the patient, IPSS-R category, monosomal karyotype, hematopoietic cell transplantation (HCT)-specifc comorbidity
index, and refractoriness to induction chemotherapy.
In addition to cytogenetics, other disease characteristics have
been associated with a poor prognosis in patients with MDS.
These include severe bone marrow fbrosis,79,80 refractory lifethreatening cytopenias,81-83 and gene mutations.2,18,24,25,28,29,84-89
As to the effect on alloSCT outcome, bone marrow fbrosis,
a recent EBMT retrospective analysis of 721 patients with
MDS demonstrated that only severe fbrosis was shown to
affect survival, whereas patients with mild or moderate fbrosis had an alloSCT outcome comparable to patients without
bone marrow fbrosis.79 For gene mutations, an independent
association with a shorter post-transplant overall survival,
after adjusting for clinical variables and complex karyotype status, recently has been reported for mutations in
TP53 and TET2.90
Patient Characteristics
Apart from disease characteristics, host-specifc risk assessment in determining indications for alloSCT always should
be grounded on essential patient-related factors, including
age, comorbidities, and donor availability.
Although usually considered as a treatment option for patients younger than age 60, over the last 2 decades the development of reduced-intensity conditioning (RIC) regimens,
together with substantial progress in supportive care measures, have resulted in an increase in the upper age limit to
age 70 (occasionally even older) in carefully selected very-ft
patients. Because MDS are much more common in older
people (median age at diagnosis, over age 70), with only 10%
of patients younger than age 50, this age-limit extension
translates to a considerable expansion in the proportion of
patients for whom an alloSCT treatment strategy might be
presently contemplated.91,92 Indeed, an international collaborative retrospective comparison of two well-balanced cohorts of medically ft patients with high-risk MDS defned by
age 60 to 70 and ECOG PS of 2 or less, treated with alloSCT
(103 patients) in case of donor availability, or 5-azacytidine
(75 patients) in case of no donor availability, suggested a survival advantage in favor of allogeneic transplantation.93 Ad-
When to Transplant
Although very heterogeneous, the natural course of MDS
typically is characterized by a disease progression with patients exhibiting gradual worsening of peripheral blood cytopenias, which eventually lead to transfusion dependency.
Sequential marrow examination, especially in the presence of
myeloblast excess (i.e., 5%), often can demonstrate an increase in marrow blast count culminating in AML evolution. Cytogenetics tend to remain stable, even though the
occurrence of chromosome aberrancies (or additional ones,
when already present at diagnosis) occasionally may be observed. Time-dependent disease modifcations are outlined
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e403
as phase progression by the WPSS and the IPSS/IPSS-R classifcation system, IPSS-R.15,16,19
The Markov retrospective analyses cited above have shown
a substantial survival advantage for patients who are in highrisk categories of MDS (intermediate-2 and high-risk, according to IPSS) undergoing early alloSCT from HLAmatched donor, whereas a transplant deferment until disease
progression seems to confer longer life expectancies in patients with lower-risk MDS (low- and intermediate-1 risk, according to IPSS).61,94 In general, because the status of the
disease at transplant has a major effect on all outcomes, better
long-term results seem to be achieved when transplantation
is performed earlier during the course of the disease.62,111,112
In addition to disease progression, risk associated with transplant delay may include occurrence of infectious complications, acquisition of transfusion refractoriness, iron overload
secondary to transfusion history, performance status decline,
and acquisition of additional comorbidities, which lead to a
substantially higher risk of nonrelapse mortality following
transplantation. Nonetheless, the question of the optimal
time for alloSCT in individual patients may be diffcult, because of the unavoidable morbidity and nonrelapse mortality
risks associated with the transplantation procedure and to
the current availability of alternative treatment options, such
as HMAs. In a recent GITMO decision study that included
660 patients with MDS who received best supportive care and
449 who underwent transplantation, a continuous-time multistate Markov model was applied to describe the natural history of the disease and to evaluate the effect of alloSCT on
survival.113 Results of this study indicate that a delayed transplantation is advisable only for patients with early disease
(low-risk by IPSS, very low- and low-risk by WPSS), with the
best survival beneft deriving from alloSCT for patients
classifed in the intermediate-1, according to IPSS (in the
presence of multilineage dysplasia and/or transfusion dependency) or the intermediate WPSS risk category.
Furthermore, new and interesting information that could
be combined for clinical decision making in patients with
MDS may originate from a further retrospective GITMO
study. This study was recently performed in a large population of 529 patients with MDS without a compatible family
donor but with plain indication for alloSCT. A competing
risk analysis unveiled high pretransplant risk of disease evolution and mortality resulting from the time spent waiting for
the identifcation of a suitable unrelated donor, both on the
entire population of patients with MDS and on specifc subgroups stratifed by disease risk and age (GITMO Registry,
M. Della Porta, personal communication, 2015). If confrmed in other series, these fndings would support selection
of haploidentical donors to perform immediate alloSCT in
patients with high-risk MDS without a promptly available
HLA-matched donor.114,115
Apart from obviously depending on donor availability, the
decision on when to transplant in MDS often has to consider
potential treatment to be administered before transplantation, especially in patients with a higher percentage of
marrow to possibly downstage the disease to a lower-risk
e404
GENETICS IN MYELODYSPLASTIC
SYNDROMES/MYELOPROLIFERATIVE NEOPLASMS
MDS/MPNs represent an optimal disease model for the clinical implementation of broad spectrum mutational profling.
First, the clinical and pathologic characteristics of MDS/
MPNs are challenging to recognize, and they often can
change within the context of cytoreductive agents or other
therapies. Second, the spectrum of mutations in MDS/MPNs
is relatively well-characterized and allow for the sensitive
annotation of clonality in most patients. Lastly, although
substantial overlap occurs among recurrent mutations in
MDS/MPNs, it could be argued that each disease entity is
characterized by a unique genetic fngerprint that may aid in
diagnosis. Emerging evidence suggests that these genetic
lesions are independently prognostic and may aid in therapeutic decisions. Below is a disease-specifc summary of recurrent mutations and their clinical relevance (Table 2).
CMML
40
JMML
aCML
MDS/MPN-U
69
Unknown
RARS-T
Clinical Signicance
15
Adverse
Unknown
CALR
CBL
10*
15**
Unknown
Adverse/Favorable
CSF3R
Variable
Predictive
DNMT3A
Unknown
Unknown
15
Unknown
ETV6
Unknown
Unknown
Unknown
EZH2
Unknown
10
Unknown
Unknown
IDH1/2
Unknown
Unknown
Unknown
Unknown
JAK2
JAK3
K/N RAS
Unknown
19
12
19
57*
Unknown
Unknown
Favorable
Unknown
Neutral
39
35
14
Unknown
Neutral
NF1
13
Unknown
Unknown
Unknown
Neutral
PTPN11
44
Unknown
Unknown
Unknown
Neutral
Unknown
14
Unknown
Neutral
RUNX1
15
SETBP1
15*
48
10
SF3B1
Unknown
Unknown
93
SRSF2
46
Unknown
Unknown
Adverse
TET2
58
Unknown
30
25
Neutral
TP53
Unknown
Unknown
U2AF1
Unknown
Unknown
Unknown
ZRSF2
Unknown
Unknown
Unknown
Unknown
Adverse
Favorable
Unknown
Abbreviations: WHO, World Health Organization; MDS/MPNs, myelodysplastic syndromes/myeloproliferative neoplasms; CMML, chronic myelomonocytic leukemia; JMML, juvenile myelomonocytic
leukemia; aCML, atypical chronic myeloid leukemia; MDS/MPN-U, myelodysplastic syndromes/myeloproliferative neoplasms unclassiable; RARS-T, refractory anemia with ring sideroblost and
thrombocytosis.
hypersensitivity, has resulted in major advances in the molecular understanding of JMML.128 Further, the presence of
these mutations can alter treatment decisions and management. Patients with CBL mutations and its associated congenital syndrome can manifest a JMML phenotype that is
self-limited.131 Therefore, a watchful waiting strategy is often
employed in these children, as opposed to allogeneic transplant in other RAS-mutated JMML cases.137
e405
Myelodysplastic Syndromes/Myeloproliferative
NeoplasmsUnclassiable
The genetic study of MDS/MPN-Unclassifable (U) has been
limited by diffculties in the diagnostic standardization of this
entity. MDS/MPN-U is defned by having clinicopathologic
features of myeloproliferation, dysplasia, and cytopenias but
not meeting criteria for other well-defned MDS/MPNs. It is
hypothesized that many MDS/MPN-U cases may be reclassifced into other WHO-defned MDS/MPNs with mutational
profling. To this end, a recent retrospective study identifed a
clinical and genetic signature that could identify aCML among
those cases initially identifed as MDS/MPN-U.144 More investigation is needed to better annotate disease-specifc genetic fngerprints to confdently allow for reclassifcation of MDS/MPN
cases.
proach for the treatment of these groups of diseases is to focus on therapeutic strategies tailored to symptomatology
with individual patients. There is little evidence to suggest
that patients with asymptomatic MDS/MPN beneft from
current standard treatment. However, it is strongly recommended that all patients with MDS/MPN be considered for
clinical trial when available. Allogeneic stem cell transplant
has the most robust data suggesting a disease modifying effect in MDS/MPNs94,150-152 and should therefore be considered in higher-risk patients with MDS/MPN. Although there
has been substantial progress in the prognostication of CMML
cases, challenges remain in adequately risk-stratifying other
MDS/MPNs for clinical transplant decision making.48,153,154 Below is a summary of treatment options and their disease-specifc
supporting data.
Hypomethylating Agents
Very limited data are available for the use of HMAs for the
treatment of aCML, MDS/MPN-U, or RARS-T.155 However,
robust data exist that demonstrate the activity of HMAs in
CMML. Several phase II studies have demonstrated that
azacitadine is active in CMML and associated with acceptable
therapy-associated toxicity.156,157 Oral azacitadine more recently has been tested for the treatment of CMML with clinical responses seen in 35% of patients previously treated with
HMA for MDS and CMML, and in 73% of patients receiving
azacitadine as frst-line therapy.158 Decitabine also has been
examined in multiple phase II trials, with response rates
ranging from 10 to 58% in patients with CMML.159 However,
despite well-documented activity, no evidence exists that
HMAs increase overall survival or decrease progression to
AML. Therefore, we reserve this therapy for patients with
CMML in which cytopenias are the predominant symptom.
We would not favor HMAs in rapidly proliferative patients
with CMML, given the relatively long median time to HMA
response. There is no CMML-specifc evidence to favor one
HMA over another.
Cytoreductive Agents
Patients with MDS/MPN with rapid and severe myeloproliferative or constitutional symptoms should be considered for
treatment with cytoreductive agents. These therapies range
Future Therapies
Although other therapeutic options have the potential to improve the symptomatology of patients with MDS/MPN, the
current pharmacologic landscape is limited. Ongoing studies
testing JAK2 inhibitors in aCML and CMML hold promise171
(NCT02092324 and NCT01776723). However, only a small
number of studies currently are addressing MDS/MPN cases
specifcally. Hopefully, improved molecular understanding
of MDS/MPNs will lead to disease-specifc clinical trials with
promising agents that will affect the natural history of this
group of lethal diseases.
CONCLUSION
Our burgeoning knowledge of the molecular complexity of
MDS and MDS/MPNs is rapidly providing novel insights
into the pathobiology of these diseases. The clinical application and relevance of these insights currently is largely limited to the refnement of prognostic risk models.
Hopefully, this knowledge ultimately will translate into
targeted therapies with the potential to change the natural
history of these diseases. Presently, judicial selection of
patients for treatment with currently available therapies,
including alloSCT and nontransplant disease-modifying
therapies, coupled with an improved knowledge into the
best approaches to use these therapies, is of paramount
importance. Given the current paucity of effective therapies for these diseases, an urgent need remains for the development of novel approaches and combinations with the
potential of moving the feld forward.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Eric Padron, Incyte Corporation, Novartis.
Consulting or Advisory Role: Olatoyosi Odenike, Algeta, Incyte, Sano, Spectrum Pharmaceuticals, Suneisis. Speakers Bureau: None. Research Funding:
Olatoyosi Odenike, Astex Therapeutics (Inst), Celgene (Inst), Eisai (Inst), Incyte Corporation (Inst), NS-Pharma (Inst), S*Bio (Inst), Sano (Inst), Spectrum
Pharmaceuticals (Inst), Suneisis (Inst). Eric Padron, Cell Therapeutics (Inst), FORMA Therapeutics (Inst), Incyte (Inst). Patents, Royalties, or Other
Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: Francesco Onida, Celgene, Gentium, Mundipharma, Pierre
Fabre. Other Relationships: None.
References
1.
2.
3.
4.
5.
6.
7.
8.
e407
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
e408
28. Papaemmanuil E, Cazzola M, Boultwood J, et al. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med. 2011;
365:1384-1395.
29. Yoshida K, Sanada M, Shiraishi Y, et al. Frequent pathway mutations
of splicing machinery in myelodysplasia. Nature. 2011;478:64-69.
30. Walter MJ, Shen D, Ding L, et al. Clonal architecture of secondary
acute myeloid leukemia. N Engl J Med. 2012;366:1090-1098.
31. Malcovati L, Papaemmanuil E, Ambaglio I, et al. Driver somatic mutations identify distinct disease entities within myeloid neoplasms with
myelodysplasia. Blood. 2014;124:1513-1521.
32. Hellstrom-Lindberg E, Gulbrandsen N, Lindberg G, et al. A validated
decision model for treating the anaemia of myelodysplastic syndromes
with erythropoietin granulocyte colony-stimulating factor: signifcant effects on quality of life. Br J Haematol. 2003;120:1037-1046.
33. Olnes MJ, Sloand EM. Targeting immune dysregulation in myelodysplastic syndromes. JAMA. 2011;305:814-819.
34. Saunthararajah Y, Nakamura R, Wesley R, et al. A simple method to
predict response to immunosuppressive therapy in patients with myelodysplastic syndrome. Blood. 2003;102:3025-3027.
35. Lim ZY, Killick S, Germing U, et al. Low IPSS score and bone marrow
hypocellularity in MDS patients predict hematological responses to
antithymocyte globulin. Leukemia. 2007;21:1436-1441.
36. Kadia TM, Borthakur G, Garcia-Manero G, et al. Final results of the
phase II study of rabbit anti-thymocyte globulin, ciclosporin, methylprednisone, and granulocyte colony-stimulating factor in patients
with aplastic anaemia and myelodysplastic syndrome. Br J Haematol.
2012;157:312-320.
37. Komrokji RS, Mailloux AW, Chen DT, et al. A phase II multicenter
rabbit anti-thymocyte globulin trial in patients with myelodysplastic
syndromes identifying a novel model for response prediction. Haematologica. 2014;99:1176-1183.
38. List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic
syndrome with chromosome 5q deletion. N Engl J Med. 2006;355:
1456-1465.
39. Raza A, Reeves JA, Feldman EJ, et al. Phase 2 study of lenalidomide in
transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood. 2008;
111:86-93.
40. Mallo M, Del Rey M, Ibanez M, et al. Response to lenalidomide in myelodysplastic syndromes with del(5q): influence of cytogenetics and
mutations. Br J Haematol. 2013;162:74-86.
41. Komrokji RS, Lancet JE, Swern AS, et al. Combined treatment with
lenalidomide and epoetin alfa in lower-risk patients with myelodysplastic syndrome. Blood. 2012;120:3419-3424.
42. Fink EC, Kronke J, Hurst S, et al. Lenalidomide induces ubiquitination
and degradation of CSNK1A1 in MDS with Del(5q). Paper presented
at: 56th Annual Meeting of the American Society of Hematology; December 2014; San Francisco, CA.
43. Chen J, Odenike O, Rowley JD. Leukaemogenesis: more than mutant
genes. Nat Rev Cancer. 2010;10:23-36.
44. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Azacitidine prolongs
overall survival compared with conventional care regimens in elderly
patients with low bone marrow blast count acute myeloid leukemia.
J Clin Oncol. 2010;28:562-569.
45. Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient
outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106:1794-1803.
46. Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled
trial of azacitidine in patients with the myelodysplastic syndrome: a
study of the cancer and leukemia group B. J Clin Oncol. 2002;20:24292440.
47. Wang R, Gross CP, Frick K, et al. The impact of hypomethylating
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
agents on the cost of care and survival of elderly patients with myelodysplastic syndromes. Leuk Res. 2012;36:1370-1375.
Itzykson R, Kosmider O, Renneville A, et al. Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol.
2013;31:2428-2436.
Traina F, Visconte V, Elson P, et al. Impact of molecular mutations on
treatment response to DNMT inhibitors in myelodysplasia and related
neoplasms. Leukemia. 2014;28:78-87.
Bejar R, Lord A, Stevenson K, et al. TET2 mutations predict response
to hypomethylating agents in myelodysplastic syndrome patients.
Blood. 2014;124:2705-2712.
Blum W, Klisovic RB, Hackanson B, et al. Phase I study of decitabine
alone or in combination with valproic acid in acute myeloid leukemia.
J Clin Oncol. 2007;25:3884-3891.
Fandy TE, Herman JG, Kerns P, et al. Early epigenetic changes and
DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies. Blood. 2009;114:2764-2773.
Garcia-Manero G, Yang H, Bueso-Ramos C, et al. Phase 1 study of the
histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic
acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood. 2008;111:1060-1066.
Gore SD, Baylin S, Sugar E, et al. Combined DNA methyltransferase
and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res. 2006;66:6361-6369.
Odenike O, Halpern A, Godley LA, et al. A phase I and pharmacodynamic study of the histone deacetylase inhibitor belinostat plus azacitidine in advanced myeloid neoplasia. Invest New Drugs. Epub 2014
Dec 9.
Silverman LR, Verma, A,, Odchimar-Reissig R, et al. A phase II trial of
Epigenetic modulators vorinostat in combination with azacitidine
(azaC) in patients with the myelodysplastic syndrome (MDS): initial
results of study 6898 of the New York Cancer Consortium. Paper presented at: 55th Annual Meeting of the American Society of Hematology; December 2013; New Orleans, LA.
Sekeres MA, Tiu RV, Komrokji R, et al. Phase 2 study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syndromes. Blood. 2012;120:4945-4951.
Prebet T, Sun Z, Figueroa ME, et al. Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and
acute myeloid leukemia with myelodysplasia-related changes: results
of the U.S. Leukemia Intergroup trial E1905. J Clin Oncol. 2014;32:
1242-1248.
Sekeres MA, Othus M, List AF, et al. A randomized phase II study of
azacitidine combined with lenalidomide or with vorinostat vs azacitidine monotherapy in higher risk myelodysplastic syndromes (MDS)
and chronic myelomonocytic leukemia (CMML): North American Intergroup study SWOG S1117. Paper presented at: 56th Annual Meeting of the American Society of Hematology; December 2014; San
Francisco, CA.
Wetzko K, Platzbecker U. Transplants in myelodysplastic syndromes.
Hematol Oncol Clin North Am. 2014;28:1011-1022.
Cutler CS, Lee SJ, Greenberg P, et al. A decision analysis of allogeneic
bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with
improved outcome. Blood. 2004;104:579-585.
Alessandrino EP, Della Porta MG, Bacigalupo A, et al. WHO classifcation and WPSS predict posttransplantation outcome in patients with
myelodysplastic syndrome: a study from the Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Blood. 2008;112:895-902.
Ma L, Hao S, Diong C, et al. WPSS is a strong prognostic indicator for
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
clinical outcome of allogeneic transplant for myelodysplastic syndrome in Southeast Asian patients. Ann Hematol. Epub 2014 Dec 18.
Appelbaum FR, Anderson J. Allogeneic bone marrow transplantation
for myelodysplastic syndrome: outcomes analysis according to IPSS
score. Leukemia. 1998;12: S25-S29 (suppl 1).
Armand P, Deeg HJ, Kim HT, et al. Multicenter validation study of a
transplantation-specifc cytogenetics grouping scheme for patients
with myelodysplastic syndromes. Bone Marrow Transplant. 2010;45:
877-885.
Armand P, Kim HT, DeAngelo DJ, et al. Impact of cytogenetics on
outcome of de novo and therapy-related AML and MDS after allogeneic transplantation. Biol Blood Marrow Transplant. 2007;13:655-664.
Nevill TJ, Fung HC, Shepherd JD, et al. Cytogenetic abnormalities in
primary myelodysplastic syndrome are highly predictive of outcome
after allogeneic bone marrow transplantation. Blood. 1998;92:19101917.
Nevill TJ, Shepherd JD, Sutherland HJ, et al. IPSS poor-risk karyotype
as a predictor of outcome for patients with myelodysplastic syndrome
following myeloablative stem cell transplantation. Biol Blood Marrow
Transplant. 2009;15:205-213.
Onida F, Brand R, van Biezen A, et al. Impact of the International Prognostic Scoring System cytogenetic risk groups on the outcome of patients with primary myelodysplastic syndromes undergoing allogeneic
stem cell transplantation from human leukocyte antigen-identical siblings: a retrospective analysis of the European Society for Blood and
Marrow Transplantation-Chronic Malignancies Working Party.
Haematologica. 2014;99:1582-1590.
Deeg HJ, Scott BL, Fang M, et al. Five-group cytogenetic risk classifcation, monosomal karyotype, and outcome after hematopoietic cell
transplantation for MDS or acute leukemia evolving from MDS. Blood.
2012;120:1398-1408.
Belli CB, Bengio R, Aranguren PN, et al. Partial and total monosomal
karyotypes in myelodysplastic syndromes: comparative prognostic
relevance among 421 patients. Am J Hematol. 2011;86:540-545.
Gangat N, Patnaik MM, Begna K, et al. Evaluation of revised IPSS cytogenetic risk stratifcation and prognostic impact of monosomal
karyotype in 783 patients with primary myelodysplastic syndromes.
Am J Hematol. 2013;88:690-693.
Patnaik MM, Hanson CA, Hodnefeld JM, et al. Monosomal karyotype
in myelodysplastic syndromes, with or without monosomy 7 or 5, is
prognostically worse than an otherwise complex karyotype. Leukemia.
2011;25:266-270.
Schanz J, Tuchler H, Sole F, et al. Monosomal karyotype in MDS: explaining the poor prognosis? Leukemia. 2013;27:1988-1995.
Kelaidi C, Tzannou I, Baltadakis I, et al. Specifc abnormalities versus
number of abnormalities and cytogenetic scoring systems for outcome
prediction after allogeneic hematopoietic SCT for myelodysplastic
syndromes. Bone Marrow Transplant. 2014;49:1022-1028.
Oran B, Kongtim P, Popat U, et al. Cytogenetics, donor type, and use of
hypomethylating agents in myelodysplastic syndrome with allogeneic
stem cell transplantation. Biol Blood Marrow Transplant. 2014;20:
1618-1625.
Wudhikarn K, Van Rheeden R, Leopold C, et al. Outcome of allogeneic
stem cell transplantation in myelodysplastic syndrome patients: prognostic implication of monosomal karyotype. Eur J Haematol. 2012;89:
294-301.
Della Porta MG, Alessandrino EP, Bacigalupo A, et al. Predictive factors for the outcome of allogeneic transplantation in patients with
MDS stratifed according to the revised IPSS-R. Blood. 2014;123:23332342.
Kroger N, Zabelina T, van Biezen A, et al. Allogeneic stem cell trans-
e409
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
e410
114. Di Stasi A, Milton DR, Poon LM, et al. Similar transplantation outcomes for acute myeloid leukemia and myelodysplastic syndrome patients with haploidentical versus 10/10 human leukocyte antigenmatched unrelated and related donors. Biol Blood Marrow Transplant.
2014;20:1975-1981.
115. Raj K. Haploidentical versus matched donor stem cell transplantations
for acute myeloid leukemia/myelodysplastic syndrome patients. Biol
Blood Marrow Transplant. 2014;20:1875-1876.
116. de Witte T, Suciu S, Verhoef G, et al. Intensive chemotherapy followed
by allogeneic or autologous stem cell transplantation for patients with
myelodysplastic syndromes (MDSs) and acute myeloid leukemia following MDS. Blood. 2001;98:2326-2331.
117. Sierra J, Perez WS, Rozman C, et al. Bone marrow transplantation from
HLA-identical siblings as treatment for myelodysplasia. Blood. 2002;
100:1997-2004.
118. Guardiola P, Runde V, Bacigalupo A, et al. Retrospective comparison
of bone marrow and granulocyte colony-stimulating factor-mobilized
peripheral blood progenitor cells for allogeneic stem cell transplantation using HLA identical sibling donors in myelodysplastic syndromes. Blood. 2002;99:4370-4378.
119. Prebet T, Gore SD, Esterni B, et al. Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol. 2011;
29:3322-3327.
120. Lee JH, Choi Y, Kim SD, et al. Clinical outcome after failure of hypomethylating therapy for myelodysplastic syndrome. Eur J Haematol.
Epub 2014 Oct 15.
121. Sekeres MA, Cutler C. How we treat higher-risk myelodysplastic syndromes. Blood. 2014;123:829-836.
122. Padron E, Komrokji R, List AF. The clinical management of chronic
myelomonocytic leukemia. Clin Adv Hematol Oncol. 2014;12:172-178.
123. Kohlmann A, Grossmann V, Klein HU, et al. Next-generation sequencing technology reveals a characteristic pattern of molecular mutations in 72.8% of chronic myelomonocytic leukemia by detecting
frequent alterations in TET2, CBL, RAS, and RUNX1. J Clin Oncol.
2010;28:3858-3865.
124. Jankowska AM, Makishima H, Tiu RV, et al. Mutational spectrum
analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A. Blood.
2011;118:3932-3941.
125. Meggendorfer M, Roller A, Haferlach T, et al. SRSF2 mutations in 275
cases with chronic myelomonocytic leukemia (CMML). Blood. 2012;
120:3080-3088.
126. Abdel-Wahab O, Mullally A, Hedvat C, et al. Genetic characterization
of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood.
2009;114:144-147.
127. Smith AE, Mohamedali AM, Kulasekararaj A, et al. Next-generation
sequencing of the TET2 gene in 355 MDS and CMML patients reveals
low-abundance mutant clones with early origins, but indicates no definite prognostic value. Blood. 2010;116:3923-3932.
128. Emanuel PD. Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia. Leukemia. 2008;22:1335-1342.
129. Loh ML. Recent advances in the pathogenesis and treatment of juvenile myelomonocytic leukaemia. Br J Haematol. 2011;152:677-687.
130. Sanada M, Suzuki T, Shih LY, et al. Gain-of-function of mutated
C-CBL tumour suppressor in myeloid neoplasms. Nature. 2009;460:
904-908.
131. Niemeyer CM, Kang MW, Shin DH, et al. Germline CBL mutations
cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet. 2010;42:794-800.
132. Kratz CP, Niemeyer CM, Castleberry RP, et al. The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan
syndrome/myeloproliferative disease. Blood. 2005;106:2183-2185.
e411
154.
155.
156.
157.
158.
159.
160.
161.
162.
e412
163. Huls G, Mulder AB, Rosati S, et al. Effcacy of single-agent lenalidomide in patients with JAK2 (V617F) mutated refractory anemia with
ring sideroblasts and thrombocytosis. Blood. 2010;116:180-182.
164. Zhang X, Pan J, Guo J. Presence of the JAK2 V617F mutation in a patient with chronic neutrophilic leukemia and effective response to interferon -2b. Acta Haematol. 2013;130:44-46.
165. Jabbour E, Kantarjian H, Cortes J, et al. PEG-IFN-alpha-2b therapy in
BCR-ABL-negative myeloproliferative disorders: fnal result of a phase
2 study. Cancer. 2007;110:2012-2018.
166. Weihrauch MR, Staib P, Seiberlich B, et al. Phase I/II clinical study of
topotecan and cytarabine in patients with myelodysplastic syndrome,
chronic myelomonocytic leukemia, and acute myeloid leukemia. Leuk
Lymphoma. 2004;45:699-704.
167. Beran M, Estey E, OBrien S, et al. Topotecan and cytarabine is an
active combination regimen in myelodysplastic syndromes and
chronic myelomonocytic leukemia. J Clin Oncol. 1999;17:28192830.
168. Wattel E, Guerci A, Hecquet B, et al. A randomized trial of hydroxyurea versus VP16 in adult chronic myelomonocytic leukemia.
Groupe Francais des Myelodysplasies and European CMML Group.
Blood. 1996;88:2480-2487.
169. Cambier N, Wattel E, Menot ML, et al. All-trans retinoic acid in adult
chronic myelomonocytic leukemia: results of a pilot study. Leukemia.
1996;10:1164-1167.
170. Bejanyan N, Tiu RV, Raza A, et al. A phase 2 trial of combination therapy with thalidomide, arsenic trioxide, dexamethasone, and ascorbic
acid (TADA) in patients with overlap myelodysplastic/myeloproliferative neoplasms (MDS/MPN) or primary myelofbrosis (PMF). Cancer. 2012;118:3968-3976.
171. Padron E, Painter JS, Kunigal S, et al. GM-CSF-dependent pSTAT5
sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia. Blood. 2013;121:5068-5077.
LUNG CANCER
SPEAKERS
Gregory J. Riely, MD, PhD
Memorial Sloan Kettering Cancer Center, Weill Cornell
Medical College
New York, NY
Renato G. Martins, MD
Seattle Cancer Care Alliance, University of Washington
Seattle, WA
lthough there once was a single algorithm for the treatment of patients with advanced lung cancer, the modern treatment of advanced nonsmall cell lung cancer
(NSCLC) has multiple treatment pathways that depend on
many factors including histology and molecular subtype of
disease. In addition, new molecular targets, targeted agents,
and modes of therapy, including immunotherapy, are being
identifed at an accelerating pace. These advances are changing outcomes and the treatment landscape, but the rapid
introduction of many new therapies may be somewhat bewildering for the practicing oncologist. In this context, a discussion of therapys role beyond second line is outdated.
However, more relevant than ever is the medical oncologists
role in advocating for patients to have access to these advances, discerning the patients care goals, and sparing them
from the toxicities of unproven therapies.1 This article will
review critical factors for decision making in this changing
treatment environment.
From Seattle Cancer Care Alliance, University of Washington, Seattle, WA; US Oncology Research, Ocala, FL; Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Craig Reynolds, MD, US Oncology Research, 433 SW 10th St., Ocala, FL; email: craig.reynolds@usoncology.com.
2015 by American Society of Clinical Oncology.
e414
Patients
ORR
mOS
Third Line/
Fourth Line
Third Line/
Fourth Line
Third Line/
Fourth Line
43/14
2%/0%
5 mo/6 mo
Asahina23
230/106
17%/11%
12 mo/10 mo
Younes24
214/NA
7%/NA
Chen25
123
Massarelli22
8 mo/n/a
13 mo/13 mo
Abbreviations: NSCLC, nonsmall cell lung cancer; ORR, overall response rate; mOS, median
overall survival; mo, months; NA, not available.
KEY POINTS
Although there are no randomized studies, data suggest
patients with good performance status and previous
response to chemotherapy are more likely to benet from
further chemotherapy.
Targeted therapy can have signicant benet in previously
treated patients, particularly when new targets are identied.
All patients with advanced lung cancer should receive
palliative care.
Advanced care planning and conveyance of realistic
expectations about outcomes should be discussed with all
patients.
e415
GUIDELINES
Emerging data suggest that interventions in community practice can affect end-of-life care. The US Oncology Networks My
Care My Wishes program (MCMW) gives formal counseling to
patients with advanced cancer, including discussions of prognosis and desires regarding code status and end of life. A recent
analysis suggests that MCMW improves documentation of
code status in electronic medical records in the community setting, perhaps reducing the likelihood of unwanted and futile
end-of-life interventions.17 A study at this meeting suggests that
advanced care planning reduces hospitalization and increases
hospice referrals in patients with advanced cancer.18
In 2014, the Institute of Medicine released Dying in
America: Improving Quality and Honoring Individual Preferences Near the End of Life.19 This document addresses all
patients with potentially terminal illness, not just oncology
patients. There were fve main recommendations:
e416
CONCLUSION
After years of slow progress, the speed of innovation in advanced NSCLC has increased greatly, with an explosion of
new therapies, targeted therapies, and immunotherapies. Although these new options offer great promise for patients,
they may also paradoxically increase the risk of ineffective
and potentially harmful treatment near the end of life. When
there is general pessimism about the role of treatment in
advanced lung cancer, it is less likely to be given, either appropriately or inappropriately. As enthusiasm grows for
treatment, practicing oncologist struggles to provide those
treatments to patients in a way that maximizes potential beneft and minimizes risk. This is a diffcult dilemma given the
absence of randomized data in the third- and fourth-line settings. However, the available data suggests some principles:
Every patient with advanced NSCLC should receive early
palliative care and advance care planning with regard to
end-of-life care. This will reduce the risk of futile and
unwanted treatments, has been shown to improve outcomes, and empowers patients to make informed decisions about their care.
Routine use of cytotoxic chemotherapy in the third and
fourth line is not supported by prospective data. Patients with previous response to therapy and continuing good performance status seem most likely to
beneft from further lines of therapy.
For patients with NSCLC, molecular analysis is a necessary component of care and may identify treatment options even after conventional second-line therapy.
The therapy options for patients with NSCLC have greatly expanded. These therapies have improved the overall survival and
quality of life of many patients affected by the disease. Their high
cost is a challenge to patients, physicians, and society in general.
Medical oncologists have the responsibility to gather all evidence to identify therapies likely to beneft and protect patients
from the toxicities of ineffective therapies.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: Craig H. Reynolds, Gilead Sciences. Honoraria: Craig H. Reynolds,
Boehringer Ingelheim, Celgene, Genentech, Lilly. Gregory J. Riely, Celgene. Consulting or Advisory Role: Craig H. Reynolds, Boehringer Ingelheim,
Genentech. Gregory J. Riely, ARIAD, Mersana, Novartis, Roche. Speakers Bureau: Craig H. Reynolds, Boehringer Ingelheim, Celgene, Genentech, Lilly.
Research Funding: Renato Martins, Astex Therapeutics (Inst), Bayer (Inst), Bristol-Myers Squibb (Inst), Celgene (Inst), Eisai (Inst), Eli Lilly (Inst), Genentech
(Inst), GlaxoSmithKline (Inst), Novartis (Inst), OSI Pharmaceuticals (Inst), Pzer (Inst), VentiRx (Inst). Gregory J. Riely, GSK (Inst), Innity (Inst), Millennium
(Inst), Novartis (Inst), Pzer (Inst), Roche/Genentech (Inst). Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel,
Accommodations, Expenses: Craig H. Reynolds, Lilly. Gregory J. Riely, Novartis. Other Relationships: None.
References
1. Sullivan R, Peppercorn J, Sikora K, et al. Delivering affordable cancer
care in high-income countries. Lancet Oncol. 2011;12:933-980.
2. Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of
docetaxel versus best supportive care in patients with non-small-cell
e417
4. Paik PK, Hasanovic A, Wang L, et al. Multiplex testing for driver mutations in squamous cell carcinomas of the lung. J Clin Oncol. 2012;30
(suppl; abstr 7505).
5. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in
patients with ALK-positive non-small-cell lung cancer: updated results
from a phase 1 study. Lancet Oncol. 2012;13:1011-1019.
6. Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-rearranged nonsmall-cell lung cancer. N Engl J Med. 2014;371:1963-1971.
7. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens
at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:
2240-2247.
8. Janne PA, Ramalingam SS, Yang JC-H, et al. Clinical activity of the
mutant-selective EGFR inhibitor AZD9291 in patients (pts) with EGFR
inhibitor-resistant non-small cell lung cancer (NSCLC). J Clin Oncol.
2014;32:5s (suppl; abstr 8009).
9. Sequist LV, Soria J-C, Gadgeel SM, et al. First-in-human evaluation of
CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of
mutations of EGFR (activating and T790M). J Clin Oncol. 2014;32:5s
(suppl; abstr 8010).
10. Drilon A, Wang L, Arcila ME, et al. Broad, hybrid capture-based nextgeneration sequencing identifes actionable genomic alterations in drivernegative lung adenocarcinomas. Clin Cancer Res. Epub 2015 Jan 7.
11. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients
with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363:733742.
12. Hui D, Elsayem A, De la Cruz M, et al. Availability and integration of
palliative care at US cancer centers. JAMA. 2010;303:1054-1061.
13. Rabow MW, ORiordan DL, Pantilat SZ. A statewide survey of adult and
pediatric outpatient palliative care services. J Palliat Med. 2014;17:13111316.
14. Emanuel EJ, Young-Xu Y, Levinsky NG, et al. Chemotherapy use
among medicare benefciaries at the end of life. Ann Intern Med. 2003;
138:639-643.
e418
LUNG CANCER
SPEAKERS
Paul K. Paik, MD
Memorial Sloan Kettering Cancer Center
New York, NY
Afshin Dowlati, MD
Case Western Reserve University
Cleveland, OH
ecent therapeutic advances in lung cancer have been almost exclusively limited to adenocarcinoma histology.
Molecular profling efforts to identify genomic alterations,
driver oncogenes, and druggable targets have focused on adenocarcinoma. Until recently, antiangiogenic treatments
were limited to nonsquamous NSCLC because of concerns of
heightened toxicity (life-threatening hemoptysis) in squamous cases. Additionally, use of the well-tolerated, convenient, and effective cytotoxic agent pemetrexed is also
restricted to nonsquamous cases because of inferior outcomes in squamous cases.
Lung cancer encompasses numerous diverse histologic
types (Sidebar 1). After decades of inactivity, recent years
have seen advances in our understanding and treatment of
lung cancer types beyond adenocarcinoma. Genomic alterations that may provide therapeutic targets have been identifed in squamous cell carcinoma, and newer antiangiogenic
agents appear to be tolerated in this histologic subtype. Gene
sequencing efforts in small cell lung cancer have identifed
one of the highest mutational burdens of any malignancy,
and prophylactic cranial irradiation in extensive stage disease
has been shown to improve neurologic outcomes and overall
From The University of Texas Southwestern Medical Center, Dallas, TX; Memorial Sloan Kettering Cancer Center, New York, NY; Case Western Reserve University, Cleveland, OH.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: David E. Gerber, MD, Division of Hematology-Oncology, Harold C. Simmons Cancer Center, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd.,
Mail Code 8852, Dallas, TX 75390; email: david.gerber@utsouthwestern.edu.
2015 by American Society of Clinical Oncology.
147
a tumor that is well differentiated and exhibits classic structural features such as keratinization, intercellular bridges,
and pearl formation.1,2 Histopathologic subtypes include papillary, basaloid, clear cell, and small cell variants. Most squamous
lung cancers are marked by the expression of p40/p63, cytokeratins 5/6, high molecular weight keratin, and carcinoembryonic
antigen. Most cases do not express cytokeratin 7 and thyroid
transcription factor 1 (TTF-1).3
There are a number of diagnostic challenges inherent to
this disease. Small biopsy specimens and poorly differentiated tumors often lack the histologic hallmarks of squamous
differentiation. In such cases, immunohistochemical (IHC)
profling for both p40/p63 (positive in squamous cases) and
TTF-1 (negative in squamous cases) has been established as a
useful approach for determining lineage.1,3 A number of
studies have also addressed the issue of adenosquamous
carcinomas, tumors that have most likely arisen from a
common clone but exhibit divergence in histologic appearance. In terms of molecular biology, these tumors appear to be more closely aligned with adenocarcinomas
than squamous cell carcinomas, which has important
therapeutic implications as it relates to current guidelines
for EGFR and ALK testing.1
In 2012, The Cancer Genome Atlas published a comprehensive molecular analysis of 178 early-stage squamous lung
tumors and, from a conceptual standpoint, ushered in an era
of personalized medicine for patients with this disease.4
These data, coupled with discoveries made by other
researchers,5-7 crystallized the notion that a potentially actionable oncogenic driver could be found in the majority of
squamous cases. Key targets are discussed below, and include
KEY POINTS
Although most recent lung cancer developments have been
limited to adenocarcinoma histology, numerous discoveries
for squamous, small cell, and other histologies have also
been made.
A putative oncogenic driver can be identied in the
majority of patients with squamous cell lung cancer. Key
druggable targets include FGFR1 amplication, PI3K
pathway alterations, cell cycle checkpoint disturbances,
and DDR2 mutations.
Ramucirumab, a monoclonal antibody against VEGFR-2, is
now FDA-approved in conjunction with docetaxel for the
treatment of patients with nonsmall cell lung cancers,
including squamous cell lung cancers, making this the rst
antiangiogenesis drug available to patients with this
disease.
Comprehensive genomic analyses of small cell lung cancer
have been conducted. Current experimental treatment
approaches are focusing on targeting mitotic, cell cycle,
and DNA repair regulation, as well as immunotherapy.
Pulmonary neuroendocrine tumors represent a diverse
spectrum of diseases. Radiolabeled somatostatin analogs
and molecularly targeted agents are under investigation.
148
FIGURE 1. Oncoprint of Selected Oncogenes and Tumor Suppressors from 178 Resected Squamous Cell Lung
Cancers Analyzed by the Cancer Genome Atlas153
Note the substantial degree of target overlap for many of these patients.
149
The epidermal growth factor receptor (EGFR) is a wellcharacterized proto-oncogene that, when mutated, engenders a state of oncogene addiction that has been successfully
150
targeted by small molecular inhibitors.37,38 The role of wildtype protein overexpression as a target for therapy has been
less clear. Both squamous cell cancers and adenocarcinomas
are marked by high levels of EGFR expression, although this
does not predict sensitivity to EGFR tyrosine kinase inhibitors.39 Cetuximab, a chimeric monoclonal antibody against
EGFR, has effcacy when coupled with chemotherapy in patients with advanced NSCLC.40 Additionally, a subset analysis showed that patients with squamous cancers that highly
expressed EGFR had a signifcant improvement in OS that
favored the cetuximab combination (HR 0.62; 95% CI, 0.43
to 0.88), providing an impetus to study this strategy further.41
More recently, a randomized phase III trial of cisplatin plus
gemcitabine with or without necitumumab, a fully human
anti-EGFR monoclonal antibody, showed a signifcant,
though modest, improvement in OS with the addition of necitumumab (median OS 11.5 vs. 9.9 months favoring necitumumab, HR 0.84, p 0.01). EGFR expression did not predict
for therapeutic beneft. Despite the OS beneft, there was
minimal improvement in PFS (5.7 vs. 5.5 months, p
0.020) and ORR (31% vs. 29%, p 0.4).42
Immunotherapy
After decades of efforts to develop cancer immunotherapies,
treatments directed against the checkpoints that negatively
regulate the adaptive immune response have recently shown
promising effcacy across a wide range of malignancies, including lung cancers. Most of this activity is centered on the
inhibitory programmed death protein 1 (PD-1), which is expressed on T cells and attenuates T-cell activation upon binding to programmed death-ligand 1 (PD-L1) and PD-L2.43 A
number of monoclonal antibodies against PD-1 or PD-L1 are
in clinical development in lung cancer, including nivolumab,
pembrolizumab, MEDI4736, and MPDL3280A. Although
the initial data for some of these drugs showed heightened
activity in patients with squamous lung cancers, subsequent
data have shown that histology by itself is not a predictor of
response. Instead, PD-L1 expression has emerged as a potentially informative biomarker, with ORRs of between 20% and
30% in patients with PD-L1 tumors. Notably, a subset of
patients have experienced durable responses to treatment
captured in the tails of the overall survival curves that have
been presented, underscoring the need for better predictors
of response to these agents.44-46 Both nivolumab and pembrolizumab have received accelerated FDA approval for the
treatment of advanced melanoma and several clinical trials
are ongoing in lung cancer.
151
A number of constitutively active signal transduction pathways have been identied. At the nuclear level a number of tumor suppressor genes (denoted by boxes) are inactivated (X within the
box). In addition, a number of dominant oncogenes (denoted by the oval shape) are overexpressed, including transcription factors. The antiapoptotic protein Bcl2 is commonly overexpressed in
SCLC. Chromosomal gains and loss are common in SCLC. Increased telomerase activity is commonly seen, as well as epigenetic silencing of a number of important genes.
153
Atypical Carcinoid
LCNEC
SCLC
NE Features
Well differentiated
Well differentiated
Poorly differentiated
Poorly differentiated
Cell Size
Intermediate
Intermediate
Large to Intermediate
Small to Intermediate
Mitotic Rate
Low
Intermediate
High
High
2 mitoses/2 mm2
NE Markers by IHC
to
to
Necrosis
(focal)
KI-67 Index
5%
520%
50100%
80100%
5-yr survival
9095%
6070%
1040%
510%
Abbreviations: IHC, immunohistochemistry; LCNEC, large cell neuroendocrine carcinoma; NE, neuroendocrine; SCLC, small cell lung cancer.
Reprinted with permission of Oxford University Press.
bioactive substances. Furthermore, because the risk of carcinoid crisis is considerably lower than with gastrointestinal
carcinoids,86,87 prophylactic treatment with octreotide before
biopsy or resection is not typically recommended, although it
may be considered before liver-directed therapy. Bronchial
carcinoids with liver metastases are associated with carcinoid
syndrome in more than 80% of cases.
Clinical features of carcinoid syndrome (flushing, wheezing,
diarrhea) have considerable overlap with normal physiology,
and may be atypical in cases of bronchial carcinoids. In contrast
to physiologic flushing, which tends to involve the entire body,
carcinoid flushing has been described as particularly apparent in
the face, neck, upper torso, and the palms of the hands or soles of
the feet. It is unlikely to be accompanied by diaphoresis.
Whereas patients with midgut primaries have typical flushes
lasting several seconds to several minutes, those with foregut
(including bronchial) primaries may have atypical episodes that
last minutes to hours and also feature periorbital edema, disorientation, lacrimation, salivation, hypotension, and tachycardia.
In the setting of localized disease, carcinoid syndrome typically
resolves after curative resection. For advanced disease, somatostatin analogs such as octreotide (described later) are highly
effective. Less commonly (in 1% to 2% of cases), bronchial carcinoids (which are the most common cause of ectopic adrenocorticotropic hormone [ACTH] secretion) may associate with
paraneoplastic Cushing Syndrome, which often has acute onset
and presents with refractory profound hypokalemia and
hypertension.88-91 Treatment is directed at inhibiting adrenal
function and includes high-dose ketoconazole, aminoglutethimide, metyrapone, mitotane, mifepristone, and adrenalectomy.92 Although this is quite a rare occurrence, bronchial
carcinoid is also the most common cause of extrapituitary
growth hormone releasing hormone (GHRH), which can result
in acromegaly.93,94
Diagnostic Evaluation
In 75% of cases, bronchial carcinoids are centrally located
and amenable to bronchoscopic biopsy. Atypical carcinoids
are more likely to present as peripheral lesions appropriate
SIDEBAR 3. Factors That Can Modify Chromogranin A and Urine 5-Hydroxyindoleacetic Acid156,157
Elevated Chromogranin A
Gastroenteropancreatic neuroendocrine tumors
- GI tract (carcinoid tumors)
- Pancreatic NETs (islet cell tumors [e.g., gastrinomas, VIPomas, somatostatinomas, glucagonomas, non-functioning neuroendocrine
tumors])
Endocrine disease: hyperparathyroidism, hyperthyroidism, pheochromocytoma, pituitary tumors, medullary thyroid carcinoma
GI disorders: chronic atrophic gastritis, chronic hepatitis, colon cancer, hepatocellular carcinoma, inammatory bowel disease, irritable
bowel syndrome, liver cirrhosis, pancreatic adenocarcinoma, pancreatitis
Cardiovascular disease: acute coronary syndrome, arterial hypertension, cardiac insufciency/failure, essential hypertension, giant cell
arteritis
Drugs: proton pump inhibitors, histamine-2 receptor antagonists
Inammatory disease: airway obstruction in smokers, chronic bronchitis, systemic rheumatoid arthritis, systemic inammatory response
syndrome
Renal disorders: renal insufciency/failure
Non-gastrointestinal cancers: breast, ovarian, prostate, small cell lung, neuroblastoma
Urine 5HIAA
Foods to avoid 48 hours prior to testing: avocados, bananas, cantaloupe, eggplant, pineapple, plums, tomatoes, hickory nuts/pecans,
plantains, kiwi, dates, grapefruit, honeydew, walnuts
Avoid coffee, alcohol, smoking
Medications that can increase 5HIAA: acetaminophen, ephedrine, diazepam, nicotine, glyceryl guaiacolate (found in some cough medicines),
phenobarbital
Medications that can decrease 5HIAA: corticotrophin, ethanol, imiprimine, levodopa, MAO inhibitors, phenothiazines, aspirin, isoniazid,
gentisic acid, methenamine, streptozocin, heparin, methyldopa
Abbreviations: 5HIAA, urine 5-hydroxyindoleacetic acid.
155
Treatment
Well-differentiated bronchial NETs are staged in the same
fashion as more common lung carcinomas. For early-stage
disease, the principal goal of treatment is curative en bloc surgical resection with negative margins and maximal preservation of lung function. Although a number of bronchoplastic
techniques such as sleeve, wedge, and flap resections to avoid
lobectomy and larger operations have been described,105-108
extraluminal tumor components usually preclude such approaches. Unless medically contraindicated, lobectomy and
lymph node dissection are generally considered the optimal
operation for these cancers, as for other lung tumors,109,110
although some experts support more limited resections
(wedge resection or segmentectomy) for peripheral typical
carcinoids given the low likelihood of local recurrence.111 Endobronchial management, such as bronchoscopic resection
with neodymium yttrium aluminum garnet (Nd-YAG) laser
and cryotherapy, may be considered for central tumors in
medically inoperable patients.112-114 Recommendations regarding adjuvant therapy are confounded by a lack of applicable high-level data and disagreement among disease
experts. Although adjuvant therapy (e.g., platinum/etoposide) is recommended by the National Comprehensive Cancer Network (NCCN) for resected stage II or III atypical
carcinoid and for stage IIIB typical carcinoid, postoperative
chemotherapy is not recommended by the North American
Neuroendocrine Tumor Society (NANETS). Both groups
recommend observation alone for resected stage I-III typical carcinoid. Thoracic radiation therapy may have a role
for atypical carcinoids with residual disease after surgery
and for stage III locally advanced tumors not amenable to
resection.115,116
Systemic therapy of metastatic well-differentiated NETs
may include octreotide, chemotherapy, and molecularly targeted therapies. Because of the lack of prospective trials for
bronchial NETs, most recommendations come from either
retrospective series or extrapolation from experience with
clinical trials primarily enrolling gastrointestinal NETs. A
proposed approach to treatment is as follows: (1) Low-grade
tumor without hormonal syndrome: consider observation
with tumor markers and radiographic studies every 3 to 12
months or somatostatin analog (octreotide, lanreotide) if
SRS-positive; (2) Low-grade tumor with hormonal syndrome: somatostatin analog; (3) Intermediate-grade tumor
without hormonal syndrome: cytotoxic agents or targeted
therapies (see below); (4) Intermediate-grade tumor with
hormonal syndrome: somatostatin analog plus cytotoxic
agents or targeted therapies; (5) High-grade tumor: platinum/etoposide combination chemotherapy. If there is no response to therapy, one may consider subsequent treatment
with a regimen for a lower grade tumor.
156
CONCLUSION
Although most recent advances in lung cancer advances have
been focused on adenocarcinoma tumors, new diagnostic
and treatment approaches are emerging for squamous cell,
small cell, and the rare lung cancer histologies. These developments will hopefully improve the outcomes of patients
with these challenging diseases.
ACKNOWLEDGMENT
The authors thank Vincy Alex for assistance with manuscript
preparation.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
157
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: David E. Gerber, Gilead Sciences. Honoraria: Paul K. Paik, Celgene.
Consulting or Advisory Role: David E. Gerber, Bristol-Myers Squibb (Inst), Genentech (Inst). Paul K. Paik, Celgene, Threshold Pharmaceuticals. Speakers
Bureau: None. Research Funding: David E. Gerber, ArQule (Inst), Celgene (Inst), Genentech (Inst), ImClone Systems (Inst), Immunogen (Inst), Synta (Inst).
Paul K. Paik, AstraZeneca, GlaxoSmithKline. Patents, Royalties, or Other Intellectual Property: David E. Gerber, Royalties from Decision Support in
Medicine from the Clinical Decision SupportOncology online program, royalties from Oxford University Press from two books. Expert Testimony: None.
Travel, Accommodations, Expenses: David E. Gerber, ArQule, Eli Lilly, Lilly. Other Relationships: None.
|References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
158
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
study of AZD4547 in patients with advanced squamous cell lung cancers: preliminary antitumor activity and pharmacodynamic data.
J Clin Oncol. 2014;32:5s (suppl; abstr 8035).
Rekhtman N, Paik PK, Arcila ME, et al. Clarifying the spectrum of
driver oncogene mutations in biomarker-verifed squamous carcinoma of lung: lack of EGFR/KRAS and presence of PIK3CA/AKT1
mutations. Clin Cancer Res. 2012;18:1167-1176.
Yamamoto H, Shigematsu H, Nomura M, et al. PIK3CA mutations
and copy number gains in human lung cancers. Cancer Res. 2008;68:
6913-6921.
Okudela K, Suzuki M, Kageyama S, et al. PIK3CA mutation and amplifcation in human lung cancer. Pathol Int. 2007;57:664-671.
Xu C, Fillmore CM, Koyama S, et al. Loss of Lkb1 and Pten leads to
lung squamous cell carcinoma with elevated PD-L1 expression. Cancer
Cell. 2014;25:590-604.
Soria JC, Lee HY, Lee JI, et al. Lack of PTEN expression in non-small
cell lung cancer could be related to promoter methylation. Clin Cancer
Res. 2002;8:1178-1184.
Spoerke JM, OBrien C, Huw L, et al. Phosphoinositide 3-kinase
(PI3K) pathway alterations are associated with histologic subtypes and
are predictive of sensitivity to PI3K inhibitors in lung cancer preclinical models. Clin Cancer Res. 2012;18:6771-6783.
Engelman JA, Chen L, Tan X, et al. Effective use of PI3K and MEK
inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine
lung cancers. Nat Med. 2008;14:1351-1356.
Ikeda K, Wang LH, Torres R, et al. Discoidin domain receptor 2 interacts with Src and Shc following its activation by type I collagen. J Biol
Chem. 2002;277:19206-19212.
Olaso E, Labrador JP, Wang L, et al. Discoidin domain receptor 2 regulates fbroblast proliferation and migration through the extracellular
matrix in association with transcriptional activation of matrix
metalloproteinase-2. J Biol Chem. 2002;277:3606-3613.
Haura EB, Tanvetyanon T, Chiappori A, et al. Phase I/II study of the
Src inhibitor dasatinib in combination with erlotinib in advanced nonsmall-cell lung cancer. J Clin Oncol. 2010;28:1387-1394.
Johnson FM, Bekele BN, Feng L, et al. Phase II study of dasatinib in
patients with advanced non-small-cell lung cancer. J Clin Oncol. 2010;
28:4609-4615.
Pitini V, Arrigo C, Di Mirto C, et al. Response to dasatinib in a patient
with SQCC of the lung harboring a discoid-receptor-2 and synchronous chronic myelogenous leukemia. Lung Cancer. 2013;82:171-172.
Dickson MA, Schwartz GK. Development of cell-cycle inhibitors for
cancer therapy. Current Oncology. 2009;16:36-43.
Gelbert L, Cai S, Lin X, et al. Preclinical characterization of the CDK4/6
inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
159
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
160
88. Limper AH, Carpenter PC, Scheithauer B, et al. The Cushing syndrome induced by bronchial carcinoid tumors. Ann Intern Med. 1992;
117:209-214.
89. Jones JE, Shane SR, Gilbert E, et al. Cushings syndrome induced by the
ectopic production of ACTH by a bronchial carcinoid. J Clin Endocrinol Metab. 1969;29:1-5.
90. DeStephano DB, Lloyd RV, Schteingart DE. Cushings syndrome produced by a bronchial carcinoid tumor. Hum Pathol. 1984;15:890-892.
91. Scanagatta P, Montresor E, Pergher S, et al. Cushings syndrome induced by bronchopulmonary carcinoid tumours: a review of 98 cases
and our experience of two cases. Chir Ital. 2004;56:63-70.
92. Pelosof LC, Gerber DE. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin Proc. 2010;85:838-854.
93. Filosso PL, Donati G, Rena O, et al. Acromegaly as manifestation of a
bronchial carcinoid tumour. Asian Cardiovasc Thorac Ann. 2003;11:
189.
94. Athanassiadi K, Exarchos D, Tsagarakis S, et al. Acromegaly caused by
ectopic growth hormone-releasing hormone secretion by a carcinoid
bronchial tumor: a rare entity. J Thorac Cardiovasc Surg. 2004;128:631632.
95. Jeung MY, Gasser B, Gangi A, et al. Bronchial carcinoid tumors of the
thorax: spectrum of radiologic fndings. Radiographics. 2002;22:351365.
96. Pasieka JL, McKinnon JG, Kinnear S, et al. Carcinoid syndrome symposium on treatment modalities for gastrointestinal carcinoid tumours: symposium summary. Can J Surg. 2001;44:25-32.
97. Thorson AH. Studies on carcinoid disease. Acta Med Scand. 1958;334:
1-132.
98. Righi L, Volante M, Tavaglione V, et al. Somatostatin receptor tissue
distribution in lung neuroendocrine tumours: a clinicopathologic and
immunohistochemical study of 218 clinically aggressive cases. Ann
Oncol. 2010;21:548-555.
99. Granberg D, Sundin A, Janson ET, et al. Octreoscan in patients with
bronchial carcinoid tumours. Clin Endocrinol (Oxf). 2003;59:793-799.
100. Reubi JC, Kvols LK, Waser B, et al. Detection of somatostatin receptors
in surgical and percutaneous needle biopsy samples of carcinoids and
islet cell carcinomas. Cancer Res. 1990;50:5969-5977.
101. Weiss M, Yellin A, Huszar M, et al. Localization of adrenocorticotropic hormone-secreting bronchial carcinoid tumor by somatostatinreceptor scintigraphy. Ann Intern Med. 1994;121:198-199.
102. Reidy-Lagunes DL, Gollub MJ, Saltz LB. Addition of octreotide functional imaging to cross-sectional computed tomography or magnetic
resonance imaging for the detection of neuroendocrine tumors: added
value or an anachronism? J Clin Oncol. 2011;29:e74-e75.
103. Yao JC, Lombard-Bohas C, Baudin E, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors
after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol.
2010;28:69-76.
104. Campana D, Nori F, Piscitelli L, et al. Chromogranin A: is it a useful
marker of neuroendocrine tumors? J Clin Oncol. 2007;25:1967-1973.
105. Terzi A, Lonardoni A, Feil B, et al. Bronchoplastic procedures for central carcinoid tumors: clinical experience. Eur J Cardiothrac Surg.
2004;26:1196-1199.
106. El Jamal M, Nicholson AG, Goldstraw P. The feasibility of conservative
resection for carcinoid tumours: is pneumonectomy ever necessary for
uncomplicated cases? Eur J Cardiothrac Surg. 2000;18:301-306.
107. Lucchi M, Melf F, Ribechini A, et al. Sleeve and wedge parenchymasparing bronchial resections in low-grade neoplasms of the bronchial
airway. J Thorac Cardiovasc Surg. 2007;134:373-377.
108. Cerfolio RJ, Deschamps C, Allen MS, et al. Mainstem bronchial sleeve
resection with pulmonary preservation. Ann Thorac Surg. 1996;61:
1458-1462.
109. Phan AT, Oberg K, Choi J, et al. NANETS consensus guideline for the
diagnosis and management of neuroendocrine tumors: welldifferentiated neuroendocrine tumors of the thorax (includes lung and
thymus). Pancreas. 2010;39:784-798.
110. Darling GE, Allen MS, Decker PA, et al. Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during
pulmonary resection in the patient with N0 or N1 (less than hilar) nonsmall cell carcinoma: results of the American College of Surgery Oncology Group Z0030 Trial. J Thorac Cardiovasc Surg. 2011;141:662670.
111. Ferguson MK, Landreneau RJ, Hazelrigg SR, et al. Long-term outcome
after resection for bronchial carcinoid tumors. Eur J Cardiothrac Surg.
2000;18:156-161.
112. Cardillo G, Sera F, Di Martino M, et al. Bronchial carcinoid tumors:
nodal status and long-term survival after resection. Ann Thorac Surg.
2004;77:1781-1785.
113. Brokx HA, Risse EK, Paul MA, et al. Initial bronchoscopic treatment
for patients with intraluminal bronchial carcinoids. J Thorac Cardiovasc Surg. 2007;133:973-978.
114. Bertoletti L, Elleuch R, Kaczmarek D, et al. Bronchoscopic cryotherapy
treatment of isolated endoluminal typical carcinoid tumor. Chest.
2006;130:1405-1411.
115. Mackley HB, Videtic GM. Primary carcinoid tumors of the lung: a role
for radiotherapy. Oncology (Williston Park). 2006;20:1537-1543.
116. Chakravarthy A, Abrams RA. Radiation therapy in the management of
patients with malignant carcinoid tumors. Cancer. 1995;75:1386-1390.
|117. De Dosso S, Bajetta E, Procopio G, et al. Pulmonary carcinoid tumours:
indolent but not benign. Oncology. 2007;73:162-168.
118. Rinke A, Muller HH, Schade-Brittinger C, et al. Placebo-controlled,
double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic
neuroendocrine midgut tumors: a report from the PROMID Study
Group. J Clin Oncol. 2009;27:4656-4663.
119. Caplin ME, Pavel M, Cwikla JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371:224-233.
120. Ekeblad S, Sundin A, Janson ET, et al. Temozolomide as monotherapy
is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007;13:2986-2991.
121. Fine RL, Gulati AP, Krantz BA, et al. Capecitabine and temozolomide
(CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: The Pancreas Center at Columbia University experience. Cancer
Chemother Pharmacol. 2013;71:663-670.
122. Sun W, Lipsitz S, Catalano P, et al. Phase II/III study of doxorubicin
with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol. 2005;23:48974904.
123. Bajetta E, Rimassa L, Carnaghi C, et al. 5-Fluorouracil, dacarbazine,
and epirubicin in the treatment of patients with neuroendocrine tumors. Cancer. 1998;83:372-378.
124. Fan JT, Ortiz RG, Buettner H. Regression of choroidal metastases from
a bronchial carcinoid tumor after chemotherapy with cisplatin and
etoposide. Am J Ophthalmol. 1994;117:111-113.
125. Granberg D, Eriksson B, Wilander E, et al. Experience in treatment of
metastatic pulmonary carcinoid tumors. Ann Oncol. 2001;12:13831391.
126. Medley L, Morel AN, Farrugia D, et al. Phase II study of single agent
capecitabine in the treatment of metastatic non-pancreatic neuroendocrine tumours. Br J Cancer. 2011;104:1067-1070.
127. Bajetta E, Catena L, Procopio G, et al. Are capecitabine and oxaliplatin
(XELOX) suitable treatments for progressing low-grade and high-
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
161
147.
148.
149.
150.
151.
162
LUNG CANCER
SPEAKERS
Rogerio Lilenbaum, MD
Yale University Cancer Center
New Haven, CT
Marcus Neubauer, MD
McKesson Specialty Health
The Woodlands, TX
likely the results were obtained by chance or that the null hypothesis was true.1 On the other hand, there is no accepted definition of clinical signifcance. The closest concept is the
minimally clinically important difference, which is the smallest
treatment effcacy that leads to a change in a patients management.2 Others have attempted to defne clinical signifcance by
highlighting absolute risk reduction, as opposed to relative risk
reduction, or the number needed to treat as a means to translate
results of clinical trials into patient management. Quality-of-life
issues and patient-reported outcomes also have been proposed
as measures of clinical signifcance.
Chemotherapy
During the modern chemotherapy era, between the 1990s and
early 2000s, when the median survival of patients with advanced
NSCLC was approximately 8 months, clinical trials were designed to demonstrate a difference in median survival of approximately 2 months, arbitrarily set as a balance between a 1
month or less difference (considered not meaningful) and a 3
month or more improvement (considered very meaningful).
Several of such trials, including several thousands of patients,
were conducted but showed no signifcant differences among
the various combination chemotherapy regimens.3 One trial,
which compared cisplatin/docetaxel with cisplatin/vinorelbine,
raised considerable debate in its interpretation and applicability
to clinical practice.4 The difference in survival, in favor of cisplatin/docetaxel, was borderline statistically signifcant, but was not
considered clinically signifcant by most clinicians. Although a
commonly used combination, cisplatin/docetaxel did not gain
widespread endorsement as the regimen of choice in advanced NSCLC.
More recently, the combination of cisplatin/pemetrexed
was compared with cisplatin/gemcitabine, and a clear advantage emerged for the former in patients with nonsquamous
histology.5 This study debunked an old paradigm as the frst
From the Yale Cancer Center, New Haven, CT; Princess Margaret Cancer Center, Toronto, Canada; McKesson Specialty Health, The Woodlands, TX.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Rogerio Lilenbaum, MD, Yale Cancer Center, 20 York St. NP5, New Haven, CT 06510; email: rogerio.lilenbaum@yale.edu.
2015 by American Society of Clinical Oncology.
e420
to show a difference in outcome by histologic type in advanced disease. Likewise, the trials that tested the concept of
maintenance have yielded solid benefts for patients and are
considered both statistically and clinically signifcant.6
Monoclonal Antibodies
Two trials involving monoclonal antibodies illustrate the issues
of statistical and clinical signifcance. The frst showed that the
addition of bevacizumab to chemotherapy improved survival,
albeit at the cost of additional toxicity.7 Although a similar trial
in Europe did not show an overall survival advantage (despite an
improvement in progression-free survival [PFS]), bevacizumab
has been adopted in the United States for eligible patients. From
a clinicians perspective, reluctance to add bevacizumab to chemotherapy is usually related to toxicity concerns and not so
much the clinical signifcance of the trial. The cost-effectiveness
implications are discussed below.
The second trial added cetuximab to chemotherapy in advanced NSCLC.8 Although the study met its primary endpoint
of improvement in overall survival, cetuximab was not incorporated in frst-line regimens, because the difference in median
survival was not felt to be clinically meaningful despite multiple
subsequent attempts to refne the target patient population.
More recently, ramucirumab was combined with docetaxel in
the second-line treatment of NSCLC and led to a statistically signifcant improvement in survival compared with docetaxel
alone.9 The magnitude of the difference in median survival was
relatively small, but the results are unprecedented in the sense
that no other agent, biologic or otherwise, has been shown to
improve outcomes when added to a cytotoxic drug in the
second-line treatment of NSCLC. It remains to be seen how
these results will be interpreted by clinicians and adopted in
clinical practice.
Targeted Therapy
The discovery that certain types of lung tumors harbor activating mutations that are sensitive to targeted agents has rev-
KEY POINTS
Although statistical signicance is easier to dene, clinical
signicance is by and large a subjective assessment and
must be interpreted in the context of the clinical question
addressed by the trial.
ASCO recently proposed more aggressive outcomes for
clinical trials of advanced nonsmall cell lung cancer, for
both squamous and non-squamous histologies.
The applicability of clinical trial data to real-life patients
requires assessment of a patients individual
circumstances, which may not have been addressed in the
study. This is particularly true in older patients and
patients with a poor performance status.
Clinical pathways reduce variability and decrease costs in
patients with advanced nonsmall cell lung cancer.
Other measures, such as a decrease in emergency
department visits and prevention of hospitalization, can
reduce costs while improving the quality of care.
e421
that multiple factors, including patient performance status, comorbidity, organ function, patient preference, and treatment
access, all factor into treatment decisions. In a real-world analysis of Canadian patients with advanced NSCLC who were
treated in a single-payer public health care system, 70% of patients were assessed by an oncologist at some point, but only
26% received systemic therapy.14 In those who received platinum doublet therapy and pemetrexed, outcomes were similar to
or better than outcomes reported in clinical trials. However,
older patients and those who had tumors with a squamous histology were signifcantly less likely to receive treatment for their
disease. Similar data have been reported by Earle et al15 from
U.S. SEER Medicare data, in which 23% of patients with advanced lung cancer received systemic therapy.15
Thus, although oncologists are able to achieve excellent results in clinical practice, similar to those seen in trials, the
achievement requires not only evidence-based practice but
also careful patient selection and shared decision making.
Special Populations
Most clinical trials, from which practice guidelines are derived, include highly selected patients who have an Eastern
Cooperative Oncology Group (ECOG) performance status
(PS) of 0 or 1, few or no comorbidities, and a younger age.
However, given that the median age of diagnosis in lung cancer is at least age 70 and that a majority of patients have an
ECOG PS of 2 or greater, how useful are clinical trial results
in the patients we actually see in practice?
In a recent review of the inclusion of older adults in advanced lung cancer trials, a third of commonly cited trials
specifcally excluded older patients.16 Fortunately, there are
multiple trials focused on the older patient population with
lung cancer,17,18 but, again, not all patients in routine practice
are suitable for the recommended therapy. Real-world analyses of older adults with lung cancer suggest that older patients do beneft from systemic therapy.14,19 Earle et al20 have
examined the influence of age on systemic treatment for patients with advanced NSCLC in a real-world setting, using
the SEER database.20 As age increased, the likelihood of receiving chemotherapy decreased, even though patients were still referred to medical oncologists for an opinion. Treatment rates
varied inversely with the number of comorbidities.
In the case of potentially curative adjuvant chemotherapy,
Cuffe et al21 demonstrated that, although older patients are
prescribed adjuvant chemotherapy, the rate of uptake is approximately half of that seen in the entire population of patients with early-stage disease (16% vs. 31% overall).21 This
population-based study confrmed that a survival beneft was
seen in all age groups, and the tolerability of therapy in those
patients older than age 70 selected to receive treatment appeared similar to that of younger patients.
The PS presents a similar challenge, because most patients
with advanced lung cancer do not present with a PS of 0 or 1.
Trials have shown that platinum-based doublet therapy is superior to single-agent treatment in patients who have a PS of 2,22-24
whereas guidelines recommend against treatment of patients
who have a PS of 3.25 This decision is more challenging in prace422
Employment: None. Leadership Position: Marcus A. Neubauer, McKesson Specialty Health. Stock or Other Ownership Interests: None. Honoraria: None.
Consulting or Advisory Role: Rogerio Lilenbaum, Boehringer Ingelheim, Genentech/Roche. Speakers Bureau: None. Research Funding: Natasha B. Leighl,
Roche Canada (Inst). Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: Rogerio
Lilenbaum, Roche. Marcus A. Neubauer, McKesson Specialty Health. Other Relationships: None.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e423
References
1. Goodman S. A dirty dozen: twelve p-value misconceptions. Semin Hematol. 2008;45:135-140.
2. Jaeschke R, Singer J, Guyatt GH. Measurement of health status: ascertaining the minimal clinically important difference. Control Clin Trials.
1989;10:407-415.
3. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl
J Med. 2002;346:92-98.
4. Fossella F, Pereira JR, von Pawel J, et al. Randomized, multinational,
phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX
326 study group. J Clin Oncol. 2003;21:3016-3024.
5. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing
cisplatin plus gemcitabine with cisplatin plus pemetrexed in
chemotherapy-naive patients with advanced-stage non-small-cell lung
cancer. J Clin Oncol. 2008;26:3543-3551.
6. Paz-Ares LG, de Marinis F, Dediu M, et al. PARAMOUNT: fnal overall
survival results of the phase iii study of maintenance pemetrexed versus
placebo immediately after induction treatment with pemetrexed plus
cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin
Oncol. 2013;31:2895-2902.
7. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with
bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:
2542-2550.
8. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in
patients with advanced non-small-cell lung cancer (FLEX): an openlabel randomised phase III trial. Lancet. 2009;373:1525-1531.
9. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel
versus placebo plus docetaxel for second-line treatment of stage IV nonsmall-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial.
Lancet. 2014;384:665-673.
10. Lee CK, Brown C, Gralla RJ, et al. Impact of EGFR inhibitor in nonsmall cell lung cancer on progression-free and overall survival: a metaanalysis. J Natl Cancer Inst. 2013;105:595-605.
11. Ellis LM, Bernstein DS, Voest EE, et al. American Society of Clinical
Oncology perspective: raising the bar for clinical trials by defning clinically meaningful outcomes. J Clin Oncol. 2014;32:1277-1280.
12. Booth CM, Shepherd FA, Peng Y, et al. Adoption of adjuvant chemotherapy for non-small-cell lung cancer: a population-based outcomes
study. J Clin Oncol. 2010;28:3472-3478.
13. Owonikoko TK, Ragin C, Chen Z, et al. Real-world effectiveness of systemic agents approved for advanced non-small cell lung cancer: a SEERMedicare analysis. Oncologist. 2013;18:600-610.
14. Sacher AG, Le LW, Leighl NB. Real-world chemotherapy treatment patterns in metastatic non-small cell lung cancer: are patients undertreated? Cancer. In press.
15. Earle CC, Venditti LN, Neumann PJ, et al. Who gets chemotherapy for
metastatic lung cancer? Chest. 2000;117:1239-1246.
16. Sacher AG, Le LW, Leighl NB, et al. Elderly patients with advanced
NSCLC in phase III clinical trials: are the elderly excluded from
practice-changing trials in advanced NSCLC? J Thorac Oncol. 2013;8:
366-368.
17. Quoix E, Zalcman G, Oster JP, et al. Carboplatin and weekly paclitaxel
doublet chemotherapy compared with monotherapy in elderly patients
with advanced non-small-cell lung cancer: IFCT-0501 randomized,
phase 3 trial. Lancet. 2011;378:1079-1088.
18. Gridelli C. The ELVIS trial: a phase III study of single-agent vinorelbine
as frst-line treatment in elderly patients with advanced non-small cell
e424
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
LUNG CANCER
SPEAKERS
Claudia I. Henschke, MD, PhD
Icahn School of Medicine at Mount Sinai
New York, NY
Denise R. Aberle, MD
UCLA David Geffen School of Medicine
Los Angeles, CA
The harms imposed by false-positive results and overdiagnoses may outweigh the benefts of screening in realworld settings.15,16
Centers with lower expertise in lung cancer CT screening
may not be able to reproduce the mortality benefts seen in
the NLST.17,18
Infrastructure gaps need to be addressed before screening implementation (e.g., consistent documentation of
smoking history).19,20
Notwithstanding the opposing views, regulatory agencies
have gradually taken a favorable position regarding the adoption of lung cancer CT screening. In December 2013, the U.S.
Preventive Services Task Force (USPSTF) released a grade B
recommendation to screen high-risk individuals, defned as
those age 55 to 80 who have a minimum smoking history of
30 pack-years and who currently smoke or have quit within
the past 15 years.21 The Affordable Care Act requires that
commercial insurance plans cover screening services that receive a grade B USPSTF recommendation, essentially guaranteeing coverage of CT screening to insured patients
younger than age 65.22 Likewise, the Centers for Medicare &
Medicaid Services (CMS) has recently released a fnal decision to cover CT screening for Medicare benefciaries who
are age 55 to 77 and have the same minimum smoking history
required by the USPSTF.23 The USPSTF and CMS determi-
From the Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Bernardo H.L. Goulart, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. North, PO Box 19024, Seattle, WA 98109; email: bgoulart@fhcrc.org.
2015 by American Society of Clinical Oncology.
e426
KEY POINTS
Lung cancer computed tomography (CT) screening will
become routine practice.
Lung cancer CT screening will be an expensive public
health investment.
The value of CT screening in practice will depend on the
strategies used to implement it.
Cost-effective implementation of screening will require the
creation of a broad infrastructure.
Physician education, patient counseling, smoking cessation,
and adherence to guidelines should be core elements of a
CT screening implementation plan.
e427
Reference
Analysis Type
Perspective
1.4 to 2.2
Actuarial analysis
269
4.8
Forecast model
Medicare
NR
3.5 to 5.5
Actuarial analysis
Medicare
241
1.7
Cressman et al, 201439 Prospective cohort study Canadian public single 550
payer
NR
Abbreviations: NLST, National Lung Screening Trial; NR, not reported; USPSTF, U.S. Preventive Services Task Force.
*Costs are inated to 2014 U.S. dollars.
Costs reect total expenditures in the entire target population from the respective healthcare system perspective.
tially when screening is performed in a lower-risk population, including individuals who met the NLST inclusion
criteria. This negative impact on value occurs because many
more additional scans need to be performed to detect one
early-stage lung cancer in lower-risk screenees. The costs of
CT screening will become prohibitive if new programs routinely screen individuals irrespective of their lung cancer risk
(e.g., light or never smokers), potentially reaching $19 billion
per year, and such practice should be strongly discouraged.41
The value of any screening program, and CT screening in
particular, also depends on identifying and offering this intervention to high-risk individuals. Failure to offer screening
to all eligible individuals will decrease the effectiveness and
value of screening in any given health care system.19
Early evidence suggests that new screening programs are
performing CT screening in lower-risk patients while at the
same time potentially missing the opportunity to screen
high-risk individuals (Table 2). Unawareness by primary
care providers (PCPs) of the role of CT screening is one of the
main reasons for ineffcient selection of screening candidates. A recent survey of 212 PCPs from an academic medical
center showed that only 12% of them had ordered CT screening in the prior year; 52% knew fewer than three of six guideline components of CT screening, and 24% did not know any
screening guidelines.42 Of 89 patients included in our singlecenter screening registry, 19 (21%) did not meet any eligibility criteria for screening; PCPs were the referral source for the
majority of these ineligible individuals.43
Physician education should take priority in the early phases
of screening implementation, because PCPs are the major
source of screening referrals.44,45 The Lahey clinic received
more than 500 referrals of eligible high-risk candidates
within 1 year of launching a CT screening program after conducting extensive PCP-oriented educational campaigns.46
Most other screening programs have had lower referral num-
TABLE 2. Potential Inefciencies That May Decrease the Value of Lung Cancer CT Screening and Potential
Solutions
Screening-Related Process
Potential Inefciency
Potential Solution(s)
Selection of Eligible
Individuals
2 Screening effectiveness
Patient counseling
Follow-up of Positive
Screening Results
Smoking Cessation
Patient counseling
Adherence to guidelines
Multidisciplinary management
2 Screening effectiveness
1 Costs
Physician education
Patient anxiety
Overlook clinically relevant, incidental
ndings
2 Screening effectiveness
bers, mostly because of PCP unawareness and lack of insurance coverage for screening.43,47,48
Many low-risk individuals may demand to undergo CT
screening because of a fear of developing lung cancer, despite
being ineligible for screening (i.e., worried well patients).20
Some of these patients will self-refer to a screening program,
whereas others will request a referral from their PCPs who, in
many cases, will order screening to honor the patients request. Media campaigns usually target high-risk individuals,
but an unintended consequence of these campaigns is that
low-risk individuals feel that they need to pursue screening.
Screening programs should offer evidence-based counseling to all patients undergoing screening, particularly those
who are at low risk and are ineligible by guidelines criteria.20,21 A balanced discussion about the benefts and harms
of screening based on patients risk may ensure that screening is performed preferably in high-risk individuals.
Decision-aid and risk-prediction tools may be particularly
useful to inform patients about their individual risk of developing lung cancer and whether screening is more likely to be
benefcial or harmful.49 Although validated decision aids for
CT screening are not available routinely, clinical trials
currently are testing the effectiveness of these tools in
counseling individuals.50 To incentivize physicians to
counsel patients, health insurance plans should create
payment fees for CT screening counseling visits. In fact,
e429
every 6 months in primary care clinics. In the 3 months before implementing this strategy, the program identifed and
screened four patients. In the 7 subsequent months, the program screened 58 eligible patients.48
This may represent an opportunity for comparativeeffectiveness studies of treatment modalities that potentially
involve less morbidity than lobectomies, including minimally invasive surgery and stereotactic radiation techniques.56 The role of
these alternative treatments in screening-detected lung cancers remains an area of investigation; clinical trials and costeffectiveness analyses of these approaches should receive
priority as strategies offering high potential to increase the
value of CT screening.
FINAL CONSIDERATIONS
Lung cancer CT screening may save thousands of lives and
add value to society if implemented in a manner that reproduces the mortality benefts seen in the NLST while minimizing harms and costs.
Screening programs should implement practices that will
likely increase the value of CT screening, including counseling and selecting high-risk patients for screening, monitoring adherence to guidelines for screening-detected lung
nodules, offering smoking cessation interventions, and making specifc recommendations for follow-up of screening incidental fndings.
Finally, value is only one angle to consider when implementing CT screening. Policy makers and clinicians also need to take
into account sociodemographic disparities and other issues that
can prevent equitable access to screening. Only by taking a comprehensive approach will we achieve the promise of CT screening: decrease the huge burden imposed by lung cancer.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: None.
Speakers Bureau: None. Research Funding: Bernardo H.L. Goulart, Bayer (Inst). Patents, Royalties, or Other Intellectual Property: None. Expert
Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Wood DE. The importance of lung cancer screening with low-dose
computed tomography for Medicare benefciaries. JAMA Intern Med.
2014;174:2016-2018.
2. Woolf SH, Harris RP, Campos-Outcalt D. Low-dose computed tomography screening for lung cancer: how strong is the evidence? JAMA Intern Med. 2014;174:2019-2022.
3. American College of Radiology. Burwell answers Medicare lung cancer
e431
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
e432
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59. Jha P, Peto R. Global effects of smoking, of quitting, and of taxing tobacco. N Engl J Med. 2014;370:60-68.
60. National Cancer Institute. Smoking quitline. www.acr.org/QualitySafety/Resources/LungRADS. Accessed February, 2nd, 2015.
61. Bricker J, Wyszynski C, Comstock B, et al. Pilot randomized controlled
trial of web-based acceptance and commitment therapy for smoking
cessation. Nicotine Tob Res. 2013;15:1756-1764.
62. Mets OM, de Jong PA, Prokop M. Computed tomographic screening for
lung cancer: an opportunity to evaluate other diseases. JAMA. 2012;308:
1433-1434.
63. van de Wiel JC, Wang Y, Xu DM, et al. Neglectable beneft of searching for
incidental fndings in the Dutch-Belgian lung cancer screening trial
(NELSON) using low-dose multidetector CT. Eur Radiol. 2007;17:1474-1482.
64. National Lung Screening Trial Research Team, Church TR, Black WC,
et al. Results of initial low-dose computed tomographic screening for
lung cancer. N Engl J Med. 2013;368:1980-1991.
65. McKee BJ, Hashim JA, French RJ, et al. Experience with a CT screening
program for individuals at high risk for developing lung cancer. J Am
Coll Radiol. 2015;12:192-197.
66. LikeForex. Quality currency counter. www.likeforex.com/currencyconverter/canadian-dollar-cad_usd-us-dollar.htm/2013. Accessed January 25, 2015.
e433
LUNG CANCER
SPEAKERS
Nasser Hanna, MD
Indiana University Melvin and Bren Simon Cancer Center
Indianapolis, IN
David M. Jablons, MD
University of California, San Francisco
San Francisco, CA
tage IIIA nonsmall cell lung cancer (NSCLC) encompasses a heterogeneous group of tumors with a wide range
of sizes, degrees of local invasion, and mediastinal lymph node
involvement. The variety of presentation within this stage poses
an ongoing challenge to thoracic oncologists to make evidencebased treatment recommendations and accurately predict outcomes in different subgroups of patients. The features that
defne stage IIIA presentation suggest imminent systemic disease, and 5-year overall survival outcomes remain poor at only
24% for stage IIIA tumors and 9% for stage IIIB tumors.1 However, certain patient populations, particularly those whose tumors are downstaged by induction therapy and those who
undergo lobectomy, have decent outcomes with the appropriate
multimodality regimens. Thoracic surgeons play an important
role as part of an interdisciplinary care team in selecting operative candidates with stage IIIA disease for whom defnitive local
control offers the best chance of long-term survival.
e435
KEY POINTS
Thoracic surgeons should be involved early in the
multidisciplinary management of stage IIIA disease in
patients to identify operative candidates and help guide
pathologic staging of the mediastinum.
A triple-modality treatment approach in patients with N2
mediastinal disease can achieve 5-year overall survival
rates of up to 30% to 40%; good prognostic indicators
are a response to induction treatment and the need for
lobectomy instead of pneumonectomy.
Pneumonectomy outcomes have improved over time, and
the need for a pneumonectomy is not a reason to avoid a
surgical resection in patients who can tolerate the
procedure.
Video-assisted thoracic surgery survival outcomes are
comparable to those after open thoracotomy, though no
randomized trials have directly compared the two
approaches in stage IIIA disease.
In the era of personalized medicine, genetic proling of
stage IIIA tumors for prognostic risk stratication is a
promising area of new research that could help guide
treatment decisions and better predict patient-specic
outcomes within this heterogeneous stage.
e436
published outcomes demonstrating its safety. Marra et al7 reported repeat mediastinoscopy in 104 patients with lung
cancer after induction chemoradiotherapy. Repeat mediastinoscopy was possible in 98% of patients, with 0% mortality
and 1.9% morbidity as a result of left recurrent nerve palsy.
Repeat mediastinoscopy had a sensitivity of 61%, a specifcity
of 100%, a positive predictive value of 100%, and a negative
predictive value of 85%. Successful biopsy results are dependent on the lymph node station; the best results are seen for
stations 2R, 4R, 4L, and 7, with successful biopsy rates of 88%
to 98% at frst mediastinoscopy and 63% to 84% at repeat
mediastinoscopy. Station 2L, which must be approached
with caution because of its proximity to the left recurrent laryngeal nerve, was successfully biopsied during only 56% of
frst mediastinoscopies and 21% of repeat procedures.7 Call
et al8 during a similar experience with 101 repeat mediastinoscopies reported a sensitivity of 74%, a specifcity of 100%,
a positive predictive value of 100%, and a negative predictive
value of 79%.8 These data show that repeat mediastinoscopy
is feasible; however, individual surgeon experience and comfort level are of paramount importance before attempting a
repeat mediastinoscopy.
EBUS- and EUS-FNA are useful and accurate alternatives
for staging the mediastinum. EBUS-FNA has a reported sensitivity of 92%, a specifcity of 100%, a positive predictive
value of 100%, and a negative predictive value of 97% for
staging mediastinal lymph nodes in NSCLC.2 EUS-FNA is an
additional technique that was frst developed to stage gastric
and esophageal cancer but that has gained popularity in lung
cancer as well, because it provides access to the posterior mediastinum through the esophageal wall. A meta-analysis
demonstrated an overall sensitivity of 83% and a specifcity of
97% of EUS-FNA at detecting malignant lymph nodes in patients with NSCLC.9 After induction treatment, Annema et
al10 reported their experience with 19 consecutive patients
who had NSCLC with mediastinal disease who required restaging. Biopsy specimens were successfully obtained via
EUS-FNA from at least one lymph node station in 89% of
patients and from two different lymph node stations in 47%
of patients.10 Both EBUS and EUS can be performed safely
and accurately after induction treatment for restaging purposes. At our institution, we preferentially use EBUS and
EUS-FNA for initial mediastinal staging and reserve the frst
attempt at mediastinoscopy for restaging before surgery.
Patient selection for surgery in stage IIIA disease depends
on the surgeons experience and the patients ability to tolerate a pulmonary resection. At our institution, we strongly believe in the benefts of defnitive local control and have an
aggressive surgical approach. We offer resection to patients
who have stage IIIA tumors despite size, invasion into the
main bronchus, mediastinal pleura, parietal pericardium, or
resectable N2 disease as long as a complete R0 resection with
clean margins is achievable. We also offer resection to select
patients with T4 disease on the basis of the presence of isolated but resectable tumor nodules in a different ipsilateral
lobe and tumors invading mediastinal structures, vena cava,
e437
e439
Analysis of nonsquamous stage III NSCLC tumors with a molecular assay divides patients
into low, intermediate, and high risk groups on the basis of the genetic proles of the
tumors. Risk stratication by the molecular assay successfully predicts survival, with
signicant differences in 5-year overall survival rates (p 0.0044). Prognostic assays such
as this one may help guide future management of stage III NSCLC, but current data are
limited and further investigation in this area is needed.25
later-stage disease. Shen et al29 examined microRNA expression profles in stages IIB and IIIA, fully resected, EGFRmutant NSCLC and found that certain mRNA expression
levels were predictive of disease recurrence, survival, and response to geftinib.29
This is an emerging area of research, and much more work
is still needed. However, preliminary studies are interesting
and suggest that there is important prognostic information to
be gained from genetic profling of late-stage tumors. This
information can predict recurrence or overall survival times
within patients who have stage IIIA disease and also could be
used to make more informed adjuvant treatment decisions.
On preoperative biopsy specimens, patients with stage IIIA
disease and favorable tumor genetics may be more likely to
have limited local disease and, therefore, would beneft the
most from local control with a surgical resection. Specifc
molecular assays might be developed to predict which tumors
are most likely to be downstaged by induction therapy or to predict the response to certain chemotherapy or radiation regimens. As tumor mutation analysis and personalized medicine
become the standard of care, patients with NSCLC will expect a
more detailed tumor assessment, an individualized treatment
plan, and an enhanced survival risk stratifcation.
CONCLUSION
and tumor biopsies, with high-risk profles suggestive of
ominous genetics, and imminent systemic disease could
predict shorter survival times or the high likelihood for
recurrence after surgery, which therefore would allow
physicians to make more informed decisions about surgical candidacy.
A 14-gene expression assay was developed at our institution to stratify the mortality risk in nonsquamous NSCLC
tumor specimens. This molecular assay has been internationally validated in more than 2,000 patients to predict disease
recurrence and has repeatedly outperformed conventional
staging criteria and high-risk NCCN clinicopathologic
features.25-28 Among a validation cohort from the China Clinical Trials Consortium that included 266 patients with stage IIIA
disease who underwent an attempt at surgical resection, Kratz et
al25 demonstrated that there were signifcant differences in survival based on a tumors genetic profle. Of these 266 patients,
molecular profling determined that 73% had high-risk tumors,
17% had intermediate-risk tumors, and 10% had low-risk tumors. The 5-year overall survival outcomes were signifcantly
different between these groups, with only a 25% 5-year survival
rate in high-risk patients compared with approximately a
50% 5-year survival rate in the low- and intermediate-risk
groups (p 0.0044; Fig. 1). The genetic profle of a tumor
provides additional prognostic information to predict
which patients within the same clinicopathologic stage are
at higher risk of disease recurrence.25
Other studies have examined the use of markers from surgical pathology specimens to predict treatment response in
e440
Stage IIIA NSCLC includes a heterogeneous group of patients and an overall grim prognosis. Management of this
stage involves separating patients who have curable local disease from those who essentially have early systemic disease.
In appropriate surgical candidates, a complete a surgical resection provides optimal local control and has real survival
benefts beyond chemotherapy and radiation alone. Surgical
resections likely improve survival by removing the resilient
and treatment-resistant cancer stem cell populations. Cancer
stem cells make up a small percentage of all tumor cells and
are unique in that they posses the qualities of self-renewal
and pluripotency, a high proliferative capacity, and the
ability to resist chemotherapy and radiation.30 Tumor recurrence after dramatic responses to chemotherapy and radiation has been attributed to the lingering presence of isolated
stem cells, which have the ability to repopulate an entire tumor after surviving treatment.31 Eradication of this critical
cell population is best achieved by removing any residual, microscopic tumor foci via a surgical resection after induction
therapy.
The real future in managing stage IIIA disease lies in the development of better systemic therapies to successfully downstage tumors before obtaining defnitive local control with a
surgical resection. In addition, there is a need for improved
prognostic molecular testing in later-stage tumors to help predict which patients will respond to induction therapy and to
provide improved survival risk stratifcation after surgery. As
these new technologies are developed, a multidisciplinary thoracic oncology team remains critical to make individualized
treatment recommendations that optimize long-term survival.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: David Jablons, Rescue Therapeutics. Honoraria: None. Consulting
or Advisory Role: None. Speakers Bureau: None. Research Funding: None. Patents, Royalties, or Other Intellectual Property: David Jablons, multiple
patents owned by UCSF. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Detterbeck FC, Boffa DJ, Tanoue LT. The new lung cancer staging system. Chest. 2009;136:260-271.
2. Yasufuku K, Nakajima T, Motoori K, et al. Comparison of endobronchial ultrasound, positron emission tomography, and CT for lymph
node staging of lung cancer. Chest. 2006;130:710-718.
3. Rebollo-Aguirre AC, Ramos-Font C, Villegas Portero R, et al. Is FDGPET suitable for evaluating neoadjuvant therapy in non-small cell lung
cancer? Evidence with systematic review of the literature. J Surg Oncol.
2010;101:486-494.
4. Martins RG, DAmico TA, Loo BW Jr, et al. The management of patients
with stage IIIA non-small cell lung cancer with N2 mediastinal node
involvement. J Natl Compr Canc Netw. 2012;10:599-613.
5. Lemaire A, Nikolic I, Petersen T, et al. Nine-year single center experience with cervical mediastinoscopy: complications and false negative
rate. Ann Thorac Surg. 2006;82:1185-1189; discussion, 1189-1190.
6. Hammoud ZT, Anderson RC, Meyers BF, et al. The current role of mediastinoscopy in the evaluation of thoracic disease. J Thorac Cardiovasc
Surg. 1999;118:894-899.
7. Marra A, Hillejan L, Fechner S, et al. Remediastinoscopy in restaging of
lung cancer after induction therapy. J Thorac Cardiovasc Surg. 2008;135:
843-849.
8. Call S, Rami-Porta R, Obiols C, et al. Repeat mediastinoscopy in all its
indications: experience with 96 patients and 101 procedures. Eur J Cardiothorac Surg. 2011;39:1022-1027.
9. Micames CG, McCrory DC, Pavey DA, et al. Endoscopic ultrasoundguided fne-needle aspiration for non-small cell lung cancer staging: a
systematic review and metaanalysis. Chest. 2007;131:539-548.
10. Annema JT, Veselic M, Versteegh MI, et al. Mediastinal restaging: EUSFNA offers a new perspective. Lung Cancer. 2003;42:311-318.
11. Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide
plus chest radiotherapy followed by surgery for stages IIIA (N2) and
IIIB non-small-cell lung cancer: mature results of Southwest Oncology
Group phase II study 8805. J Clin Oncol. 1995;13:1880-1892.
12. van Meerbeeck JP, Kramer GW, Van Schil PE, et al. Randomized controlled
trial of resection versus radiotherapy after induction chemotherapy in stage
IIIA-N2 non-small cell lung cancer. J Natl Cancer Inst. 2007;99:442-450.
13. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy
with or without surgical resection for stage III non-small cell lung cancer: a
phase III randomised controlled trial. Lancet. 2009;374:379-386.
14. Douillard JY, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IBIIIA non-small-cell lung cancer (Adjuvant Navelbine International
Trialist Association [ANITA]): a randomised controlled trial. Lancet
Oncol. 2006;7:719-727.
15. Askoxylakis V, Tanner J, Kappes J, et al. Trimodal therapy for stage
III-N2 non-small cell lung carcinoma: a single center retrospective analysis. BMC Cancer. 2014;14:572.
16. Stefani A, Alifano M, Bobbio A, et al. Which patients should be operated
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
e441
NASSER HANNA
From the Division of Hematology/Oncology, Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Nasser Hanna, MD, Division of Hematology/Oncology, Department of Medicine, Indiana University Health Simon Cancer Center, 535 Barnhill Dr., RT 473, Indianapolis, IN
46202; email: nhanna@iupui.edu.
2015 by American Society of Clinical Oncology.
e442
TABLE 1. Key Historic Clinical Trials in Unresectable or Inoperable Stage III NSCLC
Group
Design
Comment
CALGB7
Established the role of sequential chemotherapy followed by radiation in stage III disease
WJLCG9
RTOG8
CALGB16
Induction therapy prior to concurrent chemoradiation does not prolong survival compared to concurrent
chemoradiation alone
Consolidation docetaxel does not improve survival compared to concurrent chemoradiation alone
South Korea
Consolidation therapy utilizing cisplatin and docetaxel does not improve survival when added to weekly
platinum/taxane/XRT
SWOG21
RTOG12
ChemoXRT versus ChemoXRT Cetuximab The addition of cetuximab to concurrent chemoradiation does not improve survival compared with
concurrent chemoradiation alone
HOG/USO17
13
Abbreviations: NSCLC, non-small cell lung cancer; CALGB, Cancer and Leukemia Group B; XRT, external beam radiation therapy; WJLCG, West Japan Lung Cancer Group; Chemo, chemotherapy;
RTOG, Radiation Therapy Oncology Group; HOG, Hoosier Oncology Group; USO, US Oncology; SWOG, Southwest Oncology Group.
KEY POINTS
Stage III nonsmall cell lung cancer comprises a
heterogeneous group of patients.
Concurrent chemoradiation is the standard of care for most
t patients with stage III disease.
The optimal chemotherapy agents and duration of therapy
remain undened.
Early results incorporating targeted agents or
antiangiogenics have proven ineffective or, in some cases,
unsafe.
Newer strategies with molecularly targeted agents,
including inhibitors of EGFR, ALK, RAS, and PD-1, are under
investigation.
prospectively conducted randomized phase III trial comparing these two regimens has not been reported.
e443
NASSER HANNA
Schema
Randomized phase II
NCT Registry
Number
01822496
01909752
Randomized phase II
00828009
02186847
Single-arm phase II
ChemoXRT followed by
pembrolizumab
01912625
02343952
02125461
Arm 1: MED14736
Arm 2: Placebo
Abbreviations: NSCLC, non-small cell lung cancer; NCT, National Clinical Trial; Chemo,
chemotherapy; XRT, external beam radiation therapy; mut, mutated; GM-CSF, granulocyte
macrophage colony-stimulating factor; d, days.
lection based on the tumor molecular profle. Continued efforts to target the EGFR in stage III disease are underway.
Radiation is known to increase the expression of EGFR, resulting in radiation resistance.27 Proposed mechanisms for
this include EGFR interaction with DNA repair enzymes;
EGFR activation of PI3K/AKT signaling which suppresses
DNA damage-induced apoptosis; and activation of downstream signaling through the RAS and STAT pathways to
promote cancer cell repopulation. Furthermore, tumors with
activating EGFR mutations appear to be more sensitive to radiation than their EGFR wild-type counterparts.27,28 This
may be because mutated EGFR fails to bind to a key enzyme
in DNA repair. Similarly, in vitro studies suggest that cell
lines that harbor ALK fusion proteins may be more sensitive
to ALK inhibition combined with radiation.29 In one experiment, the combination of crizotinib with radiation resulted
in greater tumor growth inhibition than either treatment
alone in a cell line with an ALK fusion protein. Similar effects
were not seen in a cell line without the ALK fusion protein.
Based on this preclinical data, a study of erlotinib or crizotinib as induction therapy in patients with stage III NSCLC is
ongoing (NCT 01822496). Approximately 234 patients with
nonsquamous NSCLC will be stratifed based on EGFR mutation and ALK gene-rearrangement status and randomly assigned to one of four arms. Patients on arm 1 and 3 receive
erlotinib or crizotinib, respectively, as induction therapy for
up to 12 weeks. Those who have no disease response after 6
weeks will undergo immediate chemoradiation. After 2
weeks of completion of induction therapy, patients receive
concurrent chemoradiation with cisplatin and etoposide or
carboplatin and paclitaxel. Patients on arm 2 (EGFR mutation cohort) or arm 4 (ALK gene-rearranged cohort) receive
concurrent chemoradiation beginning on day 1. The primary
objective is to assess whether patients treated with targeted
agents based on molecular characteristics have a longer
progression-free survival than those treated with chemoradiation alone.
The RAS oncogene has also been proposed to play a role in
radiation resistance.30 Although targeting RAS activation directly has yielded disappointing results, downstream targets
of RAS, including MEK, may be feasible. In vitro studies demonstrate an increased radiosensitization when such downstream pathways are inhibited. It has also been proposed that
PI3K is a mediator of RAS-induced radiation resistance. Efforts are underway within the National Cancer Institute to
incorporate trametinib (NCT 01912625), a MEK inhibitor,
into chemoradiation in patients with KRAS mutations. Approximately 30 patients with any histology NSCLC with a
KRAS mutation in exons G12, G13, or Q61 will receive daily
oral trametinib with concurrent carboplatin, paclitaxel, and
radiation for 6 weeks followed by two cycles of consolidation
carboplatin and paclitaxel alone. The primary objective is to
determine the maximum tolerated dose of trametinib when
combined with chemoradiation. Future efforts with PI3K inhibitors may also be worth testing.
from the Eastern Cooperative Oncology Group, combining tecemotide with bevacizumab after chemoradiation, has recently
completed accrual (NCT 00828009). Patients with stage III nonsquamous NSCLC received concurrent chemoradiation using
weekly carboplatin and paclitaxel for 6.5 weeks. Patients with nonprogression receive two additional cycles of consolidation chemotherapy. On completion of consolidation chemotherapy, patients
receive a single dose of cyclophosphamide 3 days before the frst
tecemotide and bevacizumab treatment. Patients then receive bevacizumabonday1andtecemotidesubcutaneouslyondays1,8,and
15 for cycles 1 and 2 then every other cycle beginning in course 4.
Treatment continues every 21 days for up to 34 cycles. The primary
endpoint is to determine the safety of bevacizumab plus tecemotide
as maintenance therapy in this setting.
Evidence indicates radiation therapy induces tumor antigen release from the dying tumor cells that can be recognized
by the immune system.32,33 Therefore, radiation is an immune stimulator that enhances T-cell activation and infltration. Furthermore, radiation has been shown to increase the
expression of PD-L1, an immune checkpoint. Combining radiation with checkpoint inhibitors, such as PD-1 or PD-L1
inhibitors, including MED14736, pembrolizumab, and nivolumab, are being investigated. MED14736, an antibody to
PD-L1, will be tested in a phase III industry-sponsored trial
(PACIFIC) involving 702 patients across 100 sites around the
globe (NCT 02125461). Patients with unresectable stage III
NSCLC will be treated with concurrent chemoradiation utilizing at least two cycles of platinum-based chemotherapy. If
no evidence of progression is seen, patients will then be
treated with MED14736 or placebo (2:1 randomization) for
up to 1 year. The primary endpoint is overall survival. A
phase II single-arm study evaluating pembrolizumab as consolidation therapy after concurrent chemoradiotherapy will
be conducted by the Hoosier Cancer Research Network
(NCT 02343952). In this trial, approximately 83 patients will
receive either weekly carboplatin/paclitaxel or cisplatin/etoposide with 59.4 to 66 Gy radiation. Patients with nonprogressive disease will then receive pembrolizumab every 3
weeks for up to 1 year. A safety analysis will take place after
the initial 10 patients have been treated and received at least
three cycles of pembrolizumab. Given the possibility of pneumonitis after chemoradiation and the expected activation of
T cells with pembrolizumab, the incidence of delayed or severe pneumonitis and/or recurrent esophagitis in the radiated feld will be of special importance. The primary
endpoint is to assess the time to distant relapse. Secondary
analyses will evaluate the effect of PDL-1 status on outcomes.
In addition, a randomized trial with nivolumab after chemoradiation is under development (personal communication,
Jeffrey Bradley, February 2015).
CONCLUSION
Therapeutic advances in the treatment of stage III NSCLC
are diffcult to achieve. Many factors contribute to the diffasco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e445
NASSER HANNA
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: None.
Speakers Bureau: None. Research Funding: Nasser Hanna, Merck KGaA (Inst). Patents, Royalties, or Other Intellectual Property: None. Expert
Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Berghmans T, Paesmans M, Sculier JP. Prognostic factors in stage III
non-small cell lung cancer: a review of conventional, metabolic and new
biological variables. Ther Adv Med Oncol. 2011;3:127-138.
2. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small cell lung
cancer: a phase III randomized controlled trial. Lancet. 2009;374:379386.
3. Palma DA, Senan S, Tsujino K, et al. Predicting radiation pneumonitis
after chemoradiation therapy for lung cancer: an international individual patient data meta-analysis. Int J Radiat Oncol Bio Phys. 2013;85:444450.
4. Auperin A, Le Pechoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced nonsmall-cell lung cancer. J Clin Oncol. 2010;28:2181-2190.
5. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26:3552-3559.
6. Schaake-Koning C, van den Bogaert W, Dalesio O, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung
cancer. N Engl J Med. 1992;326:524-530.
7. Dillman RO, Seagren SL, Propert KJ, et al. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in
stage III non-small-cell lung cancer. N Engl J Med. 1990;323:940-945.
8. Curran WJ Jr, Paulus R, Langer CJ, et al. Sequential vs. concurrent
chemoradiation for stage III non-small cell lung cancer: randomized
phase III trial RTOG 9410. J Natl Cancer Inst. 2011;103:1452-1460.
9. Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent
versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung
cancer. J Clin Oncol. 1999;17:2692-2699.
10. Yamamoto N, Nakagawa K, Nishimura Y, et al. Phase III study comparing second- and third-generation regimens with concurrent thoracic radiotherapy in patients with unresectable stage III non-small-cell lung
cancer: West Japan Thoracic Oncology Group WJTOG0105. J Clin Oncol. 2010;28:3739-3745.
11. Govindan R, Bogart J, Stinchcombe T, et al. Randomized phase II study
of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small-cell
lung cancer: Cancer and Leukemia Group B trial 30407. J Clin Oncol.
2011;29:3120-3125.
12. Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose
conformal radiotherapy with concurrent and consolidation carboplatin
e446
13.
14.
15.
16.
17.
18.
19.
20.
plus paclitaxel with or without cetuximab for patients with stage IIIA or
IIIB non-small-cell lung cancer (RTOG 0617): a randomized, two-bytwo factorial phase 3 study. Lancet Oncol. 2015;16:187-199.
Park K, Ahn Y, Ahn J, et al. A multinational phase III randomized trial
with or without consolidation chemotherapy using docetaxel and
cisplatin after concurrent chemoradiation in inoperable stage III
non-small cell lung cancer (CCheIN). J Clin Oncol. 2014;32:5s (suppl;
abstr 7500).
Segawa Y, Kiura K, Takigawa N, et al. Phase III trial comparing docetaxel and cisplatin combination chemotherapy with mitomycin, vindesine, and cisplatin combination chemotherapy with concurrent
thoracic radiotherapy in locally advanced non-small-cell lung cancer:
OLCSG 0007. J Clin Oncol. 2010;28:3299-3306.
Vokes E, Wang L, Vansteenkiste J, et al. Preliminary safety and treatment delivery data during concurrent phase of chemoradiation therapy
of the PROCLAIM trial: a phase 3 trial of pemetrexed, cisplatin, and
radiotherapy followed by consolidation pemetrexed versus etoposide,
cisplatin, and radiotherapy followed by consolidation cytotoxic chemotherapy of choice in patients with stage III nonsquamous cell lung cancer. J Thorac Oncol. 2013;8:S551-S552.
Santana-Davila R, Devisetty K, Szabo A, et al. Cisplatin and etoposide
versus carboplatin and paclitaxel with concurrent radiotherapy for stage
III non-small-cell lung cancer: an analysis of Veterans Health Administration data. J Clin Oncol. 2015;33:567-574.
Vokes EE, Herndon JE 2nd, Kelley MJ, et al. Induction chemotherapy
followed by chemoradiotherapy compared with chemoradiotherapy
alone for regionally advanced unresectable stage III non-small-cell lung
cancer: Cancer and Leukemia Group B. J Clin Oncol. 2007;25:16981704.
Hanna N, Neubauer M, Yiannoutsos C, et al. Phase III study of cisplatin,
etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung
cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin Oncol.
2008;26:5755-5760.
Huber RM, Engel-Riedel W, Kollmeier J, et al. GILT study: Oral vinorelbine (NVBo) and cisplatin (P) with concomitant radiotherapy (RT) followed by either consolidation (C) with NVBo plus P plus best
supportive care (BSC) or BSC alone in stage (st) III non-small cell lung
cancer (NSCLC): fnal results of a phase (ph) III study. J Clin Oncol.
2012;30 (suppl; abstr 7001).
Tsujino K, Kurata T, Yamamoto S, et al. Is consolidation chemotherapy
after concurrent chemo-radiotherapy benefcial for patients with locally
21.
22.
23.
24.
25.
26.
advanced non-small-cell lung cancer? A pooled analysis of the literature. J Thorac Oncol. 2013;8:1181-1189.
Dinan MA, Curtis LH, Carpenter WR, et al. Stage migration, selection
bias, and survival associated with the adoption of positron emission tomography among Medicare benefciaries with non-small-cell lung cancer. J Clin Oncol. 2012;30:2725-2730.
Kelly K, Chansky K, Gaspar LE, et al. Phase III trial of maintenance
geftinib or placebo after concurrent chemoradiotherapy and docetaxel
consolidation in inoperable stage III non-small-cell lung cancer: SWOG
S0023. J Clin Oncol. 2008;26:2450-2456.
Wozniak AJ, Moon J, Thomas CR, et al. SWOG S0533: a pilot trial of
cisplatin (C)/etoposide (E)/radiotherapy (RT) followed by consolidation docetaxel (D) and bevacizumab (B) (NSC-704865) in three cohorts
of patients (pts) with inoperable locally advanced stage III non-small
cell lung cancer (NSCLC). J Clin Oncol. 2012;30 (suppl; abstr 7018).
Spigel DR, Hainsworth JD, Yardley DA, et al. Tracheoesophageal fstula
formation in patients with lung cancer treated with chemoradiation and
bevacizumab. J Clin Oncol. 2009;28:43-48.
Lu C, Lee JJ, Komaki R, et al. Chemoradiotherapy with or without AE941 in stage III non-small cell lung cancer: a randomized phase III trial.
J Natl Cancer Inst. 2010;102:859-865.
Hoang T, Dahlberg SE, Schiller JH, et al. Randomized phase III study of
thoracic radiation in combination with paclitaxel and carboplatin with
27.
28.
29.
30.
31.
32.
33.
e447
SPEAKERS
David W. Scott, MBCHB, PhD
BC Cancer Agency
Vancouver, BC, Canada
Myron S. Czuczman, MD
Roswell Park Cancer Institute
Buffalo, NY
phase III trial including 1,080 patients with previously untreated DLBCL, no additional clinical beneft was observed in
patients treated with R-CHOP every 14 days (R-CHOP14)
versus every 21 days (R-CHOP21).6 Although evaluation of
some of these intensifcation strategies is still ongoing, recent
insight into the biology of DLBCL allowed the development
of strategies based on the addition of novel agents (X) to
R-CHOP in so-called XR-CHOP combinations9 that target
specifc oncogenic pathways (Fig. 1). In the development of
these strategies, molecular characterization of DLBCL and
the development of biomarkers is a critical step to identify
patients who might beneft from the addition of novel
agent(s). Indeed, because of the molecular heterogeneity of
DLBCL, addition of a novel agent may beneft only a subgroup of patients with DLBCL. In this regard, preclinical and
clinical studies of novel agents as monotherapies in relapsed
and refractory DLBCL often provide important initial indications regarding the subtype of DLBCL that might beneft
from specifc targeted therapy.
Gene expression profling (GEP) of DLBCL resulted in the
identifcation of two major and clinically distinct subtypes
that are classifed based on cell of origin (COO) and are as-
From the Division of Hematology, Mayo Clinic, Rochester, MN; Roswell Park Cancer Institute, Buffalo, NY.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Grzegorz S. Nowakowski, MD, Division of Hematology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905; email: nowakowski.grzegorz@mayo.edu.
2015 by American Society of Clinical Oncology.
e449
sociated with differences in clinical outcome: GCB and nonGCB, which is further comprised of ABC and primary
mediastinal B-cell types.10,11 DLBCL subtypes have striking
differences in clinical outcome, with the ABC DLBCL subtype being associated with poor outcome. Until recently,
COO classifcation of DLBCL had little influence on clinical
practice. However, COO classifcations have become more
clinically relevant as a result of two major factors: (1) the development of new real-time COO assessment methods, including
immunohistochemistry (IHC) and Nanostrings technology and
(2) the identifcation of novel agents with activity in a specifc
DLBCL subtype (particularly ABC DLBCL).
KEY POINTS
The activated B-cell (ABC) subset of diffuse large B-cell
lymphoma (DLBCL) is biologically distinct, characterized by
clonic B-cell receptor signaling, and associated with poor
outcomes when treated with a standard therapy. Activation
of the clonic B-cell receptor pathway allows for therapeutic
targeting.
Targeted agents in relapsed DLBCL can be combined with
R-CHOP in front-line therapy of DLBCL. Since most of these
agents are active in ABC DLBCL, many ongoing studies
select patients who have this subset.
The germinal center B-cell (GCB) subset of DLBCL is
associated with better outcomes and may require different
therapeutic approaches.
Double-hit lymphoma (DHL) is responsible for a substantial
number of relapses in GCB DLBCL (DHL is usually a GCB
phenotype). All newly diagnosed DLBCL biopsy samples
should be tested for DHL by uorescent in situ
hybridization and by immunohistochemistry for doubleexpressor DLBCL and, whenever possible, patients should
be referred to participation in clinical trials.
Off-study treatment of DHL should be dose-intense
whenever feasible, with current data supporting the use of
dose-adjusted R-EPOCH plus central nervous system
prophylaxis until more effective novel targeted agents for
this lymphoma subtype are developed.
e450
FIGURE 1. Pathways Targeted By Treatments Currently in Development for Patients with DLBCL
Abbreviations: AKT, protein kinase B; BAD, BCL2-associated death promoter; BAK, BCL2 antagonist killer; BAX, BCL2-associated X protein; BCL, B-cell lymphoma; BTK, Brutons tyrosine kinase;
CARD11, caspase recruitment domain family, member 11; CRBN, cereblon; DLBCL, diffuse large B-cell lymphoma; Me, methylation; DNMT, DNA methyltransferase; JAK1, Janus kinase 1; IL, interleukin;
IRF-4, interferon regulatory factor 4; MALT1, mucosa-associated lymphoid tissue lymphoma translocation protein 1; MTOR, mammalian target of rapamycin; P, phosphorylation; NFB, nuclear
factor kappa B; PI3K, phosphoinositide 3-kinase; PKC-beta, protein kinase C beta; SFK, Src family kinase; STAT3, signal transducer and activator of transcription 3; SYK, spleen tyrosine kinase.
spleen tyrosine kinase (SYK) inhibitor fostamatinib demonstrated a median PFS of 2.7 months and achieved an
ORR of 22%.24
suppress apoptosis through interaction with, and inactivation of, proapoptotic proteins such as BH3.26 In contrast to
most agents active in ABC DLBCL, which appear to have low
activity in the GCB subtype, BCL2 inhibitors might be active
in both ABC and GCB DLBCL. Whereas in the GCB subtype
BCL2 is often overexpressed as a result of translocation, some
patients with the ABC subtype appear to overexpress BCL2 at
the protein level.27 ABT-737 and its oral equivalent ABT-263
target multiple antiapoptotic members of the BCL-2 family,
including BCL-2, BCL-XL, and BCL-w, whereas ABT-199
potently and selectively inhibits BCL-2, thereby sequestering
the proapoptotic proteins and facilitating death of malignant
cells.26,28,29
e451
R2-CHOP
Patients treated with the immunomodulatory agent lenalidomide (R) in combination with R-CHOP (R2-CHOP)
achieved ORRs and CRs of 90% to 100% and 77% to 86%,
respectively, in phase I and phase II trials.33-36 In one phase II
trial, the most frequent grade 3/4 hematologic adverse events
(AEs) included neutropenia (31%), leukocytopenia (28%),
and thrombocytopenia (13%); no grade 4 nonhematologic
AEs were reported.36 Response to R2-CHOP in patients with
GCB versus non-GCB DLBCL was similar in a phase II trial
(32 tissue samples available), and the 2-year PFS was 71% and
81%, respectively.36 Interestingly, in a separate phase II trial involving patients with newly diagnosed DLBCL who were treated
with R2-CHOP, the 2-year OS was 75% for patients with GCB
DLBCL compared with 83% for non-GCB subtypes. In patients
treated with R-CHOP alone, a 2-year OS of 78% and 46% was
achieved in GCB and non-GCB subgroups, respectively, suggesting that the addition of lenalidomide can improve the poor
prognosis usually reported in the non-GCB population in response to standard R-CHOP therapy (Fig. 2).37
A randomized phase II trial designed to evaluate the effect
of R-CHOP versus R2-CHOP in patients with newly diagnosed DLBCL (NCT01856192) is ongoing.38 A separate
IR-CHOP
The Brutons tyrosine kinase (BTK) inhibitor ibrutinib has
been investigated in combination with R-CHOP (IR-CHOP)
in a phase Ib, nonrandomized, open-label trial in 33 patients
with newly diagnosed DLBCL, mantle cell lymphoma, or follicular lymphoma. At the interim evaluation, the ORR was
100% (CR 64% and PR 36%) in 22 patients with DLBCL. The
most common all-grade AEs reported in all patients were
neutropenia (67%), nausea (67%), thrombocytopenia (61%),
vomiting (48%), and anemia (36%).39 Additionally, a randomized, double-blind, phase III study is currently comparing event-free survival in patients treated with IR-CHOP
versus R-CHOP (NCT01855750).34
FIGURE 2. Outcomes of Patients Treated with R-CHOP or R2-CHOP according to GCB versus Non-GCB DLBCL
Subtype
Outcomes are shown for historic control patients treated with R-CHOP and study patients treated with R2CHOP based on germinal center B-cell (GCB) versus non-GCB diffuse large B-cell
lymphoma (DLBCL) subtype. (A) Progression-free survival in patients treated with R-CHOP for non-GCB versus GCB DLBCL. (B) Progression-free survival in patients treated with R2CHOP for nonGCB versus GCB DLBCL. (C) Overall survival in patients treated with R2CHOP for non-GCB versus GCB DLBCL. (D) Overall survival in patients treated with R2CHOP for non-GCB versus GCB DLBCL.
e452
TABLE 1. Agents with Differential Single Agent and in Combination of XR-CHOP Activity in DLBCL Subtypes
Agent
Combination
No. of Patients
Phase
Front-Line
ORR (%)
GCB
CR (%)
ABC/NGCB
GCB
ABC/NGCB
PFS (%)
GCB
OS (%)
ABC/NGCB
GCB
ABC/NGCB
94
Lenalidomide 36
R-CHOP
32
II
88
88
81
88
71
81
88
Lenalidomide 37
R-CHOP
64
II
59
60
75
83
64
28
78
46
R-CHOP*
Relapse/Refractory
Bortezomib 13
DA-EPOCH
44
13
83
42
3.4
10.8
9.5
5.8
Lenalidomide 42
40
II
53
24
1.7
6.2
13.5
14
Ibrutinib 23
70
II
40
1.3
2.5
Abbreviations: ABC, activated B-cell typeCR, complete response; DA-EPOCH, dose-adjusted etoposide, vincristine, doxorubicin, with cyclophosphamide and prednisone; DLBCL, diffuse large B-cell
lymphoma; GCB, germinal center B-cell type; NGCB, non-GCB type; mo, month; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; R-CHOP, rituximab with
cyclophosphamide, doxorubicin, vincristine, prednisone; XR, addition of novel agents to R-CHOP.
*R-CHOP without lenalidomide.
or rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP). Patients whose disease relapsed early ( 1
year) following front-line rituximab chemotherapy had a
very poor prognosis, with a 3-year PFS of 20% compared with
45% for patients whose disesase relapsed after 1 year.40
e453
No. of Patients
Treatment
Outcome (Median)
Comments
Petrich et al50
311
R-CHOP (32%)
Median follow-up: 23 mo
R-EPOCH (21%)
R-CoDox-M/IVAC (14%)
129 (93 with both MYC
and BCL2 translocation)
Oki et al60
R-CHOP
2-yr EFS
R-Hyper CVAD/MA
R-EPOCH
R-CHOP: 25%
R-Hyper CVAD/MA: 32%
Consolidative SCT: no
improvement in OS in
CR patients (p 0.14)
R-EPOCH: 67%
CR
R-CHOP: 20%
R-EPOCH: 68%
R-Hyper CVAD/MA: 70%
Johnson et al
61
54
CHOP-like (43%)
OS
R-CHOP (20%)
R-CHOP: 1.4 yr
HDT (11%)
CHOP: 5 mo
R-CHOP (39%)
Palliative (26%)
Li et al62
OS: 18.6 mo
Median age: 55
Aggressive chemotherapy nor
SCT associated with
increased PFS/OS
Abbrevations: BCL-U, B-cell lymphoma, unclassiable with features intermediate between DLBCL and BL; R, rituximab; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; Hyper CVAD/
MA, hyper-fractionated cyclophosphamide, doxorubicin, vincristine, dexamethasone/methotrexate, cytarabine; EPOCH, etoposide, prednisone, doxorubicin, cyclophosphamide, doxorubicin; CoDox-M/
IVAC, cyclophosphamide, vincristine, doxorubicin, methotrexate, ifosfamide, etoposide, cytarabine; PFS, progression-free survival; OS, overall survival; SCT, stem cell transplant.
*Consolidative SCT in 50% R-EPOCH versus 4% R-CHOP group.
Comment
ABT-199
Reference
28, 63
6466
CAR-T cells
67, 68
69, 70
mTor inhibition
71, 72
MLN9708/Ixazomib (second
generation proteasome inhibitor)
Preclinical model: Degraded MYC and can induce lymphoma cell death at nanomolar concentrations
73
PI3K inhibition
High percent GCB-DLBCL cases: loss of PTEN 3 activation of PI3K/AKT pathway 3 MYC upregulation
74
75
SIRT4 protein
76
Abbreviations: mTOR, mammalian target of rapamycin; GCB, germinal B cell; DLBCL, diffuse large B-cell lymphoma.
e454
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Myron S. Czuczman, Algeta, Boehringer
Ingelheim, Celgene, Gilead Sciences, Mundipharma, T G Therapeutics, Teva. Consulting or Advisory Role: Myron S. Czuczman, Algeta, Boehringer Ingelheim,
Celgene, Gilead Sciences, Mundipharma, T G Therapeutics, Teva. Grzegorz S. Nowakowski, Celgene, Morphosis. Speakers Bureau: None. Research Funding:
Grzegorz S. Nowakowski, Celgene (Inst). Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations,
Expenses: None. Other Relationships: None.
References
1. Coiffer B, Thieblemont C, Van Den Neste E, et al. Long-term outcome
of patients in the LNH-98.5 trial, the frst randomized study comparing
rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe dEtudes des Lymphomes de lAdulte.
Blood. 2010;116:2040-2045.
2. Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with
diffuse large B-cell lymphoma. J Clin Oncol. 2006;24:3121-3127.
3. Sehn LH, Donaldson J, Chhanabhai M, et al. Introduction of combined
CHOP plus rituximab therapy dramatically improved outcome of diffuse
large B-cell lymphoma in British Columbia. J Clin Oncol. 2005;23:50275033.
4. Sehn LH. Paramount prognostic factors that guide therapeutic strategies in diffuse large B-cell lymphoma. Hematology Am Soc of Hematol
Educ Program. 2012;2012;402-409.
5. Coiffer B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab
compared with CHOP alone in elderly patients with diffuse large-B-cell
lymphoma. N Engl J Med. 2002;346:235-242.
6. Cunningham D, Hawkes EA, Jack A, et al. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with
newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3
comparison of dose intensifcation with 14-day versus 21-day cycles.
Lancet. 2013;381:1817-1826.
7. Purroy N, Lopez A, Vallespi T, et al. Dose-adjusted EPOCH plus rituximab (DA-EPOCH-R) in untreated patients with poor risk large B-cell
lymphoma: a phase 2 study conducted by the Spanish PETHEMA
group. Blood. 2009;114 (suppl; abstr 2701).
8. Cai QC, Gao Y, Wang XX, et al. Long-term results of the R-CEOP 90 in
the treatment of young patients with chemotherapy-naive diffuse large
B cell lymphoma: a phase II study. Leuk Lymphoma. 2014;55:2387-2388.
9. Vaidya R, Witzig TE. Prognostic factors for diffuse large B-cell lymphoma in the R(X)CHOP era. Ann Oncol. 2014;25:2124-2133.
10. Rosenwald A, Wright G, Chan WC, et al. The use of molecular profling
to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:1937-1947.
11. Shipp MA, Ross KN, Tamayo P, et al. Diffuse large B-cell lymphoma
outcome prediction by gene-expression profling and supervised machine learning. Nat Med. 2002;8:68-74.
12. Crawford LJ, Walker B, Irvine AE. Proteasome inhibitors in cancer therapy. J Cell Commun Signal. 2011;5:101-110.
13. Dunleavy K, Pittaluga S, Czuczman MS, et al. Differential effcacy of
bortezomib plus chemotherapy within molecular subtypes of diffuse
large B-cell lymphoma. Blood. 2009;113:6069-6076.
14. Bartlett JB, Dredge K, Dalgleish AG. The evolution of thalidomide and
its IMiD derivatives as anticancer agents. Nat Rev Cancer. 2004;4:314322.
e455
e456
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30:3460-3467.
Hu S, Xu-Monette ZY, Tzankov A, et al. MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of
diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL RituximabCHOP Consortium Program. Blood. 2013;121:4021-4031;4250.
Johnson NA, Slack GW, Savage KJ, et al. Concurrent expression of MYC
and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus
cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin
Oncol. 2012;30:3452-3459.
Perry AM, Alvarado-Bernal Y, Laurini JA, et al. MYC and BCL2 protein
expression predicts survival in patients with diffuse large B-cell lymphoma treated with rituximab. Br J Haematol. 2014;165:382-391.
Cheah CY, Oki Y, Westin JR, et al. A clinicians guide to double hit lymphomas. Br J Haematol. Epub 2014 Dec 22.
Lindsley RC, LaCasce AS. Biology of double-hit B-cell lymphomas. Curr
Opin Hematol. 2012;19:299-304.
Howlett C, Landsburg DJ, Chang EA, et al. Front-line, dose-escalated
immunochemotherapy is associated with a signifcant PFS (but not
OS) advantage in 401 patients (pts) with double-hit lymphomas
(DHL): A SYSTEMIC REVIEW AND META-ANALYSis. Blood. 2014;
124: (suppl; abstr 3056).
Dunleavy K, Fanale M, LaCasce AS, et al. Preliminary report of a multicenter prospective phase II study of DA-EPOCH-R in MYC-rearranged
aggressive B-cell lymphoma. Blood. 2014;124: (suppl; abstr 395).
Greenwood M, Amytage T, Fay K, et al. Outcomes of allogeneic stem
cell transplantation for non-Hodgkin lymphoma with concurrent MYC
and BCL2 translocations: a single centre retrospective analysis. Hematol
Oncol. 2013;31:96-150.
Oki Y, Noorani M, Lin P, et al. Double hit lymphoma: the MD Anderson
Cancer Center clinical experience. Br J Haematol. 2014;166:891-901.
Johnson NA, Savage KJ, Ludkovski O, et al. Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with
survival. Blood. 2009;114:2273-2279.
Li S, Lin P, Fayad LE, et al. B-cell lymphomas with MYC/8q24 rearrangements and IGH@BCL2/t(14;18)(q32;q21): an aggressive disease
with heterogeneous histology, germinal center B-cell immunophenotype and poor outcome. Mod Pathol. 2012;25:145-156.
Davids MD, Seymour JF, Gerecitano JF, et al. Phase I study of ABT-199
(GDC-0199) in patients with relapsed/refractory (R/R) non-Hodgkin
lymphoma (NHL): responses observed in diffuse large B-cell (DLBCL)
and follicular lymphoma (FL) at higher cohort doses. J Clin Oncol. 2014;
32: (suppl, abstr 8522).
Thieblemont C, Stathis A, Inghirami G, et al. A Phase I study of the
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
e457
DAVID W. SCOTT
iffuse large B-cell lymphoma is the most frequent nonHodgkin lymphoma (NHL), making up about 30% to
40% of diagnoses of NHL worldwide.1 It is increasingly recognized that DLBCL represents a heterogeneous group of
malignancies that have previously been grouped together on
the basis of a shared morphology, immunophenotype, and
aggressive clinical behavior.1 The standard of care for patients
with DLBCL, established over a decade ago, is rituximab,
cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy. This one-size ftsall approach results in cure for 50% to 60% of patients.2,3
However, the outcomes for those that experience disease
progression or relapse are poor, making identifcation of this
clinical subgroup and improving their up-front treatment a
major priority for the feld.
A major step toward precision medicine in DLBCL was
taken 15 years ago, when examination of the gene expression
of DLBCL tumors revealed previously unrecognized molecular heterogeneity in this malignancy.4 The resulting COO
classifcation divided tumors into those with gene expression
reminiscent of germinal center B cells (the GCB group) and
those with gene expression similar to activated B cells (the
ABC group). The division of DLBCL tumors into these two
groups has provided a scaffold on which a substantial amount of
From the Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada; Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: David W. Scott, MBChB, PhD, BC Cancer Research Centre, 675 West 10th Avenue, Room 11-114, Vancouver, BC V5Z 1L3, Canada; email: dscott8@bccancer.bc.ca.
2015 by American Society of Clinical Oncology.
e458
croarrays, covering a broad range of genes expressed by lymphoid cells and others suspected of being involved in cancer
and immunology, to compare the gene expression profles of
lymphoid tumors against profles from normal lymphoid
cells.4 Using hierarchical clustering (a method of grouping
tumors together based on similarity of gene expression), it
was shown that there were at least two distinct groups within
DLBCL. The frst group, which was designated as GCB, was
characterized by high expression of genes expressed in normal B cells from the germinal center. The second group
showed very low expression of these germinal center B cell
genes, but high expression of genes normally expressed by
activated B cells and was thus named ABC DLBCL. Importantly, these groupings explained some of the clinical heterogeneity in DLBCL, as patients with ABC DLBCL
experienced substantially worse outcomes compared with
patients with GCB DLBCL.
This work was expanded by the Leukemia Lymphoma
Molecular Profling Project (LLMPP), by applying the same
microarray technology to a larger cohort of patients.5 Hierarchical clustering, using the 100 genes that were most highly
differentially expressed between GCB and ABC, identifed
three clusters within DLBCL: the aforementioned GCB and
ABC, and a third group of cases that had gene expression that
fell between these two groups, which they named type 3.
With cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) chemotherapy (the standard at that time), this
group of patients had outcomes similar to those with ABC
DLBCL. This type 3 nomenclature gave the impression that
this was a biologically distinct third group of tumors. In hind-
KEY POINTS
Diffuse large B-cell lymphoma comprises at least two
distinct molecular subtypes, dened by gene expression
proling, with different mutation landscapes, outcomes
following treatment, and responses to novel targeted
agents: the activated B-cell-like and germinal center B-celllike cell-of-origin groups.
Accurate and robust cell-of-origin assignment applicable to
routinely produced formalin-xed parafn-embedded tissue
biopsies is critically needed to support clinical trials and,
ultimately, to guide disease management.
The immunohistochemistry-based algorithms cannot
currently be deployed with sufcient reproducibility or
accuracy to support their use to guide clinical decisionmaking.
A number of gene expressionbased assays applicable to
formalin-xed parafn-embedded tissue biopsies have been
described with two of these assays now supporting patient
selection in phase III randomized controlled trials of
targeted agents.
It is anticipated that a robust, accurate gene expression
based assay will be widely available by the time
substantive evidence is produced that cell-of-origin should
be used to guide initial treatment decisions in the clinic.
e459
DAVID W. SCOTT
The model is shown in the form of a heatmap of gene expression data from 274 fresh frozen tissue biopsies using the Lymphochip microarray. Each column represents the relative gene
expression of a tumor. The rows are the 27 genes that contribute to the models linear predictor score (LPS). The 14 genes that were also present on the commercially available Affymetrix
microarrays are highlighted in blue (overexpressed in ABC DLBCL) and orange (overexpressed in GCB DLBCL). Arrows designate genes, where antibodies against their corresponding protein have
been used in immunohistochemistry-based COO assays. For an individual LPS score, a probability is determined as to whether the tumor is likely to be part of the ABC group or the GCB group
(shown at top). Tumors with a probability of being ABC greater than 90% are considered ABC, whereas those with a probability of less than 10% are considered GCB.
This research was originally published in Proceedings of the National Academy of Sciences, Volume 100, Issue 17, G Wright et al, A gene expression-based method to diagnose clinically distinct
subgroups of diffuse large B cell lymphoma. Pages 9991-9996, Copyright 2003.
IHC-Based Assays
The wide availability and familiarity of pathologists with IHC
makes assays based on this technology highly desirable. In
2004, Hans et al developed an IHC-based algorithm applicable to FFPET biopsies that aimed to replicate the COO assignments made using GEP on fresh frozen tissue with the
Lymphochip microarray.5,24 A tissue microarray (TMA) was
produced comprising FFPET from 152 de novo DLBCL tumor, with 142 of these having matching GEP results. IHC was
performed with antibodies against CD10 (HUGO designation MME), BCL6, MUM1 (HUGO designation IRF4),
CCND2, and FOXP1fve proteins that are highly differentially expressed between ABC and GCB (Fig. 1). No one single IHC stain was suffcient to accurately assign COO and a
sequential algorithm was developed using CD10, BCL6, and
MUM1 (Fig. 2) to separate GCB DLBCL from non-GCB
DLBCL, with the latter group including both ABC DLBCL
e461
DAVID W. SCOTT
The four immunohistochemistry-based algorithms that were trained against gold standard gene expression proling are shown. Accuracy is dened as the concordance with the gold standard.
Sensitivity and specicity are shown for the ABC subtype--as they are binary assays, the specicity for ABC is the sensitivity for GCB, whereas the sensitivity for ABC is the specicity for GCB.
The positive predictive value (PPV) and negative predictive value (NPV) are for the ABC subtype. The performance values are determined from independent validation cohorts, except where
marked with an *, where they are from the training cohort and thus may overestimate the performance of the assay.
e462
e463
DAVID W. SCOTT
Panel A: The assay in the form of a heatmap from the independent validation cohort. The rows represent the 20 genes in the assay, with those highlighted in blue being overexpressed in the
ABC group and those in orange being overexpressed in the GCB group. Genes in the middle are the house-keeping genes used to normalize for the number of quantiable RNA species present.
The columns are the relative gene expression of the 67 patients, arrayed from left to right based on ascending values of the assays linear predictor score (LPS). Below the heatmap is the
assignment according to the Lymph2Cx assay, with the gold standard assignments, from gene expression proling from matched fresh frozen tissue using microarrays, at the bottom.
Panel B: Comparison of the LPSs from the Lymph2Cx assay between two independent laboratories. As indicated, lower LPS values indicates an assignment of GCB, whereas higher scores
indicate an assignment of ABC. The concordance between the two sites was 95% (63 out of 66 cases) with no case being frankly misclassied (i.e., an ABC assigned GCB, or vice versa).
This research was originally published in Blood, Volume 123, Issue 8, DW Scott et al, Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalinxed parafn-embedded tissue. Pages 1214-1217, Copyright 2014.
in an independent cohort of 68 FFPET biopsies from the validation cohort of Lenz et al cases that have never contributed
to COO model building. Compared with the gold standard,
only one case was frankly misclassifed (ABC to GCB) and
the assay had a similar rate of unclassifed cases to the gold
standard. The Lymph2Cx was tested across two independent
laboratories and showed 95% agreement of COO assignment, with discordant cases having shifted from a defnitive
assignment to unclassifed, or vice versa (Fig. 3B). To the authors knowledge, this is the only published data addressing
interlaboratory performance of the gene expressionbased
COO assays. The Lymph2Cx has subsequently been applied
to FFPET biopsies from a population-based cohort of patients with de novo DLBCL, displaying a low failure rate of
1%, an unclassifed rate of 11%, and substantial separation of
e464
ACKNOWLEDGMENT
Many thanks to Drs. Randy Gascoyne and Joseph Connors
for their constructive comments. DWS is supported by the
BC Cancer Foundation.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: David W. Scott, Celgene. Consulting or Advisory
Role: David W. Scott, Celgene. Speakers Bureau: None. Research Funding: None. Patents, Royalties, or Other Intellectual Property: David W. Scott,
As a member of the LLMPP, I am potentially a named inventor on a pending patent on the use of gene expression proling to assign cell-of-origin in diffuse
large B-cell lymphoma, Named inventor on a pending patent describing gene expression proling in prognostication in classical Hodgkin lymphoma. Expert
Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Swerdlow SH, Campo E, Harris NL, et al. World Health Organization
classifcation of tumours of haematopoietic and lymphoid tissues. 4th ed.
Lyon: IARC Press; 2008.
2. Sehn LH, Donaldson J, Chhanabhai M, et al. Introduction of combined
CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol. 2005;23:
5027-5033.
3. Coiffer B, Thieblemont C, Van Den Neste E, et al. Long-term outcome
of patients in the LNH-98.5 trial, the frst randomized study comparing
rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe dEtudes des Lymphomes de lAdulte.
Blood. 2010;116:2040-2045.
4. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large
B-cell lymphoma identifed by gene expression profling. Nature. 2000;
403:503-511.
e465
DAVID W. SCOTT
10. Shaffer AL 3rd, Young RM, Staudt LM. Pathogenesis of human B cell
lymphomas. Annu Rev Immunol. 2012;30:565-610.
11. Lenz G, Davis RE, Ngo VN, et al. Oncogenic CARD11 mutations in human
diffuse large B cell lymphoma. Science. 2008;319:1676-1679.
12. Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010;463:88-92.
13. Ngo VN, Young RM, Schmitz R, et al. Oncogenically active MYD88
mutations in human lymphoma. Nature. 2010;470:115-119.
14. Morin RD, Johnson NA, Severson TM, et al. Somatic mutations altering
EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of
germinal-center origin. Nat Genet. 2010;42:181-185.
15. Mandelbaum J, Bhagat G, Tang H, et al. BLIMP1 is a tumor suppressor
gene frequently disrupted in activated B cell-like diffuse large B cell lymphoma. Cancer Cell. 2010;18:568-579.
16. Morin RD, Mendez-Lago M, Mungall AJ, et al. Frequent mutation of
histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011;
476:298-303.
17. Pasqualucci L, Trifonov V, Fabbri G, et al. Analysis of the coding genome of
diffuse large B-cell lymphoma. Nat Genet. 2011;43:830-837.
18. Zhang J, Grubor V, Love CL, et al. Genetic heterogeneity of diffuse large
B-cell lymphoma. Proc Natl Acad Sci U S A. 2013;110:1398-1403.
19. Lenz G, Wright GW, Emre NC, et al. Molecular subtypes of diffuse large
B-cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci
U S A. 2008;105:13520-13525.
20. Monti S, Chapuy B, Takeyama K, et al. Integrative analysis reveals an
outcome-associated and targetable pattern of p53 and cell cycle deregulation in diffuse large B cell lymphoma. Cancer Cell. 2012;22:359-372.
21. Beguelin W, Popovic R, Teater M, et al. EZH2 is required for germinal
center formation and somatic EZH2 mutations promote lymphoid
transformation. Cancer Cell. 2013;23:677-692.
22. Thieblemont C, Briere J, Mounier N, et al. The germinal center/activated B-cell subclassifcation has a prognostic impact for response to
salvage therapy in relapsed/refractory diffuse large B-cell lymphoma: a
bio-CORAL study. J Clin Oncol. 2011;29:4079-4087.
23. Molina TJ, Canioni D, Copie-Bergman C, et al. Young patients with
non-germinal center B-cell-like diffuse large B-cell lymphoma beneft
from intensifed chemotherapy with ACVBP plus rituximab compared
with CHOP plus rituximab: analysis of data from the Groupe dEtudes
des Lymphomes de lAdulte/Lymphoma Study Association phase III
trial LNH 03-2B. J Clin Oncol. 2014;32:3996-4003. Epub 2014 Nov 10.
24. Hans CP, Weisenburger DD, Greiner TC, et al. Confrmation of the molecular classifcation of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103:275-282.
25. Choi WW, Weisenburger DD, Greiner TC, et al. A new immunostain
algorithm classifes diffuse large B-cell lymphoma into molecular subtypes with high accuracy. Clin Cancer Res. 2009;15:5494-5502.
26. Meyer PN, Fu K, Greiner TC, et al. Immunohistochemical methods for
predicting cell of origin and survival in patients with diffuse large B-cell
lymphoma treated with rituximab. J Clin Oncol. 2010;29:200-207.
27. Visco C, Li Y, Xu-Monette ZY, et al. Comprehensive gene expression
profling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classifcation in diffuse large B-cell lymphoma: a report from the International DLBCL
Rituximab-CHOP Consortium Program Study. Leukemia. 2012;26:
2103-2113.
28. Nyman H, Jerkeman M, Karjalainen-Lindsberg ML, et al. Prognostic impact of activated B-cell focused classifcation in diffuse large B-cell lymphoma patients treated with R-CHOP. Mod Pathol. 2009;22:1094-1101.
29. Muris JJ, Meijer CJ, Vos W, et al. Immunohistochemical profling based
on Bcl-2, CD10 and MUM1 expression improves risk stratifcation in
patients with primary nodal diffuse large B cell lymphoma. J Pathol.
2006;208:714-723.
e466
30. Natkunam Y, Farinha P, Hsi ED, et al. LMO2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with
anthracycline-based chemotherapy with and without rituximab. J Clin
Oncol. 2008;26:447-454.
31. de Jong D, Rosenwald A, Chhanabhai M, et al. Immunohistochemical
prognostic markers in diffuse large B-cell lymphoma: validation of tissue microarray as a prerequisite for broad clinical applications--a study
from the Lunenburg Lymphoma Biomarker Consortium. J Clin Oncol.
2007;25:805-812.
32. Coutinho R, Clear AJ, Owen A, et al. Poor concordance among nine
immunohistochemistry classifers of cell-of-origin for diffuse large
B-cell lymphoma: implications for therapeutic strategies. Clin Cancer
Res. 2013;19:6686-6695.
33. Gutierrez-Garca G, Cardesa-Salzmann T, Climent F, et al. Geneexpression profling and not immunophenotypic algorithms predicts
prognosis in patients with diffuse large B-cell lymphoma treated with
immunochemotherapy. Blood. 2011;117:4836-4843.
34. Read JA, Koff JL, Nastoupil LJ, et al. Evaluating cell-of-origin subtype
methods for predicting diffuse large B-cell lymphoma survival: a metaanalysis of gene expression profling and immunohistochemistry algorithms. Clin Lymphoma Myeloma Leuk. 2014;14:460-467.e2.
35. Williams PM, Li R, Johnson NA, et al. A novel method of amplifcation
of FFPET-derived RNA enables accurate disease classifcation with microarrays. J Mol Diagn. 2010;12:680-686.
36. Rimsza LM, Wright G, Schwartz M, et al. Accurate classifcation of diffuse large B-cell lymphoma into germinal center and activated B-cell
subtypes using a nuclease protection assay on formalin-fxed, paraffnembedded tissues. Clin Cancer Res. 2011;17:3727-3732.
37. Collie AM, Nolling J, Divakar KM, et al. Molecular subtype classifcation of formalin-fxed, paraffn-embedded diffuse large B-Cell lymphoma samples on the ICEPlex system. Br J Haematol. 2014;167:281285. Epub 2014 Jun 25.
38. Xue X, Zeng N, Gao Z, et al. Diffuse large B-cell lymphoma: subclassifcation by massive parallel quantitative RT-PCR. Lab Invest. 2015;
95:113-120. Epub 2014 Nov 24.
39. Ruminy P, Mareschal S, Bagacean C, et al. Accurate classifcation of
GCB/ABC and MYC/BCL2 diffuse large B-cell lymphoma with a 14
genes expression signature and a simple and robust RT-MLPA assay.
Blood. 2013;122 (abstr 84).
40. Barrans SL, Crouch S, Care MA, et al. Whole genome expression profling based on paraffn embedded tissue can be used to classify diffuse
large B-cell lymphoma and predict clinical outcome. Br J Haematol.
2012;159:441-453. Epub 2012 Sep 13.
41. Masque-Soler N, Szczepanowski M, Kohler CW, et al. Molecular classifcation of mature aggressive B-cell lymphoma using digital multiplexed
gene expression on formalin-fxed paraffn-embedded biopsy specimens. Blood. 2013;122:1985-1986.
42. Veldman-Jones M, Lai Z, Wappett M, et al. Reproducible, quantitative
and flexible molecular sub-typing of clinical DLBCL samples using the
NanoString nCounter system. Clin Cancer Res. Epub 2014 Oct 9.
43. Scott DW, Wright GW, Williams PM, et al. Determining cell-of-origin
subtypes of diffuse large B-cell lymphoma using gene expression in
formalin-fxed paraffn-embedded tissue. Blood. 2014;123:1214-1217.
44. Care MA, Barrans S, Worrillow L, et al. A microarray platformindependent classifcation tool for cell of origin class allows comparative
analysis of gene expression in diffuse large B-cell lymphoma. PLoS ONE.
2013;8:e55895.
45. Scott DW, Mottok A, Ennishi D, et al. Cell-of-origin assignment in diffuse large B-cell lymphoma determined by gene expression in formalinfxed paraffn-embedded tissue has prognostic signifcance independent
of IPI and MYC/BCL2 immunohistochemistry. Blood. 2014;124 (abstr
1624).
SPEAKERS
Gilles A. Salles, MD, PhD
Hospices Civils de Lyon, Universite Claude Bernard
Pierre Benite, France
Stephen Ansell, MD, PhD
Mayo Clinic
Rochester, MN
eripheral T-cell lymphomas (PTCLs) are a heterogeneous group of diseases that account for 10 to 15% of
non-Hodgkin lymphomas (NHLs) in most Western countries. Although the WHO 2008 classifcation system includes
22 distinct mature T-cell and natural killer (NK) cell neoplasms,1 they can be functionally grouped according to
typical presentation as nodal, extranodal, leukemic, and cutaneous (Fig. 1). Three entities account for approximately
60% of T-cell lymphomas: PTCL not otherwise specifed
(PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL),
and systemic anaplastic large cell lymphoma (ALCL), which
may be positive or negative for anaplastic lymphoma kinase
(ALK).2 For the purpose of this review, we will focus primarily
on these most common subtypes.
From the Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Michelle A. Fanale, MD, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd #429, Houston, TX 77030; email: mfanale@mdanderson.org.
2015 by American Society of Clinical Oncology.
e468
FIGURE 1. WHO 2008 Classication of Mature T-Cell Neoplasms According to Typical Presentation
mat ure T-cell and NK-cell neoplasms
nodal
Peripheral T-cell lymphoma,
NOS
Angioimmunoblastic T-cell
lymphoma
Anaplastic large cell lymphoma,
ALK positive
Anaplastic large cell lymphoma,
ALK negative
ext ranodal
Extranodal NK/T-cell lymphoma,
nasal type
Enteropathy-associated T-cell
lymphoma
Hepatosplenic T-cell lymphoma
Subcutaneous panniculitis-like Tcell lymphoma ( subtype only)
KEY POINTS
Outcomes for patients with peripheral T-cell lymphoma
treated with cyclophosphamide/doxorubicin/vincristine/
prednisone (CHOP)-like induction regimens with and without
front-line consolidative stem cell transplantation will be
summarized.
Clinical data supporting the regulatory approval of
pralatrexate, romidepsin, brentuximab vedotin, and
belinostat for patients with relapsed/refractory disease will
be reviewed.
Trials combining these novel agents in combination with
CHOP-like chemotherapy in previously untreated patients
will be outlined.
Studies using combinations of new agents in biologic
doublets as salvage regimens will be described.
Emerging clinical data on agents with promising clinical
efcacy in phase I studies will be highlighted.
leukemic
T-cell prolymphocytic leukemia
T-cell large granular lymphocytic
leukemia
Aggressive NK-cell leukemia
Adult T-cell leukemia/lymphoma
cut aneous
Mycosis fungoides
Szary syndrome
Primary cutaneous CD30-positive Tcell lymphoproliferative disorders
Primary cutaneous anaplastic large cell
lymphoma
Lymphomatoid papulosis
Primary cutaneous peripheral T-cell
lymphomas, rare subtypes Primary
cutaneous gamma-delta T-cell
lymphoma
Primary cutaneous CD8 aggressive
epidermotropic T-cell lymphoma
Primary cutaneous CD4 small/medium
T-cell lymphoma
e469
Pralatrexate
Folates are critical for DNA synthesis and folate antagonism
was one of the earliest successful chemotherapeutic pathways.20 Pralatrexate is an inhibitor of dihydrofolate reductase
that was designed to have increased affnity for the reduced
folate carrier and therefore accumulates within cells and exhibits increased potency compared with methotrexate.21 A
phase I study demonstrated promising activity in T-cell lymphomas,22 prompting an international phase II study
(PROPEL). In this trial, 111 patients with relapsed or refractory aggressive PTCL were treated with single-agent pralatrexate (30 mg/m2 administered intravenously once weekly),
TABLE 1. Summary of Selected Novel Agents Currently Being Evaluated for Efcacy in Peripheral T-Cell
Lymphoma
Agent
Mechanism
Phase
Grade 3 Toxicities
ORR
CRR
DOR
Folate antagonist
II
111
Mucositis
29%
11%
10.3 mo
Romidepsin27,28
HDAC inhibitor
II
47
38%
17%
8.9 mo
II
130
25%
15%
28 mo*
Brentuximab vedotin38
Antibody-drug conjugate
II
35
41%
24%
7.6 mo
Belinostat31
HDAC inhibitor
II
129
Hematologic
26%
10%
13.6 mo
Anti-CCR4 mAb
II
37
Neutropenia, rash
34%
17%
8.2 mo**
Alisertib (MLN8237)54
II
37
24%
5%
NR
Duvelisib (IPI145)69
PI3K inhibitor
33
47%
12%
NR
Crizotinib89
ALK inhibitor
II
14
60%
36%
Nivolumab88
Anti-PD1 mAb
40%
0%
8.3 mo
NR
Abbreviations: ORR, objective response rate; CRR, complete response rate; DOR, duration of response; PI3K, phosphoinositide-3-kinase; CCR4, chemokine receptor-4; HDAC, histone deacetylase;
ALK, anaplastic lymphoma kinase; NR, not reported; PD-1, programmed cell death-1; mAb, monoclonal antibody.
Response rates refer to patients with nodal PTCL subtypes where information available.
*Duration of response reported from updated report.29
**Median progression-free survival of patients with PTCL achieving response.
e470
sequently attributed to antiemetic therapy and clinically signifcant dysrhythmias were not seen. Romidepsin gained
FDA approval in 2011 for patients with PTCL who have at
least one prior systemic therapy. Chihara et al reported a
single-center phase I study to determine the safety profle of
romidepsin administered on days 1 and 4 with ifosfamide/
carboplatin/etoposide (ICE), with the hope that this combination would improve the CR rate over ICE alone and thus
facilitate a greater proportion of patients receiving SCT.30
The main toxicities were hematologic, with reversible grade 3
or greater thrombocytopenia in 87% of patients, and 5/7
(71%) response-evaluable patients achieved CR. This encouraging preliminary observation requires further confrmation in an expanded cohort and enrollment is ongoing.
Alemtuzumab
CD52 is a pan-lymphoid antigen with variable expression in
PTCL.39 The anti-CD52 mAb alemtuzumab was used as a
single agent in two small European studies in patients with
pretreated PTCL.40,41 Enblad et al treated 14 patients with 30
mg alemtuzumab administered intravenously three times
weekly for up to 12 weeks.40 Despite chemoprophylaxis with
trimethoprim/sulfamethoxazole and valaciclovir, fatal opportunistic infections occurred in 5/14 (35%) patients, resulting in early study termination. The observed ORR was
36%. Interestingly, Zinzani et al showed that a reduced dose
(10 mg) and a shorter schedule was better tolerated and effective, with an ORR of 50% in six patients with PTCL.41
However, the toxic deaths that occurred in the frst study
have dampened enthusiasm for further development in patients with pretreated PTCL.
Brentuximab Vedotin
Although naked monoclonal antibodies (mAbs) against
CD30 showed preclinical promise, clinical activity in patients
with CD30 lymphomas was disappointing.32 Brentuximab
vedotin (BV) was designed to improve effcacy by conjugating the anti-CD30 mAb to the antimicrotubule agent
monomethylauristatin E (MMAE). Binding to CD30 on the
cell surface results in proteolytic release, internalization, and
lysosomal uptake of MMAE, and tubule disruption, cell cycle
arrest, and apoptosis.33 ALCL has uniform strong CD30 expression, and on the basis of positive data from BV phase I
trials,34,35 a multicenter phase II study in patients with relapsed/refractory systemic ALCL (ALK-positive and
-negative) was conducted.36 Fifty-eight patients with a median number of two prior treatments were treated with 1.8
mg/kg BV intravenously every 3 weeks for up to 16 doses.
The ORR was 86% (CR 57%) with 97% of patients having a
reduction in tumor volume; responses occurred after a median of 6 weeks and the median DOR was 12.3 months. The
most common toxicities were nausea, fatigue, GI disturbance, rash, and neutropenia (mostly grade 1 to 2). Peripheral sensory neuropathy was mainly grade 1 (all grades, 41%;
grade 3, 12%) and was manageable with dose reductions and
delays. Rare but potentially fatal adverse events reported include posterior multifocal leukoencephalopathy and pancreatitis.37 Horwitz et al treated 35 patients with non-ALCL
Mogamulizumab
Mogamulizumab, a defucoslyated mAb against chemokine
receptor-4 (CCR4), was found to have single-agent activity in
patients with relapsed/refractory T-cell lymphomas in a
phase I study.42 Ogura et al performed a phase II study in
Japanese patients with relapsed/refractory T-cell lymphoma
with 1.0 mg/kg mogamulizumab administered intravenously
weekly for 8 weeks.43 Among 37 patients treated, the median
number of prior therapies was two and the main histologic
subtypes were PTCL-NOS (16 patients), AITL (12 patients),
and CTCL (8 patients). The ORR was 35% (CR 13%), with a
median PFS of 3.0 months. The main toxicities reported were
neutropenia (any grade, 38%; grade 3, 19%), fever (grade
12, 30%), infusion reaction (grade 12, 24%), and skin disorders (any grade, 51%; grade 3, 11%). Although CCR4 expression by immunohistochemistry was required for study
entry, there was little correlation between expression of target antigen and response, similar to the data for BV and
CD30. The authors hypothesized depletion of CCR4 regulatory T (Treg) cells, resulting in an increase in the number of
CD8 cytotoxic T-cells, as a mechanism of tumor control,
and on the basis of these data mogamulizumab gained approval for the treatment of relapsed PTCL in Japan in 2014.
Zinzani et al performed a multicenter European phase II
study with 38 patients and reported a lower ORR of 11% with
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e471
Lenalidomide
With many drugs demonstrating effcacy in relapsed/refractory PTCL, integrating agents into front-line therapy is a major focus of drug development efforts. The conventional
approach has been to be combine novel agents with chemotherapy in an attempt to discover an R-CHOP equivalent
for PTCL; a summary of these studies is provided in Table 2.
Alisertib
Aurora A kinase regulates mitotic entry and spindle formation; it is overexpressed in aggressive lymphomas and has a
potential role in oncogenesis.51 The orally available, smallmolecule competitive inhibitor alisertib induces cytotoxicity
in a range of solid and hematologic tumors.52 Friedberg et al
performed a multicenter phase II study of alisertib in 48 patients with heavily pretreated aggressive lymphomas.53 Although the ORR was 27% overall, it was 4/8 (50%) among
patients with T-cell lymphoma, with 3/4 (75%) maintaining a
response for more than 1 year at the time of reporting. Subsequently, the SWOG1108 phase II study extended this observation in an additional 37 heavily pretreated patients with
a range of PTCL subtypes.54 Alisertib was administered at a
dosage of 50 mg twice daily for 7 days in a 21-day cycle. The
most common adverse events (AEs) of grade 3 or greater
TABLE 2. Summary of Selected Chemotherapy/Novel Agent Combinations for Untreated Peripheral T-Cell
Lymphoma
Combination
Study Group
Major Histologies
Phase
ORR
CRR
PFS
OS
CHOP romidepsin57
LYSARC
NR
Ib/II
35
68%
51%
18 mo 57%
18 mo 76%
CHOP vorinostat60
MDACC
14
93%
93%
2 yr 79%
2 yr 81%
CHOP-14 alemtuzumab62
GITIL
II
24
75%
71%
2 yr 48%
2 yr 53%
CHOP alemtuzumab63
HOVON
II
20
90%
60%
2 yr 27%*
2 yr 55%
CHO(E)P alemtuzumab61
DSHNHL
II
41
61%
58%
3 yr 32%
3 yr 62%
U.S./European multicenter
39
100%**
88%**
1 yr 71%**
1 yr 88%**
CEOP pralatrexate
T-cell consortium
II
33
70%
45%
1 yr 48%
1 yr 80%
U.S. multicenter
II
49
65%
50%
2 yr 43%
2 yr 65%
CHOP bortezomib74
CISL
II
46
76%
65%
3 yr 35%
3 yr 47%
56
Abbreviations: ORR, objective response rate; CRR, complete response rate; DOR, duration of response; NR, not reported; CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; ICE,
ifosfamide/carboplatin/etoposide; CHP, cyclophosphamide/doxorubicin/prednisone; CEOP, cyclophosphamide/etoposide/doxorubicin, prednisone; CHOEP, cyclophosphamide, doxorubicin, vincristine/
etoposide/prednisone; LYSARC, Lymphoma Academic Research Organization; MDACC, MD Anderson Cancer Center; GITIL, Italian Group for Innovative Lymphoma Therapies; HOVON, Dutch-Belgian
Haemato-Oncology Group; CISL, Consortium for Improving the Survival of Lymphoma; PTCL-NOS, peripheral T-cell lymphoma not otherwise specied; AITL, angioimmunoblastic T-cell lymphoma;
ALCL, anaplastic large cell lymphoma; ATLL, adult T-cell leukemia/lymphoma; ENKTL, extranodal NK/T-cell lymphoma.
*Event-free survival.
**Results for combination CHP brentuximab arm.
e472
e473
TABLE 3. Selected Ongoing Studies Testing Biologic Doublets in Peripheral T-Cell Lymphoma
Agents
Phase
Population
Sponsor/Site
ClinicalTrials.gov
Romidepsin lenalidomide
Untreated PTCL
Northwestern University
NCT02232516
RR lymphoma/myeloma
NCT01742793
RR lymphoma/myeloma
NCT01755975
RR lymphoid malignancies
Columbia University
NCT01998035
Romidepsin alisertib
RR aggressive NHL
NCT01897012
67
Alisertib vorinostat
RR lymphoma
NCT01567709
Carizomib belinostat
RR NHL
NCT02142530
NCT01276717
Carlzomib vorinostat
RR lymphoma
University of Rochester
Pralatrexate romidepsin
I/II
RR lymphoid malignancies
Columbia University
NCT01947140
Bortezomib romidepsin
NCT00963274
Abbreviations: PTCL, peripheral T-cell lymphoma; NHL, non-Hodgkin lymphoma; RR, relapsed/refractory.
Proteasome Inhibitors
The frst agent in this class, bortezomib, had moderate activity as a single agent in CTCL73 and in combination with
e474
CHOP in untreated patients with PTCL.74 The secondgeneration proteasome inhibitor carflzomib is being investigated in an ongoing phase I study (NCT01336920).
IDH2 Inhibitors
Gain-of-function mutations in the genes encoding the metabolic enzymes isocitrate dehydrogenase 1 and 2 (IDH1 and
IDH2) result in accumulation of R-2-hydroxyglutarate, a metabolite that induces epigenetic changes that drive oncogenesis.75 Mutations in IDH1 and IDH2 have been reported in a
range of hematologic and solid tumors, including 45% of cases
of AITL.76,77 AG-221 is a frst-in-class, oral selective inhibitor of
mutant IDH2 enzyme that appears to be well tolerated, with
promising activity and durable responses in a preliminary report of a phase I study in advanced IDH2-positive hematologic
malignancies.78 It is being evaluated in a phase I/II study including patients with IDH2-positive AITL (NCT02273739).
Retinoids
Vitamin A derivatives have demonstrated a range of anticancer functions including antiangiogenesis activity and induction of apoptosis and differentiation.79 With the exception of
acute promyelocytic leukemia, their clinical development has
been limited by their toxicity profle. The synthetic retinoic
acid (fenretinide) appears to be better tolerated than all-trans
retinoic acid, and a phase I study using a pharmacologically
optimized emulsion formulation resulted in a clinical beneft
rate (CRPRSD) of 64% among 11 patients with relapsed
T-cell lymphomas.80
ALK Inhibitors
For patients with ALK ALCL, the EML4-ALK fusion oncogene provides an attractive target. Crizotinib, the frstgeneration ALK inhibitor, was used in a phase Ib study of 15
patients with ALK lymphomas (14 with ALK ALCL).89
The main toxicities were diarrhea, vomiting, and visual impairment; the ORR was 60%. This agent is being tested in a
phase I/II study in combination with chemotherapy in untreated patients (NCT01979536) and in a study of relapsed/
refractory ALK ALCL (NCT00939770). As with many
tyrosine kinase inhibitors, secondary resistance has been reported and second-generation agents such as ceritinib
(LDK378) will undoubtedly be explored in patients who experience treatment failure.90-93 A phase I study that includes
an arm enrolling patients with ALK malignancies other
than lung cancer is in progress (NCT01283516).
CONCLUSION
Cooperative studies in the last 5 years have successfully enabled
the rapid completion of phase I/II studies and brought four new
drugs for patients with T-cell lymphoma to the clinic. Continuing efforts are needed to complete confrmatory randomized
phase III studies in combination with chemotherapy. The development of chemotherapy-free regimens using the most active
biologic agents in PTCL will be a critical focus of research efforts
in the future. Additional efforts to develop molecular targeted
approaches are also clearly needed in order to rationally select a
treatment plan that would be predicted to have the highest effcacy for a particular patient.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Michelle A. Fanale, Plexus, Research to Practice,
Seattle Genetics, Takeda. Consulting or Advisory Role: Michelle A. Fanale, Acetylon Pharmaceuticals, Amgen, Clarient, Spectrum Pharmaceuticals.
Speakers Bureau: None. Research Funding: Michelle A. Fanale, Bristol-Myers Squibb, Celgene, Genentech, Gilead Sciences, MedImmune, Millennium,
Molecular Templates, Novartis, Seattle Genetics. Yasuhiro Oki, Curis, Seattle Genetics, Novartis, Janssen Pharmaceuticals, Innity, Millennium, Cell Medica,
Spectrum Pharmaceuticals. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses:
Michelle A. Fanale, Plexus, Research to Practice, Spectrum Pharmaceuticals, Takeda. Yasuhiro Oki, DAVAOncology. Other Relationships: None.
References
1. Swerdlow SH CE, Harris N, et al. WHO Classifcation of Tumours of the
Haematopoietic and Lymphoid Tissues, Fourth edition. Lyon: IARC. 2008.
2. International T-Cell Lymphoma Project. International peripheral T-cell
and natural killer/T-cell lymphoma study: pathology fndings and clinical outcomes. J Clin Oncol. 2008;26:4124-4130.
3. Weisenburger DD, Savage KJ, Harris NL, et al. Peripheral T-cell lymphoma, not otherwise specifed: a report of 340 cases from the International
Peripheral T-cell Lymphoma Project. Blood. 2011;117:3402-3408.
4. Simon A, Peoch M, Casassus P, et al. Upfront VIP-reinforced-ABVD
(VIP-rABVD) is not superior to CHOP/21 in newly diagnosed periph-
e475
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
e476
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
e477
77. Cairns RA, Iqbal J, Lemonnier F, et al. IDH2 mutations are frequent in
angioimmunoblastic T-cell lymphoma. Blood. 2012;119:1901-1903.
78. Stein EM, Altman JK, Collins R, et al. ag-221, an oral. selective, frst-inclass, potent inhibitor of the IDH2 mutant metabolic enzyme, induces
durable remissions in a phase I Study in patients with IDH2 mutation
positive advanced hematologic malignancies [abstract]. Blood. 2014;
124:115.
79. Ulukaya E, Wood EJ. Fenretinide and its relation to cancer. Cancer
Treat Rev. 1999;25:229-235.
80. Mohrbacher A, Kang MH, Yang AS, et al. Phase I trial of fenretinide
(4-HPR) intravenous emulsion in hematologic malignancies: A California Cancer Consortium study (PhI-42). J Clin Oncol. 2012; 30 (suppl;
abstr 8073).
81. Parikh K, Cang S, Sekhri A, et al. Selective inhibitors of nuclear export
(SINE)- a novel class of anti-cancer agents. J Hematol Oncol. 2014;7:78.
82. Etchin J, Sanda T, Mansour MR, et al. KPT-330 inhibitor of CRM1
(XPO1)-mediated nuclear export has selective anti-leukaemic activity
in preclinical models of T-cell acute lymphoblastic leukaemia and acute
myeloid leukaemia. Br J Haematol. 2013;161:117-127.
83. Walker CJ, Oaks JJ, Santhanam R, et al. Preclinical and clinical effcacy
of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in
Ph leukemias. Blood. 2013;122:3034-3044.
84. Zhong Y, El-Gamal D, Dubovsky JA, et al. Selinexor suppresses downstream effectors of B-cell activation, proliferation and migration in
chronic lymphocytic leukemia cells. Leukemia. 2014;28:1158-1163.
85. Kuruvilla J, Byrd JC, Flynn JM, et al. The oral selective inhibitor of nuclear export (SINE) selinexor (KPT-330) demonstrates broad and durable clinical activity in relapsed/refractory non Hodgkins lymphoma
(NHL) [abstract]. Blood. 2014;124:396.
86. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkins lymphoma. N Engl J Med.
2015;372:311-319.
87. Wilcox RA, Feldman AL, Wada DA, et al. B7-H1 (PD-L1, CD274) suppresses host immunity in T-cell lymphoproliferative disorders. Blood.
2009;114:2149-2158.
88. Lesokhin AM, Ansell SM, Armand P, et al. Preliminary results of a phase
e478
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
I study of nivolumab (BMS-936558) in patients with relapsed or refractory lymphoid malignancies [abstract]. Blood. 2014;124:291.
Gambacorti-Passerini C, Horibe K, Braiteh F, et al. Safety and clinical
activity of crizotinib in patients with ALK-rearranged hematologic malignancies [abstract]. Blood. 2013;122:4342.
Friboulet L, Li N, Katayama R, et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov. 2014;4:662-673.
Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged nonsmall-cell lung cancer. N Engl J Med. 2014;370:1189-1197.
Piccaluga PP, Fuligni F, De Leo A, et al. Molecular profling improves
classifcation and prognostication of nodal peripheral T-cell lymphomas: results of a phase III diagnostic accuracy study. J Clin Oncol. 2013;
31:3019-3025.
Parrilla Castellar ER, Jaffe ES, Said JW, et al. ALK-negative anaplastic
large cell lymphoma is a genetically heterogeneous disease with widely
disparate clinical outcomes. Blood. 2014;124:1473-1480.
Lemonnier F, Couronne L, Parrens M, et al. Recurrent TET2 mutations
in peripheral T-cell lymphomas correlate with TFH-like features and
adverse clinical parameters. Blood. 2012;120:1466-1469.
Sakata-Yanagimoto M, Enami T, Yoshida K, et al. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat Genet. 2014;46:171-175.
Yoo HY, Sung MK, Lee SH, et al. A recurrent inactivating mutation in
RHOA GTPase in angioimmunoblastic T cell lymphoma. Nat Genet.
2014;46:371-375.
Streubel B, Vinatzer U, Willheim M, et al. Novel t(5;9)(q33;q22) fuses
ITK to SYK in unspecifed peripheral T-cell lymphoma. Leukemia.
2006;20:313-318.
Valleron W, Ysebaert L, Berquet L, et al. Small nucleolar RNA expression profling identifes potential prognostic markers in peripheral
T-cell lymphoma. Blood. 2012;120:3997-4005.
Foss FM, Sjak-Shie N, Goy A, et al. A multicenter phase II trial to determine the safety and effcacy of combination therapy with denileukin
diftitox and cyclophosphamide, doxorubicin, vincristine and prednisone in untreated peripheral T-cell lymphoma: the CONCEPT study.
Leuk Lymphoma. 2013;54:1373-1379.
e479
STEPHEN ANSELL
Brentuximab Vedotin
Brentuximab vedotin, although not strictly a new agent,
demonstrates the beneft of specifcally targeting the ReedSternberg cell. Initial clinical trials utilizing this CD30directed antibody-drug conjugate included large numbers of
patients with HL. In an initial phase I trial, patients received
brentuximab every 3 weeks. The trial confrmed that 17 patients with HL had objective responses (ORs) (11 patients
had complete responses).13 Of the 12 patients with HL who
received treatment at the maximum tolerated dose, an OR
rate of 50% was seen. These results were confrmed in a pivotal phase II trial using brentuximab vedotin in patients with
relapsed and refractory HL, all of whom had previously been
treated with an autologous stem cell transplant.14 In a cohort
of 102 patients, all of whom received brentuximab vedotin at
KEY POINTS
Hodgkin lymhoma has a unique histologic picture that
provides opportunities for therapeutic targeting.
Brentuximab vedotin is an approved agent in relapsed Hodgkin
lymphoma and is now used as part of front-line therapy.
New agents targeting the phosphatidylinositide 3-kinase
pathway, the JAK-STAT pathway, and the tumor
microenvironment show promising activity.
Initial studies using antiprogrammed death-1 antibodies,
such as nivolumab and pembrolizumab, have reported very
high response rates in relapsed and refractory patients
with Hodgkin lymphoma.
The future will require combination approaches.
e480
Everolimus
The phosphatidylinositide 3-kinase/mammalian target of
rapamycin (PI3K/mTOR) signaling pathway has been shown
to be activated in patients with HL. Everolimus is an oral antineoplastic agent that targets this pathway, specifcally the
mTOR complex 1 (mTORC1). Everolimus not only may target the signaling pathways within the Reed-Sternberg cells
but may also suppress signaling within the immune infltrate
and production of cytokines present in the tumor microenvironment. A clinical trial of everolimus administered at a
dose of 10 mg orally every day, was performed among 19 patients with relapsed and refractory HL.17 The majority of patients had received multiple previous lines of therapy and
84% of the patients had undergone a previous autologous
stem cell transplant. In this small cohort of patients the ORR
was 47%, with one patient experiencing a complete remission
and eight patients achieving partial remissions. The median
time to disease progression was 7.2 months. Overall, the
treatment was well tolerated and four of the responding patients remain progression free at 12 months. This study confrmed that everolimus has single-agent activity in patients
with relapsed and refractory HL and confrmed that targeting
the mTOR pathway in HL is clinically warranted.
JAK Inhibitors
JAKs are a family of intracellular non-receptor tyrosine
kinases that transduce signals from cell surface receptors activated by cytokines and growth factors. After phosphorylation, JAKs lead to recruitment of STAT proteins. The STAT
proteins subsequently translocate to the nucleus and trigger
transcription of target genes involved in cell proliferation,
cell survival, and immune response.
Aberrant activation of the JAK-STAT pathway has been
linked to a variety of malignancies, including HL. SB1518 is a
small molecule inhibitor of JAK2 kinase with preclinical activity in lymphoid malignancies. This JAK inhibitor has been
tested in a phase I clinical trial of a variety of lymphomas,
including refractory HL.20 Doses of 100 to 600 mg/day were
tested, and the drug was found to be well tolerated. Among
the studys 34 patients, the ORR was 14%, including three
partial remissions. In the group of patients with HL, however,
none of the 14 patients had a partial remission or better.
However, at least fve of the patients with HL did beneft from
the treatment, with a decrease in the sites of active disease.
Lenalidomide
Lenalidomide has a diverse set of possible mechanisms of action. It is proposed to directly induce cell death in malignant
B cells and to indirectly regulate the tumor microenvironment. Lenalidomide has immunomodulatory and antiangiogenic properties and may specifcally modulate many
of the changes in the microenvironment, including the
skewing of the cytokine profle, the altered immune cell
infltrate, and the recruitment of macrophages to the tumor microenvironment.
In view of the potential benefts to modulating the microenvironment by using lenalidomide, this agent has been
tested in a clinical trial of relapsed and refractory classical
HL.21 In a study of 38 patients with classical HL, most of
Anti-PD-1 Antibodies
The PD-1 pathway serves as an immune checkpoint to
dampen immune responses. As outlined above, the tumor
microenvironment in classical HL overexpresses the PD-1 ligands, resulting in a successful mechanism of tumor immune
escape. Blocking PD-1 interactions with its ligands is therefore a promising treatment approach, particularly as genetic
alterations result in PD-L1 and PD-L2 copy gain and thus
overexpression of PD-1 ligands. As mentioned above,
Epstein-Barr virus infection is a further mechanism that upregulates PD-1 ligand expression. Two recent clinical trials
targeting PD-1/PD-1-ligand interactions have been reported, both with remarkable clinical results. In a clinical trial
utilizing nivolumab, 23 patients with relapsed or refractory
HL were treated every 2 weeks with 3 mg/kg of the antibody.22 The majority of these patients had previously received an autologous stem cell transplant, and most had
received previous brentuximab vedotin. In this group of patients, an ORR of 87% (20 out of 23) patients was seen, with a
CRR of 17% and a PR rate of 70%. The PFS at 24 weeks was
86% and 11 of the patients continued on therapy, suggesting
that the responses were durable.
In a second clinical trial utilizing the anti-PD-1 monoclonal antibody pembrolizumab (MK-3475), patients received
the drug at a dose of 10 mg/kg administered every 2 weeks.23
In this group of very heavily previously treated patients, pembrolizumab was well tolerated and similar dramatic clinical
responses were seen. The ORR was 53%, with three patients
(20%) having a complete remission and fve additional patients (33%) having a partial remission. Virtually all patients
appeared to have beneftted from therapy and the responses
also appeared durable.
e481
STEPHEN ANSELL
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Stephen
Ansell, Research to Practice. Speakers Bureau: None. Research Funding: Stephen Ansell, Bristol-Myers Squibb, Celldex, Seattle Genetics. Patents,
Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Ansell SM. Hodgkin lymphoma: 2014 update on diagnosis, riskstratifcation, and management. Am J Hematol. 2014;89:771-779.
2. Stein H, Delsol G, Pileri SA, et al. WHO classifcation of tumours of
haematopoietic and lymphoid tissues. Lyon, France: International
Agency for Research on Cancer. 2008;326-329.
3. Montes-Moreno S. Hodgkins Lymphomas: a Tumor recognized by its
microenvironment. Adv Hematol. 2011;2011;142395.
4. Steidl C, Connors JM, Gascoyne RD. Molecular pathogenesis of Hodgkins lymphoma: increasing evidence of the importance of the microenvironment. J Clin Oncol. 2011;29:1812-1826.
5. van den Berg A, Visser L, Poppema S. High expression of the CC chemokine TARC in Reed-Sternberg cells: a possible explanation for the characteristic T-cell infltrate in Hodgkins lymphoma. Am J Pathol. 1999;
154:1685-1691.
6. Marri PR, Hodge LS, Maurer MJ, et al. Prognostic signifcance of pretreatment serum cytokines in classical Hodgkin lymphoma. Clin Cancer
Res. 2013;19:6812-6819.
7. Greaves P, Clear A, Owen A, et al. Defning characteristics of classical
Hodgkin lymphoma microenvironment T-helper cells. Blood. 2013;122:
2856-2863.
8. Green MR, Rodig S, Juszczynski P, et al. Constitutive AP-1 activity and
EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy.
Clin Cancer Res. 2012;18:1611-1618.
9. Steidl C, Lee T, Shah SP, et al. Tumor-associated macrophages and
survival in classic Hodgkins lymphoma. N Engl J Med. 2010;362:
875-885.
10. Porrata LF, Ristow K, Colgan JP, et al. Peripheral blood lymphocyte/
monocyte ratio at diagnosis and survival in classical Hodgkins lymphoma. Haematologica. 2012;97:262-269.
11. Durkop H, Latza U, Hummel M, et al. Molecular cloning and expression
of a new member of the nerve growth factor receptor family that is characteristic for Hodgkins disease. Cell. 1992;68:421-427.
12. Smith CA, Gruss HJ, Davis T, et al. CD30 antigen, a marker for Hodgkins lymphoma, is a receptor whose ligand defnes an emerging family
of cytokines with homology to TNF. Cell. 1993;73:1349-1360.
13. Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-
e482
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
SPEAKERS
Mara-Victoria Mateos, MD, PhD
University Hospital of Salamanca
Salamanca, Spain
Philippe Moreau, MD
University Hospital Htel-Dieu
Nantes, France
amine how patients may be managed, particularly with respect to the possibility of early treatment.
From the University Hospital of Salamanca/IBSAL, Salamanca, Spain; Clnica Universidad de Navarra/CIMA, Navarra, Spain.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Mara-Victoria Mateos, MD, PhD, University Hospital of Salamanca/IBSAL, Paseo San Vicente, 58-182, 37007 Salamanca, Spain; email: mvmateos@usal.es.
2015 by American Society of Clinical Oncology.
e484
MGUS
SMM
Serum-M protein
3 g/dL and
3 g/dL and/or
MM
Clonal BMPC
inltration
10%
10-60%
10% or biopsyproven
plasmacytoma
Symptomatology
Absence of
CRAB*
Absence of MDE**
or amyloidosis
Presence of MDE**
age, then myeloma-related symptomatology should be considered. Finally, if there is a single bone lesion present with no
other symptoms, it is essential to rule out the presence of a
benign bone cyst.
DIAGNOSTIC EVALUATION
Initial investigation of a patient with suspected SMM should
include the tests shown in Sidebar 1, which are coincidental
KEY POINTS
Smoldering multiple myeloma is not a homogeneous plasma
cell disorder and includes patients at low, intermediate,
and high risk of progression to symptomatic multiple
myeloma.
All newly diagnosed SMM patients should be stratied
according to their risk.
It is essential to identify asymptomatic patients at high
risk of progression to symptomatic disease, in which the
progression risk is 50% at 2 years following diagnosis,
because they require close follow-up and, if possible,
inclusion in clinical trials.
Although the standard of care has been not to administer
treatment until symptoms arise, early treatment with
lenalidomide plus dexamethasone has helped change the
treatment paradigm for patients with high-risk SMM.
The updated International Myeloma Working Group criteria
allow us to initiate therapy in patients who would
previously have been considered asymptomatic on the
basis of the absence of calcium, renal insufciency,
anemia, or bone lesions (CRAB) features, but who possess
a specic biomarker predicting ultra-high risk of
progression.
In the future, novel therapeutic approaches will determine
whether early treatment of patients with asymptomatic
high-risk disease can denitively prevent the development
of myeloma-related symptoms.
e485
for the frst 5 years, 5% per year during the following 5 years,
and only 1% per year after 10 years.12
Several studies have reported possible predictors of progression to symptomatic MM, and this information is useful
for physicians and could also be used to help explain to patients their risk of progression to active MM (Sidebar 2).
Oncology Grup (SWOG) also found that patients with an increase in the M component of at least 3 g/dL during the 3
months since their previous determination had an associated
risk of progression of approximately 50% at 2 years.18
e487
previously mentioned. However, the new imaging assessments can also help predict progression risk in patients with
SMM. The frst studies with spinal MRI were conducted in
patients with asymptomatic MM and the presence of a focal
pattern was associated with a shorter TTP than those patients
with a diffuse or variegated pattern (median, 6 vs. 16 vs. 22
months, respectively). Hillengass et al recently evaluated the
role of MRI during the follow-up of patients with SMM. Radiologic progressive disease (MRI-PD), defned as the detection of new focal lesions or the increase in diameter of
existing focal lesions, and a novel or progressive diffuse infltration was identifed as a feature for classifying patients with
SMM at high risk of progression to symptomatic disease.21
The role of PET/CT has also been evaluated in SMM. The
Italian group recently reported that in a series of 73 patients
with SMM, approximately 10% had a positive result with
PET/CT with no underlying osteolytic lesion and were predicted to be at high risk of progression to symptomatic disease (48% at 2 years compared with 32% for PET/CTnegative patients; p 0.007).22 The Mayo Clinic group also
identifed a subgroup within a series of 132 patients with
SMM who had a positive result with PET/CT in which the
rate of progression to MM within 2 years was 56% compared
with 28% among patients who had a negative PET/CT result
(p 0.001). The rate of progression was even higher among
patients in whom PET/CT was performed within 3 months of
their diagnosis of SMM (74% vs. 27% in PET/CT-negative
patients).23
CYTOGENETIC ABNORMALITIES
Neben et al have identifed t(4;14), gain of 1q21, or hyperdiploidy as independent prognostic factors of shorter TTP. The
median TTP for patients with del(17p13) was 2.7 years compared with 4.9 years for patients without the deletion (p
0.019), 2.9 years for patients with t(4;14) compared with 5.2
years for patients without the deletion (p 0.021), and 3.7
years for patients with 1q21 compared with 5.3 years for
those without the deletion (p 0.013). In addition, hyperdiploidy was associated with a signifcantly shorter median
TTP of 3.9 years compared with 5.7 years for patients without
hyperdiploidy (p 0.036).24 The Mayo Clinic group also analyzed the cytogenetic abnormalities in a series of 351 patients with SMM and identifed a high-risk subgroup of
patients with t(4;14) and/or del(17p) with a substantially
shorter median TTP (24 months) than the intermediate-,
standard- and low-risk patient subgroups.25 Finally, the
SWOG evaluated the Gene Expression Profling 40 (GEP40)
model in a group of 105 patients with SMM, and estimated
7.05 to be the optimal cut point for risk of progression to active disease. The 3-year TTP probability was 83% compared
with only 11% for patients with scores below this threshold.26
In summary, the diagnosis of SMM is associated with a
variable risk of progression to active disease, and the presence of the aforementioned prognostic factors can discriminate subgroups of patients with respect to their degree of risk
(Sidebar 2).
e488
MANAGEMENT OF SMM
The standard of care for the management of SMM was observation until MM develops. However, because of the heterogeneity of the disease, several groups evaluated the role of
early intervention in patients with SMM using conventional
and novel agents.
Three small studies compared early therapy consisting of
melphalan and prednisone (MP) with observation alone. In
the Hjorth study, the response rate to therapy in patients
treated at diagnosis was similar to that of patients who received deferred therapy at the time of progression (52% vs.
55%).27 In the other two trials, there were no differences in
OS between early treatment and observation (54 vs. 58
months in the former, and 64 vs. 71 months in the latter).28,29
Two small phase II trials, one by the Mayo Clinic and the
other by The University of Texas MD Anderson Cancer Center, evaluated the role of thalidomide as a single agent in patients with SMM.30,31 The rates of partial response (PR) or
better were 34% and 36%, respectively, and most patients
who discontinued treatment did so because of peripheral
neuropathy. Barlogie et al conducted another nonrandomized phase II trial with thalidomide plus pamidronate in 76
patients with SMM, obtaining a PR rate of at least 42%, with
a 6-year median TTP to symptomatic disease. The development of peripheral neuropathy was the main problem in patients who received long-term thalidomide treatment.32
Novel agents have also been evaluated in SMM. Anakinra is
an antagonist of the receptor of interleukin (IL)-1 and produced stabilization of the disease (in 8 patients), minor responses (3 patients), and partial responses (5 patients) in a
group of 47 patients with SMM, with a median TTP of 37
months.33 A phase II study of an anti-KIR monoclonal antibody in 21 patients found no clinical response.34 Immunotherapy using a vaccine consisting of peptides from unique
regions of three MM-associated antigens is currently being
evaluated in patients with SMM and is producing promising
effcacy results.35 It is diffcult to draw frm conclusions from
the results of these trials, only one of which was randomized,
although we can be confdent that approximately one-third
of patients with SMM responded to thalidomide. Only one
randomized trial has compared the outcome of thalidomide
plus zolendronic acid and that of zolendronic acid alone in
patients with SMM. The rate of PR was a minimum of 37% in
the thalidomide arm compared with 0% in the zoledronic acid only arm, but there were no differences in the TTP to symptomatic MM (4.3 vs. 3.3 years) or in the 5-year OS (74% vs.
73%).36 The role of bisphosphonates has also been analyzed in
three trials, considering pamidronate as a single agent in one of
them,37 pamidronate versus abstention in another,38 and zolendronic acid versus observation in the third.39 All three studies
confrmed that bisphosphonates have no antitumoral effect but
reported an increase in bone density and a decrease in bone resorption, both of which were related to the bone markers. It is
important to note that in the two randomized trials comparing
bisphosphonates with abstention, a substantial reduction in the
incidence of skeletal-related events in the bisphosphonate arms
each individual patient with SMM. The Mayo Clinic and Spanish models enable initial risk stratifcation of SMM and both
were validated in a prospective trial. However, new risk models
are emerging that incorporate new clinical and biologic features
(Table 2).10,12,14,17,18,24,43,44 The components of these models are
not identical, and each patients risk should probably be defned
on the basis of all the available data rather than through the use
of a restricted model (Sidebar 2).
FUTURE DIRECTIONS
The treatment philosophy for patients with MM has mainly
focused on symptomatic patients. This approach is clearly
different from those adopted to treat other malignancies,
such as cancers of the breast, colon, or prostate, for which
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e489
Risk of Progression to MM
Mayo Clinic
1 risk factor
10
2 risk factors
3 risk factors
1.9
No risk factor
NR
Immunoparesis
1 risk factor
2 risk factors
1.9
15%
t(4;14), del17p, or 1q
42%
64%
55%
Spanish Myeloma
Heidelberg
3-year TTP
SWOG
2-year TTP
No risk factor
30%
1 risk factor
29%
2 risk factors
71%
No risk factor
16%
sFLC ratio 50
1 risk factor
44%
2 risk factors
81%
2 risk factors
67.5%
Penn
2-year TTP
Japanese
2-year TTP
2-year TTP
Immunoparesis
No risk factor
5.3%
1 risk factor
7.5%
Involved/uninvolved sFLC 30
2 risk factors
44.8%
3 risk factors
81.3%
Barcelona
2-year TTP
0 points
1 point
31%
Immunoparesis 1 point
2 points
52%
3 points
80%
2.4%
Abbreviations: SMM, smoldering multiple myeloma; MM, multiple myeloma; TTP, time to progression.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Mara-Victoria Mateos, Celgene, Janssen-Cilag.
Consulting or Advisory Role: Mara-Victoria Mateos, Celgene, Janssen-Cilag, Onyx, Takeda. Speakers Bureau: None. Research Funding: None. Patents,
Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Kyle RA, Greipp PR. Smoldering multiple myeloma. N Engl J Med. 1980;
302:1347-1349.
2. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple
myeloma. Lancet Oncol. 2014;15:e538-e548.
3. Blade J, Dimopoulos M, Rosinol L, et al. Smoldering (asymptomatic)
multiple myeloma: current diagnostic criteria, new predictors of outcome, and follow-up recommendations. J Clin Oncol. 2010;28:690-697.
4. Kristinsson SY, Holmberg E, Blimark C. Treatment for high-risk smoldering myeloma. N Engl J Med. 2013;369:1762-1763.
5. Dimopoulos M, Kyle R, Fermand JP, et al. Consensus recommendations
for standard investigative workup: report of the International Myeloma
Workshop Consensus Panel 3. Blood. 2011;117:4701-4705.
6. Hillengass J, Fechtner K, Weber MA, et al. Prognostic signifcance of
focal lesions in whole-body magnetic resonance imaging in patients
with asymptomatic multiple myeloma. J Clin Oncol. 2010;28:1606-1610.
7. Kastritis E, Moulopoulos LA, Terpos E, et al. The prognostic importance of the presence of more than one focal lesion in spine MRI of
patients with asymptomatic (smoldering) multiple myeloma. Leukemia.
2014;28:2402-2403.
8. Rajkumar SV, Larson D, Kyle RA. Diagnosis of smoldering multiple
myeloma. N Engl J Med. 2011;365:474-475.
9. Kastritis E, Terpos E, Moulopoulos L, et al. Extensive bone marrow infltration and abnormal free light chain ratio identifes patients with
asymptomatic myeloma at high risk for progression to symptomatic
disease. Leukemia. 2013;27:947-953.
10. Waxman AJ, Mick R, Garfall AL, et al. Classifying ultra-high risk smoldering myeloma. Leukemia. Epub 2014 Nov 5.
11. Larsen JT, Kumar SK, Dispenzieri A, et al. Serum free light chain ratio as
a biomarker for high-risk smoldering multiple myeloma. Leukemia.
2013;27:941-946.
12. Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med.
2007;356:2582-2590.
13. Perez-Persona E, Vidriales MB, Mateo G, et al. New criteria to identify
risk of progression in monoclonal gammopathy of uncertain signifcance and smoldering multiple myeloma based on multiparameter flow
cytometry analysis of bone marrow plasma cells. Blood. 2007;110:25862592.
14. Perez-Persona E, Mateo G, Garca-Sanz R, et al. Risk of progression in
smouldering myeloma and monoclonal gammopathies of unknown signifcance: comparative analysis of the evolution of monoclonal component and multiparameter flow cytometry of bone marrow plasma cells.
Br J Haematol. 2010;148:110-114.
15. Dispenzieri A, Kyle RA, Katzmann JA, et al. Immunoglobulin free light
chain ratio is an independent risk factor for progression of smoldering
(asymptomatic) multiple myeloma. Blood. 2008;111:785-789.
16. Bianchi G, Kyle RA, Larson DR, et al. High levels of peripheral blood
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
circulating plasma cells as a specifc risk factor for progression of smoldering multiple myeloma. Leukemia. 2013;27:680-685.
Fernandez de Larrea C, Isola I, Cibeira MT, et al. Smoldering multiple
myeloma: impact of the evolving pattern on early progression. Blood.
2014;124 (suppl; abstr 3363).
Dhodapkar MV, Sexton R, Waheed S, et al. Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120). Blood. 2014;123:78-85.
Dispenzieri A, Kyle R, Merlini G, et al. International Myeloma Working
Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia. 2009;23:215-224.
Gonzalez de la Calle V, Garcia-Sanz R, Sobejano E, et al. Bence Jones
proteinuria in smoldering multiple myeloma as predictor marker of
progression to symptomatic multiple myeloma. Blood. 2014;124 (suppl;
abstr 3369).
Merz M, Hielscher T, Wagner B, et al. Predictive value of longitudinal
whole-body magnetic resonance imaging in patients with smoldering
multiple myeloma. Leukemia. 2014;28:1902-1908.
Zamagni E, Nanni C, Gay F, et al. The presence of FDG PET/CT focal,
not osteolytic, lesion(s) identifes a sub-group of patients with smoldering multiple myeloma with high-risk of progression into symptomatic
disease. Blood. 2014;124 (suppl; abstr 3371).
Dykstra BL, Kumar S, Dispenzieri A, et al. PET-CT has major diagnostic
value in the evaluation of smoldering multiple myeloma. Blood. 2014;
124 (suppl; abstr 3382).
Neben K, Jauch A, Hielscher T, et al. Progression in smoldering myeloma is independently determined by the chromosomal abnormalities
del(17p), t(4;14), gain 1q, hyperdiploidy, and tumor load. J Clin Oncol.
2013;31:4325-4332.
Rajkumar SV, Gupta V, Fonseca R, et al. Impact of primary molecular
cytogenetic abnormalities and risk of progression in smoldering multiple myeloma. Leukemia. 2013;27:1738-1744.
Khan RZ, Heuck C, Rosenthal A, et al. Identifying a gene expression
(GEP)-based model predicting for progression from AMM to Cmm requiring therapy in S0120 patients treated at Mirt. Blood. 2014;124
(suppl; abstr 2078).
Hjorth M, Hellquist L, Holmberg E, et al. Initial versus deferred
melphalan-prednisone therapy for asymptomatic multiple myeloma
stage I-a randomized study. Myeloma Group of Western Sweden. Eur J
Haematol. 1993;50:95-102.
Grignani G, Gobbi PG, Formisano R, et al. A prognostic index for multiple myeloma. Br J Cancer. 1996;73:1101-1107.
Riccardi A, Mora O, Tinelli C, et al. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression
of the disease: a multicentre randomized study. Cooperative Group of
Study and Treatment of Multiple Myeloma. Br J Cancer. 2000;82:12541260.
e491
30. Rajkumar SV, Gertz MA, Lacy MQ, et al. Thalidomide as initial therapy
for early-stage myeloma. Leukemia. 2003;17:775-779.
31. Weber D, Rankin K, Gavino M, et al. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol.
2003;21:16-19.
32. Barlogie B, van Rhee F, Shaughnessy JD Jr, et al. Seven-year median time
to progression with thalidomide for smoldering myeloma: partial response identifes subset requiring earlier salvage therapy for symptomatic disease. Blood. 2008;112:3122-3125.
33. Lust JA, Lacy MQ, Zeldenrust SR, et al. Induction of a chronic disease
state in patients with smoldering or indolent multiple myeloma by targeting interleukin 1{beta}-induced interleukin 6 production and the
myeloma proliferative component. Mayo Clin Proc. 2009;84:114-122.
34. Korde N, Carlsten M, Lee MJ, et al. A phase II trial of pan-KIR2D blockade with IPH2101 in smoldering multiple myeloma. Haematologica.
2014;99:e81-e83.
35. Wang ML, Nooka AK, Yee AJ, et al. Initial results of a phase 1/2a, dose
escalation study of PVX-410 multi-peptide cancer vaccine in patients
with smoldering multiple myeloma (SMM). Blood. 2014;124 (suppl;
abstr 4737).
36. Witzig TE, Laumann KM, Lacy MQ, et al. A phase III randomized trial of
thalidomide plus zoledronic acid versus zoledronic acid alone in patients
with asymptomatic multiple myeloma. Leukemia. 2013;27:220-225.
37. Martn A, Garca-Sanz R, Hernandez J, et al. Pamidronate induces bone
formation in patients with smouldering or indolent myeloma, with no
signifcant anti-tumour effect. Br J Haematol. 2002;118:239-242.
38. DArena G, Gobbi PG, Broglia C, et al. Pamidronate versus observation
e492
39.
40.
41.
42.
43.
44.
45.
From the Department of Hematologic Oncology & Blood Disorders, Levine Cancer Institute/Carolinas Healthcare System, Charlotte, NC; Myeloma Service, Department of Medicine, Memorial Sloan
Kettering Cancer Center, New York, NY.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Saad Z. Usmani, MD, FACP, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC 28204; email: saad.usmani@carolinashealthcare.org.
2015 by American Society of Clinical Oncology.
e493
of therapeutic agents. Second, it is becoming increasingly apparent that certain biomarkers offer the promise of distinguishing aggressive from indolent disease evolution, such
that individuals most at risk of progressing from precursor
states to MM can be targeted at the earliest and most treatable
stage. The third area of thrust is biomarkers of beneft, which
indicate the effect of therapeutic intervention and predict
sensitivity or resistance, and thus correlate with outcomes.
Additionally, the technologies for standardization and interpretation of MRD continue to evolve. Clinical trials based on
integral and integrated biomarkers remain a key area of research, and correlative science within the context of these trials will be vital in determining the signifcance of defned
biomarkers. We provide an overview of the current knowledge in each area in which biomarkers are being explored in
MM. In addition, we discuss the potential and limitations of
designing biomarker-driven clinical trials.
KEY POINTS
Intra- and interpatient heterogeneity in multiple myeloma
underscores the need for personalized treatment
approaches.
New International Myeloma Working Group 2014 biomarkerbased denitions identify a subset of patients that require
therapy in the absence of clinical manifestations of serious
end-organ damage.
At present, there is no strong evidence for escalating or
de-escalating therapy based on favorable, standard, and
high-risk categories.
The new generation of biomarkersincluding epigenetics,
novel imaging, clone burden, GEP signature, and nextgeneration sequencingcoupled with established prognostic
biomarkers holds promise for improved stratication of
patients with myeloma into specic therapies and clinical
trials.
Improvement in patient outcomes can be achieved through
adaptive clinical trials involving risk models based on
multiple biomarkers.
e494
the presence of clonality in approximately one-third of patients with MGUS and in at least 90% of patients with MM.9
The assay is particularly indicated for the diagnosis and
follow-up of patients with nonsecretory and oligosecretory
myeloma, light chain myeloma, and amyloidosis.10 Revised
International Myeloma Working Group (IMWG) 2014 criteria defne myeloma biomarkers that indicate a requirement
for therapy in asymptomatic individuals, including bone
marrow plasmacytosis of 60% or greater and involved FLC
ratio greater than 100 (Table 1).11 In an era of broadened
treatment options, there are substantial data showing the association of depth of response and outcome. Following treatment, complete response (CR) criteria include negative
immunofxation of serum and urine and the presence of less
than 5% plasma cells. Normalization of the FLC ratio plus the
absence of clonal plasma cells by immunochemistry or immunofluorescence is considered a deeper level of response
that is termed stringent CR (sCR).12 Achievement of CR is
considered one of the strongest prognostic biomarkers in
MM, both in the transplant and nontransplant settings, although the sCR criteria have failed to unequivocally demonstrate superior prognostic value compared with CR.13,14
More sensitive ways of measuring CR are required when
results from serum protein electrophoresis are diffcult to interpret, including problems resulting from polyclonal immunoglobulins, comigration of monoclonal bands, and poor
sensitivity at low levels of monoclonal protein (10 g/L).
These drawbacks could be overcome by the new U.S. Food
and Drug Administration (FDA)-approved heavy/light
chain (HLC) assay (Hevylite). The unique ability of this assay
to measure suppression of the uninvolved HLC pair (e.g.,
IgG-lambda, IgA-kappa, and IgA-lambda for a patient with
IgG-kappa disease) adds sensitivity for monitoring disease
response and detecting residual disease. The HLC ratio reflects the balance between monoclonal and polyclonal immunoglobulins of involved and uninvolved isotypes taking into
account the polyclonal plasma cell suppression or expansion
that occurs with the treatment. A few studies have shown that
this assay affords additional prognostic information in
MGUS and MM.15,16 If confrmed by other studies and longterm follow-up, HLC could be a noninvasive marker of
response.
Old
Updated
Future
Prognostic
Multiple Myeloma
Diagnostic
Plasmacytoma PLUS
Low/Standard Risk
Trisomies
Hyperdiploidy
Age 55
ISS I
t(11;14)
t(6;14)
Standard/Intermediate Risk
ISS II
t(4:14)
1q gain
Deletion 13 or hypodiploidy by
conventional karyotyping
Complex karyotype
Plasma cell labeling index 3%
High Risk
ISS III
Monosomy 13
t(14;16)
Hypodiploidy
t(4;14)
LDH 2 ULN
GEP 70 High Risk Signature
Treatment/Response
CR
sCR
MRD-negative
Immunophenotypic CR
HLC ratio
Immune signature
Proteasome signature
IMiD signature
Clone burden/Clone status
Imaging Prognostic
DCE-MRI diffusion/perfusion
Abbreviations: LDH, lactate dehydrogenase; ULN, upper limit of normal; sCR, stringent CR; GEP, gene expression proling; MRD, minimal residual disease; IMiD, immunomodulatory drugs; DCE-MRI,
dynamic contrast enhanced-magnetic resonance imaging.
*Clonality should be established by the demonstration of /-light-chain restriction on ow cytometry, immunohistochemistry, or immunouorescence. Bone marrow plasma cell percentage
should preferably be estimated from a core biopsy specimen; in cases of disparity between the aspirate and core biopsy, the highest value should be used. M-protein: monoclonal protein.
**Aberrant immunophenotype of plasma cells on ow cytometry: absence of CD19 and/or CD45 expression, overexpression of CD56, or weak expression of CD38. CRAB: hypercalcemia, renal
insufciency, anemia, and bone lesions.
Mayo Clinic risk classication includes standard risk, intermediate risk, and high-risk categories; International Myeloma Working Group consensus risk classication includes low risk, standard
risk, and high-risk categories. ISS: International Staging System: stage I: serum beta-2 microglobulin 3.5 mg/L, albumin 3.5 g/dL; stage II: beta-2 microglobulin between 3.5 and 5.5, or
albumin 3.5 g/dL; stage III: beta-2 microglobulin 5 mg/L. CR: complete response.
These values are based on the serum Freelite assay (The Binding Site Group, Birmingham, UK). The involved free light chain must be 100 mg/L.
Each focal lesion must be at least 5 mm in size. PET-CT: 18F-uorodeoxyglucose PET with CT.
e495
laborious and time consuming, relatively expensive, and requires high-quality DNA, not only for post-treatment samples but also at baseline. Moreover, the genetic mutations are
not stable longitudinally. Systematic assessment of MRD by
next-generation sequencing (NGS) offers a novel platform
with increased sensitivity, in particular for serial monitoring
of mutational shifts between diagnosis and relapse.41 Progression is characterized by dynamic clonal equilibrium resulting from multiclonal presentation, clonal dominance,
and post-treatment clonal selection. With respect to the potential need for frequent MRD sampling, the question of
whether NGS of peripheral blood plasma cells could replace
bone marrow testing is being studied. It should be noted that
MRD negativity does not equate with complete tumor eradication, particularly in a disease that is typically characterized
by patchy marrow infltration and extramedullary involvement. In parallel with standardizing assays and validating
prognostic MRD thresholds, there is an increasing interest in
MRD monitoring as a tool for risk-adapted clinical trials.42
IMAGING BIOMARKERS
Paralleling the improvements in laboratory techniques, great
advances have been made in imaging biomarkers. For a disease like MM that is characterized by bone involvement in at
least 80% of patients, imaging plays a critical role in diagnosis. The use of imaging biomarkers is as old as skeletal surveying itself; moreover, as the feld of medical imaging has
expanded to include MRI and PET, the number of available
biomarkers has also increased. The principal imaging biomarkers are currently topographic markers such as lytic bone
lesions and/or abnormal plasma cell proliferations in bone
marrow or soft tissues. The major advantages of MRI and
PET/CT compared with skeletal survey are discrimination
between normal and invaded bone marrow, visualization of
extramedullary disease (EMD) and cord involvement, and
better sensitivity for lytic bone lesions. MRI and PET/CT biomarkers of focal marrow abnormalities (with or without osteolysis) provide a method to assess disease burden and
prognosis and monitor response to therapy. The number of
focal lesions at baseline on MRI or 18F-FDG PET/CT adversely affected both OS and event-free survival (EFS), as did
the presence of EMD and failure of FDG suppression. Specifcally, more than three baseline PET focal lesions and more
than seven baseline MRI focal lesions (present in 32% and
36% of newly diagnosed patients with MM, respectively)
were each associated with shorter EFS and OS.43-45 Moreover,
complete suppression of FDG before the frst ASCT conferred a favorable outcome.44 Additionally, the absence of
PET suppression by day 7 of the frst induction cycle in patients with MM who were treated in the Total Therapy 3 trials
was associated with inferior OS and PFS.46 These observations have important implications and require further validation in the era of novel therapy induction regimens.
PET/CT provides a complementary tool to biopsy for assessing heterogeneity and the effect of treatment within and across
multiple disease sites. Emerging biomarkers, such as novel PET
EPIGENETIC BIOMARKERS
There is now substantial evidence supporting the notion that
epigenetic changes, including DNA methylation, histone
acetylation, and microRNAs, are important for MM development and progression. Normal B cells, plasma cells, and
MGUS cells have a methylation pattern that is distinct from
that of malignant cells in patients with newly diagnosed MM
and plasma cell leukemia.58 The transition from MM to
plasma cell leukemia has been associated with promoter hypermethylation of genes involved in cell signaling and cell
adhesion pathways, and with patterns of global hypomethylation.59,60 Unsupervised clustering of myeloma samples deasco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e497
involving 149 patients with SMM, focal marrow abnormalities were identifed in 28% of subjects and the presence of two
or more focal lesions was shown to have independent prognostic signifcance for progression to symptomatic disease.73
A recently published trial of longitudinal MRI in untreated
SMM patients revealed that MRI-progressive disease, as defned by new or increasing focal or diffuse bone marrow abnormalities, was associated with a 16.5-fold increased risk of
progression to MM compared with MRI-stable disease (p
0.0001).74 Although further technical refnement is needed, it
is likely that biomarkers based on GEP, imaging, and immunophenotyping that can be followed in patients with MGUS
or SMM will be introduced into the clinic, allowing us to better understand variations in sequential trajectories and predict those patients who are at high risk of disease progression
and for whom treatment intervention is essential to prevent
the emergence of serious end-organ damage.
e498
Target/Biomarker
Prevalence
Prognosis
t(4;14) FGFR3/MMSET
10-15%
Intermediate
t(14;16) c-MAF
t(14;20) MAFB
MAF overexpression
5-10%
Poor
MEK inhibitors
t(11;14) CCND1
t(6;14) CCND3
Cyclins
19%
Standard
Cyclin D inhibitors
c-MYC
Poor
Poor
39%
Targeted Drug
11%
Poor
Mutant or WT TP53
10%
Poor
Proliferative myeloma
Poor
Poor
Cyclins
50%
MAPK/RAS pathway
20-35% BRAF
mutations (4%)
Cyclins
Epigenetic changes
Histone methyltransferase
activity of MMSET
15%
e499
FIGURE 1. Roadmap for the Identication of Fit, Robust, Valid, and Clinically Useful Biomarkers
In the future, several new biomarkers will be identied through a discovery approach utilizing techniques such as high-throughput sequencing, omics technologies, gene expression arrays,
mass spectroscopy, multiplex ow cytometry, and innovative imaging strategies. Several steps must be completed before the marker can be applied in the clinic. First, a cohort of samples is
analyzed to determine whether the effects observed in cell assays or animal models are recapitulated in humans. After demonstrating target engagement/modulation, subsequent testing
involves analyzing an independent sample cohort to validate the original hypothesis-generating ndings, and evaluation to conrm that the new biomarker will provide additional information
that is useful for clinical decision-making. These concepts have been termed analytic validity, clinical validity, and clinical utility. Based on the new set of biomarkers, risk stratication schemas
and treatment response/resistance signatures are expected to evolve. It will be important to utilize the correct biomarker-focused trial designs to evaluate a biomarkers ability to predict
treatment response. Biomarker-stratied designs (A) that aim to evaluate both a new treatment and a biomarker within the same trial by enrolling all-comers to new versus standard treatment
with a planned biomarker subset analysis will be more suitable for evaluating biomarkers such as t(4;14). If phase IIb shows a signicant interaction of effects in patients with/without t(4;14),
the integral selection of only patients with t(4;14) for the conrmatory phase III trial would follow. Development of multibiomarker risk assessment models for clinical applications will require
well-designed clinical trials within the framework of carefully selected questions, such as whether maintenance can be omitted for a standard biologic risk group (B), whether up-front
autologous transplant is a uniform requirement for all eligible patients (C), and whether the high-risk group can be offered alternative investigational strategies to improve outcome (D).
CONCLUDING REMARKS
Studies performed over the last few years have emphasized
that MM is a complex disease that is not amenable to treatment through a single therapeutic approach or inhibition of a
single target or single pathway. A new generation of biomarkers based on cytogenetics, epigenetics, focal lesions,
clone status, and GEP signature is beginning to provide clinicians with more information about the clinical behavior of
the disease, providing a basis on which risk stratifcation
models and therapies can be continuously refned. The new
biomarker-based defnition of MM has direct clinical implications for initiating treatment in a biomarker-positive subgroup. Further studies should apply risk stratifcation in the
trial design to specifcally answer questions regarding treatment within each risk group. Currently, few data are available
to support the use of biomarker-guided treatment optimization, although with a robust pipeline of novel targeted agents
and standardized defnitions of MRD linked to traditional
clinical endpoints, this remains an important goal of ongoing
research. A systems-based approach including collaboration
across multiple institutions and investigators will enhance
our ability to conduct biomarker-focused clinical trials in a
more effective manner.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Ola Landgren, Celgene, BMS, Onyx, Medscape
Education. Consulting or Advisory Role: Saad Z. Usmani, Celgene, Millennium Takeda, Onyx, Sano. Ola Landgren, BMS, Celgene, Onyx. Speakers Bureau:
Saad Z. Usmani, Celgene, Millennium Takeda, Onyx. Research Funding: Saad Z. Usmani, Array BioPharma, Celgene, Janssen Oncology, Millennium Takeda,
Onyx, Pharmacyclics. Ola Landgren, Amgen. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: Ola Landgren, Onyx, Celgene, Millennium Takeda. Other Relationships: None.
References
1. Barlogie B, Attal M, Crowley J, et al. Long-term follow-up of autotransplantation trials for multiple myeloma: Update of protocols conducted
by the Intergroupe Francophone du Myelome, Southwest Oncology
group, and University of Arkansas for Medical Sciences. J Clin Oncol.
2010;28:1209-1214.
2. Lokhorst HM, van der Holt B, Zweegman S, et al. A randomized phase
3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010;115:1113-1120.
3. Chapman MA, Lawrence MS, Keats JJ, et al. Initial genome sequencing
and analysis of multiple myeloma. Nature. 2011;471:467-472.
4. Lohr JG, Stojanov P, Carter SL, et al. Widespread genetic heterogeneity
in multiple myeloma: implications for targeted therapy. Cancer Cell.
2014;25:91-101.
5. Biomarkers Defnitions Working Group. Biomarkers and surrogate
endpoints: preferred defnitions and conceptual framework. Clin Pharmacol Ther. 2001;69:89-95.
6. McShane LM, Hayes DF. Publication of tumor marker research results:
the necessity for complete and transparent reporting. J Clin Oncol. 2012;
30:4223-4232.
7. Jones HB. On a new substance occurring in the urine of a patient with
mollities ossium. Phil Trans R Soc Lond. 1848;138:55-62.
8. International Myeloma Working Group. Criteria for the classifcation
9.
10.
11.
12.
13.
14.
e501
15. Katzmann JA, Clark R, Kyle RA, et al. Suppression of uninvolved immunoglobulins defned by heavy/light chain pair suppression is a risk
factor for progression of MGUS. Leukemia. 2013;27:208-212.
16. Koulieris E, Panayiotidis P, Harding SJ, et al. Ratio of involved/uninvolved immunoglobulin quantifcation by Hevylite assay: clinical and
prognostic impact in multiple myeloma. Exp Hematol Oncol. 2012;1:9.
17. Tricot G, Sawyer JR, Jagannath S, et al. Unique role of cytogenetics in the
prognosis of patients with myeloma receiving high-dose therapy and
autotransplants. J Clin Oncol. 1997;15:2659-2666.
18. Chang H, Qi C, Yi QL, et al. p53 gene deletion detected by fluorescence
in situ hybridization is an adverse prognostic factor for patients with
multiple myeloma following autologous stem cell transplantation.
Blood. 2005;105:358-360.
19. Fonseca R, Bergsagel PL, Drach J, et al. International Myeloma Working
Group molecular classifcation of multiple myeloma: spotlight review.
Leukemia. 2009;23:2210-2221.
20. Avet-Loiseau H, Malard F, Campion L, et al. Translocation t(14;16) and
multiple myeloma: is it really an independent prognostic factor? Blood.
2011;117:2009-2011.
21. Avet-Loiseau H, Attal M, Moreau P, et al. Genetic abnormalities and
survival in multiple myeloma: the experience of the Intergroupe Francophone du Myelome. Blood. 2007;109:3489-3495.
22. Munshi NC, Anderson KC, Bergsagel PL, et al. Consensus recommendations for risk stratifcation in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. Blood. 2011;117:
4696-4700.
23. Boyd KD, Ross FM, Chiecchio L, et al. A novel prognostic model in
myeloma based on co-segregating adverse FISH lesions and the ISS:
analysis of patients treated in the MRC Myeloma IX trial. Leukemia.
2012;26:349-355.
24. Hanamura I, Stewart JP, Huang Y, et al. Frequent gain of chromosome
band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and
is related to prognosis and disease progression following tandem stemcell transplantation. Blood. 2006;108:1724-1732.
25. Zojer N, Konigsberg R, Ackermann J, et al. Deletion of 13q14 remains
an independent adverse prognostic variable in multiple myeloma despite its frequent detection by interphase fluorescence in situ hybridization. Blood. 2000;95:1925-1930.
26. Boyd KD, Ross FM, Walker BA, et al. Mapping of chromosome 1p deletions in myeloma identifes FAM46C at 1p12 and CDKN2C at 1p32.3
as being genes in regions associated with adverse survival. Clin Cancer
Res. 2011;17:7776-7784.
27. Avet-Loiseau H, Leleu X, Roussel M, et al. Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma
but not outcome of patients with del(17p). J Clin Oncol. 2010;28:46304634.
28. Barlogie B, Anaissie E, van Rhee F, et al. Incorporating bortezomib into
upfront treatment for multiple myeloma: early results of total therapy 3.
Br J Haematol. 2007;138:176-185.
29. Greipp PR, San Miguel J, Durie BG, et al. International staging system
for multiple myeloma. J Clin Oncol. 2005;23:3412-3420.
30. Avet-Loiseau H, Durie BG, Cavo M, et al. Combining fluorescent in situ
hybridization data with ISS staging improves risk assessment in myeloma: an International Myeloma Working Group collaborative project. Leukemia. 2013;27:711-717.
31. Shaughnessy JD Jr, Zhan F, Burington BE, et al. A validated gene expression model of high-risk multiple myeloma is defned by deregulated expression of genes mapping to chromosome 1. Blood. 2007;109:22762284.
32. Kuiper R, Broyl A, de Knegt Y, et al. A gene expression signature for
high-risk multiple myeloma. Leukemia. 2012;26:2406-2413.
e502
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
[carboxy-terminal telopeptide of type-I collagen (ICTP), aminoterminal collagen type-I telopeptide (NTx), and deoxypyridinoline
(Dpd)] in MGUS and multiple myeloma. Eur J Haematol. 2002;69:
37-42.
Abildgaard N, Brixen K, Kristensen JE, et al. Comparison of fve biochemical markers of bone resorption in multiple myeloma: elevated
pre-treatment levels of S-ICTP and U-Ntx are predictive for early progression of the bone disease during standard chemotherapy. Br J
Haematol. 2003;120:235-242.
Jakob C, Sterz J, Liebisch P, et al. Incorporation of the bone marker
carboxy-terminal telopeptide of type-1 collagen improves prognostic
information of the International Staging System in newly diagnosed
symptomatic multiple myeloma. Leukemia. 2008;22:1767-1772.
Schutt P, Rebmann V, Brandhorst D, et al. The clinical signifcance of
soluble human leukocyte antigen class-I, ICTP, and RANKL molecules
in multiple myeloma patients. Hum Immunol. 2008;69:79-87.
Christenson RH. Biochemical markers of bone metabolism: an overview. Clin Biochem. 1997;30:573-593.
Terpos E, Politou M, Szydlo R, et al. Autologous stem cell transplantation normalizes abnormal bone remodeling and sRANKL/osteoprotegerin ratio in patients with multiple myeloma. Leukemia. 2004;18:14201426.
Dowling P, Hayes C, Ting KR, et al. Identifcation of proteins found to
be signifcantly altered when comparing the serum proteome from Multiple Myeloma patients with varying degrees of bone disease. BMC
Genomics. 2014;15:904.
Heuck CJ, Mehta J, Bhagat T, et al. Myeloma is characterized by stagespecifc alterations in DNA methylation that occur early during myelomagenesis. J Immunol. 2013;190:2966-2975.
Walker BA, Wardell CP, Chiecchio L, et al. Aberrant global methylation
patterns affect the molecular pathogenesis and prognosis of multiple
myeloma. Blood. 2011;117:553-562.
Kaiser MF, Johnson DC, Wu P, et al. Global methylation analysis identifes prognostically important epigenetically inactivated tumor suppressor genes in multiple myeloma. Blood. 2013;122:219-226.
Marango J, Shimoyama M, Nishio H, et al. The MMSET protein is a
histone methyltransferase with characteristics of a transcriptional corepressor. Blood. 2008;111:3145-3154.
Pichiorri F, Suh SS, Ladetto M, et al. MicroRNAs regulate critical genes
associated with multiple myeloma pathogenesis. Proc Natl Acad Sci U S
A. 2008;105:12885-12890.
Dimopoulos K, Gimsing P, Grnbk K. The role of epigenetics in the
biology of multiple myeloma. Blood Cancer J. 2014;4:e207.
Perez-Persona E, Vidriales MB, Mateo G, et al. New criteria to identify
risk of progression in monoclonal gammopathy of uncertain signifcance and smoldering multiple myeloma based on multiparameter flow
cytometry analysis of bone marrow plasma cells. Blood. 2007;110:25862592.
Dispenzieri A, Kyle RA, Katzmann JA, et al. Immunoglobulin free light
chain ratio is an independent risk factor for progression of smoldering
(asymptomatic) multiple myeloma. Blood. 2008;111:785-789.
Rajkumar SV, Gupta V, Fonseca R, et al. Impact of primary molecular
cytogenetic abnormalities and risk of progression in smoldering multiple myeloma. Leukemia. 2013;27:1738-1744.
67. Neben K, Jauch A, Hielscher T, et al. Progression in smoldering myeloma is independently determined by the chromosomal abnormalities
del(17p), t(4;14), gain 1q, hyperdiploidy, and tumor load. J Clin Oncol.
2013;31:4325-4332.
68. Davies FE, Dring AM, Li C, et al. Insights into the multistep transformation of MGUS to myeloma using microarray expression analysis.
Blood. 2003;102:4504-4511.
69. Zhan F, Hardin J, Kordsmeier B, et al. Global gene expression profling
of multiple myeloma, monoclonal gammopathy of undetermined signifcance, and normal bone marrow plasma cells. Blood. 2002;99:17451757.
70. Zhan F, Barlogie B, Arzoumanian V, et al. Gene-expression signature of
benign monoclonal gammopathy evident in multiple myeloma is linked
to good prognosis. Blood. 2007;109:1692-1700.
71. Dhodapkar MV, Sexton R, Waheed S, et al. Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120). Blood. 2014;123:78-85.
72. Bhutani M, Turkbey B, Tan E, et al. Bone marrow angiogenesis in myeloma and its precursor disease: a prospective clinical trial. Leukemia.
2014;28:413-416.
73. Hillengass J, Fechtner K, Weber MA, et al. Prognostic signifcance of
focal lesions in whole-body magnetic resonance imaging in patients
with asymptomatic multiple myeloma. J Clin Oncol. 2010;28:1606-1610.
74. Merz M, Hielscher T, Wagner B, et al. Predictive value of longitudinal
whole-body magnetic resonance imaging in patients with smoldering
multiple myeloma. Leukemia. 2014;28:1902-1908.
75. Chng WJ, Dispenzieri A, Chim CS, et al. IMWG consensus on risk stratifcation in multiple myeloma. Leukemia. 2014;28:269-277.
76. Kumar SK, Mikhael JR, Buadi FK, et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratifcation of
Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines. Mayo Clin Proc. 2009;84:1095-1110.
77. Mikhael JR, Dingli D, Roy V, et al. Management of newly diagnosed
symptomatic multiple myeloma: updated Mayo Stratifcation of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines
2013. Mayo Clin Proc. 2013;88:360-376.
78. Moreau P, Garban F, Attal M, et al. Long-term follow-up results of
IFM99-03 and IFM99-04 trials comparing nonmyeloablative allotransplantation with autologous transplantation in high-risk de novo multiple myeloma. Blood. 2008;112:3914-3915.
79. Auner HW, Szydlo R, van Biezen A, et al. Reduced intensityconditioned allogeneic stem cell transplantation for multiple myeloma
relapsing or progressing after autologous transplantation: a study by the
European Group for Blood and Marrow Transplantation. Bone Marrow
Transplant. 2013;48:1395-1400.
80. Boyd KD, Pawlyn C, Morgan GJ, et al. Understanding the molecular
biology of myeloma and its therapeutic implications. Expert Rev Hematol. 2012;5:603-617.
81. Landgren O, Morgan GJ. Biologic frontiers in multiple myeloma: from
biomarker identifcation to clinical practice. Clin Cancer Res. 2014;20:
804-813.
82. McShane LM, Altman DG, Sauerbrei W, et al. REporting recommendations for tumor MARKer prognostic studies (REMARK). Nat Clin Pract
Urol. 2005;2:416-422.
e503
agents, such as monoclonal antibodies and histone deacetylase (HDAC) inhibitors, currently are being investigated.
These agents will further add to the therapeutic armamentarium and possibly increase the number of lines of therapy that
patients will receive during the course of their disease treatment.6 The optimal sequence of combination therapies from
the time of diagnosis to the time of the most advanced phase
of myeloma has to be considered carefully to minimize resistance and toxicity, and to improve quality of life (QOL), the
treatment-free interval (TFI), and, most importantly, overall
survival (OS).
e504
imens,4,6,9 the 2015 recommendation is the use of a threedrug regimen based on bortezomib/dexamethasone, with
the third agent cyclophosphamide, adriamycin, thalidomide, or lenalidomide.4,10
Novel agents also have been included in the post-ASCT setting. Their incorporation into consolidation therapy11 has
resulted in the achievement of deep molecular- or flow cytometry defned complete responses, with some patients remaining alive and free of disease, with a minimal residual
disease (MRD) negativity, which are vital prerequisites for
extended disease-free survival.12 These unprecedented
results were only possible previously with allogeneic transplantation (alloSCT), the routine use of which is not recommended outside clinical trials in MM because of excessive
transplant-related mortality.13 Recent data also show that
maintenance following HDT may dramatically increase
progression-free survival (PFS) by almost 2 years.14 The implementation of an optimal strategy, consisting of novel
agent-based induction, HDT, and the use of novel agents in
consolidation and maintenance, may result in a 5-year survival rate of 80%, which is unprecedented. Moreover, a subset
of patients who present with good prognostic features at the
time of diagnosis might be considered cured.15-16 However,
the strategy of optimized induction, HDT, and ASCT followed by PI- and/or IMiD-based consolidation and maintenance is currently restricted to clinical trials.
The high effcacy of novel agents has resulted in questioning of the role of up-front ASCT. A number of studies have
been initiated to investigate these agents up front without
ASCT. In a nonrandomized phase II trial of RVD (lenalidomide,
bortezomib, dexamethasone) in the up-front setting, no difference in outcome was seen for patients undergoing HDT or
not.17 Impressive results, including high rates of MRD-negative
responses, also have been reported for the combination of carflzomib/lenalidomide and low-dose dexamethasone (KRd) without up-front ASCT in another phase II study.18 Based on these
results, some physicians are considering that delaying ASCT to
the time of the frst disease relapse could be an attractive option.
In 2015, only limited data from randomized studies are available
to address the issue of early versus late ASCT. However, preliminary results favor early ASCT plus novel agents over novel
agents alone. The frst prospective study comparing conventional chemotherapy plus novel agents to tandem ASCT in
newly diagnosed MM patients is being conducted by the Italian
myeloma group and was recently reported by Palumbo et al.19
Patients received lenalidomide/dexamethasone (Rd) induction
and then were randomly assigned to melphalan/prednisone/lenalidomide (MPR) or tandem ASCT. Both PFS and OS were
substantially longer with high-dose melphalan plus ASCT than
with MPR (median PFS, 43.0 vs. 22.4 months; and 4-year OS,
81.6 vs. 65.3%). Two other ongoing trials, one conducted by the
European Myeloma Network (EMN02 study, NCT01208766)
and another by the IFM in conjunction with a U.S. consortium
(IFM/DFCI 2009 study, NCT01208662) are investigating the
same question and have enrolled 1,500 and 1,000 patients, respectively. Although variability in consolidation and maintenance strategies may affect PFS when comparing early versus
late transplant approaches, these two studies will solve many issues regarding the role of systematic front-line ASCT in the
treatment of young patients eligible for HDT. Results, however,
are not expected before the end of 2015.
e505
induction with the PAD (bortezomib, doxorubicinm dexamethasone) regimen and were randomly assigned to either
ASCT or cyclophosphamide. Although the median time to progression was substantialy longer for patients undergoing ASCT
(19 vs. 11 months), the OS did not differ between the two arms.
Many experts considered the cyclophosphamide arm of this
trial to be suboptimal. Since salvage regimens that are more effective than single-agent cyclophosphamide are now available,
additional prospective randomized trials comparing novel triplet combination therapies to salvage ASCT are needed.
TABLE 1. Recent and Ongoing Phase III Trials in Relapsed Multiple Myeloma: Two- versus Three-Drug
Combinations
No. of Patients
OS
IFM 2005-04/MMVAR35
TD
134
72
13.6
24 mo, 65%
VTD
135
88
18.3, p 0.001
71%, p 0.09
PANORAMA 136
VD
387
54.6
8.08
Median 30.4
VD-Panobinostat
381
60.7, p 0.09
11.99, p 0.0001
33.6, p 0.26
NA
NA
NA
NA
Rd
396
66.7
17.6
24 mo, 65%
Rd-Carlzomib
396
87.1, p 0.001
26.3, p 0.0001
73.3%, p 0.04
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
ELOQUENT-2 (NCT01239797)
Rd
Rd-Elotuzumab
POLLUX-MMY3003 (NCT02076009)
Rd
Rd-Daratumumab
TOURMALINE-1 (NCT61564537)
Rd
Rd-Ixazomib
Abbreviations: ORR: overall response rate, PR: partial response; PFS: progression-free survival; mo, months; OS: overall survival; TD: thalidomide-dexamethasone; VTD: bortezomib-thalidomidedexamethasone; VD: bortezomib-dexamethasone; Rd: lenalidomide-dexamethasone; NA, not available.
phase III randomized trial POLLUX. Daratumumab, a monoclonal antibody targeting CD38, has shown impressive activity
as a single agent in patients with advanced disease39 and in combination with Rd in phase II trials.40 Another monoclonal antibody targeting CD38, SAR650984, currently is also being
developed in relapsed disease.41 A further phase III trial using
Rd as a control arm could change the treatment landscape of
relapsed myeloma. The placebo-controlled TOURMALINEMM1 study is currently comparing Rd versus Rd-ixazomib in
patients with relapsed disease. This combination also was tested
along with Rd as front-line treatment in a phase II study resulting in impressive response rates.42 The all-oral triplet combination Rd-ixazomib could become a convenient rescue treatment,
provided that toxicity in relapse is similar to that observed in the
front-line setting. VD is, as mentioned above, another backbone
regimen in relapsed myeloma, and this combination also is currently being compared to VD plus pomalidomide in a prospective phase III international trial.
e507
was able to induce a long TFI or switch to a different treatment regimen. Several factors influence this decision, including drug availability in the specifc country, patient age,
comorbidities, performance status, prior treatment, duration
of remission to the front-line regimen, and initial toxicities.
Although anti-MM treatments have proven effcacious in
older patients with relapsed MM, their use is often associated
with substantial adverse effects that can affect treatment
choice. As such, older and frail patients usually are treated
with mild, low-dose regimens, typically thalidomide or bortezomib combined with either melphalan/prednisone or cyclophosphamide/dexamethasone.
RELAPSE FOLLOWING RD
The FIRST trial demonstrated the superiority of continuous
Rd over MPT in terms of ORR, PFS, and OS. When approved, Rd will be a well-tolerated and effective oral frontline regimen. At the time of progression on Rd, the addition
e508
POMALIDOMIDE
In the pivotal phase I/II study MM-002, the combination of
pomalidomide with low-dose dexamethasone (Pd) was
found to be more effcacious than single-agent pomalidomide in patients with relapsed and refractory MM (ORR, 34
and 15%, respectively).46 In a randomized phase III study
(MM-003), Pd was compared to high-dose dexamethasone
in patients with primary refractory or relapsed and refractory
MM. At 10 months median follow-up, the PFS was substantially longer in patients treated with Pd versus patients
treated with high-dose dexamethasone alone (median PFS,
4.0 vs. 1.9 months, respectively).47 Comparable results were
seen in a subgroup analysis of patients who were dualrefractory to bortezomib and lenalidomide (74% of patients
in the MM-003 trial) (median PFS, 3.7 months).47 A substantial improvement in OS was observed in the fnal analysis
(median OS, 12.7 vs. 8.1 months).47
Pomalidomide in combination with low-dose dexamethasone has been approved in Europe and the United States for
patients with relapsed and refractory MM whose disease has
progressed following at least two prior therapies, including
lenalidomide and bortezomib. As discussed previously, ongoing studies are examining pomalidomide in combination
CARFILZOMIB
Carflzomib initially was evaluated in patients with very advanced MM. In the single-arm phase II study PX-171-003A1, the treatment of patients with relapsed and refractory
MM with single-agent carflzomib led to durable responses,
resulting in an ORR of 23.7%, a median DOR of 7.8 months,
and a median OS of 15.6 months.48 Furthermore, the phase II
study PX-171-004 examined carflzomib in patients with relapsed and/or refractory MM who were treated previously
with bortezomib and in patients who were bortezomibnaive.49,50 In patients previously treated with bortezomib, the
ORR was 17.1%, with a median DOR of more than10.6
months and a median TTP of 4.6 months,50 whereas in 126
response-evaluable bortezomib-naive patients, an ORR of
47.6% and a median TTP of 12.0 months were seen.49 The
lower ORR in patients previously treated with bortezomib
may be attributable to a subset of patients who developed resistance to the class of PIs.
CONCLUSION
The tremendously active research into treatments for MM
has resulted in a number of highly active new agents and encourages optimism to the goal of transforming MM into a
chronic disease. Although none of the agents with novel
mechanisms of action (those following the PIs or IMiDs) are
yet to be approved, it is reasonable to believe that several will
be in the near future. Our task will be to defne the optimal
sequence of treatment, the optimal combinations both for
front-line and relapsed myeloma, according to age, comorbidities, cost, drug availability, and patients choice.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: None.
Speakers Bureau: None. Research Funding: Cyrille Touzeau, Abbvie (Inst). Patents, Royalties, or Other Intellectual Property: None. Expert
Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Siegel R, Ma J, Zou Z, et al. Cancer Statistics, 2014. CA Cancer J Clin.
2014;64:9-29.
2. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics
Review, 1975-2010. http://seer.cancer.gov/csr/1975_2010/2013.
3. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence
and mortality patterns in Europe: estimates for 40 countries in 2012. Eur
J Cancer. 2013;49:1374-1403.
4. Moreau P, San Miguel J, Ludwig H, et al. Multiple myeloma: ESMO
Clinical Practice Guidelines for diagnosis, treatment, and follow-up.
Ann Oncol. 2013;24 (suppl 6; vi133-vi137).
5. Anderson KC. The 39th David A. Karnofsky Lecture: bench-to-bedside
translation of targeted therapies in multiple myeloma. J Clin Oncol.
2012;30:445-452.
6. Ocio EM, Richardson PG, Rajkumar SV, et al. New drugs and novel
mechanisms of action in multiple myeloma in 2013: a report from the
International Myeloma Working Group (IMWG). Leukemia. 2014;28:
525-542.
7. Moreau P, Avet-Loiseau H, Harousseau JL, et al. Current trends in autologous stem- cell transplantation for myeloma in the era of novel therapies. J Clin Oncol. 2011;29:1898-1906.
8. Cavo M, Rajkumar SV, Palumbo A, et al. International Myeloma Working Group consensus approach to the treatment of multiple myeloma
9.
10.
11.
12.
13.
e509
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
e510
29. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus highdose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an openlabel randomised controlled trial. Lancet Oncol. 2010;11:29-37.
30. Benboubker L, Dimopoulos MA, Dispenzieri A, et al. Lenalidomide and
dexamethasone in transplant-ineligible patients with myeloma. N Engl
J Med. 2014;371:906-917.
31. Holstein SA, Richardson PG, Laubach JP, et al. Management of relapsed
multiple myeloma after autologous stem cell transplant. Biol Blood Marrow Transplant. Epub 2015 Jan 31.
32. Dimopoulos MA, Richardson PG, Moreau P, et al. Current treatment
landscape for relapsed and/or refractory multiple myeloma. Nat Rev
Clin Oncol. 2015;12:42-54.
33. Lemieux E, Hulin C, Caillot D, et al. Autologous stem cell transplantation: an effective salvage therapy in multiple myeloma. Biol Blood Marrow Transplant. 2013;19:445-449.
34. Cook G, Williams C, Brown JM, et al. High-dose chemotherapy plus
autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stemcell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a
randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15:874-885.
35. Garderet L, Iacobelli S, Moreau P, et al. Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple
myeloma progressing or relapsing after autologous transplantation: the
MMVAR/IFM 2005-04 Randomized Phase III Trial from the Chronic
Leukemia Working Party of the European Group for Blood and Marrow
Transplantation. J Clin Oncol. 2012;30:2475-2482.
36. San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple
myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet
Oncol. 2014;15:1195-1206.
37. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carflzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl
J Med. 2015;372:142-152.
38. Lonial S, Jagannath S, Moreau P, et al. Phase (Ph) I/II study of elotuzumab (Elo) plus lenalidomide/dexamethasone (Len/dex) in relapsed/
refractory multiple myeloma (RR MM): updated Ph II results and Ph
I/II long-term safety. J Clin Oncol. 2013;31(15s) (suppl; abstr 8542).
39. Plesner T, Lokhorst H, Gimsing P, et al. Daratumumab, a CD38 monoclonal antibody in patients with multiple myeloma data from a doseescalation phase I/II study Blood. 2012;120 (suppl; abstr 73).
40. Plesner T, Arkenau HT, Lokhorst HM, et al. Safety and effcacy of daratumumab with lenalidomide and dexamethasone in relapsed or relapsed, refractory multiple myeloma. Blood. 2014;124 (suppl; abstr 84).
41. Martin TG, Baz R, Benson DM, et al. A Phase Ib dose escalation trial of
SAR650984 (anti-CD-38 mAb) in combination with lenalidomide and
dexamethasone in relapsed/refractory multiple myeloma. Blood. 2014;
124 (suppl; abstr 83).
42. Kumar SK, Berdeja JG, Niesvizky R, et al. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple
myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014;15:15031512.
43. Richardson PG, Xie W, Jagannath S, et al. A phase 2 trial of lenalidomide, bortezomib, and dexamethasone in patients with relapsed and relapsed/refractory myeloma. Blood. 2014;123:1461-1469.
44. Rodon P, Hulin C, Pegourie B, et al. Phase II study of bendamustine,
bortezomib, and dexamethasone as second-line treatment for elderly
patients with multiple myeloma: the Intergroupe Francophone du Myelome 2009-01 trial. Haematologica. 2015;100:e56-e59.
45. Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in
multiple myeloma relapsing after therapy with IMiDs and bortezomib: a
multicenter international myeloma working group study. Leukemia.
2012;26:149-157.
46. Richardson PG, Siegel DS, Vij R, et al. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014;123:1826-1832.
47. San Miguel J, Weisel K, Moreau P, et al. Pomalidomide plus lowdose dexamethasone versus high-dose dexamethasone alone for patients
with relapsed and refractory multiple myeloma (MM-003): a randomised,
open-label, phase 3 trial. Lancet Oncol. 2013;14:1055-1066.
e511
SPEAKERS
Stephan Stilgenbauer, MD
Ulm University
Ulm, Germany
Richard R. Furman, MD
Weill Cornell Medical College
New York, NY
hronic lymphocytic leukemia/small lymphocytic lymphoma is the most prevalent lymphoid malignancy in
many parts of the world, and approximately 90% of patients
are diagnosed with asymptomatic, early-intermediate stage
(Rai 0-I, Binet A) disease.1-3 Many of these patients have indolent disease and could have a normal life expectancy,
whereas others have rapid disease progression and poor outcome. There is no proven survival beneft from early therapy
in patients with CLL.4,5 There are now multiple prognostic
factors that can be used to predict the risk of disease progression including serum thymidine kinase (TK) and beta-2microglobulin (2MG) levels, genomic aberrations assessed
by fluorescence in situ hybridization (FISH), ZAP70, CD38,
and CD49 expression, somatic hypermutation of the immunoglobulin heavy chain variable region genes (IGHV), and
mutations of other genes, most prominently TP53.6,7 Despite
multiple published studies of these prognostic factors in
early-stage CLL, none have been prospectively validated.8-14
Moreover, there is currently no evidence that early, risk factorguided intervention with chemoimmunotherapy can alter the natural course of early-stage CLL.4,5 Therefore, watch
and wait remains the standard of care for patients with
early-stage, asymptomatic CLL. The intervals of monitoring
can be adjusted to a patients risk profle, that is, with
From Ulm University, Ulm, Germany; Weill Cornell Medical College, New York, NY; University of Rochester, Rochester, NY.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Clive S. Zent, MD, Wilmot Cancer Institute, University of Rochester Medical Center, 601 Elmwood Ave., Box 704, Rochester, NY 14642; email: clive_zent@urmc.rochester.edu.
2015 by American Society of Clinical Oncology.
164
MANAGEMENT OF CLL
KEY POINTS
Careful observation for disease progression and
complications, together with appropriate preventative
interventions, remains the standard of care for patients
with early-stage, asymptomatic, chronic lymphocytic
leukemia. Patients with very high-risk chronic lymphocytic
leukemia should not receive treatment until they meet
standard criteria for progressive disease.
The most critical determinants of treatment choice are the
presence of 17p-/TP53mut, physical tness/age, and
duration of prior response in patients who have received
previous treatment. In addition, 17p-/TP53mut analysis
should be repeated before initiation of therapy.
The combination of anti-CD20 antibody (rituximab,
ofatumumab, or obinutuzumab) and chemotherapy (FC,
bendamustine, or chlorambucil) is the standard up-front
treatment for the majority of patients with chronic
lymphocytic leukemia, with the specic choice of agents
mostly determined by tness of the patient. Based on the
dramatic efcacy and favorable toxicity prole of the BCR
and BCL2 inhibitors compared with historic
chemoimmunotherapy regimens, these agents are the
preferred treatment approach for very high-risk chronic
lymphocytic leukemia (17p-/TP53mut and early relapse).
Ongoing and future clinical trials are essential to further
improve treatment efcacy, determine treatment duration,
and eventually develop curative therapy.
The role of allogeneic stem cell transplant in the management
of chronic lymphocytic leukemia requires careful and early
discussion in patients who are very high-risk.
165
A
Earlier stage,
asymptomatic
all
(go go)
observe
No 17pNoTP53mut
<65 years
>65 years
FCR
BR
frail
(no go)
(slow go)
17p- or
TP53mut
No 17pnoTP53mut
17p- or
TP53mut
Ibr
BR
Ibr
or
or
or
R-Idela
R-Clb
R-Idela
or
or
or
(Alem)
Obi-Clb
Alem
Supportive
care
or
Ofa-Clb
or
Ofa-B
CR / PR
SD / PD
CR / PR
SD / PD
Observe
2nd line
Observe
2nd line
Relapsed/refractory disease
SD / PD
Late relapse
SD / PD
or
or
Early relapse
Early relapse
or
or
17p-/TP53mut
17p-/TP53mut
Ibr
or
Chemoimmunotherapy
or
R-Idela
or
(Alem)
frail
(no go)
(slow go)
(go go)
Ibr
or
Late relapse
Repeat prior
regimen
R-Idela
or
Ibr
or
Ibr
or
(Alem)
R-Idela
Supportive
care
or
R-Idela
or
Discuss
allo SCT
Other
chemoimmunotherapy
(e.g. BR, Ofa-B)
Optimal therapy for patients with CLL requires evaluation of disease biology, patient tness, and treatment history. (A) Initial treatment of patients with CLL requires determination that they
meet the International Workshop on CLL (IWCLL) criteria for active disease. These patients should then be clinically evaluated for tness, and those considered t for treatment then require
FISH analysis for 17p13 deletion (17p-) and gene sequencing for mutations in TP53 considered to be dysfunctional (TP53mut). (B) In patients with relapsed/refractory CLL, the response to
previous treatment should also be considered when determining the treatment of choice. Patients who previously responded to chemoimmunotherapy with a response duration of 2 years or
longer (late relapse) can be considered for retreatment with a chemoimmunotherapy regimen. In contrast, patients with a response duration of less than 2 years should be considered to have
early relapse and should be treated with nonchemotherapy regimens.
Abbreviations: CLL, chronic lymphocytic leukemia; FISH, uorescence in situ hybridization; Alem, alemtuzumab; BR, bendamustine/rituximab; Clb, chlorambucil; CR, complete response; FCR,
udarabine/cyclophosphamide/rituximab; Ibr, ibrutinib; Idela, idelalisib; Obi, obinutuzumab; Ofa, ofatumumab; PD, progressive disease; PR, partial response; SD, stable disease.
Modied from the Onkopedia Guidelines of the German Society of Hematology and Oncology, available at www.onkopedia-guidelines.info.
from the U.K. CLL4 and GCLLSG CLL8 clinical trials have
only partly confrmed the independent prognostic role of
these gene mutations and their effect was less pronounced
MANAGEMENT OF CLL
167
pared with patients without 17p- CLL.41 In addition, the effcacy of idelalisib/rituximab appeared to not be impacted by
17p-/TP53mut in a retrospective subgroup analysis,47 suggesting that this regimen is another treatment option for this
subgroup.
Whereas the BCR antagonists very rarely achieve CR in the
relapsed/refractory setting, the results may be different when
these drugs are used as front-line therapy. For example, two
CRs were recorded in the four treatment-naive patients with
17p- CLL enrolled in the ibrutinib/rituximab study,48 and in
a study of front-line idelalisib and rituximab, ORR and CRR
of 100% and 33%, respectively, were reported in nine patients
with 17p- CLL.49 Prospective studies of these agents in the
front-line setting are currently underway. Notably, both the
U.S. Food and Drug Administration (FDA) and European
Medicines Agency have granted approval of ibrutinib and the
European Medicine Agency has approved idelalisib/rituximab for the up-front treatment of patients with 17p-/
TP53mut, clearly underlining the dramatically superior
effcacy of these agents in these patients. However, there are
data that suggest that resistance to novel agents may be related to genomic instability of the CLL clone, resulting in either development of diffuse large B-cell lymphoma (DLBCL;
Richter transformation) or acquired resistance to ibrutinib (see
below).50,51 These observations suggest that patients with 17p-/
TP53mut CLL, which is associated with a high degree of
genomic instability, could still beneft from ASCT.
The antiapoptotic members of the BCL2 family are targeted by BH3-mimetics (ABT-737, ABT-263, and ABT199).44,52 The current drug in clinical development for CLL is
venetoclax (ABT-199, GDC-0199), which is a specifc inhibitor of BCL2 and does not cause BCLXL inhibitionrelated
thrombocytopenia.45 The results of venetoclax in CLL have
been presented in abstract form.51,53 Both as single-agent and
in combination with rituximab, venetoclax achieved high response rates of approximately 80%, and importantlyand
differently from the results of BCR antagonists complete
remission rates of approximately 25% were reported even in
the relapsed/refractory 17p- setting.51,53 A number of patients have become negative for minimal residual disease
(MRD) following venetoclax (with or without rituximab)
therapy, and fve have discontinued venetoclax in remission
without recurrent disease at early follow-up. A pivotal phase
II study of venetoclax in 17p- CLL (front-line and relapsed/
refractory) is currently underway.
the initial lymphocytosis seen with these agents would be considered progressive disease based on the standard IWCLL criteria.1 This lymphocytosis likely results from the inhibition of
several adhesion molecule pathways, including CXCR4/5, and
could contribute to the effcacy of these agents.55,56 Fortunately,
the lymphocytosis is usually accompanied by a very rapid decrease in lymphadenopathy, and improvement in cytopenias
and symptoms. As a result, the IWCLL criteria have been revised by a group sponsored by the Lymphoma Research Foundation57 to exclude use of lymphocytosis as the sole indicator of
progression in patients who are receiving treatment with a BCR
antagonist. This new response category has been termed PR
with lymphocytosis.
Second, maximal response is often measured shortly after
the completion of therapy. The German CLL Study Group
validated the prognostic effect of measuring MRD 2 months
after completion of cycle six in the CLL8 study.18,58 For the
BCR signaling pathway inhibitors, responses evolved over
time41 and treatment is often ongoing. Patients receiving
treatment typically move from stable disease (or partial response with lymphocytosis) to partial response when the lymphocytosis resolves, to CR. Although we know the median time
to response to treatment, the median time to CR has not yet been
determined because half of the population has not yet achieved
CR or had progressive disease. In addition, although we can assume that negative MRD studies will predict for an excellent
outcome, the presence of MRD can no longer be seen as indicative of a poor response. Thus, comparison of responses to therapy with BCR signaling inhibitors to chemoimmunotherapy in
clinical trials should not use the previously used conventional
endpoints of partial response, CR, and MRD status, but should
rather focus on PFS and OS.
The third issue to re-evaluate is the role of prognostic
markers. Although the prognostic markers commonly used
in clinical practice (CD38, ZAP70, IGHV mutation status,
and interphase FISH) retain their predictive value for time to
treatment, they do not predict response to treatment with
BCR antagonists.41,42 It is also worth noting that in the frst
publication of the phase II data on ibrutinib therapy in CLL,41
patients with mutated IGHV were reported to have poorer
responses. However, analysis at a later time point showed no
difference in response rates based on IGHV mutation status.59 The initial difference could have been because the CLL
cells in patients with unmutated IGHV were more dependent
on BCR signaling, and therefore more sensitive to its inhibition. With regard to possible predictors of resistance developing to ibrutinib, complex karyotype and a mutator
phenotype might predict for the development of resistance.
Resistance to ibrutinib has been shown to occur because of a
single base pair mutation resulting in a cysteine-to-serine
change at amino acid 481 in BTK that alters the ibrutinib
binding site, or gain-of-function mutations in the PLC2
gene that overcome the inhibition of BTK.50,60 These data alter the role of use of prognostic factors in treatment planning
for patients with CLL. Important considerations include the role
of ASCT and the ability to avoid DNA-damaging drugs that
MANAGEMENT OF CLL
subsequent phase III trials to ascertain, but for now, clinicians might consider cardiac risks when making treatment
decisions.
Data for ibrutinib in patients with 17p- CLL are derived
from three studies.46,49,63,64 In the pivotal RESONATE study,
127 of the 391 patients had 17p-. The overall response rate,
excluding partial response with lymphocytosis, was 47.6%
with ibrutinib, compared with 4.7% with ofatumumab. The
median PFS for ibrutinib was not reached compared with 5.8
months for ofatumumab. In patients who received ibrutinib,
83% with 17p- were progression-free at 6 months. There was
no difference in response rate or PFS based on the presence
or absence of 17p-.46 An NIH phase II study of 51 patients
with TP53 aberrations demonstrated a 97% response rate in
previously untreated patients, with a 91% PFS at 24 months
(35 patients), and an 80% response rate in previously treated
patients, with an 80% PFS at 24 months (16 patients). The
third study, RESONATE-17, involved 144 patients with CLL
with 17p- whose disease had relapsed or was refractory to one
prior therapy. The overall response rate was 82.6%, with a
PFS at 12 months of 79.3%. Progressive disease occurred in
20 patients (13.9%), including Richter transformation in 11
patients, seven of which occurred within the frst 24 weeks of
treatment.49,64 These data suggest that treatment of patients
with relapsed/refractory CLL and 17p-/TP53mut using ibrutinib results in better outcomes than that achieved with any
previously used therapies.
Idelalisib therapy. Idelalisib, which targets PI3K-delta, demonstrated excellent effcacy and tolerability in patients with
relapsed/refractory CLL. Across its phase I/II studies, idelalisib used as a single agent resulted in a 72% response rate with
a median PFS of 15.8 months65 in a high- to very high-risk
relapsed/refractory CLL population (70% treatment-refractory,
24% 17p-/TP53mut). Severe adverse events included diarrhea/
colitis (5.6%), transaminitis (1.9%), and pneumonia (20.4%).
Idelalisibs pivotal phase III study was conducted in a heavily pretreated population of patients considered unlikely to
beneft from chemotherapy because of a previous response
duration of less than 2 years who had additional comorbidities (persistent myelosuppression or creatinine clearance
60 mL/min).42 Two-hundred and twenty patients were randomly assigned to receive rituximab/placebo or rituximab/
idelalisib (150 mg twice daily). The patient population had a
median CIRS score of eight, median creatinine clearance of
64.5 mL/min, and 43.5% had 17p-. The study met its primary
endpoint at the frst interim analysis with an 85% reduction
in the risk of progression or death between the two arms (median PFS, 5.5 months for placebo vs. not reached for idelalisib) and a substantial improvement in OS (survival at 12
months of 80% for placebo vs. 92% for idelalisib). A subsequent update after the second interim analysis demonstrated
a 12-month PFS for the idelalisib/rituximab arm of 66% compared with 13% for the placebo/rituximab arm.47 PFS and response rates were not affected by prognostic factors,
including deletion 17p-/TP53mut, ZAP70 expression, or
IGHV mutational status. Severe adverse events occurred in
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
169
COMPLICATIONS OF CLL
Acquired immune defects occur early in the course of CLL
and increase the risk of infection and autoimmune disease.
Defective immune surveillance could also contribute to the
increased risk of second malignancy. In addition, clonal evolution can cause transformation to DLBCL.
Infections
Patients with CLL have a high risk of serious infection, which
causes considerable morbidity and mortality.66 Defective
nonmalignant B-cell function impairs humoral responses to
antigens, and although absolute T-cell counts are usually increased, CD4/CD8 ratios are reversed with decreased T-cell
receptor repertoire, and impaired T-cell function.66-68
Monocyte, dendritic, and natural killer cell dysfunction,
decreased serum complement levels, and bone marrow failureassociated neutropenia result in defective innate
immunity.66,69-71 Immune dysfunction is further impaired by
chemotherapy and monoclonal antibody therapy.
170
MANAGEMENT OF CLL
171
and these malignancies are more likely to be locally aggressive and metastatic.74,92-94 Melanoma is also more common
and aggressive with poorer outcome.88,92,93,95
Patients require education on avoidance of ultraviolet
radiation and should be evaluated by a dermatologist at
diagnosis and then at least annually. Patients and families
need to be educated on how to conduct monthly skin inspections.
Other malignancies. Noncutaneous second malignancies are a
major cause of morbidity and mortality in patients with
CLL.88,92,96,97 Patients should be encouraged to avoid smoking and excessive alcohol use, and to undergo routine preventative screening.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Richard R. Furman, Gilead Sciences, Janssen
Pharmaceuticals, Pharmacyclics. Consulting or Advisory Role: Richard R. Furman, Gilead Sciences, Janssen Biotech, Inc., Pharmacyclics. Speakers
Bureau: Richard R. Furman, Genentech, Janssen Pharmaceuticals, Pharmacyclics. Research Funding: Richard R. Furman, Acerta. Clive Zent, Biothera (Inst),
GlaxoSmithKline (Inst), Novartis (Inst). Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations,
Expenses: Richard R. Furman, Gilead Sciences, Janssen Pharmaceuticals, Pharmacyclics. Other Relationships: None.
References
1. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis
and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the
National Cancer Institute-Working Group 1996 guidelines. Blood.
2008;111:5446-5456.
2. Rai KR, Sawitsky A, Cronkite EP, et al. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46:219-234.
3. Binet JL, Auquier A, Dighiero G, et al. A new prognostic classifcation of
chronic lymphocytic leukemia derived from a multivariate survival
analysis. Cancer. 1981;48:198-205.
4. Dighiero G, Maloum K, Desablens B, et al. Chlorambucil in indolent
chronic lymphocytic leukemia. French Cooperative Group on Chronic
Lymphocytic Leukemia. N Engl J Med. 1998;338:1506-1514.
5. Schweighofer CD, Cymbalista F, Muller C, et al. Early Versus Deferred
Treatment With Combined Fludarabine. Cyclophosphamide and
Rituximab (FCR) Improves Event-Free Survival In Patients With HighRisk Binet Stage A Chronic Lymphocytic Leukemia - First Results Of a
Randomized German-French Cooperative Phase III Trial. Blood.
2013:21 (suppl; abstr 524). Epub 2013 Dec 6.
6. Stilgenbauer S, Zenz T. Understanding and managing ultra high-risk
chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2010;2010:481-488.
7. Zent CS, Burack WR. Mutations in chronic lymphocytic leukemia
and how they affect therapy choice: focus on NOTCH1, SF3B1 and
TP53. Hematology Am Soc Hematol Educ Program. 2014;2014:119124. Epub 2014 Nov 18.
8. Wierda WG, OBrien S, Wang X, et al. Prognostic nomogram and index
172
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
for overall survival in previously untreated patients with chronic lymphocytic leukemia. Blood. 2007;109:4679-4685.
Shanafelt TD, Jenkins G, Call TG, et al. Validation of a new prognostic
index for patients with chronic lymphocytic leukemia. Cancer. 2009;
115:363-372.
Abrisqueta P, Pereira A, Rozman C, et al. Improving survival in patients
with chronic lymphocytic leukemia (1980-2008): the Hospital Clinic of
Barcelona experience. Blood. 2009;114:2044-2050.
Molica S, Mauro FR, Callea V, et al. The utility of a prognostic index for
predicting time to frst treatment in early chronic lymphocytic leukemia: the GIMEMA experience. Haematologica. 2010;95:464-469.
Letestu R, Levy V, Eclache V, et al. Prognosis of Binet stage A chronic
lymphocytic leukemia patients: the strength of routine parameters.
Blood. 2010;116:4588-4590.
Pepper C, Majid A, Lin TT, et al. Defning the prognosis of early stage
chronic lymphocytic leukaemia patients. Br J Haematol. 2012;156:499-507.
Pflug N, Bahlo J, Shanafelt TD, et al. Development of a comprehensive
prognostic index for patients with chronic lymphocytic leukemia.
Blood. 2014;124:49-62.
Best OG, Gardiner AC, Davis ZA, et al. A subset of Binet stage A CLL
patients with TP53 abnormalities and mutated IGHV genes have stable
disease. Leukemia. 2009;23:212-214.
Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910-1916.
Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus
cyclophosphamide for patients with chronic lymphocytic leukaemia (the
LRF CLL4 Trial): a randomised controlled trial. Lancet. 2007;370:230-239.
Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to
MANAGEMENT OF CLL
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;
376:1164-1174.
Oscier DG, Rose-Zerilli MJ, Winkelmann N, et al. The clinical signifcance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial.
Blood. 2013;121:468-475.
Rossi D, Rasi S, Spina V, et al. Integrated mutational and cytogenetic
analysis identifes new prognostic subgroups in chronic lymphocytic
leukemia. Blood. 2013;121:1403-1412.
Stilgenbauer S, Cymbalista F, Leblond V, et al. Alemtuzumab combined
with dexamethasone followed by alemtuzumab maintenance or alloSCT in ultra High-risk CLL: fnal results from the CLL2O phase II
study. Blood. 2014;124 (suppl; abstr 1991). Epub 2014 Dec 5.
Tam CS, Shanafelt TD, Wierda WG, et al. De novo deletion 17p13.1
chronic lymphocytic leukemia shows signifcant clinical heterogeneity:
the M. D. Anderson and Mayo Clinic experience. Blood. 2009;114:957964.
Tam CS, OBrien S, Wierda W, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of
chronic lymphocytic leukemia. Blood. 2008;112:975-980.
Eichhorst B, Fink AM, Busch R, et al. Frontline chemoimmunotherapy
with fludarabine (F), cyclophosphamide (C), and Rituximab (R) (FCR)
shows superior effcacy in comparison to bendamustine (B) and rituximab (BR) in previously untreated and physically ft patients (pts) with
advanced chronic lymphocytic leukemia (CLL): fnal analysis of an international, randomized study of the German CLL Study Group
(GCLLSG) (CLL10 Study). Blood. 2014;124 (suppl; abstr 19).
Hillmen P, Robak T, Janssens A, et al. Chlorambucil plus ofatumumab
verses chlorambucil alone in previously untreated patients with chronic
lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet. In press.
Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in
patients with CLL and coexisting conditions. N Engl J Med. 2014;370:
1101-1110. Epub 2014 Jan 8.
Stilgenbauer S, Schnaiter A, Paschka P, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8
trial. Blood. 2014;123:3247-3254.
Bosch F, Abrisqueta P, Villamor N, et al. Rituximab, fludarabine, cyclophosphamide, and mitoxantrone: a new, highly active chemoimmunotherapy regimen for chronic lymphocytic leukemia. J Clin Oncol. 2009;
27:4578-4584.
Lamanna N, Kalaycio M, Maslak P, et al. Pentostatin, cyclophosphamide, and rituximab is an active, well-tolerated regimen for patients
with previously treated chronic lymphocytic leukemia. J Clin Oncol.
2006;24:1575-1581.
Fischer K, Cramer P, Busch R, et al. Bendamustine in combination with
rituximab for previously untreated patients with chronic lymphocytic
leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2012;30:3209-3216.
Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtuzumab
(Campath-1H) in patients who have failed fludarabine: results of a large
international study. Blood. 2002;99:3554-3561.
Stilgenbauer S, Zenz T, Winkler D, et al. Subcutaneous alemtuzumab in
fludarabine-refractory chronic lymphocytic leukemia: clinical results
and prognostic marker analyses from the CLL2H study of the German
Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2009;27:
3994-4001.
Pettitt AR, Jackson R, Carruthers S, et al. Alemtuzumab in combination
with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: fnal
results of the national cancer research institute CLL206 trial. J Clin Oncol. 2012;30:1647-1655.
34. Khouri IF, Keating MJ, Saliba RM, et al. Long-term follow-up of patients
with CLL treated with allogeneic hematopoietic transplantation. Cytotherapy. 2002;4:217-221.
35. Moreno C, Villamor N, Colomer D, et al. Allogeneic stem-cell transplantation may overcome the adverse prognosis of unmutated VH gene
in patients with chronic lymphocytic leukemia. J Clin Oncol. 2005;23:
3433-3438.
36. Gribben JG, Zahrieh D, Stephans K, et al. Autologous and allogeneic
stem cell transplantations for poor-risk chronic lymphocytic leukemia.
Blood. 2005;106:4389-4396.
37. Dreger P, Corradini P, Kimby E, et al. Indications for allogeneic stem
cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia. 2007;21:12-17.
38. Schetelig J, van Biezen A, Brand R, et al. Allogeneic hematopoietic stemcell transplantation for chronic lymphocytic leukemia with 17p deletion: a retrospective European Group for Blood and Marrow
Transplantation analysis. J Clin Oncol. 2008;26:5094-5100.
39. Dreger P, Dohner H, Ritgen M, et al. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic
leukemia: long-term clinical and MRD results of the German CLL Study
Group CLL3X trial. Blood. 2010;116:2438-2447.
40. Dreger P, Schetelig J, Andersen N, et al. Managing high-risk CLL during
transition to a new treatment era: stem cell transplantation or novel
agents? Blood. 2014;124:3841-3849.
41. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in
relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32-42.
42. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed
chronic lymphocytic leukemia. N Engl J Med. 2014;370:997-1007.
43. Jones JA, Byrd JC. How will B-cell-receptor-targeted therapies change
future CLL therapy? Blood. 2014;123:1455-1460.
44. Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19:202-208.
45. OBrien SM, Furman RR, Coutre SE, et al. Independent evaluation of
ibrutinib effcacy 3 years post-initiation of monotherapy in patients
with chronic lymphocytic leukemia/small lymphocytic leukemia including deletion 17p disease. J Clin Oncol. 2014;32 (suppl; abstr 7014).
46. Byrd JC, Brown JR, OBrien S, et al. Ibrutinib versus ofatumumab in
previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:
213-223.
47. Sharman JP, Coutre SE, Furman RR, et al. Second interim analysis of a
phase 3 study of idelalisib (ZYDELIG) plus rituximab (R) for relapsed
chronic lymphocytic leukemia (CLL): effcacy analysis in patient subpopulations with del(17p) and other adverse prognostic factors. Blood.
2014;124 (suppl; abstr 330).
48. Burger JA, Keating MJ, Wierda WG, et al. Safety and activity of ibrutinib
plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2014;15:1090-1099.
49. OBrien S, Lamanna N, Kipps TJ, et al. Update on a phase 2 study of
idelalisib in combination with rituximab in treatment-nave patients
65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Blood. 2014;124 (suppl; abstr 1994).
50. WoyachJA,FurmanRR,LiuTM,etal.ResistancemechanismsfortheBrutons
tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370:2286-2294.
51. Seymour JF, Davids MS, Pagel JM, et al. ABT-199 (GDC-0199) in relapsed/refractory chronic lymphocytic leukemia and small lymphocytic
lymphoma: high response rates among patients with high risk disease
features including unmutated IGHV. Haematologica. 2014;99 (suppl 1;
abstr S1348).
52. Roberts AW, Seymour JF, Brown JR, et al. Substantial susceptibility of
chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I
173
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
174
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
MANAGEMENT OF CLL
lymphocytic leukemia: Updates on biology, clinical features and therapy. Leuk Lymphoma. 2015;1-10.
92. Royle JA, Baade PD, Joske D, et al. Second cancer incidence and cancer mortality among chronic lymphocytic leukaemia patients: a
population-based study. Br J Cancer. 2011;105:1076-1081.
93. Brewer JD, Habermann TM, Shanafelt TD. Lymphoma-associated skin
cancer: incidence, natural history, and clinical management. Int J Dermatol. 2014;53:267-274.
94. Velez NF, Karia PS, Vartanov AR, et al. Association of advanced leukemic stage and skin cancer tumor stage with poor skin cancer outcomes
175
MELANOMA/SKIN CANCERS
SPEAKERS
Sandro V. Porceddu, MD
Princess Alexandra Hospital
Brisbane, Australia
Jean Y. Tang, MD, PhD
Stanford University School of Medicine
Redwood City, CA
PROGNOSTIC FACTORS
Clinicopathologic Factors
Studies have identifed a number of adverse clinicopathologic prognostic factors that predict for recurrence in NMSC.
The majority of recurrences tend to occur within 2 years
of the initial primary diagnosis.4 BCC and cSCC generally
share the same risk factors for locoregional recurrence, although regional recurrences in BCC seldom occur. Many of
the factors that predict for local recurrence in both BCC and
cSCC also tend to predict for regional nodal involvement or
relapse. In BCC, the development of distant metastases is rare
( 1%).4,5,6 Division into low- and high-risk categories for
NMSC is somewhat arbitrary since the disease falls on a continuous spectrum, as determined from retrospective series
reports that found different prognostic factors between published series.
From the Division of Cancer Services, Princess Alexandra Hospital, Brisbane, Australia.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Sandro V. Porceddu, MD, Division of Cancer Services, Princess Alexandra Hospital, 199 Ipswich Rd., Woolloongabba, Brisbane, Australia, 4012;
email: sandro.porceddu@health.qld.gov.au.
2015 by American Society of Clinical Oncology.
e513
SANDRO V. PORCEDDU
A review by Alam and Ratner reported that the risk for local recurrence and metastases for cSCC increases in the presence of factors such as rapid growth, greater than 2 cm
diameter, primary site of lip or ear, immunosuppression,
previous RT, recurrence, greater than 4 mm thickness or
Clark level IV, poor differentiation, infltrative or peripheral
margins, spindle or acantholytic features, and perineural invasion (PNI).2
Brantsch et al published the results of a prospective study
assessing the risk factors for recurrence and regional metastases in cSCC. They reported that patients with a tumor
thickness of 2.0 mm or smaller did not develop metastases.
Metastases occurred at a rate of 4% among patients with tumors between 2.1 to 6.0 mm and 16% for tumors larger than
6.0 mm. The risk for local recurrence depended on increasing
tumor thickness and desmoplasia.5
The National Comprehensive Cancer Network (NCCN)
has produced a table detailing high- and low-risk factors for
recurrence of BCC and cSCC based on a combination of
available evidence and workshop group consensus.6
Clayman et al identifed several factors that reduce diseasespecifc survival (DSS) in patients with cSCC. These factors
include local recurrence at presentation, increasing tumor
size and depth, invasion beyond subcutaneous tissues, and
PNI. Patients with one or more risk factors, when compared
with patients with no risk factors, had a signifcantly inferior
3-year DSS of 70% vs. 100%, respectively (p 0.001, log-rank
test).7
PNI, immunosuppression, and regional nodal involvement are well-recognized prognostic risk factors for LRC and
distant relapse, and are discussed in greater detail below.
Table 1 summarizes the commonly accepted prognostic
risk factors in NMSC of the head and neck.
KEY POINTS
Non-melanoma skin cancer (NMSC) is the most common
cancer worldwide. Approximately 75% to 80% of cases
are basal cell carcinoma and 20% to 25% of cases are
cutaneous squamous cell carcinoma.
Division into low- and high-risk NMSC is somewhat arbitrary
since disease type falls on a continuous spectrum, as data
from retrospective series have shown.
Approximately 5% of patients with NMSC (mainly
cutaneous squamous cell carcinoma) are considered to be
at high risk for relapse, either local, regional, or distant
(rarely), following surgery.
Because of the dearth of high-level evidence on the
benets of adjuvant radiation therapy (RT), there is a lack
of universally adopted guidelines regarding its use. Use of
adjuvant RT is commonly based on individual institutional
policy.
Retrospective series support consideration of adjuvant RT
in the presence of advanced primary disease (stages T3T4), regional nodal involvement, clinical perineural invasion
(cPNI) and immunosuppression.
e514
Low Risk
High Risk
2 cm
2 cm
T1-2
Stages T3-T4
2 mm
2 mm
Clark level 4
Sites
Differentiation
Subtype (SCC)
Poor
Basosquamous,
desmoplastic,
adenosquamous
Perineural invasion
Absent or single
small nerve
Rapid growth
Absent
Present
Borders
Well-dened
Lymphovascular space
invasion
Absent
Present
Margin status
Negative
Positive
Immune status
Immunosuppressed
Chronic inammation,
scars (SCC)
Absent
Present
Absent
Present
Present
Absent
Recurrent disease
No
Yes
Perineural Invasion
PNI can be divided into two categories: (1) disease detected
incidentally on pathologic assessment (pPNI) and (2) involving a named nerve (cPNI). For patients with cPNI, a prior
history of pPNI is not always present.
PNI is more frequently seen in patients with cSCC (5% to
10%) than in patients with BCC (2% to 5%).8,9 In the case of
cPNI, the Trigeminal (V) and Facial (VII) cranial nerves
(CN) are commonly affected, typically involving retrograde
progression (progression of disease from the periphery
(skin) toward the brain/brainstem). Diagnosis may be delayed with VII CN involvement because of an initial misdiagnosis of Bells palsy. Diagnosis can be facilitated with the
use of targeted 3 Tesla MRI neurography, which provides superior sensitivity and specifcity compared with computed
tomography (CT).10
There is some evidence that extratumoral disease (PNI
seen extending beyond the main tumor mass), large nerve
diameter involvement, and multifocal PNI are associated
with more aggressive disease behavior.8,11
cPNI is more aggressive when seen in cSCC compared with
BCC. Jackson et al reported 5-year local control (LC) rates of
90% for pPNI compared with 57% for cPNI (p 0.0001). The
pPNI and cPNI groups also differed in relapse-free survival
(76% vs. 46%, p 0.003), DSS (90% vs. 76%, p 0.002), and
IMMUNOSUPPRESSION
The importance of immunosuppression as a factor that increases the risk for both developing NMSC and experiencing
poorer outcomes is well documented.2,4 Patients with immunosuppression are more likely to develop regional nodal metastases, to be at greater risk for death, and to have tumors
that exhibit higher rates of adverse risk features such as
PNI.2,13 In a study by Tomaszewski et al, 36% of patients with
node-negative cSCC and chronic lymphocytic leukemia developed regional nodal recurrence, with disease-specifc
death reported for 33% of patients.14
TREATMENT
A number of guidelines recommend that complex and highrisk cases should be referred for consultation and management by a multidisciplinary tumor board. These cases may
require the primary disease to undergo extensive resection
with reconstructive surgery, elective or therapeutic nodal
treatment, adjuvant RT, and close follow-up monitoring.4,6
Table 3 summarizes the factors that might be considered for
a referral to a multidisciplinary tumor board.
e515
SANDRO V. PORCEDDU
e516
nerve that are proximal and distal to the tumor site, skin that
is innervated by the involved nerve, major communicating
branches, and the compartment in which the nerve is embedded, such as the parotid gland for CN VII.29
CONCLUSION
Evidence, mainly from retrospective series, has identifed adverse prognostic factors that predict for locoregional relapse
in patients with NMSC; however, there is a lack of confrmatory prospective data examining the beneft of adjuvant RT in
these patients. And although there is strong retrospective
data supporting the role of adjuvant RT in high-risk diseasefor example, in disease with metastatic regional nodal
involvementthe data is less certain about the ways in which
adverse features and the extent of disease should factor into
the consideration of treatment with adjuvant RT. As a result
of this uncertainty, the use of adjuvant RT in the treatment of
NMSC is predominantly based on individual institutional
policy. Further prospective studies in this area are warranted.
References
1. Rogers HW, Weinstock MA, Harris AR, et al. Incidence estimate of
nonmelanoma skin cancer in the United States, 2006. Arch Dermatol.
2010;146:283-287.
2. Alam M, Ratner D. Cutaneous squamous-cell carcinoma. N Engl J Med.
2001;344:975-983.
3. Soyer HP, Rigel, Wurm EMT, et al. Actinic keratosis, basal cell carcinoma and squamous cell carcinoma. In Bolognia JL, Jorizzo JL,
Schaffer JV (ed). Dermatology (3rd Ed). London, England: Elsevier,
2012;1773-1794.
4. Cancer Council Australia. Clinical Practice Guide: Basal Cell Carcinoma, Squamous Cell Carcinoma (and Related Lesions)A Guide to
Clinical Management in Australia. Sydney: Cancer Council Australia
and Australian Cancer Network; 2008.
5. Brantsch KD, Meisner C, Schonfsch B, et al. Analysis of risk factors
determining prognosis of cutaneous squamous-cell carcinoma: a prospective study. Lancet Oncol. 2008;9:713-720.
6. NCCN Clinical Practice Guidelines in Oncology. Basal Cell and
Squamous Cell Skin Cancers. Version 2.2012. www.nccn.org/
professionals/physician_gls/f_guidelines.asp. Accessed January 27,
2015.
7. Clayman GL, Lee JJ, Holsinger FC, et al. Mortality risk from squamous
cell skin cancer. J Clin Oncol. 2005;23:759-765.
8. Carter JB, Johnson MM, Chua TL, et al. Outcomes of primary cutaneous
9.
10.
11.
12.
13.
14.
e517
SANDRO V. PORCEDDU
15. Andruchow JL, Veness MJ, Morgan GJ, et al. Implications for clinical
staging of metastatic cutaneous squamous carcinoma of the head and
neck based on a multicenter study of treatment outcomes. Cancer. 2006;
106:1078-1083.
16. Veness MJ, Porceddu S, Palme CE, et al. Cutaneous head and neck squamous cell carcinoma metastatic to parotid and cervical lymph nodes.
Head Neck. 2007;29:621-631.
17. OHara J, Ferlito A, Takes RP, et al. Cutaneous squamous cell carcinoma
of the head and neck metastasizing to the parotid glanda review of
current recommendations. Head Neck. 2011;33:1789-1795.
18. Veness MJ, Morgan GJ, Palme CE, et al. Surgery and adjuvant radiotherapy in patients with cutaneous head and neck squamous cell carcinoma metastatic to lymph nodes: combined treatment should be
considered best practice. Laryngoscope. 2005;115:870-875.
19. Veness MJ, Palme CE, Smith M, et al. Cutaneous head and neck squamous cell carcinoma metastatic to cervical lymph nodes (nonparotid): a
better outcome with surgery and adjuvant radiotherapy. Laryngoscope.
2003;113:1827-1833.
20. Ebrahim A, Clark JR, Lorincz BB, et al. Metastatic head and neck cutaneous squamous cell carcinoma: defning a low-risk patient. Head Neck.
2012;34:365-370.
21. Kirke DN, Porceddu S, Wallwork BD, et al. Pathologic occult neck disease in patients with metastatic cutaneous squamous cell carcinoma to
the parotid. Otolaryngol Head Neck Surg. 2011;144:549-551.
22. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent ra-
e518
23.
24.
25.
26.
27.
28.
29.
BIOLOGY
Merkel Cell Polyoma Virus
A higher risk of developing MCC in patients who are immunosuppressed provided a strong impetus to search for a viral
etiology in MCC. The search for viral sequences in tumors
was subsequently enabled by the development of deep transcriptome sequencing, which led to the seminal discovery of
the MCV in 2008.3 Despite the now clear oncogenic role of
the virus, MCV is likely to be part of normal skin flora, as viral
DNA can frequently be detected at low levels in the normal
skin of healthy individuals.9 This is further supported by serologic studies showing that children can be infected by
MCV from a very young age and that up to 80% of adults in
North America have been exposed to the virus by age 50.10
MCV is a double-stranded DNA virus that harbors large and
small-T antigens (LT; ST) required for modulation of the
host cell and viral replication. The oncogenic potential of
MCV is thought to only occur on chance sequential events of
clonal integration into the host genome and then acquisition
of mutations in the 3 end of the LT. Mutations in the LT
truncate the C-terminus of the oncoprotein, disrupting the
helicase domain, which renders the virus replication incompetent. This may be important for several reasons, but primarily to prevent cell death through inappropriate DNA
replication at integration sites, which would lead to
From the Division of Research, Peter MacCallum Cancer Centre, and the Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia; Department of Radiation Oncology and
Skin and Melanoma Tumour Stream, Peter MacCallum Cancer Centre, and the Department of Pathology, University of Melbourne, Melbourne, Australia; Division of Cancer Medicine, and Head and Neck
Tumour Stream, Peter MacCallum Cancer Centre, the Sir Peter MacCallum Department of Oncology and Department of Medicine, University of Melbourne, Melbourne, Australia.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Danny Rischin, MBBS, MD, FRACP, Division of Cancer Medicine, Peter MacCallum Cancer Centre, St. Andrews Pl East Melbourne, Australia 3002;
email: danny.rischin@petermac.org.
2015 by American Society of Clinical Oncology.
e519
replication-fork collisions and DNA-strand breakage.11 Importantly, the mutation does not affect the functional ability
of LT to sequester the retinoblastoma protein (RB), a cell cycle regulator and tumor suppressor that is frequently disrupted in cancer.
Continuous expression of T-antigens have been shown to
be required for maintenance of MCV-positive cell lines.12
However, unlike the related and intensively studied simian
vacuolating virus 40 (SV40), the expression of MCV LT alone
does not appear to be suffcient to transform cells, which is in
contrast to the MCV ST, which has more potent oncogenic
potential.13 MCV ST has been shown to act downstream
of mTOR in the PI3K/AKT/mTOR signaling pathway, preventing dephosphorylation of 4E-BP1, which regulates capdependent translation of mRNAs.13 More recently, the MCV
ST has been shown to bind to cellular FBXW7, which is a
subunit of the SKP1/CULLIN1/F-box (SCF) protein ubiquitin ligase complex that negatively regulates the LT and other
cellular proto-oncogenes such as cMYC and cyclin E.14 A
transgenic mouse harboring MCV ST driven by a bovine keratin 5 promoter has been recently described (K5-ST). Induction of K5-ST in adult mice resulted in epidermal
transformation and squamous cell carcinoma in situ. The
mice, however, failed to develop MCC, which indicates there
is perhaps a requirement of both LT and ST expression or
that targeted expression is required in an alternative Merkel
cell precursor cell type. Development of an immunocompetent MCC animal model would be an invaluable research tool
for the preclinical evaluation of novel therapies.
Viral-Negative MCC
In Europe, the United States, and Japan, the frequency of
cases with MCV is variable, but generally thought to be approximately 80% of MCC tumors.15 This still leaves a substantial fraction of viral-negative cases with a relatively
KEY POINTS
Merkel cell carcinoma is an uncommon aggressive
neuroendocrine cutaneous malignancy that predominantly
occurs in patients who are older and is associated with a
high rate of distant failure and death.
Current management strategies that incorporate surgery
and radiotherapy achieve high rates of locoregional
control.
Progress has been hampered by the lack of high-quality
evidence, with current management strategies largely
derived from retrospective studies.
Merkel cell polyomavirus has been identied as a causative
agent, but emerging data suggests MCC may be two
distinct entities, viral-associated and viral-negative.
Recent developments in our knowledge about the biology
of Merkel cell carcinoma have led to the identication of
new potential therapeutic targets and clinical trials
investigating novel treatments including immunotherapeutic
approaches.
e520
unknown biology. Clues to the underlying origins of viralnegative tumors can be drawn from observations in different
geographic regions. In Australia, the association of MCV infection with MCC appears to be much lower. Three independent studies from major Australian cities report a frequency
of 18% to 24%,15-17 with the exception being a study from
Sydney reporting a similar frequency to that found in Germany (80%).18 Variability in the reported prevalence of
viral-associated MCC between studies has been attributed
to the choice of the individual antibody used for IHC detection of viral LT expression in tumors.19 However, the
difference between studies in Australia and the Northern
hemisphere would appear outside the expected variance
between IHC assays. Furthermore, IHC and polymerase
chain reaction detection of viral DNA have both been used
in Australian studies and these assays have been shown to
be mostly concordant.20
A higher prevalence of MCC in the Australian population
with a predominance of viral-negative tumors suggests that excessive sun damage is likely key to the pathogenesis of the viralnegative subtype. Potential mechanisms explaining increased
risk associated with sun damage could involve combined effects
of localized immune suppression and the strong mutagenic effects of UV-mediated DNA damage.21 A telling indicator of UV
damage is the DNA mutation signature involving C to T transitions at dipyrimidine bases (i.e., CC to TT) frequently observed
in skin cancers such as melanoma.22 Importantly, these types of
mutations have been identifed in MCC tumors through sequencing the TP53 tumor-suppressor gene.23
Further cumulative evidence to support the notion of
two subtypes includes the histologic, clinical, and molecular differences that have been observed between viral and
nonviral MCC. MCV-positive and -negative tumors have
been reported to have specifc morphologic differences.24
Viral status has also been associated with different growth
properties of the respective cell lines.11 Gene expression
profling can also broadly cluster MCC tumors, which is
predominantly driven by an elevated immune signature in
the viral-positive group.25 A poorer prognosis has been associated with viral-negative MCC in some studies, although this has not been consistently demonstrated in
different patient cohorts.17,18,26-29
Genetic differences observed between MCC tumors
based on viral status can be explained in part by the convergent, yet distinct mechanisms for disruption of common pathways. As previously mentioned, the tumorsuppressor protein RB is a key target of the polyoma virus
LT.30 Viral-negative tumors show low to absent protein
expression of RB20 and RB1 copy number loss and loss-offunction mutations account for genetic disruption in a
large proportion of viral-negative MCC tumors.31-33
Pathogenic mutations in TP53 and overexpression of the
p53 protein (commonly associated with TP53 mutation),
also appear to be largely restricted to viral-negative tumors.20 Curiously, unlike SV40, the MCV LT is not
thought to directly regulate p53 and therefore may be altered through an indirect mechanism.34 Oncogenic muta-
MANAGEMENT OF MCC
The main aim of current treatment strategies is to obtain
locoregional control without inducing unnecessary toxicity. Cases should be managed in the context of a specialized multidisciplinary team to ensure care can be
individualized and all potential treatment modalities considered.
Optimal management of MCC is a therapeutic challenge
in part because of its rarity and lack of high-quality evidence to direct treatment. Although we can extrapolate
management principles from other skin cancers, such as
melanoma and squamous cell carcinoma, MCC differs importantly from these conditions by being extremely sensitive to radiotherapy.
Potential treatment paradigms have been published previously, are readily available, and include the 2015 National
Comprehensive Cancer Network (NCCN) guidelines.38 In
this review, we highlight recent developments and some of
the differences in approach to the management of MCC.
Staging
MCC is associated with high rates of early nodal and distant metastatic spread. Relapse in nodal stations reportedly occurs in up to 76% of cases39-42 and is associated with
a substantial reduction in survival.43,44 Effective staging of
nodal and distant metastatic disease at diagnosis is essen-
e521
Denitive Management
Stage I and II disease (node-negative). Treatment in stage I
and II MCC generally involves surgical resection of the primary tumor with clear margins followed by adjuvant radiotherapy. However, it is not necessary to obtain wide or even
clear surgical margins if this would compromise cosmesis or
function, or delay planned adjuvant radiotherapy.38,58,59 Adjuvant radiotherapy provides superior locoregional control
rates compared with surgery alone.43,60-62 Patients with very
small primary tumors ( 1 cm), or negative SLNB with clear
margins and no adverse features, such as lymphovascular invasion and immunosuppression, may be able to avoid adjuvant radiotherapy.63 If surgery is not feasible or refused,
defnitive radiotherapy can achieve high rates of locoregional
control. Veness et al reported a 3-year locoregional control
rate of 75% with radiation alone in a population with poor
prognosis, but overall 60% of patients relapsed, most commonly outside the radiation feld.64
Stage III disease (node-positive). Stage IIIA disease (microscopic nodal) is usually detected via SLNB, and treatment of
the nodal basin is recommended with radiotherapy or
lymphadenectomy. Both modalities achieve excellent results,56 with radiotherapy permitting concurrent adjuvant
treatment to the primary site.
In IIIB disease, clinically evident node disease can be
treated with lymphadenectomy and radiotherapy, or defnitive radiotherapy. The NCCN guidelines recommend initial
surgery as the standard therapy in this setting,38 although a
different approach may be adopted, particularly for MCC localized to the head and neck. Radiotherapy alone has been
shown to provide good regional control of gross node disease, with isolated regional recurrence being uncommon.56,65,66 The MD Anderson Cancer Center has recently
reported its experience with radiotherapy in MCC localized
e522
in the head and neck with 96% local and regional control
rates, and notably no regional recurrences in 22 patients with
gross nodal disease who were treated with radiation alone.65
If IIIB disease is treated surgically it is likely that the majority of patients would be recommended for postoperative
radiotherapy based on multiple nodes or extracapsular extension. Decisions about the optimal approach must take
into account the lack of evidence that bimodality treatment is
more effective in achieving regional control than radiotherapy alone, as well as the predominant distant pattern of failure, and the additional toxicity and effect on quality of life
associated with bimodality treatment.
In view of the high risk of distant metastases, and the similarities to small cell carcinoma of the lung, there has been
interest in incorporating chemotherapy into the defnitive
management of patients at high risk. The TROG 96.07 trial
evaluated the treatment of 53 patients with high-risk local
and nodal MCC with radiotherapy and four cycles of carboplatin and etoposide.67 Radiotherapy doses were moderate
(50 Gy/25 fractions), and the bulk of disease treated ranged
from microscopic to lesions larger than 5 cm. Gross node disease was present in 62% of patients. The 3-year overall survival, locoregional control, and distant control was 76%,
75%, and 76%, respectively. However, a high febrile neutropenia rate was observed that predominantly occurred during
the peak of the radiation skin reaction. A subsequent trial
demonstrated that giving weekly carboplatin during radiation followed by adjuvant carboplatin and etoposide was much
better tolerated.68 However, the single arm design of these trials
does not permit any defnitive conclusions about effcacy. Retrospective comparisons to patients treated with radiation alone
have yielded mixed results with some studies fnding no evidence of beneft, whereas a recent analysis restricted to head and
neck primaries has suggested improved overall survival with
chemoradiation. The role of chemotherapy in this setting remains unproven, and could only be established by a randomized
trial.
Stage IV disease (distant metastases). Distant metastases
develop in 20% to 30% of patients with MCC.50,65,69,70 The mainstay of anticancer management of metastatic MCC has been
chemotherapy, which achieves high response rates (60% to
75%), but of limited duration. Based on apparent similarities to
small cell carcinoma, regimens such as platinum and etoposide
or cyclophosphamide, doxorubicin, and vincristine are most
commonly used for frst-line chemotherapy.71 However, there is
limited evidence to guide decision making, with no randomized
trials evaluating different regimens, and limited data about the
effect of chemotherapy on survival, symptom beneft, or quality
of life. Bearing in mind that patients are frequently older with
comorbidities, many patients are not good candidates for chemotherapy and are best managed by supportive care alone.
NEW TREATMENTS
The viral etiology and an epidemiologic link to immunosuppression suggest that immunotherapies may be effective in
treating MCC tumors. Many MCC tumors elicit a strong immune response with brisk infltrates of intratumoral CD8
T-cells (TILs), which is an independent indicator of better
survival.72-74 Viral-antigen specifc CD8 T-cells can also be
detected in the peripheral blood of patients with MCC and
fluctuate in response to treatment.75 Antibody blockade of
immune checkpoint receptors and ligands, such as CTLA-4
and PD-1/PD-L1 that reactivate cytotoxic T-cell activity,
have demonstrated durable responses in the treatment of refractory solid tumors.76,77 Importantly, viral specifc T-cells
in MCC express PD-1 and high tumor specifc expression of
the ligand PD-L1 has been observed in viral-positive, but not
viral-negative tumors.75,78 Phase II trials using anti-PD-L1
(MSB0010718C; NCT02155647), anti-PD-1 (pembrolizumab; NCT02267603), and anti-CTLA-4 (ipilimumab;
NCT02196961) are currently open. An alternative or complementary immune strategy is adoptive immunotherapy,
which involves the isolation of tumor-specifc autologous
T-cells from a patient, which are then cultured in vivo and
infused back into the patient. This strategy has proven effective for treating melanoma.79 Methods have been described
for the isolation of MCV-specifc cytotoxic T-cells from patients with MCC,80 and a phase I/II clinical trial using autologous T-cell therapy with aldesleukin is currently underway
(NCT01758458).
Targeting dysregulated cell growth and proliferation pathways within MCC tumors present another potential therapeutic avenue. MCC tumors overexpress receptor tyrosine
kinases such as cKIT, PDGFR, and VEGFR2.81-83 Despite
promising early preclinical evaluation of imatinib (targeting
KIT and PDFGR), a low response rate was observed in a clinical trial, although a complete response has been reported
elsewhere.84 The multikinase inhibitor pazopanib targets receptor tyrosine kinases, including cKIT, FGFR, PDGFR, and
VEGFR, and a complete response to this drug has been observed in MCC resistant to cytotoxic therapy.85 A phase II trial of
pazopanib in patients with neuroendocrine tumors including
MCC is currently open (NCT01841736). Cabozantinib, which
targets VEGFR2/cMET, is being investigated in a phase II MCC
trial (NCT02036476). As previously mentioned, MCC tumors
may be responsive to inhibition of the PI3K/AKT/mTOR axis,
and a number of clinical trials are currently active for treatment
of solid tumors using PI3K inhibitors.
A low level of apoptosis is a feature of MCC. BCL-2, a
prosurvival member of the intrinsic apoptosis pathway, is
overexpressed in approximately 80% of MCC tumors.86
Oblimersen sodium (G3139), a phosphorothioate antisense oligonucleotide that targets BCL-2, demonstrated
good effcacy in a preclinical assessment,87 but proved ineffective in patients with MCC.88 The orally available drug
ABT-263, which targets multiple BCL-2 family members,
has also demonstrated preclinical activity against MCC
cell lines by inducing apoptotic death.89 Theoretically,
ABT-263 may be more effective than G3139 in patients,
given that it targets multiple BCL-2-family members. Survivin is a member of the inhibitor of apoptosis family and is
upregulated by MCV LT.90 High survivin expression corre-
CONCLUSION
Current management strategies achieve high rates of locoregional control, but distant failure rates remain problematic.
Management of metastatic disease is challenging; chemotherapy can achieve high response rates of limited duration
and is often associated with toxicity in this older population.
The recent upsurge in our understanding of the biology of
MCC is opening up new potential therapeutic targets and
treatments. Finally, the recognition that MCC may be two
distinct entities, viral-associated and viral-negative MCC, is
likely to have implications for the management of MCC in
the future and for the development of new treatments, somewhat analogous to oropharyngeal cancer following the identifcation of the HPV as a causative agent.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e523
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Danny
Rischin, Threshold. Speakers Bureau: None. Research Funding: Danny Rischin, Genentech/Roche, Merckserono. Patents, Royalties, or Other Intellectual
Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
e524
Albores-Saavedra J, Batich K, Chable-Montero F, et al. Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases:
a population based study. J Cutan Pathol. 2010;37:20-27.
Girschik J, Thorn K, Beer TW, et al. Merkel cell carcinoma in Western
Australia: a population-based study of incidence and survival. Br J Dermatol. 2011;165:1051-1057.
Feng H, Shuda M, Chang Y, et al. Clonal integration of a polyomavirus
in human Merkel cell carcinoma. Science. 2008;319:1096-1100.
Tang CK, Toker C. Trabecular carcinoma of the skin: an ultrastructural study. Cancer. 1978;42:2311-2321.
Tang CK, Toker C. Trabecular carcinoma of the skin: further clinicopathologic and ultrastructural study. Mt Sinai J Med. 1979;46:516-523.
Hanly AJ, Elgart GW, Jorda M, et al. Analysis of thyroid transcription
factor-1 and cytokeratin 20 separates merkel cell carcinoma from small
cell carcinoma of lung. J Cutan Pathol. 2000;27:118-120.
Foote M, Veness M, Zarate D, et al. Merkel cell carcinoma: the prognostic implications of an occult primary in stage IIIB (nodal) disease.
J Am Acad Dermatol. 2012;67:395-399.
Heath M, Jaimes N, Lemos B, et al. Clinical characteristics of Merkel
cell carcinoma at diagnosis in 195 patients: the AEIOU features. J Am
Acad Dermatol. 2008;58:375-381.
Schowalter RM, Pastrana DV, Pumphrey KA, et al. Merkel cell polyomavirus and two previously unknown polyomaviruses are chronically
shed from human skin. Cell Host Microbe. 2010;7:509-515.
Tolstov YL, Pastrana DV, Feng H, et al. Human Merkel cell polyomavirus infection II. MCV is a common human infection that can be detected by conformational capsid epitope immunoassays. Int J Cancer.
2009;125:1250-1256.
Shuda M, Feng H, Kwun HJ, et al. T antigen mutations are a human
tumor-specifc signature for Merkel cell polyomavirus. Proc Natl Acad
Sci USA. 2008;105:16272-16277.
Houben R, Shuda M, Weinkam R, et al. Merkel cell polyomavirusinfected Merkel cell carcinoma cells require expression of viral T antigens. J Virol. 2010;84:7064-7072.
Shuda M, Kwun HJ, Feng H, et al. Human Merkel cell polyomavirus
small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator. J Clin Investig. 2011;121:3623-3634.
Kwun HJ, Shuda M, Feng H, et al. Merkel cell polyomavirus small T
antigen controls viral replication and oncoprotein expression by targeting the cellular ubiquitin ligase SCFFbw7. Cell Host Microbe. 2013;
14:125-135.
Paik JY, Hall G, Clarkson A, et al. Immunohistochemistry for Merkel
cell polyomavirus is highly specifc but not sensitive for the diagnosis
of Merkel cell carcinoma in the Australian population. Hum Pathol.
2011;42:1385-1390.
Garneski KM, Warcola AH, Feng Q, et al. Merkel cell polyomavirus is
more frequently present in North American than Australian Merkel
cell carcinoma tumors. J Invest Dermatol. 2009;129:246-248.
17. Dabner M, McClure RJ, Harvey NT, et al. Merkel cell polyomavirus
and p63 status in Merkel cell carcinoma by immunohistochemistry:
Merkel cell polyomavirus positivity is inversely correlated with sun
damage, but neither is correlated with outcome. Pathology. 2014;46:
205-210.
18. Schrama D, Peitsch WK, Zapatka M, et al. Merkel cell polyomavirus
status is not associated with clinical course of Merkel cell carcinoma.
J Invest Dermatol. 2011;131:1631-1638.
19. Rodig SJ, Cheng J, Wardzala J, et al. Improved detection suggests all
Merkel cell carcinomas harbor Merkel polyomavirus. J Clin Invest.
2012;122:4645-4653.
20. Sihto H, Kukko H, Koljonen V, et al. Merkel cell polyomavirus infection, large T antigen, retinoblastoma protein and outcome in Merkel
cell carcinoma. Clin Cancer Res. 2011;17:4806-4813.
21. Nishigori C. Cellular aspects of photocarcinogenesis. Photochem Photobiol Sci. 2006;5:208-214.
22. Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Deciphering signatures
of mutational processes operative in human cancer. Cell Reports. 2013;
3:246-259.
23. Popp S, Waltering S, Herbst C, et al. UV-B-type mutations and chromosomal imbalances indicate common pathways for the development
of Merkel and skin squamous cell carcinomas. Int J Cancer. 2002;99:
352-360.
24. Iwasaki T, Matsushita M, Kuwamoto S, et al. Usefulness of signifcant
morphologic characteristics in distinguishing between Merkel cell
polyomavirus-positive and Merkel cell polyomavirus-negative Merkel
cell carcinomas. Hum Pathol. 2013;44:1912-1917.
25. Harms PW, Patel RM, Verhaegen ME, et al. Distinct gene expression profles of viral- and nonviral-associated merkel cell carcinoma revealed by transcriptome analysis. J Invest Derm. 2013;133:
936-945.
26. Andres C, Belloni B, Puchta U, et al. Clinical factors associated with
Merkel cell polyomavirus infection in Merkel cell carcinoma. J Natl
Cancer Inst. 2009;101:1655-1656 author reply 1656-1657.
27. Sihto H, Kukko H, Koljonen V, et al. Clinical factors associated with
Merkel cell polyomavirus infection in Merkel cell carcinoma. J Natl
Cancer Inst. 2009;101:938-945.
28. Bhatia K, Goedert JJ, Modali R, et al. Merkel cell carcinoma subgroups
by Merkel cell polyomavirus DNA relative abundance and oncogene
expression. Int J Cancer. 2010;126:2240-2246.
29. Handschel J, Muller D, Depprich RA, et al. The new polyomavirus
(MCPyV) does not affect the clinical course in MCCs. Int J Oral Maxillofac Surg. 2010;39:1086-1090.
30. Pipas JM, Levine AJ. Role of T antigen interactions with p53 in tumorigenesis. Semin Cancer Biol. 2001;11:23-30.
31. Paulson KG, Lemos BD, Feng B, et al. Array-CGH reveals recurrent
genomic changes in Merkel cell carcinoma including amplifcation of
L-Myc. J Invest Dermatol. 2009;129:1547-1555.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
tients with Merkel cell carcinoma: a systematic review and metaanalysis. Am J Clin Dermatol. 2013;14:437-447.
Gupta SG, Wang LC, Penas PF, et al. Sentinel lymph node biopsy for
evaluation and treatment of patients with Merkel cell carcinoma: the
Dana-Farber experience and meta-analysis of the literature. Arch Dermatol. 2006;142:685-690.
Rodrigues LK, Leong SP, Kashani-Sabet M, et al. Early experience with
sentinel lymph node mapping for Merkel cell carcinoma. J Am Acad
Dermatol. 2001;45:303-308.
Fields RC, Busam KJ, Chou JF, et al. Recurrence and survival in patients undergoing sentinel lymph node biopsy for merkel cell carcinoma: analysis of 153 patients from a single institution. Ann Surg
Oncol. 2011;18:2529-2537.
Lemos BD, Storer BE, Iyer JG, et al. Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823
cases as the basis of the frst consensus staging system. J Am Acad Dermatol. 2010;63:751-761.
Fang LC, Lemos B, Douglas J, et al. Radiation monotherapy as regional
treatment for lymph node-positive Merkel cell carcinoma. Cancer.
2010;116:1783-1790.
Howle J, Veness M. Sentinel lymph node biopsy in patients with
Merkel cell carcinoma: an emerging role and the Westmead hospital
experience. Australas J Dermatol. 2012;53:26-31.
Finnigan R, Hruby G, Wratten C, et al. The impact of preradiation
residual disease volume on time to locoregional failure in cutaneous
Merkel cell carcinoma-a TROG substudy. Int J Radiat Oncol Biol Phys.
2013;86:91-95.
Foote M, Harvey J, Porceddu S, et al. Effect of radiotherapy dose and
volume on relapse in Merkel cell cancer of the skin. Int J Radiat Oncol
Biol Phys. 2010;77:677-684.
Mojica P, Smith D, Ellenhorn JD. Adjuvant radiation therapy is associated with improved survival in Merkel cell carcinoma of the skin.
J Clin Oncol. 2007;25:1043-1047.
Jouary T, Leyral C, Dreno B, et al. Adjuvant prophylactic regional radiotherapy versus observation in stage I Merkel cell carcinoma: a multicentric prospective randomized study. Ann Oncol. 2012;23:10741080.
Bhattia S IJ, Storer B. Adjuvant radiation therapy and chemotherapy in
Merkel cell carcinoma: survival analysis of 6,908 cases from the National Cancer Data Base. J Clin Oncol. 32:5s, 2014 (suppl; abstr 9014).
Miller SJ, Alam M, Andersen J, et al. Merkel cell carcinoma. J Natl
Compr Cancer Netw. 2009;7:322-332.
Veness M, Foote M, Gebski V, et al. The role of radiotherapy alone in
patients with merkel cell carcinoma: reporting the Australian experience of 43 patients. Int J Radiat Oncol Biol Phys. 2010;78:703-709.
Bishop AJ, Garden AS, Gunn GB, et al. Merkel cell carcinoma of the
head and neck: favorable outcomes with radiotherapy. Head Neck.
Epub 2015 Feb 2.
Sundaresan P, Hruby G, Hamilton A, et al. Defnitive radiotherapy or
chemoradiotherapy in the treatment of Merkel cell carcinoma. Clin
Oncol (R Coll Radiol). 2012;24:e131-e136. Epub 2012 May 23.
Poulsen M, Rischin D, Walpole E, et al. High-risk Merkel cell carcinoma of the skin treated with synchronous carboplatin/etoposide and
radiation: a Trans-Tasman Radiation Oncology Group Study-TROG
96:07. J Clin Oncol. 2003;21:4371-4376.
Poulsen M, Walpole E, Harvey J, et al. Weekly carboplatin reduces toxicity during synchronous chemoradiotherapy for Merkel cell carcinoma of skin. Int J Radiat Oncol Biol Phys. 2008;72:1070-1074.
Poulsen MG, Rischin D, Porter I, et al. Does chemotherapy improve
survival in high-risk stage I and II Merkel cell carcinoma of the skin?
Int J Radiat Oncol Biol Phys. 2006;64:114-119.
Allen PJ, Bowne WB, Jaques DP, et al. Merkel cell carcinoma: progno-
e525
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
e526
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
MELANOMA/SKIN CANCERS
SPEAKERS
Ahmad A. Tarhini, MD, PhD
University of Pittsburgh
Pittsburgh, PA
Dirk J. Grunhagen, MD, PhD
Erasmus MC Cancer Institute
Rotterdam, Netherlands
ILP TECHNIQUE
Until recently, melanoma was infamously refractory to any
kind of systemic treatment. This resistance stimulated the
search for techniques that could deliver high concentrations
of chemotherapy or other agents to the affected limb, without
the risk for systemic toxicity. In this way, drug concentrations would potentially suffce to achieve antitumor effect. As
IT-mets of extremity melanomas are, per defnition, confned
to a limb, isolation of the affected limb from the systemic circulation would offer such an opportunity. This isolation can
be achieved by surgical access to the artery and vein on either
iliac, femoral, popliteal, axillary, or brachial level. The artery
and vein are clamped and cannulated after which the catheters can be connected to a heart-lung machine to get an oxygenated circuit. To further isolate the limb, a tourniquet is
placed proximal to the site of the perfusion. Melphalan (Lphenylalanine mustard) has been the standard drug used in
ILP because of its effcacy and toxicity profle.4 Drug concentrations in the limb are 20-times higher than can be achieved
e528
systemically using this isolated circuit. Melphalan concentrations of 10 mg/L (leg) or 13 mg/L (arm) are considered standard dosages. The major concern of ILP is potential leakage
of the effective agents to the systemic circulation. Therefore,
leakage monitoring is mandatory and a precordial scintillation probe is placed to detect any radioactively labeled albumen administered to the isolated circuit that has potentially
leaked to the systemic circulation.
Melphalan-based ILPs have been used for decades in the
previous century as complete response (CR) rates of 40% to
50% and overall response rates of 75% to 80% were achieved,
unmet by any other treatment modality.
ILP MODIFICATIONS
Since the introduction of ILP, many modifcations have
been applied to improve tumor response. These modifcations have led to an improved insight in the optimal temperature, the optimal drugs, and the optimal indications
for the procedure.
Temperature
Temperature of the perfused tissue is important in more than
one way. The temperature of the skin has to be warmed during perfusion to prevent vasoconstriction in the dermal and
subdermal tissues. Especially in superfcial IT-mets, application of a warm water mattress can improve the local drug
delivery as the uptake of the drug by in-transit metastases in
vivo has proven to be twice as high at 39.5C than at 37C.5
The second reason for hyperthermia is the idiosyncratic sensitivity of tumor cells to heat. Moreover, hyperthermia can
improve the uptake of the drug in tumor cells, especially at
temperatures greater than 41C.6,7 However, hyperthermia is
associated with increased local toxicity. Tissue temperatures
of 41.5C to 43C during ILP can yield high response rates,8
but the local toxicity of these procedures can lead to major
complications and even amputation of the perfused limb.9
KEY POINTS
Therapy for patients with extensive melanoma in-transit
metastases should be effective in providing local control.
Tumor necrosis factor-based isolated limb perfusion (TMILP) is effective in the treatment of bulky melanoma intransit metastases; isolated limb infusion (ILI) is effective
in the treatment of lower-burden disease.
Modern TM-ILP and ILI treatment is safe.
New systemic agents for melanoma treatment have
changed the treatment of patients with stage IV melanoma
drastically, but response and local control rates do not
reach ILI/ILP standards.
Combination of ILI/ILP to induce rapid local response,
followed by effective systemic therapy to increase overall
survival, has great potential to become standard therapy in
patients with extensive melanoma in-transit metastases.
Drugs
Several attempts have been made to improve the response on
ILP by using other cytostatic drugs than melphalan. Commonly used drugs in the treatment of systemically metastasized melanoma, either alone or in a combination schedule,
are dacarbazine and cisplatinum. Therefore, among others,
these drugs were tested in the ILP-setting, but no drug or
drug combination used for patients with melanoma has
proven to achieve results superior to melphalan.4,10 Probably
the only alternative schedule still in use is the combination of
melphalan and actinomycin-D.11
Probably the most influential adjustment of ILP has been
the introduction of TNF by Lejeune and Lienard in 1988.
TNF was isolated as an endogenous factor, especially active
in inflammation, with necrotizing ability on tumor cells.12
We now know that TNF has a dual mechanism of action:
the direct cytotoxic effect of high-dose TNF to tumor cells
certainly plays a role in antitumor activity,13 but more importantly the TNF effect on the so-called tumor-associated
vasculature induces a rapid change in tumor morphology
characterized by hemorrhagic necrosis.14 However, the systemic application in patients with melanoma was very disappointing.15 TNF turned out to be a potent mediator in septic
shock and, therefore, the systemic side effects (acute drop in
vascular resistance leading to low blood pressure, fever, etc.)
were the major factors hindering systemic application of this
cytokine.16 The maximum tolerated dose of TNF in humans
turned out to be 10-times to 50-times lower than required for
antitumor effect,17 so that systemic, but also intralesional administration of TNF, was not clinically applicable. The concept of ILP combines the advantages of the TNF antitumor
activity with the avoidance of systemic effects. Moreover, the
cytotoxic effects of TNF are known to be enhanced in hyperthermic conditions and with the addition of alkylating chemotherapeutics,18,19 both prerequisites already existing in the
ILP model. The reintroduction of TNF in anticancer therapy
by application in the ILP protocol combined optimal activity
with minimal toxicity.20
Indications
The success of ILP in the treatment of melanoma IT-mets has
prompted trials to test the effcacy of ILP in the adjuvant setting after excision of the primary melanoma. After the frst
disappointing results, this indication was largely abandoned
by most melanoma centers.21 Recently, the long-term results
of a Swedish trial were published that affrmed the conclusion
that adjuvant ILP after excision of high-risk primary melanomas does not improve survival of these patients.22 Another
plausible thought has been the repetition of perfusion soon
after the frst ILP, the so-called double perfusion schedule.
The premise that repeated administration of chemotherapeutic agents is more effective than single use is adopted from
the systemic chemotherapy situation and is based on the idea
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e529
that residual tumor cells after the frst treatment may be eliminated and that partially damaged tumor cell after frst exposure may be more vulnerable to chemotherapy on repeated
exposures. In the ILP situation, the double perfusion schedule (interval 3 to 4 weeks, second perfusion with reduced
melphalan dose, normothermic ILP) led to higher CR rates
than single ILP,23 but the median duration of response was
not altered. Fractioning of melphalan administration and the
use of true hyperthermia have been used in a double perfusion schedule in which a true hyperthermic perfusion with no
chemotherapeutic agents was followed by a normothermic
melphalan-ILP 1 week later. The achieved response rates
with this protocol are high, probably because of the synergistic effect of hyperthermia and melphalan, whereas, because
of to the fractioning, no increased toxicity was observed compared with single ILP.24 It was postulated that the double perfusion schedule could be an alternative for a TNF-based ILP.
In the TNF era, no further trials of repeat ILPs at short intervals have been conducted.
Year
No. of
Patients
CR
PR
OR
Melphalan
Klaase60
1994
120
64
25
89
Lingam61
1996
103
76
23
99
2005
58
57
31
88
2007
120
69
16
85
62
Aloia
Melphalan
Actinomycin-D
Sanki11
Melphalan TNF
Noorda33
Cornett
2004
32
2006
Alexander34
Rossi36
2010
2010
35
Hoekstra
2014
90
TM-ILP
59
ns
ns
40
M-ILP
45
ns
ns
58
TM-ILP
26
43
69
58
M-ILP
25
39
64
43
TM-ILP
69*
26*
95*
47
M-ILP
58
TM-ILP
61
29
90
53
M-ILP
42
49
91
39
TM-ILP
54
ns
93
18
M-ILP
33
ns
84
ILI
Kroon41
2008
185
38
46
84
Beasley42
2009
128
31
33
64
Wong63
2013
79
37
37
74
Coventry43
2013
131
27
36
63
2009
113
63
25
88
Melphalan TNF
(since 2000)
Di Philippo37
38
Deroose
Olofsson
22
2012
167
61
28
89
2013
155
65
20
85
Abbreviations: CR, complete response; ILI, isolated limb infusion; ILP, isolated limb
perfusion; PR, partial response; M-ILP, melphalan isolated limb perfusion; NS, not stated; OR,
overall response; TM-ILP, application of tumor necrosis factor to M-ILP; TNF, tumor necrosis
factor.
*Response rates are stated for the combined TM-ILP and M-ILP cohort.
TOXICITY OF PERFUSION
An area of concern in the feld of perfusions is the toxicity
that is associated with the procedure. This can be divided into
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e531
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Cornelis Verhoef, Roche. Consulting or Advisory
Role: Cornelis Verhoef, Roche. Speakers Bureau: None. Research Funding: None. Patents, Royalties, or Other Intellectual Property: None. Expert
Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. SEER Stat Fact Sheets. Melanoma of the skin. http://seer.cancer.gov/
statfacts/html/melan.html. Accessed February 12, 2015.
2. Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC
melanoma staging and classifcation. J Clin Oncol. 2009;27:6199-6206.
3. Creech O Jr, Krementz ET, Ryan RF, et al. Chemotherapy of cancer:
regional perfusion utilizing an extracorporeal circuit. Ann Surg. 1958;
148:616-632.
4. Thompson JF, Gianoutsos MP. Isolated limb perfusion for melanoma:
effectiveness and toxicity of cisplatin compared with that of melphalan
and other drugs. World J Surg. 1992;16:227-233.
5. Omlor G. Optimization of isolated hyperthermic limb perfusion. World
J Surg. 1993;17:134.
6. Cavaliere R, Ciocatto EC, Giovanella BC, et al. Selective heat sensitivity of
cancer cells. Biochemical and clinical studies. Cancer. 1967;20:1351-1381.
7. Clark J, Grabs AJ, Parsons PG, et al. Melphalan uptake, hyperthermic
synergism and drug resistance in a human cell culture model for the
isolated limb perfusion of melanoma. Melanoma Res. 1994;4:365-370.
8. Di Filippo F, Anza` M, Rossi CR, et al. The application of hyperthermia
in regional chemotherapy. Semin Surg Oncol. 1998;14:215-223.
9. Kroon BB, Klaase JM, van Geel AN, et al. Application of hyperthermia
in regional isolated perfusion for melanoma of the limbs. Reg Cancer
Treat. 1992;4:223-226.
10. Vrouenraets BC, Nieweg OE, Kroon BB. Thirty-fve years of isolated
limb perfusion for melanoma: indications and results. Br J Surg. 1996;
83:1319-1328.
11. Sanki A, Kam PC, Thompson JF. Long-term results of hyperthermic,
isolated limb perfusion for melanoma: a reflection of tumor biology.
Ann Surg. 2007;245:591-596.
12. Carswell EA, Old LJ, Kassel RL, et al. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A. 1975;72:
3666-3670.
13. Sugarman BJ, Aggarwal BB, Hass PE, et al. Recombinant human tumor
necrosis factor-alpha: effects on proliferation of normal and transformed cells in vitro. Science. 1985;230:943-945.
14. Watanabe N, Niitsu Y, Umeno H, et al. Toxic effect of tumor necrosis
factor on tumor vasculature in mice. Cancer Res. 1988;48:2179-2183.
15. Feldman ER, Creagan ET, Schaid DJ, et al. Phase II trial of recombinant
tumor necrosis factor in disseminated malignant melanoma. Am J Clin
Oncol. 1992;15:256-259.
16. Feinberg B, Kurzrock R, Talpaz M, et al. A phase I trial of intravenouslyadministered recombinant tumor necrosis factor-alpha in cancer patients. J Clin Oncol. 1988;6:1328-1334.
17. Asher A, Mule JJ, Reichert CM, et al. Studies on the anti-tumor effcacy
of systemically administered recombinant tumor necrosis factor against
several murine tumors in vivo. J Immunol. 1987;138:963-974.
18. Watanabe N, Niitsu Y, Umeno H, et al. Synergistic cytotoxic and antitumor effects of recombinant human tumor necrosis factor and hyperthermia. Cancer Res. 1988;48:650-653.
19. Regenass U, Muller M, Curschellas E, et al. Anti-tumor effects of tumor
necrosis factor in combination with chemotherapeutic agents. Int J Cancer. 1987;39:266-273.
20. Lienard D, Ewalenko P, Delmotte JJ, et al. High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and
melphalan in isolation perfusion of the limbs for melanoma and sarcoma. J Clin Oncol. 1992;10:52-60.
21. Koops HS, Vaglini M, Suciu S, et al. Prophylactic isolated limb perfusion
for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol
18832, the World Health Organization Melanoma Program Trial 15,
and the North American Perfusion Group Southwest Oncology Group8593. J Clin Oncol. 1998;16:2906-2912.
22. Olofsson Bagge R, Mattsson J, Hafstrom L. Regional hyperthermic perfusion with melphalan after surgery for recurrent malignant melanoma
of the extremities-long-term follow-up of a randomised trial. Int J Hyperthermia. 2014;30:295-298.
23. Klaase JM, Kroon BB, van Geel AN, et al. A retrospective comparative
study evaluating the results of a single-perfusion versus doubleperfusion schedule with melphalan in patients with recurrent melanoma of the lower limb. Cancer. 1993;71:2990-2994.
24. Noorda EM, Vrouenraets BC, Nieweg OE, et al. Long-term results of a
double perfusion schedule using high dose hyperthermia and melphalan sequentially in extensive melanoma of the lower limb. Melanoma Res. 2003;13:395-399.
25. Thompson JF, Kam PC, Waugh RC, et al. Isolated limb infusion with
cytotoxic agents: a simple alternative to isolated limb perfusion. Semin
Surg Oncol. 1998;14:238-247.
e533
26. Kroon HM, Thompson JF. Isolated limb infusion: a review. J Surg Oncol.
2009;100:169-177.
27. Wu ZY, Smithers BM, Parsons PG, et al. The effects of perfusion conditions on melphalan distribution in the isolated perfused rat hindlimb
bearing a human melanoma xenograft. Br J Cancer. 1997;75:1160-1166.
28. Wu ZY, Smithers BM, Roberts MS. Tissue and perfusate pharmacokinetics of melphalan in isolated perfused rat hindlimb. J Pharmacol Exp
Ther. 1997;282:1131-1138.
29. Kroon HM, Huismans A, Waugh RC, et al. Isolated limb infusion: technical aspects. J Surg Oncol. 2014;109:352-356.
30. Klaase JM, Kroon BB, Benckhuijsen C, et al. Results of regional isolation
perfusion with cytostatics in patients with soft tissue tumors of the extremities. Cancer. 1989;64:616-621.
31. Deroose JP, Grunhagen DJ, de Wilt JH, et al. Treatment modifcations
in tumour necrosis factor- (TNF)-based isolated limb perfusion in patients with advanced extremity soft tissue sarcomas. Eur J Cancer. 2015;
51:367-373.
32. Cornett WR, McCall LM, Petersen RP, et al. Randomized multicenter
trial of hyperthermic isolated limb perfusion with melphalan alone
compared with melphalan plus tumor necrosis factor: American College of Surgeons Oncology Group Trial Z0020. J Clin Oncol. 2006;24:
4196-4201.
33. Noorda EM, Vrouenraets BC, Nieweg OE, et al. Isolated limb perfusion
for unresectable melanoma of the extremities. Arch Surg. 2004;139:
1237-1242.
34. Alexander HR Jr, Fraker DL, Bartlett DL, et al. Analysis of factors influencing outcome in patients with in-transit malignant melanoma undergoing isolated limb perfusion using modern treatment parameters.
J Clin Oncol. 2010;28:114-118.
35. Hoekstra HJ, Veerman K, van Ginkel RJ. Isolated limb perfusion for
in-transit melanoma metastases: melphalan or TNF-melphalan perfusion? J Surg Oncol. 2014;109:338-347.
36. Rossi CR, Pasquali S, Mocellin S, et al. Long-term results of melphalanbased isolated limb perfusion with or without low-dose TNF for intransit melanoma metastases. Ann Surg Oncol. 2010;17:3000-3007.
37. Di Filippo F, Giacomini P, Rossi CR, et al. Prognostic factors influencing
tumor response, locoregional control and survival, in melanoma patients with multiple limb in-transit metastases treated with TNFalphabased isolated limb perfusion. In Vivo. 2009;23:347-352.
38. Deroose JP, Eggermont AM, van Geel AN, et al. 20 years experience of
TNF-based isolated limb perfusion for in-transit melanoma metastases:
TNF dose matters. Ann Surg Oncol. 2012;19:627-635.
39. Olofsson R, Mattsson J, Lindner P. Long-term follow-up of 163 consecutive patients treated with isolated limb perfusion for in-transit metastases of malignant melanoma. Int J Hyperthermia. 2013;29:551-557.
40. Deroose JP, Eggermont AM, van Geel AN, et al. Isolated limb perfusion for
melanoma in-transit metastases: developments in recent years and the role
of tumor necrosis factor alpha. Curr Opin Oncol. 2011;23:183-188.
41. Kroon HM, Moncrieff M, Kam PC, et al. Outcomes following isolated
limb infusion for melanoma. A 14-year experience. Ann Surg Oncol.
2008;15:3003-3013.
42. Beasley GM, Caudle A, Petersen RP, et al. A multi-institutional experience of isolated limb infusion: defning response and toxicity in the US.
J Am Coll Surg. 2009;208:706-715; discussion 715-717.
43. Coventry BJ, Kroon HM, Giles MH, et al. Australian multi-center experience outside of the Sydney Melanoma Unit of isolated limb infusion
chemotherapy for melanoma. J Surg Oncol. 2014;109:780-785.
44. Kroon HM, Huismans AM, Kam PC, et al. Isolated limb infusion with
melphalan and actinomycin D for melanoma: a systematic review. J Surg
Oncol. 2014;109:348-351.
45. Wong J, Chen YA, Fisher KJ, et al. Resection of residual disease after
isolated limb infusion (ILI) is equivalent to a complete response after
e534
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
From the University of Pittsburgh School of Medicine and Cancer Institute, Pittsburgh, PA.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Ahmad A. Tarhini, MD, PhD, University of Pittsburgh School of Medicine and Cancer Institute, UPMC Cancer Pavilion, 5150 Centre Ave. (555), Pittsburgh, PA 15232; email:
tarhiniaa@upmc.edu.
2015 by American Society of Clinical Oncology.
e535
AHMAD A. TARHINI
KEY POINTS
Patients with locoregionally advanced melanoma continue
to experience a high risk of relapse and death despite the
best available standard management approaches.
Neoadjuvant biochemotherapy demonstrated high tumor
response rates but was eventually abandoned after failure
to deliver survival benets in randomized trials of
metastatic disease.
Neoadjuvant immunotherapy with interferon alfa and
ipilimumab have yielded several important clinical and
mechanistic ndings.
In drug development, biomarker and mechanistic studies
can be accelerated through neoadjuvant studies because of
the access to biospecimens before and during therapy.
Newer targeted and immunotherapeutic agents and
combinations currently are being translated into the
neoadjuvant setting at an accelerated pace and carry
signicant promise.
e536
Study
Buzaid et al
19
64
Design
Primary
Objective
Phase II
single
arm
Tumor response
Regimen
Important Findings
2
Gibbs et al20
48
Phase II
single
arm
Tumor response
Shah et al18
19
Phase II
single
arm
Tumor response
Moschos
et al30
20
Phase II
single
arm
Tumor response
Phase I/II
single
arm
Safety,
biomarker
Tarhini
et al35
33
Abbreviations: IV, intravenously; IL, interleukin; SC, subcutaneously; IFN, interferon; HDI, high-dose IFN alfa; MDSC, myeloid-derived suppressor cells; TIL, tumor-inltrating lymphocytes.
with high-risk, locoregionally advanced disease.5,10 Spontaneous regression has been reported in melanoma, which suggests a role for host immunity that is indirectly supported by
the presence of lymphoid infltrates at primary melanoma
sites associated with tumor regression.25 Host cellular immune response within melanoma has potential disease prognostic and immunotherapeutic predictive signifcance. T-cell
infltrates are prognostic of disease outcome in primary melanoma and in melanoma that is metastatic to regional
nodes.25-28 Furthermore, T-cell infltrates within regional
nodal metastasis are signifcantly associated with beneft
from neoadjuvant IFN alfa therapy.26,29,30 Further, evidence
supports a difference in the quality of the host immune response of patients with earlier (operable) and more advanced
(inoperable) melanoma. Although T-helper type 1 (Th1)
type CD4 antitumor T-cell function appears critical to the
induction and maintenance of antitumor cytotoxic T-lymphocyte
responses in vivo, and although Th2- or Th3/T regulatory-type
CD4 T-cell responses may subvert Th1-type cell-mediated
immunity and provide a microenvironment conducive to
disease progression, patients with advanced melanoma or renal cell carcinoma have displayed strong tumor antigenspecifc Th2-type polarization. Conversely, normal donors
and patients who were disease free after therapy demonstrated either a weak mixed Th1-/Th2-type or a strongly polarized Th1-type response to the same epitopes.31 Therefore,
factors of host immune tolerance that seem to impede immunotherapeutic benefts in advanced disease may be less pronounced in the high-risk, operable setting. In patients with
earlier-stage melanoma, the host may be more susceptible to im-
e537
AHMAD A. TARHINI
e539
AHMAD A. TARHINI
with earlier disease stages treated in the adjuvant and neoadjuvant settings.31 Targeting PD-1 and PDL-1 in clinical trials has
demonstrated early results of signifcant clinical activity, which
has led to the regulatory approval of two potent and highly selective humanized monoclonal antibodies: pembrolizumab and
nivolumab.59,60 These agents have shown an unprecedented rate
of durable tumor responses, exceeding 20% to 30% with singleagent immunotherapy.
Efforts in combination immunotherapy have already demonstrated signifcant results with the combination of ipilimumab and either nivolumab, GM-CSF, bevacizumab, or
IL-2 and the combination of IFN alfa and tremelimumab;
these efforts have led to subsequent randomized trials.37,62-65
An impressive 2-year survival rate of 79% was reported recently in an update of the nivolumab/ipilimumab phase I
combination trial.66 Several other combination studies are
underway that take advantage of nonredundant immune activation and T-cell differentiation mechanisms. Studies of
novel immune checkpoint modulators targeting CD40,
OX40, CD137, TIM3, and LAG3, among others, also are ongoing.67 In addition, combination studies testing checkpoint
inhibitors and other proinflammatory cytokines (IL-12, IL15) are in the planning phases. These agents and combinations currently are being translated into the neoadjuvant
setting; ongoing studies involve the combinations of ipilimumab and HDI (NCT01608594) and pembrolizumab and
HDI (NCT02339324).
biospecimens before and after the initiation of systemic therapy provide an ideal platform for investigating such biomarkers that, ideally, can be evaluated simultaneously in the
circulation and in the TME according to the common systems of biology.35 Signifcant efforts in melanoma biomarker
studies are underway, and preliminary dataincluding gene
expression signatures reflective of an inflamed TME that may
predict clinical beneft in patients treated with ipilimumab,
tumor vaccines, and IL-2are very promising.35,40,69 Similarly, exome sequencing studies have elucidated a neoantigen
landscape specifc for tumors that respond to CTLA-4 blockade.70 Further, immunohistochemistry studies of CD8 expression at the tumor invasive margin support the predictive
value of this biomarker in relation to anti-PD1 therapeutic
beneft.71 Similar efforts are underway that may allow the
prediction of patients who are more likely to experience
severe immune-related toxicities. Such biomarker and mechanistic studies can be accelerated through neoadjuvant studies, given the access to biospecimens.
CONCLUSION
Neoadjuvant therapy has the potential to improve the outcomesincluding survival, surgical resectability, local control, and organ preservation of patients with locoregionally
advanced melanoma. Other advantages are the ability to
evaluate the clinical and pathologic responses and the potential to identify immunologic and histologic correlates of
tumor response. Access to tumor tissue before and after neoadjuvant therapy may allow a better understanding of the antitumor mechanisms of action that may enable more selective
application of therapeutic agents to those patients who are
more likely to beneft. Neoadjuvant immunotherapy with
HDI and ipilimumab has yielded several important fndings,
and multiple studies involving newer immunotherapeutic
and targeted agents and combinations are underway. Neoadjuvant therapy in melanoma continues to be investigational
and should only be pursued in the context of a clinical trial.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Ahmad A.
Tarhini, Amgen, Bristol-Myers Squibb, Castle Biosciences Inc., Genentech/Roche, Merck Sharp & Dohme. Speakers Bureau: None. Research Funding: Ahmad
A. Tarhini, Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Morphotek, Novartis, Pzer Oncology. Patents, Royalties, or Other Intellectual Property:
None. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Balch CM, Buzaid AC, Soong SJ, et al. Final version of the American
Joint Committee on Cancer staging system for cutaneous melanoma.
J Clin Oncol. 2001;19:3635-3648.
2. Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009
e540
23. Su YB, Sohn S, Krown SE, et al. Selective CD4 lymphopenia in melanoma patients treated with temozolomide: a toxicity with therapeutic
implications. J Clin Oncol. 2004;22:610-616.
24. Flaherty LE, Othus M, Atkins MB, et al. Southwest Oncology Group
S0008: a phase III trial of high-dose interferon Alfa-2b versus cisplatin,
vinblastine, and dacarbazine, plus interleukin-2 and interferon in patients with high-risk melanomaan intergroup study of cancer and leukemia Group B, Childrens Oncology Group, Eastern Cooperative
Oncology Group, and Southwest Oncology Group. J Clin Oncol. 2014;
32:3771-3778.
25. Clemente CG, Mihm MC Jr, Bufalino R, et al. Prognostic value of tumor
infltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer. 1996;77:1303-1310.
26. Mihm MC Jr, Clemente CG, Cascinelli N. Tumor infltrating lymphocytes in lymph node melanoma metastases: a histopathologic prognostic indicator and an expression of local immune response. Lab Invest.
1996;74:43-47.
27. Erdag G, Schaefer JT, Smolkin ME, et al. Immunotype and immunohistologic characteristics of tumor-infltrating immune cells are associated
with clinical outcome in metastatic melanoma. Cancer Res. 2012;72:
1070-1080.
28. Bogunovic D, ONeill DW, Belitskaya-Levy I, et al. Immune profle and
mitotic index of metastatic melanoma lesions enhance clinical staging
in predicting patient survival. Proc Natl Acad Sci U S A. 2009;106:2042920434.
29. Hkansson A, Gustafsson B, Krysander L, et al. Tumour-infltrating
lymphocytes in metastatic malignant melanoma and response to interferon alpha treatment. Br J Cancer. 1996;74:670-676.
30. Moschos SJ, Edington HD, Land SR, et al. Neoadjuvant treatment of
regional stage IIIB melanoma with high-dose interferon alfa-2b induces
objective tumor regression in association with modulation of tumor infltrating host cellular immune responses. J Clin Oncol. 2006;24:31643171.
31. Tatsumi T, Kierstead LS, Ranieri E, et al. Disease-associated bias in T
helper type 1 (Th1)/Th2 CD4() T cell responses against MAGE-6 in
HLA-DRB10401() patients with renal cell carcinoma or melanoma.
J Exp Med. 2002;196:619-628.
32. Kirkwood JM, Ernstoff MS, Davis CA, et al. Comparison of intramuscular and intravenous recombinant alpha-2 interferon in melanoma
and other cancers. Ann Intern Med. 1985;103:32-36.
33. Wang W, Edington HD, Rao UN, et al. Modulation of signal transducers and activators of transcription 1 and 3 signaling in melanoma by
high-dose IFNalpha2b. Clin Cancer Res. 2007;13:1523-1531.
34. Wang W, Edington HD, Jukic DM, et al. Impact of IFNalpha2b upon
pSTAT3 and the MEK/ERK MAPK pathway in melanoma. Cancer Immunol Immunother. 2008;57:1315-1321.
35. Tarhini AA, Edington H, Butterfeld LH, et al. Immune monitoring of
the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab. PloS
One. 2014;9:e87705.
36. Tarhini AA, Edington H, Butterfeld LH, et al. Neoadjuvant ipilimumab
in locally/regionally advanced melanoma: clinical outcome and immune monitoring. J Clin Oncol. 2012;30 (suppl; abstr 8533).
37. Tarhini AA, Cherian J, Moschos SJ, et al. Safety and effcacy of combination immunotherapy with interferon alfa-2b and tremelimumab in
patients with stage IV melanoma. J Clin Oncol. 2012;30:322-328.
38. Tarhini AA. Overcoming melanoma immune tolerance: non-specifc
CTLA-4 blockade/interferon alfa and antigen-specifc immunization
with TLR-9 stimulation/local GM-CSF as components of a melanoma
immunotherapeutic strategy and associated biomarkers of therapeutic
beneft [dissertation]. Pittsburgh, PA: University of Pittsburgh; 2011.
39. Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of
e541
AHMAD A. TARHINI
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
e542
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
agent, coxsackievirus A21, in patients with stage IIIc and stage IV malignant melanoma. Paper presented at: 50th Annual Meeting of the
American Society of Clinical Oncology; May 30 to June 3, 2014; Chicago, IL.
Bedikian AY, Richards J, Kharkevitch D, et al. A phase 2 study of highdose allovectin-7 in patients with advanced metastatic melanoma. Melanoma Res. 2010;20:218-226.
Kaufman HL, Andtbacka RH, Collichio FH, et al. Primary overall survival (OS) from OPTiM, a randomized phase III trial of talimogene
laherparepvec (T-VEC) versus subcutaneous (SC) granulocytemacrophage colony-stimulating factor (GM-CSF) for the treatment (tx)
of unresected stage IIIB/C and IV melanoma. Paper presented at: 50th
Annual Meeting of the American Society of Clinical Oncology; May 30
to June 3, 2014; Chicago, IL.
Schadendorf D, Hodi FS, Robert C, et al. Pooled Analysis of Long-Term
Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. J Clin Oncol. Epub 2015 Feb 9.
Hamid O, Robert C, Daud A, et al. Safety and tumor responses with
lambrolizumab (anti-PD-1) in melanoma. New Engl J Med. 2013;369:
134-144.
Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated
melanoma without BRAF mutation. New Engl J Med. 2015;372:320-330.
Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab
in advanced melanoma. New Engl J Med. 2013;369:122-133.
Hodi FS, Lee S, McDermott DF, et al. Ipilimumab plus sargramostim vs
ipilimumab alone for treatment of metastatic melanoma: a randomized
clinical trial. JAMA. 2014;312:1744-1753.
Hodi FS, Lawrence D, Lezcano C, et al. Bevacizumab plus ipilimumab in
patients with metastatic melanoma. Cancer Immunol Res. 2014;2:632642.
Maker AV, Phan GQ, Attia P, et al. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen
4 blockade and interleukin 2: a phase I/II study. Ann Surg Oncol. 2005;
12:1005-1016.
Sznol M, Kluger HM, Callahan MK, et al. Survival, response duration,
and activity by BRAF mutation (MT) status of nivolumab (NIVO, antiPD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent
therapy in advanced melanoma (MEL). Paper presented at: 50th Annual
Meeting of the American Society of Clinical Oncology; May 30 to June 3,
2014; Chicago, IL.
Kirkwood JM, Butterfeld LH, Tarhini AA, et al. Immunotherapy of
cancer in 2012. CA Cancer J Clin. 2012;62:309-335.
Sullivan RJ, Hoshida Y, Brunet J, et al. A single center experience with
high-dose IL-2 treatment for patients with advanced melanoma and pilot investigation of a novel gene expression signature as a predictor of
response. J Clin Oncol. 2009;27:15s (suppl;abstr 9003).
Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. New Engl J Med. 2014;371:
2189-2199.
Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515:
568-571.
MELANOMA/SKIN CANCERS
SPEAKERS
Ryan Sullivan, MD
Massachusetts General Hospital Cancer Center
Boston, MA
Reinhard Dummer, MD
University Hospital of Zurich
Zurich, Switzerland
From the Massachusetts General Hospital Cancer Center, Boston, MA; Yale Cancer Center, New Haven, CT; Yale University, New Haven, CT; University Hospital of Zurich, Zurich, Switzerland.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Ryan J. Sullivan, MD, Massachusetts General Hospital Cancer Center, 226 Great Plain Ave., Needham, MA 02492; email: rsullivan7@partners.org.
2015 by American Society of Clinical Oncology.
177
SULLIVAN ET AL
Multiple mediators and regulators of the MAPK and PI3K pathways have been linked to melanoma. (A) Key oncogenic mutations (red), amplications (purple), and tumor suppressor genes
(gray). (B) Genetic aberrations that mediate resistance to treatment with BRAF inhibitors (driving mutation, red; genomic amplication, purple; and loss of tumor suppressor, gray).
aberrations lead to MAPK signaling.11,12,14-16 Recently, a number of small-molecule inhibitors have been developed that inhibit many of the key mediators of the MAPK pathway
including RAF (pan-RAF and BRAF-specifc), MEK, and
ERK, as well as upstream activators of the pathway such as
CKIT.
KEY POINTS
The great majority of patients with melanoma have
mutations in genes (oncogenes and/or tumor suppressor
genes) that drive MAPK pathway activation.
Potent and specic inhibitors of MAPK pathway mediators
have been discovered and include BRAF inhibitors
(vemurafenib, dabrafenib, encorafenib), MEK inhibitors
(trametinib, selumetinib, cobimetinib, binimetinib), ERK
inhibitors (BVD-523, GDC-0994), and pan-RAF inhibitors
(LY3009120).
Combination BRAF/MEK inhibition is superior to single-agent
BRAF inhibition in patients with BRAFV600-mutant
melanoma; a number of trials of BRAF/MEK inhibition plus a
third targeted agent are underway to determine whether
triplet therapy is superior to BRAF/MEK doublet therapy.
Single-agent pan-RAF, MEK, and ERK inhibitor therapies
may be effective strategies for the treatment of other
molecular subsets of melanoma, including uveal melanoma
(typically either GNAQ or GNA11 mutant), NRAS-mutant,
MEK-mutant, non-V600 BRAF mutant, and NF-1 loss of
function.
The use of novel molecular targeted therapies, alone or in
combination, holds great promise for the treatment of
melanoma, but is not without challenges.
178
were benefting from these therapies. As a result, both RocheGenentech and GlaxoSmithKline (GSK) developed companion diagnostics that were used to prescreen patients for the
pivotal trials of vemurafenib and dabrafenib, respectively.
Whereas the frst generation of mutation detection analytics
used direct sequencing, both the Roche assay (known as the
cobas 4800 BRAF V600 Mutation Test) and the assay developed by GSK (THxID-BRAF test, licensed by Quest Diagnostics and bioMerieux) involve polymerase chain reaction
(PCR) techniquesreal-time PCR for the cobas assay and
amplifcation refractory mutation system (ARMS)-PCR for
the THxID-BRAF assay using primers designed to quantify predominantly V600E (cobas) or both V600E and V600K
(THxID-BRAF).17,18 Both assays have been shown to be superior to Sanger sequencing, although the cobas assay only
detects 70% of V600K mutations whereas the THxID-BRAF
test is able to detect these with great accuracy, and both received FDA approval concurrently with vemurafenib (cobas)
and dabrafenib (THxID-BRAF).17-19 However, as described
above, a number of additional mutations have been identifed
that might similarly be targeted with small-molecule inhibitors, including non-V600 BRAF, NRAS, CKIT, and NF1 loss;
thus molecular analysis platforms that can accurately and
cost-effectively analyze multiple mutations are required.
A number of novel techniques to target mutant epitopes
across relevant genes have been developed, including those
that use mass spectrometry (Sequenom) and florescent tags
(SNaPshot), but these are now being replaced by massively
parallel sequencing techniques that can detect single nucleotide variants, insertions, deletions, and gene rearrangements
with deep coverage.20-22 As these assays become more widely
available, the challenge for providers will be to determine
how best to utilize the vast amount of information. It is expected that these types of effort will identify small subsets of
patients with novel genetic aberrations that predict response
to agents not previously used in melanoma.
179
SULLIVAN ET AL
Targeting CKIT
A number of inhibitors of CKIT have been tested in melanoma, with varying results. The frst was a phase II trial of
imatinib that enrolled 26 patients with metastatic melanoma
independent of mutation or amplifcation status.89 In retrospect, it is not surprising that there were no responses to therapy in this initial study; however, in three subsequent clinical
trials of imatinib in patients with mucosal or acral melanoma,
responses were seen in 17% to 29% of patients.90-92 Responses
were observed in nearly 30% of patients with CKIT mutations
or amplifcations, particularly in either exon 11 or 13. Phase
II trials of nilotinib (NCT00788775, NCT01099514,
NCT01028222), dasatinib (NCT00700882), and sunitinib
(NCT00577382) have either completed accrual or are ongoing.
Targeting NRAS
Activating mutations of NRAS are the second most common
oncogenic mutations in melanoma and are present in 20% to
30% of patients with cancer associated with MAPK activation.3,8 As such, targeting mediators of this pathway is a logical approach that is supported by preclinical evidence; panRAF inhibitors, MEK inhibitors, and ERK inhibitors all have
substantial preclinical activity in these tumors.71,72,77,78 The
MEK inhibitor binimetinib is associated with a 20% response
rate and 4.8-month PFS in NRAS-mutant patients.93 Based
on these data, a randomized phase III trial comparing binimetinib with dacarbazine is underway (NCT01763164) and
positive results would change the standard of care for this
patient population. A randomized phase II trial of the MEK
inhibitor pimasertib compared to dacarbazine has completed
enrollment (NCT01693068).
Despite promising early clinical data, it is clear that the majority of patients with NRAS-mutant melanoma will either
not beneft, or will only transiently beneft, from treatment
with MEK inhibitors.93 Thus, strategies to overcome either
Targeting Angiogenesis
Tumor angiogenesis in melanoma has been well documented. Numerous molecules that promote angiogenesis are
overexpressed in melanoma, including VEGF, PDGF, fbroblast growth factor (FGF), and interleukin 8.96,97 Furthermore, their expression is associated with invasion and
metastasis in preclinical models and may be associated with
worse prognosis in patients with melanoma. Based on these
fndings and the effectiveness of angiogenesis inhibitors in
other cancers (including renal cell carcinoma, breast cancer,
and colon cancer), a number of antiangiogenic agents have
been tested in patients with advanced melanoma. Bevacizumab, a monoclonal antibody targeting VEGF, has been
evaluated in patients with melanoma with the most promising results seen for the combination of carboplatin/paclitaxel/bevacizumab. In an initial phase II trial of 53 patients, 9
(17%) patients achieved a partial response (PR) and an additional 30 (57%) had stable disease for at least 8 weeks.98 Based
on these results, a multicenter, randomized phase II trial was
performed evaluating the combination of carboplatin/paclitaxel with or without bevacizumab. Specifcally, 214 patients
were enrolled via a 2:1 random allocation to receive carboplatin/paclitaxel plus bevacizumab (143 patients) or carboplatin/paclitaxel plus placebo (71 patients). The response rate
(25.5 vs. 16.4%; p 0.16), median PFS (5.6 vs. 4.2 months;
p 0.14), median OS (12.3 vs. 9.2 months; p 0.19), and
1-year OS (53 vs. 39%; p 0.06) were all better in patients
receiving carboplatin/paclitaxel with bevacizumab; however, none of these fndings were signifcant.99 The addition of bevacizumab appeared to provide particular
beneft with regard to improved OS in patients with M1c
disease (HR for OS 0.64; 95% CI, 0.44 to 0.95), especially
among patients who had elevated levels of lactate dehydrogenase (LDH; HR 0.53; 95% CI, 0.32 to 0.88).99 The
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
181
SULLIVAN ET AL
TABLE 1. Clinical Trial Results of Targeted Therapy in Genetically Dened Patient Populations
Inhibitor(s)
Target
Trial
Phase
CR PR
(%)
Median PFS/TTP
(Months)
Reference
Vemurafenib
BRAFV600
III
53
6.9
Chapman et al28
V600
BRAF Mutant
Dabrafenib
BRAF
III
50
6.7
Hauschild et al30
Trametinib
MEK1/2
III
22
4.8
Flaherty et al29
Binimetinib*
MEK1/2
II
20
3.5
Ascierto et al93
V600
BRAF
III
68
9.9
Larkin et al33
I/II
76
9.4
Flaherty et al31
III
67
9.2
Long et al34
V600
BRAF
MEK 1/2
III
64
11.4
Robert et al36
II
40
5.6
Robert et al111
NRAS Mutant
Binimetinib
MEK1/2
II
20
3.7
Ascierto et al93
33
N/A
Sosmna et al95
Imatinib
CKIT
II
16
Carvajal et al92
Imatinib
CKIT
II
30
3.5
Guo et al90
Imatinib
CKIT
II
29
3.7
Hodi et al91
CKIT Mutant/Amplied
Abbreviations: CR, complete response; PR, partial response; PFS, progression-free survival; TTP, time to progression: N/A, not available.
*Some patients pretreated with BRAF inhibitor.
toxicity will result, perhaps caused by nonspecifc targets, requiring substantial dose reductions. For example, the combination of the selective MEK 1/2 inhibitor binimetinib with
the CDK 4/6 inhibitor LEE01 demonstrated promising antitumor activity in patients with advanced NRAS-mutant melanoma, but also resulted in frequent adverse events that
necessitated multiple dosing reductions and interruptions.95
In general, however, combinations that target parallel pathways are less likely to have overlapping toxicity and may be
better tolerated, as are agents with greater specifcity.105 For
example, the combination of the BRAF inhibitor dabrafenib
with the MEK inhibitor trametinib in patients with BRAFmutant melanoma showed a decrease in many class-related
toxicities associated with BRAF inhibitors compared to dabrafenib monotherapy.31,105,106
As novel targeted therapies continue through development, the translation of preclinical data into the clinical setting is often diffcult. Cell lines and animal models may not
effectively mimic human tumors, the tumor microenvironment, or immune responses, and may not demonstrate the
same mechanisms of resistance. For novel drug combinations, this translation can be fraught with complications if
laboratory and animal models used for one class of agents
differ from those used for another.
Identifying appropriate biomarkers is critical for the detection, treatment, and monitoring of targeted therapies. Biomarker identifcation and analysis has typically relied on the
use of tumor tissue, which involves a great cost, logistical diffculties, and risk to the patient. The continued development
of noninvasive tools such as circulating tumor DNA
(ctDNA) will be important for use as a tissue surrogate for a
CONCLUSION
Although not without challenges, the use of novel targeted
therapies in the context of molecular testing has opened new
avenues for a precision medicine approach for metastatic
melanoma, including a signifcant beneft already realized for
this patient population. In some cases impressive tumor regressions have been demonstrated (Table 1); however, responses are not seen in the majority of patients with nonBRAF mutated cancer who are treated with targeted therapy
and relapse is frequent in such cases despite combination
therapy with BRAF and MEK inhibitors. Intensive translational research has highlighted the complexity of the resistance mechanisms involved and offers opportunities for
interventions and improved patient outcomes. There is a
need for additional clinical trials accompanied by highthroughput biomarker analyses to further improve these outcomes. Overcoming the scientifc challenges, as well as
satisfying the priorities of the various stakeholders involved
in the development of novel therapies, will be critical for improving the treatment of patients with melanoma.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Reinhard Dummer, BMS, GSK, MSD, Novartis,
Roche. Consulting or Advisory Role: Reinhard Dummer, BMS, GSK, MSD, Novartis, Roche. Patricia LoRusso, Astex, Novartis, Astellas, Genentech. Ryan J.
Sullivan, Astex Therapeutics. Speakers Bureau: Patricia LoRusso, Genentech. Research Funding: Reinhard Dummer, BMS, GSK, MSD, Novartis, Roche.
Patricia LoRusso, Genentech (Inst), Novartis (Inst), Merrimack (Inst), Immunogen (Inst), Tensha (Inst), Tailho (Inst). Patents, Royalties, or Other
Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
183
SULLIVAN ET AL
184
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. Lancet Oncol. 2014;15:954-965.
Robert C, Karaszewska B, Schachter J, et al. Improved overall survival
in melanoma with combined dabrafenib and trametinib. N Engl J Med.
2015;372:30-39.
Dummer R, Flaherty KT. Resistance patterns with tyrosine kinase inhibitors in melanoma: new insights. Curr Opin Oncol. 2012;24:150154.
Frederick DT, Salas Fragomeni RA, Schalck A, et al. Clinical profling
of BCL-2 family members in the setting of BRAF inhibition offers a
rationale for targeting de novo resistance using BH3 mimetics. PloS
One. 2014;9:e101286.
Haq R, Yokoyama S, Hawryluk EB, et al. BCL2A1 is a lineage-specifc
antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition. Proc Natl Acad Sci U S A. 2013;110:4321-4326.
McArthur GA, Young RJ, Sheppard KE, et al. Clinical signifcance of genomic
alterations of the CDK4-pathway and sensitivity to the CDK4 inhibitor PD
0332991 in melanoma. J Clin Oncol. 2012;30 (suppl; abstr 8520).
Nathanson KL, Martin AM, Wubbenhorst B, et al. Tumor genetic analyses of
patients with metastatic melanoma treated with the BRAF inhibitor dabrafenib (GSK2118436). Clin Cancer Res. 2013;19:4868-4878.
Smalley KS, Lioni M, Dalla Palma M, et al. Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated
melanomas. Mol Cancer Ther. 2008;7:2876-2883.
Hoek KS, Eichhoff OM, Schlegel NC, et al. In vivo switching of human
melanoma cells between proliferative and invasive states. Cancer Res.
2008;68:650-656.
Zipser MC, Eichhoff OM, Widmer DS, et al. A proliferative melanoma
cell phenotype is responsive to RAF/MEK inhibition independent of
BRAF mutation status. Pigment Cell Melanoma Res. 2011;24:326-333.
Trunzer K, Pavlick AC, Schuchter L, et al. Pharmacodynamic effects
and mechanisms of resistance to vemurafenib in patients with metastatic melanoma. J Clin Oncol. 2013;31:1767-1774.
Emery CM, Vijayendran KG, Zipser MC, et al. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci U S A.
2009;106:20411-20416.
Van Allen EM, Wagle N, Sucker A, et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 2014;4:94-109.
Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to
B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature.
2010;468:973-977.
Shi H, Hugo W, Kong X, et al. Acquired resistance and clonal evolution
in melanoma during BRAF inhibitor therapy. Cancer Discov. 2014;4:
80-93.
Oberholzer PA, Kee D, Dziunycz P, et al. RAS mutations are associated
with the development of cutaneous squamous cell tumors in patients
treated with RAF inhibitors. J Clin Oncol. 2012;30:316-321.
Su F, Viros A, Milagre C, et al. RAS mutations in cutaneous squamouscell carcinomas in patients treated with BRAF inhibitors. New Engl
J Med. 2012;366:207-215.
Lin WM, Baker AC, Beroukhim R, et al. Modeling genomic diversity
and tumor dependency in malignant melanoma. Cancer Res. 2008;68:
664-673.
Shi H, Moriceau G, Kong X, et al. Melanoma whole-exome sequencing
identifes (V600E)B-RAF amplifcation-mediated acquired B-RAF inhibitor resistance. Nat Commun. 2012;3:724.
Poulikakos PI, Persaud Y, Janakiraman M, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E).
Nature. 2011;480:387-390.
Villanueva J, Vultur A, Lee JT, et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be over-
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov. 2013;3:742-750.
Rebecca VW, Alicea GM, Paraiso KH, et al. Vertical inhibition of the
MAPK pathway enhances therapeutic responses in NRAS-mutant
melanoma. Pigment Cell Melanoma Res. 2014;27:1154-1158.
Wong DJ, Robert L, Atef MS, et al. Antitumor activity of the ERK
inhibitor SCH722984 against BRAF mutant, NRAS mutant and wildtype melanoma. Mol Cancer. 2014;13:194.
Ambrosini G, Musi E, Ho AL, et al. Inhibition of mutant GNAQ signaling in uveal melanoma induces AMPK-dependent autophagic cell
death. Mol Cancer Ther. 2013;12:768-776.
Ambrosini G, Pratilas CA, Qin LX, et al. Identifcation of unique MEKdependent genes in GNAQ mutant uveal melanoma involved in cell
growth, tumor cell invasion, and MEK resistance. Clin Cancer Res.
2012;18:3552-3561.
Ho AL, Musi E, Ambrosini G, et al. Impact of combined mTOR and
MEK inhibition in uveal melanoma is driven by tumor genotype. PloS
One. 2012;7:e40439.
Musi E, Ambrosini G, de Stanchina E, et al. The phosphoinositide
3-kinase alpha selective inhibitor BYL719 enhances the effect of the
protein kinase C inhibitor AEB071 in GNAQ/GNA11-mutant uveal
melanoma cells. Mol Cancer Ther. 2014;13:1044-1053.
Surriga O, Rajasekhar VK, Ambrosini G, et al. Crizotinib, a c-Met inhibitor, prevents metastasis in a metastatic uveal melanoma model.
Mol Cancer Ther. 2013;12:2817-2826.
Chen X, Wu Q, Tan L, et al. Combined PKC and MEK inhibition in
uveal melanoma with GNAQ and GNA11 mutations. Oncogene. 2014;
33:4724-4734.
Sagoo MS, Harbour JW, Stebbing J, et al. Combined PKC and MEK
inhibition for treating metastatic uveal melanoma. Oncogene. 2014;33:
4722-4723.
Chattopadhyay C, Grimm EA, Woodman SE. Simultaneous inhibition
of the HGF/MET and Erk1/2 pathways affect uveal melanoma cell
growth and migration. PloS One. 2014;9:e83957.
von Euw E, Atef M, Attar N, et al. Antitumor effects of the investigational selective MEK inhibitor TAK733 against cutaneous and uveal
melanoma cell lines. Mol Cancer. 2012;11:22.
Carvajal RD, Sosman JA, Quevedo JF, et al. Effect of selumetinib vs
chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. JAMA. 2014;311:2397-2405.
Wyman K, Atkins MB, Prieto V, et al. Multicenter Phase II trial of
high-dose imatinib mesylate in metastatic melanoma: signifcant toxicity with no clinical effcacy. Cancer. 2006;106:2005-2011.
Guo J, Si L, Kong Y, et al. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit
mutation or amplifcation. J Clin Oncol. 2011;29:2904-2909.
Hodi FS, Corless CL, Giobbie-Hurder A, et al. Imatinib for melanomas
harboring mutationally activated or amplifed KIT arising on mucosal,
acral, and chronically sun-damaged skin. J Clin Oncol. 2013;31:31823190.
Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic
target in metastatic melanoma. JAMA. 2011;305:2327-2334.
Ascierto PA, Schadendorf D, Berking C, et al. MEK162 for patients
with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol.
2013;14:249-256.
Kwong LN, Costello JC, Liu H, et al. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat Med.
2012;18:1503-1510.
Sosman JA, Kittaneh M, Lolkema MPJK, et al. A phase 1b/2 study of
LEE011 in combination with binimetinib (MEK162) in patients with
185
SULLIVAN ET AL
96.
97.
98.
99.
100.
101.
102.
103.
104.
186
105.
106.
107.
108.
109.
110.
111.
SPEAKERS
Miriam Rodin, MD, PhD
St. Louis University School of Medicine
St. Louis, MO
Heidi D. Klepin, MD, MS
Wake Forest School of Medicine
Winston-Salem, NC
From the Section on Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC; Division of Geriatrics, Saint Louis University School of Medicine, St. Louis, MO; Department of
Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Heidi D. Klepin, MD, MS, Section on Hematology and Oncology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem,
NC 27147; email: hklepin@wakehealth.edu.
2015 by American Society of Clinical Oncology.
e544
TABLE 1. Characteristics Associated with Chemotherapy Toxicity among Older Adults with Cancer
Study (No. of Patients)
Physical Limitations
Sensory Impairment
Hurria et al20
(500, mixed sample)
Extermann et al17
(510, mixed sample)
N/A
N/A
N/A
18
Cognitive Impairment
Depressive Symptoms
Nutrition
Polypharmacy
N/A
N/A
Functional Status
A functional status assessment focuses on the need for assistance with daily activities to maintain independence in the
home (Activities of Daily Living [ADL]) and in the community (Instrumental Activities of Daily Living [IADL]). Activities of Daily Living include basic self-care skills such as
bathing, dressing, toileting, transferring, and maintaining
continence. IADL are activities needed to maintain independence in the community such as shopping, taking
transportation, preparing meals, doing housework, taking
medications, and managing personal fnances. Among the
geriatric population, the need for assistance with these activities is predictive of overall life expectancy and resource requirement (such as nursing home placement).21 For the older
patient with cancer, understanding the need for assistance
with these activities is critical for treatment planning. For example, an integral part of cancer treatment is the use of sup-
KEY POINTS
Oncologists need to be familiar with practical strategies to
assess physiologic and functional capacity in older patients
to inform optimal management.
Geriatric assessment can predict treatment outcomes.
Incorporation of geriatric assessment strategies and
geriatric medicine consultation can help individualize initial
treatment decisions and inform management strategies
during the course of treatment and survivorship.
Dose modication for vulnerable older adults reviewing
palliative therapy is common and may optimize therapeutic
benet for some patients.
Consideration of patient-centered outcomes inclusive of
functional independence, health care utilization, and
psychosocial health are critical for clinical trial design and
to inform management of older adults receiving
chemotherapy.
Comorbidity
An assessment of comorbidity is an integral part of cancer
treatment planning. It is particularly important for older
adults, due to the increased prevalence of multiple chronic
conditions with age and the variability of comorbidity burden among similarly aged older adults. First, it can be utilized
to assess overall life expectancy and to weigh competing
causes of morbidity and mortality.23 Second, it can be utilized
to tailor cancer treatment. Key questions include whether the
patients other medical problems affect the ability to tolerate
cancer treatments. For example, in a patient with diabetes,
supportive care medications, such as steroids, may exacerbate diabetes. If steroids will be used, education and blood
sugar management need to be considered. Furthermore, the
choice of chemotherapy may be influenced by diabetic comasco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e545
plications. For example, one may choose to avoid chemotherapy drugs that increase the risk for neuropathy (such as
taxanes).
Cognition
With aging, there is an increased prevalence of cognitive impairment that poses distinct risks when considering cancer
therapy.24 The fndings of cognitive impairment can be subtle
and easily missed, but may be unmasked during a stressor
such as cancer treatment. Studies suggest that the prevalence
of cognitive impairment among older adults receiving chemotherapy may be 20% or greater.25-27 Even mild cognitive
impairment increases the risk for delirium, the risk for being
unable to follow instructions for self-management of toxicities,
the risk for nutritional depletion, and the ability to communicate important personal information to caregivers. A key component of assessing cognitive function is evaluating capacity for
decision making. Even in the setting of cognitive impairment,
individuals could have the capacity to make medical decisions if
they meet the following four criteria: (1) understands the relevant information, (2) appreciates the situation, (3) uses reason
to make a decision, and (4) communicates their choices.28 Careful attention to cognitive status should be given at every clinical
contact. Any abnormality on any of the short screening tools
warrants further attention and referral.
It is important to recognize that screening for cognitive impairment may help identify delirium among older patients
with cancer, especially during acute illness and treatment
stress. Delirium is an acute, fluctuating disorder of attention
that is common among acutely ill and postoperative older
adults including those on inpatient oncology units.29,30 Presence of delirium increases the risk for mortality. The agitated
form is easily recognized, but the hypoactive form is easily
overlooked if there is not a concerted effort to screen. There is
some evidence that delirium is preventable with specialized
acute care for the elderly teams.31 Recognition of delirium provides an opportunity to identify and treat underlying causes
(commonly infection, medications, or stress) and, potentially,
prevent common complications including falls, malnutrition,
aspiration, decubitus ulcers, and deconditioning.
Nutrition
Poor nutrition has been identifed as a risk factor for chemotherapy toxicity.17 Some simple screening questions for nutrition can include whether the patient has a low body mass
index (less than 22 kg/m2) or whether they had unintentional
weight loss (greater than 5%). Patients with either a low body
mass index or unintentional weight loss should be referred
for a nutrition consult. Other standardized screening tools
such as the Mini Nutritional Assessment can be readily implemented in routine practice.17 If an older adult with cancer
is fatigued or sick, they will need additional family or friend
support to prepare meals. Therefore, assessing social support
is an important part of the GA.32,33 National programs such
as the Meals On Wheels Association of America could also be
implemented for those with inadequate social support.
e546
Medication Review
Medication review and reconciliation are a key part of a GA.
Older adults often take several medications prescribed by different health care providers, increasing the risk for medication duplications, dosing errors, and drugs inappropriate for
older patients.37-39 Older patients with cancer are taking
an average of fve medications or more.25,40,41 Use of multiple
medications at the time of chemotherapy treatment may increase the risk for toxicity because of adverse drug events or
interactions. Studies investigating the prognostic signifcance of polypharmacy on treatment outcomes among older
patients with cancer have shown mixed results. Most studies
that incorporated polypharmacy as a risk factor in the context of a GA have not shown a clear association between
number of medications and treatment toxicity.17,26,42 These
study cohorts are typically heterogeneous and include mixed
cancer types and varied treatments. In a study of older
women with advanced ovarian cancer, use of six or more
medications at chemotherapy initiation was associated with
decreased survival.18 A study of older women with advanced
breast cancer receiving chemotherapy showed use of fve or
more medications was independently associated with treatment toxicity.19 Finally, among older adults with acute myeloid leukemia use of four or more medications at the time of
induction chemotherapy was associated with increased early
death, lower remission rates, and shorter survival.43 Taken
together, the current data suggest that the implications of
polypharmacy may be specifc to the clinical scenario and
most evident in patients at high risk for toxicity.
Although polypharmacy may be a surrogate marker for unmeasured vulnerability, it also increases the risk for drug interactions during treatment. One study of older patients with
cancer identifed potential drug problems in 62% of patients
with 50% of these rated as moderate or severe.41 Another
study of older adults receiving chemotherapy identifed a potential drug interaction among 75% of patients (244 patients)
and found an association between potential drug interaction
and nonhematologic toxicity.44 Although much more research needs to be done on this topic, proactive management
strategies can be advocated to minimize risks for patients.
Careful review of medications, including consideration of
discontinuation of any medications without clear indication,
may beneft many older adults. This is frequently an overlooked opportunity in oncology practice and may be facilitated by communication with a primary care physician or
geriatrician. Use of available drug interaction software can
help avoid initiation of new high-risk medications.
When
At present, most studies report on GA or other assessments
shortly after diagnosis to predict how older patients will tolerate frst-line therapy. However, we would argue that some
aspects of the GA should be repeated at each visit. Toxicity is
cumulative, and patients often minimize discomfort unless
they are directly asked. This is a major part of the rationale for
having supportive and palliative care for symptom control
and for help in disclosing bad news.60 Some toxicities, however, may be less obvious, such as delirium, neuropathy affecting gait and balance, drug interactions, depression, and
bowel or bladder dysfunction. Very little has been published
about the functional trajectory of older adults with cancer
even though KPS or Eastern Cooperative Oncology Group
(ECOG) Performance Status scores are routinely recorded.
As demonstrated in several studies, these scales are global,
impressionistic assessments that may miss key items of relevance to the geriatric population.
Where
Several research reports now show that gathering GA data on
all older adults and following it with a routine or unsolicited
consultation has an effect on cancer treatment decisions;
however, several questions remain regarding how to best integrate GA and consultation into oncology care. In a recent
systematic review summarizing the effect of geriatric evaluations on treatment decisions, a modifcation in treatment
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e547
plan was prescribed in almost 40% of patients, with less intensive treatment accounting for two-thirds of these plans.61
In one French study, GA followed tumor board deliberation
for the initial treatment of 191 patients older than 70. There
was a slight tendency to decrease the intensity of treatment
after reviewing the GA fndings, but it is not clear from this
report how the geriatric consultation was integrated into the
fnal treatment plan.62 A second French study introduced inpatient GA for hospitalized older adults with cancer.63 Of 107
patients, the geriatric consultant agreed with the oncology
treatment plan 68% of the time. When there was disagreement, approximately half of the time the oncology team ignored the geriatrics recommendations, whereas, the other
half of the time the oncology team stepped down the treatment or changed to palliative care in concordance with
geriatrics recommendations. Interestingly, a recent metaanalysis of the effect of inpatient geriatric consultation in a
general hospital population concluded that the main beneft
was to be seen in decreased mortality 6 to 8 months after discharge, not necessarily during the index admission.64 In
other words, it seems that geriatric inpatient consultation can
help oncologists identify and plan care for the frailest and
sickest patients on the one hand, and help with postacute care
and planning as they do with any other hospitalized older
adult.
In the outpatient setting, where most cancer treatment is
delivered, GA has followed oncology assessment in two recently published reports. One clinic planned to refer all patients with gastrointestinal and lung cancer older than age 70
to the geriatrician for a GA. However, the actual referral rate
was only 29%, and only 25% actually completed the appointment. The GA information affected only those patients for
whom the oncologist had not decided what to do.65 We see a
different result in a report of geriatric consultation in an outpatient oncology setting in which patients were already receiving their frst-line therapy.66 Of 161 patients older than
age 70, 49% had their treatment changed based on the geriatricians assessment of ADLs, cognitive function, depression,
and malnutrition: 34 had less intense treatment and 45 had
more intensive treatment after consultation.
Why
Geriatricians anticipate, diagnose, and manage syndromes
that do not necessarily involve only one organ, for which
there is no diagnostic test, and for which there is ample evidence of increased morbidity, mortality, and disablement.
Older patients who have these syndromes, whether at home
or in the hospital, may end their lives in nursing homes or
suffer other preventable losses in dignity and quality of life.
Current evidence supports the value of geriatric medicine
consultation for at least some older adults with cancer. Consultation should be sought when validated screening tools indicate a problem with performing daily activities required for
self-care (ADLs) and maintaining a household independently (IADLs). Consultation should be considered for older
adults with polypharmacy, particularly in the setting of multimorbidity, frequent falls, and any change in mental status
e548
A novel randomized trial published by Seymour et al addressed, in part, the issue of dose reduction in frst-line treatment for older adults with advanced stage colorectal cancer.
This study used a 2-by-2 factorial design to randomize 459
frail (considered not ft for full-dose combination chemotherapy by their physician) older adults with metastatic colorectal cancer to one of four frst-line systemic therapies using
an attenuated starting dose (80% of standard).71 The study
design allowed for escalation to full-dose therapy after 6
weeks, if tolerated. Patients (median age 74) were randomly
assigned to one of the following arms: (1) 48-hour intravenous fluorouracil (5-FU), (2) oxaliplatin/5-FU, (3) capecitabine, or (4) oxaliplatin/capecitabine. In addition to a
quality-of-life questionnaire, a composite outcome termed
overall treatment utility was incorporated in an attempt to
capture patient and physician satisfaction with the outcome
of each treatment decision. Several lessons can be learned
from this study. First, recruiting unft patients to a randomized trial was feasible. Second, few patients achieved dose escalation, with almost half (49%) requiring additional dose
reductions. Third, the unique trial design, inclusive of
patient-centered endpoints, provided relevant information
suggesting that use of oxaliplatin in this attenuated dosing
schedule may provide a palliative beneft, whereas, capecitabine may be associated with more toxicity compared with
5-FU. This study provides evidence for considering up-front
dose attenuation when treating non-ft older adults with metastatic colorectal cancer, and introduces additional outcome
measures to help quantify the palliative beneft of therapy.
Questions regarding optimal dosing schedules, including
treatment breaks, for older patients are also common. Again,
few studies specifcally have addressed this issue in older patients, yet, older patients are most likely to suffer debilitating
consequences from ongoing therapy. For colorectal cancer,
some data can be extrapolated from existing studies investigating chemotherapy-free intervals (CFI).72-75 For patients ft
enough to initiate combination chemotherapy, evidence
would suggest that CFI have minimal effect on overall survival with some potential benefts in quality of life. Although
only a fraction of patients enrolled in these studies were older
than 75, there is suggestion of similar outcomes among older
compared with younger patients when using this strategy.74
It is reasonable to incorporate these data into treatment planning for older patients in an attempt to minimize the negative
consequences of therapy on functional independence and
quality of life.
e549
CONCLUSION
Caring for older patients with cancer presents unique challenges. Incorporation of GA strategies can help individualize
initial treatment decisions and inform management strategies during the course of treatment and survivorship. Incorporation of GA strategies into clinical trial design will
provide needed evidence to optimize therapy for vulnerable
and frail older adults.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Arti Hurria,
GTx, Seattle Genetics, Boehringer Ingelheim Pharmaceuticals, Inc. Speakers Bureau: None. Research Funding: Arti Hurria, GSK (Inst), Celgene (Inst).
Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships:
None.
References
1. U.S. Department of Commerce. Population projections of the United
States by age, sex, race, and Hispanic origin: 1995 to 2050. http://www.
census.gov/prod/1/pop/p25-1130/p251130.pdf. Accessed March 4,
2015.
2. Smith RA, Manassaram-Baptiste D, Brooks D, et al. Cancer screening in
the United States, 2014: a review of current American Cancer Society
guidelines and current issues in cancer screening. CA Cancer J Clin.
2014;64:30-51.
3. Institute of Medicine. Retooling for an Aging America: Building the
Health Care Workforce. Washington, DC: The National Academies
Press; 2008.
4. Kirkwood MK, Kosty MP, Bajorin DF, et al. Tracking the workforce: the
American Society of Clinical Oncology workforce information system.
J Oncol Pract. 2013;9:3-8.
5. Reuben DB, Rubenstein LV, Hirsch SH, et al. Value of functional status
as a predictor of mortality: results of a prospective study. Am J Med.
1992;93:663-669.
6. Inouye SK, Peduzzi PN, Robison JT, et al. Importance of functional
measures in predicting mortality among older hospitalized patients.
JAMA. 1998;279:1187-1193.
7. Lee SJ, Lindquist K, Segal MR, et al. Development and validation of a
prognostic index for 4-year mortality in older adults. JAMA. 2006;295:
801-808.
8. Walter LC, Brand RJ, Counsell SR, et al. Development and validation of
a prognostic index for 1-year mortality in older adults after hospitalization. JAMA. 2001;285:2987-2994.
9. Seeman TE, Kaplan GA, Knudsen L, et al. Social network ties and mortality among the elderly in the Alameda County Study. Am J Epidemiol.
1987;126:714-723.
10. Landi F, Onder G, Gambassi G, et al. Body mass index and mortality
among hospitalized patients. Arch Intern Med. 2000;160:2641-2644.
11. Seeman TE, Berkman LF, Kohout F, et al. Intercommunity variations in
e550
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
the association between social ties and mortality in the elderly. A comparative analysis of three communities. Ann Epidemiol. 1993;3:325-335.
Kanesvaran R, Wang W, Yang Y, et al. Characteristics and treatment
options of elderly Chinese patients with cancer as determined by Comprehensive Geriatric Assessment (CGA). J Geriatr Oncol. 2014;5:171178.
Cappellani A, Di Vita M, Zanghi A, et al. Prognostic factors in elderly
patients with breast cancer. BMC Surgery. 2013;13:S2.
Ellis G, Langhorne P. Comprehensive geriatric assessment for older
hospital patients. Br Med Bull. 2004;71:45-59.
Yourman LC, Lee SJ, Schonberg MA, et al. Prognostic indices for older
adults: a systematic review. JAMA. 2012;307:182-192.
Aparicio T, Girard L, Bouarioua N, et al. A mini geriatric assessment
helps treatment decision in elderly patients with digestive cancer. A pilot study. Crit Rev Oncol Hematol. 2011;77:63-69.
Extermann M, Boler I, Reich RR, et al. Predicting the risk of chemotherapy toxicity in older patients: the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score. Cancer. 2012;118:
3377-3386.
Freyer G, Geay JF, Touzet S, et al. Comprehensive geriatric assessment
predicts tolerance to chemotherapy and survival in elderly patients with
advanced ovarian carcinoma: a GINECO study. Ann Oncol. 2005;16:
1795-1800.
Hamaker ME, Seynaeve C, Wymenga AN, et al. Baseline comprehensive
geriatric assessment is associated with toxicity and survival in elderly
metastatic breast cancer patients receiving single-agent chemotherapy:
results from the OMEGA study of the Dutch breast cancer trialists
group. Breast. 2014;23:81-87.
Hurria A, Togawa K, Mohile SG, et al. Predicting chemotherapy toxicity
in older adults with cancer: a prospective multicenter study. J Clin Oncol. 2011;29:3457-3465.
Mor V, Wilcox V, Rakowski W, et al. Functional transitions among the
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
e551
62. Blanc M, Dialla O, Manckoundia P, et al. Influence of the geriatric oncology consultation on the fnal therapeutic decision in elderly subjects
with cancer: analysis of 191 patients. J Nutr Health Aging. 2014;18:76-82.
63. Rouge-Bugat ME, Gerard S, Balardy L, et al. Impact of an oncogeriatric
consulting team on therapeutic decision-making. J Nutr Health Aging.
2013;17:473-478.
64. Deschodt M, Flamaing J, Haentjens P, et al. Impact of geriatric consultation teams on clinical outcome in acute hospitals: a systematic review
and meta-analysis. BMC Med. 2013;11:48.
65. Horgan AM, Leighl NB, Coate L, et al. Impact and feasibility of a comprehensive geriatric assessment in the oncology setting: a pilot study.
Am J Clin Oncol. 2012;35:322-328.
66. Chabi P, Magne N, Breton S, et al. Influence of geriatric consultation
with comprehensive geriatric assessment on fnal therapeutic decision
in elderly cancer patients. Crit Rev Oncol Hematol. 2011;79:302-307.
67. Shayne M, Crawford J, Dale DC, et al. Predictors of reduced dose intensity in patients with early-stage breast cancer receiving adjuvant chemotherapy. Breast Cancer Res Treat. 2006;100:255-262.
68. Shayne M, Culakova E, Poniewierski MS, et al. Dose intensity and hematologic toxicity in older cancer patients receiving systemic chemotherapy. Cancer. 2007;110:1611-1620.
69. Garja A, Klepin HD, Feng T, et al. Predictors of chemotherapy dose
reduction at frst cycle in patients age 65 years and older. J Geriatr Oncol.
2015 Feb 6.
70. Lichtman SM, Wildiers H, Launay-Vacher V, et al. International Society
of Geriatric Oncology (SIOG) recommendations for the adjustment of
e552
71.
72.
73.
74.
75.
76.
77.
SPEAKERS
Barbara L. Andersen, PhD
The Ohio State University
Columbus, OH
Guido Cavaletti, MD
University of Milan-Bicocca
Monza, Italy
Paul B. Jacobsen, PhD
Moftt Cancer Center
Tampa, FL
tled issue are still present in this feld. First, the precise clinical
manifestations and their incidence and severity are not always
properly assessed, and the several tools used so far have very
rarely been validated for this specifc use. Second, the pathogenesis of the clinical signs of PNS damage is unknown for most
chemotherapy-related conditions. Third, the available pharmacologic and nonpharmacologic strategies designed to limit the
incidence and severity of chemotherapy-induced neurotoxicity
are not particularly effective in most instances. Finally, the longterm course and reversibility of symptoms and signs have very
rarely been investigated so far.4-9
Overall, the importance of chemotherapy-related toxicity
caused by PNS damage is underestimated. This aspect is
becoming increasingly important, and the National Comprehensive Cancer Network has recently expanded its survivorship guidelines to include long-term chemotherapy-induced
peripheral neurotoxicity (CIPN).
From the Experimental Neurology Unit and Milan Center for Neuroscience, Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Guido Cavaletti, MD, Department of Surgery and Translational Medicine, University of Milano-Bicocca, via Cadore 48, 20900 Monza (MB), Italy;
email: guido.cavaletti@unimib.it.
2015 by American Society of Clinical Oncology.
e553
The PNS is a common target for the neurotoxicity of several conventional chemotherapy drugs. This is mostly because of the less effcient bloodnervous system barrier in the
PNS, namely at the dorsal root ganglia (DRG) level, which
allows easy access to nerve fbers and neurons. However, the
most recent cancer-targeted drugs also are not completely
safe.6 The peripheral neurotoxicity of both conventional and
targeted compounds will be treated separately.
In most cases, CIPN ensuing after conventional treatments
consists of dose-dependent, predominantly sensory, lengthdependent neuropathies/neuronopathies. More rarely, motor, autonomic, or cranial nerve involvement also can be
observed. The conventional drugs associated with CIPN are
platinum compounds, taxanes, vinca alkaloids, epothilones,
proteasome inhibitors, and thalidomide.
Patients with CIPN can experience negative (i.e., impairment in touch, pin and vibration perception, sensory ataxia
with imbalance and falls) as well as positive (i.e., paresthesias/
dysesthesias, neuropathic pain) symptoms. All of these
symptoms generally develop at limb extremities and then
show a distal-to-proximal progression. The frequency, severity, and time course of CIPN can be very variable. In patients
with CIPN who are treated with platinum drugs, a peculiar
temporal pattern can be observed, which is represented by
symptoms that worsen months after chemotherapy suspensionthe so-called coasting phenomenon. As it will be discussed later in more detail, it is now clear that CIPN-related
signs and symptoms may be long lasting or even permanent.
The typical clinical features of CIPN have been extensively
reviewed (Table 1).10-13
The epidemiology of CIPN is still unclear, and one of the
main reasons for this uncertainty is the lack of a gold standard in its assessment.5 In fact, the reliability and reproducibility of a CIPN assessment in patients with cancer are still
unmet clinical and scientifc needs. In the past, several methodological issues were not clearly recognized, and different
nonvalidated scales were used, which led to conflicting re-
KEY POINTS
Anticancer chemotherapy can permanently damage both
the central and the peripheral nervous systems, but the
mechanism(s) of this toxicity is largely unknown.
The recognition of chemotherapy-induced peripheral
neurotoxicity is simple, if education is provided and a high
level of attention is maintained.
Chemotherapy-induced peripheral neurotoxicity is probably
an underestimated clinical problem in cancer survivors.
Patients and health-care providers perceptions of the
severity of chemotherapy-induced peripheral neurotoxicity
may be very different, as demonstrated by recent studies
focused on this highly relevant issue.
No effective treatments are available for alleviating
persistent symptoms of chemotherapy-induced peripheral
neurotoxicity.
e554
TABLE 1. Typical Clinical Features of Chemotherapy-Induced Peripheral Neurotoxicity Associated with Standard
Chemotherapeutic Agents
Drug
Typical Symptoms/Signs
Platinum
Cisplatin
Carboplatin
Oxalipatin
Acute
Cold-induced transient paresthesias in mouth, throat, and limb extremities
Cramps/muscle spasm in throat muscle, jaw spasm
Chronic
Very similar to cisplatin
Bortezomib
Reduction/loss of DTR
Mild to moderate, distal, symmetric loss of all sensory modalities occurs. Small myelinated and unmyelinated
bers are markedly affected, leading to severe neuropathic pain.
Mild distal weakness in lower limbs is possible
Reduction/loss of DTR
Myalgia syndrome is frequent (as an atypical neuropathic pain?)
Distal, symmetric, upper and lower limb impairment/loss of all sensory modalities
Gait unsteadiness is possible because of proprioceptive loss
Distal, symmetric weakness in lower limbs is generally mild
Signs and symptoms are similar to taxanes, but neuropathic pain is less frequent, and recovery is
reportedly faster
Reduction/loss of DTR
Neuropathic pain/paresthesia at limb extremities is relatively frequent
Distal, symmetric, upper and lower limb impairment/loss of all sensory modalities
Distal, symmetric weakness in lower limbs progressing to foot drop
Autonomic symptoms (eg, orthostatic hypotension, constipation) may be severe
Thalidomide
Reduction/loss of DTR
Relatively frequent neuropathic pain at limb extremities
Mild to moderate, distal, symmetric loss of all sensory modalities
Weakness is rare
neurotrophins, caused by either activation of the mitochondrialbased apoptotic pathway or inhibition of the transcription of
factors necessary for neuron survival, also have been reported.26
Recently, increased tubulin polymeration has been demonstrated in cultured DRG neurons and in animal models.27,28
Despite the evident neurotoxic effects of thalidomide,29 no
convincing pathogenetic explanation for thalidomide neurotoxicity has been provided, and its more recent and highly
active derivatives lenalidomide and pomalidomide are defnitely less neurotoxic.30
At the moment, no effective preventive or curative strategy is available for the treatment of CIPN, as documented
by a systematic Cochrane review of platinum drugs.31 A
focused American Society for Clinical Oncology (ASCO)
expert panel extended this review substantially to the
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e555
autoimmune cascade that results from indiscriminate dysregulation of regulatory T cells or from a molecular mimicry.
In addition to the immune-mediated effect on the PNS,
clinical pictures compatible with classical CIPN also have
been described with cancer-targeted drugs. The administration of brentuximab vedotin can be associated with a dosedependent peripheral neuropathy that can limit prolonged
administration of the drug. In phase I studies, cumulative
dose-related peripheral neuropathy, probably associated with
unconjugated microtubule inhibitor monomethyl auristatin E
(i.e., the active part of the molecule acting as the classical chemotherapy drugs) was clinically relevant; 37% of patients showed
persistent symptoms, which led to drug discontinuation in 25%
of patients.35 In another study, 73% of patients treated with
brentuximab vedotin developed peripheral neuropathy, mostly
mild to moderate, and similar data were replicated in phase II
studies.36 However, dramatic motor neuropathy also has been
associated with brentuximab vedotin use.37
It can be concluded that careful monitoring that is based on
a formal neurologic assessment of the possible PNS toxicity
of all of these new drugs is mandatory to ascertain in prospective clinical trials their real toxicity profles, alone or in combination treatments.
Alemtuzumab
None
Brentuximab vedotin
Carlzomib
Lenalidomide or thalidomide
Ibritumomab
Imatinib
Cytarabine
Ipilipumab
Carboplatin
Guillain-Barr syndrome
Lapatinib
Taxanes, vinorelbine
Regorafenib
Oxaliplatin
Rituximab
Guillain-Barr syndrome
None
Guillain-Barr syndrome
Sorafenib
Vemurafenib
Vorinostat
Abbreviations: CVP, cyclophosphamide, vincristine, prednisone; COP, cyclophosphamide, vincristine, prednisone; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; ProMACE CytaBOM,
cyclophosphamide, doxorubicin, etoposide cytozar, bleomycin, vincristine, methotrexate, prednisone.
e556
tween CIPN and QoL. Because at least two of the three negative
studies had substantial methodological flaws, the overall conclusion drawn from the review is that CIPN is very likely to be negatively associated with QoL in cancer survivors.
In a study that was not included in the previous review by
Mols et al, Tofthagen et al investigated a cohort of patients
treated with oxaliplatin up to 7 years after treatment and observed that 89% of them reported at least one symptom of
neuropathy;45,46 among these patients, 24% had diffculties in
driving and 60% in exercising. All of the subscales of the
short-form (SF)-36 were signifcantly associated with the
presence and severity of CIPN, but no objective assessment
of CIPN presence was included in the study design.
Another study was reported in 2014 by Ezendam et al,47
who investigated a cohort of patients with ovarian cancer by
using two EORTC QoL scales; the results demonstrated that
CIPN symptoms were signifcantly associated with QoL impairment. However, because a quarter of the women who did
not receive neurotoxic chemotherapy were affected by peripheral neuropathy symptoms, this result, in the absence of
any objective evaluation, raises some concern about the validity of the selected assessment tool to really detect CIPN.
A specifc and underestimated aspect of long-term CIPN is
the possibility that neurologic impairment might cause an increased propensity to fall. This concern was raised originally
by Tofthagen et al in 2012 in a small series of patients with
cancer and CIPN; 20% of them had fallen recently.48 An increased incidence of falls had already been reported in patients with cancer and in older populations.49 Gewandter et al
investigated a cohort of 471 patients with CIPN; 27% of participants reported functional impairment (e.g., diffculty in
shopping or in doing common tasks necessary to live in their
home independently), whereas 12% had a fall in the 3-month
period preceding enrollment on the study.50 When these results were analyzed in relation to the type of CIPN, motor
neuropathy was signifcantly associated with falls, which suggests that, in the study cohort, taxanes used as breast cancer
treatment were responsible for these events.50
e557
CONCLUSION
The cure of cancer frequently is based on complex, hazardous, and toxic treatments, which are accepted because of
their potential life-saving effects. However, cancer survivors
deserve and ask for the best possible quality of survival after
cancer treatment, particularly over the long term. Unfortunately, in several instances, this need is still unmet. Among
the reasons for this situation, the insuffcient knowledge of
the pathogenesis of cancer treatmentrelated neurotoxicity
is defnitely one of the most important issues.
To achieve a better understanding of chemotherapyinduced neurotoxicity, accurate preclinical studies might
provide very useful suggestions, but the translation of their
results into the clinical setting is sometimes diffcult. On the
clinical side, a very important contribution to better knowledge of cancer treatmentrelated neurotoxicity could come
from a more homogeneous, reliable, and systematic collection of the clinical data of treated patients. This will highlight
similarities and differences between treatments to identify
early predictors and to clarify individual susceptibilities to
neurotoxicity that might represent invaluable clues to drive
research into the proper direction and, eventually, provide
reliable guidelines to manage CIPN.
The fnal aim of these investigations is to offer patients
with cancer the possibility to be treated with affordable
neurotoxicity or, at least, to provide them effective treatments. To this aim, a virtuous alliance among patients and
treating physicians is needed. In fact, physicians should be
trained not only at the use of treatments but also at the
recognition and proper assessment of the frst signs of
neurotoxicity, and patients should be made aware of it to
report early symptoms with the common goal of preventing irreversible damage.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Guido
Cavaletti, Shire Pharmaceuticals. Paola Marmiroli, Shire (I), Acetylon Pharmaceuticals (I), Methys (I). Speakers Bureau: None. Research Funding: Paola
Marmiroli, Merck Serono (I). Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses:
Guido Cavaletti, Biogen Idec, Merck Serono. Paola Marmiroli, Kedrion (I). Other Relationships: None.
References
1. Howlader N, Noone AM, Krapcho M, et al (eds). SEER Cancer Statistics
Review, 1975-2010. http://seer.cancer.gov/csr/1975_2010/. Published
April 2013. Updated June 13, 2013. Accessed March 6, 2015.
2. Pachman DR, Barton DL, Swetz KM, et al. Troublesome symptoms in
cancer survivors: fatigue, insomnia, neuropathy, and pain. J Clin Oncol.
2012;30:3687-3696.
3. Bennion AE, Molassiotis A. Qualitative research into the symptom experiences of adult cancer patients after treatments: a systematic review
and meta-synthesis. Support Care Cancer. 2013;21:9-25.
4. Cavaletti G, Cornblath DR, Merkies IS, et al. The chemotherapyinduced peripheral neuropathy outcome measures standardization
study: from consensus to the frst validity and reliability fndings. Ann
Oncol. 2013;24:454-462.
5. Cavaletti G, Frigeni B, Lanzani F, et al. Chemotherapy-induced periph-
e558
6.
7.
8.
9.
10.
eral neurotoxicity assessment: a critical revision of the currently available tools. Eur J Cancer. 2010;46:479-494.
Grisold W, Cavaletti G, Windebank AJ. Peripheral neuropathies from
chemotherapeutics and targeted agents: diagnosis, treatment, and prevention. Neuro Oncol. 2012;14 (suppl 4):iv45-54.
Ahles TA. Cognitive changes associated with cancer and cancer treatment. Semin Oncol Nurs. 2013;29:229-231.
Mandelblatt JS, Hurria A, McDonald BC, et al. Cognitive effects of cancer and its treatments at the intersection of aging: what do we know;
what do we need to know? Semin Oncol. 2013;40:709-725.
Jim H, Rodin G, Ahles TA. Long-term effects of chemo on the cognitive function of cancer patients. Oncology (Williston Park). 2012;26:1012, 1014, 1042.
Miltenburg NC, Boogerd W. Chemotherapy-induced neuropathy: a
comprehensive survey. Cancer Treat Rev. 2014;40:872-882.
11. Argyriou AA, Bruna J, Marmiroli P, et al. Chemotherapy-induced peripheral neurotoxicity (CIPN): an update. Crit Rev Oncol Hematol.
2012;82:51-77.
12. Cavaletti G, Alberti P, Marmiroli P. Chemotherapy-induced peripheral
neurotoxicity in the era of pharmacogenomics. Lancet Oncol. 2011;12:
1151-1161.
13. Cavaletti G, Marmiroli P. Chemotherapy-induced peripheral neurotoxicity. Nat Rev Neurol. 2010;6:657-666.
14. Alberti P, Rossi E, Cornblath DR, et al. Physician-assessed and patientreported outcome measures in chemotherapy-induced sensory peripheral
neurotoxicity: two sides of the same coin. Ann Oncol. 2014;25:257-264.
15. Gill JS, Windebank AJ. Cisplatin-induced apoptosis in rat dorsal root
ganglion neurons is associated with attempted entry into the cell cycle.
J Clin Invest. 1998;101:2842-2850.
16. Sprowl JA, Ciarimboli G, Lancaster CS, et al. Oxaliplatin-induced neurotoxicity is dependent on the organic cation transporter OCT2. Proc
Natl Acad Sci U S A. 2013;110:11199-11204.
17. Cavaletti G, Ceresa C, Nicolini G, et al. Neuronal drug transporters in
platinum drugs-induced peripheral neurotoxicity. Anticancer Res. 2014;
34:483-486.
18. Park SB, Krishnan AV, Lin CS, et al. Mechanisms underlying
chemotherapy-induced neurotoxicity and the potential for neuroprotective strategies. Curr Med Chem. 2008;15:3081-3094.
19. Persohn E, Canta A, Schoepfer S, et al. Morphological and morphometric analysis of paclitaxel and docetaxel-induced peripheral neuropathy
in rats. Eur J Cancer. 2005;41:1460-1466.
20. Peters CM, Jimenez-Andrade JM, Jonas BM, et al. Intravenous paclitaxel administration in the rat induces a peripheral sensory neuropathy
characterized by macrophage infltration and injury to sensory neurons
and their supporting cells. Exp Neurol. 2007;203:42-54.
21. Jin HW, Flatters SJ, Xiao WH, et al. Prevention of paclitaxel-evoked
painful peripheral neuropathy by acetyl-l-carnitine: effects on axonal
mitochondria, sensory nerve fber terminal arbors, and cutaneous Langerhans cells. Exp Neurol. 2008;210:229-237.
22. Topp KS, Tanner KD, Levine JD. Damage to the cytoskeleton of large diameter sensory neurons and myelinated axons in vincristine-induced painful peripheral neuropathy in the rat. J Comp Neurol. 2000;424:563-576.
23. Carozzi VA, Renn CL, Bardini M, et al. Bortezomib-induced painful
peripheral neuropathy: an electrophysiological, behavioral, morphological and mechanistic study in the mouse. PLoS One. 2013;8:e72995.
24. Meregalli C, Canta A, Carozzi VA, et al. Bortezomib-induced painful
neuropathy in rats: a behavioral, neurophysiological and pathological
study in rats. Eur J Pain. 2010;14:343-350.
25. Casafont I, Berciano MT, Lafarga M. Bortezomib induces the formation
of nuclear poly(A) RNA granules enriched in Sam68 and PABPN1 in
sensory ganglia neurons. Neurotox Res. 2010:17:167-178.
26. Montagut C, Rovira A, Mellado B, et al. Preclinical and clinical development of the proteasome inhibitor bortezomib in cancer treatment.
Drugs Today (Barc). 2005;41:299-315.
27. Poruchynsky MS, Sackett DL, Robey RW, et al. Proteasome inhibitors increase tubulin polymerization and stabilization in tissue culture cells: a possible mechanism contributing to peripheral
neuropathy and cellular toxicity following proteasome inhibition.
Cell Cycle. 2008;7:940-949.
28. Meregalli C, Chiorazzi A, Carozzi VA, et al. Evaluation of tubulin polymerization and chronic inhibition of proteasome as citotoxicity
mechanisms in bortezomib-induced peripheral neuropathy. Cell Cycle.
2014;13:612-621.
29. Cavaletti G, Beronio A, Reni L, et al. Thalidomide sensory neurotoxicity: a
clinical and neurophysiologic study. Neurology. 2004;62:2291-2293.
e559
with peripheral neuropathy and high risk of fall: current evidence and implications for future research. Oncol Nurs Forum. 2012;39:E416-E424.
49. Mohile SG, Xian Y, Dale W, et al. Association of a cancer diagnosis with
vulnerability and frailty in older Medicare benefciaries. J Natl Cancer
Inst. 2009;101:1206-1215.
50. Gewandter JS, Fan L, Magnuson A, et al. Falls and functional impairments in cancer survivors with chemotherapy-induced peripheral neuropathy (CIPN): a University of Rochester CCOP study. Support Care
Cancer. 2013;21:2059-2066.
51. Armes J, Crowe M, Colbourne L, et al. Patients supportive care needs
e560
From the Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; Moftt Cancer Center, Tampa, FL; Department of Psychology, The Ohio State University, Columbus, OH.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Ann H. Partridge, MD, MPH, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215; email: ahpartridge@partners.org.
2015 by American Society of Clinical Oncology.
188
KEY POINTS
Standardizing survivorship care poses unique challenges.
Increased awareness and prioritization of survivors issues
is necessary.
A growing array of recommendations and tools are
becoming available to improve survivorship care.
Fatigue is a common effect that should be screened for
and managed.
Routine anxiety and depression screening in cancer
survivors should lead to improved psychosocial outcomes.
189
General Recommendations
Screening. All patients should be screened for psychologic
symptoms at their initial visit, at appropriate intervals, and as
clinically indicated, especially with changes in disease status
(e.g., post-treatment, recurrence, progression) and when there
is a transition to palliative and end-of-life care. Screening should
be done using valid and reliable measures of anxiety or depressive symptoms that feature reportable scores (dimensions) that
are clinically meaningful (established cutoffs). A phased screening and assessment that does not rely simply on a symptom
count from the screening measure is recommended. Consider
the need to use culturally sensitive measures. Tailor further assessment or treatment for those with learning disabilities or cognitive impairments.
Identifcation or determination of the presence or absence of pertinent history or risk factors is important for
interpretation of the screen and decision making for subsequent follow-up assessment. Other concerns that may
become evident with screening, such as risk of harm to self
and/or others, severe anxiety or agitation, or the presence
of psychosis or confusion (delirium) requires referral to a
psychiatrist, psychologist, physician, or equivalently
trained professional for emergency evaluation. Facilitate a
safe environment and one-to-one observation, and initiate appropriate harm-reduction interventions to reduce
risk of harm to self and/or others.
Follow-up assessment. When moderate-to-severe or severe
symptomatology is detected through screening, individuals
should have a diagnostic assessment to identify the nature
and extent of the symptoms and the presence or absence of
anxiety disorder(s) or mood disorders. The clinical team
must decide when referral to a psychiatrist, psychologist, or
equivalently trained professional is needed for diagnostic assessment. The clinical team should share responsibility for
assessments, designating those who are expected to conduct
assessments as per scope of practice. If a patient needs a referral for the treatment of anxiety or depression, discuss with
the patient the reason(s) for and anticipated benefts from the
referral. Further, the clinical team should subsequently determine the patients compliance with the referral.
Treatment. Medical (e.g., unrelieved symptoms such as pain
and fatigue, or delirium brought on by infection or electrolyte imbalance) or substance abuse causes of anxiety or
191
often necessary with benzodiazepines, particularly with potent or rapidly eliminated medications.
If compliance is poor, assess and construct a plan to circumvent obstacles to compliance, or discuss alternative interventions that present fewer obstacles. After 8 weeks of treatment, if
symptom reduction and satisfaction with treatment are poor despite good compliance, alter the treatment course.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Paul B.
Jacobsen, Onyx, Philips Healthcare. Speakers Bureau: None. Research Funding: Paul B. Jacobsen, On Q Health, Pzer. Patents, Royalties, or Other
Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: Paul B. Jacobsen, Onyx. Other Relationships: None.
References
1. DeSantis CE, Lin CC, Mariotto AB, et al. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin. 2014;64:252-271.
2. Institute of Medicine and National Research Council of the National Academies. From Cancer Patient to Cancer Survivor: Lost in Transition, in Hewitt M,
Greenfeld S, Stovall E (eds). Washington, DC: The National Academies; 2006.
3. Rechis R, Beckford EB, Arvey SR, et al. The essential elements of survivorship
care: a LIVESTRONG brief. Austin, TX. Lance Armstrong Foundation (now
the Livestrong Foundation); 2011. http://www.livestrong.org/pdfs/
3-0/EssentialElementsBrief. Accessed February 22, 2015.
4. Salz T, Oeffnger KC, McCabe MS, et al. Survivorship care plans in research and practice. CA Cancer J Clin. 2012;62:101-117.
5. Salz T, McCabe MS, Onstad EE, et al. Survivorship care plans: is there
buy-in from community oncology providers? Cancer. 2014;120:722730.
6. Coyle D, Grunfeld E, Coyle K, et al. Cost effectiveness of a survivorship
care plan for breast cancer survivors. J Oncol Pract. 2014;10:e86-e92.
7. Henry NL, Hayes DF, Ramsey SD, et al. Promoting quality and
evidence-based care in early-stage breast cancer follow-up. J Natl Cancer Inst. 2014;106:dju034.
8. Earle CC, Ganz PA. Cancer survivorship care: dont let the perfect be the
enemy of the good. J Clin Oncol. 2012;30:3764-3768.
9. McCabe MS, Partridge AH, Grunfeld E, et al. Risk-based health care, the
cancer survivor, the oncologist, and the primary care physician. Semin
Oncol. 2013;40:804-812.
10. McCabe MS, Bhatia S, Oeffnger KC, et al. American Society of Clinical
Oncology statement: achieving high-quality cancer survivorship care.
J Clin Oncol. 2013;31:631-640.
11. Reilly CM, Bruner DW, Mitchell SA, et al. A literature synthesis of
symptom prevalence and severity in persons receiving active cancer
treatment. Support Care Cancer. 2013;21:1525-1550.
12. Bower JE, Ganz PA, Desmond KA, et al. Fatigue in breast cancer survivors: occurrence, correlates and impact on quality of life. J Clin Oncol.
2000;18:743-753.
13. Bower JE, Bak K, Berger A, et al. Screening, assessment, and management of fatigue in adult survivors of cancer: an American Society of
Clinical Oncology clinical practice guideline adaptation. J Clin Oncol.
2014;32:1840-1850.
14. Howell D, Keller-Olaman S, Oliver TK, et al. A pan-Canadian practice
guideline and algorithm: screening, assessment, and supportive care of
adults with cancer-related fatigue. Curr Oncol. 2013;20:e233-e246.
15. Mitchell SA, Beck SL, Hood LE, et al. Putting evidence into practice:
evidence-based interventions for fatigue during and following cancer
and its treatment. Clin J Oncol Nurs. 2007;11:99-113.
16. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Cancer-Related Fatigue (version 2. 2015). http://www.
nccn.org/professionals/physician_gls/pdf/fatigue.pdf. Accessed March 21,
2015.
17. National Comprehensive Cancer Network. NCCN Clinical Practice Guide-
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
193
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
194
52. Stanton AL. Psychosocial concerns and interventions for cancer survivors. J Clin Oncol. 2006;24:5132-5137.
53. Andersen BL, Yang HC, Farrar WB, et al. Psychologic intervention improves survival for breast cancer patients: a randomized clinical trial.
Cancer. 2008;113:3450-3458.
54. Andersen BL, Thornton LM, Shapiro CL, et al. Biobehavioral, immune,
and health benefts following recurrence for psychological intervention
participants. Clin Cancer Res. 2010;16:3270-3278.
55. Olfson M, Marcus SC, Druss B, et al. National trends in the outpatient
treatment of depression. JAMA. 2002;287:203-209.
56. Rapaport MH, Clary C, Fayyad R, et al. Quality-of-life impairment in
depressive and anxiety disorders. Am J Psychiatry. 2005;162:1171-1178.
57. Kleiboer A, Bennett F, Hodges L, et al. The problems reported by cancer
patients with major depression. Psychooncology. 2011;20:62-68.
58. Mystakidou K, Tsilika E, Parpa E, et al. Assessment of anxiety and depression in advanced cancer patients and their relationship with quality
of life. Qual Life Res. 2005;14:1825-1833.
59. Sadler IJ, Jacobsen PB, Booth-Jones M, et al. Preliminary evaluation of a
clinical syndrome approach to assessing cancer-related fatigue. J Pain
Symptom Manage. 2002;23:406-416.
60. Smith EM, Gomm SA, Dickens CM. Assessing the independent contribution to quality of life from anxiety and depression in patients with
advanced cancer. Palliat Med. 2003;17:509-513.
61. Carver CS, Pozo C, Harris SD, et al. How coping mediates the effect of
optimism on distress: a study of women with early stage breast cancer. J
Pers Soc Psychol. 1993;65:375-390.
62. Satin JR, Linden W, Phillips MJ. Depression as a predictor of disease
progression and mortality in cancer patients: a meta-analysis. Cancer.
2009;115:5349-5361.
63. Beard CJ, Travis LB, Chen MH, et al. Outcomes in stage I testicular seminoma: a population-based study of 9193 patients. Cancer. 2013;119:
2771-2777.
64. Schairer C, Brown LM, Chen BE, et al. Suicide after breast cancer: an
international population-based study of 723,810 women. J Natl Cancer
Inst. 2006;98:1416-1419.
65. Mitchell AJ, Ferguson DW, Gill J, et al. Depression and anxiety in
long-term cancer survivors compared with spouses and healthy controls: a systematic review and meta-analysis. Lancet Oncol. 2013;14:
721-732.
66. Teunissen SC, de Graeff A, Voest EE, et al. Are anxiety and depressed
mood related to physical symptom burden? A study in hospitalized advanced cancer patients. Palliat Med. 2007;21:341-346.
67. Aass N, Fossa SD, Dahl AA, et al. Prevalence of anxiety and depression
in cancer patients seen at the Norwegian Radium Hospital. Eur J Cancer.
1997;33:1597-1604.
68. Ashing-Giwa KT, Padilla G, Tejero J, et al. Understanding the breast
cancer experience of women: a qualitative study of African American,
Asian American, Latina and Caucasian cancer survivors. Psychooncology. 2004;13:408-428.
69. Booth K, Beaver K, Kitchener H, et al. Womens experiences of information, psychological distress and worry after treatment for gynaecological cancer. Patient Educ Couns. 2005;56:225-232.
70. Miller GE, Chen E, Zhou ES. If it goes up, must it come down? Chronic
stress and the hypothalamic-pituitary-adrenocortical axis in humans.
Psychol Bull. 2007;133:25-45.
71. Chida Y, Hamer M, Wardle J, et al. Do stress-related psychosocial factors contribute to cancer incidence and survival? Nat Clin Pract Oncol.
2008;5:466-475.
SPEAKERS
Catherine H. Van Poznak, MD
University of Michigan
Ann Arbor, MI
Leslie R. Schover, PhD
The University of Texas MD Anderson Cancer Center
Houston, TX
LESLIE R. SCHOVER
n 1998 I spoke about sexuality for men with prostate cancer and their partners at a large symposium at the University of Michigan. Only about 5 minutes of my 25-minute talk
was devoted to sexual function and androgen deprivation
therapy. I acknowledged that most men noticed a decrease in
their desire for sex, had diffculty getting and keeping erections, and required more effort to reach an orgasm. However,
I pointed out that as many as 20% of men had satisfying sex
with a partner at times, although it took more mental and
physical stimulation to get aroused and have an orgasm. Men
with erection problems also might still enjoy sex enough to
get medical or surgical treatment to improve their erections.
The next day, a woman told me how important my presentation was to her and her husband. During his 3 years on hormone therapy, they never had sex. His oncologist said it
would not be possible. My talk inspired them to go back to
the hotel and try. The result was a very satisfying session of
lovemaking that included intercourse with a frm erection
and orgasms for both partners.
Such instant cures have not been common during my career, but this incident highlights the importance of providing
men and their partners more optimistic, though accurate, expectations about sexuality during hormone therapy. Our culture tends to believe that hormones have absolute power to
control sexual desire and function instead of seeing them as
From the Department of Behavioral Science, The University of Texas MD Anderson Cancer Center, Houston, TX.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Leslie R. Schover, PhD, Department of Behavioral Science, The University of Texas MD Anderson Cancer Center, Unit 1330, PO Box 301439, Houston, TX 77230-1439; email:
lschover@mdanderson.org.
2015 by American Society of Clinical Oncology.
e562
KEY POINTS
Men with prostate cancer have a high prevalence of sexual
dysfunction because of age, comorbidities, and damage
from denitive treatment for localized disease.
Androgen deprivation therapy adds to the problem because
of the loss of hormone stimulation in the brain and direct
damage to the erectile tissue.
Men who have good sexual function at the time of prostate
cancer diagnosis and who are in a sexual relationship with
a partner who wants to stay active are more bothered by
the sexual dysfunction.
Preventing and treating problems may involve counseling
the man or couple on how to achieve more intense sexual
stimulation, how to improve sexual communication and
avoid performance anxiety, and how to decide whether to
try a treatment to restore better erections.
Men who have sex with men have some special issues,
including a greater emphasis on the sensual qualities of
semen at ejaculation and sometimes a need for a more
rigid erection to allow anal penetration.
e563
LESLIE R. SCHOVER
the penis.32 After external beam radiotherapy or brachytherapy, semen volume is often greatly reduced. Since dihydrotestosterone in the prostate regulates semen production,
even men who begin ADT without prior defnitive treatment
of local prostate cancer usually have greatly reduced semen
volume. Men often believe that women can feel semen spurting into the vagina during intercourse. In fact, most women
do not miss having semen at ejaculation. Some women feel
more comfortable giving a man oral stimulation if he has dry
orgasms. In gay couples, however, loss of semen volume is
more often viewed as making sex less sensual and enjoyable.31 Other changes in orgasm after prostate cancer treatment may include less intensity and pleasure, pain at the
moment of orgasm, or after radical prostatectomy, leaking
urine during sexual arousal or orgasm.32 Putting a tension
ring at the base of the penis that occludes the urethra during
sex can be helpful when leaking urine bothers a man or his
partner.33
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: None.
Speakers Bureau: None. Research Funding: Leslie R. Schover, Fidia Farmaceutici SPA, Laclede, Inc. Patents, Royalties, or Other Intellectual Property:
None. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Walz J, Perrotte P, Suardi N, et al. Baseline prevalence of erectile dysfunction in a prostate cancer screening population. J Sex Med. 2008;5:
428-435.
2. Steinsvik EA, Axcrona K, Dahl AA, et al. Can sexual bother after radical
prostatectomy be predicted preoperatively? Findings from a prospective
national study of the relation between sexual function, activity, and
bother. BJU Int. 2012;109:1366-1374.
3. Resnick MJ, Barocas DA, Morgans AK, et al. Contemporary prevalence
of pretreatment urinary, sexual, hormonal, and bowel dysfunction: defning the population at risk for harms of prostate cancer treatment.
Cancer. 2014;120:1263-1271.
4. Johansson E, Steineck G, Holmberg L, et al. SPCG-4 Investigators.
Long-term quality-of-life outcomes after radical prostatectomy or
watchful waiting: the Scandinavian Prostate Cancer Group-4 randomised trial. Lancet Oncol. 2011;12:891-899.
5. Fujita K, Landis P, McNeil BK, et al. Serial prostate biopsies are associated with an increased risk of erectile dysfunction in men with
prostate cancer on active surveillance. J Urol. 2009;182:26642669.
6. Kyrdalen AE, Dahl AA, Hernes E, et al. A national study of adverse ef-
7.
8.
9.
10.
11.
fects and global quality of life among candidates for curative treatment
for prostate cancer. BJU Int. 2013;111:221-232.
Andriole GL, Crawford ED, Grubb RL 3rd, et al. PLCO Project Team.
Prostate cancer screening in the randomized Prostate, Lung, Colorectal,
and Ovarian Cancer Screening Trial: mortality results after 13 years of
follow-up. J Natl Cancer Inst. 2012;104:125-132.
Taylor KL, Luta G, Miller AB, et al. Long-term disease-specifc functioning among prostate cancer survivors and noncancer controls in the
Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. J Clin
Oncol. 2012;30:2768-2775.
Heemers HV, Mohler JL. Revisiting nomenclature for the description of
prostate cancer androgen-responsiveness. Am J Clin Exp Urol. 2014;2:
121-126.
Pagliarulo V, Bracarda S, Eisenberger MA, et al. Contemporary role
of androgen deprivation therapy for prostate cancer. Eur Urol. 2012;
61:11-25.
Sammon JD, Abdollah F, Reznor G, et al. Patterns of declining use
and the adverse effect of primary androgen deprivation on all-cause
mortality in elderly men with prostate cancer. Eur Urol. Epub 2014
Oct 29.
e565
LESLIE R. SCHOVER
12. Potosky AL, Haque R, Cassidy-Bushrow AE, et al. Effectiveness of primary androgen-deprivation therapy for clinically localized prostate
cancer. J Clin Oncol. 2014;32:1324-1330.
13. Elliott S, Latini DM, Walker LM, et al. Androgen deprivation therapy
for prostate cancer: recommendations to improve patient and partner
quality of life. J Sex Med. 2010;7:2996-3010.
14. Denham JW, Wilcox C, Joseph D, et al. Quality of life in men with locally
advanced prostate cancer treated with leuprorelin and radiotherapy
with or without zoledronic acid (TROG 03.04 RADAR): secondary endpoints from a randomised phase 3 factorial trial. Lancet Oncol. 2012;13:
1260-1270.
15. Son CH, Chennupati SK, Kunnavakkam R, et al. The impact of hormonal therapy on sexual quality of life in men receiving intensity modulated radiation therapy for prostate cancer. Pract Radiat Oncol. Epub
2014 Dec 6.
16. Benedict C, Traeger L, Dahn JR, et al. Sexual bother in men with advanced prostate cancer undergoing androgen deprivation therapy. J Sex
Med. 2014;11:2571-2580.
17. Schover LR, Fouladi RT, Warneke CL, et al. Defning sexual outcomes
after treatment for localized prostate carcinoma. Cancer. 2002;95:17731785.
18. Sevilla C, Maliski SL, Kwan L, et al. Long-term quality of life in disadvantaged men with prostate cancer on androgen-deprivation therapy.
Prostate Cancer Prostatic Dis. 2012;15:237-243.
19. Mazzola CR, Deveci S, Heck M, et al. Androgen deprivation therapy
before radical prostatectomy is associated with poorer postoperative
erectile function outcomes. BJU Int. 2012;110:112-116.
20. Harden J, Sanda MG, Wei JT, et al. Survivorship after prostate cancer
treatment: spouses quality of life at 36 months. Oncol Nurs Forum.
2013;40:567-573.
21. Klotz L, Nabid A, Higano C, et al. Effect of dutasteride in men receiving
intermittent androgen ablation therapy: the AVIAS trial. Can Urol Assoc J. 2014;8:E789-E794.
22. Traish AM, Mulgaonkar A, Giordano N. The dark side of 5-reductase
inhibitors therapy: sexual dysfunction, high Gleason grade prostate
cancer and depression. Korean J Urol. 2014;55:367-379.
23. Klotz L. Intermittent versus continuous androgen deprivation therapy
in advanced prostate cancer. Curr Urol Rep. 2013;14:159-167.
24. Langenhuijsen JF, Badhauser D, Schaaf B, et al. Continuous vs. intermittent androgen deprivation therapy for metastatic prostate cancer.
Urol Oncol. 2013;31:549-556.
e566
25. Wibowo E, Wassersug RJ. The effect of estrogen on the sexual interest of
castrated males: implications to prostate cancer patients on androgendeprivation therapy. Crit Rev Oncol Hematol. 2013;87:224-238.
26. Ng E, Woo HH, Turner S, et al. The influence of testosterone suppression and recovery on sexual function in men with prostate cancer: observations from a prospective study in men undergoing intermittent
androgen suppression. J Urol. 2012;187:2162-2166.
27. Carani C, Bancroft J, Granata A, et al. Testosterone and erectile function, nocturnal penile tumescence and rigidity, and erectile response to
visual erotic stimuli in hypogonadal and eugonadal men. Psychoneuroendocrinology. 1992;17:647-654.
28. Schover LR, Canada AL, Yuan Y, et al. A randomized trial of Internetbased versus traditional sexual counseling for couples after localized
prostate cancer treatment. Cancer. 2012; 118:500-509.
29. Basal S, Wambi C, Acikel C, et al. Optimal strategy for penile rehabilitation after robot-assisted radical prostatectomy based on preoperative
erectile function. BJU Int. 2013;111:658-665.
30. Tal R, Valenzuela R, Aviv N, et al. Persistent erectile dysfunction following radical prostatectomy: the association between nerve-sparing status
and the prevalence and chronology of venous leak. J Sex Med. 2009;6:
2813-2819.
31. Dowsett GW, Lyons A, Duncan D, et al. Flexibility in mens sexual practices in response to iatrogenic erectile dysfunction after prostate cancer
treatment. Sex Med. 2014;2:115-120.
32. Frey AU, Snksen J, Fode M. Neglected side effects after radical prostatectomy: a systematic review. J Sex Med. 2014;11:374-385.
33. Mehta A, Deveci S, Mulhall JP. Effcacy of a penile variable tension loop
for improving climacturia after radical prostatectomy. BJU Int. 2013;
111:500-504.
34. Carmack Taylor CL, Demoor C, Smith MA, et al. Active for life after
cancer: a randomized trial examining a lifestyle physical activity program for prostate cancer patients. Psychooncology. 2006;15:847-862.
35. Jones LW, Hornsby WE, Freedland SJ, et al. Effects of nonlinear aerobic
training on erectile dysfunction and cardiovascular function following
radical prostatectomy for clinically localized prostate cancer. Eur Urol.
2014;65:852-855.
36. Cormie P, Newton RU, Taaffe DR, et al. Exercise maintains sexual activity in men undergoing androgen suppression for prostate cancer: a
randomized controlled trial. Prostate Cancer Prostatic Dis. 2013;16:170175.
From the Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI 5848.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Catherine Van Poznak, MD, Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, 1500 E Medical Center Dr., Ann Arbor, MI 48109;
email: cvanpoz@med.umich.edu.
2015 by American Society of Clinical Oncology.
e567
T Score
Normal
Osteopenia
Osteoporosis
Severe
BMD 2.5 SD or more below the young 2.5 and clinical
Osteoporosis
female adult mean in the presence
fragility fracture
of one or more fragility
fractures
Abbreviations: WHO, World Health Organization; DXA, dual energy x-ray absorptiometry; BMD,
bone mineral density; SD, standard deviation.
KEY POINTS
In managing bone health, the overarching goal is to reduce
the morbidity and mortality associated with fractures.
Low bone mass and increased risk for osteoporotic
fracture may be a comorbid condition in patients diagnosed
with breast cancer or prostate cancer.
Endocrine therapies used in the management of breast
cancer or prostate cancer may decrease bone mineral
density and increase the risk for fracture.
Guidelines for the management of osteoporosis can be
applied to those affected by breast cancer and prostate
cancer with consideration that the endocrine therapy be
considered a risk factor for secondary osteoporosis. Not all
medications that are FDA approved for the prevention and
treatment of osteoporosis may be appropriate for patients
with a history of breast cancer or prostate cancer.
With our aging population, it is expected that the number
of people affected by both osteoporosis and cancer will
increase, thereby heightening the need for future research
to dene optimal interventions to reduce the risk of
osteoporotic fractures.
e568
TABLE 2. Overview of Two Prominent Bone Health Screening and Treatment Guidelines5
Vitamin D Screening
USPSTF
NOF
Not specically addressed Women under the age of 50
Advises universal counseling
1,000 mg of calcium from all
on risks, nutrition, exercise,
sources daily
and behaviors
Osteoporosis BMD
Screening
Recommends screening in
women age 65 and
older and in younger
women with signicant
fracture risk
Monitoring
Evidence is insufcient to
assess the benet/
harm in men; men most
likely to benet from
screening have a 10-yr risk
for osteoporotic fracture
greater than a 65-year-old
white woman without
risk factors
Postmenopausal women and Clinical or asymptomatic hip
BMD 12 years after
men over the age of 50
or vertebral fracture
initiating therapy
with an adult age fracture
T score -2.5 in femoral neck,
& every 2 years
Postmenopausal woman and
total hip or lumbar spine by DXA
thereafter
men above age 5069 based Postmenopausal women and
on risk factor prole
men age 50 and older with
Women age 65 and older
low bone mass (-1.0 to -2.5)
Men age 70 and older
and a high-risk FRAX score (*)
approximately 30% to 50%.18 Current guidelines recommending the use of targeted antiestrogen therapy for earlystage HR breast cancer include those published by the
American Society of Clinical Oncology (ASCO).19 The
ASCO guideline supports the use of adjuvant tamoxifen in
premenopausal and perimenopausal women with HR
breast cancer. For women with HR early breast cancer who
are postmenopausal, the use of an aromatase inhibitor (AI) is
favored either as the sole adjuvant endocrine therapy or in
sequence with tamoxifen. The menopausal status of the patient, the drug used, and the duration of treatment all affect
how adjuvant breast cancer endocrine therapy will affect
bone and may influence treatment decisions.
Tamoxifen is a selective estrogen receptor modulator
(SERM) with both agonist and antagonist effects. In postmenopausal women, tamoxifen acts as a partial estrogen agonist on bone, stabilizing or even increasing bone mass. In a
randomized placebo-controlled study 20 mg tamoxifen administered daily increased the lumbar spine BMD by 0.61%
per year, whereas treatment with the placebo was associated
with a 1% decrease in BMD per year (p 0.001).14 With longer follow-up of these patients the sample size dwindled; at 5
years there was a trend for the tamoxifen-treated group to
have a higher BMD, but the difference was not signifcant
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e569
e571
TABLE 3. FDA-Approved Pharmacologic Therapies for the Prevention and/or Treatment of Osteoporosis*
Drug Class
Drug Name
Bisphosphonates Alendronate
Ibandronate
Risedronate
Monoclonal
Antibody
Treatment of postmenopausal
osteoporosis with high risk
for fracture. Treatment to
increase bone mass in
women at high risk for
fracture who are receiving
adjuvant AI for breast cancer
Hormonal
Raloxifene
Postmenopausal osteoporosis
with high risk for fracture
Concerns/Warnings
Treat or prevent postmenopausal Increase bone mass in osteoporosis Uncommon risks include hypocalcemia,
osteoporosis
osteonecrosis of the jaw, and atypical
fractures. Intravenous formulations
may cause acute phase reactions and
renal dysfunction
antiresorptive therapy or those with low risk of fracture. Interesting data generated from the Study of Osteoporotic
Fractures demonstrated that postmenopausal women with
normal BMD at baseline transition to osteoporosis at a
slower rate than postmenopausal women with severe osteopenia (T score -2.0 to -2.49).47 These data suggest that the
interval of monitoring BMD might be influenced by the baseline DXA result. However, the data do not lend themselves
directly to patients with breast cancer or prostate cancer receiving endocrine therapy.
Osteoporosis may be underdiagnosed.6 A SEER-Medicare
study of health care utilization of DXA in women over the age
of 65 with a history of nonmetastatic breast cancer revealed
that less than 10% of the study population underwent BMD
testing.48 Another SEER-Medicare study suggests that the
frequency of BMD screening was less than 20% in the year
2002.49 Screening of men for osteoporosis is also occurring at
a low rate. A SEER-Medicare study of men on ADT for nonmetastatic prostate cancer revealed fewer than 10% of patients with BMD measurements.50
BMD thresholds for pharmacologic intervention typically
include osteoporosis (T score -2.5) or low bone mass and
additional risk factors for fracture. Once the risk for a fragility fracture is suffciently high to warrant pharmacologic ine572
FUTURE DIRECTIONS
With our aging population, it is expected that the number of
people affected by osteoporosis and with cancer will increase.
The need to co-manage these diagnoses will continue into the
foreseeable future. Areas of osteoporosis research include
targeting sclerostin and thereby potentially inducing osteoanabolic activity, which may or may not be appropriate for
use in patients with a history of breast or prostate cancer. As
novel bone signaling pathways are targeted, the effect on cancer signaling must also be considered. Likewise, as novel anticancer therapies are developed, their effects on bone health
should be investigated.
There are insuffcient data to guide all possible clinically
relevant bone and endocrine situations faced in the medical
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: None.
Speakers Bureau: None. Research Funding: Catherine H. Van Poznak, Amgen (Inst), Novartis (Inst). Patents, Royalties, or Other Intellectual Property:
Catherine H. Van Poznak, UpToDate. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. American Cancer Society. http://www.cancer.org/cancer/breastcancer/
detailedguide/breast-cancer-key-statistics. Accessed February 04, 2015.
2. American Cancer Society http://www.cancer.org/cancer/prostatecancer/
detailedguide/prostate-cancer-key-statistics. Accessed February 04, 2015.
3. Cosman F, de Beur SJ, LeBoff MS, et al. Clinicians guide to prevention
and treatment of osteoporosis. Osteoporos Int. 2014;25:2359-2381.
4. National Institute of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases. http://www.niams.nih.gov/health_info/
bone/osteoporosis/overview.asp. Accessed February 04, 2015.
5. World Health Organization. http://www.iofbonehealth.org/sites/
default/fles/WHO_Technical_Report-2007.pdf. Accessed February
04, 2015.
6. Siris ES, Adler R, Bilezikian J, et al. The clinical diagnosis of osteoporosis: a position statement from the National Bone Health Alliance Working Group. Osteoporos Int. 2014;25:1439-1443.
7. Raisz LG. Clinical practice. Screening for osteoporosis N Engl J Med.
2005;353:164-171.
8. National Institutes of Health. http://www.nlm.nih.gov/medlineplus/
osteoporosis.html. Accessed February 04, 2015.
9. Centers for Disease Control and Prevention. http://www.cdc.gov/nchs/
fastats/osteoporosis.htm. Accessed February 04, 2015.
10. U.S. Department of Health and Human Services Agency for Healthcare
Research and Quality. http://effectivehealthcare.ahrq.gov/index.cfm/
search-for-guides-reviews-and-reports/?pageactiondisplayproduct&
productid1049&PCTOLAND. Accessed February 04, 2015.
11. National Osteoporosis Foundation. http://nof.org. Accessed February
04, 2015.
12. Riggs BL, Khosla S, Melton LJ 3rd. Sex steroids and the construction and
conservation of the adult skeleton. Endocr Rev. 2002;23:279-302.
13. Offce of the Surgeon General (US). Bone health and osteoporosis: a
14.
15.
16.
17.
18.
19.
20.
21.
22.
e573
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
e574
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
hormone ablation for prostate cancer: state of the art. BJU Int. 2007;
100:2-4.
Smith MR. Osteoporosis during androgen deprivation therapy for prostate cancer. Urology. 2002;60:79-86.
Shahinian VB, Kuo YF, Freeman JL, et al. Risk of fracture after androgen
deprivation for prostate cancer. N Engl J Med. 2005;352:154-164.
Smith MR, Boyce SP, Moyneur E, et al. Risk of clinical fracture after
gonadotropin-releasing hormone agonist therapy for prostate cancer.
J Urol. 2006;175:136-139.
U.S. Prevention Services Task Force. http://www.uspreventiveservices
taskforce.org/uspstopics.htm. Accessed February 04, 2015.
Qaseem A, Snow V, Shekelle P, et al. Screening for osteoporosis in men:
a clinical practice guideline from the American College of Physicians.
Ann Intern Med. 2008;148:680-684.
Coleman R, Body JJ, Aapro M, et al. Bone health in cancer patients:
ESMO Clinical Practice Guidelines. Ann Oncol. 2014;25 Suppl
3:iii124-iii137.
WHO Fracture Risk Assessment Tool. http://www.shef.ac.uk/FRAX/.
Accessed February 04, 2015.
Mann GB, Kang YC, Brand C, et al. Secondary causes of low bone mass
in patients with breast cancer: a need for greater vigilance. J Clin Oncol.
2009;27:3605-3610.
Gourlay ML, Fine JP, Preisser JS, et al. Bone-density testing interval
and transition to osteoporosis in older women. N Engl J Med. 2012;
366:225-233.
Earle CC, Burstein HJ, Winer EP, et al. Quality of non-breast cancer
health maintenance among elderly breast cancer survivors. J Clin Oncol.
2003;21:1447-1451.
Snyder CF, Frick KD, Kantsiper ME, et al. Prevention, screening, and
surveillance care for breast cancer survivors compared with controls:
changes from 1998 to 2002. J Clin Oncol. 2009;27:1054-1061.
Holt A, Khan MA, Gujja S, et al. Utilization of bone densitometry for
prediction and administration of bisphosphonates to prevent osteoporosis in patients with prostate cancer without bone metastases receiving
antiandrogen therapy. Cancer Manag Res. 2014;7:13-18.
Gralow JR, Biermann JS, Farooki A, et al. NCCN Task Force report:
bone health in cancer care. J Natl Compr Canc Netw. 2013;11 Suppl
3:S1-S50.
U.S. Preventive Services Task Force. Screening for osteoporosis: U.S.
Preventive Services Task Force recommendation statement. Ann Intern
Med. 2011;154:356-364.
Nelson HD, Haney EM, Dana T, et al. Screening for osteoporosis: an
update for the U.S. Preventive Services Task Force. Ann Intern Med.
2010;153:99-111.
Baum M, Budzar AU, Cuzick J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of
postmenopausal women with early breast cancer: frst results of the
ATAC randomised trial [published correction appears in Lancet. 2002;
360:1520]. Lancet. 2002;359:2131-2139.
ENDOCRINE THERAPY
Tamoxifen
Tamoxifen is a selective estrogen receptor modulator
(SERM), which has both partial estrogen agonist and antagonist activity. It competitively binds to the estrogen receptor
(ER), which leads to interrupted cell proliferation and ultimately cell death by causing cells to remain in the G1 phase of
the cell cycle.7 Tamoxifen mimics estrogen in certain tissues,
such as the bone and uterus, which has both benefcial and
adverse effects. For example, tamoxifen improves lipid profles and prevents bone demineralization, increasing bone
density. However, it also increases the risk of uterine cancer
by 2.5 times and the risk of a thromboembolic event by 1.9
times.8 In breast tissue, tamoxifen antagonizes the action of
estrogen, which both treats breast cancer and decreases the
risk of a new primary breast cancer. The U.S. Food and Drug
Administration (FDA) initially approved tamoxifen for the
treatment of metastatic breast cancer in 1977 and for adju-
Aromatase Inhibitors
Aromatase is an enzyme of the cytochrome P450 (CYP) family and the product of the CYP19 gene, which is the primary
enzyme used for the synthesis of estrogen in postmenopausal
women. It is found in peripheral tissues including muscle,
normal breast tissue, breast cancer tissue, fat, liver, and
brain.9 Aromatase inhibitors (AIs) decrease estrogen production by blocking aromatase and thus decrease peripheral
conversion of testosterone to estradiol and androstenedione
to estrone. Third generation AIs decrease estrogen production by over 95%, resulting in subphysiologic levels of
estrogen. AIs are only effective in postmenopausal women
because they are unable to overcome ovarian aromatase
activity.
From the Departments of Medicine and Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, and Department of Medicine, Weill Cornell Medical College.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Shari Goldfarb, MD, Breast and Imaging Center, Memorial Sloan Kettering Cancer Center, 300 East 66th St., New York, NY 10065; email: goldfars@mskcc.org.
2015 by American Society of Clinical Oncology.
e575
SHARI GOLDFARB
KEY POINTS
Breast cancer and its treatment, especially endocrine
therapy, can cause sexual dysfunction, which is often
multifactorial in nature with both a physical and mental
component.
Clinicians should discuss sexual health with all women with
breast cancer and survivors of the disease.
Women with breast cancer often experience premature
menopause, which causes greater intensity and duration of
symptoms than women undergoing natural menopause.
Hot ashes, vaginal dryness, urogenital atrophy,
dyspareunia, decreased libido, and changes in sexual
response have been shown to negatively affect quality of
life, compliance with medication, and overall outcome.
Treatment options for sexual dysfunction in women with
breast cancer depend on the etiology of the problem and
concomitant medical conditions. Some possible treatments
include: lubricants, moisturizers, counseling, sex therapy,
altering contributing medications, physical therapy for
pelvic oor disorders, and mechanical devices/vibrators.
Fulvestrant
Fulvestrant is a selective estrogen receptor degrader that was
FDA approved in April 2002 for the treatment of hormone
receptorpositive metastatic breast cancer. Fulvestrant
downregulates the ER by binding to it and inducing a change
in conformational shape that prevents ER dimerization, resulting in the loss of cellular ER.14,15
Lubricants
Lubricants are recommended to reduce friction and pain
during vaginal penetration for women with vaginal atrophy
and/or dryness. They are used on the woman and her partner
(or sexual device) as needed before penetration. There are
three different classes of lubricants: water-based, oil-based,
and silicone-based. Water-based lubricants decrease pain
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e577
SHARI GOLDFARB
Moisturizers
For postmenopausal women taking an AI with subphysiologic levels of estrogen, chronic vaginal dryness (e.g., genitals feel dry, irritated, pruritic, and/or painful during
intercourse, gynecologic exams, and even with walking or sitting) is common and lubricants are often not enough to treat
it.33 Nonhormonal moisturizers are a safe treatment for vaginal dryness and atrophy in both pre- and postmenopausal
women with breast cancer.34-36 Intravaginal moisturizers
(gels, creams, suppositories, or ovules) should be used every
two to three nights to hydrate the vulvo-vaginal tissues,
achieve optimal absorption, and minimize leakage. They also
improve vaginal pH, dryness, elasticity, irritation, discomfort, and pruritus and are not solely used for sexual contact.33,37 Regular treatment for 8 to 12 weeks is needed to see
maximum beneft. The most commonly used moisturizer in
the United States and Canada is Replens.
Replens is a polycarbophil-based gel that binds to the vaginal epithelium and delivers water and electrolytes to the
underlying cells.37 It normalizes vaginal pH, improves morphology of epithelial cells in vaginal smears, and alleviates
vaginal symptoms.37,38 Patients should be educated about the
differences between lubricants and moisturizers to ensure
proper usage of both types of treatment. In women with hormone receptorpositive breast cancer receiving endocrine
therapy, there is currently limited information regarding the
effcacy of moisturizers and if benefts can be maintained
over time. Several small clinical trials performed in postmenopausal women with vaginal atrophy evaluated the effcacy of Replens, but did not follow patients long enough to
determine effectiveness over time.34,37 Clinical trial results
with Replens are variable. Two small studies in postmenopausal women showed an improvement in vaginal discomfort, pruritus, and dyspareunia equivalent to the relief seen
with intravaginal estrogen creams.34,39 Two other small
double-blind studies (one in women with breast cancer) did
not show better effcacy with Replens compared with lubricants.40,41 Replens has also been used as part of a multifaceted
intervention to alleviate menopausal symptoms in women
e578
Hyaluronic Acid
Hyaluronic acid is the main component of other moisturizers
such as Hyalogyn and Hyalofemme. It is a high molecular
weight glycosaminoglycan that moisturizes the vaginal epithelium by retaining high amounts of water and creating an
extracellular water flm with swelling.43,44 By delivering water
and electrolytes into underlying cells, hyaluronic acid improves epithelial elasticity and hydration.45 In a group of
postmenopausal women without cancer, an intravaginal gel
containing hyaluronic acid was compared with vaginal 17-
estradiol tablets. Both treatments demonstrated an improvement in vaginal pH and atrophy with relief of vaginal symptoms. Two small pilot studies suggest possible benefts of
hyaluronic acid in women with endometrial or breast cancer.45 Further research on the effcacy of hyaluronic acid in
the breast cancer population is needed.
Ospemifene
Ospemifene, a SERM with tissue-selective effects, was FDA
approved on February 26, 2013 for the treatment of dyspareunia in postmenopausal women. Two phase III clinical trials showed that the effcacy of ospemifene was substantially
greater than placebo in terms of improving dyspareunia, vaginal pH, and increasing superfcial cells.46,47 The most frequently reported treatment-related adverse event was hot
flashes, which were reported in 6.6% of study participants in
the ospemifene cohort compared with 3.6% in the placebo
treatment group. Ospemifene can also increase the risk of endometrial cancer and blood clots, including deep vein thrombosis, pulmonary emboli, and cerebrovascular events. The
effect of ospemifene on breast tissue has never been studied
clinically and until it is evaluated, it should not be given to
women with a history of breast cancer.
Dilators
AIs can cause marked alteration of the vulvar and vaginal
anatomy causing vaginal stenosis from loss of rugae, which
transforms the vaginal canal into a smooth, inflexible tube.
Stenosis causes the vagina to feel stretched, painful, or taut
during vaginal penetration. Vaginal stenosis is best treated
with a multimodal approach using dilators, moisturizers, lubricants, pelvic floor physical therapy, and patient education.
Dilators are available in sets of increasing size and are used
for a gradual stretching process starting with the smallest dilator. They alleviate anxiety and improve a womans confdence that something can comfortably be placed into the
vagina without discomfort.33 Dilators are essential for maintaining vaginal health if a patient is not sexually active or
lacks a partner, treating vaginal pain, and improving tolerability of pelvic examinations.33 Compliance with dilators is
poor, but women are more likely to be compliant if they believe dilators will make their pelvic exams more comfortable48 or if they are using vaginal health promotion strategies,
such as lubricants (p 0.029) or vaginal moisturizers (p
Antidepressants
Women with breast cancer are frequently treated with antidepressants for depression, anxiety, and management of
their hot flashes. Many SSRIs are extremely helpful in treating psychologic diffculties, but cause sexual side effects.52,53
Therefore, a conversation about the risk and benefts of SSRIs
should occur before prescribing these medications. A study
in patients with cancer showed that up to 79% of patients
were receiving one or more psychotropic medications.54
SSRI-induced sexual dysfunction may improve with phosphodiesterase type 5 inhibitor treatment, but this therapy has
never been studied in patients with cancer and the medications are not FDA approved for this indication.55 Bupropion
is an antidepressant that does not have the adverse sexual side
effect profle of most SSRIs and has been shown to actually
improve overall sexual satisfaction, arousal, orgasm intensity, and desire.55 An effective treatment strategy is to change
a patient to bupropion from a different SSRI, if they are experiencing sexual side effects.
Psychologic Treatment
During endocrine therapy, patients with cancer often experience persistent sexual diffculties (e.g., dyspareunia, diffculty with lubrication, decreased libido) and attention to
their effect on QoL should be an essential part of their clinical
care. Sexual function and a persons sexual self-schema can
also be adversely affected by depression and distress that often accompany a breast cancer diagnosis.56,57 Therefore, it is
essential to screen for psychologic problems and intervene
early to improve a patients confdence, psychologic wellbeing, and self-perception during and after treatment. Counseling and/or sex therapy can be effective treatment options
to help patients cope and adjust to changes, especially when
performed in combination with other treatment strategies.
Therapy can help a woman understand the effect of breast
cancer and its treatment on sexuality, reduce fear about
intimacy, learn strategies to address pain (i.e., intravaginal
moisturizers and dilator therapy), promote vaginal health,
increase sexual knowledge, expand the sexual repertoire, and
promote positive sexual identity. Psychologic and physical
consequences of cancer that affect sexuality and sexual function should be addressed proactively with all patients with
cancer. Therapy can also help a patient cope with an altered
body image, decreased self-esteem, depression, anxiety, and
fatigue.
Sensate Focus is a technique used for women experiencing
dyspareunia that helps to reduce anxiety associated with sexual touch. Sexual function for women is often multifactorial
in nature with both a physical and mental component. This is
evident when an individual overcomes sexual challenges despite physical impairments through adaptation. For example,
a recent mindfulness intervention demonstrated improvement in the perception of arousal, even when no physical improvements in engorgement were noted.58 In female patients
with cancer, decrease distress was associated with increased
sexual satisfaction.59 Psychologic interventions appear to be
effective, but additional randomized controlled trials are necessary to develop a standardized evidence-based approach to
treatment.60
Investigational Treatments
Currently there are no FDA-approved medications for decreased libido, arousal, or orgasmic diffculties in women.
However, this is an area of active drug development by pharmaceutical companies and both investigational nonhormonal and hormonal treatments are being studied.
Bremelanotide or PT 141 is a promising nonhormonal agent
for female sexual interest/arousal disorder. It is a melanocortin 1 and 4 receptor agonist that binds to the melanocortin 4
receptor in the hypothalamus. Flibanserin, a 5-HT1A receptor agonist and 5-HT2A receptor antagonist, is another nonhormonal drug being studied for treatment of hypoactive
sexual desire disorder. The combined formulation of sildenafl plus testosterone, as well as buspirone plus testosterone,
are two hormonal agents that are being studied for hypoactive sexual desire disorder, low sexual motivation, and insensitivity to sexual cues.
CONCLUSION
As women live longer after a breast cancer diagnosis and
treatment, attention to QoL and symptoms are of increasing
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e579
SHARI GOLDFARB
importance both during treatment and throughout survivorship. Well-conducted research is needed to improve
prevention, diagnosis, and treatment of female sexual dysfunction throughout breast cancer treatment and survivorship. In addition, more evidence about the short and
long-term sexual side effects of endocrine therapy is
needed to appropriately counsel patients about the relative
morbidity of cancer treatment strategies. Clinical trials are
needed to identify safe and effective interventions to ameliorate sexual dysfunction and ultimately improve patient
outcomes through evidence based treatment. There are
currently no FDA approved medications for decreased libido, arousal, or orgasmic diffculties in women. Pharmacologic medications for treating female sexual dysfunction
lag behind male therapies, but there are many drugs in development that will hopefully beneft women in the future.
References
1. American Cancer Society. Cancer Facts & Figures 2014. American Cancer Society. 2014. http://www.cancer.org/research/cancerfactsstatistics/
cancerfactsfgures2014/. Accessed March 15, 2015.
2. Beatson GT. On the treatment of inoperable carcinoma of the mamma:
suggestions for a new method of treatment, with illustrative cases.
Lancet. 1896;2:104-107.
3. Love RR, Philips J. Oophorectomy for breast cancer: history revisited.
J Natl Cancer Inst. 2002;94:1433-1434.
4. Ganz PA, Coscarelli A, Fred C, et al. Breast cancer survivors: psychosocial concerns and quality of life. Breast Cancer Res Treat. 1996;38:
183-199.
5. Broeckel JA, Thors CL, Jacobsen PB, et al. Sexual functioning in longterm breast cancer survivors treated with adjuvant chemotherapy.
Breast Cancer Res Treat. 2002;75:241-248.
6. Ganz PA, Rowland JH, Desmond K, et al. Life after breast cancer: understanding womens health-related quality of life and sexual functioning. J Clin Oncol. 1998;16:501-514.
7. Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J Med.
1998;339:1609-1618.
8. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention
of breast cancer: report of the National Surgical Adjuvant Breast and
Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371-1388.
9. Goss PE, Strasser K. Aromatase inhibitors in the treatment and prevention of breast cancer. J Clin Oncol. 2001;19:881-894.
10. Simpson ER, Dowsett M. Aromatase and its inhibitors: signifcance for
breast cancer therapy. Recent Prog Horm Res. 2002;57:317-338.
11. Geisler J, Haynes B, Anker G, et al. Influence of letrozole and anastrozole
on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over
study. J Clin Oncol. 2002;20:751-757.
12. Geisler J, King N, Anker G, et al. In vivo inhibition of aromatization by
exemestane, a novel irreversible aromatase inhibitor, in postmenopausal breast cancer patients. Clin Cancer Res. 1998;4:2089-2093.
13. Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl
J Med. 2003;348:2431-2442.
14. DeFriend DJ, Howell A, Nicholson RI, et al. Investigation of a new pure
antiestrogen (ICI 182780) in women with primary breast cancer. Cancer
Res. 1994;54:408-414.
15. Chia S, Gradishar W, Mauriac L, et al. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after
prior nonsteroidal aromatase inhibitor therapy in postmenopausal
women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol. 2008;26:1664-1670.
e580
16. Harvey HA, Lipton A, Max DT, et al. Medical castration produced by
the GnRH analogue leuprolide to treat metastatic breast cancer. J Clin
Oncol. 1985;3:1068-1072.
17. Taylor CW, Green S, Dalton WS, et al. Multicenter randomized clinical
trial of goserelin versus surgical ovariectomy in premenopausal patients
with receptor-positive metastatic breast cancer: an intergroup study.
J Clin Oncol. 1998;16:994-999.
18. Harvey HA, Lipton A, Max DT, et al. Medical castration produced by
the GnRH analogue leuprolide to treat metastatic breast cancer. J Clin
Oncol. 1985;3:1068-1072.
19. Pagani O, Regan MM, Walley BA, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014;
371:107-118.
20. Lindau ST, Sandbo S, Goldfarb SB, et al. Breast Cancer. In Mulhall JP,
Incrocci L, Goldstein I, Rosen R (eds). Cancer and Sexual Health. New
York, NY: Humana Press, 2011;415-456.
21. Goldstein AT, Belkin ZR, Krapf JM, et al. Polymorphisms of the androgen receptor gene and hormonal contraceptive induced provoked vestibulodynia. J Sex Med. 2014;11:2764-2771.
22. Barni S, Mondin R. Sexual dysfunction in treated breast cancer patients.
Ann Oncol. 1997;8:149-153.
23. Ganz PA, Desmond KA, Belin TR, et al. Predictors of sexual health in
women after a breast cancer diagnosis. J Clin Oncol. 1999;17:2371-2380.
24. Trinkaus M, Chin S, Wolfman W, et al. Should urogenital atrophy in
breast cancer survivors be treated with topical estrogens? Oncologist.
2008;13:222-231.
25. Mok K, Juraskova I, Friedlander M. The impact of aromatase inhibitors
on sexual functioning: current knowledge and future research directions. Breast. 2008;17:436-440.
26. Mourits MJ, Bockermann I, de Vries EG, et al. Tamoxifen effects on
subjective and psychosexual well-being, in a randomised breast cancer
study comparing high-dose and standard-dose chemotherapy. Br J Cancer. 2002;86:1546-1550.
27. Su HI, Sammell MD, Springer E, et al. Weight gain is associated with
increased risk of hot flashes in breast cancer survivors on aromatase inhibitors. Breast Cancer Res Treat. 2010;124:205-211.
28. Suckling J, Lethaby A, Kennedy R. Local oestrogen for vaginal atrophy
in postmenopausal women. Cochrane Database Syst Rev. 2006;
CD001500.
29. Holmberg L, Iversen OE, Rudenstam CM, et al. Increased risk of recurrence after hormone replacement therapy in breast cancer survivors.
J Natl Cancer Inst. 2008;100:475-482.
30. Speroff L. The LIBERATE tibolone trial in breast cancer survivors. Maturitas. 2009;63:1-3.
31. von Schoultz E, Rutqvist LE, Stockholm Breast Cancer Study Group.
Menopausal hormone therapy after breast cancer: the Stockholm randomized trial. J Natl Cancer Inst. 2005;97:533-535.
32. Derzko C, Elliott S, Lam W. Management of sexual dysfunction in postmenopausal breast cancer patients taking adjuvant aromatase inhibitor
therapy. Curr Oncol. 2007;14 Suppl 1:S20-S40.
33. Carter J, Goldfrank D, Schover LR. Simple strategies for vaginal health
promotion in cancer survivors. J Sexual Med. 2011;8:549-559.
34. Nachtigall LE. Comparative study: Replens versus local estrogen in
menopausal women. Fertil Steril. 1994;61:178-180.
35. Morali G, Polatti F, Metelitsa EN, et al. Open, non-controlled clinical
studies to assess the effcacy and safety of a medical device in form of gel
topically and intravaginally used in postmenopausal women with genital atrophy. Arzneimittelforschung. 2006;56:230-238.
36. Le Donne M, Caruso C, Mancuso A, et al. The effect of vaginally administered genistein in comparison with hyaluronic acid on atrophic epithelium in postmenopause. Arch Gynecol Obstet. 2011;283:1319-1323.
37. van der Laak JA, de Bie LM, de Leeuw H, et al. The effect of Replens on
vaginal cytology in the treatment of postmenopausal atrophy: cytomorphology versus computerised cytometry. J Clin Pathol. 2002;55:446-451.
38. Gelfand M, Wendman E. Treating vaginal dryness in breast cancer patients: results of applying a polycarbophil moisturizing gel. J Womens
Health. 1994;3:427-433.
39. Bygdeman M, Swahn ML. Replens versus dienoestrol cream in the
symptomatic treatment of vaginal atrophy in postmenopausal women.
Maturitas. 1996;23:259-263.
40. Loprinzi CL, Abu-Ghazaleh S, Sloan JA, et al. Phase III randomized
double-blind study to evaluate the effcacy of a polycarbophil-based
vaginal moisturizer in women with breast cancer. J Clin Oncol. 1997;15:
969-973.
41. Caswell M, Kane M. Comparison of the moisturization effcacy of two
vaginal moisturizers: pectin versus polycarbophil technologies. J Cosmet Sci. 2002;53:81-87.
42. Ganz PA, Greendale GA, Petersen L, et al. Managing menopausal symptoms in breast cancer survivors: results of a randomized controlled trial.
J Natl Cancer Inst. 2000;92:1054-1064.
43. Costantino D, Guaraldi C. Effectiveness and safety of vaginal suppositories for the treatment of the vaginal atrophy in postmenopausal women: an open, non-controlled clinical trial. Eur Rev Med Pharmacol Sci.
2008;12:411-416.
44. Ekin M, Yasar L, Savan K, et al. The comparison of hyaluronic acid vaginal tablets with estradiol vaginal tablets in the treatment of atrophic
vaginitis: a randomized controlled trial. Arch Gynecol Obstet. 2011;283:
539-543.
45. Markowska J, Madry R, Markowska A. The effect of hyaluronic acid
(Cicatridine) on healing and regeneration of the uterine cervix and vagina
and vulvar dystrophy therapy. Eur J Gynaecol Oncol. 2011;32:65-68.
46. Portman DJ, Bachmann GA, Simon JA, et al. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated
with postmenopausal vulvar and vaginal atrophy. Menopause. 2013;20:
623-630.
47. Simon JA, Lin VH, Radovich C, et al. One-year long-term safety extension study of ospemifene for the treatment of vulvar and vaginal atrophy
in postmenopausal women with a uterus. Menopause. 2013;20:418-427.
e581
SPEAKERS
Charles L. Shapiro, MD
Mount Sinai School of Medicine
New York, NY
Deborah K. Mayer, PhD, RN, AOCN, FAAN
UNC Lineberger Comprehensive Cancer Center
Chapel Hill, NC
ncreasingly, the feld of oncology is focused on the implementation of strategies to improve care with an emphasis
on evaluation. However, this process of implementation and
evaluation is not linear; rather, it is a cyclical process in
which, ideally, evidence is translated into practice and practice is reviewed and improved on the basis of evaluation,
which in turn leads to new research hypotheses. Clinical
practice guidelines (CPGs), quality metrics, and performance improvement projects are the key tools of this national movement to improve and assure quality cancer care.
As identifed in the 2013 Institute of Medicine report, Delivering High-Quality Cancer Care, cancer quality measures are
intended to provide objective descriptors of the consequences of care and transform the nebulous concept of good
medicine into a measurable discipline.1 Identifying and assessing quality require measures that assist and support health
care systems, practices, and clinicians. Each of these instruments
of evaluation is intended to evaluate quality from a unique perspective. For example, CPGs translate research results into
evidence-based guidance for clinicians; performance improvement projects are operational at the local level as a means of
making improvements, often at the site of care.1 Quality metrics
From the School of Nursing, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC; Dubin Breast Center, Translational Breast Cancer Research, Tisch Cancer Institute, Mount Sinai
Medical Center, Division of Hematology/Medical Oncology, Tisch Cancer Institute, New York, NY; Clinical Programs, Survivorship Center, Memorial Sloan Kettering Cancer Center, New York, NY.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Mary S. McCabe, RN, BA, BS, MA, Memorial Sloan Kettering Cancer Center, Room M2101J, 1275 York Ave., New York, NY 10065; email: mccabem@mskcc.org.
2015 by American Society of Clinical Oncology.
e583
MAYER ET AL
Description
Benets
Challenges
Structure
Process
Clinical Outcome
Cost
Patient-Reported
Outcomes
Adapted with permission from Delivering High-Quality Cancer Care, by the National Academy of Sciences, 2013,1 courtesy of the National Academies Press, Washington, DC.
KEY POINTS
Increasingly, oncology is focused on the implementation of
strategies to improve care, with an emphasis on
evaluation.
Survivorship-specic measures are essential to include in
the suite of cancer guidelines and metrics to assure quality
care during this period.
Survivorship care plans need to be integrated into standard
cancer care, and electronic health records can facilitate
this implementation.
The ASCO Quality Oncology Practice Initiative is an
excellent mechanism to evaluate how well physician
practices adhere to quality measures, including survivorship
measures, over time.
More effective ways to disseminate guideline
recommendations and additional tools to measure quality
are needed, especially in the area of cancer survivorship.
e584
measured and will make a difference in the health of the cancer survivor? Where do we stand with respect to quality metrics for cancer survivors? Do we begin with process measures,
or are we ready for the outcome measures described in Table
1? This is the challenge before us and the focus of this brief
paper.
Survivorship is relatively young as a formal period along
the cancer care continuum and, as such, has only recently
been considered by national organizations that develop oncology guidelines and quality metrics. At the forefront in
cancer survivorship guideline development are the American
Cancer Society, the National Comprehensive Cancer Network (NCCN), and ASCO. Each of these leaders in oncology
has taken a unique approach to developing guidelines, focusing on either a disease-specifc approach or a symptom approach to survivorship care. In addition to a growing body of
guidelines, two professional societies, ASCO, through its
QOPI, and ACoS, with its Commission on Cancer (CoC)
Cancer Program Standards, have developed cancer measures
that include metrics specifc to the survivorship period.6,7
The next section of the paper will highlight the focused efforts of these two organizations.
e585
MAYER ET AL
Structure
One must decide what elements to include in an SCP. There
are a number of free-standing, independent templates (e.g.,
Journey Forward, LIVESTRONG) that have been used, but
they have operability issues within EHRs. ASCO recently reviewed and revised the essential elements to include in an
SCP.15 These elements, endorsed and adopted by the CoC,
can be identifed or created within a template to be autocompleted or to provide standard options for completion
within any EHRs (Table 2). Where these documents will be
stored within EHRs, how they can be shared with intended
users (survivor, primary care provider, and other relevant
providers), and how they can be tracked and reported are
other structural issues that need to be resolved.
Process
A number of process issues need to be addressed (see sidebar). These decisions need to be discussed, decided, tried,
and revised based on experience with the stakeholders of this
process. Furthermore, how these issues are addressed may
vary by type and size of oncology practices.16,17 Effective
change management is needed and includes engaging key
stakeholders, standardizing terminology, clinical practices,
and processes.16 Articulating and agreeing on key assumptions help guide the approach and assure that this process,
and ultimately the document, is patient and primary care
centered. This process should be standardized as much as
possible but should allow for variations to reflect the complexity of cancer care. It is helpful to have at least one champion and to work with an interested and willing early-adopter
group to pilot this process.18
Implementation of this process will take time and require
flexibility until the system for developing and delivering
SCPs becomes standardized and incorporated into practice.
For example, in a large academic medical center, there may
be a number of disease-specifc groups with differing approaches about who sees the patient and how often. Decisions about who completes and delivers the SCP when all
three treatment modalities are delivered versus when one is
delivered could vary. For example, these decisions could fall
on the last person who treats the patient or the frst person
e586
who sees the patient during the frst follow-up visit. To say
that the devil is in the details is an understatement in trying to
delineate and implement a new process such as this. The
good news is that one is not trying to undo a previous way of
implementing the SCPthis is a new endeavor.
Another important questions about the process is how is it
delivered once it is completed. The SCP is a paper document
and it does not serve the original intent by merely handing it
to the patient and checking off that it was delivered. The SCP
is meant to serve as a communication tool to facilitate review
of the patients diagnosis and treatment, guide discussion of
planned surveillance and who will be responsible, and encourage identifcation and discussion of any current or future
concerns or issues the patient may face post-treatment. In
one study in patients with colon cancer, the delivery of the
SCP did not lengthen the usual surveillance visit, but it did
provide structure to what was discussed.19 Nutritional concerns and bowel management problems quickly became
identifed as issues most of these patients raised, and these
topics were then incorporated routinely into the SCP and
visit.
There are many barriers to SCP implementation and these
need to be addressed as they are identifed. Working closely
with the EHR vendor during the development and piloting
phase is critical. Receiving input from anticipated users and
having them try to use the SCP EHR system as intended will
identify many issues with implementation. Answering the
questions in the sidebar can be time consuming, and the approach may need to change over time with experience. One
of the critical issues is reimbursement for SCP completion.
As of January 1, 2015, SCP preparation can be billed as a new
CPT code, 99490 (chronic care management services, at least
20 minutes of clinical staff time directed by a physician or
No. of Practices
310
313
181
181
111
98
95
Outcomes
A barrier to adoption has been the minimal amount of evidence demonstrating benefts for SCPs.21 Receiving an SCP
from an oncologist is associated with primary care providers
reporting always or almost always discussing recommendations and delineation of provider responsibility with survivors (OR 9.22; 95% CI, 5.74 to 14.82; p 0.001) compared to
primary care providers reporting receiving SCP less than always or almost always from the oncologist.22 Immediate outcomes may include increased knowledge about surveillance
plans and satisfaction with care, while longer-term outcomes
may include increased adherence to surveillance plans, with
decreased undertesting and overtesting and identifcation
and management of long-term effects. Other provider level
FIGURE 1. Chemotherapy Treatment Summary Completed within 3 Months of Chemotherapy End (310 Practices)
e587
MAYER ET AL
FIGURE 2. (A) Infertility Risks Discussed before Chemotherapy (181 Practices); (B) Fertility Preservation
Options Discussed or Referral to Specialist (181 Practices)
Treatment Summary
The development and implementation of the SCP has been
described earlier in this article, and the QOPI effort to document uptake of this recommendation to provide a treatment
summary within 3 months of completing treatment is documented in Fig. 1. The percentage of physician practices in
which a treatment summary is documented decreased from
35% in 2009% to 20% in 2014. However, recent initiatives to
simplify the ASCO SCP, along with extensive efforts to assure
integration of the SCP with electronic medical records, and
the requirement of the CoC that by January 2019 all individuals receive an SCP should begin to reverse this decreasing
trend.7 However, to be successful, the barriers previously described will need to be addressed.
e588
Tobacco Cessation
In 2003, ASCO released a policy statement on tobacco cessation,32 and an update was published in 2013.26 A cornerstone
of this policy is that every individual should be queried about
smoking status, and appropriate interventions and referrals
to smoking cessation programs should be undertaken. There
were consistently 81% to 84% of medical records that documented a smoking/tobacco cessation discussion in the years
2009 to 2014. Although guideline adherence is consistently
greater than 80%, one wonders whether that goal should be
higher.
Risk of Infertility
The ASCO clinical practice guideline on fertility preservation
was published in 2006 and recently was updated in 2013.27
Among the key recommendations were to discuss fertility
preservation with all individuals of reproductive age and to
refer those interested in fertility preservation to reproductive
FIGURE 4. (A) Genetic Testing for Invasive Breast Cancer (95 Patients) (B) Complete Family History
Documented for Invasive Breast Cancer (98 Patients)
e589
MAYER ET AL
References
1. Institute of Medicine. Delivering High Quality Cancer Care: Charting a
New Course for a System in Crisis. Washington, DC: National Academy
Press; 2013.
2. National Quality Forum. NQF-endorsed standards. www.qualityforum.
org/measures_list.aspx. Accessed January 29, 2015.
3. NationalQualityForum.Funding.www.qualityforum.org/About_NQF/
funding.aspx. Accessed January 29, 2015.
4. Agency for Healthcare Research and Quality. National quality measures
clearinghouse: measures by topic. www.ahrq.gov/browse/by-topicdetail.aspx. Accessed January 29, 2015.
5. Siegel R, DeSantis C, Virgo K, et al. Cancer treatment and survivorship
statistics, 2012. CA Cancer J Clin. 2012;62:220-241.
6. American Society of Clinical Oncology. QOPI summary of measures.
http://qopi.org/methodology.htm. Accessed January 29, 2015.
7. American College of Surgeons. Cancer program standards. www.facs.
org/quality/020programs/cancer/coc/standards. Accessed January 29,
2015.
8. Hewitt M, Greenfeld S, Stovall E. From Cancer Patient to Cancer Survivor: Lost in Transition. Washington, DC: National Academies Press;
2006.
9. Birken SA, Deal AM, Mayer DK, et al. Following through: the consistency of survivorship care plan use in United States cancer programs.
J Cancer Educ. 2014;29:689-697.
10. Birken SA, Deal AM, Mayer DK, et al. Determinants of survivorship
care plan use in US cancer programs. J Cancer Educ. 2014;29:720-727.
11. Yu P, Artz D, Warner J. Electronic health records (EHRs): supporting
e590
12.
13.
14.
15.
16.
17.
18.
19.
ASCOs vision of cancer care. Am Soc Clin Oncol Educ Book. 2014;34:
225-231.
Charles D, King J, Pael V, et al. Adoption of Electronic Health Record
Systems among U.S. Non-Federal Acute Care Hospitals: 2008-2012.
Washington, DC: Offce of the National Coordinator for Health Information Technology; 2013.
Fasola G, Macerelli M, Follador A, et al. Health information technology
in oncology practice: a literature review. Cancer Inform. 2014;13:131139.
McDonald KM, Sundaram V, Bravata DM, et al. AHRQ Technical Reviews. Closing the Quality Gap: A Critical Analysis of Quality Improvement Strategies (Vol. 7: Care Coordination). Rockville, MD: Agency for
Healthcare Research and Quality; 2007.
Mayer DK, Nekhlyudov L, Snyder CF, et al. American Society of Clinical
Oncology clinical expert statement on cancer survivorship care planning. J Oncol Pract. 2014;10:345-351.
Detwiller M, Petillion W. Change management and clinical engagement: critical elements for a successful clinical information system implementation. Comput Inform Nurs. 2014;32:267-273.
Evans WK, Ashbury FD, Hogue GL, et al. Implementing a regional oncology information system: approach and lessons learned. Curr Oncol.
2014;21:224-233.
Dearing JW. Applying diffusion of innovation theory to intervention
development. Res Soc Work Pract. 2009;19:503-518.
Mayer DK, Gerstel A, Walton AL, et al. Implementing survivorship care
plans for colon cancer survivors. Oncol Nurs Forum. 2014;41:266-273.
20. Outland B. Chronic care management at last, and how to code for it.
www.acpinternist.org/archives/2015/01/coding.htm. Accessed January
26, 2015.
21. Mayer DK, Birken SA, Check DK, et al. Summing it up: an integrative
review of studies of cancer survivorship care plans (2006-2013). Cancer.
Epub 2014 Sep 23.
22. Blanch-Hartigan D, Forsythe LP, Alfano CM, et al. Provision and discussion of survivorship care plans among cancer survivors: results of a
nationally representative survey of oncologists and primary care physicians. J Clin Oncol. 2014;32:1578-1585.
23. Mayer DK, Gerstel A, Leak AN, et al. Patient and provider preferences
for survivorship care plans. J Oncol Pract. 2012;8:e80-e86.
24. Neuss MN, Desch CE, McNiff KK, et al. A process for measuring the
quality of cancer care: the Quality Oncology Practice Initiative. J Clin
Oncol. 2005;23:6233-6239.
25. Neuss MN, Malin JL, Chan S, et al. Measuring the improving quality of
outpatient care in medical oncology practices in the United States. J Clin
Oncol. 2013;31:1471-1477.
26. Hanna N, Mulshine J, Wollins DS, et al. Tobacco cessation and control
a decade later: American Society of Clinical Oncology policy statement
update. J Clin Oncol. 2013;31:3147-3157.
27. Loren AW, Mangu PB, Beck LN, et al. Fertility preservation for patients
with cancer: American Society of Clinical Oncology clinical practice
guideline update. J Clin Oncol. 2013;31:2500-2510.
28. Khatcheressian JL, Hurley P, Bantug E, et al. Breast cancer follow-up and
management after primary treatment: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31:961-965.
29. Basch E, Oliver TK, Vickers A, et al. Screening for prostate cancer with
prostate-specifc antigen testing: American Society of Clinical Oncology
provisional clinical opinion. J Clin Oncol. 2012;30:3020-3025.
30. Lu KH, Wood ME, Daniels M, et al. American Society of Clinical Oncology expert statement: collection and use of a cancer family history for
oncology providers. J Clin Oncol. 2014;32:833-840.
31. Robson ME, Storm CD, Weitzel J, et al. American Society of Clinical
Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2010;28:893-901.
32. American Society of Clinical Oncology. American Society of Clinical
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
Oncology policy statement update: tobacco control-reducing cancer incidence and saving lives. 2003. J Clin Oncol. 2003;21:2777-2786.
American Society of Clinical Oncology. Statement of the American
Society of Clinical Oncology: genetic testing for cancer susceptibility, adopted on February 20, 1996. J Clin Oncol. 1996;14:1730-1736.
American Society of Clinical Oncology. American Society of Clinical
Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol. 2003;21:2397-2406.
Blayney DW, McNiff K, Eisenberg PD, et al. Development and future of
the American Society of Clinical Oncologys Quality Oncology Practice
Initiative. J Clin Oncol. 2014;32:3907-3913.
ASCO Institute for Quality. www.instituteforquality.org/practiceguidelines. Accessed January 26, 2015.
National Comprehensive Cancer Network. www.nccn.org. Accessed
January 26, 2015.
Gagliardi AR, Brouwers MC, Palda VA, et al. How can we improve
guideline use? A conceptual framework of implementability. Implement
Sci. 2011;6:26.
Eccles M, Grimshaw J, Walker A, et al. Changing the behavior of healthcare professionals: the use of theory in promoting the uptake of research
fndings. J Clin Epidemiol. 2005;58:107-112.
Kastner M, Estey E, Perrier L, et al. Understanding the relationship
between the perceived characteristics of clinical practice guidelines
and their uptake: protocol for a realist review. Implement Sci. 2011;
6:69.
Gulmezoglu AM, Villar J, Grimshaw J, et al. Cluster randomized trial of
an active, multifaceted information dissemination intervention based
on the WHO reproductive health library to change obstetric practices:
methods and design issues [ISRCTN14055385]. BMC Med Res Methodol. 2004;4:2.
Boaz A, Baeza J, Fraser A, et al. Effective implementation of research
into practice: an overview of systematic reviews of the health literature.
BMC Res Notes. 2011;4:212.
American College of Surgeons. Accreditation Committee Clarifcation for
Standard 3.3 Survivorship Care Plan. https://www.facs.org/publications/
newsletters/coc-source/special-source/standard33. Accessed March 16,
2015.
e591
SPEAKERS
Toby Christopher Campbell, MD
University of Wisconsin Carbone Cancer Center
Madison, WI
Eduardo Bruera, MD
The University of Texas MD Anderson Cancer Center
Houston, TX
From the The University of Texas MD Anderson Cancer Center, Houston, TX; Feinberg School of Medicine, Northwestern University, Chicago, IL; Feinberg School of Medicine, Robert H. Lurie
Comprehensive Cancer Center, Chicago, IL.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Judith A. Paice, PhD, RN, Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, 676 N St. Clair St., Suite 850, Chicago, IL 60611;
email: j-paice@northwestern.edu.
2015 by American Society of Clinical Oncology.
e593
KEY POINTS
Safe and effective control of cancer pain demands
thorough knowledge of the pharmacokinetics and
pharmacodynamics of opioids that guide dosing, titration,
and rotation.
Prevention and management of adverse effects of opioids
requires careful assessment and knowledge regarding
agents used to treat these complications.
Overtreatment of cancer pain can occur when opioids are
used to treat symptoms other than pain or dyspnea,
including anxiety, depression, or sleep disorders.
Evaluation of risk factors for opioid misuse, including
current or past use of illicit substances, family history of
substance use disorder, environmental exposure, along with
a history of sexual or physical abuse, guides safe and
effective care.
Universal precautions, including measures to advance
adherence and safe storage, will promote safe use of these
medications while protecting the patient, the prescriber,
and the community.
e594
Cytochrome
Morphine
None
Hydromorphone
None
Oxymorphone
None
Fentanyl
3A4
Oxycodone
3A4
Noroxycodone
2D6
Oxymorphone*
3A4
Norhydrocodeine
Hydrocodone
Results
Norfentanyl
2D6
Hydromorphone*
Codeine
2D6
Morphine*
Methadone
3A4
M1-M2
Tramadol
2D6
Desmethyltramadol*
*Active metabolite.
Route
Frequency
Morphine
Oral
Every 12 hours
Hydromorphone
Oral
Every 24 hours
Oxycodone
Oral
Every 12 hours
Fentanyl
Transdermal
Every 72 hours
Oxymorphone
Oral
Every 12 hours
Hydrocodone
Oral
Every 12 hours
to chronic treatment for patients as compared to taking immediate release opioids such as morphine, hydrocodone, hydromorphone, or codeine every 4 hours day and night.
However, extended release opioids are generally fve times
more expensive than immediate release opioids, and insurance payers frequently deny payment for these agents.9
Therefore, the insurance company occasionally may request that patients change opioid analgesic or pay large
amounts of money out of pocket. In these cases, chronic
management with immediate release opioid is an appropriate alternative.
All patients with chronic cancer pain should be started on
regular opioids, ideally using an extended release formulation (Sidebar 1). In addition, patients with cancer pain require access to immediate release opioids for episodes of
break-through pain. Each dose should be approximately 10%
(ranging between 5% and 20%) of the daily regular opioid
dose. Close to 100% of the patients need to be prescribed a
regular laxative every day since constipation is a universal
and frequently under diagnosed problem. In addition, patients should be prescribed antiemetics since approximately
half of the patients started on an opioid agonist will develop
nausea for the frst 3 days. Metoclopramide is an excellent
option because of its combination of central and pro-kinetic
effects. After the frst 3 to 4 days, nausea is either minimal or
absent.
Opioid titration. Even after ideal management, only approximately 50% of the patients will reach their personalized pain
goal (3/10) after one visit.10 Therefore, it is important to ei-
ther follow up or phone the patient less than 1 week after the
initial management to further titrate the opioid dose and to
consider adjuvant drugs or drugs for the management of side
effects. The minimal clinically important increase or decrease in dose will be approximately 30% of the daily dose.
Opioid titration is always conducted as a percentage rather
than an absolute number because of the large dose range. For
example, a patient coming for follow-up in poor pain control
receiving 100 mg of equivalent morphine daily dose will require an increase of at least 30 mg per day. A patient coming
with a similar degree of poor pain control but receiving a dose
of 300 mg of equivalent morphine per day will require an increase of approximately 100 mg per day.
When calculating the daily morphine equivalent dose, ask
the patient how many extra opioid doses they received per
day. For example, a patient started on 15 mg of extended release morphine every 12 hours and 7.5 mg of immediate release morphine orally every 4 hours as needed. One week
later the patient complains of pain 8/10. The patient is receiving four immediate release doses per day. Total morphine
equivalent dose for this patient is regular daily dose 30 plus
breakthrough pain 30, making a total daily dose of 60 mg. An
appropriate increase for this patient would be approximately
30% to 50% of the daily dose (20 30 mg). Therefore, the new
regular opioid dose should be approximately 90 mg/day (either 30 mg every 8 hours or 45 mg every 12 hours). The new
extra dose will need to be approximately 9 to 10 mg every 4
hours as needed since the ideal extra dose is approximately
10% of the daily dose.
Opioid rotation. Approximately 80% of patients with cancer
will need at least one change in the type of opioid. The main
reasons for opioid rotation are the development of opioid induced neurotoxicity or lack of appropriate pain control after
appropriate dose titration. Sidebar 2 summarizes the main
clinical features of patients who develop opioid-induced neurotoxicity. Whenever patients develop clinical fndingsincluding a combination of sedation, myoclonus, hyperalgesia
either localized at the area of the existing pain or generalized
cutaneous hyperalgesia, or elements of delirium (confusion,
inattention, disorientation, hallucinations, psychomotor agitation)an opioid rotation should be conducted. Opioid rotation works by eliminating the offending drug, and it is more
important to make the diagnosis of opioid-induced neuro-
Sedation
Myoclonus
Hyperalgesia (localized or generalized)
Hallucinations
Psychomotor agitation
Confusion
e595
e596
Universal Precautions
To provide safe and effective pain care, experts suggest implementing universal precautions. These measures are considered universal because we cannot predict who has a
substance use disorder. These precautions employ screening,
agreements, and adherence monitoring strategies.17 Comprehensive assessment of the current and past use of legal
(e.g., tobacco, alcohol) and illicit substances (e.g., prescription drugs obtained from family or purchased illegally) is
e597
SUMMARY
Safe and effective opioid use in patients with cancer requires
balance and skill. These skills include comprehensive assessment, understanding the pharmacokinetics and dynamics of
these agents, and knowledge of dosing, titration, and rotation. Balance speaks to the awareness that opioids might be
misused, either inadvertently by patients who note they fall
asleep or feel less anxious when using these drugs, or purposefully by those with substance use disorders or criminal
intent. Universal precautions can support adherence and
prevent diversion. Caring for patients with misuse requires
interdiscplinary care, with input from supportive oncology/
palliative care and addiction specialists.
References
1. Greco MT, Roberto A, Corli O, et al. Quality of cancer pain management: an update of a systematic review of undertreatment of patients
with cancer. J Clin Oncol. 2014;34:4149-4154.
2. Breuer B, Chang VT, Von Roenn JH, et al. How well do medical oncologists manage chronic cancer pain? A national survey. Oncologist. 2015;
20:202-209.
3. Fisch MJ, Lee JW, Weiss M, et al. Prospective, observational study of
pain and analgesic prescribing in medical oncology outpatients with
breast, colorectal, lung, or prostate cancer. J Clin Oncol. 2012;30:19801988.
4. Kwon JH. Overcoming barriers in cancer pain management. J Clin Oncol. 2014;32:1727-1733.
5. Paice JA, Ferrell B. The management of cancer pain. CA Cancer J Clin.
2011;61:157-182.
6. Kurita GP, Kaasa S, Sjgren P. Opioid Analgesics. In Bruera E, Higginson, I, von Gunten C (Eds).Textbook of Palliative Medicine and Supportive Care 2nd Edition. Boca Raton, FL: CRC Press Taylor and Francis
Group, 2015;395-408.
7. Pasternak GW, Pan YX. Mu opioids and their receptors: evolution of a
concept. Pharmacol Rev. 2013;65:1257-1317.
8. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450
2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther.
2014;95(4):376-382.
9. Dalal S, Tanco KC, Bruera E. State of art of managing pain in patients
with cancer. Cancer J. 2013;19:379-389.
10. Dalal S, Hui D, Nguyen L, et al. Achievement of personalized pain goal
in cancer patients referred to a supportive care clinic at a comprehensive
cancer center. Cancer. 2012;118:3829-3877.
11. Parsons HA, de la Cruz M, El Osta B, et al. Methadone initiation and
rotation in the outpatient setting for patients with cancer pain. Cancer.
2010;116:520-528.
12. Reissig JE, Rybarczyk AM. Pharmacologic treatment of opioid-induced
sedation in chronic pain. Ann Pharmacother. 2015;39:727-731.
13. Merrill JO, Von Korff M, Banta-Green CJ, et al. Prescribed opioid diffculties, depression and opioid dose among chronic opioid therapy patients. Gen Hosp Psychiatry. 2012;34:581-587.
14. Sullivan MD, Von Korff M, Banta-Green C, et al. Problems and con-
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
cerns of patients receiving chronic opioid therapy for chronic noncancer pain. Pain. 2010;149:345-9353.
Afsharimani B, Cabot P, Parat MO. Morphine and tumor growth and
metastasis. Cancer Metastasis Rev. 2011;30:225-238.
Glare PA, Davies PS, Finlay E, et al. Pain in cancer survivors. J Clin Oncol. 2014;32:1739-1747.
Volkow ND, McLellan TA. Curtailing diversion and abuse of opioid
analgesics without jeopardizing pain treatment. JAMA. 2011;305:13461347.
Dev R, Parsons HA, Palla S, et al. Undocumented alcoholism and its
correlation with tobacco and illegal drug use in advanced cancer patients. Cancer. 2011;117:4551-4556.
Blackhall LJ, Alfson ED, Barclay JS. Screening for substance abuse and
diversion in Virginia hospices. J Palliat Med. 2013;16:237-242.
Starrels JL, Becker WC, Alford DP, et al. Systematic review: treatment
agreements and urine drug testing to reduce opioid misuse in patients
with chronic pain. Ann Intern Med. 2010;152:712-720.
Peppin JF, Passik SD, Couto JE, et al. Recommendations for urine drug
monitoring as a component of opioid therapy in the treatment of
chronic pain. Pain Med. 2012;13:886-896.
Francoeur RB. Ensuring safe access to medication for palliative care
while preventing prescription drug abuse: innovations for American inner cities, rural areas, and communities overwhelmed by addiction. Risk
Manag Healthc Policy. 2011;4:97-105.
Reddy A, de la Cruz M, Rodriguez EM, et al. Patterns of storage, use, and
disposal of opioids among cancer outpatients. Oncologist. 2014;19:780785.
Nguyen LM, Rhondali W, de la Cruz M, et al. Frequency and predictors
of patient deviation from prescribed opioids and barriers to opioid pain
management in patients with advanced cancer. J Pain Symptom Manage. 2013;45:505-516.
Kircher S, Zacny J, Apfelbaum SM, et al. Understanding and treating
opioid addiction in a patient with cancer pain. J Pain. 2011;12:10251031.
Santos SP, Bruckenthal P, Barkin RL. Strategies to reduce the tampering
and subsequent abuse of long-acting opioid potential risks and benefts
of formulations with physical or pharmacologic deterrents to tampering. Mayo Clin Proc. 2012;87:683-694.
e599
PEDIATRIC ONCOLOGY
SPEAKERS
Donald Williams Parsons, MD, PhD
Texas Childrens Cancer Center, Baylor College of Medicine
Houston, TX
William L. Carroll, MD
NYU Langone Medical Center
New York, NY
From the Division of Pediatric Hematology/Oncology, Department of Pediatrics, NYU Langone Medical Center, New York, NY; Perlmutter Cancer Center, NYU Langone Medical Center, New York,
NY; Department of Pediatrics, University of Utah, Salt Lake City, UT; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: William L. Carroll, MD, NYU Cancer Institute, Smilow 1207, 522 First Ave., New York, NY 10016; email: william.carroll@nyumc.org.
2015 by American Society of Clinical Oncology.
e601
noprecipitation (ChIP) sequencing, which determines chemical changes to the surrounding chromatin that are also likely
to affect gene expression. In some cases, data can be produced on an individual in less than a day. Ideally, all platforms would be used to create a full portrait of the genetic and
epigenetic landscape of an individual, and there are many examples where combining data (e.g., copy number, gene
expression, methylation, and DNA sequencing) shows convergence on alterations in pathways shared among patients
of an individual tumor type and/or pathways used by tumor
cells to evade therapy. However, the prohibitive cost of sequencing and data analysis now prevents simultaneous deployment of multiple strategies.
The details of these approaches vary but, in general, involve
the generation of single-stranded DNA (from genomic DNA,
hybridization captured [exome], cDNA [RNA sequencing],
bisulfte treated DNA [methyl sequencing] or immunoprecipitated DNA [ChIP sequencing]) with ligation of DNA
adapters. Rounds of amplifcation on beads or glass slides allow adequate coverage of the DNA, and strands can then be
sequenced by the sequential addition of fluorescently labeled
nucleotides. Varieties of bioinformatic approaches are used
to determine quality, align sequences to the genome, and
determine variations in sequence. Each approach has advantages and disadvantages. For example, whole-exome sequencing (WES) is less expensive than whole-genome
sequencing and focuses on somatic variants in protein coding domains that are likely to contain critical lesions. However, it can miss fusion transcripts and does not provide gene
expression information that may highlight activation of biologic pathways.
The sequencing of an individual cancer genome in a short
period of time to allow integration into clinical practice is
now a reality. However, the cost of a single sequencing run,
including analysis and validation, is signifcant, especially
since reimbursement of such assays is still uncertain in many
cases. The $1,000 genome has been often quoted as a holy
grail for clinical sequencing, and the recent development of
the HiSeq X Ten system (Illumina) has fnally laid claim to
this title. However, achieving this goal requires the purchase
of 10 systems costing approximately $10 million and opera-
KEY POINTS
The genetic landscape of childhood cancer is far less
complex than that of tumors that occur in adulthood.
Tumor proling has revealed genetic alterations unique to
traditional histological tumor subtypes as well as changes
that are shared across seemingly disparate tumors.
With few exceptions, high-frequency shared genetic
alterations are not observed, but low frequency individual
genetic alterations may coalesce into biological pathways
that offer the possibility of novel treatment approaches.
The impact of precision medicine is best evaluated in the
context of carefully controlled clinical trials.
e602
have failed. However, the development of BET bromodomain inhibitors is emerging as a powerful approach to target
MYC-overexpressing tumors. These agents effectively displace BRD4, a protein targeted to acetylated lysines, from the
MYCN promoter, thereby downregulating MYCN expression as well as downstream targets. The clinical effcacy has
been documented in preclinical models and clinical trials are
underway.11 Likewise CDK7 inhibitors selectively suppress
MYC-driven cancers.12
Interestingly, even in tumors that harbor sentinel genetic
translocations, there may be surprising heterogeneity of
additional genetic alterations. Ewing sarcoma is characterized by translocations between EWSR1 on chromosome 22
(q11.2) and members of the ETS family; usually FLI1 (11q12).
More than 90% of Ewing sarcomas contain EWSR1 fusions.
Recent sequencing efforts have noted that samples had an average of 10 coding variants per tumor, consistent with what
has been observed for other childhood cancers.13,14 However,
despite this relatively uniform genetic class, only a minority
of sequence variants were shared. The most consistent lesions were STAG2 mutations, which were observed in only
17% of cases, followed by CDKN2A deletions (12%) and
TP53 mutations (7%). EZH2, BCOR, and ZMYM3 mutations
were each seen in 2.7% of samples. STAG2 and TP53 mutations often coexisted and were associated with an inferior
outcome. Thus, the majority of single nucleotide variants
were unique. Likewise the poor prognosis alveolar subtype of
rhabdomyosarcoma is characterized by genetic fusions between the PAX3 or PAX7 genes and FOXO1. Interestingly,
these tumors have far fewer nonsynonymous mutations
compared with fusion-negative embryonal tumors that have
a better prognosis (average 6.4 vs. 17.8).15 Moreover, there
was no signifcant sharing of mutations across PAX-FOXO1
samples and individual mutations did not converge on biologic pathways (see below).
Overall survival for the most common pediatric bone tumor osteosarcoma has remained at a plateau for three decades. Osteosarcoma stands out among all pediatric tumors
for its relatively high mutation rate and number of structural
variations per sample. A recently published analysis showed
that on average osteosarcoma samples have 37 nonsynonymous mutations, which is at least three-fold greater than that
observed for other pediatric cancers.16 In addition, osteosarcomas contain frequent copy number alterations including
deletions in RB1, TP53, and CDKN2A/B, and amplifcations
in COPS3, CCNE1, CDK4, and MYC. Inactivation of TP53
either by mutation and/or deletion is seen in three-fourths of
cases (some cases have germ line TP53 mutations), whereas,
RB1 deletion is seen in approximately 60% of samples. Combined RB1/TP53 inactivation occurs in half of all cases. In
examining the mutation spectrum, little to no shared mutations were seen beyond the 22% of samples containing TP53
mutations. However, gene set enrichment analysis indicates
that 24% of patients have tumors with alterations in the
PI3K/mTOR pathway. This observation was validated in a
genome-wide pooled shRNA screen and murine xenograft
experiments confrmed therapeutic effcacy for dual PI3K/
mTOR inhibitors (GSK2126458, BEZ235) and the PIK3CA
inhibitor (PIK75).
Although the outcome for all subtypes of childhood ALL
has improved considerably, patients who relapse have a dismal prognosis even with high-dose chemotherapy and stem
cell rescue. In an effort to identify the underlying biologic
pathways that drive drug resistance and relapse, many investigators have performed gene expression, copy number,
methylation, and sequencing analyses on diagnosis relapse
pairs. These efforts have identifed alterations enriched at relapse and in some cases these alterations have been shown to
alter drug sensitivity to individual agents (e.g., BTG1 and
TBLXR1 deletions and decreased sensitivity to glucocorticoids and NT5C2 mutations and resistance to purine analogs).17,18 However, these alterations occur in a small but
signifcant subpopulation of patients. When changes across
three platforms were integrated (copy number alterations,
changes in methylation, and gene expression) there was signifcant convergence on activation of the WNT and MAPK
pathways. Activation has been subsequently validated by
phosphoflow protein levels and inhibitors of both pathways
have been shown to synergize with chemotherapy in cell lines
and patient samples.19-21
These examples illustrate the value of sequencing a large
collection of samples and emphasize the importance of pathway analysis and validation.
e603
most are treated with surgical excision, but 50% of cases also
show an ALK rearrangement, most commonly with TPM3
and TPM4. Finally, the majority of familial neuroblastomas
and, as described above, 8% to 10% of sporadic cases have
ALK activating point mutations. Another 2% to 3% of sporadic cases have ALK amplifcation. Early phase clinical trial
experience with the ALK inhibitor crizotinib (originally designed as an MEK inhibitor) shows a remarkable response in
patients with refractory ALCL (eight of nine patients) and
IMT (three of seven patients), but less activity in ALKactivated neuroblastoma (one of 11 patients).22 These encouraging results, in part, led to the development of the
currently open Childrens Oncology Group (COG)
ANHL12P1 randomized phase II trial for newly diagnosed
ALCL using brentuximab vedotin or crizotinib in combination with chemotherapy.
Successful introduction of imatinib into conventional chemotherapy for Ph ALL has had a profound effect on survival, and this success has been followed by the investigation
of the second-generation tyrosine kinase inhibitor, dasatinib
in combination with chemotherapy.1,23-25 Most children can
now be successfully cured without the use of stem cell transplantation. Perhaps even more importantly from a population base effect standpoint, approximately 10% of children
with standard-risk ALL and 27% of young adults with ALL
have Philadelphia-like (Ph-like) ALL that share a gene expression profle like Ph ALL but lack the BCR-ABL1 fusion
protein. These cases often share IKZF1 deletions, CRLF overexpression, and have a poor prognosis. Recent large-scale sequencing efforts have documented that the overwhelming
majority (91%) of samples from patients with Ph-like disease
carry kinase-activating alterations.26 In particular, 12.6% of a
recent series of such patients had fusions that would respond
to ABL1 inhibitors such as imatinib (e.g., ABL1, ABL2,
CSF1R, and PDGFRB fusions) and more than one-half
had JAK-STAT pathway lesions such as CRLF2 rearrangements with and without JAK2 mutations and other JAKSTAT alterations. In vivo and in vitro models have confrmed
response to ABL1 inhibitors and JAK1/2 inhibitors, respectively.26-28 There have now been numerous anecdotal reports of patients with ABL1 class fusions showing dramatic
responses to tyrosine kinase inhibitors.29,30 As a result, COG
plans to open a prospective trial comparing the outcome of
patients with ABL1 fusion treated with a combination of dasatinib and chemotherapy with a historic control of recently
treated patients (chemotherapy alone).
These two trials for ALK-positive ALCL and Ph-like ALL
(as well as the previous two COG studies for Ph ALL) illustrate the rapid integration of new agents for newly diagnosed
patients in a nonrandomized fashion. Preclinical data indicate that the targets are essential for tumorigenesis and early
experience (some anecdotal for Ph-like ALL) shows spectacular clinical effcacy. Given the strong biologic rationale and
preclinical data for certain targeted agents a randomized trial
may not always be feasible, and in this case the two trials differ remarkably in technical approaches. Simple ALK staining
indicates ALK activity, whereas, expression profling is being
e604
A pre-leukemic stem cell (LSC; light blue) gives rise to frank ALL (dark blue cells).
Intrinsically, drug-resistant clones (red) may be present and detected at diagnosis at low
levels in approximately 34% of cases. However, relapse might emerge from an ancestral
clone or LSC (52% of cases). LSCs and other subclones may survive initial treatment and
may acquire additional lesions that result in acquired drug resistance and relapsed disease
(52% of cases). Rarely, relapse clones are genetically distinct from that at diagnosis
(second malignancy; 6% of cases).33,45.
patients that consented to the study, clinically relevant mutations were identifed in 28% of tumor cases (22 of 80
cases).38 Similar data were obtained by another group profling high-risk and refractory pediatric solid tumors.39 Using
targeted NGS, Sequenom assay or array comparative
genomic hybridization individualized cancer therapy recommendations were made in 30% of cases based on profling
results.
In addition to WES, targeted NGS panels are currently being developed that are specifcally tailored to capture cancerrelated genes and introns of genes commonly rearranged in
pediatric tumors. The hybridization capture assay currently
offered by Foundation Medicine, which can be completed in
14 to 17 days, surveys 236 genes and 47 introns of genes commonly involved in chromosome translocations. Recent analysis of 400 cases profled by this method, consisting of both
solid and hematopoietic tumors, showed 60% of samples obtained at least one alteration associated with a FDA-approved
or experimental therapy in an open clinical trial.40 Although
these studies show that sequencing can lead to therapeutic
decisions, additional research is still needed to determine the
effect NGS has on overall survival and outcome.
Although most WES studies have focused on somatic variants, germ line data is also routinely profled in pediatric tumors
in tandem to provide an analysis of pathogenic mutations in
cancer susceptibility genes as well as mutations present in
nononcogenic-related diseases. In a large study surveying 565
genes in 1,120 pediatric cancers, 8.6% of patients were found to
have a pathologic or likely pathologic germ line variant.41 Likewise, 14% of cases harbored a predisposing pathogenic mutation in the germ line DNA in 80 solid tumor cases mentioned
previously.38 This demonstrates that the number of pediatric
cancers caused in part by inherited variation may be much
higher than anticipated previously, and in many of these cases a
family history was not suggestive of a predisposition. Additionally, the discovery of unanticipated incidental germline fndings
raises a considerable debate about the return of such information to patients.38 Early recommendations included mandatory
return of germ line results on 56 genes associated with 24 inherited conditions, but an early revision of this policy is that patients
may opt out from receiving such information.42
e605
markers and interventions are defned at the outset. The National Cancer Institute (NCI) MATCH prospective clinical trial
will open for patients age 18 or older in which standard therapy
has failed and who are willing to undergo a rebiopsy.44 Analysis
of approximately 200 genes that have been selected for alignment with a targeted agent will be performed in one of four
Clinical Laboratory Improvement Amendment-certifed laboratories. The trial will use FDA-approved drugs outside of their
indication as well as agents not yet approved but that have
shown activity in a given tumor type. The NCI MATCH study
will be open to all four adult cooperative groups. NCI is now
planning a Pediatric MATCH study with COG, thus, paving the
way for precision medicine for all COG members.
References
1. Schultz KR, Bowman WP, Aledo A, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a childrens oncology group study. J Clin Oncol.
2009;27:5175-5181.
2. Garraway LA. Genomics-driven oncology: framework for an emerging
paradigm. J Clin Oncol. 2013;31:1806-1814.
3. Janeway KA, Place AE, Kieran MW, et al. Future of clinical genomics in
pediatric oncology. J Clin Oncol. 2013;31:1893-1903.
4. Sheridan C. Illumina claims $1,000 genome win. Nat Biotechnol. 2014;
32:115.
5. Vogelstein B, Papadopoulos N, Velculescu VE, et al. Cancer genome
landscapes. Science. 2013;339:1546-1558.
6. Zhang J, Wu G, Miller CP, et al. Whole-genome sequencing identifes
genetic alterations in pediatric low-grade gliomas. Nat Genet. 2013;45:
602-612.
7. Lee RS, Stewart C, Carter SL, et al. A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. J Clin Invest. 2012;122:
2983-2988.
8. Jones C, Baker SJ. Unique genetic and epigenetic mechanisms driving
paediatric diffuse high-grade glioma. Nat Rev Cancer. 2014;14.
9. Maris JM. Recent advances in neuroblastoma. N Engl J Med. 2010;362:
2202-2211.
10. Pugh TJ, Morozova O, Attiyeh EF, et al. The genetic landscape of highrisk neuroblastoma. Nat Genet. 2013;45:279-284.
11. Puissant A, Frumm SM, Alexe G, et al. Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013;3:308-323.
12. Chipumuro E, Marco E, Christensen CL, et al. CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCNdriven cancer. Cell. 2014;159:1126-1139.
13. Brohl AS, Solomon DA, Chang W, et al. The genomic landscape of the
Ewing Sarcoma family of tumors reveals recurrent STAG2 mutation.
PLoS Genet. 2014;10:e1004475.
14. Tirode F, Surdez D, Ma X, et al. Genomic landscape of Ewing sarcoma
defnes an aggressive subtype with co-association of STAG2 and TP53
mutations. Cancer Discov. 2014;4:1342-1353.
15. Shern JF, Chen L, Chmielecki J, et al. Comprehensive genomic analysis
of rhabdomyosarcoma reveals a landscape of alterations affecting a
e606
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
ALL): Childrens Oncology Group (COG) Trial AALL0622. Paper presented at: American Society of Hematology ASH Annual Meeting and
Exposition; December 2012; Atlanta, GA.
Roberts KG, Li Y, Payne-Turner D, et al. Targetable kinase-activating
lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014;371:
1005-1015.
Roberts KG, Morin RD, Zhang J, et al. Genetic alterations activating
kinase and cytokine receptor signaling in high-risk acute lymphoblastic
leukemia. Cancer Cell. 2012;22:153-166.
Suryani S, Bracken LS, Harvey RC, et al. Evaluation of the in vitro and in
vivo effcacy of the JAK inhibitor AZD1480 against JAK-mutated acute
lymphoblastic leukemia. Mol Cancer Ther. 2015;14:364-374.
Weston BW, Hayden MA, Roberts KG, et al. Tyrosine kinase inhibitor
therapy induces remission in a patient with refractory EBF1-PDGFRBpositive acute lymphoblastic leukemia. J Clin Oncol. 2013;31:e413-e416.
Lengline E, Beldjord K, Dombret H, et al. Successful tyrosine kinase inhibitor therapy in a refractory B-cell precursor acute lymphoblastic leukemia with EBF1-PDGFRB fusion. Haematologica. 2013;98:e146-e148.
McGranahan N, Swanton C. Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell. 2015;27:15-26.
Anderson K, Lutz C, van Delft FW, et al. Genetic variegation of clonal
architecture and propagating cells in leukaemia. Nature. 2011;469:356361.
Mullighan CG, Phillips LA, Su X, et al. Genomic analysis of the clonal
origins of relapsed acute lymphoblastic leukemia. Science. 2008;322:
1377-1380.
Irving J, Matheson E, Minto L, et al. Ras pathway mutations are prevalent in relapsed childhood acute lymphoblastic leukemia and confer
sensitivity to MEK inhibition. Blood. 2014;124:3420-3430.
Rehm HL, Bale SJ, Bayrak-Toydemir P, et al. ACMG clinical laboratory
standards for next-generation sequencing. Genet Med. 2013;15:733-747.
Majewski J, Schwartzentruber J, Lalonde E, et al. What can exome sequencing do for you? J Med Genet. 2011;48:580-589.
e607
PEDIATRIC ONCOLOGY
SPEAKERS
Leontien C. Kremer, MD, PhD
Emma Childrens Hospital, Academic Medical Center
Amsterdam, Netherlands
Charles Sklar, MD
Memorial Sloan Kettering Cancer Center
New York, NY
Approaches to Reduce the Long-Term Burden of TreatmentRelated Complications in Survivors of Childhood Cancer
Saro H. Armenian, DO, MPH, Leontien C. Kremer, MD, PhD, and Charles Sklar, MD
OVERVIEW
Advances in diagnostics, treatment strategies, and supportive care have contributed to a marked improvement in outcomes for children
with cancer. This has resulted in a growing number of long-term childhood cancer survivors. Currently there are over 360,000
individuals who are survivors of childhood cancer in the United States. However, treatment for patients with childhood cancer with
chemotherapy, radiation, and/or hematopoietic stem cell transplantation can result in health-related complications that may not
become evident until years after completion of treatment. As a result, several initiatives have been established to help standardize the
surveillance for treatment-related late effects in childhood cancer survivors. This review highlights emerging concepts related to commonly
reported late effects, such as subsequent malignant neoplasms, cardiovascular disease, and endocrinopathies. It also discusses relevant
population-based screening strategies to mitigate the long-term health-related burden in vulnerable populations of survivors.
From the Department of Population Sciences, City of Hope, Duarte, CA; Department of Pediatric Oncology, Emma Childrens Hospital/Academic Medical Center, Amsterdam, Netherlands;
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Saro H. Armenian, DO, MPH, City of Hope, 1500 East Duarte Rd., Duarte, CA 91010-3000; email: sarmenian@coh.org.
2015 by American Society of Clinical Oncology.
196
KEY POINTS
There are a growing number of long-term survivors of
childhood cancer at risk for treatment-related
complications later in life.
There are well-established associations between
therapeutic exposures and adverse health-related outcomes
such as subsequent malignant neoplasms, cardiovascular
disease, and endocrinopathies.
A number of risk-based exposure-related guidelines have
been established to facilitate the long-term follow-up care
of childhood cancer survivors.
These surveillance guidelines are an integral component of
the lifelong follow-up of childhood cancer survivors.
Studies are needed to evaluate the efcacy of these
recommendations in survivors who have the highest risk
for treatment-related complications.
197
Cancer Treatment
Screening Tests
Breast Cancer
Females:
Clinical breast exam yearly beginning at puberty until age 25, then every 6 mo
Mammogram and breast MRI yearly for patients who received 20 Gy beginning 8 yr
after radiation or at age 25, whichever occurs last. For patients who received 10-19 Gy,
clinicians should discuss benets and risks/harms of screening with patients.
Thyroid Cancer
Brain Tumor
Cranial irradiation
Skin Cancer
Colorectal Cancer
Abdominal/pelvic irradiation
Spinal irradiation
tMDS/AML
Abbreviations: mo, months; yr, years; tMDS, trilineage myelodysplasia; AML, acute myeloid leukemia.
Chemotherapy-Related TMDS/AML
Survivors treated with alkylating agents (e.g., cyclophosphamide, ifosfamide, mechlorethamine, melphalan, busulfan,
nitrosureas, chlorambucil, dacarbizine, and platinum compounds) or topoisomerase-II inhibitors (e.g., epidophyllotoxins, anthracyclines) are at risk for developing tMDS/
AML.18,42 The risk of alkylating-agentassociated tMDS/
AML is dose-dependent, with a latency of 3 to 5 years after
exposure. Typically, it is associated with cytogenetic abnormalities involving chromosomes 5 (5/del[5q]) and 7 (7/
del[7q]). Topoisomerase-II inhibitor-related tMDS/AML
has a shorter latency ( 3 years), and is associated with balanced translocations involving chromosome bands 11q23 or
21q22.18,42
Since chemotherapy-related tMDS/AML usually develops
by 10 years after exposure to these agents, current recommendations are to monitor at-risk survivors with a targeted
history and physical examination for up to 10 years postexposure.5 A complete blood count and bone marrow examination may be warranted for those with a history or physical
examination fndings suspicious for tMDS/AML (e.g., easy
bruising, fatigue, pallor, and petechiae).5
CARDIOVASCULAR DISEASE
Cardiovascular disease is a major health problem in children
and adults after treatment for childhood cancer.43 In fact,
childhood cancer survivors have a sevenfold increased risk of
cardiac death when compared with the general population.
198
Cardiomyopathy
Childhood cancer survivors treated with cardiotoxic therapies (anthracycline chemotherapy and/or chest radiation)
are at risk for developing asymptomatic cardiomyopathy that
can progress to symptomatic heart failure over time.43 The
risk of heart failure is 15-fold greater in survivors of childhood cancer when compared to the general population,3 and
there is a dose-dependent association with anthracycline
(doxorubicin, daunorubicin, epirubicin, idarubicin, and mitoxantrone) chemotherapy and risk of heart failure. This risk
is further increased by exposure to chest radiation.43 Among
anthracycline-exposed survivors, asymptomatic cardiomyopathy is characterized by a decrease in left ventricular systolic function, which often presents with a clinical picture
similar to dilated cardiomyopathy.43 Patients treated with
phy on later outcomes, such as heart failure or cardiac mortality. However, decision-modeling studies52,53 have found
that echocardiographic screening in survivors of childhood
cancer can be cost-effective when compared to no screening,
which supports the screening recommendations outlined
below.
Echocardiography should be used as the primary cardiomyopathy surveillance modality for assessment of left
ventricular systolic function in survivors treated with anthracyclines or chest radiation.11 Screening with radionuclide angiography or CMR may be considered in patients for whom
echocardiography is not technically feasible or optimal. Additional diagnostic studies, such as cardiac blood biomarkers,
should be considered in conjunction with imaging, based on
availability of resources and clinical suspicion for cardiac
dysfunction.11
199
Additional Considerations
Studies conducted of nononcology populations support the
benefts of interventions to reduce modifable risk factors,
such as obesity, smoking, hypertension, diabetes, and dyslipidemia.56,57 Childhood cancer survivors are at a higher risk of
developing many of these conditions when compared to the
general population, which places them at increased risk of
developing cardiovascular disease.58,59 In fact, survivors with
hypertension or diabetes in addition to past exposure to anthracyclines and/or radiation are at an especially high risk of
developing cardiomyopathy and heart failure.60 Findings
from studies of nononcology populations strongly suggest
that routine screening for these risk factors can be benefcial
and set the stage for interventions (e.g., lifestyle modifcation
and pharmacologic therapy) to mitigate adverse cardiovascular outcomes. Lastly, cardioprotectants such as dexrazoxane have been shown to minimize cardiac injury shortly after
anthracycline administration without compromising its
anti-tumor effcacy.61,62 However, long-term data on effcacy
of dexrazoxane is lacking. Studies are needed to address this
gap in knowledge, setting the stage for the implementation of
primary prevention strategies in survivors at highest risk for
developing cardiovascular disease.
Hyperthyroidism. Treatment-related hyperthyroidism occurs less often than primary hypothyroidism in childhood
cancer survivors. It most often results after exposure of the
thyroid gland to radiation. In survivors of HL, a radiation
dose of more than 35 Gy to the thyroid has been identifed as
a risk factor for developing hyperthyroidism.63 Survivors of
acute lymphoblastic leukemia treated with a radiation dose of
more than 15 Gy to the thyroid also appear to have an increased risk of hyperthyroidism.64 Immune-mediated hyperthyroidism, as a result of adoptive transfer of abnormal
clones of T or B cells from donor to recipient, also has been
reported after stem cell transplantation.73
Given the low incidence of hyperthyroidism, routine screening is not currently recommended. However, at-risk survivors
who present with clinical signs or symptoms (e.g., unexplained
weight loss, tachycardia, bilateral exophthalmos, or goiter) suggestive of hyperthyroidism should have, at minimum, a blood
level of TSH. A TSH level below the lower limit of normal is
highly suggestive of a diagnosis of hyperthyroidism and warrants referral to an endocrinologist for further work up.
Thyroid Disorders
The human testis has two primary functions: sperm production and testosterone production. One or both of these functions may be negatively affected by cancer treatment. Germ
cells and Sertoli cells form the seminiferous tubules in which
spermatogenesis occurs; Leydig cells are responsible for the
production of testosterone.
Primary hypothyroidism. Primary hypothyroidism frequently occurs after treatment for patients with childhood
cancer. Survivors at risk include those treated with radiation
to the thyroid gland, including nasopharyngeal, cervical,
mantle/supraclavicular, and craniospinal felds, as well as
those exposed to TBI.63-67 The risk of primary hypothyroidism is observed beginning at about 10 Gy of thyroidal irradiation and it increases as the dose of radiation increases above
this dose.63 The risk is greatest within the frst 5 years after
radiation, but it continues to increase over time. Other risk
factors include female sex, white race, and older age at diagnosis.63
Patients treated with radiolabeled agents, such as 131-Imetaiodobenzylguanidine68,69 or 131-I-labeled monoclonal
antibody,70,71 and those treated with tyrosine kinase inhibitors,73 also are at risk. Although standard-dose chemotherapy alone does not appear to be a risk factor for hypothyroidism,63 patients who have received stem cell transplants
following treatment with myeloablative doses of alkylating
agents (e.g., busulfan and cyclophosphamide) are at increased risk for developing primary hypothyroidism.73
At-risk childhood cancer survivors should have their thyroid function serially monitored, generally at least annually.
Measurement of plasma levels of thyroid-stimulating hormone (TSH) is the most sensitive means of diagnosing primary hypothyroidism (Table 2). Since hypothyroidism can
develop more than 25 years after cancer treatment, the need
for lifelong screening is essential.74
ENDOCRINE COMPLICATIONS
200
Cancer Treatment
Screening Tests
Thyroid Dysfunction
TSH, Free T4
Gonadal Dysfunction
(Female)
Alkylating agents
Nitrosoureas
Cisplatin
Radiation to the gonads
Gonadal Dysfunction
(Male)
Alkylating agents
Nitrosoureas
Cisplatin
Radiation to the gonads
Abbreviations: LH, luteinizing hormone; FSH, follicle stimulating hormone; TSH, thyroid
stimulating hormone.
CONCLUSION
Research on survivorship-related issues has identifed important associations between certain therapeutic exposures
and long-term complications in survivors of childhood cancer. This has facilitated the development of a number of
recommendations for early screening in asymptomatic surasco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
201
vivors. Ongoing studies exploring gene-environment interactions92 continue to refne our understanding of high-risk
categories. Studies are needed to integrate emerging information on genetic susceptibility with established clinical risk
factors. Novel interventions aimed at reducing the long-term
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Charles Sklar, Sandoz. Consulting or Advisory
Role: None. Speakers Bureau: None. Research Funding: None. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None.
Travel, Accommodations, Expenses: Charles Sklar, Sandoz. Other Relationships: None.
References
1. Mariotto AB, Rowland JH, Yabroff KR, et al. Long-term survivors of
childhood cancers in the United States. Cancer Epidemiol Biomarkers
Prev. 2009;18:1033-1040.
2. Armenian SH, Landier W, Hudson MM, et al. Childrens Oncology
Groups 2013 blueprint for research: survivorship and outcomes. Pediatr Blood Cancer. 2013;60:1063-1068.
3. Oeffnger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med. 2006;355:
1572-1582.
4. Landier W, Armenian S, Bhatia S. Late effects of childhood cancer and
its treatment. Pediatr Clin North Am. 2015;62:275-300.
5. Childrens Oncology Group. Long-term follow-up guidelines for survivors of childhood, adolescent and young adult cancer. www.survivor
shipguidelines.org. 2014.
6. Mud MS, Kremer LC, Sieswerda E, et al. Care for survivors of childhood
cancer in the Netherlands. Ned Tijdschr Geneeskd. 2012;156:A4199.
7. United Kingdom Childrens Cancer Study Group Late Effects Group.
Therapy based long term follow up practice statement. http://www.cclg.
org.uk/dynamic_fles/LTFU-full.pdf. Accessed January 15, 2015.
8. Scottish Intercollegiate Guidelines Network. Long term follow up of
survivors of childhood cancer: a national clinical guideline. 2013.
www.sign.ac.uk/. Accessed January 15, 2015.
9. Kremer LC, Mulder RL, Oeffnger KC, et al. A worldwide collaboration
to harmonize guidelines for the long-term follow-up of childhood and
young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Pediatr
Blood Cancer. 2013;60:543-549.
10. Mulder RL, Kremer LC, Hudson MM, et al. Recommendations for
breast cancer surveillance for female survivors of childhood, adolescent,
and young adult cancer given chest radiation: a report from the International Late Effects of Childhood Cancer Guideline Harmonization
Group. Lancet Oncol. 2013;14:e621-e629.
11. Armenian SH, Hudson MM, Mulder RL, et al. Recommendations for
veillance for breast cancer in women treated with chest radiation for
from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol. 2015;16:e123-e136.
12. Mertens AC, Yong J, Dietz AC, et al. Conditional survival in pediatric
malignancies: analysis of data from the Childhood Cancer Survivor
202
152:444-455; W144-W154.
23. Travis LB, Hill DA, Dores GM, et al. Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease.
JAMA. 2003;290:465-475.
24. Moskowitz CS, Chou JF, Wolden SL, et al. Breast cancer after chest radiation therapy for childhood cancer. J Clin Oncol. 2014;32:2217-2223.
25. Inskip PD, Robison LL, Stovall M, et al. Radiation dose and breast can-
44. Felker GM, Thompson RE, Hare JM, et al. Underlying causes and long-
cer risk in the childhood cancer survivor study. J Clin Oncol. 2009;27:
3901-3907.
45. Sieswerda E, Postma A, van Dalen EC, et al. The Dutch Childhood On-
30. Veiga LH, Bhatti P, Ronckers CM, et al. Chemotherapy and thyroid can-
cer risk: a report from the childhood cancer survivor study. Cancer Epi-
Oncol. 2012;30:1415-1421.
49. Armenian SH, Gelehrter SK, Vase T, et al. Screening for cardiac dysfunction in anthracycline-exposed childhood cancer survivors. Clin
Cancer Res. 2014;20:6314-6323.
50. Hudson MM, Rai SN, Nunez C, et al. Noninvasive evaluation of late
anthracycline cardiac toxicity in childhood cancer survivors. J Clin Oncol. 2007;25:3635-3643.
51. Armstrong GT, Plana JC, Zhang N, et al. Screening adult survivors of
childhood cancer for cardiomyopathy: comparison of echocardiography and cardiac magnetic resonance imaging. J Clin Oncol. 2012;30:
2876-2884.
52. Yeh JM, Nohria A, Diller L. Routine echocardiography screening for
asymptomatic left ventricular dysfunction in childhood cancer survivors: a model-based estimation of the clinical and economic effects. Ann
Intern Med. 2014;160:661-671.
53. Wong FL, Bhatia S, Landier W, et al. Cost-effectiveness of the childrens
oncology group long-term follow-up screening guidelines for childhood cancer survivors at risk for treatment-related heart failure. Ann
Intern Med. 2014;160:672-683.
54. Rosenthal D, Chrisant MR, Edens E, et al. International Society for
Heart and Lung Transplantation: practice guidelines for management
of heart failure in children. J Heart Lung Transplant. 2004;23:1313-1333.
55. Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update incorpo-
38. Wong JR, Morton LM, Tucker MA, et al. Risk of subsequent malignant
rated into the ACC/AHA 2005 guidelines for the diagnosis and man-
39. Kleinerman RA, Tucker MA, Tarone RE, et al. Risk of new cancers after
53:e1-e90.
56. Smith SC Jr, Collins A, Ferrari R, et al. Our time: a call to save prevent-
43. Lipshultz SE, Adams MJ, Colan SD, et al. Long-term cardiovascular tox-
58. Meacham LR, Chow EJ, Ness KK, et al. Cardiovascular risk factors in
icity in children, adolescents, and young adults who receive cancer ther-
203
59. Oeffnger KC, Adams-Huet B, Victor RG, et al. Insulin resistance and
risk factors for cardiovascular disease in young adult survivors of childhood acute lymphoblastic leukemia. J Clin Oncol. 2009;27:3698-3704.
60. Armstrong GT, Oeffnger KC, Chen Y, et al. Modifable risk factors and
major cardiac events among adult survivors of childhood cancer. J Clin
Oncol. 2013;31:3673-3680.
61. van Dalen EC, Caron HN, Dickinson HO, et al. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev. 2008:CD003917.
62. Lipshultz SE, Scully RE, Lipsitz SR, et al. Assessment of dexrazoxane as
a cardioprotectant in doxorubicin-treated children with high-risk acute
lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial. Lancet Oncol. 2010;11:950-961.
63. Sklar C, Whitton J, Mertens A, et al. Abnormalities of the thyroid in
survivors of Hodgkins disease: data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab. 2000;85:3227-3232.
64. Chow EJ, Friedman DL, Stovall M, et al. Risk of thyroid dysfunction and
subsequent thyroid cancer among survivors of acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. Pediatr
Blood Cancer. 2009;53:432-437.
65. Laughton SJ, Merchant TE, Sklar CA, et al. Endocrine outcomes for children with embryonal brain tumors after risk-adapted craniospinal and
conformal primary-site irradiation and high-dose chemotherapy with
stem-cell rescue on the SJMB-96 trial. J Clin Oncol. 2008;26:1112-1118.
66. Hancock SL, Cox RS, McDougall IR. Thyroid diseases after treatment of
Hodgkins disease. N Engl J Med. 1991;325:599-605.
67. Boulad F, Bromley M, Black P, et al. Thyroid dysfunction following
bone marrow transplantation using hyperfractionated radiation. Bone
Marrow Transplant. 1995;15:71-76.
68. Picco P, Garaventa A, Claudiani F, et al. Primary hypothyroidism and
131I-MIBG therapy in neuroblastoma. Lancet. 1993;342:57.
69. van Santen HM, de Kraker J, van Eck BL, et al. High incidence of thyroid
dysfunction despite prophylaxis with potassium iodide during (131)Imeta-iodobenzylguanidine treatment in children with neuroblastoma.
Cancer. 2002;94:2081-2089.
70. Laverdie`re C, Cheung NK, Kushner BH, et al. Long-term complications
in survivors of advanced stage neuroblastoma. Pediatr Blood Cancer.
2005;45:324-332.
71. Bhandari S, Cheung NK, Kushner BH, et al. Hypothyroidism after 131Imonoclonal antibody treatment of neuroblastoma. Pediatr Blood Cancer. 2010;55:76-80.
72. Torino F, Corsello SM, Longo R, et al. Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy.
Nat Rev Clin Oncol. 2009;6:219-228.
73. Chemaitilly W, Sklar CA. Endocrine complications of hematopoietic
stem cell transplantation. Endocrinol Metab Clin North Am. 2007;36:
983-998;ix.
74. Chemaitilly W, Sklar CA. Endocrine complications in long-term survivors of childhood cancers. Endocr Relat Cancer. 2010;17:R141-R159.
75. Green DM, Kawashima T, Stovall M, et al. Fertility of male survivors of
childhood cancer: a report from the Childhood Cancer Survivor Study.
J Clin Oncol. 2010;28:332-339.
76. Kenney LB, Cohen LE, Shnorhavorian M, et al. Male reproductive
health after childhood, adolescent, and young adult cancers: a report
from the Childrens Oncology Group. J Clin Oncol. 2012;30:3408-3416.
204
77. Green DM, Liu W, Kutteh WH, et al. Cumulative alkylating agent
exposure and semen parameters in adult survivors of childhood cancer: a report from the St, Jude Lifetime Cohort Study. Lancet Oncol.
2014;15:1215-1223.
78. Green DM, Zhu L, Zhang N, et al. Lack of specifcity of plasma concentrations of inhibin B and follicle-stimulating hormone for identifcation
of azoospermic survivors of childhood cancer: a report from the St. Jude
lifetime cohort study. J Clin Oncol. 2013;31:1324-1328.
79. Sklar C. Reproductive physiology and treatment-related loss of sex hormone production. Med Pediatr Oncol. 1999;33:2-8.
80. Shalet SM, Horner A, Ahmed SR, et al. Leydig cell damage after testicular irradiation for lymphoblastic leukaemia. Med Pediatr Oncol. 1985;
13:65-68.
81. Metzger ML, Meacham LR, Patterson B, et al. Female reproductive
health after childhood, adolescent, and young adult cancers: guidelines
for the assessment and management of female reproductive complications. J Clin Oncol. 2013;31:1239-1247.
82. Chemaitilly W, Mertens AC, Mitby P, et al. Acute ovarian failure in the
childhood cancer survivor study. J Clin Endocrinol Metab. 2006;91:
1723-1728.
83. Sklar CA, Mertens AC, Mitby P, et al. Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor
study. J Natl Cancer Inst. 2006;98:890-896.
84. Michel G, Socie G, Gebhard F, et al. Late effects of allogeneic bone marrow transplantation for children with acute myeloblastic leukemia in
frst complete remission: the impact of conditioning regimen without
total-body irradiationa report from the Societe Francaise de Greffe de
Moelle. J Clin Oncol. 1997;15:2238-2246.
85. Green DM, Sklar CA, Boice JD Jr, et al. Ovarian failure and reproductive
outcomes after childhood cancer treatment: results from the Childhood
Cancer Survivor Study. J Clin Oncol. 2009;27:2374-2381.
86. Barton SE, Najita JS, Ginsburg ES, et al. Infertility, infertility treatment,
and achievement of pregnancy in female survivors of childhood cancer:
a report from the Childhood Cancer Survivor Study cohort. Lancet Oncol. 2013;14:873-881.
87. Green DM, Whitton JA, Stovall M, et al. Pregnancy outcome of female
survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Am J Obstet Gynecol. 2002;187:1070-1080.
88. Signorello LB, Mulvihill JJ, Green DM, et al. Stillbirth and neonatal
death in relation to radiation exposure before conception: a retrospective cohort study. Lancet. 2010;376:624-630.
89. Signorello LB, Mulvihill JJ, Green DM, et al. Congenital anomalies in the
children of cancer survivors: a report from the childhood cancer survivor study. J Clin Oncol. 2012;30:239-245.
90. Winther JF, Olsen JH, Wu H, et al. Genetic disease in the children of
Danish survivors of childhood and adolescent cancer. J Clin Oncol.
2012;30:27-33.
91. Lie Fong S, Visser JA, Welt CK, et al. Serum anti-mullerian hormone
levels in healthy females: a nomogram ranging from infancy to adulthood. J Clin Endocrinol Metab. 2012;97:4650-4655.
92. Armenian SH, Bhatia S. Chronic health conditions in childhood cancer
survivors: is it all treatment-related or do genetics play a role? J Gen
Intern Med. 2009;24:S395-S400 (suppl 2).
PROFESSIONAL DEVELOPMENT
SPEAKERS
Michael A. Thompson, MD, PhD
Aurora Research Institute
Milwaukee, WI
Laura E. Strong, PhD
Quintessence Biosciences, Inc.
Madison, WI
From the Division of Hematology/Oncology, Department of Medicine, Vanderbilt University, Nashville, TN; Department of Biomedical Informatics, Vanderbilt University, Nashville, TN.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Jeremy L. Warner, 2220 Pierce Ave., Preston Research Building 777, Nashville, TN 37232; email: jeremy.warner@vanderbilt.edu.
2015 by American Society of Clinical Oncology.
e608
PubMed
Every website is a circle on the map, and its size is determined by website trafcthe
larger the amount of trafc, the bigger the circle (Google.com is the largest). Color is
based on the country where the website is hosted (teal being the United States). Users
switching between websites form links, and the stronger the link, the closer the websites
tend to arrange themselves to each other.
Permission to reproduce granted by Ruslan Enikeev.
media outlets of interest to the medical practitioner. Although we have attempted to be exhaustive in this overview,
we apologize in advance for any unintentional oversights or
omissions.
KEY POINTS
The Internet is vast and is now used on a regular basis by
the majority of physicians, especially those that were born
into the digital generation.
The organization of the Internet can be understood by
applying the data, information, knowledge, wisdom
management framework.
General medical knowledge bases (e.g., PubMed, UpToDate,
and Wikipedia) each have advantages and disadvantages for
the practicing oncologist.
There are an increasing number of oncology-specic
website resources, including those maintained by
professional organizations such as the American Society of
Clinical Oncology and unafliated entities.
Social media will take a role of increasing importance for
the practicing oncologist, although it must be approached
with caution, especially given the for-prot nature of many
of the current endeavors.
Developed and maintained by the National Center for Biotechnology Information, PubMed is a free online search engine of the MEDLINE database containing over 24-million
citations of biomedical and health literature.9 The primary
user interface consists of a single search feld, but multiple
advanced search options are possible using specifc flters and
syntax. Given the vast size of the MEDLINE database (Fig. 2),
searches to produce only relevant articles are diffcult. Using
multiple search terms, Booleans, and additional search tools
will produce more relevant results.10 Some training programs, such as the University of California, San Franciscos
Program in Medical Education for the Urban Underserved,11
explicitly teach searching strategies. For most currently practicing clinicians, optimizing the use of PubMed is an example
of on-the-job training. PubMed indexes large amounts of
biomedical literature in near real time; therefore, it is likely to
outperform other information resources when searching for
recently published information, primary literature, or uncommon questions. However, for general questions other information resources could be considered.
Google
The most popular search engine in the world, Google
(Google Inc. Mountain View, CA), is a common starting
point for medical queries. The algorithm by which Google
produces search results, PageRank, performs numerical
weighting to websites based on the number and authoritativeness of webpages that link to them.12 This produces
search results based on relevancy to the entire population of
Internet users. Google Scholar (scholar.google.com) restricts
searches to scientifc literature, such as conference proceedings (which are not generally indexed in MEDLINE). Since a
physician-specifc version of Google does not exist, using generic terms would be more likely to return websites without
information directed specifcally at clinicians.13 A savvy
googler would use technical terminology for search terms
that would be specifc to sources directed at clinicians.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e609
In 2014, 154,654 articles referencing cancer were added to MEDLINE. This amounts to a new article approximately every 3 minutes for the entire year. Extracting utility from this deluge of
information for a clinician is impossible without the help of digital searches and information aggregators. Depending on the resource used and the information sought, different strategies must
be employed to efciently nd accurate information.
UptoDate
The subscription service UpToDate (Wolters Kluwer NV,
Alphen aan den Rijn, the Netherlands) provides original content rather than aggregation of existing resources. The oncology content is provided via two editors in chief, three deputy
editors, 35 section editors, and approximately 1,100 authors.14 Article content draws from primary articles, national
guidelines, text books, and expert opinion to generate knowledge and wisdom. Insomuch as there is variation in clinical
practice; articles can also represent these regional, institutional, or personal variations. Although articles are updated
continuously, the human authors do not necessarily update
content immediately on newly published evidence. The
trade-off for this content curation is a fltering of irrelevant
information that encumbers searches of the primary literature, such that searching content in UpToDate results in satisfactory answers faster than a search engine such as
PubMed.15,16 For clinicians who have access to UpToDate, it
can serve as an effcient means of reviewing clinical content
but would require additional searching to fnd breaking
news information or primary literature.
Ovid
Another Wolters Kluwer subscription service, Ovid is a content aggregator that provides searches across 307 books, 74
journals, 12 databases, and nine collections of oncology content predominantly published by Wolters Kluwer.17 Additionally, OvidMD is a curated resource for clinician queries
optimized to return clinically relevant results. The OvidMD
e610
Medscape
Similar to Ovid, Medscape (WebMD, New York City, NY) is
a hybrid of content aggregator with authors of reviews and
literature synopses; however, in contrast it is free to use but
requires a login. Additionally, Medscape and its parent company, WebMD, exist in a content zone targeting somewhere
between medical professional and lay audience. Medscape
has not been evaluated against other information resources
in the published literature.
Wikipedia
Wikipedia (Wikimedia Foundation, Inc., San Francisco, CA)
is a free online encyclopedia and has 4,704,035 articles in
English (as of January 25, 2015). Any individual can edit articles on any topic, although in practice the number of contributors compared to users is quite small.18 It is neither
medical- nor oncology-specifc in its content. Initially, based
on several high-profle inaccuracies mostly pertaining to malicious individuals or state actors, there was skepticism about
the accuracy and reliability of Wikipedia as a knowledge
source.19 Outside of this concern over factual inaccuracy,
concerns about incompleteness, especially in the medical
arena, have also persisted.20 For example, a study comparing
Wikipedia to the Medscape Drug Reference in 2008 found a
lack of information such as dosing (0% versus 90%, respectively). However, several recent studies have demonstrated
that Wikipedia has markedly improved with regards to
health information. In 2014, Kraenbring et al systematically
compared the accuracy and completeness of drug information in the German and English language versions of Wikipedia to several standard pharmacology textbooks. They
found that the accuracy of the drug information in Wikipedia
was 99.7% 0.2% when compared with the textbook data.22
Completeness was less robust but still reasonable, at 85%. To
our knowledge, no published article has systematically addressed the information content of clinician-oriented,
cancer-related articles in Wikipedia (patient-oriented content has previously been examined).23 Some have suggested
that medical Wikipedia articles be subject to formal peer review,24 although this is unlikely to become commonplace.
Given the uneven content coverage and the lack of editorial
controls, answers from Wikipedia for clinical queries would
likely need cross-validation from other sources to be accepted confdently.
ClinicalTrials.gov
As opposed to the resources described above, which are primarily educational, ClinicalTrials.gov is devoted to the identifcation of clinical trials. At frst a voluntary registry,
registration for most types of clinical trials became mandatory after the passing of Section 801 of the U.S. Food and
Drug Administration Amendments Act of 2007 on September 27, 2007. Once a trial is registered, it is given a National
Clinical Trials (NCT) number that can then be used to trace
the trials status and associated published results. With some
practice, a clinician or patient user can quickly locate open
trials by region, and scan at least the basic eligibility criteria.
Less robust are the results section of each trial, although an
notice of proposed rule making was recently issued to encourage more transparent reporting of trial results.25 Thus,
this portal will become increasingly useful to practicing oncologists both as a means of identifying clinical trials outside
of their home institution and learning about results of completed trials.
UNAFFILIATED SITES
There are many efforts by individuals, institutions, and other
collaborations that aim to bring oncology information to
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e611
Acronym
URL
ACS
cancer.org
AcoS
facs.org
AJCC
cancerstaging.org
ASTRO
astro.org
ASH
hematology.org
CDC
cdc.gov/cancer
CAP
cap.org
EHA
ehaweb.org
ESMO
esmo.org
NCI
cancer.gov
NCCN
nccn.org
ONS
ons.org
RSNA
rsna.org
practitioners. Unfortunately, oftentimes the result is a needless duplication of effort. Here, we focus on a few mostly notfor-proft endeavors that offer a fairly unique, extensive, or
centralized source of information.
HemOnc.org
This knowledge base for chemotherapy regimens and antineoplastic drugs began 2011 as a freely available collaborative
Notes
For each regimen variant, a table has a link directly to the original published article and links to comparator regimens in the case of randomized trials (as shown here). Level of evidence and
comparative efcacy as reported in the original literature (for randomized trials) are shown using a simple green-yellow-red schema. Below this table, the regimen details are shown with links
to individual drug pages for each drug. When relevant, additional links to external sites are provided, such as the link to the ASCO guidelines for the use of G-CSF. Not shown are ve
additional R-CHOP variants, 10 references to the original studies, and two references to updates of the original studies.
e612
URL
Description
Access Restrictions
Adjuvant Online
adjuvantonline.com/index.jsp
Requires registration
of free account
BloodRef.com
bloodref.com
Free to use
www-users.med.cornell.edu/spon/
picu/calc/bsacalc.htm
Free to use
CancerMath.net
cancer.lifemath.net
Free to use
ePocrates
epocrates.com
ePrognosis
eprognosis.ucsf.edu
Free to use
labs.fccc.edu/nomograms/
www.healthcare.uiowa.edu/igec/tools/
Free to use
globalrph.com/medcalcs.htm
Free to use
skynet.ohsu.edu/nomograms/
Free to use
socialsecurity.gov/OACT/population/
longevity.html
Free to use
.mcw.edu/MCW-Health-Calculators.htm
Free to use
mdanderson.org/education-and-research/
resources-for-professionals/clinicaltools-and-resources/clinicalcalculators/index.html
Free to use
MDCalc
mdcalc.com
Free to use
Medal
medal.org
Requires registration
of free account
Medscape
reference.Medscape.com/guide/medicalcalculators
Free to use
melanomaprognosis.org/
Free to use
mskcc.org/nomograms
QxMD
qxmd.com/calculate-online/hematology
Free to use
bmt.stanford.edu/calculators
Free to use
WolframAlpha
https://www.wolframalpha.com/
Free to use
e613
MyCancerGenome.org
MyCancerGenome.org was established in 2011 by the
Vanderbilt-Ingram Cancer Center as part of their personalized cancer medicine initiative.30,31 The goal is to provide a
portal for genotype-specifc cancer information, along with
links to genotype-directed clinical trials. The site contains extensive information on 21 types of cancer and many associated genes; it is regularly visited by a worldwide audience.
The content of MyCancerGenome.org is now licensed
through GenomOncology LLP (Cleveland, OH).
Oncolink.org
This website was established by the University of Pennsylvania in 1994 and contains a wealth of information that is primarily patient-oriented. However, there are also some useful
resources for the practicing oncologist, including links to
continuing medical education activities and prebuilt teaching sheet bundles for common chemotherapy regimens.
users create their own nomograms through a simple interface. Table 2 lists several of these resources.
SOCIAL MEDIA
The implications of social media for the practicing oncologist
are just beginning to be realized. These include both the beneft of networking with colleagues as well as the challenge of
presenting a professional identity and of interacting with patients in this arena. Tips on how to best use social media and
links to some of the most important social media outlets can
be found on the ASCO social media microsite (asco.org/
about-asco/social-media). Table 3 lists the social media portals likely to be of most interest to practicing oncologists. Note
that in distinction from the previously mentioned resources, a
majority of these sites are for-proft, although a majority are also
free to join, with some (notably LinkedIn) providing a basic
and premier access tier. A recent content analysis of healthrelated content on Facebook raises a red flag: the most common
type of page (32.2% of results) was marketing or promotional.33
Another study of Twitter prostate and breast cancer communities (defned through the social relationships of community
members) found that health organizations and news media, despite their focus on health, did not play a signifcant role in the
core communities, suggesting a disconnect between patients
and practitioners.34 It is not clear at this time which of these
many social media outlets will become the preferred site for
oncologists, and whether oncology-specifc social media outlets
will emerge.
Online Calculators
In addition to the more extensive sites described above, there
are many purpose-built resources such as online calculators
for diagnosis, prognosis, chemotherapy dosing, and other areas that may be of interest to the practicing oncologist. Some
sites, for example, Cleveland Clinics R-Calc (r-calc.com) let
CONCLUSION
As the complexity of cancer care accelerates, the need for
knowledge has never been greater. Fortunately, the Internet
offers a wealth of knowledge. In fact, the problem is not a lack
of information but the ability to quickly identify the best
URL
Notes
doc2doc
doc2doc.bmj.com
A community of doctors and health care providers run by the British Medical Journal
Doximity
doximity.com
Claims 50% of U.S. doctors are veried members; the single largest physician-specic social network
ecancer.org
ecancer.org
Claims to be the leading oncology channel; mainly a source of oncology news with some social media features
facebook.com
plus.google.com
linkedin.com
OncLive
onclive.com
Ozmosis
ozmosis.org
In addition to social networking, the site also provides virtual grand rounds, clinical cases, and journal club
ResearchGate
researchgate.net
Mission is stated as to connect researchers and make it easy for them to share and access scientic output,
knowledge, and expertise
SERMO
sermo.com
Claims 40% of U.S. doctors are veried members. They focus on allowing anonymous discussions between physicians.
Storify
storify.com/ASCO
twitter.com/
YouTube
youtube.com/
e614
References
1. Berners-Lee T, Cailliau R. WorldWideWeb: Proposal for a HyperText
Project. http://www.w3.org/Proposal.html. Published November 12,
1990. Accessed February 16, 2015.
2. Netcraft. January 2015 Web Server Survey. http://news.netcraft.com/
archives/category/web-server-survey/. Published January 15, 2015. Accessed February 16, 2015.
3. Sandars J, Morrison C. What is the Net Generation? The challenge for
future medical education. Med Teach. 2007;29:85-88.
4. Hughes B, Joshi I, Lemonde H, et al. Junior physicians use of Web 2.0
for information seeking and medical education: a qualitative study. Int
J Med Inform. 2009;78:645-655.
5. Rowley J. The wisdom hierarchy: representations of the DIKW hierarchy. J Inf Sci. 2007;33:163-180.
6. Boulding K. Notes on the information concept. Exploration. 1955;6:
103-112.
7. Matney S, Brewster PJ, Sward KA, et al. Philosophical approaches to the
nursing informatics data-information-knowledge-wisdom framework.
ANS Adv Nurs Sci. 2011;34:6-18.
8. Thiele RH, Poiro NC, Scalzo DC, et al. Speed, accuracy, and confdence
in Google, Ovid, PubMed, and UpToDate: Results of a randomised trial.
Postgrad Med J. 2010;86:459-465.
9. PubMed: MEDLINE Retrieval on the World Wide Web Fact Sheet.
National Institutes of Health U.S. National Libraries of Medicine.
http://www.nlm.nih.gov/pubs/factsheets/pubmed.html. Published June 7,
2002. Updated August 27, 2014. Accessed February 16, 2015.
10. Hoogendam A, Stalenhoef AF, Robbe PF, et al. Analysis of queries
sent to PubMed at the point of care: observation of search behaviour
in a medical teaching hospital. BMC Med Inform Decis Mak. 2008;
8:42.
11. Kohlwes RJ, Shunk RL, Avins A, et al. The PRIME curriculum. Clinical research training during residency. J Gen Intern Med. 2006;21:
506-509.
12. Brin S, Page L. The anatomy of a large-scale hypertextual Web search
engine. Computer networks and ISDN systems. 1998;30:107-117.
13. Falagas ME, Pitsouni EI, Malietzis GA, et al. Comparison of PubMed,
Scopus, Web of Science, and Google Scholar: strengths and weaknesses.
FASEB J. 2008;22:338-342.
14. Wolters Kluwer Health. Physician Authors and Editors. http://www.
uptodate.com/home/physician-authors-and-editors. Accessed February 1, 2015.
15. Ensan LS, Faghankhani M, Javanbakht A, et al. To compare PubMed
Clinical Queries and UpToDate in teaching information mastery to
clinical residents: a crossover randomized controlled trial. PLoS One.
2011;6:e23487.
16. Hoogendam A, Stalenhoef AF, Robbe PF, et al. Answers to questions
posed during daily patient care are more likely to be answered by UpToDate than PubMed. J Med Internet Res. 2008;10:e29.
e615
MICHAEL A. THOMPSON
he prominent social mediasavvy physician Bryan Vartabedian, MD, FAAP (@Doctor_V) asked, Is Social Media Over? on his blog, 33charts.1 To that provocative title he
added, Or is it just part of the background? suggesting that
the novelty of social media is wearing off and that invited
talks or expert opinion on social media may be reaching a
decline. Just as we do not have American Society of Clinical
Oncology (ASCO) Education Sessions on What Is Email?
we may now focus less on the communication tool itself and
more on the content and contextualization. We understand
that educational content reaches us by multiple mechanisms
including social media. Also, many of us are now able to interact with social media rather than just consume it. In another post titled, Social Media Has Been Introduced to
Physicians,2 Vartabedian noted several salient points:
At some point we must go beyond the introduction and
into application.
Repeatedly pitching the terminally skeptical does not work.
While newbie public physicians need to be educated,
there are great resources available.
Weve reached a point where social media is now part of
the professional workflow.
The genuinely curious and motivated will fgure it out
just like we did.
With this in mind, I will not over elaborate on what social media is or why physicians should use it, but rather focus on social
media use cases. I would suggest to my social mediausing colleagues that instead of the cocktail party [being] over,3 social
media use by physicians is just starting to get interesting.
some new and failing, and some already well interwoven into
our digital lives. Social media is not a monomorphic phenomenon. It consists of a spectrum of the most trivial human
interests as well as news, highly curated thoughts, and small
and large communities.
I have previously discussed that Social Media is a Form of
Media,4 and that social media represents tools that may be
used to store and deliver information and content disseminated through social interactions or networks. Social media
includes various forms such as Facebook, blogs (e.g., ASCO
Connection), forums (e.g., Doximity, Sermo, HealthTap),
LinkedIn, image/video (e.g., YouTube, Vine, Instagram,
SnapChat), and Twitter. There is increasing blurring between these various tools, and the social media platforms
have evolved and will continue to evolve. They will not be the
same years from now.
Social media differs from traditional media in several
respects. Social media is generally faster, permanent (archived), interactive, and searchable. In addition, the conversations that emerge around a specifc topic or piece of content
on social media means that there can be amplifed effect beyond the initial broadcast audience. Different social media
tools may be more appropriate for various venues. My favorite social media platform is Twitter, so that is where I will
focus. However, others have used video, blogs, and other social media effectively.
Social media is no longer new. We have moved beyond the
early adopter phase in medicine. At previous ASCO and
other meetings, a group of social media proponents have promulgated signing up and using social media. At the 2014
ASCO Annual Meeting (hashtag #ASCO14), cancer advocates noted that their lung cancer hashtag (#LCSM) was not
being promoted by ASCO via its social media URL
From the Aurora Cancer Care, Aurora Health Care, Milwaukee, WI.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Michael A. Thompson, MD, PhD, Aurora Research Institute, 960 N 12th St., Room 3144, Milwaukee, WI 53233; email: michael.a.thompson@aurora.org.
2015 by American Society of Clinical Oncology.
206
Author(s) (Date)
Link
http://ow.ly/sUlLO
http://ow.ly/xcaKk
http://ow.ly/IHi6q
http://ow.ly/xc8Wq
http://ow.ly/xc8MO
http://ow.ly/xc7OA
http://ow.ly/xEy8f
http://slidesha.re/1Jqa6B0
KEY POINTS
Social media is a form of media.
Social media is not dead.
Social media offers rapid incoming and outgoing forms of
communication.
Twitter and other forms of social media are tools.
Tools are only tools if they are useful.
However, the information on social media can be overwhelming. Choosing sources to follow, including Twitter users that create context for content, is one method. Katz et al
have created an oncology/cancer hashtag system or ontology,
allowing users to watch one specifc topic and avoid the overwhelming crush of irrelevant content, thereby boosting the
signal-to-noise ratio.9-14 This may be especially helpful
when the cancer type is not obvious in the title of a publication or for cross-disciplinary posts such as CardioOncology (#CardioOnc).
These hashtags were in widespread use at the 2014 ASCO
Annual Meeting (e.g., #bcsm for breast cancer social media).
Boolean searches (with an implied AND), such as
#ASCO14 #bcsm, can fnd #bcsm tweets at the 2014 ASCO
Annual Meeting. This can help track conversations about
topics over time. According to Katz, Twitter may be relevant
to how effective professional societies are at sharing research
and the organizational mission.15 Another example of improving social media content delivery came from Ekins and
Perlstein in Ten Simple Rules of Live Tweeting at Scientifc
Conferences.16
There is a suggestion that physician social networks may be
more effective than medical journals at spreading information
about clinical decision making.17 However, a randomized trial
of social media published in Circulation seemed contrary to that
conclusion, suggesting that a journals use of social media did
not increase views to a given article.18 Christian Assad-Kottner,
MD, countered that conclusion by noting Social Media is not
about just posting, sharing and retweeting. There are many variables that play an important role on how social media would
impact a particular outcome, and that We live in an empowering world, with intelligent patients that also want to learn
about medical advances and many are more than ft to understand our articles even without a medical degree, this I guarantee.19
Some have remarked If [William] Osler were alive today,
were confdent hed be on Twitter.20 Dr. Meyskens noted in
his ASCO Connection blog post White Coat Conversations
that he had deep concern about the disappearing physician
scientist and I became aware that to move forward, I
needed to be engaged in the national dialogue.21 Others have
asked, Are physicians obligated to share their knowledge
online?22 This may be critical in creating useful information
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
207
MICHAEL A. THOMPSON
about public health issues such as vaccinations as well as understanding the risk/beneft of cancer screening, the complexities of cancer treatments, the role of research in
medicine, and end-of-life decisions. In contrast, many physicians feel, regarding doctors and social media, we are
damned if you engage, damned if you do not.23
between 2012 and 2013.27 Many other disease-specifc support groups use Twitter or Facebook to communicate. A Facebook example is the page run by Dana Holmes titled,
Asymptomatic Smoldering Multiple Myeloma aka-SMM Information Exchange.28 Although clinicians cannot participate in every online discussion group (and may not want to
participate in any), knowing they exist and what information is
exchanged can be enlightening. Many patients and advocates
are highly educated, highly informed, and can help drive public
perspective, funding, and clinical trial accrual.
USE: CROWDSOURCING/CROWDFUNDING
A group of highly informed patients (i.e., crowd) may help
brainstorm ideas (i.e., source) for drug development including
clinical trials (i.e., crowdsourcing). Additionally, patients and
the public may help fund research by crowdfunding. The concept of Can We Build A Kickstarter For Cancer? has been explored by Forbes as a way of funding a virtual biotech for a
single patient.29 Oncology Times also asked, Should clinical trials be crowdsourced?29 and The Lancet Oncology looked at
#trial: clinical research in the age of social media.31
Although not everyone is ready for these concepts, especially those with established research funding via traditional
mechanisms, engaging with patient communities can help us
understand the patient perspective. An educated and engaged public (via social media and in real life) is necessary
to sustain a national clinical trials infrastructure. This has
been embraced by the clinical trial cooperative group Alliance for Clinical Trials in Oncology (@ALLIANCE_Org;
#AllianceNCTN) to crowdsource its cancer clinical trial concepts from the general public.32
The generalizability and utility of such social media efforts
will become clearer over time. Other medical crowdfunding
sites include Experiment, MedStartr, and (the now dead?)
Petridish. A patient advocatecentral model of crowdfunding with crowdsourced ideas vetted/curated by scientifc and
patient advisory boards is underway with the Myeloma
Crowd Research Initiative (MCRI, www.myelomacrowd.org/
mcri/). This hybrid approach may allow new ideas with
thought-leader input.
USE: COLLABORATION
Although patients may share medical information on social
media without legal ramifcations, patient confdentiality
complicates discussions among professionals. We lack a
strong Health Insurance Portability and Accountability Act
(HIPAA)-compliant mechanism for open online multidisciplinary conferences/clinics (MDCs). For rare tumor types,
physicians have gone social with older media, such as the
2013 ASCO Annual Meeting presentation A Model for
Multi-Institutional, Multidisciplinary Sarcoma Videoconferencing.33 At an institutional level, options include proprietary applications such as Yammer or corporate email with
possible encryption. HIPAA-compliant online discussion fo-
USE: PROMOTION
Many individuals, hospitals, and other groups use social media to promote myriad business interests such as increasing
referrals to a private practice or to a second opinion program,
raising awareness of a cancer center, or disseminating
disease-specifc or general cancer information. The NCI
Clinical Trials Network (NCTN) groups have used social media to share annual meeting information, clinical trial information, and educational resources.
Institutions have embraced social media with various levels
of enthusiasm, engagement, and effectiveness. Some push
promotional information derived from other marketing materials, whereas others have an active and vibrant online presence. The best efforts engage in interactive discussions and
highlight their faculty and staff.
The pharmaceutical industry has for the most part moved
slowly into social media, but interest has increased since the
release of some U.S. Food and Drug Administration guidance on the use of social media.37,38 A noncomprehensive
listing of entities and examples of specifc uses, including
some with multiple channels used for very specifc purposes
by a given entity (e.g., NCI), are shown in Table 2. By following users or hashtags, either individually or by combining
Boolean searches, one can flter the near infnite volume of
information down to something usable.
Social media is not perfect and not every platform is ideal
for every use, but using social media can add a valuable com-
Examples
Advocacy
ASCO
ASH
@ASH_hematology, @ASHClinicalNews
Cancer centers
Disease focus
@MayoLymphoma, @MayoMyeloma
FDA
@US_FDA
Hospital system
@Aurora_Cancer, @Aurora_Health
Journals
NCI
NCTN
News
@CancerTodayMag, @OncologyTimes
People
Pharmaceutical
industry
Universities
@StanfordCancer, @uw_medicine
CONCLUSION
Social media is a growing form of health communication and
is still evolving. Social media offers rapid incoming and outgoing forms of communication. Twitter and other forms of
social media can be valuable learning and informationsharing tools. However, these tools are only helpful if they are
found useful by the user. A book chapter or lecture can not
determine that. Only you can. Find a social media mentor
and see what you can learn.
ACKNOWLEDGMENT
I am appreciative to Joseph Grundle at the Aurora Research
Institute for reviewing and editing this chapter. I am thankful
for the inspiration from many of my social media colleagues
(some mentioned herein and many more not mentioned)
and their prepublication comments on this document.
209
MICHAEL A. THOMPSON
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Michael
A. Thompson, Best Doctors, Celgene, CytRx Corporation, Health Tap, Image32, Onyx, Seattle Genetics. Speakers Bureau: None. Research Funding: None.
Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships:
Michael A. Thompson, Doximity, Xconomy.
References
1. Vartabedian B. Is Social Media Over? 33charts, January 2, 2015.
http://33charts.com/2015/01/is-social-media-over.html.
2. Vartabedian B. Social Media Has Been Introduced to Physicians. 33
charts, January 24, 2015. http://33charts.com/2015/01/social-mediaintroduced-to-physicians.html?utm_sourcefeedburner&utm_medium
email:&utm_campaignFeed:33Charts(33Charts).
3. Vartabedian B. Doctors Using Social Media. No Longer New. 33
charts, June 9, 2013. http://33charts.com/2013/06/doctors-socialmedia-no-longer-new.html.
4. Thompson MA. Social Media Is a Form of Media. ASCO Connection,
May 29, 2013. http://connection.asco.org/Commentary/Article/ID/3543/
Social-Media-Is-a-Form-of-Media.aspx.
5. Dizon DS, Graham D, Thompson MA, et al. Practical guidance: the use
of social media in oncology practice. J Oncol Pract. 2012;8:e114-e124.
6. Thompson MA, Younes A, Miller RS. Using social media in oncology
for education and patient engagement. Oncology (Williston Park). 2012;
26:782, 784-785, 791.
7. Reid BB, Rodriguez KN, ThompsonMA, et al. An analysis of cancerspecifc Twitter conversations among physicians in 2013. J Clin Oncol.
2014;32(suppl; abstr e17644).
8. Secemsky B. Why Every Young Physician Should Have a Professional
Twitter Account. Huffpost Healthy Living, January 15, 2015. http://
www.huffngtonpost.com/brian-secemsky/why-every-young-physician_
b_6162450.html.
9. Katz MS. Hashtag Folksonomy for Cancer Communities on Twitter.
ASCO Connection, July 3, 2013. http://connection.asco.org/Commentary/
Article/ID/3590/Hashtag-Folksonomy-for-Cancer-Communities-onTwitter.aspx.
10. Katz MS. Hashtags in Cancer Care. Embedding Meaning in Digital
Health. Cancer Tag Ontology, November 4, 2013. http://www.
symplur.com/blog/hashtags-cancer-care-embedding-meaning-digitalhealth/.
11. Katz MS. The Next Step. Expanding Cancer Care-Centered Hashtags.
ASCO Connection, August 30, 2014. http://connection.asco.org/
Commentary/Article/id/4001/The-Next-Step-Expanding-CancerCareCentered-Hashtags-.aspx.
12. Katz MS. The Oncology Tag Ontology. Professional-Centered Collaboration and Networking. Oncology Tag Ontology, December 22, 2014.
http://www.symplur.com/blog/oncology-tag-ontology-professionalcentered-collaboration-networking/?utm_sourceConnectingthe
dotsinhealthcaresocialmedia&utm_campaignc86ec919c5Connecting_the_dots_in_healthcare_social_media&utm_medium
email:&utm_term0_85a0d703f4-c86ec919c5-308726445.
13. Symplur. Oncology tag ontology. http://www.symplur.com/healthcarehashtags/ontology/oncology/. Accessed February 10, 2015.
14. Symplur. About cancer tag ontology. http://www.symplur.com/
healthcare-hashtags/ontology/cancer/. Accessed February 10, 2015.
210
15. Katz MS. Annual Meeting Twitter Activity in 2013: Four Professional
Societies. ASCO Connection, November 25, 2013. http://connection.
asco.org/Commentary/Article/id/3710/Annual-Meeting-TwitterActivity-in-2013-Four-Professional-Societies.aspx.
16. Ekins S, Perlstein EO. Ten simple rules of live tweeting at scientifc conferences. PLoS Comput Biol. 2014;10:e1003789.
17. McCarthy K. Study: physician social networks may be more effective
than medical journals. NueMD Industry News, November 5, 2014.
http://www.nuemd.com/news/2014/11/05/study-physician-socialnetworks-may-be-more-effective-medical-journals.
18. Fox CS, Bonaca MA, Ryan JJ, et al. A randomized trial of social media
from Circulation. Circulation. 2015;131:28-33.
19. Assad-Kottner C. Social Media DOES Impact Number of Views on a
Scientifc Article. LinkedIn Pulse, February 26, 2015. https://www.
linkedin.com/pulse/social-media-does-impact-number-views-scientifcassad-kottner.
20. Sherbino J, Frank JR. @SirBill: the power of social media to transform
medical education. Postgrad Med J. 2014;90:545-546.
21. Meyskens FL Jr. White Coat Conversations. ASCO Connection, November 18, 2014. http://connection.asco.org/Commentary/Article/id/
4074/White-Coat-Conversations.aspx.
22. Matthews G. Are Physicians Obligated to Share Their Knowledge Online? MDigitalLife, October 7, 2014. http://mdigitallife.com/arephysicians-obligated-to-share-their-knowledge-online/.
23. Vartabedian B. Doctors and social media: damned if you engage,
damned if you dont. 33charts, August 15, 2014. http://33charts.com/
2014/08/doctors-damned-if-you-engage.html.
24. Weiss M, Jacobus S, Abonour R, et al. Identifcation of signifcant barriers to accrual (BtA) to NCI sponsored multiple myeloma-clinical trials
(MM-CT): a step towards improving accrual to clinical trials. Blood
(ASH Annual Meeting Abstracts). 2012;120 (suppl; abstr 3165).
25. Weiss M, Gertz MA, Little RF, et al. Strategies to overcome barriers to
accrual (BtA) to NCI-sponsored clinical trials: a project of the NCIMyeloma Steering Committee Accrual Working Group (NCI-MYSC
AWG). J Clin Oncol. 2013;31(suppl; abstr 8592).
26. Thompson MA. Online Patient Communities for the E-Patient: Betwixt and Between a New Patient and an Expert. ASCO Connection,
August 29, 2013. http://connection.asco.org/Commentary/Article/id/
3645/Online-Patient-Communities-for-the-EPatient-Betwixt-andBetween-a-New-Patient-and-an-Expert.aspx.
27. New MDigitalLife Analysis Shows Breast Cancer Dominates Physician
Tweets About Oncology. BusinessWire. May 14, 2014. http://www.
businesswire.com/news/home/20140514006754/en/MDigitalLifeAnalysis-Shows-Breast-Cancer-Dominates-Physician#.VNpT8PnF_f.
Accessed March 6, 2015.
28. Holmes D. Asymptomatic Smoldering Multiple Myeloma aka-SMM -
29.
30.
31.
32.
33.
34.
35.
211
LAURA E. STRONG
lthough the conversation about patient-centered medicine gained traction in the United States with the formation of the nonproft Patient-Centered Outcomes
Research Institute as part of the Affordable Care Act in 2010,
the discussion was started within several organizations 2 decades ago.1-4 These, and other, organizations have facilitated
processes that allow patients to contribute their voice.
A critical step in involving patients in their care is to capture their experience, but historically this information has
not been captured in a format that can be broadly useful. The
U.S. Food and Drug Administration (FDA) has described
four ways in which a patients condition can be assessed:
Patient-reported outcome (PRO)
Clinician-reported outcome (ClinRO)
Observer-reported outcome (ObsRO)
Performance outcome (PerfO; e.g., timed walk test)
These assessments focus on the physical, mental, and social
health of the patient and can be used to evaluate disease
symptoms or adverse events caused by intervention such as
drugs or surgery. The major distinction of the PRO is the direct involvement of the patient rather than indirect reporting
by others. Although often thought of as symptoms or functional status, PROs can also include satisfaction with care and
treatment adherence. The signifcance of the patients voice
in oncology has been demonstrated in studies comparing reporting of symptoms by patients and clinicians. Patient reporting of Common Terminology Criteria for Adverse
Events (CTCAE) is more strongly associated with measures
of daily health status than that of clinicians.5,6 The direct potential benefts of PROs for patients include improved man-
From Quintessence Biosciences, Inc, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Laura E. Strong, PhD, Quintessence Biosciences Inc., 3300 Commercial Ave., Madison, WI 53714; email: lstrong@wisc.edu.
2015 by American Society of Clinical Oncology.
e616
rum (NQF) convened workshops of stakeholders and provided a report defning the concepts. The NQF report also
provides a detailed pathway for the development of PROPMs starting with PROs and working through the PROMs.13
The Quality of Care Committee of the American Society of
Clinical Oncology (ASCO) has reported on their efforts to
develop outcome measures for pain associated with bone metastases and postchemotherapy nausea (Table 1).14 As these
measures work through the delivery of health care, payers
will likely to take an interest in measures that correlate to
drug use. Although PROs have been used for drug approval
in the United States, their utility in drug cost and reimbursement decisions has not been tested.15,16 As better measures
and systems are developed, the E.U. experience may provide
useful insight.17
KEY POINTS
Patient-reported outcomes provide a unique and important
perspective in oncology.
PROs are used in clinical practice, including via electronic
capture.
U.S. Food and Drug Administrationapproved drugs can
include patient-reported outcomes in their label claims.
Patient-reported outcomes can be used for research,
including studies of disease progression.
The future of patient-reported outcomes will include
technology to help patients capture data and help
providers identify the information that is meaningful and
actionable.
Postchemotherapy Nausea
PRO
Pain
Nausea
PROM
PRO-PM
Abbreviations: PRO, patient-reported outcome; PM, performance measure; PROM, patientreported outcome measures; CTCAE, Common Terminology Criteria for Adverse Events.
included sending alerts to clinicians and/or providing educational material or care advice to patients.19
Although the potential benefts of PROs in general practice
are clear, a recent review of 24 controlled clinical trials suggests that additional work is necessary to translate PROMs
into clinically meaningful and actionable tools.20 The authors
evaluated three types of outcomes from these trials: patient
outcomes, health service outcomes, and processes of care,
which was the most frequently studied in the trials. The authors came to the following conclusion:
The routine use of PROMs increases the frequency of discussion of patient outcomes during consultations. In some
studies, PROMs are associated with improved symptom
control, increased supportive care measures, and patient satisfaction. Additional effort is required to ensure patient adherence, as well as additional support to clinicians who will
respond to patient concerns and issues, with clear system
guidelines in place to guide their responses. More research is
required to support PROM cost-beneft in terms of patient
safety, clinician burden, and health services usage.20
This review supports the efforts described above to develop
outcome measures that properly evaluate the success or failure of PROs in changing outcomes for patients, providers,
and health care systems.
Patient Viewpoint
(Johns Hopkins)
STAR Prostatectomy
Project (MSKCC)
Population
Goal
Survey
Content
Information Patient can see score reports Changes in function over time
to Patient
showing changes over time
compared to other patients
and expected improvement
based on prediction model
Abbreviatons: ePRO, electronic patient-reported outcomes; STAR, Symptom Tracking &
Reporting; MSKCC, Memorial Sloan Kettering Cancer Center.
e617
LAURA E. STRONG
Employment: Laura E. Strong, Quintessence Biosciences, Inc. Leadership Position: Laura E. Strong, Quintessence Biosciences. Stock or Other Ownership
Interests: Laura E. Strong, Quintessence Biosciences. Honoraria: None. Consulting or Advisory Role: None. Speakers Bureau: None. Research Funding:
None. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other
Relationships: None.
References
1. Institute P-COR. About Us. www.pcori.org/about-us. Accessed February 13, 2015.
2. European Regulatory Issues on Quality of Life Assessment Group.
http://www.eriqa-project.com/. Accessed February 13, 2015.
3. Trust MR. About Us. www.mapi-trust.org/about-the-trust/experience.
Accessed February 13, 2015.
4. Acquadro C, Berzon R, Dubois D, et al. Incorporating the patients perspective into drug development and communication: an ad hoc task
force report of the Patient-Reported Outcomes (PRO) Harmonization
Group meeting at the Food and Drug Administration, February 16,
2001. Value Health. 2003;6:522-531.
5. Basch E, Jia X, Heller G, et al. Adverse symptom event reporting by
e619
LAURA E. STRONG
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
e620
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
PROFESSIONAL DEVELOPMENT
SPEAKERS
Anupama Kurup Acheson, MD
Providence Oncology and Hematology Care Clinic
Portland, OR
Eric D. Tetzlaff, PA-C
Fox Chase Cancer Center
Philadelphia, PA
From the Division of Hematology/Oncology, Scripps Clinic, La Jolla, CA; Providence Oncology and Hematology Care, Providence Cancer Center, Portland, OR; Department of Hematology/Oncology,
Fox Chase Cancer Center, Philadelphia, PA.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Michael P. Kosty, MD, FACP, FASCO; Division of Hematology/Oncology, Scripps Clinic, 10666 N. Torrey Pines Rd., La Jolla, CA 92037; email: mkosty@scripps.edu.
2015 by American Society of Clinical Oncology.
e622
160
1,600
140
1,400
120
1,200
# of APNs & PAs
# of practices
100
80
60
1,000
800
600
40
400
20
200
0
Midwest
Northeast
South
West
Census Region
Academic practice
0
Academic practice
# APN (n=2752)
Physician-owned practice
KEY POINTS
ASCO Oncology Census continues to show shifts away from
private practice to more alignment/consolidation.
Practices are concerned about payer issues, cost
pressures, competitive pressures, and drug pricing.
True team-based approaches to oncology care may provide
a means of optimizing resource utilization and improving
the quality of care.
Utilization of advanced practice providers in oncology will
help meet workforce needs, although signicant
importunities still exist to improve the engagement of
providers, national organizations, and policy makers.
Restrictive barriers in legislation, reimbursement, provider
bias, and educational infrastructure reduce the benets of
utilizing advanced practice providers in oncology and
inhibit the ability to expand and effectively employ
advanced practice providers in the workforce.
Hospital/health system-owned
practice
Physician-owned practice
# PA (n=1136)
2.0%
4.0%
6.0%
2012
8.0%
2013
10.0%
12.0%
14.0%
16.0%
18.0%
20.0%
2014
e623
(6.8, 6.7, and 7.0 patients seen per 4-hour session, respectively). Both physician and APPs were very satisfed with the
IVM and reported patient-centered and productivity-based
reasons influencing the decision to use their chosen model.
For the SVM, physicians were still very satisfed with the
model, whereas, APPs were only moderately satisfed. Reasons for utilizing the SVM were more physician-centered,
focusing on physician preferences and perceptions. Importantly, there were extremely high levels of patient satisfaction
for both models (100% satisfaction with care received from
either model).
In a much larger study of the private practice setting, the
results of the ASCO study of collaborative practice arrangements also noted high levels of patient and provider satisfaction with the APP models.11 The most common model in the
survey was the independent model. The IVM was also 19%
more productive (based on relative value units, [RVUs])
when the APP worked with the entire group of physicians as
compared with an IVM when the APP worked exclusively
with a limited number of physicians. However, one should be
cautious to conclude that the more productive RVU model is
the ideal model to utilize APPs. Further insight into measures
of quality and continuity of care of the two models would be
important to distinguish. In addition, RVUs as the sole productivity measure is a limited assessment of the value an APP
adds to a practice. The study did not take into account the
non-revenue generating activity performed for each model,
which would be important in defning the preferred models.
BARRIERS TO INTEGRATION
Provider and Patient
ASCOs study of the collaborative practice arrangements of
APPs identifed physician lack of interest in working with
APPs as the most common reason not to utilize them in their
practice.11 To determine how to best motivate attitudinal
change, it is important to explore the reasons for lack of interest. As the ASCO report was primarily physician-owned
private practices (73%) with only 8% surveyed in academic
practice, it is possible that the lack of interest is based on the
fear of decreased personal compensation for the physician. It
has been shown that the private-practice model has signifcantly more oncologists compensated on an incentive-based
model compared with academic models (39.3% vs. 3.1%;
p 0.001).16 Therefore, it may be important to focus on the
increased practice productivity when using APPs to encourage utilization in private practice. Furthermore, as a
pure incentive-based model is associated with the highest
rate of burnout, the increased professional satisfaction
when working with APPs can be another educational
point to change perceptions.
There are other challenges to incorporating APPs into clinical practice that are largely historic or based more on personal bias than fact.17 For example, the belief that utilizing
APPs will negatively affect the physician/provider relationship or that patients will not accept APPs as part of the care
team is not founded. Studies have demonstrated high levels
Legislative
With modern medicine should come modern legislation.
Unfortunately, despite widespread acceptance of PAs and
NPs, there remain substantial historic and dated legislative
barriers that limit the effect that APPs have in providing
quality care. Despite differences in regulations between PAs
and NPs, there is common ground in the interest to ensure
that PAs and NP are practicing to the highest level of their
degree and professional training. Both the AANP and AAPA
have written position statements and established policy priorities to improve access to health care through removing
barriers in federal and state regulations. Specifcally, some of
the shared priorities nationally for APPs that will directly affect oncologic care include authorizing APPs to provide hospice care and allowing APPs to certify home care services and
order durable medical equipment. At the state level, limitations on the prescriptive authority and scope of practice are
also shared concerns between PAs and NPs. For example, 14
states still prohibit PAs from prescribing schedule II narcotics. Practice productivity is highest when APPs are used for
advanced activities.21 Therefore, by expanding the prescriptive privileges and allowing APPs to practice at the highest
level of their scope of practice will help ensure that quality
and effcient care will continue for patients with cancer.
To highlight the benefts of improving legislation for APPs,
a study was conducted to simulate the effect that enacting
policy changes would have on the supply of PAs and NPs in
primary care in Alabama.22 This simulation was based on
policy changes that facilitated obtaining licensure, expanded
prescriptive privileges, and removed several limitations on
scope of practice. The results demonstrated the potential for
substantial health care savings and increased access to care in
Alabama with simple policy changes. The specifc results of
this study cannot be directly applied to the current and projected work demands in oncology. However, the proof of
principle should be helpful to policymakers and advocacy
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e625
Educational Systems
One of the biggest barriers to utilizing APPs to help meet the
oncologic workforce demands may be in the educational infrastructure in place for the education of APPs. The education of APPs generally provides a general medical education
with limited time dedicated to oncology in the curriculum. In
a survey of PA programs, cancer prevention and diagnosis
were the primary focus of the oncologic curriculum with no
or little focus on acute management, oncologic emergencies,
and supportive and survivorship care.24 In addition, although nearly all PA programs offer locally available, elective
rotations in oncology, less than 15% of students participate in
such opportunities. Similarly, in a survey of the educational
experience of oncology NPs, most reported being poorly
prepared to provide cancer care and not at all prepared to
perform oncologic procedures or manage oncologic emergencies.25 Once APPs enter the oncologic workforce, the
majority report on-the-job training through mentorship
with supervising/collaborating physicians, as well as, selfstudy as the means to obtaining the core competencies for
their position.
To overcome the educational barriers to expanding the
APP workforce will require efforts both during and immediately after the graduate training of APPs. With less than 15%
of students pursuing elective rotations in oncology, the current workforce of APPs in oncology should help engage students during their didactic year to increase participation.
This could be done by developing relationships with local
APP programs and educating students about a career in oncology. The national organizations that represent APPs in
oncology should also engage new student members to help
increase interest in the feld. As an example, the Association
of Physician Assistants in Oncology has created a student day
seminar at the annual continuing medication education
(CME) meeting that offers students a free day of participation in the conference, as well as seminars for students about
pursuing a career in oncology.
To help APPs gain the knowledge they need to meet the
demands of caring for patients with cancer will require improvements in the core curriculum in graduate education.
Unfortunately, it will be hard to expand the curriculum given
the limited time available during the didactic year. It is possible that a flipped-curriculum model may be helpful to meet
this challenge. In this model, standardized lectures can be
viewed outside of the classroom and time spent in the classroom can be used for more active learning opportunities such
as teamed-based learning and skills training.24 The active
classroom time would also be another opportunity for clinical preceptors and other APPs in oncology to engage students in oncology. The core curriculum for the flippedcurriculum model could be provided through standardized
programs similar to ASCOs Curricula for Advanced Practice
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Eric D.
Tetzlaff, Novartis. Speakers Bureau: Michael P. Kosty, Astellas Pharma, Genentech/Roche, Sano, Lilly, Bayer. Research Funding: Michael P. Kosty,
Genentech/Roche (Inst), Merck Serono (Inst). Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Forte GJ, Hanley A, Hagerty K, et al. American Society of Clinical Oncology National Census of Oncology Practices: preliminary report.
J Oncol Pract. 2013;9:9-19.
2. Yang W, Williams JH, Hogan PF, et al. Projected supply of and demand
for oncologists and radiation oncologists through 2025: an aging,
better-insured population will result in shortage. J Oncol Pract. 2014;10:
39-45.
3. Hanley A, Hagerty K, Towle EL, et al. Results of 2013 American Society
of Clinical Oncology National Oncology Census. J Oncol Pract. 2014;10:
143-148.
4. Welch WP, Cuellar AE, Stearns SC, et al. Proportion of physicians in
large group practices continue to grow in 2009-11. Health Aff (Millwood). 2013;32:1659-1666.
5. Taplin SH, Weaver S, Salas E, et al. Reviewing cancer care team effectiveness. J Oncol Pract. In press.
6. Taplin SH, Weaver SJ, Chollette VC, et al. Teams and teamwork during
a cancer diagnosis: Interdependency within and between teams. J Oncol
Pract. In press.
7. Weaver AC, Callaghan M, Cooper AL, et al. Assessing interprofessional
teamwork in inpatient medical oncology units. J Oncol Pract. Epub 2014
Oct 28.
8. Childress SB. Team communication: its about patient safety. J Oncol
Pract. 2015;11:23-25.
9. Manojlovich M. Linking the practice environment to nurses job satisfaction through nurse-physician communication. J Nurs Scholarsh.
2005;37:367-373.
10. Larrabee JH, Janney MA, Ostrow CL, et al. Predicting registered nurse
job satisfaction and intent to leave. J Nurs Adm. 2003;33:271-283.
11. Towle EL, Barr TR, Hanley A, et al. Results of the ASCO Study of Collaborative Practice Arrangements. J Oncol Pract. 2011;7:278-282.
12. American Academy of Physician Assistants. 2013 AAPA Annual Survey
Report. American Academy of Physician Assistants: Alexandria, VA.
2014.
13. American Academy of Physician Assistants. 2010 Physician Assistant Census. American Academy of Physician Assistants: Alexandria, VA. 2011.
14. American Association of Nurse Practitioners. 2013 NP Fact Sheet.
http://www.aanp.org/all-about-nps/np-fact-sheet. Accessed March 11,
2015.
15. Buswell LA, Ponte PR, Shulman LN. Provider practice models in ambulatory oncology practice: analysis of productivity, revenue, and provider
and patient satisfaction. J Oncol Pract. 2009;5:188-192.
16. Shanafelt TD, Gradishar WJ, Kosty M, et al. Burnout and career satisfaction among US oncologists. J Clin Oncol. 2014;32:678-686.
17. Tetzlaff E, Polansky M, Carr K, et al. Physician assistants in oncology.
J Oncol Pract. 2007;3:283.
18. Oliver DR, Conboy JE, Donahue WJ, et al. Patients satisfaction with
physician assistant services. Physician Assist. 1986;10:51-54, 57-60.
19. Moote M, Krsek C, Kleinpell R, et al. Physician assistant and nurse practitioner utilization in academic medical centers. Am J Med Qual. 2011;
26:452-460.
20. Kosty MP. Informational Items-WAG, Classic References, QOPI for
Fellows. Presented at: 2011 ASCO Annual Meeting; 2011; Chicago, IL.
21. Erikson C, Salsberg E, Forte G, et al. Future supply and demand for
oncologists: challenges to assuring access to oncology services. J Oncol
Pract. 2007;3:79-86.
22. Hooker RS, Muchow AN. Modifying State Laws for Nurse Practitioners
and Physician Assistants Can Reduce Cost of Medical Services. http://
www.nursingeconomics.net/necfles/14ND/Hooker.pdf. Accessed on
March 11, 2015.
23. Pickard T. Calculating your worth: understanding productivity and
value. J Adv Pract Oncol. 2014;5:128-133.
24. Polansky M, Ross AC, Coniglio D, et al. Cancer education in physician
assistant programs. J Physician Assist Educ. 2014;25:4-11.
25. Nevidjon B, Rieger P, Miller Murphy C, et al. Filling the gap: development of the oncology nurse practitioner workforce. J Oncol Pract. 2010;
6:2-6.
e627
SARCOMA
SPEAKERS
H. Thomas Temple, MD
Universtiy of Miami
Miami, FL
Brian OSullivan, MD, FRCPC
Princess Margaret Cancer Centre
Toronto, ON
e629
PAOLO G. CASALI
institution to another, with a view toward local cytoreduction, in addition to its possible systemic effects.
In conclusion, there is a huge need for effective adjuvant
and/or neoadjuvant treatments in STS. The proportion of
potentially amenable patients may roughly amount to onehalf of cases. This applies to adult-type STS, because extraskeletal Ewing sarcomas and embryonal or alveolar
rhabdomyosarcoma fall in a distinct group of sarcomas, even
when they occur in the adult, which deserves chemotherapy
in all cases as a key component of the standard treatment.
AVAILABLE EVIDENCE
Several randomized, controlled trials have been performed
with adjuvant chemotherapy for STS, starting from the
1970s, when chemotherapy was shown to be crucial in revolutionizing the prognosis of childhood sarcomas, (i.e., osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma). Trials
performed in STS can be divided into two generations. Firstgeneration trials used anthracycline-based regimensthat
is, either doxorubicin alone or combinations that today
would be regarded as exploiting doxorubicin as virtually the
only, or nearly only, active drug. Second-generation trials
have been based on combinations of anthracyclines and ifosfamide. Doses varied substantially, but at least the two main
active drugs in STS were incorporated. A high degree of heterogeneity can be found in all these studies also, as far as the
patient populations are concerned, and the number of patients ranged from a few dozens to hundreds.
A meta-analysis of these randomized clinical trials, published in 2008, confrmed the beneft that a previous metaanalysis, done on individual patient data, had already shown
in terms of local and distant relapse rate; the 2008 publication
also noted a statistically signifcant beneft in terms of overall
KEY POINTS
Adjuvant chemotherapy is not standard treatment in soft
tissue sarcoma (STS), but it is an option to share with the
patient in conditions of uncertainty when the risk of
relapse is high.
Controlled evidence is available, and was also pooled in
meta-analyses, but its weakness is that studies have been
conicting.
If the decision is to resort to chemotherapy in the patient
with localized high-risk STS, chemotherapy can be
administered preoperatively if cytoreduction is felt to help
improve the quality of surgical margins and/or sequelae.
Personalization of adjuvant chemotherapy across diverse
STS subgroups is worth testing in clinical research as a
way forward, to improve its efcacy.
Personalized, rational decision making in conditions of
uncertainty on adjuvant treatment for patients with STS is
the every-day challenge that multidisciplinary tumor boards
face at reference sarcoma centers or within sarcoma
networks.
e630
This observation is diffcult to explain, especially in the presence of a questionable beneft for distant relapse. However,
one should recall that the local control in some patients with
high-risk STS may be challenging. In addition, some local relapses in STS may well lead to death. This might explain the
differences in survival in the absence of comparable differences in distant relapses. In addition, this could add to the
rationale of placing chemotherapy preoperatively, as long as
the decision has been made in the single case to use it as an
adjunct to surgery. The ISG trial allowed the combination of
neoadjuvant chemotherapy with preoperative radiation
therapy, and this proved to be tolerable in the proportion of
patients in whom it was used.
With an incidence in the range of 0.5 per 100,000 per year,
uterine sarcomas are a relevant subgroup in the STS family.
They entail a signifcant risk of relapse. Leiomyosarcoma is
the main subgroup, if one excludes mixed mullerian tumors
(carcinosarcomas), which are currently held to be epithelial
in nature. Other highly malignant subgroups are high-grade
endometrial stromal sarcomas and undifferentiated uterine
sarcomas. Recent, uncontrolled evidence was provided on a
regimen employing four cycles of gemcitabine plus docetaxel
and another that was based on four cycles of the same chemotherapy followed by four cycles of doxorubicin.14,15 The
latter regimen was associated with an interesting relapse-free
survival rate compared with external controls, though the
rate decreased with a longer follow-up time. A randomized trial is ongoing to compare this regimen to a nochemotherapy arm in uterine leiomyosarcomas.
CURRENT RECOMMENDATIONS
The 2014 National Comprehensive Cancer Network (NCCN)
clinical practice guidelines state that adjuvant chemotherapy
for STS greater than 5 cm and intermediate to high grade in
the extremities, superfcial trunk, or head and neck, can be
viewed as an appropriate intervention on the basis of lowerlevel evidence marked by limited and conflicting data.16
Thus, adjuvant chemotherapy is a legitimate option, but is
not standard. In essence, the same applies to uterine leiomyosarcomas or undifferentiated sarcomas.
The 2015 European Society for Medical Oncology (ESMO)
clinical practice guidelines state that chemotherapy can be
regarded as an option for patients with high-grade, deep STS
that is greater than 5 cm as adjuvant or neoadjuvant treatment, but they acknowledge no consensus on its role, given
the conflicting results of available studies.17 In uterine leiomyosarcomas, the value of adjuvant chemotherapy also is
said to be undetermined.
In brief, clinical practice guidelines must take into account
that some evidence was provided on the potential value of
adjuvant chemotherapy in STS but that this evidence is insuffcient to make chemotherapy standard practice. Thus, a
clinical decision shared with the patient to resort to adjuvant
chemotherapy in the presence of a high risk of relapse is
fully justifed according to current consensus recommen-
ISSUES
Available studies mainly refer to the most typical presentations, that is, limb and superfcial trunk STS. Their results are
conflicting, and uncertainty has not been settled, but at least
they can help by providing direct evidence. In clinical practice, one may be challenged by patients with STS who fall outside the average STS patient. In general, the primary site can
be regarded as a minor source of discrepancy for the effcacy
of systemic therapy, because there is no major reason, ultimately, why the same histology should beneft differently depending on the primary site. Sometimes, an atypical site
entails an additional risk of relapse. For example, a pleural
synovial sarcoma is likely to entail a higher risk than a limb
synovial sarcoma because of the additional locoregional risk
of pleural spread. Thus, one may estimate that an additional
reason for selecting adjuvant chemotherapy is in place. It
goes without saying that the reverse may be true as well; that
is, the additional risk is even less likely to be covered by available adjuvant treatments.
Some rare histologies may pose further uncertainty, because their behavior may be less known and, most important,
their chemotherapy sensitivity may deviate from that of
average STS. Indeed, some histologies (e.g., epithelioid sarcoma, or alveolar soft part sarcoma) are less sensitive to standard chemotherapy for STS, and this may be a good reason to
refrain from using adjuvant chemotherapy for them, when
the lack of any tumor lesion prevents one from the opportunity to check tumor response (i.e., tumor sensitivity). In these
cases, delaying chemotherapy to the time of relapse may be a
reasonable choice, though the pursued effect of chemotherapy as an adjuvant would be different by defnition. Sometimes, these histologies are less sensitive to anthracyclines
plus ifosfamide but may be sensitive to other agents (e.g.,
leiomyosarcoma is less sensitive to ifosfamide and more sensitive to dacarbazine). In these cases, one may try to personalize the choice of the medical therapy. Of course, this adds to
the uncertainty of adjuvant chemotherapy in STS, and the
patient needs to be informed accordingly within a deeply
shared decision-making process. In general, because the approach to the medical therapy of STS is increasingly histology
driven, the assessment of whether an histology-driven approach to the adjuvant therapy of STS may improve its effectiveness is a priority for clinical research. However, when
single histologies are considered, the number of eligible patients for clinical studies further diminishes, and conventional statistics faces major challenges.
With regard to the regimen choice in the adjuvant setting,
aside from the possible role of histology-driven options, fulldose anthracycline-plus-ifosfamide combinations should
be regarded as standard. Certainly, this conclusion may be
challenged by the unclear superiority of the combination of
these two drugs over single-agent doxorubicin in advanced
disease, as recently suggested by a randomized trial.18 Howasco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e631
PAOLO G. CASALI
CONCLUSION
The rarity and the heterogeneity of STS have been formidable
obstacles to generating reliable evidence in favor of or against
adjuvant and neoadjuvant chemotherapy. Available data are
consistent with a limited degree of effectiveness, but a lack of
beneft cannot be ruled out. In fact, several institutions worldwide propose systemic therapy to selected patients with STS in a
shared decision-making process in conditions of uncertainty.
Eligible patients are those with a high risk of relapse, which
largely is dictated by the malignancy grade and the clinical
presentation. There are some rare histologies that are poorly
sensitive to chemotherapy: in patients who have these histologies, adjuvant chemotherapy usually is not proposed, even
when the risk would be high enough to justify adjuvant treatment, if available.
There is some evidence that systemic therapy may be
placed before or after surgery with similar results, with the
obvious advantage for preoperative chemotherapy to exert a
local effect, which sometimes may be benefcial for the qual-
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Paolo G. Casali, Novartis, Pzer, PharmaMar.
Consulting or Advisory Role: Paolo G. Casali, Amgen Domp, ARIAD/Merck, Bayer, Blueprint Medicines, GlaxoSmithKline, Lilly, Merck Serono, Merck Sharp
& Dohme, Novartis, Pzer, PharmaMar. Speakers Bureau: None. Research Funding: Paolo G. Casali, Amgen Domp (Inst), Bayer (Inst), Eisai (Inst),
GlaxoSmithKline (Inst), MolMed S.p.A. (Inst), Novartis (Inst), Pzer (Inst), PharmaMar (Inst). Patents, Royalties, or Other Intellectual Property: None.
Expert Testimony: None. Travel, Accommodations, Expenses: Paolo G. Casali, Novartis, PharmaMar. Other Relationships: None.
References
1. Fletcher CDM, Bridge JA, Hogendoorn PCW, et al (eds). WHO Classifcation of Tumours of Soft Tissue and Bone. Lyon: IARC; 2013.
2. Gatta G, van der Zwan JM, Casali PG, et al. Rare cancers are not so
rare: the rare cancer burden in Europe. Eur J Cancer. 2011;47:24932511.
3. Eilber FC, Brennan MF, Eilber FR, et al. Validation of the postoperative
e632
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
improvement in survival: a study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.
J Clin Oncol. 1994;12:1137-1149.
Hensley ML, Ishill N, Soslow R, et al. Adjuvant gemcitabine plus
docetaxel for completely resected stages I-IV high grade uterine leiomyosarcoma: results of a prospective study. Gynecol Oncol. 2009;
112:563-567.
Hensley ML, Wathen JK, Maki RG, et al. Adjuvant therapy for highgrade, uterus-limited leiomyosarcoma: results of a phase 2 trial (SARC
005). Cancer. 2013;119:1555-1561.
von Mehren M, Randall RL, Benjamin RS, et al. Soft tissue sarcoma,
version 2.2014. J Natl Compr Canc Netw. 2014;12:473-483.
ESMO/European Sarcoma Network Working Group. Soft tissue and
visceral sarcomas: ESMO clinical practice guidelines for diagnosis,
treatment and follow-up. Ann Oncol. 2014;25 (suppl 3):iii102-iii112.
Judson I, Verweij J, Gelderblom H, et al. Doxorubicin alone versus intensifed doxorubicin plus ifosfamide for frst-line treatment of advanced or metastatic soft-tissue sarcoma: A randomised controlled
phase 3 trial. Lancet Oncol. 2014;15:415-423.
van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic
soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebocontrolled phase 3 trial. Lancet. 2012;379:1879-1886.
Casali PG, Fumagalli E, Gronchi A. Adjuvant therapy of gastrointestinal
stromal tumors (GIST). Curr Treat Options Oncol. 2012;13:277-284.
Casali PG, Bruzzi P, Bogaerts J, et al. Rare Cancers Europe (RCE) methodological recommendations for clinical studies in rare cancers: a European consensus position paper. Ann Oncol. 2015;26:300-306.
e633
Brachytherapy
Brachytherapy has several theoretical advantages. With appropriate selection, local dose intensifcation to target structures with surrounding normal tissue protection is feasible.
The treatment time is shorter, theoretically limiting tumor
From the Department of Radiation Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada; Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada; Department
of Radiotherapy, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Brian OSullivan, MD, FRCPC, Princess Margaret Hospital, University of Toronto, Rm 5-624, 610 University Ave., Toronto, ON M5G 2M9, Canada;
email: brian.osullivan@rmp.uhn.on.ca.
2015 by American Society of Clinical Oncology.
e634
TABLE 1. Difference between Two Prospective IMRT Trials for Extremity Soft Tissue Sarcoma
Characteristic
RTOG 06304
PMH5
Technique
3D conformal or IMRT
IMRT alone
Anatomic Site
Chemotherapy
No chemotherapy
No postoperative boost
Secondary Endpoints
Target Denitions
Abbreviations: IGRT, image guided radiotherapy; RTOG, Radiation Therapy Oncology Group; PMH, Princess Margaret Hospital; 3D, 3-dimensional; IMRT, intensity modulated radiotherapy; RT,
radiotherapy; EBRT, external beam radiotherapy; BRT, brachytherapy; LDR, low dose rate; HDR, high dose rate; IORT, intraoperative radiotherapy; EORTC, European Organisation for Research and
Treatment of Cancer; CTV, clinical target volume; NCIC SR2, National Cancer Institute of Canada SR2 trial.
cell repopulation. Moreover, brachytherapy permits radiation volumes to be mapped according to intraoperative fndings. The American Brachytherapy Society Guidelines differ
from those for EBRT and also advise that brachytherapy as a
sole treatment modality is contraindicated in the following
situations: (1) the CTV cannot be adequately encompassed
by the implant geometry, (2) the proximity of critical anatomy, such as neurovascular structures, is anticipated to interfere with meaningful dose administration, (3) the surgical
resection margins are positive, and (4) there is skin involved
by tumor.
KEY POINTS
Trials investigating adjuvant radiotherapy for extremity soft
tissue sarcoma have demonstrated a substantial benet in
local disease control for high-grade, deep seated, large
tumors with control in excess of 90%.
A paucity of clinical trial evidence for retroperitoneal
sarcoma is available. The preoperative radiotherapy
approach is associated with favorable local control and
overall survival with low treatment related toxicity rates.
Pre- and postoperative radiotherapy prospective trials
questioning historic clinical target volume concepts have
been completed and results are anticipated.
Toxicity proles associated with the timing of radiotherapy
must be considered for the individual patient and in the
decision algorithm for the different approaches and types
of adjuvant radiotherapy, including brachytherapy, external
beam, intraoperative radiation therapy, and particle
treatment.
Emerging evidence from prospective intensity-modulated
radiation therapy trials and retrospective series
demonstrate comparable local disease control with reduced
acute and late morbidities including wound complication
rates, limb edema, brosis, joint stiffness, and bone
fracture incidence.
A randomized trial of 164 patients reported from Memorial Sloan Kettering Cancer Center evaluated adjuvant
brachytherapy versus surgery alone and showed 10-year actuarial local control rates of 81% in the brachytherapy group
and 67% in the nonbrachytherapy group (p 0.03).7 This
improvement in local control was limited to histologically
high-grade tumors without effect on low-grade lesions,
which remains a matter of conjecture and uncertainty.
Brachytherapy also seems less useful where implant geometry is not optimal, such as in the upper extremity or more
proximal limb regions.8 In addition, brachytherapy has been
compared retrospectively with IMRT in 134 high-grade early
STS9 with similar adverse features. The 5-year local control
rate was 92% for IMRT compared with 81% for brachytherapy (p 0.04). Unfortunately, although the results of
brachytherapy, including its more restrictive criteria for use,
suggest lower effcacy compared with EBRT, there is no randomized, controlled trial comparing these seemingly effective local adjuvants.
Traditional brachytherapy studies, including those
mentioned above, used low-dose rate techniques. High
dose-rate brachytherapy has potential logistic advantages
including lower radiation staff exposure, outpatient delivery, and optimized dose distributions by varying dwell
times. However, wound healing complications may occur
in sarcoma management and caution is also recommended
when placing catheters adjacent to neurovascular structures. As yet, no large series evaluating high-dose rate
brachytherapy for STS is available, nor has it been directly
compared with low-dose rate, partly because of technical
differences.
Particle Therapy
Emerging approaches using hadrons have putative effcacy
advantages over conventional photon therapy because of
their physical and radiobiologic properties. However, their
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e635
Altered Fractionation
Altered fractionation can deliver doses in a shorter time period, often using higher than normal doses per fraction, or
smaller than usual dose fractions more than once daily as a
protracted course.
Preoperative hypofractionated RT for extremity and trunk
wall STS was recently evaluated in a series of 272 patients. RT
was delivered preoperatively for fve consecutive days in 5 Gy
per fraction. The local recurrence rate was higher (19.1%)
with the hypofractionated schedule compared with many
contemporary series.11 Longer follow-up of this novel strategy is warranted.
A contrasting strategy used twice daily 1.2 Gy fractions
to a total dose of 50.4 Gy in predominantly high-grade,
large tumors, to exploit smaller dose per fractions in mitigating local toxicity.12 The local control rate was 91%,
with a wound complication rate of 16%, and bone fracture
rate of 7.7% in an era (1978 to 1987) before IMRT or conformal techniques.
Neither hyperfractionation nor hypofractionation are
likely to replace conventional daily fractionation in the short
term for a combination of reasons that include the small nonrandomized nature of studies, resources needed for some
protocols, concerns about effcacy and toxicity, and the fact
that modern targeting techniques with IMRT may offset
some of the potential benefts that underpin the choice of altered fractionation protocols.
Intraoperative Radiotherapy
Intraoperative radiotherapy (IORT) or intraoperative electron radiotherapy (IOERT) refer to the delivery of RT, including electrons, to a targeted region while the area is
exposed during surgery. Most experience has been in combination with fractionated EBRT. A small subgroup (34 patients) analysis of a prospective phase II trial of IOERT,
etoposide, ifosfamide and doxorubicin, and postoperative
EBRT in high-grade extremity STS suggested excellent local
control and overall survival (97% and 79%),13 though superiority to large series receiving conventional EBRT is not
obvious.
Interest in IORT originated in retroperitoneal sarcomas
(RPS) as a result of its challenging anatomic nature. As discussed later (see Rationale for the Use of RT), an early report
was a randomized trial at the National Cancer Institute that
e636
METHOD OF DELIVERY
RT Dose and Volume Denition
The most traditional method of delivering adjuvant RT is
postoperatively. Guidelines have been published on how to
address the technical design of the radiation volumes.17
Traditionally, the surgical bed is irradiated to a dose of 45
to 50.4 Gy in 1.8 to 2.0 Gy once daily fractions followed by a
smaller boost volume to the tumor bed (phase II). For the
latter, typically doses of 10 to 16 Gy are subsequently applied,
resulting in a total dose of 60 to 66 Gy. The surgical bed is
expanded with a 1.5-cm radial margin and a 4-cm craniocaudal margin to encompass microscopic disease in the surrounding tissues; the boost is applied to the original sarcoma
localization with a 1.5-cm radial margin and a 2-cm craniocaudal margin (Figs. 1 and 2).
Postoperative boost clinical target volume (CTV) was the same volume as the postoperative
elective CTV, except cranio-caudally. (A) In the longitudinal direction, elective CTV is 2 cm
longer on both sides than the reconstructed sarcoma GTV before surgery. (B) Expansion of
1 cm in all directions of boost CTV to produce boost PTV, although PTV can vary by local
institutional protocols, as described in text.
Reprinted from International Journal of Radiation Oncology Biology Physics, Volume 84,
Issue 3, RLM Haas et al Radiotherapy for management of extremity soft tissue sarcomas:
why, when, and where? Pages 572-580, Copyright 2012, with permission from Elsevier.
(A) Patient to receive postoperative RT. Both original sarcoma extensions (gross tumor
volume [GTV]) visualized, as well as surrounding surgical bed. (B) Margins for postoperative
RT elective clinical target volume (CTV) are shown; these margins were 1.5 cm in transverse
plane onto, but constrained at, surfaces of bones and fascia, unless involved with tumor at
surgery. Note, elective CTV remains inside the skin. Furthermore, the elective CTV is longer
than the marker of the skin scar. If 4 cm expansion of reconstructed surgical volume in
longitudinal direction is shorter than surgical scar, elective CTV will need to be expanded
to include the surgical scar. (C) Expansion of 1 cm in all directions to produce
postoperative elective planning target volume (PTV), although PTV can vary by local
institutional protocols, as described in text.
Reprinted from International Journal of Radiation Oncology Biology Physics, Volume 84,
Issue 3, RLM Haas et al, Radiotherapy for management of extremity soft tissue sarcomas:
why, when, and where? pages 572-580, copyright 2012, with permission from Elsevier.
e637
(A) Patient to be treated with preoperative RT. Sarcoma delineated using T1-weighted, postgadolinium MRI scan fused to planning CT scan. This gross tumor volume (GTV) does not include
peritumoral edema, generally best seen on T2-weighted MRI scan. (B) GTV transversely expanded with 1.5 cm, but constrained at surfaces of fascia and bones, unless invaded. Longitudinally,
expansion was 4 cm. Note, this was a sarcoma case without peritumoral edema. (C) Sarcoma case with peritumoral edema, with GTV also transversely expanded with 1.5 cm and constrained at
surfaces of fascia and bones, unless invaded. Longitudinally, expansion was 4 cm. Note, CTV has been manually edited (bold dashed line) to encompass edema zone in both transverse and
coronal planes. Peritumoral edema indicated by striped zone. (D) Delineation of nal preoperative planning target volume (PTV) by expansion of CTV with 1 cm in all directions, although PTV
can vary by local institutional protocols, as described in text.
Reprinted from International Journal of Radiation Oncology Biology Physics, Volume 84, Issue 3, RLM Haas et al, Radiotherapy for management of extremity soft tissue sarcomas: why, when,
and where? pages 572-580, copyright 2012, with permission from Elsevier.
sessed target volume coverage during inter- and intrafractional breathing.19 Four-dimensional CT simulation and
planning was suggested for superiorly located tumors (GTV
centroid above the L2/3 junction) to account for respiratory
motion most pronounced in the superior to inferior dimension (maximum of 14 mm).
40 Gy or greater was less than 64%, the mean bone dose was
less than 37 Gy, or the maximum dose along the bone length
of bone was less than 59 Gy.21 This study provides evidencebased dose volume bone avoidance objectives for RT planning, which was further investigated in additional patients
(176 patients with lower and 54 patients with upper extremity
STS) with a median follow-up of 41.2 months.22 The overall risk
of fracture was 1.7% (four out of 230 patients), which compares
favorably to the previous reported incidence of 6.3%, and suggests that efforts to achieve bone avoidance are meritorious.
STS IMRT, indicating the need for reliable on-board imaging to detect target volume changes.24
results.30 These results suggest that a beneft from a delayed postoperative boost following preoperative RT and
surgery is at best debatable, and the increased risk and
challenges of managing later RT morbidity (e.g., radiationinduced fractures) resulting from the higher radiation doses involved should be considered.
Finally, preoperative EBRT may be particularly suited to
the management of RPS. Its potential role was mentioned
briefly in the discussion of IORT because of the way these
approaches evolved. Radiotherapy delivered to an in situ
tumor has the advantages of treating a well-defned and
undisturbed tumor volume where the tumor also acts as a
tissue-expander to displace small bowel and other radiosensitive viscera from the radiation volume. Preoperative
external beam radiotherapy for RPS was associated with
minimal acute toxicity in two prospective clinical trials
from the Princess Margaret Hospital and The University
of Texas MD Anderson Cancer Center31,32 with no increase
in wound healing complications. Long-term follow-up of
both trials combined indicated that preoperative radiotherapy may be associated with favorable local control and overall survival.33 This has been further addressed in the very
long-term follow-up of the PMH study.34
The minimal early toxicity reports of preoperative EBRT were
further confrmed in an additional trial where only one of 20
patients experienced gastrointestinal toxicity of grade 2 or
greater and one additional patient experienced leucopenia during the EBRT phase.35 Additional toxicity manifesting later35,36
included a 33% severe postoperative complication rate and may
relate to the subsequent IORT phase. This underlines the importance of prospective data collection in addressing complex
toxicity reporting from sequential phases of adjuvant local
therapy that is diffcult to interpret in retrospective studies
such as those reported earlier from the Mayo Clinic and
MGH.15,16 In such retrospective studies where toxicity is
reported remotely (often years later), only aggregated toxicities can realistically be reported, since differential toxicities from separate treatments are generally neither
defned nor attributed distinctly at the time of occurrence.
e639
dose intensity for the given circumstance (e.g., the RPS setting for the Sindelar trial outlined later).
Rosenberg et al randomly assigned patients to either receive an amputation (16 patients) or limb-sparing surgery
plus adjuvant RT (27 patients). There were no local recurrences in the amputation group, but four in the limb-sparing
group (local control 85% vs. 100%, p 0.06), with no difference in overall survival.37
Two subsequent trials compared conservative surgery
alone with similar surgery combined with adjuvant RT in
predominantly ESTS. The frst study was discussed earlier,
and patients were randomly assigned to receive adjuvant
brachytherapy or surgery alone (see Types and Method of RT
Delivery, Brachytherapy).7
Yang et al at the NCI randomly assigned 141 patients to
receive postoperative RT or not. They reported that highgrade lesions (present in 91 patients) benefted from adjuvant
EBRT (10-year local control rates of 78% vs. 100%; p 0.03)
as did low-grade sarcomas (present in 50 patients; 10-year
local control rates of 68% vs. 95%; p 0.067).38 The gain in
local control by the addition of RT resulted in a substantial
and persistent reduction in joint motion. The earlier data
was recently confrmed with a median follow-up of 17.9
years.39
The high risk of local failure following surgery has made
adjuvant RT an attractive option for RPS, but its role remains controversial and there is a paucity of trials available. At the National Cancer Institute, Sindelar et al
reported the prospective, randomized trial discussed earlier (see Intraoperative Radiotherapy). In the study, 35
patients with surgically resected RPS were randomly assigned to receive postoperative EBRT (50 to 55 Gy) versus
postoperative EBRT (35 to 40 Gy) and IORT (20 Gy). The
median follow-up was 8 years. Locoregional recurrence
was substantially lower with IORT (40% vs. 80% with external beam alone), but with high toxicity and no survival
difference. However, only modest EBRT doses (35 to 40
Gy) delivered postoperatively without IORT resulted in
very high recurrence rates.
CONCLUSION
The local recurrence of ESTS following limb-sparing surgery alone is in the range of 30% to 50%. In contemporary
series employing highly conformal RT including IMRT,
the addition of pre- or postoperative RT improves local
control to approximately 90% or greater with excellent
functional outcome. For RPS, the beneft of RT has not yet
been proven, but if considered, preoperative RT seems
to be the safest process of delivery. An ongoing multiinstitutional randomized trial should confrm its role. As
experience evolves, including a better understanding of
pathology and underlying molecular disease characteristics, as well as imaging modalities, additional strategies
should further improve the therapeutic ratio following RT
for local control of STS in all anatomic sites.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Rick Haas,
Nanobiotix. Speakers Bureau: None. Research Funding: Rick Haas, GSK. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony:
None. Travel, Accommodations, Expenses: Rick Haas, Nanobiotix. Other Relationships: None.
References
1. Griffn AM, Euler CI, Sharpe MB, et al. Radiation planning comparison
for superfcial tissue avoidance in radiotherapy for soft tissue sarcoma of
the lower extremity. Int J Radiat Oncol Biol Phys. 2007;67:847-856.
2. Hong L, Alektiar KM, Hunt M, et al. Intensity-modulated radiotherapy
for soft tissue sarcoma of the thigh. Int J Radiat Oncol Biol Phys. 2004;
59:752-759.
3. Folkert MR, Singer S, Brennan MF, et al. Comparison of local recurrence with conventional and intensity-modulated radiation therapy for
primary soft-tissue sarcomas of the extremity. J Clin Oncol. 2014;32:
3236-3241.
4. Wang D, Zhang Q, Eisenberg B, et al. Signifcant reduction of late toxicities in patients with extremity sarcoma treated with image-guided radiation therapy to a reduced target volume: results of Radiation Therapy
Oncology Group RTOG-0630 trial. J Clin Oncol. Epub 2015 Feb 9.
5. OSullivan B, Griffn AM, Dickie CI, et al. Phase 2 study of preoperative
image-guided intensity-modulated radiation therapy to reduce wound
and combined modality morbidities in lower extremity soft tissue sarcoma. Cancer. 2013;119:1878-1884.
6. OSullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised
trial. Lancet. 2002;359:2235-2241.
7. Pisters PW, Harrison LB, Leung DH, et al. Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol. 1996;14:859-868.
8. Alektiar KM, Brennan MF, Singer S. Influence of site on the therapeutic
ratio of adjuvant radiotherapy in soft-tissue sarcoma of the extremity.
Int J Radiat Oncol Biol Phys. 2005;63:202-208.
9. Alektiar KM, Brennan MF, Singer S. Local control comparison of adjuvant brachytherapy to intensity-modulated radiotherapy in primary
high-grade sarcoma of the extremity. Cancer. 2011;117:3229-3234.
10. Yoon SS, Chen YL, Kirsch DG, et al. Proton-beam, intensity-modulated,
and/or intraoperative electron radiation therapy combined with aggressive anterior surgical resection for retroperitoneal sarcomas. Ann Surg
Oncol. 2010;17:1515-1529.
11. Kosela-Paterczyk H, Szacht M, Morysinski T, et al. Preoperative hypofractionated radiotherapy in the treatment of localized soft tissue sarcomas. Eur J Surg Oncol. 2014;40:1641-1647.
12. Brant TA, Parsons JT, Marcus RB Jr, et al. Preoperative irradiation for
soft tissue sarcomas of the trunk and extremities in adults. Int J Radiat
Oncol Biol Phys. 1990;19:899-906.
13. Roeder F, Lehner B, Schmitt T, et al. Excellent local control with IOERT
and postoperative EBRT in high grade extremity sarcoma: results from
a subgroup analysis of a prospective trial. BMC Cancer. 2014;1899-8994:
350.
14. Sindelar WF, Kinsella TJ, Chen PW, et al. Intraoperative radiotherapy in
retroperitoneal sarcomas. Final results of a prospective, randomized,
clinical trial. Arch Surg. 1993;128:402-410.
15. Gieschen HL, Spiro IJ, Suit HD, et al. Long-term results of intraopera-
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
tive electron beam radiotherapy for primary and recurrent retroperitoneal soft tissue sarcoma. Int J Radiat Oncol Biol Phys. 2001;50:127-131.
Petersen IA, Haddock MG, Donohue JH, et al. Use of intraoperative
electron beam radiotherapy in the management of retroperitoneal soft
tissue sarcomas. Int J Radiat Oncol Biol Phys. 2002;52:469-475.
Haas RL, Delaney TF, OSullivan B, et al. Radiotherapy for management
of extremity soft tissue sarcomas: why, when, and where? Int J Radiat
Oncol Biol Phys. 2012;84:572-580.
White LM, Wunder JS, Bell RS, et al. Histologic assessment of peritumoral edema in soft tissue sarcoma. Int J Radiat Oncol Biol Phys. 2005;
61:1439-1445.
Wong P, Dickie C, Lee D, et al. Spatial and volumetric changes of retroperitoneal sarcomas during pre-operative radiotherapy. Radiother Oncol. 2014;112:308-313.
Holt GE, Griffn AM, Pintilie M, et al. Fractures following radiotherapy
and limb-salvage surgery for lower extremity soft-tissue sarcomas. A
comparison of high-dose and low-dose radiotherapy. J Bone Joint Surg
Am. 2005;87:315-319.
Dickie CI, Parent AL, Griffn AM, et al. Bone fractures following external beam radiotherapy and limb-preservation surgery for lower extremity soft tissue sarcoma: relationship to irradiated bone length, volume,
tumor location and dose. Int J Radiat Oncol Biol Phys. 2009;75:11191124.
Dickie C, Griffn A, Sharpe M, et al. IMRT, designed with evidencebased bone avoidance objectives, reduces the risk of bone fracture in the
management of extremity soft tissue sarcoma. Paper presented at: 18th
Annual Meeting of the Connective Tissue Oncology Society; October
2013; New York, NY.
Betgen A, Haas RL, Sonke JJ. Volume changes in soft tissue sarcomas
during preoperative radiotherapy of extremities evaluated using conebeam CT. J Radiat Oncol. 2013;2:55-62.
Dickie C, Parent A, Grant K, et al. Dosimetric consequences of tumor
volume changes during preoperative IMRT for lower extremity soft tissue sarcoma. Paper presented at: 55th Annual Meeting of the American
Society for Therapeutic Radiology and Oncology; September 2013; Atlanta, Georgia.
Davis AM, OSullivan B, Turcotte R, et al. Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol. 2005;75:48-53.
Griffn A, Dickie C, Catton C, et al. The influence of time interval between preoperative radiation and surgical resection on the development
of wound healing complications in extremity soft tissue sarcoma. Ann
Surg Oncol. In press.
Bartelink H, Maingon P, Poortmans P, et al. Whole-breast irradiation
with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3
trial. Lancet Oncol. 2015;16:47-56. Epub 2014 Dec 9.
Koshy M, Rich SE, Mohiuddin MM. Improved survival with radiation
e641
29.
30.
31.
32.
33.
34.
35.
36.
37.
e642
38.
39.
40.
41.
42.
43.
44.
45.
46.
SARCOMA
SPEAKERS
Robert S. Benjamin, MD
The University of Texas MD Anderson Cancer Center
Houston, TX
Paul A. Meyers, MD
Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College
New York, NY
PAUL A. MEYERS
steosarcoma and Ewing sarcoma are the two most common primary tumors of the bone seen in children, adolescents, and young adults. Both diseases almost always present
with systemic metastasis and attempting to cure them by local
measures alone is very unlikely. Successful treatment for both
diseases requires the combination of effective systemic therapy
and local measures directed at all sites of clinically detectable disease. Substantial progress has been made in the cure rate of these
primary bone sarcomas when they present without clinically detectable metastatic disease. Curing patients who present with
metastasis is much less likely.
OSTEOSARCOMA
Before the introduction of systemic therapy, cure rates for osteosarcoma were less than 20%, even among patients who presented without clinically detectable metastatic disease.1 The
introduction of multiagent chemotherapy improved the probability for cure to 60% to 70%.1 There are only four chemotherapy
agents with evidence of objective responses in osteosarcoma.2
Anninga et al summarized the results of single-agent phase II
trials of these agents in osteosarcoma, as shown in Table 1.
The reported objective response rates are probably an underestimate of true response, as osteosarcoma tumors can exhibit
substantial necrosis following chemotherapy without change in
size because of the osteoid matrix produced by the tumor.
Various combinations of the four active agents have
been employed in clinical trials for the treatment of osteo-
From Weill Cornell Medical Center, New York, NY, and Memorial Sloan Kettering Cancer Center, New York, NY.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Paul A. Meyers, MD, Weill Cornell Medical College and Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY, 10065; email: meyersp@mskcc.org.
2015 by American Society of Clinical Oncology.
e644
Doxorubicin
43%
Ifosfamide
33%
Methotrexate
32%
Cisplatin
26%
KEY POINTS
The primary bone sarcomas of young patients require
systemic therapy for cure.
Systemic therapy for osteosarcoma can cure approximately
70% of patients who present with localized disease.
Cure rates for osteosarcoma have not changed for over 20
years.
Systemic therapy for Ewing sarcoma can cure approximately
70% of patients who present with localized disease.
Increased dose intensity of therapy improves the outcome
of treatment for Ewing sarcoma.
EWING SARCOMA
Before the introduction of systemic chemotherapy, Ewing
sarcoma had a cure rate of less than 10%, even among patients who presented with localized disease.11 The introduction of systemic chemotherapy improved the outcome for
Ewing sarcoma. Treatment with multiagent chemotherapy
will achieve long-term EFS for roughly 70% of patients
who present without clinically detectable metastatic
disease.12-14 When patients present with lung metastasis,
long-term EFS rates are 30% to 50%; when patients present
with metastasis to distant bones or bone marrow, EFS is
less than 20%.12
An intergroup study conducted by the Pediatric Oncology
Group and the Childrens Cancer Group demonstrated that
the addition of ifosfamide and etoposide to cyclophosphamide, doxorubicin, and vincristine signifcantly improved
outcomes for patients with localized Ewing sarcoma.12 Following this study, the fve-drug combination became the preferred background for treatment and for clinical trials in
North America. In these trials, chemotherapy was administered as cycles of cyclophosphamide, doxorubicin, and vincristine and cycles of ifosfamide and etoposide. A singleinstitution study from the Memorial Sloan Kettering Cancer
Center (MSKCC) reported a high rate of EFS with the use of
very high-dose alkylating agent therapy given over a shorter
duration (21 weeks).15 The Childrens Oncology Group
(COG) performed a trial in which patients treated with the
fve-drug combination were randomly selected to receive
conventional doses or higher doses of cyclophosphamide.13
They reported no improvement in outcome with higher-dose
cyclophosphamide, but the regimen called for higher doses of
cyclophosphamide in only early cycles and did not equal the
MSKCC in dose intensity over the duration of treatment. In a
subsequent trial, COG studied dose intensifcation by shortening the interval between cycles of chemotherapy.14 Administration of the usual fve-drug combination every 2 weeks for
28 weeks achieved EFS (p 0.048), which was statistically
superior to the EFS observed with the fve-drug combination
administered every 3 weeks for 42 weeks. Increasing dose intensifcation by either increasing the dose of alkylating agents
or by shortening the intervals between cycles of chemotherapy has been associated with improved outcome in the treatment of Ewing sarcoma (Table 2).
The demonstration of improved outcome with increased
dose intensifcation for patients with localized Ewing sarcoma led to the concept that even further dose intensifcation
of therapy might improve outcome for patients at higher risk
for failure. A very dose-intensive regimen including higher
doses of doxorubicin was tried with patients with Ewing sarcoma metastatic at initial presentation.16 The regimen failed
to improve EFS and was associated with a very high rate of
secondary leukemia. Administration of chemotherapy in
myeloablative doses followed by autologous stem cell reconstitution has been used for patients with Ewing sarcoma metastatic at initial presentation and for patients following
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e645
PAUL A. MEYERS
CCG 792413
AEWS 003114
MSKCC P615
Standard
Intensied
Standard
Intensied
Q3 wk
48 wk
30 wk
Q3 wk
Q2 wk
21 wk
42 wk
28 wk
Doxorubicin
7.8
12.5
8.9
13.4
14.3
Cyclophosphamide
225
366
200
300
800
Ifosfamide
1,500
2,400
1,500
2,250
2,000
Five-Year EFS
72%
70%
65%
73%
82%
Abbreviations: CCG, Childrens Cancer Group; AEWS, Ewing sarcoma study sponored by the Childrens Oncology Group; MSKCC, Memorial Sloan Kettering Cancer Center; wk, week; EFS, event-free
survival.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: Paul A. Meyers, Amgen, Bayer, Dupont, Henry Schein, Jazz
Pharmaceuticals, Mednax, Novartis, Procter & Gamble, Sigma-Aldrich. Honoraria: Paul A. Meyers, France Foundation (I). Consulting or Advisory Role: Paul
A. Meyers, Boehringer Ingelheim (I). Speakers Bureau: Paul A. Meyers, France Foundation (I). Research Funding: None. Patents, Royalties, or Other
Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: Paul A. Meyers, InterMune (I), Medison, Takeda. Other
Relationships: None.
e646
References
1. Link MP, Goorin AM, Miser AW, et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the
extremity. N Engl J Med. 1986;314:1600-1606.
2. Anninga JK, Gelderblom H, Fiocco M, et al. Chemotherapeutic adjuvant treatment for osteosarcoma: where do we stand? Eur J Cancer.
2011;47:2431-2445.
3. Meyers PA, Heller G, Healey J, et al. Chemotherapy for nonmetastatic
osteogenic sarcoma: the Memorial Sloan-Kettering experience. J Clin
Oncol. 1992;10:5-15.
4. Whelan, JS, Bielack SS, Marina N, et al. EURAMOS-1, an international
randomised study for osteosarcoma: results from pre-randomisation
treatment. Ann Oncol. 2015;26:407-414.
5. Bielack SS, Smeland S, Whelan J. MAP plus maintenance pegylated interferon -2b (MAPIfn) versus MAP alone in patients with resectable
high-grade osteosarcoma and good histologic response to preoperative
MAP: First results of the EURAMOS-1 good response randomization.
J Clin Oncol, 2013:31 (suppl; abstr LBA10504).
6. Marina N, Smeland S, Bielack SS, et al. MAPIE vs. MAP as postoperative
chemotherapy in patients with a poor response to preoperative chemotherapy for newly diagnosed osteosarcoma: Results from EURAMOS-1.
Presented at the Annual Meeting of the Connective Tissue Oncology
Society. October 2014; Berlin.
7. Meyers PA, Healey JH, Chou AJ, et al. Addition of pamidronate to chemotherapy for the treatment of osteosarcoma. Cancer. 2011;117:17361744.
8. Brugieres L, Le Deley MC, Redini F, et al. Zoledronate does not reduce
the risk of treatment failure in osteosarcoma: Results of the French multicentre OS2006 randomised trial. Presented at the Annual Meeting of
the Connective Tissue Oncology Society. October 2014. Berlin.
9. Anderson PM, Meyers P, Kleinerman E, et al. Mifamurtide in metastatic
and recurrent osteosarcoma: a patient access study with pharmacokinetic, pharmacodynamic, and safety assessments. Pediatr Blood Cancer.
2014;61:238-244.
10. Meyers PA, Schwartz CL, Krailo MD, et al. Osteosarcoma: the addition
of muramyl tripeptide to chemotherapy improves overall survival-a report from the Childrens Oncology Group. J Clin Oncol. 2008;26:633638.
11. Nesbit M. Bone tumors in infants and children. Paediatrician. 1972/
1973;1:273-287.
12. Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and eto-
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
e647
TINOCO ET AL
hondrosarcomas constitute a diverse group of neoplasms with varied morphologic features and different
clinical behaviors, defned by the production of neoplastic
cartilage matrix by the tumor cells.1 Chondrosarcomas are
the second most frequent primary sarcoma arising in bone
after osteosarcoma,2-5 accounting for 20% to 27% of malignant bone neoplasms.6 They may occur at any age, but typically they are seen more frequently in older adults.7,8 The
clinical behavior is quite variable, with low-grade tumors displaying slow growth and low metastatic potential, to highgrade tumors that can be highly aggressive with the
propensity for distant metastases. Because of the avascular
matrix and low percentage of dividing cells, most chondrosarcomas are inherently resistant to cytotoxic chemotherapy
and are relatively radiation-resistant, with the exception of
the mesenchymal subtype.7 Thus, complete surgical resection with wide margins remains the most critical component
of therapy, whenever possible, for patients with primary tumors.9 Unfortunately, many patients present with inoperable
disease at the time of diagnosis or recur with metastatic disease, and more than 10% of recurrent chondrosarcomas are
of a higher grade than the original tumor.7 Current research
CLASSIFICATION
Cartilaginous tumors are categorized based on the WHO
Classifcation of Tumours of Soft Tissue and Bone (Tables 1
and 2).11 The importance of expert pathologist review in classifcation of all sarcomas cannot be overemphasized. These
tumors may have overlapping histologic features and often
require additional immunohistologic and genetic testing for
defnitive diagnosis. Various studies have suggested that histologic grade, size, stage, and anatomic location of the lesion
are fundamental prognostic features.12,13 In an analysis of
2,890 patients with chondrosarcoma from the Surveillance,
Epidemiology, and End Results (SEER) database, only grade
and stage were identifed as independent prognostic factors
From the Sylvester Comprehensive Cancer Center, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL; Sylvester Comprehensive Cancer Center, Department of
Pathology, University of Miami Miller School of Medicine, Miami, FL.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Jonathan C. Trent, MD, PhD, Department of Medicine, University of Miami Miller School of Medicine, 1475 NW 12th Ave., Suite 3300, Miami FL 33136; email:
jtrent@med.miami.edu.
2015 by American Society of Clinical Oncology.
e648
Molecular Features
Clinical Features
Enchondroma
Osteochondroma
Chondroblastoma
H3F3B Lys36Met
Chondromyxoid Fibroma
KEY POINTS
Treatment recommendations for chondrosarcoma depend
heavily on histologic subtype, which predicts sensitivity to
chemotherapy and radiation.
RECIST response rates to anthracycline-containing
chemotherapy regimens are less than 20% for the most
common conventional and dedifferentiated subtypes.
Isocitrate dehydrogenase (IDH) enzymes normally catalyze
conversion of isocitrate into alpha-ketoglutarate during the
citric acid cycle, a function impaired in mutant enzymes.
Mutated IDH enzymes also possess a unique gain-offunction phenotype that converts alpha-ketoglutarate to an
oncometabolite, 2-hydroxyglutarate, not present in normal
cells.
IDH mutations have been identied in numerous solid and
hematologic cancers, including chondrosarcomas, which
have led to ongoing clinical trials of novel IDH1 and IDH2
inhibitors.
ries. Central conventional chondrosarcoma (CCC) represents approximately 75% of all chondrosarcomas. These
cancers arise within the medullary cavity from previously
normal-appearing bone. Although most are thought to arise
de novo, as many as 40% of central chondrosarcomas may
arise from a preexisting benign cartilage lesion (Table 1), or
enchondroma.7,8,11,21,22 These secondary chondrosarcomas
often may be lower-grade with less metastatic involvement.23
Malignant transformation has been described in patients
with Olliers disease (enchondromatosis) and Maffucci
syndrome (enchondromatosis associated with soft-tissue
hemangioma).18 Most cases of chondrosarcoma in Olliers
disease and Maffucci syndrome are linked to IDH1 or IDH2
mutations.24,25 Peripheral conventional chondrosarcoma
(PCC) is rarer, occurs in younger patients, and by defnition
arises in an osteochondroma. PCC also is a tumor that is resistant to chemotherapy and relatively resistant to radiation
therapy. A third type of chondrosarcoma is periosteal chondrosarcoma (also known as juxtacortical chondrosarcoma),
which arises from the external surface of bone.26 This tumor
accounts for less than 1% of all chondrosarcomas.14 Interestingly, despite high-grade histology, this subtype has a more
favorable prognosis with adequate surgical management.14,27
It tends to affect slightly younger adults, with slow growing
masses arising from long bones, particularly the posterior
distal femoral metaphysis or diaphysis.6
The other 10 to 15% of all chondrosarcomas are infrequent
subtypes, such as dedifferentiated, myxoid, clear cell, and
mesenchymal chondrosarcomas.11,28 Mesenchymal chondrosarcoma is a high-grade malignant bone tumor that is
comprised of biphenotypic well-differentiated cartilaginous
cells and undifferentiated high-grade small round blue cells.
These occur in younger patients, arise in the axial skeleton,
and have a high propensity of metastasis at the time of diagnosis. The small round blue cell component of this subtype of
chondrosarcoma may respond to conventional chemotherapy regimens used for Ewing sarcoma or rhabdomyosarcoma. Therefore, accurate diagnosis of the precise subtype is
critical for appropriate management and best outcomes.
Dedifferentiated Chondrosarcoma
Dedifferentiated chondrosarcoma is an uncommon but aggressive subtype of chondrosarcoma that comprises approximately 10% of all chondrosarcomas.6,11,14 The disease tends
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e649
TINOCO ET AL
Molecular Features
Clinical Features
Most common type (approx. 70%); may arise from enchondroma or Olliers disease;
arises in pelvis, humerus, femur, or ribs; chemotherapy and radiotherapy resistant
Rare (approx. 10%); always arise from osteochondroma; younger individuals; arise
in pelvis or shoulder; chemotherapy and radiotherapy resistant
Very rare (approx. 1%); younger individuals; distal femur or humerus; prognosis
better than other histologies; chemotherapy and radiotherapy resistant
Mesenchymal Chondrosarcoma
HEY1-NCOA2
Very rare (approx. 2%); younger individuals, arise in head/neck, vertebrae, ribs,
pelvis; round cell component is chemotherapy and radiotherapy sensitive
Dedifferentiated Chondrosarcoma
Mesenchymal Chondrosarcoma
Mesenchymal chondrosarcoma is a rare high-grade malignant cartilaginous tumor that may originate in either bone or
soft tissue (dura).6 These tumors are characterized by a bimorphic cellular pattern that is composed of islands of differentiated cartilage and highly cellular areas that are
composed of undifferentiated small round blue cells.11 Unlike other chondrosarcoma subtypes, the median age at presentation is age 25 and extraosseous tumors are observed.38
The principal symptoms are pain and swelling. Mesenchymal chondrosarcoma most commonly arise in the craniofacial bones, ribs, ilium, and the vertebrae.11,39 The meninges
are one of the most common sites of extra skeletal involvement.40 The overall prognosis is poor for conventional
chondrosarcomas. Approximately 20% have metastatic
disease at diagnosis.39 Reported 10-year survival rates are
10 to 20%.41 However, approximately 30% of mesenchye650
mal chondrosarcomas will respond to Ewing sarcomatype chemotherapy regimens, with evidence of improved
survival as a result.36,38,39
Myxoid Chondrosarcoma
Primary skeletal myxoid chondrosarcoma is a rare neoplasm.
It remains unclear whether this constitutes a separate clinicopathologic entity or if it is part of the spectrum of conventional chondrosarcoma with prominent myxoid stroma.23
Histologically, myxoid chondrosarcoma of bone has similar
characteristics to the extraskeletal myxoid chondrosarcoma
(EMC), but these are two distinct diagnoses.45
Extraskeletal myxoid chondrosarcoma is a malignant softtissue tumor characterized by a multinodular architecture,
abundant myxoid matrix, and malignant chondroblast-like
cells.11,46,47 Typically, EMC has a characteristic translocation,
t(9;22)(q22;q12.2), fusing EWSR1 to NR4A3 (genes formerly
termed EWS and CHN, TEC, or NOR1, respectively).48-51 A
small proportion of EMC have a different translocation, t(9;
17)(q22;q11.2), which results in a RBP56-NR4A3 fusion gene
and neuroendocrine differentiation in some cases.51 Given
that these tumors can arise in the extremities and may
mimic chondrosarcoma, this is an instance in which genetic testing for the translocation can affect therapy
may be little shrinkage even when the chemotherapy was effcacious against the small round blue cell component of the
biphenotypic tumor cells. It also has been suggested that the
expression of P-glycoprotein plays a role in resistance to
chemotherapy. P-glycoprotein is encoded by the gene multidrug resistance-1 (MDR-1) and is expressed by chondrosarcoma cells.62 It has been demonstrated that the expression of
MRD-1 in human chondrosarcoma cell lines results in resistance to doxorubicin in vitro.63
TREATMENT CONSIDERATIONS
As previously discussed, understanding the histologic subtype and grade of chondrosarcoma is helpful in predicting
biologic behavior. However, regardless of subtype, surgical
resection remains the cornerstone of therapy with the best
potential for cure of primary chondrosarcoma.9
Several retrospective studies have shown that wide excision
with negative margins is associated with higher event-free
survival and overall survival rates for patients with large tumors and pelvic localization, regardless of the histologic
grade.54,55 A meta-analysis published in 2011 showed that in
select patients with low-grade, nonpelvic chondrosarcomas,
intralesional excision may be used as an alternative to wide
excision without affecting outcomes.56 In general, the recommended approach by the National Comprehensive Cancer
Network Guidelines (Bone Sarcoma Version 1.2015) is wide
local excision of the chondrosarcoma for any intermediate or
high-grade histologies, large tumor size, pelvic locations, and
intra-articular or soft-tissue involvement. This should be
performed in a high-volume sarcoma center with experienced orthopedic oncologists.
Chondrosarcomas are relatively radiotherapy (RT)-resistant.
Currently, there is not enough data to support its routine use
in patients with this disease. However, RT may be considered
if there is incomplete resection, for palliation of symptoms, in
patients with advanced or unresectable tumors, or for mesenchymal chondrosarcoma.57 In a large series involving 229
patients with chondrosarcomas of the skull base, the combination of proton and photon beam RT resulted in a sustained
local control rate in most patients.58
The role of chemotherapy in the treatment of patients with
chondrosarcoma remains unclear and should be considered on
a case-by-case basis. At our center, we generally reserve chemotherapy for dedifferentiated and mesenchymal subtypes for patients with reasonable performance status.
Although the vast majority of patients with recurrent or
metastatic chondrosarcoma do not respond to conventional
sarcoma chemotherapy regimens, there are anecdotal reports
of successful treatment with doxorubicin-based regimens,
single-agent ifosfamide or methotrexate.36,59-61
The mechanisms contributing to resistant to chemotherapy that are seen in chondrosarcomas are not fully understood. It has been suggested that because of avascular matrix
and often a low percentage of dividing cells, these tumors
have a poor response to chemotherapy that targets cycling
cells.57 In the case of mesenchymal chondrosarcoma, the majority of the tumor may be composed of well-differentiated
chondrosarcoma cells and cartilaginous matrix. Thus, there
e651
TINOCO ET AL
The wild-type IDH protein continues to produce alpha-ketoglutarate (KG); however, the mutant IDH protein converts KG to 2-Hydroxyglutarate (2-HG). HG then is able to function as an
oncometabolite in chondrosarcomagenesis.
CONCLUSION
Chondrosarcomas are a unique, rare family of neoplasms
that pose substantial treatment challenges, particularly in the
metastatic and refractory setting. The next few years are
likely to shed light on the unique biologic nature of these
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Jonathan
C. Trent, Bayer/Onyx, GlaxoSmithKline. Breelyn Wilky, Novartis, GSK. Speakers Bureau: None. Research Funding: Breelyn Wilky, Novartis. Patents,
Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: Breelyn Wilky, Novartis. Other
Relationships: None.
References
Pollyea DA, Kohrt HE, Zhang B, et al. 2-Hydroxyglutarate in IDH
mutant acute myeloid leukemia: predicting patient responses, minimal
residual disease and correlations with methylcytosine and hydroxymethylcytosine levels. Leuk Lymphoma. 2013;54:408-410.
2. Dorfman, HD, Czerniak, B. Bone cancers. Cancer. 1995;75(1 Suppl):
203-210.
3. Hartley AL, Blair V, Harris M, et al. Sarcomas in north west England:
II. Incidence. Br J Cancer. 1991;64:1145-1150.
4. Howlader N, Noone AM, Krapcho M, et al. (eds). SEER Cancer Statistics Review, 1975-2011. Bethesda: National Cancer Institute; 2014.
5. Bjornsson J, McLeod RA, Unni KK, et al. Primary chondrosarcoma of
long bones and limb girdles. Cancer. 1998;83:2105-2119.
6. Murphey MD, Walker EA, Wilson AJ, et al. From the archives of the
AFIP: imaging of primary chondrosarcoma: radiologic-pathologic
correlation. Radiographics. 2003;23:1245-1278.
7. Gelderblom H, Hogendoorn PC, Dijkstra SD, et al. The clinical approach towards chondrosarcoma. Oncologist. 2008;13:320-329.
8. Riedel RF, Larrier N, Dodd L, et al. The clinical management of chondrosarcoma. Curr Treat Options Oncol. 2009;10:94-106.
9. Dai X, Ma W, He X, et al. Review of therapeutic strategies for osteosarcoma, chondrosarcoma, and Ewings sarcoma. Med Sci Monit. 2011;
17:RA177-RA190.
10. van Oosterwijk JG, Anninga JK, Gelderblom H, et al. Update on targets
and novel treatment options for high-grade osteosarcoma and chondrosarcoma. Hematol Oncol Clin North Am. 2013;27:1021-1048.
11. Hogendoorn PCW, Bovee JV, Nielsen GP. Chondrosarcoma (grades
I-III), including primary and secondary variants and periosteal chondrosarcoma. In: Fletcher CDM, Bridge JA, Hogendoorn PCW, et al.
(eds). World Health Organization Classifcation of Tumours of Soft Tissue and Bone. Lyon, France: International Agency for Research on
Cancer, 2013;5:264.
1.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
United States (1973 to 2003): an analysis of 2890 cases from the SEER
database. J Bone Joint Surg Am. 2009;91:1063-1072.
Silve C, Juppner H. Ollier disease. Orphanet J Rare Dis. 2006;1:37.
Pannier S, Legeai-Mallet L. Hereditary multiple exostoses and enchondromatosis. Best Pract Res Clin Rheumatol. 2008;22:45-54.
Albregts AE, Rapini RP. Malignancy in Maffuccis syndrome. Dermatol Clin. 1995;13:73-78.
Verdegaal SH, Bovee JV, Pansuriya TC, et al. Incidence, predictive factors, and prognosis of chondrosarcoma in patients with Ollier disease
and Maffucci syndrome: an international multicenter study of 161 patients. Oncologist. 2011;16:1771-1779.
Angelini A, Guerra G, Mavrogenis AF, et al. Clinical outcome of central conventional chondrosarcoma. J Surg Oncol. 2012;106:929-937.
Damron TA, Ward WG, Stewart A. Osteosarcoma, chondrosarcoma,
and Ewings sarcoma: National Cancer Data Base Report. Clin Orthop
Relat Res. 2007;459:40-47.
Mankin HJ, Cantley KP, Schiller AL, et al. The biology of human chondrosarcoma. II. Variation in chemical composition among types and
subtypes of benign and malignant cartilage tumors. J Bone Joint Surg
Am. 1980;62:176-188.
Brien E, Mirra JM, Kerr R. Benign and malignant cartilage tumors of
bone and joint: their anatomic and theoretical basis with an emphasis
on radiology, pathology, and clinical biology. I. The intramedullary
cartilage tumors. Skeletal Radiol. 1997;26:325-353.
Ahmed AR, Tan TS, Unni KK, et al. Secondary chondrosarcoma in
osteochondroma: report of 107 patients. Clin Orthop Relat Res. 2003:
193-206.
Pansuriya TC, van Eijk R, dAdamo P, et al. Somatic mosaic IDH1 and
IDH2 mutations are associated with enchondroma and spindle cell
hemangioma in Ollier disease and Maffucci syndrome. Nat Genet.
2011;43:1256-1261.
Amary MF, Damato S, Halai D, et al. Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2.
Nat Genet. 2011;43:1262-1265.
Chaabane S, Bouaziz MC, Drissi C, et al. Periosteal chondrosarcoma.
AJR Am J Roentgenol. 2009;192:W1-W6.
Schajowicz F. Juxtacortical chondrosarcoma. J Bone Joint Surg Br.
1977;59-B:473-480.
Meijer D, de Jong D, Pansuriya TC, et al. Genetic characterization of
e653
TINOCO ET AL
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
e654
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
e655
BENJAMIN ET AL
ncreasing age is an adverse prognostic factor in the treatment of primary bone tumors.1-3 There are few, if any,
randomized studies that address the treatment of primary
bone tumors in adults, and no data support the common
practice of extrapolating from the results of pediatric trials
to the adult population. We know from pediatric studies
that conclusions based on data derived from patients
younger than 18 do not always apply to those age 18 or
older. We know, for example, from the data presented at
American Society of Clinical Oncology, that compressed
VDC-IE (vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide) was not
more effective against Ewing sarcoma in patients older
than age 17 than standard dosing, but, because those patients were included in the study, the overall results are
extrapolated to apply to them.3 The therapies that we will
describe are derived from the experience of our group in
the Department of Sarcoma Medical Oncology at The
CHONDROSARCOMA
Fortunately, because no systemic therapy has proven effective, most patients with conventional chondrosarcoma have
From the Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Robert S. Benjamin, MD, Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 450, Houston, TX 77030;
email: rbenjami@mdanderson.org.
2015 by American Society of Clinical Oncology.
e656
KEY POINTS
Older patients with osteosarcoma and Ewing sarcoma have
inferior outcomes than pediatric patients.
To treat osteosarcoma, induction chemotherapy with
doxorubicin and cisplatin permits administration of full
doses of both agents.
Unlike some pediatric studies, our data support the
addition of ifosfamide as well as high-dose methotrexate to
poor responders but do not support the routine use of
high-dose methotrexate for all patients.
Our data suggest that vincristine, doxorubicin, and
ifosfamide is a good choice of primary chemotherapy for
Ewing sarcoma.
PET-CT is the best imaging modality to assess response,
especially in osteosarcoma, but MRI is the most sensitive
method to detect subtle metastases in bone or bone
marrow.
e657
BENJAMIN ET AL
OSTEOSARCOMA
Our therapy for osteosarcoma is based on experience in a
group of patients treated from 1980 to 1991 with induction
therapy of 90 mg/m2 of doxorubicin as a continuous intravenous infusion over 48 to 96 hours and 120 to 160 mg/m2 of
cisplatin intra-arterially. Initially, we found a marked difference in postoperative continuous disease-free survival
(CDFS) between those with 90% or greater (i.e., good) tumor
necrosis and those with less than 90% (i.e., poor) tumor
necrosis.20 (Fig. 1) We subsequently modifed postoperative chemotherapy, frst adding high-dose methotrexate
and later, in addition, ifosfamide. We found no beneft
from the addition of methotrexate to the good responders,
but we observed an increased CDFS in the poor responders from 13% to 34%. The subsequent addition of ifosfamide to the postoperative regimen further increased the
CDFS to 67% (Fig. 2), such that the difference between
good and poor responders was no longer statistically signifcant.21
Because we have not had additional good drugs to add to
our regimen, we have continued the practice established in
our 1988 to 1991 series of adding ifosfamide and highdose methotrexate to patients who have poor tumor necrosis. We recently reviewed a series of 46 patients with
primary osteosarcoma of the extremities who were treated
according to this approach. The median 10-year CDFS was
50%, and there was no difference between patients with
good or poor necrosis. The recent EURAMOS study concluded that addition of ifosfamide was of no beneft to
(largely) pediatric patients with osteosarcoma and poor
necrosis.22 The initial approach with modifed adjuvant
chemotherapy after poor response to neoadjuvant chemotherapy came from the sequential studies of Rosen et al,23
e658
EWING SARCOMA
It is even harder to fnd studies on Ewing sarcoma in adults than
it is to fnd studies on osteosarcoma. Our initial data on the treatment of Ewing sarcoma in adults is, unfortunately, published
only in abstract form,27 and the logistics of transition from paper
to electronic medical records and flm to digital images makes a
new review of the data cumbersome at best. The major lessons
from our initial patients treated with VAdriaC (vincristine,
doxorubicin, and cyclophosphamide) or CyVADIC (cyclophosphamide, vincristine, doxorubicin, and dacarbazine)
were that any residual viable tumor in excess of scattered
cells carried a high risk of recurrence and that, the more
doxorubicin given, the better the patients faired. Therefore, it has become our practice to add additional postoperative chemotherapy with an alternative regimen to any
patient who has less than 99% tumor necrosis.
The role of ifosfamide, questioned in the treatment of
osteosarcoma, is well established in the treatment of Ewing sarcoma in pediatrics.2,3 Because ifosfamide is one of
the most active agents in the treatment of adult sarcomas,
we have considerable experience in its use. The standard
soft tissue sarcoma chemotherapy regimen is doxorubicin
and ifosfamide, which we have studied extensively.28 Ifosfamide is superior to cyclophosphamide in the treatment
of sarcomas,29 so we saw no reason to alternate cyclophosphamide with ifosfamide and have thus adopted VAI as
our primary treatment regimen for Ewing sarcoma by simply adding vincristine to our standard soft tissue sarcoma
regimen. We give 2 mg of vincristine on day 1, 75 to 90
mg/m2 of doxorubicin as a 72-hour infusion, and 2.5 g/m2
of ifosfamide over 3 hours daily for four doses.
We reviewed the data on a series of 24 patients with primary Ewing sarcoma of bone treated with VAI. The median age was 23 (range, 17 to 54); 17% of patients were
younger than 20, and 17% of patients were older than 30.
The 5-year CDFS was 70%, and all relapses but one occurred within 1 year of treatment. The primary sites of relapse were local recurrence in bone and adjacent soft
tissue, with only a single case of pulmonary metastasis as
the frst site. Two patients experienced relapse during induction therapy. No patient who experienced relapse survived. Twenty of the 24 patients underwent surgery after
induction chemotherapy. Eleven patients (55%) who had
more than 95% tumor necrosis in the resected specimen had
an 80% 5-year CDFS compared with a 44% 5-year CDFS
for the nine patients (45%) who had less than 95% tumor necrosis. All patients with more than scattered residual tumor
cells after induction therapy underwent variable consolidation chemotherapy, including high-dose ifosfamide, ifosfamide/etoposide (IE), and irinotecan/temozolomide with or
without vincristine. Although this is a small series, the results
compare favorably with the commonly used regimen of alternating VAdriaC and IE used in the pediatric literature,
for which event-free survival for patients older than age 18
was 44%2 and was 47% in the study of compressed-interval
dosing.3
MRI is the best modality to defne an anatomic abnormality
within bone or bone marrow. A screening MRI of the spine and
pelvis can detect subtle metastatic sites missed by other imaging
modalities, even PET-CT, or blind bone marrow biopsies.
PET-CT is the best imaging modality to assess response to therapy, but it is not as critical as in osteosarcoma, because Ewing
sarcoma tends to shrink or disappear as it responds.
New approaches to the therapy of Ewing sarcoma with
insulin-like growth factor 1 receptor (IGF-1R) blockade
with30 or without31 mammalian target of rapamycin inhibitors hold some promise, but thus far have been effective in
only a minority of patients. Unfortunately, the IGF-1R target has relatively little interest to most pharmaceutical
companies, and further studies to select the subset of patients who might beneft most have been stymied by the
lack of drug supply and pharmaceutical support. Other
new approaches, interesting from a theoretical point of
view, have yet to undergo formal study.
CONCLUSION
Treatment of primary bone tumors in adults presents
challenges and opportunities. The frst challenge is fnding
effective therapy for chondrosarcomas. These tumors are
like the gastrointestinal stromal tumors of the 1990s. We
have no medical treatment. There are some interesting
targets. How do we turn it around? For giant cell tumor of
bone, we have a wonderful new agent, but is it curative?
How long does therapy need to continue? How can we take
advantage of the great activity of denosumab to design better treatments for the future? In treating osteosarcoma and
Ewing sarcoma in adults, we do not do as well as our pediatric colleagues, perhaps because younger patients can
tolerate more intensive chemotherapy and perhaps because of the differing mix of variant histologies. The VAI
regimen for Ewing sarcoma seems promising, but formal
studies and larger numbers will be required. The tragedy
of near certain death with relapse in Ewing sarcoma needs
to be addressed with better strategies, perhaps aimed at
directly inhibiting the effects of its causative translocation.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e659
BENJAMIN ET AL
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: Robert S. Benjamin, Express Scripts (I), Gilead Sciences (I), Johnson
and Johnson (I), Merck Serono (I), Pzer (I). Honoraria: None. Consulting or Advisory Role: Shreyaskumar Patel, Novartis, Johnson & Johnson/Janssen
Research & Development, CytRx Corp., EMD Serono, Daiichi Sankyo. Speakers Bureau: None. Research Funding: Shreyaskumar Patel, Johnson &
Johnson/Janssen R&D, Morphotek, Eisai, PharmaMar. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel,
Accommodations, Expenses: Robert S. Benjamin, PharmaMar. Other Relationships: None.
References
1. Longhi A, Errani C, Gonzales-Arabio D, et al. Osteosarcoma in patients
older than 65 years. J Clin Oncol. 2008;26:5368-5373.
2. Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewings sarcoma and primitive
neuroectodermal tumor of bone. N Engl J Med. 2003;348:694-701.
3. Womer RB, West DC, Krailo MD, et al. Randomized controlled trial of
interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Childrens Oncology Group. J Clin Oncol. 2012;30:
4148-4154.
4. Bovee J, Hogendoorn PCW, Wunder JS, et al. Cartilage tumours and
bone development: molecular pathology and possible therapeutic targets. Nat Rev Cancer. 2010;10:481-488.
5. Tiet TD, Hopyan S, Nadesan P, et al. Constitutive hedgehog signaling in
chondrosarcoma up-regulates tumor cell proliferation. Am J Path. 2006;
168:321-330.
6. Italiano A, Le Cesne A, Bellera C, et al. GDC-0449 in patients with advanced chondrosarcomas: a French Sarcoma Group/US and French National Cancer Institute single-arm phase II collaborative study. Ann
Oncol. 2013;24:2922-2926.
7. Amary MF, Bacsi K, Maggiani F, et al. IDH1 and IDH2 mutations are frequent
events in central chondrosarcoma and central and periosteal chondromas
but not in other mesenchymal tumours. J Pathol. 2011;224:334-343.
8. Johnson S, Tetu B, Ayala AG, et al. Chondrosarcoma with additional
mesenchymal component (dedifferentiated chondrosarcoma). I. A clinicopathologic study of 26 cases. Cancer. 1986;58:278-286.
9. Benjamin RS, Chu P, Patel SR, et al. Dedifferentiated chondrosarcoma:
a treatable disease. Proc Amer Assoc Cancer Res. 1995;36:243a.
10. Italiano A, Mir O, Cioff A, et al. Advanced chondrosarcomas: role of
chemotherapy and survival. Ann Oncol. 2013;24:2916-2922.
11. Dahlin DC. Caldwell Lecture. Giant cell tumor of bone: highlights of 407
cases. AJR Am J Roentgenol. 1985;144:955-960.
12. Eckardt JJ, Grogan TJ. Giant cell tumor of bone. Clin Orthop. 1986;204:45-58.
13. Wallace S, Granmayeh M, deSantos LA, et al. Arterial occlusion of pelvic
bone tumors. Cancer. 1979;43:322-328.
14. Lin PP, Guzel VB, Moura MF, et al. Long-term follow-up of giant cell tumor
of the sacrum treated with selective arterial embolization. Cancer. 2002;95:
1317-1325.
15. Benjamin RS, Patel SR, Gutterman JU, et al. Interferon alfa-2b as antiangiogenesis therapy of giant cell tumors of bone: implications for the study
of newer angiogenesis-inhibitors. Proc Am Soc Clin Oncol. 1999;18:548a.
16. Kaban LB, Troulis MJ, Ebb D, et al. Antiangiogenic therapy with interferon alpha for giant cell lesions of the jaws. J Oral Maxillofac Surg. 2002;60:1103-1111.
17. Thomas DM. RANKL, denosumab, and giant cell tumor of bone. Curr
Opin Oncol. 2012;24:397-403.
18. Thomas D, Henshaw R, Skubitz K, et al. Denosumab in patients with
giant-cell tumour of bone: an open-label, phase 2 study. Lancet Oncol.
2010;11:275-280.
e660
SARCOMA
Well-Differentiated and
Dedifferentiated Liposarcoma:
New Challenges and New Directions
CHAIR
Samuel Singer, MD
Memorial Sloan Kettering Cancer Center
New York, NY
SPEAKERS
Andrew Koff, PhD
Memorial Sloan Kettering Cancer Center
New York, NY
Gary K. Schwartz, MD
Columbia University School of Medicine
New York, NY
LIPOSARCOMAS
Liposarcomas are neoplasms of adipocytes that normally
grow slowly and present as a painless nonulcerated enlarging
mass. They are subclassifed into distinct categories dependent on their histology, molecular signature, and behavior4:
Well-differentiated/atypical lipomatous tumor
Dedifferentiated liposarcoma
Myxoid (round cell) liposarcoma
Pleomorphic liposarcoma
Liposarcoma, not otherwise specifed
Rarely, a specimen may have a combination of morphologic subtypes; this is referred to as mixed liposarcoma.
From the Division of Hematology and Oncology, Columbia University School of Medicine, Herbert Irving Comprehensive Cancer Center, New York, NY; Department of Surgery, Memorial Sloan
Kettering Cancer Center, New York, NY; Program in Molecular Biology, Memorial Sloan Kettering Cancer Center, New York, NY.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Gary K. Schwartz, MD, Division of Hematology and Oncology, Columbia University School of Medicine, 177 Fort Washington Ave., Ste. 6-435, New York, NY 10032; email:
schwartzg@columbia.edu.
2015 by American Society of Clinical Oncology.
213
ABBAS MANJI ET AL
ticular region.7 ALT/WDLS within the retroperitoneum, mediastinum, and spermatic cord are more likely to recur and
result in signifcant morbidity and mortality from local disease.6 Gene expression profling when compared to normal
fat has indicated overexpression of several genes in the
12q1215 amplicon, including CDK4 and MDM2.7 MDM2 is
a ubiquitin ligase that binds to the transactivation domain of
p53 and promotes its degradation.
DEDIFFERENTIATED LIPOSARCOMA
Dedifferentiated liposarcoma (DDLS) is the second most
common type of liposarcoma diagnosed. DDLS is cellular
and consists of nonlipogenic sarcoma that transitions
abruptly within an ALT.4 DDLS has morphologic and molecular similarities to ALT/WDLS but behaves aggressively.
DDLS has a higher rate of recurrence, with 20% to 30% distant metastasis, and a 6-fold higher risk of death compared to
ALT/WDLS.8,9 Many of the gene alterations found in WDLS
are also found in DDLS.7 For example, both CDK4 and
MDM2 are overexpressed in both of these diseases. Genomic
alterations of 207 STS, which included 50 DDLS specimens,
confrmed the prior fndings of amplifcations within 12q12
15, including CDK4 and MDM2.10 WDLS and DDLS respond very poorly to chemotherapy and new treatment
options are desperately needed.11
KEY POINTS
Sarcomas are rare malignancies of mesenchymal origin that
represent a heterogeneous group of over 50 subtypes, of
which liposarcomas are one of the most common subtype.
Liposarcomas contain at least four distinct subtypes for
which treatment has to be tailored.
Well-differentiated liposarcoma is the least malignant form,
does not respond to chemotherapy, and tends to recur
locally.
Dedifferentiated liposarcoma has some response to
chemotherapy and, like well-differentiated liposarcoma,
contains amplication/overexpression of murine double
minute 2 and cyclin-dependent kinase 4, inhibition of which
have shown promise in early-phase clinical trials.
Retrospective data indicate trabectedin to have activity in
myxoid (round cell) liposarcoma, which is currently under
U.S. Food and Drug Administration review for this
indication.
214
215
ABBAS MANJI ET AL
Trabectedin
Apart from chemotherapy, trabectedin (ET-743), a marine
alkaloid, is approved in Europe as second-line treatment for
advanced STS and is a promising agent, particularly in
MRCL. Trabectedin has two known functions: 1) It binds to
DNA within the minor grove of the double helix, causing a
conformational change that likely changes its interactions
with DNA-binding proteins, and 2) it causes doublestranded DNA breaks by interaction with transcriptioncoupled nucleotide excision repair complex. Owing to its
ability to alter DNAprotein interaction, it is not surprising
that trabectedin specifcally inhibited type I and II TLS-CHOP
transcripts from binding to their cognate target promoters in
an MRCL xenograft model that impeded TLS-CHOP function.31 Recent evidence has suggested that trabectedin also
affects the tumor microenvironment by targeting monocytes and macrophages that have protumoral functions,
216
PLEOMORPHIC LIPOSARCOMA
Pleomorphic liposarcoma (PLS) represents approximately
5% to 15% of liposarcomas37 and usually presents in adults
within the lower extremity.38 PLS pathologically exhibits
large, multivacuolated pleomorphic lipoblasts.39 PLS is associated with a poor prognosis, with high local recurrence and
distant metastasis in the range of 30% to 35%.40 Because of
the rarity of the disease, treatment data within this particular
subtype is limited. A retrospective study reviewed response
to chemotherapy in 39 patients with unresectable or metastatic PLS.41 Of the 32 patients assessable for response, one
(3%) had a complete response, 11 (34.5%) had a partial response, and nine (28%) had stable disease, with a median
follow-up of 62 months. The median PFS and OS were 4.3
and 14 months, respectively. The overall objective response
rate was 37%. Interestingly, anthracycline-based regimens
did not result in an improved response rate compared to
nonanthracycline-based therapies.41
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Gary K. Schwartz, AstraZeneca, BoehingerIngelheim, Novartis. Consulting or Advisory Role: Gary K. Schwartz, AstraZeneca, Boehringer Ingelheim, Novartis. Speakers Bureau: None. Research
Funding: Gulam Manji, Merck. Patents, Royalties, or Other Intellectual Property: Gary K. Schwartz, Patent pending regarding development of PNAs for
targeted cancer therapy (new technology). Expert Testimony: None. Travel, Accommodations, Expenses: Gary K. Schwartz, AstraZeneca, Boehringer
Ingelheim, Novartis. Other Relationships: None.
References
1. Maki RG, Wathen JK, Patel SR, et al. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients
with metastatic soft tissue sarcomas: results of sarcoma alliance for re-
217
ABBAS MANJI ET AL
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
218
TUMOR BIOLOGY
Implications of Intratumor
Heterogeneity for Personalized
Therapy
CHAIR
Charles Swanton, PhD, FRCP
CRUK London Research Institute
London, United Kingdom
SPEAKERS
Michalina Janiszewska, PhD
Dana-Farber Cancer Institute
Boston, MA
Liran Shlush, MD, PhD
Princess Margaret Cancer Centre
Toronto, ON, Canada
From the Princess Margaret Cancer Centre, Toronto, Canada; Rambam Health Care Campus, Haifa, Israel.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Liran I Shlush, MD, PhD, Princess Margaret Cancer Centre, 620 University Ave., Toronto, ON M5G 2M9, Canada; email: liranshlush3@gmail.com.
2015 by American Society of Clinical Oncology.
e662
KEY POINTS
Cancer evolutionary biology aims to understand the
processes shaping genotypephenotype correlations in
cancer.
Cancer evolution is a long process, usually occurring over
years, with a premalignant phase occurring in functioning
cells.
During evolution, heterogeneity is created not only at the
DNA level.
Early cancer events are tissue specic and can be used for
targeted therapies; however, if diagnosed late they might
be irrelevant to tumor survival.
The earlier a cancer is diagnosed, the lower the tumor
heterogeneity and the better the prognosis.
e663
FIGURE 1. Tissue-specic Early Evolutionary Events versus Common Late Hallmarks of Cancer Events
Early mutations are tissue specic and increase the tness of the cell of origin under a changing environment. Initial clonal expansion of functional cells will eventually lead to changes in the
environment that will in turn lead to selective pressure for the various hallmarks of cancer. Mutations (X,Y,Z) that have accumulated in the premalignant clones will be selected and gradually
reduce the functionality of the cell of origin.
Abbreviations: AML, acute myeloid leukemia; ITH, intratumoral heterogeneity.
associated with reduced survival in chronic lymphocytic leukemia,21 and patients with localized resected lung carcinoma
that had a higher fraction of sub-clonal mutations were more
likely to relapse.6 These recent fndings suggest that the degree of sub-clonality might serve as a cancer marker per se.
Higher diversity is related to a higher mutation rate or longer
tumor evolution with more replications. However, as discussed above, the survival of multiple clones suggests that
multiple phenotypes were selected under different environments (branched evolution), all of which tell us something
about the tumor biology and history.
FUTURE DIRECTIONS
The study of evolution, like the study of history, involves
looking at the past to create a better future. Recent studies14,15
suggest that early mutations in leukemia occur in cells capable of mainlining their functionality. These early events lead
to clonal expansion of cells trying to maintain function.
Clonal expansion is relatively common in the general
population.22-24 The early clonal expansion, which can last
for years, will eventually progress to uncontrolled cell growth
and the emergence of dysfunctional cells. From these studies
we learn that cancer in adults is a longstanding state, with
precancerous lesions most likely evolving as a result of the
aging environment. Accordingly, we suggest that changing
the environment and targeting early events might change the
evolutionary trajectory of cancer.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: None.
Speakers Bureau: None. Research Funding: None. Patents, Royalties, or Other Intellectual Property: Liran Shlush, January 2014 Identication of
pre-leukemic hematopoietic stem cell in human. Expert Testimony: None. Travel, Accommodations, Expenses: Dov Hershkovitz, Pzer, Roche. Other
Relationships: None.
References
1. de Bruin EC, Mc Granahan N, Mitter R, et al. Spatial and temporal diversity in genomic instability processes defnes lung cancer evolution.
Science. 2014;346:251-256.
2. Enard W, Khaitovich P, Klose J, et al. Intra- and interspecifc variation
in primate gene expression patterns. Science. 2002;296:340-343.
3. Kreso A, OBrien CA, van Galen P, et al. Variable clonal repopulation
dynamics influence chemotherapy response in colorectal cancer.
Science. 2013;339:543-548.
4. Mok TS, Wu YL, Thongprasert S, et al. Geftinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947957.
5. Garassino MC, Martelli O, Broggini M, et al. Erlotinib versus docetaxel
as second-line treatment of patients with advanced non-small-cell lung
cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol. 2013;14:981-988.
6. Zhang J, Fujimoto J, Zhang J, et al. Intratumor heterogeneity in localized
lung adenocarcinomas delineated by multiregion sequencing. Science.
2014;346:256-259.
7. Vignot S, Besse B, Andre F, et al. Discrepancies between primary tumor
and metastasis: a literature review on clinically established biomarkers.
Crit Rev Oncol Hematol. 2012;84:301-313.
8. Amir E, Clemons M, Purdie CA, et al. Tissue confrmation of disease
recurrence in breast cancer patients: pooled analysis of multi-centre,
multi-disciplinary prospective studies. Cancer Treat Rev. 2012;38:708714.
9. Hershkovitz D, Simon E, Bick T, et al. Adenoma and carcinoma components in colonic tumors show discordance for KRAS mutation. Hum
Path. 2014;45:1866-1871.
10. Baas JM, Krens LL, Guchelaar HJ, et al. Concordance of predictive
markers for EGFR inhibitors in primary tumors and metastases in colorectal cancer: a review. Oncologist. 2011;16:1239-1249.
11. Knijn N, Mekenkamp LJ, Klomp M, et al. KRAS mutation analysis: a
comparison between primary tumours and matched liver metastases in
305 colorectal cancer patients. Br J Cancer. 2011;104:1020-1026.
12. Shlush LI, Behar DM, Yudkovsky G, et al. The Druze: a population genetic refugium of the Near East. PLoS One 2008;3:e2105.
e665
TUMOR BIOLOGY
SPEAKERS
Virginia F. Borges, MD
University of Colorado Cancer Center
Aurora, CO
Deborah W. Knapp, DVM
Purdue University
West Lafayette, IN
From the Department of Veterinary Clinical Sciences, Purdue University, West Lafayette, IN; Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN; National Human
Genome Research Institute, National Institutes of Health, Bethesda, MD.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Deborah W. Knapp, DVM, Purdue University, Department of Veterinary Clinical Sciences, 625 Harrison St., West Lafayette, IN 47907-2026; email: knappd@purdue.edu.
2015 by American Society of Clinical Oncology.
e667
in dogs can help identify not yet known exposures that have
the potential to contribute to understanding of human
cancer.20-22 The compressed life span of dogs compared with
humans facilitates cancer prevention research in that a 15 to
20 year period in human life can be studied in dogs in 2 to 3
years. In an intriguing example, a 7-month study in older
dogs (physiologically equivalent to human age 62 to 69) demonstrated a U-shaped dose-response relationship between
selenium status (toenail selenium concentration) and provided target concentrations to prevent DNA damage and
induce apoptosis within the prostate.23-24 Midrange concentrations were associated with protective effects, whereas
DNA damage was most pronounced at the lowest and highest selenium concentrations along the curve. This study offered a possible explanation for the failure of the 7-year
Selenium and Vitamin E Cancer Prevention Trial (SELECT)
of 35,000 men, which had begun before the dog study; the
concentrations achieved in men in the SELECT study were
not in the benefcial range as defned by the dog study.
KEY POINTS
There is a crucial need for advances in cancer prevention,
and research in relevant animal models is key.
Of the over 80 million pet dogs in the United States, a
quarter are expected to die from cancer.
Specic forms of naturally occurring cancer in pet dogs,
including invasive urinary bladder cancer, closely mimic the
human condition.
Breed-associated risks for cancer in pet dogs offer
unparalleled opportunities to dene genetic factors, genegene interactions, and gene-environment interactions that
lead to cancer across species.
Clinical studies in dogs are considered win-win-win
opportunities in which the individual dog benets, and
knowledge is gained that can improve the outlook for dogs
and humans facing cancer.
e668
e669
Breed
Mixed Breed Dog (Reference Category)
1.0
95% CI
NA
Scottish Terrier
21.12
16.23-27.49
Eskimo Dog
6.58
3.34-12.96
Shetland Sheepdog
6.05
4.76-7.69
5.84
4.23-8.08
Keeshond
4.26
2.25-8.07
Samoyed
3.43
1.81-6.49
Beagle
3.09
2.34-4.08
oncology research a main emphasis of their career is very limited. A unique set of skills and capabilities is needed, including knowledge of veterinary oncology, the human cancer
focused in the research, and basic science that can be applied
to improve the clinical condition, as well as excellent communication and people skills to build multidisciplinary
teams (DVM, MD, PhD) to develop and accomplish the
work, writing skills for successful grants and manuscripts,
and the passion and drive to make the work happen. Forward
thinking institutions are also key. Institutions need to build
infrastructure and support, and allow individual faculty that
have high potential to be the research engines to move away
from the typical triple-threat position (equal time spent on
clinical service, teaching, and research) of an academic veterinary oncologist. Some of the more successful veterinarians
that have worked in translation research have spent time at a
medical school or have had MD mentors. This enables them
to better understand the most critical needs in human oncology and to network for collaborative research. The veterinary
scientists must also have suffcient understanding of basic
science to know how it could be applied to answer key clinical
questions and to communicate with basic scientists for successful collaborations. Even with these skills and talents
though, valuable translational research is going to require
multidisciplinary teams.
Access to adequate numbers of dogs for clinical studies is
obviously important. Currently, there is marked underutilization of dogs for clinical studies. In iUC for example, of the
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: None.
Speakers Bureau: None. Research Funding: None. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel,
Accommodations, Expenses: None. Other Relationships: Elaine Ostrander, Argus LLC.
References
1. American Cancer Society. Cancer Facts and Statistics 2015. http://
www.cancer.org/research/cancerfactsstatistics/cancerfactsfgures2015/
index. Accessed February 2, 2015.
2. World Health Organization. Cancer. http://who.int/mediacentre/
factsheets/fs297/en/. Accessed February 2, 2015.
3. Steward WP, Brown K. Cancer chemoprevention: a rapidly evolving
feld. Br J Cancer. 2013;109:1-7.
4. The time is now. Nat Rev Drug Discov. 2005;4:613.
5. Ellis LM, Fidler IJ. Finding the tumor copycat. Therapy fails, patients
dont. Nat Med. 2010;16:974-975.
6. van der Worp HB, Howells DW, Sena ES, et al. Can animal models of
disease reliably inform human studies? PLoS Med. 2010;7:e1000245.
7. Campbell EJ, Dachs GU. Current limitations of murine models in oncology for ascorbate research. Front Oncol. 2014;4:282.
8. Knapp DW, Ramos-Vara JA, Moore GE, et al. Urinary bladder cancer in
9.
10.
11.
12.
13.
dogs, a naturally occurring model for cancer biology and drug development. ILAR J. 2014;55:100-118.
Davis BW, Ostrander EA. Domestic dogs and cancer research: a breedbased genomics approach. ILAR J. 2014;55:59-68.
Khanna C, Lindblad-Toh K, Vail D, et al. The dog as a cancer model. Nat
Biotechnol. 2006;24:1065-1066.
Merlo DF, Rossi L, Pellegrino C, et al. Cancer incidence in pet dogs:
fndings of the Animal Tumor Registry of Genoa, Italy. J Vet Intern Med.
2008;22:976-984.
Adams VJ, Evans KM, Sampson J, et al. Methods and mortality results of
a health survey of purebred dogs in the UK. J Small Anim Pract. 2010;
51:512-524.
Statista. Number of dogs in the United States from 2000 to 2014 (in
millions). http://www.statista.com/statistics/198100/dogs-in-the-unitedstates-since-2000/. Accessed February 2, 2015.
e671
14. Fenger JM, London CA, Kisseberth WC. Canine osteosarcoma: a naturally occurring disease to inform pediatric oncology. ILAR J. 2014;55:
69-85.
15. Bushell KR, Kim Y, Chan FC, et al. Genetic inactivation of TRAF3 in
canine and human B-cell lymphoma. Blood. 2015;125:999-1005. Epub
2014 Dec 2.
16. Ito D, Frantz AM, Modiano JF. Canine lymphoma as a comparative
model for human non-Hodgkin lymphoma: recent progress and applications. Vet Immunol Immunopathol. 2014;159:192-201.
17. Parker HG, Shearin AL, Ostrander EA. Mans best friend becomes biologys best in show: genome analyses in the domestic dog. Annu Rev
Genet. 2010;44:309-336.
18. Ranieri G, Gadaleta CD, Patruno R, et al. A model of study for human
cancer: spontaneous occurring tumors in dogs. Biological features and
translation for new anticancer therapies. Crit Rev Oncol Hematol. 2013;
88:187-197.
19. Glickman LT, Domanski LM, Maguire TG, et al. Mesothelioma in pet
dogs associated with exposure of their owners to asbestos. Environ Res.
1983;32:305-313.
20. Reif JS. Animal sentinels for environmental and public health. Public
Health Rep. 2011;126 Suppl 1:50-57.
21. Glickman LT, Raghavan M, Knapp DW, et al. Herbicide exposure and
the risk of transitional cell carcinoma of the urinary bladder in Scottish
Terriers. J Am Vet Med Assoc. 2004;224:1290-1297.
22. Knapp DW, Peer WA, Conteh A, et al. Detection of herbicides in the
urine of pet dogs following home lawn chemical application. Sci Total
Environ. 2013;456-457:34-41.
23. Waters DJ, Shen S, Glickman LT, et al. Prostate cancer risk and DNA
damage: translational signifcance of selenium supplementation in a canine model. Carcinogenesis. 2005;26:1256-1262.
24. Chiang EC, Shen S, Kengeri SS, et al. Defning the Optimal Selenium
Dose for Prostate Cancer Risk Reduction: insights from the U-Shaped
Relationship between Selenium Status, DNA Damage, and Apoptosis.
Dose-Response. 2009;8:285-300.
25. Lindblad-Toh K, Wade CM, Mikkelsen TS, et al. Genome sequence,
comparative analysis and haplotype structure of the domestic dog.
Nature. 2005;438:803-819.
26. Alvarez CE. Naturally occurring cancers in dogs: insights for translational genetics and medicine. ILAR J. 2014;55:16-45.
27. Karlsson EK, Lindblad-Toh K. Leader of the pack: gene mapping in dogs
and other model organisms. Nat Rev Genet. 2008;9:713-725.
28. Shearin AL, Ostrander EA. Leading the way: canine models of genomics
and disease. Dis Model Mech. 2010;3:27-34.
29. Karyadi DM, Karlins E, Decker B, et al. A copy number variant at the
KITLG locus likely confers risk for canine squamous cell carcinoma of
the digit. PLoS Genet. 2013;9:e1003409.
30. Lingaas F, Comstock KE, Kirkness EF, et al. A mutation in the canine
BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofbrosis in the German Shepherd dog.
Hum Mol Genet. 2003;12:3043-3053.
31. American Cancer Society. What are the key What are the key statistics
about bladder cancer? http://www.cancer.org/cancer/bladdercancer/
detailedguide/bladder-cancer-key-statistics. Accessed February 27, 2015.
32. Cancer Research UK. Bladder cancer mortality statistics. http://www.
cancerresearchuk.org/cancer-info/cancerstats/types/bladder/mortality/
uk-bladder-cancer-mortality-statistics. Accessed February 2, 2015.
e672
33. Witjes JA, Comperat E, Cowan NC, et al. EAU guidelines on muscleinvasive and metastatic bladder cancer: summary of the 2013 guidelines.
Eur Urol. 2014;65:778-792.
34. Yaf FA, Aprikian AG, Chin JL, et al. Contemporary outcomes of 2287
patients with bladder cancer who were treated with radical cystectomy:
a Canadian multicentre experience. BJU Int. 2011;108:539-545.
35. Balar AV, Milowsky MI. Cytotoxic and DNA-targeted therapy in
urothelial cancer: have we squeezed the lemon enough? Cancer. 2015;
121:179-187.
36. Svatek RS, Hollenbeck BK, Holmang S, et al. The economics of bladder
cancer: costs and considerations of caring for this disease. Eur Urol.
2014;66:253-262.
37. Arantes-Rodrigues R, Colaco A, Pinto-Leite R, et al. In vitro and in vivo
experimental models as tools to investigate the effcacy of antineoplastic
drugs on urinary bladder cancer. Anticancer Res. 2013;33:1273-1296.
38. Wu XR, Sun TT, McConkey DJ. Animal models of bladder cancer. In
Lerner, Schoenberg M, Sternberg CN, (eds). Textbook of bladder cancer.
Oxen UK: Taylor and Francis; 2006.
39. Knapp DW, McMillan SK. Tumors of the urinary system. In Withrow
SJ, Vail DM, (eds). Withrow and MacEwens Small Animal Clinical Oncology. 5th ed. St Louis: Elsevier-Saunders; 2013.
40. Lerner SP, Schoenberg MP, Sternberg CN, et al (eds). Textbook of Bladder Cancer. Oxon, UK: Taylor and Francis; 2006.
41. Patrick DJ, Fitzgerald SD, Sesterhenn IA, et al. Classifcation of canine
urinary bladder urothelial tumours based on the World Health Organization/International Society of Urological Pathology consensus classifcation. J Comp Pathol. 2006;135:190-199.
42. Dhawan D, Ramos-Vara JA, Naughton JF, et al. Targeting folate receptors to treat invasive urinary bladder cancer. Cancer Res. 2013;73:875884.
43. Hahn NM, Bonney PL, Dhawan D, et al. Subcutaneous 5-azacitidine
treatment of naturally occurring canine urothelial carcinoma: a novel
epigenetic approach to human urothelial carcinoma drug development.
J Urol. 2012;187:302-309.
44. Alavanja MC, Bonner MR. Occupational pesticide exposures and
cancer risk: a review. J Toxicol Environ Health B Crit Rev. 2012;15:
238-263.
45. Koutros S, Lynch CF, Ma X, et al. Heterocyclic aromatic amine pesticide
use and human cancer risk: results from the U.S. Agricultural Health
Study. Int J Cancer. 2009;124:1206-1212.
46. Singh BP, Nyska A, Kissling GE, et al. Urethral carcinoma and hyperplasia in male and female B6C3F1 mice treated with 3,3,4,4tetrachloroazobenzene (TCAB). Toxicol Pathol. 2010;38:372-381.
47. Burger M, Catto JW, Dalbagni G, et al. Epidemiology and risk factors of
urothelial bladder cancer. Eur Urol. 2013;63:234-241.
48. Franekova M, Halasova E, Bukovska E, et al. Gene polymorphisms in
bladder cancer. Urol Oncol. 2008;26:1-8.
49. Murta-Nascimento C, Schmitz-Drager BJ, Zeegers MP, et al. Epidemiology of urinary bladder cancer: from tumor development to patients
death. World J Urol. 2007;25:285-295.
50. Center for Cancer Research. Comparative Oncology Trials Consortium. https://ccrod.cancer.gov/confluence/display/CCRCOPWeb/
ComparativeOncologyTrialsConsortium. Accessed February 2,
2015.
51. National Cancer Institute. The Cancer Genome Atlas. http://
cancergenome.nih.gov/. Accessed February 2, 2015.
TUMOR BIOLOGY
SPEAKERS
Jeff Rathmell, PhD
Duke University
Durham, NC
Robert Bachoo, MD, PhD
The University of Texas Southwestern Medical Center
Dallas, TX
From the Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute at the National Institutes of Health, Bethesda, MD.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: W. Marston Linehan, MD, Urologic Oncology Branch, National Cancer Institute at the National Institutes of Health, 10 Center Drive MSC 1107, CRC Room 1W-5940, Bethesda,
MD 20892-1107; email: WML@nih.gov.
2015 by American Society of Clinical Oncology.
220
KEY POINTS
Genetic and molecular mechanisms underlying renal cell
carcinomas developments drive metabolic changes in
tumor cells.
Advanced clear cell RCC and hereditary leiomyomatosis and
RCC tumors share a similar metabolic prole consisting of
a shift to aerobic glycolysis, enhanced glutamine
metabolism, and increased fatty acid synthesis.
Improvement in outcomes for patients with clear cell RCC
has been made over the last 10 years by strategically
targeting the VHL/HIF pathway.
Targeting metabolic changes supporting tumor cells
survival might have a therapeutic value for clear cell RCC
and papillary tumors.
Imbalances in redox status are symptomatic of aggressive
tumors and should be considered when developing a
targeted therapeutic approach for RCC.
221
High-grade, high-stage ccRCC present a metabolic shift toward aerobic glycolysis, decreased oxidative phosphorylation, and increased glutamine metabolism. This metabolic adaptation is
supported in part by activation of the PI3K/Akt, mTOR, and HIF pathways.
and renal cell carcinoma (HLRCC) is a hereditary cancer syndrome in which affected individuals are at risk for the development of cutaneous and uterine leiomyomas and an
aggressive form of type II papillary RCC.35 The most prevalent gene mutation(s) responsible for sporadic papillary type
II tumors are still unknown; however, studies have reported
mutations of genes in the Nrf2 complex (Nrf2, KEAP1,
CUL3).36
CONCLUSION
Over the past two decades signifcant progress has been made
in our understanding of the molecular mechanisms of RCC.
FH-decient tumor cells are characterized by elevated aerobic glycolysis and oxidative stress. Accumulation of the oncometabolite fumarate promotes Nrf2 antioxidant response transcriptional
activity via KEAP1 inhibition and ABL1 activation. ABL1 also regulates aerobic glycolysis by activating the mTOR/HIF pathway.
223
Ten years ago we had very limited options for the treatment
of patients with advanced RCC. We currently have seven approved agents for patients with advanced RCC and have
some potential approaches that could represent a new era of
targeted therapies and precision medicine designed to target
metabolic and stress response pathways critical to tumor survival. The development of new bioinformatic tools will certainly further improve our understanding of the metabolic
basis of kidney cancer and will hopefully provide the basis for
ACKNOWLEDGMENT
This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer
Institute, Center for Cancer Research.
References
1. Srinivasan R, Ricketts CJ, Sourbier C, et al. New strategies in renal cell
carcinoma: targeting the genetic and metabolic basis of disease. Clin
Cancer Res. 2015;21:10-17.
2. Jonasch E, Motzer RJ. Ten years of progress in renal cell carcinoma.
J Natl Compr Canc Netw. 2012;10:690-693.
3. Nickerson ML, Jaeger E, Shi Y, et al. Improved identifcation of von
Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer
Res. 2008;14:4726-4734.
4. Sato Y, Yoshizato T, Shiraishi Y, et al. Integrated molecular analysis of
clear-cell renal cell carcinoma. Nat Genet. 2013;45:860-867.
5. Warburg O, Posener K, Negelein E. Metabolism of the Carcinoma Cell.
Biochem Z. 1924;152:309-344.
6. Warburg O. On the origin of cancer cells. Science. 1956;123:309-314.
7. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation.
Cell. 2011;144:646-674.
8. Kroemer G, Pouyssegur J. Tumor cell metabolism: cancers Achilles
heel. Cancer Cell. 2008;13:472-482.
9. Ohh M, Park CW, Ivan M, et al. Ubiquitination of hypoxia-inducible
factor requires direct binding to the beta-domain of the von HippelLindau protein. Nat Cell Biol. 2000;2:423-427.
10. Latif F, Tory K, Gnarra J, et al. Identifcation of the von Hippel-Lindau
disease tumor suppressor gene. Science. 1993;260:1317-1320.
11. Ivan M, Kondo K, Yang H, et al. HIFalpha targeted for VHL-mediated
destruction by proline hydroxylation: implications for O2 sensing.
Science. 2001;292:464-468.
12. Linehan WM, Ricketts CJ. Decade in review-kidney cancer: discoveries,
therapies and opportunities. Nat Rev Urol. 2014;11:614-616.
13. Raval RR, Lau KW, Tran MG, et al. Contrasting properties of hypoxiainducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated
renal cell carcinoma. Mol Cell Biol. 2005;25:5675-5686.
14. Kondo K, Klco J, Nakamura E, et al. Inhibition of HIF is necessary for tumor
suppression by the von Hippel-Lindau protein. Cancer Cell. 2002;1:237-246.
15. Maranchie JK, Vasselli JR, Riss J, et al. The contribution of VHL substrate binding and HIF1-alpha to the phenotype of VHL loss in renal cell
carcinoma. Cancer Cell. 2002;1:247-255.
16. Sourbier C, Srivastava G, Ghosh MC, et al. Targeting HIF2 translation
with Tempol in VHL-defcient clear cell renal cell carcinoma. Oncotarget.
2012;3:1472-1482.
17. Zimmer M, Ebert BL, Neil C, et al. Small-molecule inhibitors of HIF-2a
translation link its 5UTR iron-responsive element to oxygen sensing.
Mol Cell. 2008;32:838-848.
224
18. Kong HS, Lee S, Beebe K, et al. Emetine promotes von Hippel-Lindauindependent degradation of hypoxia-inducible factor-in clear cell renal carcinoma. Mol Pharmacol. 2010;78:1072-1078.
19. Lin F, Zhang PL, Yang XJ, et al. Morphoproteomic and molecular concomitants of an overexpressed and activated mTOR pathway in renal
cell carcinomas. Ann Clin Lab Sci. 2006;36:283-293.
20. Sourbier C, Lindner V, Lang H, et al. The phosphoinositide 3-kinase/
Akt pathway: a new target in human renal cell carcinoma therapy. Cancer Res. 2006;66:5130-5142.
21. Sourbier C, Ricketts CJ, Matsumoto S, et al. Targeting ABL1-mediated
oxidative stress adaptation in fumarate hydratase-defcient cancer. Cancer Cell. 2014;26:840-850.
22. Tong WH, Sourbier C, Kovtunovych G, et al. The glycolytic shift in
fumarate-hydratase-defcient kidney cancer lowers AMPK levels, increases anabolic propensities and lowers cellular iron levels. Cancer Cell.
2011;20:315-327.
23. Voss MH, Molina AM, Motzer RJ. mTOR inhibitors in advanced renal
cell carcinoma. Hematol Oncol Clin North Am. 2011;25:835-852.
24. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149:274-293.
25. Plas DR, Rathmell JC, Thompson CB. Homeostatic control of lymphocyte survival: potential origins and implications. Nat Immunol. 2002;3:
515-521.
26. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499:43-49.
27. DeBerardinis RJ, Cheng T. Qs next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene. 2010;29:
313-324.
28. Filipp FV, Scott DA, Ronai ZA, et al. Reverse TCA cycle flux through
isocitrate dehydrogenases 1 and 2 is required for lipogenesis in hypoxic
melanoma cells. Pigment Cell Melanoma Res. 2012;25:375-383.
29. Wise DR, Ward PS, Shay JE, et al. Hypoxia promotes isocitrate
dehydrogenase-dependent carboxylation of -ketoglutarate to citrate to
support cell growth and viability. Proc Natl Acad Sci U S A. 2011;108:
19611-19616.
30. Gameiro PA, Yang J, Metelo AM, et al. In vivo HIF-mediated reductive
carboxylation is regulated by citrate levels and sensitizes VHL-defcient
cells to glutamine deprivation. Cell Metab. 2013;17:372-385.
31. Metallo CM, Gameiro PA, Bell EL, et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature. 2012;481:
380-384.
32. Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov. 2013;12:931-947.
33. Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism.
Nat Rev Cancer. 2011;11:85-95.
34. An J, Sun Y, Fisher M, et al. Maximal apoptosis of renal cell carcinoma
by the proteasome inhibitor bortezomib is nuclear factor-kappaB dependent. Mol Cancer Ther. 2004;3:727-736.
35. Launonen V, Vierimaa O, Kiuru M, et al. Inherited susceptibility to
uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci U S A.
2001;98:3387-3392.
36. Ooi A, Dykema K, Ansari A, et al. CUL3 and NRF2 mutations confer an
NRF2 activation phenotype in a sporadic form of papillary renal cell
carcinoma. Cancer Res. 2013;73:2044-2051.
37. Tomlinson IP, Alam NA, Rowan AJ, et al. Germline mutations in FH
predispose to dominantly inherited uterine fbroids, skin leiomyomata
and papillary renal cell cancer. Nat Genet. 2002;30:406-410.
38. Yang Y, Valera VA, Padilla-Nash HM, et al. UOK 262 cell line, fumarate
hydratase defcient (FH-/FH-) hereditary leiomyomatosis renal cell carcinoma: in vitro and in vivo model of an aberrant energy metabolic
pathway in human cancer. Cancer Genet Cytogenet. 2010;196:45-55.
39. Isaacs JS, Jung YJ, Mole DR, et al. HIF overexpression correlates with
biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell. 2005;8:143-153.
40. Linehan WM, Rouault TA. Molecular pathways: Fumarate hydratasedefcient kidney cancer-targeting the Warburg effect in cancer. Clin
Cancer Res. 2013;19:3345-3352.
41. Xie H, Valera VA, Merino MJ, et al. LDH-A inhibition, a therapeutic
strategy for treatment of hereditary leiomyomatosis and renal cell cancer. Mol Cancer Ther. 2009;8:626-635.
42. Sudarshan S, Sourbier C, Kong HS, et al. Fumarate hydratase defciency
in renal cancer induces glycolytic addiction and hypoxia-inducible transcription factor 1alpha stabilization by glucose-dependent generation of
reactive oxygen species. Mol Cell Biol. 2009;29:4080-4090.
43. Sullivan LB, Martinez-Garcia E, Nguyen H, et al. The protooncometabolite fumarate binds glutathione to amplify ROS-dependent
signaling. Mol Cell. 2013;51:236-248.
44. Sourbier C, Valera-Romero V, Giubellino A, et al. Increasing reactive
oxygen species as a therapeutic approach to treat hereditary leiomyomatosis and renal cell carcinoma. Cell Cycle. 2010;9:4183-4189.
45. Adam J, Hatipoglu E, OFlaherty L, et al. Renal cyst formation in Fh1defcient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell. 2011;20:524537.
46. Ooi A, Wong JC, Petillo D, et al. An antioxidant response phenotype
shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell. 2011;20:511-523.
47. Taguchi K, Motohashi H, Yamamoto M. Molecular mechanisms of the
Keap1-Nrf2 pathway in stress response and cancer evolution. Genes
Cells. 2011;16:123-140.
48. Wang X, McCullough KD, Franke TF, et al. Epidermal growth factor
receptor-dependent Akt activation by oxidative stress enhances cell survival. J Biol Chem. 2000;275:14624-14631.
225
Author Index
Abbas Manji, Gulam
Ahluwalia, Manmeet S.
Andersen, Barbara L.
Apolo, Andrea B.
Armenian, Saro H.
Beltran, Himisha
Bergsland, Emily
Boerner, Scott
Capasso, Anna
Castro, Gilberto
Chew, Helen
Chung, Christine H.
Cohen, Ezra E.W.
Dewey, Charlene
DiPaola, Robert S.
Dowlati, Afshin
Dummer, Reinhard
Eckhardt, S. Gail
Eng, Cathy
Fisher, George
Furman, Richard R.
Gaynor, Richard B.
Gerber, David E.
Gibbs, Peter
Gilbert, Jill
Fisher, Paul G.
Gross, Andrew M.
Horn, Leora
Hughes, Kevin S.
Hussain, Maha
Isaacsson Velho, Pedro Henrique
Jacobsen, Paul B.
Jagsi, Reshma
Kaye, Stanley B.
Kim, Edward S.
Klimstra, David S.
.................................................................................................................................................................
213
67
188
105
196
92
92
177
3
123
33
123
28
33
17
147
177
3
40
40
130
130
147
57
33
57
28
33
48
17
123
188
130
114
22
92
..........................................................................................................................................................
...............................................................................................................................................................
.............................................................................................................................................................................
.........................................................................................................................................................................
.................................................................................................................................................................................
................................................................................................................................................................................
.....................................................................................................................................................................................
...........................................................................................................................................................................................
.................................................................................................................................................................................
...............................................................................................................................................................................................
......................................................................................................................................................................
................................................................................................................................................................................
.................................................................................................................................................................................
..............................................................................................................................................................................
....................................................................................................................................................................................
........................................................................................................................................................................
.....................................................................................................................................................................................
...................................................................................................................................................................................................
.......................................................................................................................................................................................
......................................................................................................................................................................
.......................................................................................................................................................................
................................................................................................................................................................................
...............................................................................................................................................................................................
...................................................................................................................................................................................................
.......................................................................................................................................................................................
...........................................................................................................................................................................
................................................................................................................................................................................................
...............................................................................................................................................................................
..........................................................................................................................................................................................
........................................................................................................................
..........................................................................................................................................................................
.....................................................................................................................................................................................
.................................................................................................................................................................................
......................................................................................................................................................................................
.............................................................................................................................................................................
226
Koff, Andrew
Koopman, Miriam
Kremer, Leontien C.
Lilenbaum, Rogerio
Linehan, W. Marston
Longabaugh, Michele
LoRusso, Patricia
Moliterno, Alison R.
Moy, Beverly
Muss, Hyman B.
Paik, Paul K.
Partridge, Ann H.
Pemmaraju, Naveen
Postow, Michael A.
Punglia, Rinaa S.
Punt, Cornelis J.A.
Ratain, Mark J.
Roach, Nancy
Schiffman, Joshua D.
Schwartz, Gary K.
Sikov, William M.
Simkens, Lieke H.J.
Singer, Samuel
Sklar, Charles
Sonis, Stephen T.
Sourbier, Carole
Srinivasan, Ramaprasad
Stilgenbauer, Stephan
Sullivan, Ryan
Tan, David S.P.
Theodorescu, Dan
Thompson, Michael A.
Vogelzang, Nicholas J.
Winkler, Frank
Wong, Kit Man
Zent, Clive S.
213
85
196
92
220
40
177
139
130
48
147
188
139
76
48
85
130
40
57
213
44
85
213
196
9
220
220
164
177
114
105
206
105
67
3
164
..........................................................................................................................................................................................
..............................................................................................................................................................................
...................................................................................................................................................................
........................................................................................................................................................................
................................................................................................................................................................
..................................................................................................................................................................
.............................................................................................................................................................................
....................................................................................................................................................................
..........................................................................................................................................................................................
..................................................................................................................................................................................
............................................................................................................................................................................................
...........................................................................................................................................................................
...................................................................................................................................................................
.........................................................................................................................................................................
...............................................................................................................................................................................
..........................................................................................................................................................................
...................................................................................................................................................................................
..........................................................................................................................................................................................
..................................................................................................................................................................
...........................................................................................................................................................................
................................................................................................................................................................................
.......................................................................................................................................................................
....................................................................................................................................................................................
.......................................................................................................................................................................................
..................................................................................................................................................................................
..............................................................................................................................................................................
.....................................................................................................................................................
............................................................................................................................................................
.......................................................................................................................................................................................
.....................................................................................................................................................................................
..........................................................................................................................................................................
...........................................................................................................................................................
..........................................................................................................................................................
........................................................................................................................................................................................
...........................................................................................................................................................................................
.........................................................................................................................................................................................